Combination of KRAS inhibitor and ATR inhibitor for treating cancer

Abstract

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

Description

[0001] This specification claims the benefit of U.S. Provisional Application No. 63 / 496,040, filed April 14, 2023, the contents of which are incorporated herein by reference in their entirety for all purposes. Technical Field

[0002] This disclosure provides a method for treating cancer in a subject, the method 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) a KRAS inhibitor and (b) an ATR inhibitor are also disclosed. Background Technology

[0003] KRAS is a small GTPase protein that cycles between a GDP-binding inactive state and a GTP-binding active state to regulate cell signaling cascades and promote cell proliferation and survival. KRAS is frequently mutated in cancer, with gain-of-function missense mutations clustering at hotspots, such as at codons 12, 13, and 61. Oncogenic mutations at these residues disrupt intrinsic and GAP-mediated GTP hydrolysis, increasing the level of GTP-binding active KRAS, leading to inappropriate activation of the cell signaling cascade, which can drive cancer progression.

[0004] Historically, KRAS has been considered a challenging target due to the lack of drug-targetable pockets and its high affinity for nucleotides. However, several small molecules with improved potency and pharmacological properties have been developed that covalently bind mutant cysteine ​​residues in KRAS, trapping them in a GDP-bound inactive state and driving antitumor activity in preclinical KRAS models, such as sotorasib and adagrasib. However, not all patients with KRAS-mutant tumors respond strongly to treatment.

[0005] Ataxia-telangiectasia and Rad3-associated receptor (ATR) is a serine / threonine protein kinase that is a apex kinase involved in coordinating cell cycle checkpoint and DNA replication stress-induced DNA damage responses. Inhibition of ATR has been explored as a potential cancer treatment, initially focusing on targeting tumor-intrinsic mechanisms, with enhanced sensitivity to ATR inhibition due to defective DNA double-strand break (DSB) repair mechanisms. Several ATR inhibitors are known, including AZD6738 (ceralasertib, (Foote KM. et al., J Med Chem. 2018;61(22):9889-907)), M6620 / VX970 (berzosertib, (Gorecki L et al., Pharmacol Ther. 2020;210:107518)) and BAY-1895344 (elimusertib, (Lucking U et al., J Med Chem. 2020; 63(13):7293-325)). Summary of the Invention

[0006] In some embodiments, this disclosure provides a method of treating a subject's cancer, the method comprising administering to the subject: (a) a KRAS inhibitor, and (b) an ataxia-telangiectasia and Rad-3-related (ATR) inhibitor.

[0007] In some embodiments, this disclosure provides a KRAS inhibitor for use in treating cancer in a subject, wherein the treatment comprises administering the inhibitor to the subject alone, sequentially, or simultaneously:

[0008] a. The KRAS inhibitors mentioned above, and

[0009] b. ATR inhibitors.

[0010] In some embodiments, this disclosure provides an ATR inhibitor for use in treating cancer in a subject, wherein the treatment comprises administering the inhibitor to the subject alone, sequentially, or simultaneously:

[0011] a.KRAS inhibitors, and

[0012] b. The ATR inhibitor.

[0013] In some embodiments, this disclosure provides the use of a KRAS inhibitor or an ATR inhibitor in the manufacture of a medicament for the combined administration of a KRAS inhibitor and an ATR inhibitor for the treatment of a subject with cancer.

[0014] 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 implementations, the small molecule KRAS inhibitor is sotoraraciab, adagraciab, 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.

[0015] In some implementations, the small molecule KRAS inhibitor is a compound of formula (I) as defined herein:

[0016]

[0017] In some implementations, the small molecule KRAS inhibitor has a structure as defined herein:

[0018]

[0019] In some implementations, ring A is selected from the group consisting of:

[0020] .

[0021] In some embodiments, ring A, as listed above, is attached to the remainder of the compound of formula (I) at any point on the rings listed above.

[0022] In some implementation schemes, R 4 It is H. In some implementations, R 6 It is H. In some embodiments, Y is CH2. In some embodiments, Y is CH2CH2. In some embodiments, R 2 It is Cl. In some implementations, R 3 It is F. In some implementations, R 4 It is H and R 5It is Me. In some implementations, the small molecule KRAS inhibitor is selected from:

[0023] 7-[(8aS)-10-acryloyl-6-chloro-4-fluoro-8,8a,9,10,11,12-hexahydropyrazino[2',1':3,4][1,4]oxazolo[5,6,7-de]quinazolin-5-yl]-6-methyl-2,3-dihydro-1H-isoindol-1-one;

[0024] 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]oxazolo[5,6,7-de]quinazolin-10(8H)-yl]propyl-2-en-1-one;

[0025] 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]oxazolo[5,6,7-de]quinazolin-10(8H)-yl]propyl-2-en-1-one;

[0026] 5-[(8aS)-10-acryloyl-6-chloro-4-fluoro-8,8a,9,10,11,12-hexahydropyrazino[2',1':3,4][1,4]oxazolidinyl[5,6,7-de]quinazolin-5-yl]-6-methylquinazolin-4(3H)-one;

[0027] 1-[(8aS)-6-chloro-4-fluoro-5-(5-methyl-1H-benzimidazol-4-yl)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazolo[5,6,7-de]quinazolin-10(8H)-yl]propyl-2-en-1-one;

[0028] 8-[(8aS)-6-chloro-4-fluoro-10-(prop-2-enoyl)-8,8a,9,10,11,12-hexahydropyrazino[2',1':3,4][1,4]oxazolo[5,6,7-de]quinazolin-5-yl]isoquinolin-1(2H)-one;

[0029] 1-[(8aS)-6-chloro-4-fluoro-5-(1H-indazol-3-yl)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazolo[5,6,7-de]quinazolin-10(8H)-yl]propyl-2-en-1-one;

[0030] 1-[(8aS)-6-chloro-4-fluoro-5-(2-hydroxy-6-methylphenyl)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazolo[5,6,7-de]quinazolin-10(8H)-yl]propyl-2-en-1-one;

[0031] (2E)-1-[(8aS)-6-chloro-4-fluoro-5-(2-fluoro-6-hydroxyphenyl)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazolo[5,6,7-de]quinazolin-10(8H)-yl]-4-(dimethylamino)but-2-en-1-one;

[0032] 8-[(8aS)-6-chloro-4-fluoro-10-(prop-2-enoyl)-8,8a,9,10,11,12-hexahydropyrazino[2',1':3,4][1,4]oxazolo[5,6,7-de]quinazolin-5-yl]-7-methylisoquinolin-1(2H)-one;

[0033] 1-[(8aS)-6-chloro-4-fluoro-5-(5-methyl-1H-benzotriazol-4-yl)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazolo[5,6,7-de]quinazolin-10(8H)-yl]propyl-2-en-1-one;

[0034] 1-((8aS)-6-chloro-4-fluoro-5-(5-fluoro-1H-benzo[d]imidazol-4-yl)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazolo[5,6,7-de]quinazolin-10(8H)-yl)prop-2-en-1-one;

[0035] 1-[(8aS)-6-chloro-4-fluoro-5-(5-fluoro-1H-indazol-4-yl)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazolo[5,6,7-de]quinazolin-10(8H)-yl]propyl-2-en-1-one;

[0036] 1-((8aS)-6-chloro-4-fluoro-5-(5-fluoro-1-methyl-1H-benzo[d]imidazol-4-yl)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazolo[5,6,7-de]quinazolin-10(8H)-yl)prop-2-en-1-one;

[0037] 1-[(8aS)-6-chloro-4-fluoro-5-(5-fluoro-1H-benzotriazol-4-yl)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazolo[5,6,7-de]quinazolin-10(8H)-yl]propyl-2-en-1-one;

[0038] 8-[(8aS)-6-chloro-4-fluoro-10-(prop-2-enoyl)-8,8a,9,10,11,12-hexahydropyrazino[2',1':3,4][1,4]oxazolo[5,6,7-de]quinazolin-5-yl]-7-fluoroisoquinolin-1(2H)-one;

[0039] (2E)-1-[(8aS)-6-chloro-4-fluoro-5-(5-methyl-1H-indazol-4-yl)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazolo[5,6,7-de]quinazolin-10(8H)-yl]-4-(dimethylamino)but-2-en-1-one;

[0040] 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]oxazolidinone[4,3,2-de]quinazolin-8-yl]propyl-2-en-1-one;

[0041] 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]oxazolidinone[4,3,2-de]quinazolin-8-yl]propyl-2-en-1-one;

[0042] 8-[3-chloro-1-fluoro-8-(prop-2-enoyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':5,6][1,5]oxazolidinyl[4,3,2-de]quinazolin-2-yl]-7-methylisoquinolin-1(2H)-one;

[0043] 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]oxazolidinone[4,3,2-de]quinazolin-8-yl]propyl-2-en-1-one;

[0044] 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]oxazolidinone[4,3,2-de]quinazolin-8-yl]prop-2-en-1-one;

[0045] 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]oxazolidinone[4,3,2-de]quinazolin-8-yl]prop-2-en-1-one;

[0046] 1-[(8aS)-4-chloro-6-fluoro-5-(2-fluoro-6-hydroxyphenyl)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazolo[5,6,7-de]quinazolin-10(8H)-yl]propyl-2-en-1-one;

[0047] 1-[(8aS,11R)-6-chloro-4-fluoro-11-methyl-5-(5-methyl-1H-benzimidazol-4-yl)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazolo[5,6,7-de]quinazolin-10(8H)-yl]propyl-2-en-1-one;

[0048] 8-[(8aS,11R)-6-chloro-4-fluoro-11-methyl-10-(prop-2-enoyl)-8,8a,9,10,11,12-hexahydropyrazino[2',1':3,4][1,4]oxazolo[5,6,7-de]quinazolin-5-yl]-7-methylisoquinolin-1(2H)-one;

[0049] (2E)-1-[(8aS,11R)-6-chloro-4-fluoro-11-methyl-5-(5-methyl-1H-benzimidazol-4-yl)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazolo[5,6,7-de]quinazolin-10(8H)-yl]-4-(dimethylamino)but-2-en-1-one; and

[0050] (2E)-1-[(8aS,11R)-6-chloro-4-fluoro-11-methyl-5-(5-methyl-1H-indazol-4-yl)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazolo[5,6,7-de]quinazolin-10(8H)-yl]-4-(dimethylamino)but-2-en-1-one;

[0051] Or its pharmaceutically acceptable salt.

[0052] In some implementations, the small molecule KRAS inhibitor is a compound of formula (II):

[0053]

[0054] (II).

[0055] The compound of formula (II) 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]oxazolidinone[4,3,2-de]quinazolin-8-yl]prop-2-en-1-one, or a pharmaceutically acceptable salt thereof.

[0056] In some implementations, the small molecule KRAS inhibitor is a compound of formula (III) as defined herein:

[0057]

[0058] (III).

[0059] In some implementations of equation (III), i) X 1 It is CR 17 And Y 1 It is CR 18 ,ii) X 1 It is N and Y 1 It is CR 18 , or iii) X 1 It is CR 17 And Y 1 It is N. In some implementations of equation (III), Z 1 It is O. In some implementations of formula (III), R 13a and R 13b It is H. In some implementations of formula (III), R 14 It is H. In some implementations of formula (III), R 16 It is H. In some implementations of formula (III), A 1 It is phenyl. In some embodiments, the small molecule KRAS inhibitor is selected from:

[0060] (12aS)-2-Acryloyl-10-chloro-9-(5-methyl-1H-indazol-4-yl)-1,2,3,4,12,12a-hexahydro-6H-benzo[f]pyrazino[2,1-c][1,4]oxazine-6-one;

[0061] 1-((12aS)-10-chloro-9-(5-methyl-1H-indazol-4-yl)-3,4,12,12a-tetrahydro-6H-benzo[f]pyrazino[2,1-c][1,4]oxazolidin-2(1H)-yl)prop-2-en-1-one;

[0062] 1-[(12aR)-10-chloro-9-(2-fluoro-6-hydroxyphenyl)-7-methoxy-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazine-2(1H)-yl]propyl-2-en-1-one;

[0063] (12aR)-10-chloro-9-(2-fluoro-6-hydroxyphenyl)-7-hydroxy-2-(prop-2-enoyl)-1,2,3,4,12,12a-hexahydro-6H-pyrazino[2,1-c][1,4]benzoxazine-6-one;

[0064] (12aR)-10-chloro-9-(5-methyl-1H-indazol-4-yl)-2-(prop-2-enoyl)-1,2,3,4,12,12a-hexahydro-6H-pyrazino[2,1-c][1,4]benzoxazine-6-one;

[0065] 1-((12aR)-10-chloro-9-(5-methyl-1H-indazol-4-yl)-3,4,12,12a-tetrahydro-6H-benzo[f]pyrazino[2,1-c][1,4]oxazine-2(1H)-yl)prop-2-en-1-one;

[0066] (12aR)-10-chloro-8-fluoro-9-(2-fluoro-6-hydroxyphenyl)-2-(prop-2-enoyl)-1,2,3,4,12,12a-hexahydro-6H-pyrazino[2,1-c][1,4]benzoxazine-6-one;

[0067] 1-[(12aR)-8,10-dichloro-9-(2-fluoro-6-hydroxyphenyl)-7-hydroxy-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazine-2(1H)-yl]propyl-2-en-1-one;

[0068] 1-[(12aR)-10-chloro-9-(2-fluoro-6-hydroxyphenyl)-7-(1H-imidazol-1-yl)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazono-2(1H)-yl]propyl-2-en-1-one;

[0069] (12aR)-10-chloro-9-(2-fluoro-6-hydroxyphenyl)-2-(prop-2-enoyl)-1,2,3,4,12,12a-hexahydro-6H-pyrazino[2,1-c][1,4]benzoxazine-7-carboxynitrile;

[0070] 1-[(12aR)-10-chloro-9-(2-fluoro-6-hydroxyphenyl)-7-(1H-pyrazol-1-yl)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazono-2(1H)-yl]propyl-2-en-1-one;

[0071] 1-((12aR)-10-chloro-8-fluoro-9-(5-methyl-1H-benzo[d]imidazol-4-yl)-3,4,12,12a-tetrahydro-6H-benzo[f]pyrazino[2,1-c][1,4]oxazine-2(1H)-yl)prop-2-en-1-one;

[0072] (12aR)-8,10-dichloro-9-(2-fluoro-6-hydroxyphenyl)-2-(prop-2-enoyl)-1,2,3,4,12,12a-hexahydro-6H-pyrazino[2,1-c][1,4]benzoxazine-6-one;

[0073] (12aR)-10-chloro-9-(2-fluoro-6-hydroxyphenyl)-2-(prop-2-enoyl)-1,2,3,4,12,12a-hexahydro-6H-pyrazino[2,1-c][1,4]benzoxazine-8-carboxynitrile;

[0074] (12aR)-10-chloro-9-(2-fluoro-6-hydroxyphenyl)-8-methyl-2-(prop-2-enoyl)-1,2,3,4,12,12a-hexahydro-6H-pyrazino[2,1-c][1,4]benzoxazine-6-one;

[0075] 1-[(12aR)-8,10-dichloro-9-(2-fluoro-6-hydroxyphenyl)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazine-2(1H)-yl]propyl-2-en-1-one;

[0076] 8-[(12aR)-10-chloro-8-fluoro-2-(prop-2-enoyl)-1,2,3,4,12,12a-hexahydro-6H-pyrazino[2,1-c][1,4]benzoxazine-9-yl]-7-methylisoquinoline-1(2H)-one;

[0077] 1-[(12aR)-10-chloro-9-(2-fluoro-6-hydroxyphenyl)-8-methoxy-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazine-2(1H)-yl]propyl-2-en-1-one;

[0078] (12aS)-10-chloro-9-(5-methyl-1H-indazol-4-yl)-2-(prop-2-enoyl)-1,3,4,11,12,12a-hexahydropyrazino[2,1-c][1,4]benzodiazepine-6(2H)-one;

[0079] 1-[(12aR)-10-chloro-9-(2-chloro-6-hydroxyphenyl)-8-fluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazine-2(1H)-yl]propyl-2-en-1-one;

[0080] (12aS)-10-chloro-11-methyl-9-(5-methyl-1H-indazol-4-yl)-2-(prop-2-enoyl)-1,3,4,11,12,12a-hexahydropyrazino[2,1-c][1,4]benzodiazepine-6(2H)-one;

[0081] 1-[(12aR)-10-chloro-9-(2,3-difluoro-6-hydroxyphenyl)-8-fluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazine-2(1H)-yl]propyl-2-en-1-one;

[0082] (12aR)-10-chloro-9-(2-hydroxy-6-methylphenyl)-2-(prop-2-enoyl)-1,2,3,4,12,12a-hexahydro-6H-pyrazino[2,1-c][1,4]benzoxazine-8-carboxynitrile;

[0083] 1-[(12aR)-9-(2-chloro-6-hydroxyphenyl)-8,10-difluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazine-2(1H)-yl]propyl-2-en-1-one;

[0084] 1-[(12aR)-8,10-difluoro-9-(2-hydroxy-6-methylphenyl)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazine-2(1H)-yl]propyl-2-en-1-one;

[0085] 1-[(12aR)-8,10-difluoro-9-[2-fluoro-6-(hydroxymethyl)phenyl]-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazine-2(1H)-yl]propyl-2-en-1-one;

[0086] 1-[(12aR)-8,10-difluoro-9-[2-hydroxy-6-(trifluoromethyl)phenyl]-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazine-2(1H)-yl]propyl-2-en-1-one;

[0087] 1-[(12aR)-9-(2-ethyl-6-hydroxyphenyl)-8,10-difluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazine-2(1H)-yl]propyl-2-en-1-one;

[0088] 1-[(12aR)-9-[2-(difluoromethyl)-6-hydroxyphenyl]-8,10-difluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazine-2(1H)-yl]propyl-2-en-1-one;

[0089] (12aR)-9-(2-chloro-6-hydroxyphenyl)-10-fluoro-2-(prop-2-enoyl)-1,2,3,4,12,12a-hexahydro-6H-pyrazino[2,1-c][1,4]benzoxazine-8-carboxynitrile;

[0090] (12aR)-10-chloro-9-(2-chloro-6-hydroxyphenyl)-2-(prop-2-enoyl)-1,2,3,4,12,12a-hexahydro-6H-pyrazino[2,1-c][1,4]benzoxazine-8-carboxynitrile;

[0091] 1-[(12aR)-9-(2-bromo-6-hydroxyphenyl)-8,10-difluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazine-2(1H)-yl]propyl-2-en-1-one;

[0092] 1-[(12aR)-8-chloro-10-fluoro-9-(2-hydroxy-6-methylphenyl)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazine-2(1H)-yl]propyl-2-en-1-one;

[0093] 1-[(12aR)-8-chloro-10-ethynyl-9-(2-hydroxy-6-methylphenyl)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazine-2(1H)-yl]propyl-2-en-1-one;

[0094] 1-[(12aR)-10-ethynyl-8-fluoro-9-(2-hydroxy-6-methylphenyl)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazine-2(1H)-yl]propyl-2-en-1-one;

[0095] (6aR)-4-chloro-3-(2-fluoro-6-hydroxyphenyl)-2-methyl-8-(prop-2-enoyl)-2,6,6a,7,8,9,10,12-octahydro-1H-pyrazino[2,1-c]pyrido[3,4-f][1,4]oxazine-1-one;

[0096] 1-[(6aR)-1,4-dichloro-3-(2-fluoro-6-hydroxyphenyl)-6a,7,9,10-tetrahydro-12H-pyrazino[2,1-c]pyridino[3,4-f][1,4]oxazine-8(6H)-yl]propyl-2-en-1-one;

[0097] (6aR)-4-chloro-3-(2-fluoro-6-hydroxyphenyl)-8-(prop-2-enoyl)-2,6,6a,7,8,9,10,12-octahydro-1H-pyrazino[2,1-c]pyrido[3,4-f][1,4]oxazine-1-one;

[0098] 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]oxazolo-10(8H)-yl]propyl-2-en-1-one;

[0099] 1-[(7aR)-5-chloro-4-(2-fluoro-6-hydroxyphenyl)-1-methyl-1,7a,8,10,11,13-hexahydropyrazino[2',1':3,4][1,4]oxazolo[7,6-g]indazole-9(7H)-yl]propyl-2-en-1-one; and

[0100] 1-[(7aR)-5-chloro-4-(2-fluoro-6-hydroxyphenyl)-2-methyl-2,7a,8,10,11,13-hexahydropyrazino[2',1':3,4][1,4]oxazadiazino[7,6-g]indazole-9(7H)-yl]propyl-2-en-1-one;

[0101] 1-[(12aR)-9-(2-chloro-6-hydroxyphenyl)-8-ethynyl-10-fluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazine-2(1H)-yl]prop-2-en-1-one;

[0102] 1-[(12aR)-10-chloro-9-(2-chloro-6-hydroxyphenyl)-8-ethynyl-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazine-2(1H)-yl]prop-2-en-1-one;

[0103] 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]oxazine-2(1H)-yl)prop-2-en-1-one;

[0104] 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]benzoxazine-9(7H)-yl]propyl-2-en-1-one;

[0105] 1-[(12aR)-8-chloro-9-(2-chloro-6-hydroxyphenyl)-10-fluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazine-2(1H)-yl]propyl-2-en-1-one;

[0106] 1-[(12aR)-9-(2-chloro-6-hydroxyphenyl)-10-fluoro-8-(prop-1-yn-1-yl)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazine-2(1H)-yl]prop-2-en-1-one;

[0107] 1-[(6aR)-4-chloro-3-(2-chloro-6-hydroxyphenyl)-2-ethynyl-6a,7,9,10-tetrahydro-12H-pyrazino[2,1-c]pyridino[2,3-f][1,4]oxazine-8(6H)-yl]prop-2-en-1-one;

[0108] 1-[(12aR)-9-(2-chloro-6-hydroxyphenyl)-8-ethynyl-10-methyl-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazine-2(1H)-yl]propyl-2-en-1-one;

[0109] 1-[(12aR)-10-chloro-9-(2-chloro-6-hydroxyphenyl)-7,8-difluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazine-2(1H)-yl]propyl-2-en-1-one;

[0110] 1-[(12aR)-9-(2-chloro-6-hydroxyphenyl)-8-(difluoromethoxy)-10-fluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazine-2(1H)-yl]propyl-2-en-1-one;

[0111] 1-[(12aR)-9-(2-chloro-6-hydroxyphenyl)-8-ethynyl-7,10-difluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazine-2(1H)-yl]prop-2-en-1-one;

[0112] 1-[(12aR)-10-chloro-9-(2-chloro-6-hydroxyphenyl)-8-(difluoromethoxy)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazine-2(1H)-yl]propyl-2-en-1-one;

[0113] 1-[(12aR)-9-(2-chloro-6-hydroxyphenyl)-8-(cyclopropoxy)-10-fluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazine-2(1H)-yl]propyl-2-en-1-one;

[0114] 1-((12aR)-9-(2-chloro-6-hydroxyphenyl)-8-(3-(dimethylamino)prop-1-yn-1-yl)-10-fluoro-3,4,12,12a-tetrahydro-6H-benzo[f]pyrazino[2,1-c][1,4]oxazine-2(1H)-yl)prop-2-en-1-one;

[0115] 1-[(12aR)-9-(2-chloro-6-hydroxyphenyl)-10-fluoro-8-[(pyridin-4-yl)methoxy]-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazono-2(1H)-yl]propyl-2-en-1-one;

[0116] 1-[(12aR)-10-chloro-9-(2-chloro-6-hydroxyphenyl)-8-(2-methoxyethoxy)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazine-2(1H)-yl]propyl-2-en-1-one;

[0117] 1-[(12aR)-9-(2-chloro-6-hydroxyphenyl)-10-fluoro-8-[2-(piperidin-1-yl)ethoxy]-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazine-2(1H)-yl]propyl-2-en-1-one;

[0118] 1-[(12aR)-10-chloro-9-(2-chloro-6-hydroxyphenyl)-8-(prop-1-yn-1-yl)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazine-2(1H)-yl]prop-2-en-1-one;

[0119] 1-[(6aR)-4-chloro-3-(2-chloro-6-hydroxyphenyl)-2-[( 2 [H3)methoxy]-6a,7,9,10-tetrahydro-12H-pyrazino[2,1-c]pyridino[2,3-f][1,4]oxazine-8(6H)-yl]propyl-2-en-1-one;

[0120] 1-[(12aR)-10-chloro-9-(2-chloro-6-hydroxyphenyl)-8-(methoxymethyl)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazine-2(1H)-yl]propyl-2-en-1-one; and

[0121] 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]benzoxazono-2(1H)-yl]propyl-2-en-1-one;

[0122] 1-[(6aR)-4-chloro-3-(2-chloro-6-hydroxyphenyl)-1-(prop-1-yn-1-yl)-6a,7,9,10-tetrahydro-12H-pyrazino[2,1-c]pyridino[3,4-f][1,4]oxazine-8(6H)-yl]prop-2-en-1-one; and

[0123] 1-((6aR)-4-chloro-3-(2-chloro-6-hydroxyphenyl)-1-ethynyl-6a,7,9,10-tetrahydro-12H-pyrazino[2,1-c]pyridino[3,4-f][1,4]oxazine-8(6H)-yl)prop-2-en-1-one;

[0124] Or its pharmaceutically acceptable salt.

[0125] In some implementations, the small molecule KRAS inhibitor is a compound of formula (IV):

[0126] (IV).

[0127] The compound of formula (IV) is 1-[(12aR)-9-(2-chloro-6-hydroxyphenyl)-10-fluoro-8-(prop-1-yn-1-yl)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazine-2(1H)-yl]prop-2-en-1-one, or a pharmaceutically acceptable salt thereof.

[0128] 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 (bexostatin), BAY-1895344 (erristatin), RP-3500 (camonsertib), ATRN-119, SC0245, ATRN-212, LR-02, M4344 (gartisetinib), 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:

[0129] (V).

[0130] In some implementation schemes, R 24 and R 25 Together with the atoms to which they are attached, they form ring A. 2 And ring A 2 It is C 3-6 Cycloalkyl or a saturated 4-6 heterocycle containing a heteroatom selected from O and N. In some embodiments, cycloA... 2 It is a cyclopropyl, tetrahydropyranyl, or piperidinyl ring. In some embodiments, R 22A It is hydrogen; R 22B It is hydrogen; R 22C It is hydrogen; R 22D It is hydrogen; R 22E It is hydrogen; and R 22F It is hydrogen. In some implementations, R 21 It is morpholino-4-yl. In some embodiments, R 21 It is 3-methylmorpholino-4-yl. In some embodiments, the compound of formula (V) is a compound of formula (Va) as defined herein:

[0131] (Va)

[0132] In some implementations, the small molecule ATR inhibitor is selected from any of the following:

[0133] 4-{4-[(3R)-3-methylmorpholin-4-yl]-6-[((R)-S-methylsulfonylimino)methyl]pyrimidin-2-yl}-1H-pyrrolo[2,3-b]pyridine;

[0134] 4-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((S)-S-methylsulfonylimino)cyclopropyl]pyrimidin-2-yl}-1H-pyrrolo[2,3-b]pyridine;

[0135] 4-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((R)-S-methylsulfonylimino)cyclopropyl]pyrimidin-2-yl}-1H-pyrrolo[2,3-b]pyridine;

[0136] N-Methyl-1-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((R)-S-methylsulfonylimino)cyclopropyl]pyrimidin-2-yl}-1H-benzimidazole-2-amine;

[0137] N-Methyl-1-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((S)-S-methylsulfonylimino)cyclopropyl]pyrimidin-2-yl}-1H-benzimidazole-2-amine;

[0138] 4-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((R)-S-methylsulfonylimino)cyclopropyl]pyrimidin-2-yl}-1H-indole;

[0139] 4-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((S)-S-methylsulfonylimino)cyclopropyl]pyrimidin-2-yl}-1H-indole;

[0140] 1-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((R)-S-methylsulfonylimino)cyclopropyl]pyrimidin-2-yl}-1H-benzimidazol-2-amine;

[0141] 1-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((S)-S-methylsulfonylimino)cyclopropyl]pyrimidin-2-yl}-1H-benzimidazol-2-amine;

[0142] 4-Fluoro-N-methyl-1-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((R)-S-methylsulfonylimino)cyclopropyl]pyrimidin-2-yl}-1H-benzimidazol-2-amine;

[0143] 4-Fluoro-N-methyl-1-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((S)-S-methylsulfonylimino)cyclopropyl]pyrimidin-2-yl}-1H-benzimidazol-2-amine;

[0144] 4-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-(S-methylsulfonylimino)cyclopropyl]pyrimidin-2-yl}-1H-pyrrolo[2,3-c]pyridine;

[0145] N-Methyl-1-{4-[1-methyl-1-((S)-S-methylsulfonylimino)ethyl]-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-2-yl}-1H-benzimidazole-2-amine;

[0146] N-Methyl-1-{4-[1-methyl-1-((R)-S-methylsulfonylimino)ethyl]-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-2-yl}-1H-benzimidazol-2-amine;

[0147] N-Methyl-1-{4-[(3R)-3-methylmorpholin-4-yl]-6-[4-((S)-S-methylsulfonylimino)tetrahydro-2H-pyran-4-yl]pyrimidin-2-yl}-1H-benzimidazol-2-amine;

[0148] N-Methyl-1-{4-[(3R)-3-methylmorpholin-4-yl]-6-[4-((R)-S-methylsulfonylimino)tetrahydro-2H-pyran-4-yl]pyrimidin-2-yl}-1H-benzimidazol-2-amine;

[0149] 4-{4-[(3R)-3-methylmorpholin-4-yl]-6-[4-((S)-S-methylsulfonylimino)tetrahydro-2H-pyran-4-yl]pyrimidin-2-yl}-1H-indole;

[0150] 4-Fluoro-N-methyl-1-{4-[1-methyl-1-((S)-S-methylsulfonylimino)ethyl]-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-2-yl}-1H-benzimidazol-2-amine;

[0151] 4-Fluoro-N-methyl-1-{4-[1-methyl-1-((R)-S-methylsulfonylimino)ethyl]-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-2-yl}-1H-benzimidazol-2-amine;

[0152] 6-Fluoro-N-methyl-1-{4-[1-methyl-1-((R)-S-methylsulfonylimino)ethyl]-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-2-yl}-1H-benzimidazol-2-amine;

[0153] 5-Fluoro-N-methyl-1-{4-[1-methyl-1-((R)-S-methylsulfonylimino)ethyl]-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-2-yl}-1H-benzimidazol-2-amine;

[0154] 5-Fluoro-N-methyl-1-{4-[1-methyl-1-((S)-S-methylsulfonylimino)ethyl]-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-2-yl}-1H-benzimidazol-2-amine;

[0155] 6-Fluoro-N-methyl-1-{4-[1-methyl-1-((S)-S-methylsulfonylimino)ethyl]-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-2-yl}-1H-benzimidazol-2-amine;

[0156] 6-Fluoro-N-methyl-1-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((R)-S-methylsulfonylimino)cyclopropyl]pyrimidin-2-yl}-1H-benzimidazol-2-amine;

[0157] 5-Fluoro-N-methyl-1-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((R)-S-methylsulfonylimino)cyclopropyl]pyrimidin-2-yl}-1H-benzimidazol-2-amine;

[0158] 5-Fluoro-N-methyl-1-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((S)-S-methylsulfonylimino)cyclopropyl]pyrimidin-2-yl}-1H-benzimidazol-2-amine; and

[0159] 6-Fluoro-N-methyl-1-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((S)-S-methylsulfonylimino)cyclopropyl]pyrimidin-2-yl}-1H-benzimidazol-2-amine;

[0160] Or its pharmaceutically acceptable salt.

[0161] In some implementations, the small molecule ATR inhibitor is a compound of formula (VI) (cilaceltetracycline):

[0162] (VI).

[0163] The compound of formula (VI) is 4-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((R)-S-methylsulfonylimino)cyclopropyl]pyrimidin-2-yl}-1H-pyrrolo[2,3-b]pyridine, or a pharmaceutically acceptable salt thereof.

[0164] In some embodiments, (i) the KRAS inhibitor and (ii) the ATR inhibitor are one of the combinations listed in Table 4. In some embodiments, (i) the KRAS inhibitor is a compound of formula (II), and (ii) the ATR inhibitor is cilazolidinone. In some embodiments, (i) the KRAS inhibitor is a compound of formula (IV), and (ii) the ATR inhibitor is cilazolidinone.

[0165] 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 or gastric cancer, endometrial cancer, bile duct cancer, or a combination thereof.

[0166] In some embodiments, this disclosure provides a method for modulating an adaptive immune response in a subject, the method comprising administering a composition comprising: (a) a KRAS inhibitor and (b) an ATR inhibitor. In some embodiments, this disclosure provides a method for reducing the volume of a cancerous tumor in a subject, the method comprising administering a composition comprising: (a) a KRAS inhibitor and (b) an ATR inhibitor. In some embodiments, this disclosure provides a method for treating a subject in need, the method comprising administering a composition comprising: (a) a KRAS inhibitor and (b) an ATR inhibitor, wherein the subject suffers from a condition mediated by a KRAS, NRAS, or HRAS G12C mutation.

[0167] This disclosure also provides a composition comprising: (a) a KRAS inhibitor and (b) an ATR inhibitor. In some embodiments, the KRAS inhibitor is sotoraraciab, adagraciab, Ly3537982, GDC-6036, D-1553, JDQ443, BI1823911, GFH925, D35-001, JAB-21822, HBI-2438, YL-15293, GEC255, IBI351, RMC-6291, MK-1084, MRT X1133, HRS-4642, RMC-9805, JAB-2200, Vrtx153, ERAS-4, ASP3082, RMC-0708, RMC-8839, RMC-6291, JAB-23400, TEB-17231, QTX3046, compounds of formula (I), compounds of formula (II), compounds of formula (III), or compounds of formula (IV). In some implementations, the ATR inhibitor is M6620 / VX970 (bexostatet), BAY-1895344 (erristatet), RP-3500 (carmenstatet), ATRN-119, SC0245, ATRN-212, LR-02, M4344 (gatixetet), 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).

[0168] 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 a pharmaceutically acceptable excipient, diluent, or carrier.

[0169] This disclosure also provides the use of the compositions described herein in the manufacture of a medicament, optionally for the treatment of cancer.

[0170] In some embodiments, this disclosure provides a kit comprising: (a) a first container containing a first composition containing a KRAS inhibitor, and (b) a second container containing a second composition containing an ATR inhibitor. In some embodiments, the KRAS inhibitor in the kit is sotoraraxib, adagraxib, 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, compounds of formula (I), compounds of formula (II), compounds of formula (III), or compounds of formula (IV). In some implementations, the ATR inhibitor in the kit is M6620 / VX970 (bexostat), BAY-1895344 (erristat), RP-3500 (carmenstat), ATRN-119, SC0245, ATRN-212, LR-02, M4344 (gatixet), 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).

[0171] 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 pharmaceutically acceptable excipients, diluents, or carriers. Attached Figure Description

[0172] Figure 1 Inhibition of KRAS and ATR drives KRAS G12C Tumor regression in mutant models. Figure 1A: A schematic diagram showing the dosing regimens of AZD4625 (compound of formula II) and AZD6738 (cilaceltetracycline) used in the study. Tumor growth in individual animals treated with AZD4625 or AZD6738 in monotherapy, combination therapy, or control. Figure 1 B) or weight changes ( Figure 1 C).

[0173] Figure 2 It is expected to have combination activity with all allosteric G12C inhibitors. Figure 2 A: A schematic diagram showing the dosing regimens for AZD4625, compounds of formula IV, and AZD6738 used in the study. Figure 2 B: Tumor growth in individual animals treated with AZD4625, a compound of formula IV, or AZD6738 in monotherapy, combination therapy, or control.

[0174] Figure 3 KRAS and ATR inhibition provide long-term anti-tumor protection. Figure 3 A: Schematic diagram of the re-excitation study design. Figure 3 B: Following a complete antitumor response to compounds of formula IV and AZD6738, individual CT26 cells were observed in the left ventral region of primate or re-challenged mice. G12C Tumor growth.

[0175] Figure 4 Achieving durable antitumor responses in preclinical models with intact immune systems. KRAS levels in immunodeficient nude mice and immunocompetent BALB / c mice were observed during a 4-week treatment period. G12C The response of inhibitors (AZD4625 or compounds of formula (IV)) and AZD6738 to monotherapy and combination therapy for tumor growth ( Figure 4 A) or the time to reach the finish line ( Figure 4 Comparison of B). Figure 4 The gray bar in A indicates the treatment period for AZD6738. Figure 4 The gray bars in B indicate the dosing period for all treatments.

[0176] Figure 5 Achieving durable antitumor responses in preclinical models with intact immune systems. KRAS in immune-active BALB / c mice during a 4-week drug treatment period. G12C The response of inhibitors (adagraxibu or sotorasibu) and AZD6738 to monotherapy and combination therapy for tumor growth ( Figure 5 A) Time to reach the finish line ( Figure 5 B) and percentage change in weight ( Figure 5 Comparison of C). Figure 5 A and Figure 5 The gray bar in C indicates the treatment period for AZD6738. Figure 5 The gray bars in B indicate the dosing period for all treatments. Detailed Implementation

[0177] Unless otherwise defined herein, scientific and technical terms used in this disclosure shall have the meanings commonly understood by one of ordinary skill in the art.

[0178] Furthermore, unless the context requires otherwise, singular terms should include plural forms and plural terms should include singular forms. As used herein, “a” or “one” may mean one or more. As used herein, when used in conjunction with the word “contains,” the word “a” or “one” may mean one or more. As used herein, “another” or “another” may mean at least a second or more.

[0179] The use of the term "or" in the claims is intended to mean "and / or" unless expressly indicated to refer only to alternatives or the alternatives are mutually exclusive, although this disclosure supports the definition of "and / or" referring only to alternatives.

[0180] As used herein, the terms “comprising” (and any variations or forms of “comprise” and “comprises”), “having” (and any variations or forms of “have” and “has”), “including” (and any variations or forms of “includes” and “include”), or “containing” (and any variations or forms of “contains” and “contain”) are inclusive or open-ended and do not exclude additional, unlisted elements or method steps.

[0181] Throughout this application, the term "about" is used to indicate that a value includes inherent error variations in the method / apparatus used to determine that value, or variations present in study subjects. Generally, the term "about" is intended to cover variability of approximately or less than 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20% or higher ("greater than" or "less than" indicating values), depending on the specific circumstances. In the embodiments, those skilled in the art will understand the level of variability indicated by the term "about" due to the context in which it is used herein. It should also be understood that the use of the term "about" also includes specifically enumerated values.

[0182] The use of the term "for example" and its corresponding abbreviation "eg" (whether italic or not) indicates that the specific term referenced is a representative example and implementation of this disclosure, and is not intended to be limited to the specific example referenced or cited unless otherwise expressly stated.

[0183] Any range provided herein includes all values ​​within that specific range and values ​​with respect to the endpoints of that range. As used herein, “between” is a range that includes the endpoints of the range. For example, a number between x and y explicitly includes the numbers x and y, as well as any numbers falling within x and y.

[0184] The term "treatment" refers to the administration of a compound or pharmaceutical composition to an animal to achieve a change or improvement in a disease, symptom, or condition. In some embodiments, "treatment" is provided to a subject suffering from a condition suitable for treatment with the combination as described herein. In some embodiments, "treatment" is provided to subjects at high risk of having KRAS and / or ATR-dependent conditions as described herein, even before any clinical signs of such a condition appear in the subject.

[0185] The term “administration” refers to the manner in which a compound or composition provided herein is introduced into an individual to achieve its intended function. Examples of possible administration methods include, but are not limited to, parenteral administration, such as subcutaneous, intravenous or intramuscular injection or infusion, or oral administration, such as in a solid oral dosage form.

[0186] The term "subject" is intended to include any subject requiring treatment with a KRAS inhibitor / ATR inhibitor as described herein, particularly mammalian subjects. Mammal subjects include humans or non-human animals. In some embodiments, the term "subject" refers to a human subject. In some embodiments, the term "subject" refers to a female subject. In some embodiments, the term "subject" refers to a male subject. In some embodiments, human subjects are defined as those aged 12 years and older, 14 years and older, 4 to 17 years and older, or 18 years and older. Non-human animals include, but are not limited to, pigs, dogs, cats, guinea pigs, rabbits, rats, mice, horses, cattle, bears, dairy cows, apes, monkeys, orangutans, and chimpanzees.

[0187] As used herein, “subject in need” means a subject who requires treatment, such as a subject with cancer and / or KRAS mutations as described herein. In some implementations, the term “subject in need” may refer to a subject at high risk of having cancer and / or KRAS mutations as described herein, regardless of whether the subject has physical manifestations of such conditions.

[0188] "Pharmaceutically acceptable salts" refer to physiologically and pharmaceutically acceptable salts of compounds that possess the pharmacological activity required by the parent compound, and include 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 a review of pharmaceutically acceptable salts, see Stahl and Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection and Use (Wiley-VCH, Weinheim, Germany, 2002).

[0189] This disclosure relates to a method of treating a subject with cancer, the method comprising administering to the subject: (a) a KRAS inhibitor, and (b) an ataxia-telangiectasia and Rad-3-related (ATR) inhibitor.

[0190] This disclosure also relates to a KRAS inhibitor for use in treating cancer in a subject, wherein the treatment comprises administering the inhibitor to the subject alone, sequentially, or simultaneously:

[0191] a. The KRAS inhibitors mentioned above, and

[0192] b. ATR inhibitors.

[0193] This disclosure also relates to an ATR inhibitor for use in treating cancer in a subject, wherein the treatment comprises administering the inhibitor to the subject alone, sequentially, or simultaneously:

[0194] a.KRAS inhibitors, and

[0195] b. The ATR inhibitor.

[0196] This disclosure also relates to the use of a KRAS inhibitor or an ATR inhibitor in the manufacture of a medicament for the combined administration of a KRAS inhibitor and an ATR inhibitor for the treatment of a subject with cancer.

[0197] The term KRAS refers to the Kirsten rat sarcoma 2 virus oncogene homolog (according to the annotation of GenBank (http: / / www.ncbi.nlm.nih.gov / ) gene ID 3845) of the National Center for Biotechnology Information (NCBI) of the U.S. government, and refers to a small class of GTPase proteins that have been 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 isotypes, KRAS4A and KRAS4B, which differ in the C-terminal region. The amino acid sequence of the human wild-type KRAS4A isotype is annotated according to GenBank accession number: NP_203524.1 or Swissprot / Uniprot (http: / / www.uniprot.org / ) accession number: P01116-1(v1), and the NP_203524.1 sequence is reproduced in Table 1.

[0198] Table 1 (SEQ ID NO:1)

[0199]

[0200] The human wild-type KRAS4B isotype amino acid sequence can be annotated according to Genbank accession number: NP_004976.2 or Swissprot / Uniprot accession number: P01116-2 (v1). The NP_004976.2 sequence is reproduced in Table 2 below:

[0201] Table 2 (SEQ ID NO:2)

[0202]

[0203] In some implementations, KRAS may include other related Ras proteins, such as NRAS or HRAS, which are substantially identical at positions 1-86 (including the regions surrounding G12 and G13), thus the same molecule can be used to target G12 or G13 mutant human KRAS, NRAS, and HRAS proteins. The amino acid sequence of human wild-type HRAS can be found according to Genbank accession number NP_005334.1 or Swissprot / Uniprot accession number P01112 (v1). The NP_005334.1 sequence is reproduced in Table 3 below:

[0204] Table 3 (SEQ ID NO:3)

[0205]

[0206] In human cancers, KRAS is the predominantly mutated RAS isotype (85%). Notably, the amino acid sequences of human KRAS, NRAS, and HRAS are essentially identical at positions 1-86 (including the regions surrounding G12 and G13), thus the same molecules can be used to target G12 or G13 mutant human KRAS, NRAS, and HRAS proteins.

[0207] In some embodiments, KRAS inhibitors can inhibit human KRAS. The qualifier “human,” as used herein in connection with KRAS protein, may, in some interpretation, refer to the amino acid sequence of the KRAS protein. For example, KRAS proteins having the same amino acid sequence as those found in humans can also be obtained by technical means, such as through recombinant expression, cell-free translation, or non-biological peptide synthesis. Because the molecules of the present invention are intended to therapeutically target mutant KRAS proteins in humans, in some other interpretations, the qualifier “human” may more specifically refer to KRAS proteins found or present in humans, regardless of whether the KRAS protein is part of or has been at least partially isolated from a human subject, organ, cell, or tissue. Those skilled in the art will understand that the amino acid sequence of a given natural protein (such as KRAS protein) may differ between or within different individuals of the same species due to normal genetic diversity within the species (allelic variation, polymorphism) and / or due to differences in post-transcriptional or post-translational modifications. Any such variants or isotypes of a natural protein are included in the reference or name of the protein.

[0208] Various compounds that inhibit KRAS are known in the art and may include antibodies that specifically bind to KRAS. In some embodiments, KRAS inhibitors are antibodies or other therapeutic proteins that can selectively bind to KRAS, i.e., anti-KRAS antibodies.

[0209] As used herein, the term "antibody" refers to a polypeptide or group of polypeptides containing at least one binding domain formed by the folding of a polypeptide chain having a three-dimensional binding space with an inner surface shape and charge distribution complementary to the characteristics of the antigenic determinants of the antigen. Antibodies typically exist in tetrameric form, having two pairs of polypeptide chains, each pair having one "light" chain and one "heavy" chain, wherein a variable region of each light / heavy chain pair forms an antibody binding site. Typically, each light chain is linked to the heavy chain by a covalent disulfide bond, although the number of disulfide bonds between heavy chains of different immunoglobulin isotypes varies. Each heavy and light chain also has regularly spaced intrachain disulfide bridges. Typically, each heavy chain has a variable domain (VH) at one end, followed by multiple constant domains (CH), and each light chain has a variable domain (VL) at one end and a constant domain (CL) at the other end, wherein the constant domain of the light chain is aligned with the first constant domain of the heavy chain, and the variable domain of the light chain is aligned with the variable domain of the heavy chain.

[0210] As used herein, the terms “antibody,” “antibodies,” and “immunoglobulin” include 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, camelified antibodies, chimeric antibodies, single-chain Fv (scFv), single-chain antibodies, single-domain antibodies, Fab fragments, Fab' fragments, F(ab')2 fragments, antibody fragments exhibiting the desired biological activity (e.g., antigen-binding portions), disulfide-linked Fv (dsFv), and anti-idiotype (anti-Id) antibodies, intracellular antibodies, and epitope-binding fragments or derivatives of any of the above. In particular, antibodies include immunoglobulin molecules and immunoglobulin molecules containing at least one antigen-binding site with immunoactive fragments. Immunoglobulin molecules can be 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, such as G1m (f, z, a, or x), G2m (n), G3m (g, b, or c), Am, Em, and Km (1, 2, or 3)). Antibodies can be derived from any mammalian species, including but not limited to humans, monkeys, pigs, horses, rabbits, dogs, cats, and mice, or other animals such as birds, including but not limited to chickens. Antibodies can be fused to heterologous polypeptide sequences (e.g., tags for easy purification).

[0211] Antibodies can be modified in the Fc region to provide desired effector function or serum half-life. As discussed in more detail below, using an appropriate Fc region, naked antibodies bound to the cell surface can be activated via antibody-dependent cytotoxicity (ADCC), by recruiting complement in complement-dependent cytotoxicity (CDC), or by recruiting nonspecific cytotoxic cells expressing one or more effector ligands that recognize antibodies bound to influenza A virus and subsequently induce phagocytosis in antibody-dependent cell-mediated phagocytosis (ADCP), or some other mechanism. Alternatively, modified Fc regions can be used, for example, to increase binding affinity to FcRn and increase serum half-life, where it is desired to eliminate or reduce effector function (e.g., reduce side effects or treat complications). Alternatively, the Fc region can be partially conjugated to substances such as PEG or albumin to increase serum half-life.

[0212] 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. Variant antibodies may include one or more substitutions, deletions (including internal deletions), additions (including additions that produce fusion proteins), or conserved substitutions of amino acid residues of the parent antibody.

[0213] 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.

[0214] 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 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, the small molecule KRAS 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 KRAS inhibitor has an IC50 of less than about 2 nM or less than about 1 nM. In some embodiments, the small molecule KRAS 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 KRAS inhibitor has an IC50 of about 0.5 nM to about 5 nM, or about 0.5 nM to about 2 nM.

[0215] In some embodiments, the small molecule KRAS inhibitor may comprise small molecules known to those skilled in the art. For example, in some embodiments, the small molecule KRAS inhibitor is:

[0216] Sotorasis (AMG-510, Amgen, Model L)

[0217] L

[0218] Adagorasib (MRTX849, Mirati Therapeutics, Inc., M)

[0219] M

[0220] Ly3537982 (Lilly, formula N)

[0221] N

[0222] Divarasib (GDC-6036, Genetech, Formula O)

[0223] O

[0224] Garsorasib (D-1553, InventisBio, Co., Ltd., formula P)

[0225] P

[0226] Opnurasib (JDQ443, Novartis, formula Q)

[0227] Q

[0228] fulzerasib (IBI351, GFH925, Innovent Biologics, formula R)

[0229] R

[0230] BI1823911, D35-001, glecirasib (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, KRAS inhibitors may comprise a combination of small molecule KRAS inhibitors as described herein.

[0231] The small molecule KRAS inhibitor of formula (I) is described in WO2019215203, 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):

[0232]

[0233] in:

[0234] Ring A is selected from phenyl and bicyclic heteroaryl groups;

[0235] R 1 Each time it appears, it is independently selected from C. 1-4 Alkyl, halogenated, hydroxyl, C 1-4 Alkoxy, C 1-3 fluoroalkyl, C 1-3 Fluoroalkoxy, cyano, and ethynyl groups;

[0236] b is 0, 1, 2, or 3;

[0237] Y is CH2 or CH2CH2;

[0238] R 2 It is cyano, halogenated, C 1-4 Alkyl, C 1-4 Alkoxy or C 1-3 fluoroalkyl;

[0239] R 3 Is it F, Me, Et, MeO, or C? 1-2 fluoroalkyl;

[0240] R 4 It is H or Me;

[0241] R 5 It is H or Me;

[0242] R 6 It is H or CH2NMe2;

[0243] Or its pharmaceutically acceptable salt, provided that Y is CH2 and R is a chemically acceptable salt. 2 It is Cl, R 3 It is F, ring A is phenyl, b is 2, and R is... 1 When the groups are F and OH and each is located ortho to the biaryl bond, and when R 4 and R 6 When both are H, then R 5 It's me.

[0244] In some embodiments of formula (I), the small molecule KRAS inhibitor has a structural...

[0245] .

[0246] Various bicyclic aryl rings can be used for ring A of formula (I). In some embodiments, ring A in the compound of formula (I) is selected from phenyl and bicyclic heteroaryl groups. As used herein, a bicyclic heteroaryl group refers to an aromatic group comprising two fused rings and containing 1, 2, 3, or 4 N atoms, or one O atom, or one S atom, or one N atom and one S atom, or one N atom and one O atom, or two N atoms and one S atom, or two N atoms and one O atom. Bicyclic heteroaryl groups include those groups in which both fused rings are aromatic, or one fused ring is aromatic and the other is partially or fully saturated. The partially or fully saturated fused ring may also 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] ring system or a [6,5] ring system. Examples of suitable bicyclic heteroaryl groups include indolyl, benzofuranyl, benzothiophenyl, benzooxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, azaindolyl, azainzolyl, pyrrolo[1,2-b]pyridazinyl and pyrrolo[2,3-b]pyridinyl, quinolinyl, isoquinolinyl, quinazolinyl, cenolinyl, phthalazinyl, quinoxalinyl and naphridinyl, as well as their partially saturated derivatives.

[0247] In some implementations, ring A of formula (I) is selected from the group consisting of:

[0248] .

[0249] In some embodiments, ring A, as listed above, is attached to the remainder of the compound of formula (I) at any point on the ring listed above. In some embodiments, ring A, as listed above, is attached to the remainder of the compound of formula (I) at a carbon atom on the ring. In some embodiments, ring A, as listed above, is attached to the remainder of the compound of formula (I) at a heteroatom on the ring. In some embodiments, ring A, as listed above, is attached to the remainder of the compound of formula (I) at position 1, 2, 3, 4, 5, 6, 7, 8, or 9 on the ring.

[0250] In some implementation schemes, (R 1 ) b Attach to ring A listed above at any point on the rings listed above. In some embodiments, (R 1 ) b The ring is attached to the carbon portion of the ring as listed above, ring A. In some embodiments, (R 1 ) b The heteroatom on the ring is attached to ring A listed above. In some embodiments, (R 1 ) bAttach the ring to ring A listed above at positions 1, 2, 3, 4, 5, 6, 7, 8, or 9.

[0251] In some implementation schemes, R 1 Each time it appears, it is independently selected from C. 1-4 Alkyl, halogenated, hydroxyl, C 1-4 Alkoxy, C 1-3 fluoroalkyl, C 1-3 Fluoroalkoxy, cyano, and ethynyl. To avoid ambiguity, C 1-4 Alkyl refers to a straight-chain or branched alkyl group containing 1 to 4 carbon atoms; throughout the specification, numerical subscripts, for example, are used for alkoxy, fluoroalkyl, and fluoroalkoxy groups in accordance with this usage.

[0252] As used herein, the term halogenated group refers to an atom selected from F, Cl, Br, or I. In embodiments of this specification, the halogenated group in the compound of formula (I), particularly for the group R... 2 and R 1 F and Cl are preferred halogenated groups.

[0253] Group R 2 Selected from cyano, halogenated, C 1-4 Alkyl, C 1-4 Alkoxy or C 1-3 Fluoroalkyl. Preferred R 2 Examples of groups include Cl, methyl, and cyano, such as Cl. Group R 3 Selected from F, Me, Et, MeO or C 1-2 Fluoroalkyl groups, such as F, Me, or MeO.

[0254] To avoid ambiguity, when multiple substituents are independently selected from a given group, the selected substituents may include the same substituents or different substituents from within the given group. By way of example only, in formula (I), ring A is (R... 1 ) b In the case of substituted phenyl groups, and when b is 2, both R groups... 1 The groups can be the same, for example, all fluorine, or they can be different, for example, one fluorine and one hydroxyl group.

[0255] To further avoid any doubt, the formula in this specification is " The use of "" indicates the attachment point between different groups.

[0256] As described above, in some embodiments, the small molecule KRAS inhibitor is a compound of formula (I):

[0257]

[0258] in:

[0259] Ring A is selected from phenyl and bicyclic heteroaryl groups;

[0260] R 1 Each time it appears, it is independently selected from C. 1-4 Alkyl, halogenated, hydroxyl, C 1-4 Alkoxy, C 1-3 fluoroalkyl, C 1-3 Fluoroalkoxy, cyano, and ethynyl groups;

[0261] b is 0, 1, 2, or 3;

[0262] Y is CH2 or CH2CH2;

[0263] R 2 It is cyano, halogenated, C 1-4 Alkyl, C 1-4 Alkoxy or C 1-3 fluoroalkyl;

[0264] R 3 Is it F, Me, Et, MeO, or C? 1-2 fluoroalkyl;

[0265] R 4 It is H or Me;

[0266] R 5 It is H or Me;

[0267] R 6 It is H or CH2NMe2;

[0268] Or its pharmaceutically acceptable salt, provided that Y is CH2 and R is a chemically acceptable salt. 2 It is Cl, R 3 F is F, A is phenyl, b is 2, and R is... 1 When the groups are F and OH and each is located ortho to the biaryl bond, and when R 4 and R 6 When both are H, then R 5 It's me.

[0269] In one implementation, the small molecule KRAS inhibitor is a compound of formula (I) as defined above.

[0270] In one implementation, the small molecule KRAS inhibitor is a pharmaceutically acceptable salt of a compound of formula (I).

[0271] In the implementation scheme, the compound of formula (I) is the compound of formula (Ia), wherein Y is CH2.

[0272] In the implementation scheme, the compound of formula (I) is the compound of formula (Ib), wherein Y is CH2CH2.

[0273] In the embodiments, the compounds of formula (I), (Ia), or (Ib) are compounds of formula (Ic), wherein R 2 Selected from Cl, Me, or CN (cyano). In embodiments, the compound of formula (Ic) is the same as the compound of formula (Id), wherein R 2 It is Cl.

[0274] In the embodiments, the compounds of formula (I), (Ia), (Ib), (Ic), or (Id) are compounds of formula (Ie), wherein R 3 Selected from F, Me, or MeO. In embodiments, the compound of formula (Ie) is a compound of formula (If), wherein R 3 It is F.

[0275] In the embodiments, the compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If) are compounds of formula (Ig), wherein R 4 It is H.

[0276] In the embodiments, the compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig) are compounds of formula (Ih), wherein R 5 It is H. In the embodiments, the compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig) are compounds of formula (Ii), wherein R 5 It is H.

[0277] In the embodiments, the compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (Ii) are compounds of formula (Ij), wherein R 6 It is H.

[0278] In the embodiments, the compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), or (Ij) are compounds of formula (Ik), wherein ring A is phenyl.

[0279] In the implementation, the compound of formula (Ik) is a compound of formula (Il), wherein the integer b is 2 or 3 and at least one R 1 The group is OH. In the embodiments, the compound of formula (Ik) or (Il) is a compound of formula (Im), wherein at least two R groups are OH groups. 1 The group is located ortho to the biaryl bond.

[0280] In the implementation scheme, the compound of formula (Ik) is a compound of formula (In), wherein A(R) 1 ) b yes Optional of R 1 Selected from Me, F, Cl, and CN (cyano). In the embodiments, R in the compound of formula (In) 1 Selected from Me, Cl, and CN.

[0281] In the implementation scheme, the compound of formula (Ik) is the compound of formula (Io), wherein A(R) 1 ) b yes .

[0282] In the embodiments, 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 group.

[0283] In the embodiments, 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:

[0284] .

[0285] In some embodiments, the bicyclic heteroaryl group of ring A, as listed above, is attached 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 attached to the remainder of the compound of formula (Ip) at a carbon atom on the ring. In some embodiments, the bicyclic heteroaryl group of ring A, as listed above, is attached to the remainder of the compound of formula (Ip) at position 1, 2, 3, 4, 5, 6, 7, 8, or 9 on the ring.

[0286] In some implementation schemes, (R 1 ) b Attach to ring A listed above at any point on the rings listed above for formula (Ip). In some implementations, (R 1 ) b The ring of formula (Ip) is attached to the carbon portion of the ring listed above as ring A. In some embodiments, (R) 1 ) b The heteroatom on the ring of formula (Ip) is attached to the ring A listed above. In some embodiments, (R) 1 ) bAttach the ring A listed above at position 1, 2, 3, 4, 5, 6, 7, 8 or 9 of the ring in formula (Ip).

[0287] In the embodiments, the compound of formula (Ip) is a compound of formula (Ir), wherein the bicyclic heteroaryl group is selected from the group consisting of:

[0288]

[0289] In the embodiments, the compound of formula (Ip) is the compound of formula (Is), wherein the bicyclic heteroaryl group is selected from the group consisting of:

[0290] .

[0291] In the embodiments, the compound of formula (Ip) is the compound of formula (It), wherein the bicyclic heteroaryl group is selected from the group consisting of:

[0292]

[0293] In the embodiments, the compound of formula (I), i.e., any one of the compounds of formula (I), (Ia), (Ib)... to (It), is a compound of formula (Iu) or (Iv), wherein the stereochemistry is as follows:

[0294] .

[0295] In the embodiments, the compound of formula (Iu) is the compound of formula (Iui), where Y = CH2. In the embodiments, the compound of formula (Iv) is the compound of formula (Ivi), where Y = CH2CH2.

[0296] In the embodiments, the compound of formula (I), i.e., any one of the compounds of formulas (I), (Ia), (Ib)... to (Ivi), is a compound of formula (Iw), wherein R 4 It is H and R 5 It's me.

[0297] In the embodiments, the compounds of formula (I) are selected from each of the following enantiomers and transisomers:

[0298] 7-[(8aS)-10-acryloyl-6-chloro-4-fluoro-8,8a,9,10,11,12-hexahydropyrazino[2',1':3,4][1,4]oxazolo[5,6,7-de]quinazolin-5-yl]-6-methyl-2,3-dihydro-1H-isoindol-1-one;

[0299] 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]oxazolo[5,6,7-de]quinazolin-10(8H)-yl]propyl-2-en-1-one;

[0300] 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]oxazolo[5,6,7-de]quinazolin-10(8H)-yl]propyl-2-en-1-one;

[0301] 5-[(8aS)-10-acryloyl-6-chloro-4-fluoro-8,8a,9,10,11,12-hexahydropyrazino[2',1':3,4][1,4]oxazolidinyl[5,6,7-de]quinazolin-5-yl]-6-methylquinazolin-4(3H)-one;

[0302] 1-[(8aS)-6-chloro-4-fluoro-5-(5-methyl-1H-benzimidazol-4-yl)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazolo[5,6,7-de]quinazolin-10(8H)-yl]propyl-2-en-1-one;

[0303] 8-[(8aS)-6-chloro-4-fluoro-10-(prop-2-enoyl)-8,8a,9,10,11,12-hexahydropyrazino[2',1':3,4][1,4]oxazolo[5,6,7-de]quinazolin-5-yl]isoquinolin-1(2H)-one;

[0304] 1-[(8aS)-6-chloro-4-fluoro-5-(1H-indazol-3-yl)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazolo[5,6,7-de]quinazolin-10(8H)-yl]propyl-2-en-1-one;

[0305] 1-[(8aS)-6-chloro-4-fluoro-5-(2-hydroxy-6-methylphenyl)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazolo[5,6,7-de]quinazolin-10(8H)-yl]propyl-2-en-1-one;

[0306] (2E)-1-[(8aS)-6-chloro-4-fluoro-5-(2-fluoro-6-hydroxyphenyl)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazolo[5,6,7-de]quinazolin-10(8H)-yl]-4-(dimethylamino)but-2-en-1-one;

[0307] 8-[(8aS)-6-chloro-4-fluoro-10-(prop-2-enoyl)-8,8a,9,10,11,12-hexahydropyrazino[2',1':3,4][1,4]oxazolo[5,6,7-de]quinazolin-5-yl]-7-methylisoquinolin-1(2H)-one;

[0308] 1-[(8aS)-6-chloro-4-fluoro-5-(5-methyl-1H-benzotriazol-4-yl)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazolo[5,6,7-de]quinazolin-10(8H)-yl]propyl-2-en-1-one;

[0309] 1-((8aS)-6-chloro-4-fluoro-5-(5-fluoro-1H-benzo[d]imidazol-4-yl)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazolo[5,6,7-de]quinazolin-10(8H)-yl)prop-2-en-1-one;

[0310] 1-[(8aS)-6-chloro-4-fluoro-5-(5-fluoro-1H-indazol-4-yl)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazolo[5,6,7-de]quinazolin-10(8H)-yl]propyl-2-en-1-one;

[0311] 1-((8aS)-6-chloro-4-fluoro-5-(5-fluoro-1-methyl-1H-benzo[d]imidazol-4-yl)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazolo[5,6,7-de]quinazolin-10(8H)-yl)prop-2-en-1-one;

[0312] 1-[(8aS)-6-chloro-4-fluoro-5-(5-fluoro-1H-benzotriazol-4-yl)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazolo[5,6,7-de]quinazolin-10(8H)-yl]propyl-2-en-1-one;

[0313] 8-[(8aS)-6-chloro-4-fluoro-10-(prop-2-enoyl)-8,8a,9,10,11,12-hexahydropyrazino[2',1':3,4][1,4]oxazolo[5,6,7-de]quinazolin-5-yl]-7-fluoroisoquinolin-1(2H)-one;

[0314] (2E)-1-[(8aS)-6-chloro-4-fluoro-5-(5-methyl-1H-indazol-4-yl)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazolo[5,6,7-de]quinazolin-10(8H)-yl]-4-(dimethylamino)but-2-en-1-one;

[0315] 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]oxazolidinone[4,3,2-de]quinazolin-8-yl]propyl-2-en-1-one;

[0316] 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]oxazolidinone[4,3,2-de]quinazolin-8-yl]propyl-2-en-1-one;

[0317] 8-[3-chloro-1-fluoro-8-(prop-2-enoyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':5,6][1,5]oxazolidinyl[4,3,2-de]quinazolin-2-yl]-7-methylisoquinolin-1(2H)-one;

[0318] 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]oxazolidinone[4,3,2-de]quinazolin-8-yl]propyl-2-en-1-one;

[0319] 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]oxazolidinone[4,3,2-de]quinazolin-8-yl]prop-2-en-1-one;

[0320] 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]oxazolidinone[4,3,2-de]quinazolin-8-yl]prop-2-en-1-one;

[0321] 1-[(8aS)-4-chloro-6-fluoro-5-(2-fluoro-6-hydroxyphenyl)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazolo[5,6,7-de]quinazolin-10(8H)-yl]propyl-2-en-1-one;

[0322] 1-[(8aS,11R)-6-chloro-4-fluoro-11-methyl-5-(5-methyl-1H-benzimidazol-4-yl)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazolo[5,6,7-de]quinazolin-10(8H)-yl]propyl-2-en-1-one;

[0323] 8-[(8aS,11R)-6-chloro-4-fluoro-11-methyl-10-(prop-2-enoyl)-8,8a,9,10,11,12-hexahydropyrazino[2',1':3,4][1,4]oxazolo[5,6,7-de]quinazolin-5-yl]-7-methylisoquinolin-1(2H)-one;

[0324] (2E)-1-[(8aS,11R)-6-chloro-4-fluoro-11-methyl-5-(5-methyl-1H-benzimidazol-4-yl)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazolo[5,6,7-de]quinazolin-10(8H)-yl]-4-(dimethylamino)but-2-en-1-one; and

[0325] (2E)-1-[(8aS,11R)-6-chloro-4-fluoro-11-methyl-5-(5-methyl-1H-indazol-4-yl)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazolo[5,6,7-de]quinazolin-10(8H)-yl]-4-(dimethylamino)but-2-en-1-one;

[0326] Or its pharmaceutically acceptable salt.

[0327] In some implementations, the small molecule KRAS inhibitor is a compound of formula (II):

[0328]

[0329] (II),

[0330] It 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]oxazolidinone[4,3,2-de]quinazolin-8-yl]propyl-2-en-1-one, or a pharmaceutically acceptable salt thereof.

[0331] A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient may optionally further comprise 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 a diastereomeric excess (%de) of ≥90%.

[0332] A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient may optionally further comprise 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 with an enantiomeric excess (%ee) of ≥90% and a diastereomer excess (%de) of ≥90%.

[0333] Compounds of Formula (I) and their pharmaceutically acceptable salts may be prepared, used, or provided in amorphous, crystalline, or semi-crystalline forms, and any given compound of Formula (I) or its pharmaceutically acceptable salt may be formed in more than one crystalline / polymorphic form, including hydrates (e.g., hemihydrates, monohydrates, dihydrates, trihydrates, or other stoichiometric hydrates) and / or solvated forms. It should be understood that this specification covers any and all such solid forms of compounds of Formula (I) and their pharmaceutically acceptable salts.

[0334] The small molecule KRAS inhibitor of formula (A) is described in WO2020178282, 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):

[0335] (A)

[0336] in:

[0337] A 1 It is a phenyl or bicyclic heteroaryl group;

[0338] X 1 and Y 1 Connected via double bonds, and i) X 1 It is CR17 And Y 1 It is CR 18 ,ii) X 1 It is N and Y 1 It is CR 18 , or iii) X 1 It is CR 17 And Y 1 It is N; or

[0339] X 1 and Y 1 Together for C(O)NR 19 ;or

[0340] X 1 and Y 1 Is it with Z 1 The adjacent ring atoms of the substituted aromatic ring fused with the optionally substituted 5- or 6-membered N-heterocycle, and X 1 and Y 1 They are all C or C and N;

[0341] Z 1 It is O, NH, or NMe;

[0342] R 10 Independently selected from F, Cl, Br, OH, CH2OH, OMe, CH2OMe, C1-C3 alkyl and C1-C3 fluoroalkyl;

[0343] n is 0, 1, 2, or 3;

[0344] R 12 It is H, F, Cl, CCH, CCMe, CN, Br, C1-C3 alkyl, C1-C3 fluoroalkyl, OMe, or OEt;

[0345] R 13a and R 13b Together = O or R 13a and R 13b It is H;

[0346] R 14 It is H or Me;

[0347] R 15 It is H or Me;

[0348] R 16 It is H or CH2NMe2;

[0349] R 17 and R 18Independently 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 deuterated alkyl), 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 carbon rings or heterocycles; or

[0350] R 17 and R 18 They can combine to form optionally substituted 5- or 6-membered carbon rings or heterocycles;

[0351] R 19 Selected from H, Me, Et, C3H7 and C1-C3 fluoroalkyl groups;

[0352] Or its pharmaceutically acceptable salt.

[0353] In some embodiments, the compound of formula (A) is a compound of formula (III):

[0354] (III)

[0355] in:

[0356] A 1 It is a phenyl or bicyclic heteroaryl group;

[0357] X 1 and Y 1 Connected via double bonds, and i) X 1 It is CR 17 And Y 1 It is CR 18 ,ii) X 1 It is N and Y 1 It is CR 18 or iii) X 1 It is CR 17 And Y 1 It is N; or

[0358] X 1 and Y 1 Together for C(O)NR 19 ;or

[0359] X 1 and Y 1 Is it with Z 1The adjacent ring atoms of the substituted aromatic ring fused with the optionally substituted 5- or 6-membered N-heterocycle, and X 1 and Y 1 They are all C or C and N;

[0360] Z 1 It is O, NH, or NMe;

[0361] R 10 Independently selected from F, Cl, Br, OH, CH2OH, OMe, CH2OMe, C1-C3 alkyl and C1-C3 fluoroalkyl;

[0362] n is 0, 1, 2, or 3;

[0363] R 12 It is H, F, Cl, CCH, CCMe, CN, Br, C1-C3 alkyl, C1-C3 fluoroalkyl, OMe, or OEt;

[0364] R 13a and R 13b Together = O or R 13a and R 13b It is H;

[0365] R 14 It is H or Me;

[0366] R 15 It is H or Me;

[0367] R 16 It is H or CH2NMe2;

[0368] R 17 and R 18 Selected from H, F, Cl, CCH, CN, Me, OH, OMe, O (C1-C3 alkyl), C1-C3 fluoroalkyl, or optionally substituted 5- or 6-membered carbon rings or heterocycles; or

[0369] R 17 and R 18 They can combine to form optionally substituted 5- or 6-membered carbon rings or heterocycles;

[0370] R 19 Selected from H, Me, Et, C3H7 and C1-C3 fluoroalkyl groups;

[0371] Or its pharmaceutically acceptable salt.

[0372] Compounds of formula (A) (e.g., compounds of formula (III)) are characterized by a [6,7,6]-tricyclic core containing a group X. 1 and Y 1 The aromatic ring is obtained through 1,4-diazacycloheptanine (Z 1= N) or 1,4-oxazetane (Z) 1 =O) motif is attached to piperazine. Additionally, groups A selected from phenyl and bicyclic heteroaryl groups... 1 Linked to a group containing X via a biaryl bond 1 and Y 1 The aromatic ring. Due to the R group 10 R 12 and X 1 The properties of the compound are restricted, and rotation around the biaryl bond is restricted, thus compounds of formula (III) can exist stably in a trans-restricted isomer form. The acrylamide motif is attached to the tricyclic core via a non-bridgehead piperazine nitrogen.

[0373] As used herein, the term "alkyl" refers to a straight-chain or branched saturated hydrocarbon group having a specific number of carbon atoms. As used herein, the term "deuterated alkyl" refers to an alkyl group in which one or more, optionally all, of the hydrogen atoms are replaced by deuterium atoms. The term "cycloalkyl" refers to a saturated carbide ring.

[0374] The term acetylenyl refers to the ethynyl radical, i.e., the -CCH group.

[0375] In this specification, terms such as C x -C y The prefix C used in (where x and y are integers) x -C y The numerical range of carbon atoms present in the indicator group. For example, C1-C4 alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl, while examples of C1-C3 alkyl groups include methyl, ethyl, n-propyl, and isopropyl. C1-C4 alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, and tert-butoxy. Examples of C1-C3 alkoxy groups include methoxy, ethoxy, n-propoxy, and isopropoxy. 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 deuterated alkyl) groups are partially or fully deuterated O-methyl, O-ethyl, O-n-propyl, or O-isopropyl groups. C3-C6 cycloalkyl groups refer to cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl groups. 2-pyridyl groups are pyridine rings attached to the N-atom of pyridine via meta-bonding, i.e., [the group is missing from the original text]. .

[0376] Unless otherwise specified, the bonding of atoms or groups can be any suitable atom of the group; for example, propyl includes propyl-1-yl and propyl-2-yl.

[0377] Unless otherwise stated, the halogen group is selected from Cl, F, Br and I, usually from Cl, F or Br, or Cl and F.

[0378] As mentioned above, A 1 It can be a phenyl group or a bicyclic heteroaryl group. In this context, a bicyclic heteroaryl group is an aromatic group comprising two fused rings and containing 1, 2, 3, or 4 N atoms, or one O atom, or one S atom, or one N atom and one S atom, or one N atom and one O atom, or two N atoms and one S atom, or two N atoms and one O atom. Bicyclic heteroaryl groups include those in which both fused rings are aromatic, or one fused ring is aromatic while the other fused ring is partially or fully saturated. The partially or fully saturated fused ring may also contain a carbonyl group. Examples of suitable bicyclic heteroaryl groups include indolyl, benzofuranyl, benzothiophenyl, benzoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, azaindolyl, azainzolyl, pyrrolo[1,2-b]pyridazinyl, pyrrolo[2,3-b]pyridinyl, quinolinyl, isoquinolinyl, quinazolinyl, cyclolinyl, phthalazinyl, quinoxalinyl, and naphthidyl.

[0379] As described above, X in the compound of formula (III) 1 and Y 1 It can be with Z 1 The adjacent ring atoms of a fused 5- or 6-membered N-heterocycle containing substituted aromatic rings are all C or C and N. The term 5- or 6-membered N-heterocycle refers to a saturated or unsaturated ring, such as an aromatic 5- or 6-membered ring, containing at least one nitrogen atom and at most two other heteroatoms selected from O, N, and S. (The last sentence appears to be incomplete and possibly refers to a different context.) 1 The substituted aromatic ring-fused 5-membered N-heterocycle may 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. 1 The substituted aromatic ring-fused 6-membered N-heterocycle may be selected from pyridine, pyridazine, pyrimidine, and pyrazine. The 5- or 6-membered N-heterocycle may optionally be substituted by one or two substituents selected from the following: 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.

[0380] As described above, R in the compound of formula (III) 17 and R 18The substituted 5- or 6-membered carbon ring or heterocycle can be optionally substituted. The term "optionally substituted 5- or 6-membered carbon ring or heterocycle" refers to a saturated or unsaturated ring, such as an aromatic ring, containing up to three heteroatoms selected from O, N, and S. The 5-membered heterocycle can 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. The 6-membered heterocycle can be selected from pyridine, pyridazine, pyrimidine, and pyrazine. The 5- or 6-membered carbon ring or heterocycle may optionally be substituted by 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.

[0381] As mentioned above, in R 17 and R 18 Both exist in compounds of formula (A), such as in compounds of formula (III), and can combine to form compounds with Z. 1 The substituted aromatic ring is fused to an optionally substituted 5- or 6-membered carbon ring or heterocycle. The optionally substituted 5- or 6-membered carbon ring or heterocycle can be saturated or unsaturated. The 5- or 6-membered carbon ring or heterocycle may optionally be substituted by 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 groups optionally substituted with OH, OMe, NH2, NHMe, or NMe2. In R 17 and R 18 When combined to form a 5-membered ring, they can together represent C3, C2O, COC, C2N, CNC, CNO, NCO, CNS, or NCS chains. In R... 17 and R 18 When combined to form a 6-membered ring, they can together represent C4, C3O, COC2, OC2O, C3N, C2NC, NCNC, CNNC, or NCCN chains. The R atom... 17 and R 18 The chains are covalently bonded and substituted with hydrogen or optional substituents to satisfy their normal valence.

[0382] To avoid ambiguity, when multiple substituents are independently selected from a given group, the selected substituents may include the same substituents or different substituents from within the given group. By way of example only, in A... 1 Is by (R) 10 ) n In the case of substituted phenyl groups, and when n is 2, both R groups... 10The substituents can be the same, such as two fluorines, or they can be different, such as one fluorine and one hydroxyl group.

[0383] To further avoid any doubt, the formula in this specification is " The use of "" indicates the attachment point between different groups.

[0384] When any embodiment within this specification includes a group referred to as "optionally substituted", another embodiment will include an embodiment in which said group is not substituted.

[0385] In one implementation, the small molecule KRAS inhibitor is a compound of formula (A):

[0386] (A)

[0387] in:

[0388] A 1 It is a phenyl or bicyclic heteroaryl group;

[0389] X 1 and Y 1 Connected via double bonds, and i) X 1 It is CR 17 And Y 1 It is CR 18 ,ii) X 1 It is N and Y 1 It is CR 18 , or iii) X 1 It is CR 17 And Y 1 It is N; or

[0390] X 1 and Y 1 Together for C(O)NR 19 ;or

[0391] X 1 and Y 1 Is it with Z 1 The adjacent ring atoms of the substituted aromatic ring fused with the optionally substituted 5- or 6-membered N-heterocycle, and X 1 and Y 1 They are all C or C and N;

[0392] Z 1 It is O, NH, or NMe;

[0393] R 10 Independently selected from F, Cl, Br, OH, CH2OH, OMe, CH2OMe, C1-C3 alkyl and C1-C3 fluoroalkyl;

[0394] n is 0, 1, 2, or 3;

[0395] R 12 It is H, F, Cl, CCH, CCMe, CN, Br, C1-C3 alkyl, C1-C3 fluoroalkyl, OMe, or OEt;

[0396] R 13a and R 13b Together = O or R 13a and R 13b It is H;

[0397] R 14 It is H or Me;

[0398] R 15 It is H or Me;

[0399] R 16 It is H or CH2NMe2;

[0400] R 17 and R 18 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 deuterated alkyl), 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 carbon rings or heterocycles; or

[0401] R 17 and R 18 They can combine to form optionally substituted 5- or 6-membered carbon rings or heterocycles;

[0402] R 19 Selected from H, Me, Et, C3H7 and C1-C3 fluoroalkyl groups;

[0403] Or its pharmaceutically acceptable salt.

[0404] In the embodiments, the compound of formula (A) is the compound of formula (Aa), wherein R 16 It is H.

[0405] In the embodiments, the compound of formula (A) or (Aa) is a compound of formula (Ab), wherein R 15 It is H.

[0406] In the embodiments, the compounds of formula (A), (Aa), or (Ab) are compounds of formula (Ac), wherein R 14 It is H.

[0407] In the embodiments, the compounds of formula (A), (Aa), (Ab) or (Ac) are compounds of formula (Ad), wherein A is a phenyl group.

[0408] In the implementation scheme, the compound of formula (A) is the compound of formula (Ae).

[0409] (Ae).

[0410] In the implementation scheme, the compound of formula (Ae) is a compound of formula (Af), wherein R 15 It is H.

[0411] In the embodiments, compounds of formula (Ae) or (Af) are compounds of formula (Ag), wherein R 13a and R 13b It is H.

[0412] In the embodiments, compounds of formula (Ae) or (Af) are compounds of formula (Ah), wherein R 13a and R 13b Together is = O.

[0413] In the embodiments, compounds of formula (Ae), (Af), (Ag), or (Ah) are compounds of formula (Ai), wherein Z 1 It is O.

[0414] In the embodiments, compounds of formula (Ae), (Af), (Ag), (Ah), or (Ai) are compounds of formula (Aj), wherein R 12 Selected from F or Cl.

[0415] In the embodiments, the compounds of formula (Ae), (Af), (Ag), (Ah), (Ai), or (Aj) are compounds of formula (Ak), wherein n is 2 or 3, and at least two R 10 The group is located ortho to the biaryl bond.

[0416] In the embodiments, compounds of formula (Ae), (Af), (Ag), (Ah), (Ai), (Aj), or (Ak) are compounds of formula (A1), wherein at least one R 10 The radical is OH.

[0417] In the embodiments, compounds of formula (A), (Ae), (Af), (Ag), (Ai), (Aj), (Ak), or (Al) are compounds of formula (Am).

[0418] (Am).

[0419] In the embodiments, compounds of formula (A), (Ae), (Af), (Ag), (Ah), (Ai), (Aj), (Ak) or (Al) are compounds of formula (An) or (Ao).

[0420]

[0421] (An)(Ao).

[0422] In the embodiments, compounds of formula (A), (Ae), (Af), (Ag), (Ah), (Ai), (Aj), (Ak) or (Al) are compounds of formula (Ap), wherein X 1 and Y 1 It is C(O)NR 19 .

[0423] In the embodiments, compounds of formula (A), (Ae), (Af), (Ag), (Ah), (Ai), (Aj), (Ak) or (Al) are compounds of formula (Aq), wherein X 1 and Y 1 It is an adjacent ring atom of an optionally substituted pyrrole, imidazole, pyrazole, 1,2,3-triazole, 1,2,4-triazole, oxazole, isoxazole, 1,2,3-oxadiazole, thiazole or isothiazole.

[0424] In the implementation scheme, the compound of formula (Aq) is a compound of formula (Ar) containing X. 1 and Y 1 The optional substituents on the 5-membered ring are selected from C1-C3 alkyl, OC1-C2 alkyl, OMe, OH, F and Cl.

[0425] In the embodiments, the compounds of formulas (A), (Aa) to (Ar) have the following stereochemical properties.

[0426] .

[0427] As described above, in some embodiments, the small molecule KRAS inhibitor is a compound of formula (III):

[0428] (III)

[0429] in:

[0430] A 1 It is a phenyl or bicyclic heteroaryl group;

[0431] X 1and Y 1 Connected via double bonds, and i) X 1 It is CR 17 And Y 1 It is CR 18 ,ii) X 1 It is N and Y 1 It is CR 18 or iii) X 1 It is CR 17 And Y 1 It is N; or

[0432] X 1 and Y 1 Together for C(O)NR 19 ;or

[0433] X 1 and Y 1 Is it with Z 1 The adjacent ring atoms of the substituted aromatic ring fused with the optionally substituted 5- or 6-membered N-heterocycle, and X 1 and Y 1 They are all C or C and N;

[0434] Z 1 It is O, NH, or NMe;

[0435] R 10 Independently selected from F, Cl, Br, OH, CH2OH, OMe, CH2OMe, C1-C3 alkyl, C1-C3 fluoroalkyl;

[0436] n is 0, 1, 2, or 3;

[0437] R 12 It is H, F, Cl, CCH, CCMe, CN, Br, C1-C3 alkyl, C1-C3 fluoroalkyl, OMe, or OEt;

[0438] R 13a and R 13b Together = O or R 13a and R 13b It is H;

[0439] R 14 It is H or Me;

[0440] R 15 It is H or Me;

[0441] R 16 It is H or CH2NMe2;

[0442] R 17 and R 18Selected from H, F, Cl, CCH, CN, Me, OH, OMe, O (C1-C3 alkyl), C1-C3 fluoroalkyl, or optionally substituted 5- or 6-membered carbon rings or heterocycles; or

[0443] R 17 and R 18 They can combine to form optionally substituted 5- or 6-membered carbon rings or heterocycles;

[0444] R 19 Selected from H, Me, Et, C3H7 and C1-C3 fluoroalkyl groups;

[0445] Or its pharmaceutically acceptable salt.

[0446] In the implementation scheme, the compound of formula (III) is the compound of formula (IIIa), wherein R 16 It is H.

[0447] In the embodiments, the compound of formula (III) or (IIIa) is a compound of formula (IIIb), wherein R 15 It is H.

[0448] In the embodiments, the compounds of formula (III), (IIIa), or (IIIb) are compounds of formula (IIIc), wherein R 14 It is H.

[0449] In the embodiments, the compounds of formula (III), (IIIa), (IIIb) or (IIIc) are compounds of formula (IIId), wherein A 1 It is phenyl.

[0450] In the implementation scheme, formula (III) is a compound of formula (IIIe).

[0451] (IIIe).

[0452] In the implementation scheme, the compound of formula (IIIe) is the compound of formula (IIIf), wherein R 15 It is H.

[0453] In the embodiments, the compounds of formula (IIIe) or (IIIf) are compounds of formula (IIIg), wherein R 13a and R 13b It is H.

[0454] In the embodiments, the compounds of formula (IIIe) or (IIIf) are compounds of formula (IIIh), wherein R 13a and R 13b Together is = O.

[0455] In the embodiments, compounds of formula (IIIe), (IIIf), (IIIg), or (IIIh) are compounds of formula (IIIi), wherein Z 1 It is O.

[0456] In the embodiments, compounds of formula (IIIe), (IIIf), (IIIg), (IIIh) or (IIIi) are compounds of formula (IIIj), wherein R 12 Selected from F or Cl.

[0457] In the embodiments, the compounds of formula (IIIe), (IIIf), (IIIg), (IIIh), (IIIi), or (IIIj) are compounds of formula (IIIk), wherein n is 2 or 3, and at least two R 10 The group is located ortho to the biaryl bond.

[0458] In the embodiments, compounds of formula (IIIe), (IIIf), (IIIg), (IIIh), (IIIi), (IIIj), or (IIIk) are compounds of formula (IIIl), wherein at least one R 10 The radical is OH.

[0459] In the embodiments, compounds of formula (III), (IIIe), (IIIf), (IIIg), (IIIi), (IIIj), (IIIk), or (IIIl) are compounds of formula (IIIm).

[0460] (IIIm).

[0461] In the embodiments, the compounds of formula (III), (IIIe), (IIIf), (IIIg), (IIIh), (IIIi), (IIIj), (IIIk), or (IIIl) are compounds of formula (IIIn) or (IIIo).

[0462]

[0463] (IIIn)(IIIo).

[0464] In the embodiments, compounds of formula ((III), (IIIe), (IIIf), (IIIg), (IIIh), (IIIi), (IIIj), (IIIk), or (IIIl) are compounds of formula (IIIp), wherein X 1 and Y 1 It is C(O)NR 19 .

[0465] In the embodiments, compounds of formula (III), (IIIe), (IIIf), (IIIg), (IIIh), (IIIi), (IIIj), (IIIk), or (IIIl) are compounds of formula (IIIq), wherein X 1 and Y 1 It is an adjacent ring atom of an optionally substituted pyrrole, imidazole, pyrazole, 1,2,3-triazole, 1,2,4-triazole, oxazole, isoxazole, 1,2,3-oxadiazole, thiazole or isothiazole.

[0466] In the implementation scheme, the compound of formula (IIIq) is a compound of formula (IIIr) containing X. 1 and Y 1 The optional substituents on the 5-membered ring are selected from C1-C3 alkyl, OC1-C2 alkyl, OMe, OH, F and Cl.

[0467] In the embodiments, the compounds of formulas (III), (IIIa) to (IIIr) have the following stereochemical properties.

[0468] .

[0469] In one embodiment, the compound of formula (A) is selected from:

[0470] (12aS)-2-Acryloyl-10-chloro-9-(5-methyl-1H-indazol-4-yl)-1,2,3,4,12,12a-hexahydro-6H-benzo[f]pyrazino[2,1-c][1,4]oxazine-6-one;

[0471] 1-((12aS)-10-chloro-9-(5-methyl-1H-indazol-4-yl)-3,4,12,12a-tetrahydro-6H-benzo[f]pyrazino[2,1-c][1,4]oxazolidin-2(1H)-yl)prop-2-en-1-one;

[0472] 1-[(12aR)-10-chloro-9-(2-fluoro-6-hydroxyphenyl)-7-methoxy-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazine-2(1H)-yl]propyl-2-en-1-one;

[0473] (12aR)-10-chloro-9-(2-fluoro-6-hydroxyphenyl)-7-hydroxy-2-(prop-2-enoyl)-1,2,3,4,12,12a-hexahydro-6H-pyrazino[2,1-c][1,4]benzoxazine-6-one;

[0474] (12aR)-10-chloro-9-(5-methyl-1H-indazol-4-yl)-2-(prop-2-enoyl)-1,2,3,4,12,12a-hexahydro-6H-pyrazino[2,1-c][1,4]benzoxazine-6-one;

[0475] 1-((12aR)-10-chloro-9-(5-methyl-1H-indazol-4-yl)-3,4,12,12a-tetrahydro-6H-benzo[f]pyrazino[2,1-c][1,4]oxazine-2(1H)-yl)prop-2-en-1-one;

[0476] (12aR)-10-chloro-8-fluoro-9-(2-fluoro-6-hydroxyphenyl)-2-(prop-2-enoyl)-1,2,3,4,12,12a-hexahydro-6H-pyrazino[2,1-c][1,4]benzoxazine-6-one;

[0477] 1-[(12aR)-8,10-dichloro-9-(2-fluoro-6-hydroxyphenyl)-7-hydroxy-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazine-2(1H)-yl]propyl-2-en-1-one;

[0478] 1-[(12aR)-10-chloro-9-(2-fluoro-6-hydroxyphenyl)-7-(1H-imidazol-1-yl)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazono-2(1H)-yl]propyl-2-en-1-one;

[0479] (12aR)-10-chloro-9-(2-fluoro-6-hydroxyphenyl)-2-(prop-2-enoyl)-1,2,3,4,12,12a-hexahydro-6H-pyrazino[2,1-c][1,4]benzoxazine-7-carboxynitrile;

[0480] 1-[(12aR)-10-chloro-9-(2-fluoro-6-hydroxyphenyl)-7-(1H-pyrazol-1-yl)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazono-2(1H)-yl]propyl-2-en-1-one;

[0481] 1-((12aR)-10-chloro-8-fluoro-9-(5-methyl-1H-benzo[d]imidazol-4-yl)-3,4,12,12a-tetrahydro-6H-benzo[f]pyrazino[2,1-c][1,4]oxazine-2(1H)-yl)prop-2-en-1-one;

[0482] (12aR)-8,10-dichloro-9-(2-fluoro-6-hydroxyphenyl)-2-(prop-2-enoyl)-1,2,3,4,12,12a-hexahydro-6H-pyrazino[2,1-c][1,4]benzoxazine-6-one;

[0483] (12aR)-10-chloro-9-(2-fluoro-6-hydroxyphenyl)-2-(prop-2-enoyl)-1,2,3,4,12,12a-hexahydro-6H-pyrazino[2,1-c][1,4]benzoxazine-8-carboxynitrile;

[0484] (12aR)-10-chloro-9-(2-fluoro-6-hydroxyphenyl)-8-methyl-2-(prop-2-enoyl)-1,2,3,4,12,12a-hexahydro-6H-pyrazino[2,1-c][1,4]benzoxazine-6-one;

[0485] 1-[(12aR)-8,10-dichloro-9-(2-fluoro-6-hydroxyphenyl)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazine-2(1H)-yl]propyl-2-en-1-one;

[0486] 8-[(12aR)-10-chloro-8-fluoro-2-(prop-2-enoyl)-1,2,3,4,12,12a-hexahydro-6H-pyrazino[2,1-c][1,4]benzoxazine-9-yl]-7-methylisoquinoline-1(2H)-one;

[0487] 1-[(12aR)-10-chloro-9-(2-fluoro-6-hydroxyphenyl)-8-methoxy-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazine-2(1H)-yl]propyl-2-en-1-one

[0488] (12aS)-10-chloro-9-(5-methyl-1H-indazol-4-yl)-2-(prop-2-enoyl)-1,3,4,11,12,12a-hexahydropyrazino[2,1-c][1,4]benzodiazepine-6(2H)-one;

[0489] 1-[(12aR)-10-chloro-9-(2-chloro-6-hydroxyphenyl)-8-fluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazine-2(1H)-yl]propyl-2-en-1-one;

[0490] (12aS)-10-chloro-11-methyl-9-(5-methyl-1H-indazol-4-yl)-2-(prop-2-enoyl)-1,3,4,11,12,12a-hexahydropyrazino[2,1-c][1,4]benzodiazepine-6(2H)-one;

[0491] 1-[(12aR)-10-chloro-9-(2,3-difluoro-6-hydroxyphenyl)-8-fluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazine-2(1H)-yl]propyl-2-en-1-one;

[0492] (12aR)-10-chloro-9-(2-hydroxy-6-methylphenyl)-2-(prop-2-enoyl)-1,2,3,4,12,12a-hexahydro-6H-pyrazino[2,1-c][1,4]benzoxazine-8-carboxynitrile;

[0493] 1-[(12aR)-9-(2-chloro-6-hydroxyphenyl)-8,10-difluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazine-2(1H)-yl]propyl-2-en-1-one;

[0494] 1-[(12aR)-8,10-difluoro-9-(2-hydroxy-6-methylphenyl)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazine-2(1H)-yl]propyl-2-en-1-one;

[0495] 1-[(12aR)-8,10-difluoro-9-[2-fluoro-6-(hydroxymethyl)phenyl]-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazine-2(1H)-yl]propyl-2-en-1-one;

[0496] 1-[(12aR)-8,10-difluoro-9-[2-hydroxy-6-(trifluoromethyl)phenyl]-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazine-2(1H)-yl]propyl-2-en-1-one;

[0497] 1-[(12aR)-9-(2-ethyl-6-hydroxyphenyl)-8,10-difluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazine-2(1H)-yl]propyl-2-en-1-one;

[0498] 1-[(12aR)-9-[2-(difluoromethyl)-6-hydroxyphenyl]-8,10-difluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazine-2(1H)-yl]propyl-2-en-1-one;

[0499] (12aR)-9-(2-chloro-6-hydroxyphenyl)-10-fluoro-2-(prop-2-enoyl)-1,2,3,4,12,12a-hexahydro-6H-pyrazino[2,1-c][1,4]benzoxazine-8-carboxynitrile;

[0500] (12aR)-10-chloro-9-(2-chloro-6-hydroxyphenyl)-2-(prop-2-enoyl)-1,2,3,4,12,12a-hexahydro-6H-pyrazino[2,1-c][1,4]benzoxazine-8-carboxynitrile;

[0501] 1-[(12aR)-9-(2-bromo-6-hydroxyphenyl)-8,10-difluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazine-2(1H)-yl]propyl-2-en-1-one;

[0502] 1-[(12aR)-8-chloro-10-fluoro-9-(2-hydroxy-6-methylphenyl)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazine-2(1H)-yl]propyl-2-en-1-one;

[0503] 1-[(12aR)-8-chloro-10-ethynyl-9-(2-hydroxy-6-methylphenyl)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazine-2(1H)-yl]propyl-2-en-1-one;

[0504] 1-[(12aR)-10-ethynyl-8-fluoro-9-(2-hydroxy-6-methylphenyl)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazine-2(1H)-yl]propyl-2-en-1-one;

[0505] (6aR)-4-chloro-3-(2-fluoro-6-hydroxyphenyl)-2-methyl-8-(prop-2-enoyl)-2,6,6a,7,8,9,10,12-octahydro-1H-pyrazino[2,1-c]pyrido[3,4-f][1,4]oxazine-1-one;

[0506] 1-[(6aR)-1,4-dichloro-3-(2-fluoro-6-hydroxyphenyl)-6a,7,9,10-tetrahydro-12H-pyrazino[2,1-c]pyridino[3,4-f][1,4]oxazine-8(6H)-yl]propyl-2-en-1-one;

[0507] (6aR)-4-chloro-3-(2-fluoro-6-hydroxyphenyl)-8-(prop-2-enoyl)-2,6,6a,7,8,9,10,12-octahydro-1H-pyrazino[2,1-c]pyrido[3,4-f][1,4]oxazine-1-one;

[0508] 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]oxazolo-10(8H)-yl]propyl-2-en-1-one;

[0509] 1-[(7aR)-5-chloro-4-(2-fluoro-6-hydroxyphenyl)-1-methyl-1,7a,8,10,11,13-hexahydropyrazino[2',1':3,4][1,4]oxazolo[7,6-g]indazole-9(7H)-yl]propyl-2-en-1-one;

[0510] 1-[(7aR)-5-chloro-4-(2-fluoro-6-hydroxyphenyl)-2-methyl-2,7a,8,10,11,13-hexahydropyrazino[2',1':3,4][1,4]oxazadiazino[7,6-g]indazole-9(7H)-yl]propyl-2-en-1-one;

[0511] 1-[(12aR)-9-(2-chloro-6-hydroxyphenyl)-8-ethynyl-10-fluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazono-2(1H)-yl]propyl-2-en-1-one; and

[0512] 1-[(12aR)-10-chloro-9-(2-chloro-6-hydroxyphenyl)-8-ethynyl-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazine-2(1H)-yl]prop-2-en-1-one;

[0513] 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]oxazine-2(1H)-yl)prop-2-en-1-one;

[0514] 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]benzoxazine-9(7H)-yl]propyl-2-en-1-one;

[0515] 1-[(12aR)-8-chloro-9-(2-chloro-6-hydroxyphenyl)-10-fluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazine-2(1H)-yl]propyl-2-en-1-one;

[0516] 1-[(12aR)-9-(2-chloro-6-hydroxyphenyl)-10-fluoro-8-(prop-1-yn-1-yl)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazine-2(1H)-yl]prop-2-en-1-one;

[0517] 1-[(6aR)-4-chloro-3-(2-chloro-6-hydroxyphenyl)-2-ethynyl-6a,7,9,10-tetrahydro-12H-pyrazino[2,1-c]pyridino[2,3-f][1,4]oxazine-8(6H)-yl]prop-2-en-1-one;

[0518] 1-[(12aR)-9-(2-chloro-6-hydroxyphenyl)-8-ethynyl-10-methyl-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazine-2(1H)-yl]propyl-2-en-1-one;

[0519] 1-[(12aR)-10-chloro-9-(2-chloro-6-hydroxyphenyl)-7,8-difluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazine-2(1H)-yl]propyl-2-en-1-one;

[0520] 1-[(12aR)-9-(2-chloro-6-hydroxyphenyl)-8-(difluoromethoxy)-10-fluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazine-2(1H)-yl]propyl-2-en-1-one;

[0521] 1-[(12aR)-9-(2-chloro-6-hydroxyphenyl)-8-ethynyl-7,10-difluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazine-2(1H)-yl]prop-2-en-1-one;

[0522] 1-[(12aR)-10-chloro-9-(2-chloro-6-hydroxyphenyl)-8-(difluoromethoxy)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazine-2(1H)-yl]propyl-2-en-1-one;

[0523] 1-[(12aR)-9-(2-chloro-6-hydroxyphenyl)-8-(cyclopropoxy)-10-fluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazine-2(1H)-yl]propyl-2-en-1-one;

[0524] 1-((12aR)-9-(2-chloro-6-hydroxyphenyl)-8-(3-(dimethylamino)prop-1-yn-1-yl)-10-fluoro-3,4,12,12a-tetrahydro-6H-benzo[f]pyrazino[2,1-c][1,4]oxazine-2(1H)-yl)prop-2-en-1-one;

[0525] 1-[(12aR)-9-(2-chloro-6-hydroxyphenyl)-10-fluoro-8-[(pyridin-4-yl)methoxy]-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazono-2(1H)-yl]propyl-2-en-1-one;

[0526] 1-[(12aR)-10-chloro-9-(2-chloro-6-hydroxyphenyl)-8-(2-methoxyethoxy)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazine-2(1H)-yl]propyl-2-en-1-one;

[0527] 1-[(12aR)-9-(2-chloro-6-hydroxyphenyl)-10-fluoro-8-[2-(piperidin-1-yl)ethoxy]-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazine-2(1H)-yl]propyl-2-en-1-one;

[0528] 1-[(12aR)-10-chloro-9-(2-chloro-6-hydroxyphenyl)-8-(prop-1-yn-1-yl)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazine-2(1H)-yl]prop-2-en-1-one;

[0529] 1-[(6aR)-4-chloro-3-(2-chloro-6-hydroxyphenyl)-2-[( 2[H3)methoxy]-6a,7,9,10-tetrahydro-12H-pyrazino[2,1-c]pyridino[2,3-f][1,4]oxazine-8(6H)-yl]propyl-2-en-1-one;

[0530] 1-[(12aR)-10-chloro-9-(2-chloro-6-hydroxyphenyl)-8-(methoxymethyl)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazine-2(1H)-yl]propyl-2-en-1-one; and

[0531] 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]benzoxazono-2(1H)-yl]propyl-2-en-1-one;

[0532] 1-[(6aR)-4-chloro-3-(2-chloro-6-hydroxyphenyl)-1-(prop-1-yn-1-yl)-6a,7,9,10-tetrahydro-12H-pyrazino[2,1-c]pyridino[3,4-f][1,4]oxazine-8(6H)-yl]prop-2-en-1-one; and

[0533] 1-((6aR)-4-chloro-3-(2-chloro-6-hydroxyphenyl)-1-ethynyl-6a,7,9,10-tetrahydro-12H-pyrazino[2,1-c]pyridino[3,4-f][1,4]oxazine-8(6H)-yl)prop-2-en-1-one;

[0534] Or its pharmaceutically acceptable salt.

[0535] As those skilled in the art will understand, compounds of formula (A) in A 1 With X 1 and Y 1 The rings contain biaryl bonds.

[0536] Statements relating to compounds of formula (III) in the following text should be understood to apply equally to compounds of formula (A).

[0537] Compounds of formula (A) (e.g., compounds of formula (III)) such as piperazine attached to acrylamide and containing Z 1The bridgehead carbon between the rings has one or more chiral centers, and it should be recognized that compounds of formula (A) (e.g., compounds of formula (III)) can be prepared, isolated, and / or supplied with or without one or more of other possible stereoisomers of the compound of formula (A) in any relative proportion. The preparation of stereoenriched or stereopure compounds can be carried out using standard organic chemistry techniques well known in the art, such as by synthesis from stereoenriched or stereopure starting materials, using a suitable stereoenriched or stereopure catalyst during synthesis, and / or by resolving racemic or partially enriched mixtures of stereoisomers, for example via chiral chromatography. In a preferred embodiment, as shown below, when Z 1 When O is present, the compound in this specification is in the (R)- configuration.

[0538]

[0539] In particular, compounds of formula (III) can be formed due to the surrounding A 1 With X 1 and Y 1 The rotation of the biaryl bonds between the rings is restricted, resulting in axial chirality, and therefore they can exist as mixtures of enantiomeric isomers with an enantiomeric excess of about 0% to >98% ee. When the compound is a pure transisomer, the stereochemistry of each chiral center can be designated by aR or aS. Such names can also be used for mixtures rich in one transisomer. By way of example only, the following portions can exhibit transisomerism and can be resolved into aR and aS transisomers by chiral chromatography. For illustration, where A... 1 The two transisomers of the compound of formula (III) of 2-F,6-hydroxyphenyl are shown below (R is omitted for clarity). 13 R 14 R 15 and R 16 ).

[0540]

[0541] Further descriptions of hindered transisomerism, axial chirality, and configuration partitioning rules can be found in Eliel, EL, and Wilen, SH, 'Stereochemistry of Organic Compounds', John Wiley and Sons, Inc., 1994. In the compounds described in this specification, the R group may be selected. 10 R 12 and X 1 To eliminate or significantly reduce the interconversion between (aR) and (aS) isomers.

[0542] More specifically, group A 1 (R 10 ) n With substituent R 12 and / or X 1 The interaction between them can advantageously confine the area around ring A. 1 With X 1 The rotation of the bonds between the rings. Therefore, the substituent R 12 With ring A 1 and / or the substituent R on it 10 The interaction between them can be used to stabilize the transisomers of the compounds according to this specification. This, in turn, advantageously allows for the isolation of stable transisomers that exhibit higher activity as inhibitors of G12C-mutated Ras than the second transisomer. It should be understood that the more active transisomer is a preferred embodiment.

[0543] In which group X 1 In embodiments of the substituted compound of formula (III), the substituent can be like R 12 It can also stabilize the transisomers of the compounds according to this specification.

[0544] A pharmaceutical composition comprising a compound of formula (III) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient may optionally further comprise one or more other stereoisomers of a 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 ≥90% diastereomeric excess (%de.).

[0545] A pharmaceutical composition comprising a compound of formula (III) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient may optionally further comprise one or more other stereoisomers of a 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 enantiomeric excess (%ee) and an enantiomer excess (%de) of ≥90%.

[0546] Compounds of Formula (III) and their pharmaceutically acceptable salts may be prepared, used, or provided in amorphous, crystalline, or semi-crystalline forms, and any given compound of Formula (III) or its pharmaceutically acceptable salt may be formed in more than one crystalline / polymorphic form, including hydrates (e.g., hemihydrates, monohydrates, dihydrates, trihydrates, or other stoichiometric hydrates) and / or solvated forms. It should be understood that this specification covers any and all such solid forms of compounds of Formula (III) and their pharmaceutically acceptable salts.

[0547] In some implementations, the small molecule KRAS inhibitor is a compound of formula (IV):

[0548] (IV),

[0549] It is 1-[(12aR)-9-(2-chloro-6-hydroxyphenyl)-10-fluoro-8-(prop-1-yn-1-yl)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazine-2(1H)-yl]prop-2-en-1-one, or a pharmaceutically acceptable salt thereof.

[0550] Ataxia-telangiectasia mutations and RAD-3-related protein kinases, namely ATR protein kinases (also known as FRAP-associated protein 1; FRP1; MEC1; SCKL; SECKL1), are members of the PI3 kinase-like kinase (PIKK) protein family involved in genome repair, maintenance, and stability (reviewed in Cimprich KA and Cortez D. 2008, Nature Rev. Mol. Cell Biol. 9:616-627). This disclosure provides for the administration of ATR inhibitors.

[0551] In some implementations, ATR inhibitors can inhibit human ATR. As previously stated, the qualifier “human” used in connection with ATR proteins in this document may, in some interpretations, refer to the amino acid sequence of the ATR protein, but includes ATR proteins found in humans obtained through other technical means, such as recombinant expression, cell-free translation, or non-biological peptide synthesis.

[0552] 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.

[0553] 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 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.

[0554] For example, in some implementations, the small molecule ATR inhibitor is M6620 / VX970 (bexostat; MerckKGaA, formula B).

[0555] B

[0556] BAY-1895344 (ericetide, Bayer KGaA, Formula C)

[0557] C

[0558] RP-3500 (Kamensete, Roche, Type D)

[0559] D

[0560] 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 (galtisertib, Merck KGaA, Formula E)

[0561] E

[0562] M1774 (tuvusertib, Merck KGaA, Formula F)

[0563] F

[0564] 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)

[0565] G

[0566] AZ-20 (AstraZeneca, Formula H)

[0567] H

[0568] VE-821 (University of Oxford, Formula J)

[0569] J

[0570] AZD-5597 (The University of Newcastle Upon Tyne, Formula K)

[0571] K

[0572] or IMP-9064 (Impact Therapeutics).

[0573] Small molecule ATR compounds of formula (V) are described in WO2011154737, 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):

[0574] (V)

[0575] in:

[0576] R 21 Selected from morpholin-4-yl and 3-methylmorpholin-4-yl;

[0577] R 22 yes , , or ;

[0578] n is 0 or 1;

[0579] R 22A R 22C R 22E and R 22F Each can be either hydrogen or methyl;

[0580] R 22B and R 22D Each can be either hydrogen or methyl;

[0581] R 22G Selected from -NHR 27 and –NHCOR 28 ;

[0582] R 22H It is fluorine;

[0583] R 23 It is methyl;

[0584] R 24 and R 25 Each is independently hydrogen or methyl, or R 24 and R 25 Together with the atoms to which they are attached, they form ring A. 2 ;

[0585] Ring A 2 It is C 3-6 Cycloalkyl or saturated 4-6 membered heterocycles containing a heteroatom selected from O and N;

[0586] R 26 It is hydrogen;

[0587] R 27 It is hydrogen or methyl; and

[0588] R28 It is methyl.

[0589] Or its pharmaceutically acceptable salt.

[0590] According to another aspect of this disclosure, the small molecule ATR inhibitor is a compound of formula (V):

[0591] (V)

[0592] in:

[0593] R 21 It is 3-methylmorpholin-4-yl;

[0594] R 22 yes , , or ;

[0595] n is 0 or 1;

[0596] R 22A R 22C R 22E and R 22F Each can be either hydrogen or methyl;

[0597] R 22B and R 22D Each can be either hydrogen or methyl;

[0598] R 22G Selected from –NH2, -NHMe, and –NHCOMe;

[0599] R 22H It is fluorine;

[0600] R 23 It is methyl;

[0601] R 24 and R 25 Each is independently hydrogen or methyl, or R 24 and R 25 Together with the atoms to which they are attached, they form ring A. 2 ;

[0602] Ring A 2 It is C 3-6 Cycloalkyl or a saturated 4-6 membered heterocycle containing a heteroatom selected from O and N; and

[0603] R 26 It's hydrogen.

[0604] Or its pharmaceutically acceptable salt.

[0605] Some compounds of formula (V) can exist in stereoisomeric forms. It should be understood that this disclosure covers all geometrical and optical isomers of compounds of formula (V), as well as mixtures thereof, including racemic derivatives. Tautomers and mixtures thereof also constitute an aspect of this disclosure. Solvates and mixtures thereof also constitute an aspect of this disclosure. For example, suitable solvates for compounds of formula (V) are, for instance, hydrates, such as hemihydrates, monohydrates, dihydrates, or trihydrates, or alternative amounts thereof.

[0606] It should be understood that, where certain compounds of formula (V) as defined above may exist in an optically active or racemic form due to one or more asymmetric carbon or sulfur atoms, this disclosure includes, in its definition, any such optically active or racemic form having the aforementioned activity. This disclosure covers all such stereoisomers having the activity as defined herein. It should also be understood that in the name of a chiral compound, (R,S) represents any non-racemic or racemic mixture, while (R) and (S) represent enantiomers. Where (R,S), (R), or (S) is not present in the name, it should be understood that the name refers to any non-racemic or racemic mixture wherein the non-racemic mixture contains any relative proportions of R and S enantiomers, and the racemic mixture contains R and S enantiomers in a 50:50 ratio. The synthesis of the optically active form can be carried out by standard organic chemistry techniques well known in the art, such as by synthesis from an optically active starting material or by resolving the racemic form. Racemic compounds can be separated into individual enantiomers using known procedures (see, for example, Advanced Organic Chemistry: 3rd Edition: by J. March, pp. 104–107). Suitable procedures involve reacting the racemic material with a chiral auxiliary to form diastereomers, followed by separation of the diastereomers by, for example, chromatography, and then cleavage of the auxiliary substance. Similarly, the above activities can be evaluated using standard laboratory techniques mentioned below.

[0607] It should be understood that this disclosure covers compounds having one or more isotopic substitutions. For example, H can be in any isotopic form, including 1 H, 2 H(D) and 3 H(T); C can be any isotopic form, including 12 C 13 C and 14 C and O can be in any isotopic form, including 16 O and 18 O; etc.

[0608] This disclosure relates to compounds of formula (V) as defined herein and their salts. Salts used in pharmaceutical compositions will be pharmaceutically acceptable salts, but other salts may be used to produce compounds of formula (V) and their pharmaceutically acceptable salts. Pharmaceutically acceptable salts of this disclosure may, for example, include acid addition salts of compounds of formula (V) as defined herein, which are sufficiently basic to form such salts. Such acid addition salts include, but are not limited to, fumarates, methanesulfonates, hydrochlorides, hydrobromic acid salts, citrates, and maleates, as well as salts formed from phosphoric acid and sulfuric acid. Furthermore, where the compounds of formula (V) are 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., triethylamine, ethanolamine, diethanolamine, triethanolamine, morpholine, N-methylpiperidine, N-ethylpiperidine, dibenzylamine, or amino acids such as lysine).

[0609] Compounds of formula (V) may also be provided in vivo as hydrolyzable esters. Hydrolyzable esters of compounds of formula (V) containing carboxyl or hydroxyl groups are pharmaceutically acceptable esters that, for example, cleave in the human or animal body to produce a parent acid or alcohol. Such esters can be identified, for example, by intravenous administration of the test compound to a test animal and subsequent examination of the animal's bodily fluids.

[0610] Pharmaceutically acceptable esters suitable for the carboxyl group include C 1-6 Alkoxymethyl esters, such as methoxymethyl; C 1-6 Alkyloxymethyl esters, such as neopentyloxymethyl; phthaloyl esters; C 3-8 CycloalkoxycarbonyloxyC 1-6 Alkyl esters, such as 1-cyclohexylcarbonyloxyethyl; 1,3-dioxacyclopenten-2-ketomethyl esters, such as 5-methyl-1,3-dioxacyclopenten-2-ketomethyl; and C 1-6 Alkoxycarbonyl ethyl ester, such as 1-methoxycarbonyl ethyl; and may be formed at any carboxyl group in the compounds disclosed herein.

[0611] Pharmaceutically acceptable esters suitable for the hydroxyl group include inorganic esters, such as phosphate esters (including phosphoramide cyclic esters) and α-acyloxyalkyl ethers and related compounds, which decompose upon in vivo hydrolysis of the ester to produce the parent hydroxyl group. Examples of α-acyloxyalkyl ethers include acetoxymethoxy and 2,2-dimethylpropionyloxymethoxy. The choice of in vivo hydrolyzable ester-forming groups for the hydroxyl group includes C1- 10 Alkyl groups, such as formyl, acetyl, benzoyl, phenylacetyl, substituted benzoyl and phenylacetyl groups; C1- 10Alkoxycarbonyl (to give alkyl carbonates), such as ethoxycarbonyl; di-C1-4 alkylcarbamoyl and N-(di-C1-4 alkylaminoethyl)-N-C1-4 alkylcarbamoyl (to give carbamates); di-C1-4 alkylaminoacetyl and carboxyacetyl. Examples of cyclic substituents on phenylacetyl and benzoyl groups include aminomethyl, C 1-4 Alkylaminomethyl and di-(C1-4 alkyl)aminomethyl, as well as morpholino or piperazine groups attached from the cyclic nitrogen atom to the benzoyl ring at the 3- or 4-position via a methylene linker. Other in vivo hydrolyzable esters of interest include, for example, R... A C(O)OC 1-6 alkyl-CO-, where R A It is, for example, benzyloxy-C1-4 alkyl, or phenyl. Suitable substituents on the phenyl group in such esters include, for example, 4-C1-4 piperazinyl-C1-4 alkyl, piperazinyl-C1-4 alkyl, and morpholino-C1-4 alkyl.

[0612] Compounds of formula (V) can be administered as prodrugs, which are then decomposed in the human or animal body to yield compounds of formula (V). Various forms of prodrugs are known in the art. Examples of such prodrug derivatives can be found in:

[0613] 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);

[0614] b) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design and Application of Prodrugs”, edited by H. Bundgaard, pp. 113-191 (1991);

[0615] c)H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992);

[0616] d) H. Bundgaard et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); and

[0617] e) N. Kakeya et al., Chem Pharm Bull, 32, 692 (1984).

[0618] Ring A 2 , n (when it involves formula (V)), R 21 R 22 R 24 R 25 R 26 R 27 and R 28 The specific values ​​are as follows. These values ​​may be used alone or in combination where appropriate, in conjunction with any aspect or part of this disclosure and with any definition, claim, or embodiment defined herein.

[0619] n: In one respect, n is 0. In another respect, n is 1.

[0620] R 21 In one respect, R 21 Selected from morpholin-4-yl and 3-methylmorpholin-4-yl. On the other hand, R 21 It is 3-methylmorpholino-4-yl. On the other hand, R 21 yes

[0621] On the other hand, R 21 yes .

[0622] R 22 In one respect, R 22 yes In one respect, R 22 yes In one respect, R 22 yes In one respect, R 22 yes .

[0623] R 22A In one respect, R 22A It is hydrogen.

[0624] R 22B In one respect, R 22B It is hydrogen.

[0625] R 22C In one respect, R 22C It is hydrogen.

[0626] R 22D In one respect, R 22D It is hydrogen.

[0627] R22E In one respect, R 22E It is hydrogen.

[0628] R 22F In one respect, R 22F It is hydrogen.

[0629] R 22G In one aspect of this disclosure, R 22G Selected from -NHR 27 and -NHCOR 28 In one aspect of this disclosure, R 22G Yes – NHR 27 In one aspect of this disclosure, R 22G Yes – NHCOR 28 In one aspect of this disclosure, R 22G Selected from –NH2, -NHMe, and -NHCOMe. In one aspect of this disclosure, R 22G It is –NH2. In one aspect of this disclosure, R 22G Yes – NHMe. In one aspect of this disclosure, R 22G Yes –NHCOMe.

[0630] R 24 and R 25 In one aspect of this disclosure, R 24 and R 25 It is hydrogen. In one aspect of this disclosure, R 24 and R 25 It is methyl. In one aspect of this disclosure, R 24 and R 25 Together with the atoms to which they are attached, they form ring A. 2 .

[0631] Ring A 2 In one aspect of this disclosure, ring A 2 It is C 3-6 Cycloalkyl groups or saturated 4-6 heterocycles containing a heteroatom selected from O and N. In another aspect, cycloalkanes... 2 It is a cyclopropyl, cyclobutyl, cyclopentyl, oxetane, tetrahydrofuranyl, tetrahydropyranyl, azirane, pyrrolidinyl, or piperidinyl ring. In another aspect, ring A... 2 It is a cyclopropyl, cyclobutyl, cyclopentyl, tetrahydropyranyl, or piperidinyl ring. On the other hand, ring A... 2 It is a cyclopropyl, cyclopentyl, tetrahydropyranyl, or piperidinyl ring. On the other hand, ring A... 2 It is a cyclopropyl, tetrahydropyranyl, or piperidinyl ring. On the other hand, ring A... 2 It is a cyclopropyl or tetrahydropyranyl ring. On the other hand, ring A... 2It is a piperidinyl ring. On the other hand, ring A... 2 It is a tetrahydropyranyl ring. On the other hand, ring A... 2 It is a cyclopropyl ring.

[0632] R 26 In one respect, R 26 It is hydrogen.

[0633] R 27 In one respect, R 27 It is either hydrogen or methyl. In one respect, R 27 It is methyl. In one respect, R 27 It is hydrogen.

[0634] R 28 In one respect, R 28 It is a methyl group.

[0635] In one respect, small molecule ATR inhibitors are compounds of formula (V) or pharmaceutically acceptable salts thereof, wherein R 21 Selected from morpholin-4-yl and 3-methylmorpholin-4-yl; n is 0 or 1; R 22A It is hydrogen; R 22B It is hydrogen; R 22C It is hydrogen; R 22D It is hydrogen; R 22E It is hydrogen; R 22F It is hydrogen; R 22G Selected from -NHR 27 and -NHCOR 28 ;R 22H It is fluorine; R 23 It is methyl; R 24 and R 25 Together with the atoms to which they are attached, they form ring A. 2 Ring A 2 It is C 3-6 Cycloalkyl or a saturated 4-6 heterocycle containing a heteroatom selected from O and N; R 26 It is hydrogen; R 27 It is hydrogen or methyl; and R 28 It is a methyl group.

[0636] In another respect, small molecule ATR inhibitors are compounds of formula (V) or pharmaceutically acceptable salts thereof, wherein R 21 Selected from morpholin-4-yl and 3-methylmorpholin-4-yl; n is 0 or 1; R 22A It is hydrogen; R 22B It is hydrogen; R 22C It is hydrogen; R 22D It is hydrogen; R 22E It is hydrogen; R 22F It is hydrogen; R 22GSelected from –NH2, -NHMe and -NHCOMe; R 22H It is fluorine; R 23 It is methyl; R 24 and R 25 Together with the atoms to which they are attached, they form ring A. 2 Ring A 2 It is C 3-6 Cycloalkyl or a saturated 4-6 heterocycle containing a heteroatom selected from O and N; and R 26 It is hydrogen.

[0637] In another respect, small molecule ATR inhibitors are compounds of formula (V) or pharmaceutically acceptable salts thereof, wherein R 21 Selected from morpholin-4-yl and 3-methylmorpholin-4-yl; n is 0 or 1; R 22A It is hydrogen; R 22B It is hydrogen; R 22C It is hydrogen; R 22D It is hydrogen; R 22E It is hydrogen; R 22F It is hydrogen; R 22G Selected from -NHR 27 and -NHCOR 28 ;R 22H It is fluorine; R 23 It is methyl; R 24 and R 25 Together with the atoms to which they are attached, they form ring A. 2 Ring A 2 It is a cyclopropyl, cyclobutyl, cyclopentyl, oxetane, tetrahydrofuranyl, tetrahydropyranyl, azirane, pyrrolidinyl, or piperidinyl ring; R 26 It is hydrogen; R 27 It is hydrogen or methyl; and R 28 It is a methyl group.

[0638] In another respect, small molecule ATR inhibitors are compounds of formula (V) or pharmaceutically acceptable salts thereof, wherein R 21 Selected from morpholin-4-yl and 3-methylmorpholin-4-yl; n is 0 or 1; R 22A It is hydrogen; R 22B It is hydrogen; R 22C It is hydrogen; R 22D It is hydrogen; R 22E It is hydrogen; R 22F It is hydrogen; R 22G Selected from –NH2, -NHMe and -NHCOMe; R 22H It is fluorine; R 23 It is methyl; R 24 and R 5 Together with the atoms to which they are attached, they form ring A. 2 Ring A2 It is a cyclopropyl, cyclobutyl, cyclopentyl, oxetane, tetrahydrofuranyl, tetrahydropyranyl, azirane, pyrrolidinyl, or piperidinyl ring; and R 26 It is hydrogen.

[0639] In another respect, small molecule ATR inhibitors are compounds of formula (Va).

[0640] (Va)

[0641] Or its pharmaceutically acceptable salt; wherein:

[0642] Ring A 2 It is a cyclopropyl, tetrahydropyranyl, or piperidinyl ring;

[0643] R 22 yes , , or ;

[0644] n is 0 or 1; R 22A It is hydrogen; R 22B It is hydrogen; R 22C It is hydrogen; R 22D It is hydrogen; R 22E It is hydrogen; R 22F It is hydrogen; R 22G Selected from -NHR 27 and -NHCOR 28 ;R 22H It is fluorine; R 23 It is a methyl group; R 26 It is hydrogen; R 27 It is hydrogen or methyl; and R 28 It is a methyl group.

[0645] In another respect, small molecule ATR inhibitors are compounds of formula (Va).

[0646] (Va)

[0647] Or its pharmaceutically acceptable salt; wherein:

[0648] Ring A 2 It is a cyclopropyl, tetrahydropyranyl, or piperidinyl ring;

[0649] R 22 yes , , or ;

[0650] n is 0 or 1; R 22A It is hydrogen; R22B It is hydrogen; R 22C It is hydrogen; R 22D It is hydrogen; R 22E It is hydrogen; R 22F It is hydrogen; R 22G Selected from –NH2, -NHMe and -NHCOMe; R 22H It is fluorine; R 23 It is a methyl group; and R 26 It is hydrogen.

[0651] In another respect, small molecule ATR inhibitors are compounds of formula (Va).

[0652] (Va)

[0653] Or its pharmaceutically acceptable salt; wherein:

[0654] Ring A 2 It is a cyclopropyl, tetrahydropyranyl, or piperidinyl ring;

[0655] R 22 yes , , or ;

[0656] n is 0 or 1; R 22A It is hydrogen; R 22B It is hydrogen; R 22C It is hydrogen; R 22D It is hydrogen; R 22E It is hydrogen; R 22F It is hydrogen; R 22G Yes - NHR 27 ;R 22H It is fluorine; R 23 It is a methyl group; R 26 It is hydrogen; and R 27 It is hydrogen.

[0657] In another respect, small molecule ATR inhibitors are compounds of formula (Va).

[0658] (Va)

[0659] Or its pharmaceutically acceptable salt; wherein:

[0660] Ring A 2 It is a cyclopropyl ring;

[0661] R 22 yes , , or ;

[0662] n is 0; R 22A It is hydrogen; R 22B It is hydrogen; R 22C It is hydrogen; R 22D It is hydrogen; R 22E It is hydrogen; R 22F It is hydrogen; R 22G Yes – NHR 27 ;R 22H It is fluorine; R 23 It is a methyl group; R 26 It is hydrogen; and R 27 It is a methyl group.

[0663] In another respect, small molecule ATR inhibitors are compounds selected from any of the following:

[0664] 4-{4-[(3R)-3-methylmorpholin-4-yl]-6-[((R)-S-methylsulfonylimino)methyl]pyrimidin-2-yl}-1H-pyrrolo[2,3-b]pyridine;

[0665] 4-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((S)-S-methylsulfonylimino)cyclopropyl]pyrimidin-2-yl}-1H-pyrrolo[2,3-b]pyridine;

[0666] 4-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((R)-S-methylsulfonylimino)cyclopropyl]pyrimidin-2-yl}-1H-pyrrolo[2,3-b]pyridine;

[0667] N-Methyl-1-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((R)-S-methylsulfonylimino)cyclopropyl]pyrimidin-2-yl}-1H-benzimidazole-2-amine;

[0668] N-Methyl-1-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((S)-S-methylsulfonylimino)cyclopropyl]pyrimidin-2-yl}-1H-benzimidazole-2-amine;

[0669] 4-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((R)-S-methylsulfonylimino)cyclopropyl]pyrimidin-2-yl}-1H-indole;

[0670] 4-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((S)-S-methylsulfonylimino)cyclopropyl]pyrimidin-2-yl}-1H-indole;

[0671] 1-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((R)-S-methylsulfonylimino)cyclopropyl]pyrimidin-2-yl}-1H-benzimidazol-2-amine;

[0672] 1-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((S)-S-methylsulfonylimino)cyclopropyl]pyrimidin-2-yl}-1H-benzimidazol-2-amine;

[0673] 4-Fluoro-N-methyl-1-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((R)-S-methylsulfonylimino)cyclopropyl]pyrimidin-2-yl}-1H-benzimidazol-2-amine;

[0674] 4-Fluoro-N-methyl-1-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((S)-S-methylsulfonylimino)cyclopropyl]pyrimidin-2-yl}-1H-benzimidazol-2-amine;

[0675] 4-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-(S-methylsulfonylimino)cyclopropyl]pyrimidin-2-yl}-1H-pyrrolo[2,3-c]pyridine;

[0676] N-Methyl-1-{4-[1-methyl-1-((S)-S-methylsulfonylimino)ethyl]-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-2-yl}-1H-benzimidazole-2-amine;

[0677] N-Methyl-1-{4-[1-methyl-1-((R)-S-methylsulfonylimino)ethyl]-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-2-yl}-1H-benzimidazol-2-amine;

[0678] N-Methyl-1-{4-[(3R)-3-methylmorpholin-4-yl]-6-[4-((S)-S-methylsulfonylimino)tetrahydro-2H-pyran-4-yl]pyrimidin-2-yl}-1H-benzimidazol-2-amine;

[0679] N-Methyl-1-{4-[(3R)-3-methylmorpholin-4-yl]-6-[4-((R)-S-methylsulfonylimino)tetrahydro-2H-pyran-4-yl]pyrimidin-2-yl}-1H-benzimidazol-2-amine;

[0680] 4-{4-[(3R)-3-methylmorpholin-4-yl]-6-[4-((S)-S-methylsulfonylimino)tetrahydro-2H-pyran-4-yl]pyrimidin-2-yl}-1H-indole;

[0681] 4-Fluoro-N-methyl-1-{4-[1-methyl-1-((S)-S-methylsulfonylimino)ethyl]-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-2-yl}-1H-benzimidazol-2-amine;

[0682] 4-Fluoro-N-methyl-1-{4-[1-methyl-1-((R)-S-methylsulfonylimino)ethyl]-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-2-yl}-1H-benzimidazol-2-amine;

[0683] 6-Fluoro-N-methyl-1-{4-[1-methyl-1-((R)-S-methylsulfonylimino)ethyl]-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-2-yl}-1H-benzimidazol-2-amine;

[0684] 5-Fluoro-N-methyl-1-{4-[1-methyl-1-((R)-S-methylsulfonylimino)ethyl]-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-2-yl}-1H-benzimidazol-2-amine;

[0685] 5-Fluoro-N-methyl-1-{4-[1-methyl-1-((S)-S-methylsulfonylimino)ethyl]-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-2-yl}-1H-benzimidazol-2-amine;

[0686] 6-Fluoro-N-methyl-1-{4-[1-methyl-1-((S)-S-methylsulfonylimino)ethyl]-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-2-yl}-1H-benzimidazol-2-amine;

[0687] 6-Fluoro-N-methyl-1-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((R)-S-methylsulfonylimino)cyclopropyl]pyrimidin-2-yl}-1H-benzimidazol-2-amine;

[0688] 5-Fluoro-N-methyl-1-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((R)-S-methylsulfonylimino)cyclopropyl]pyrimidin-2-yl}-1H-benzimidazol-2-amine;

[0689] 5-Fluoro-N-methyl-1-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((S)-S-methylsulfonylimino)cyclopropyl]pyrimidin-2-yl}-1H-benzimidazol-2-amine; and

[0690] 6-Fluoro-N-methyl-1-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((S)-S-methylsulfonylimino)cyclopropyl]pyrimidin-2-yl}-1H-benzimidazol-2-amine;

[0691] Or its pharmaceutically acceptable salt.

[0692] In another respect, small molecule ATR inhibitors are compounds selected from any of the following:

[0693] 4-{4-[(3R)-3-methylmorpholin-4-yl]-6-[(R)-(S-methylsulfonylimino)methyl]pyrimidin-2-yl}-1H-pyrrolo[2,3-b]pyridine;

[0694] 4-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((S)-S-methylsulfonylimino)cyclopropyl]pyrimidin-2-yl}-1H-pyrrolo[2,3-b]pyridine;

[0695] 4-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((R)-S-methylsulfonylimino)cyclopropyl]pyrimidin-2-yl}-1H-pyrrolo[2,3-b]pyridine;

[0696] N-methyl-1-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-(R)-(S-methylsulfonylimino)cyclopropyl]pyrimidin-2-yl}-1H-benzimidazol-2-amine; and

[0697] N-Methyl-1-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-(S)-(S-methylsulfonylimino)cyclopropyl]pyrimidin-2-yl}-1H-benzimidazole-2-amine

[0698] Or its pharmaceutically acceptable salt.

[0699] In some implementations, the small molecule ATR inhibitor is a compound of formula (VI) (cilaceltetracycline):

[0700] (VI),

[0701] It is 4-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((R)-S-methylsulfonylimino)cyclopropyl]pyrimidin-2-yl}-1H-pyrrolo[2,3-b]pyridine, or a pharmaceutically acceptable salt thereof.

[0702] This disclosure envisions various combinations of KRAS inhibitors and ATR inhibitors. For example, in some embodiments, the combination of KRAS inhibitors and ATR inhibitors may include one of the following combinations as shown in Table 4:

[0703] Table 4

[0704]

[0705]

[0706]

[0707]

[0708]

[0709] In some implementations, (i) the KRAS inhibitor and (ii) the ATR inhibitor are combinations of 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, 181-190, 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 cilazetine. In some embodiments, (i) the KRAS inhibitor is a compound of formula (II), and (ii) the ATR inhibitor is cilazetine. In some embodiments, (i) the KRAS inhibitor is a compound of formula (III), and (ii) the ATR inhibitor is cilazetine. In some implementations, (i) the KRAS inhibitor is a compound of formula (IV), and (ii) the ATR inhibitor is cilasetraceti.

[0710] 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 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 in codon 12 or codon 13 lead to downregulation by inducing intermolecular β-sheet formation, but substantially do not alter the amount or biological activity of wild-type RAS. From this perspective, the term "wild-type" can be attributed to the conventional meaning of the KRAS variant encoded by the allele of the corresponding KRAS gene most commonly observed in the human population.

[0711] In some implementations, the subject has "G12 mutant human KRAS," where the glycine residue at position 12 (G12) has been mutated. In some implementations, the subject has a KRAS protein in which G12 has been deleted, i.e., a deletion mutant. In some implementations, the subject has a KRAS protein in which an additional amino acid is encoded near or upstream of G12, i.e., an insertion mutant. In some implementations, the subject has a KRAS protein in which G12 has been replaced by exactly one amino acid other than glycine (G12 missense mutant KRAS). Missense mutations in human RAS with virtually all other amino acids replaced by G12 have been demonstrated in the disease, including G12A, G12D, G12F, G12L, G12P, G12S, G12V, G12Y, G12C, G12E, G121, G12N, G12R, G12T, and G12W missense mutations. G12Q, G12H, G12K, and G12M missense mutations are also possible.

[0712] In some implementations, the "G13 mutant human KRAS" is mutated at position 13, specifically the glycine residue (G13). Mutant KRAS proteins in which G13 is replaced by exactly one amino acid other than glycine (G13 missense mutant KRAS) are particularly anticipated. Missense mutations in human RAS with almost all other amino acids replaced by G13 have been demonstrated in the disease, including G13A, G13D, G13F, G13M, G13P, G13S, G13Y, G13C, G13E, G131, G13N, G13R, and G13V missense mutations. G13L, G13W, G13H, G13K, G13Q, and G13T missense mutations are also possible.

[0713] In some implementations, the glutamine residue (Q61) at position 61 of the “Q61 mutant human KRAS” is mutated. Of particular interest is a mutant KRAS protein in which Q61 is replaced by exactly one amino acid other than glutamine (Q61 missense mutant KRAS). Missense mutations replacing Q61 in human KRAS can include Q61A, Q61D, Q61F, Q61M, Q61P, Q61S, Q61Y, Q61C, Q61E, Q611, Q61N, Q61R, and Q61V missense mutations. Q61L, Q61W, Q61H, Q61K, Q61G, and Q61T missense mutations are also possible.

[0714] In some implementations, G12, G13, or Q61 mutant human KRAS proteins, particularly G12 or G13 missense mutants, can cause or be associated with proliferative or neoplastic diseases and / or result in constitutively active KRAS, more particularly KRAS that is defective in GAP-mediated GTP hydrolysis.

[0715] In some embodiments, the methods described herein may be used when the amino acid at positions 12, 13, or 61 is replaced from the wild type with an uncharged amino acid. In some embodiments, the mutant amino acid at positions 12, 13, or 61 of the human KRAS protein may be a mutant 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 a mutant amino acid 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 can be a G12V, G12C, G12A, or G12S mutant human KRAS protein, such as G12V, G12C, G12A, or G12S mutant human KRAS, NRAS, or HRAS proteins, for example, G12V, G12C, G12A, or G12S mutant human KRAS proteins. In a particularly preferred embodiment, the G12 mutant human KRAS protein can be a G12V mutant human KRAS protein, such as the G12V mutant human KRAS protein. In some embodiments, the G13 mutant human KRAS protein can 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 implementations, the KRAS mutation is a G12C mutation.

[0716] In some embodiments, mutations at codon 12, codon 13, and / or codon 61 can cause proliferative or neoplastic disease in the subject (e.g., 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 or gastric cancer, endometrial cancer, bile duct cancer, or a combination thereof. In some embodiments, the subject is a human.

[0717] 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 and durable antitumor activity, wherein the subject generates a long-term immunogenic memory response against the tumor. In some embodiments, tumor growth continues to decrease and / or disappear and / or diminish after discontinuation of the KRAS inhibitor and the ATR inhibitor. Therefore, in some embodiments, the methods and compositions of this disclosure provide a method for modulating an adaptive immune response in a subject, the method comprising administering a composition comprising: (a) a KRAS inhibitor and (b) an ATR inhibitor.

[0718] In some embodiments, the methods and compositions of this disclosure can reduce the size of tumors in a subject. In some embodiments, the methods and compositions of this disclosure relate to reducing the volume of cancerous tumors in a subject, the method comprising administering a composition comprising: (a) a KRAS inhibitor and (b) an ATR inhibitor.

[0719] In some embodiments, the methods and compositions described in this disclosure are for treating subjects in need, wherein the method includes administering a composition comprising (a) a KRAS inhibitor and (b) an ATR inhibitor, wherein the subject suffers from a condition mediated by a KRAS, NRAS, or HRAS G12C mutation.

[0720] In some embodiments, this disclosure provides a composition comprising: (a) a KRAS inhibitor and (b) an ATR inhibitor. In some embodiments, the composition is in an oral dosage form (e.g., liquid, capsule, tablet, or chewable tablet), an injectable dosage form (e.g., intramuscular or intravenous), sublingual or mucosal, nasal, inhalable, dermal, or transdermal dosage form. Those skilled in the art may include appropriate excipients, diluents, binders, etc., depending on the administration method, and add them to the compositions described herein. In some embodiments, the composition comprising (a) a KRAS inhibitor and (b) an ATR inhibitor is pharmaceutically acceptable. "Pharmaceutically acceptable" as used herein to describe a composition comprising a KRAS inhibitor / ATR inhibitor means approved by a federal or state regulatory agency, or listed in the United States Pharmacopeia, the European Pharmacopoeia, or other generally recognized pharmacopoeia, for use in animals, and more specifically, for use in humans. In some implementations, the term "pharmaceutically acceptable" refers to those compositions and / or dosage forms containing KRAS inhibitors / ATR inhibitors that are suitable for use in human and animal tissue contact without excessive toxicity, irritation, allergic reactions, or other problems or complications, within the bounds of reasonable medical judgment, and that are commensurate with a reasonable benefit / risk ratio.

[0721] Various combinations of (a) KRAS inhibitors and (b) ATR inhibitors may be used in this disclosure. In some embodiments, the KRAS inhibitor is sotoraraciab, adagraciab, Ly3537982, GDC-6036, D-1553, JDQ443, BI1823911, GFH925, D35-001, JAB-21822, HBI-2438, YL-15293, GEC255, IBI351, RMC-6291, MK-1084, MRT X1133, HRS-4642, RMC-9805, JAB-2200, Vrtx153, ERAS-4, ASP3082, RMC-0708, RMC-8839, RMC-6291, JAB-23400, TEB-17231, QTX3046, compounds of formula (I), compounds of formula (II), compounds of formula (III), or compounds of formula (IV). In some implementations, the ATR inhibitor is M6620 / VX970 (bexostatet), BAY-1895344 (erristatet), RP-3500 (carmenstatet), ATRN-119, SC0245, ATRN-212, LR-02, M4344 (gatixetet), 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).

[0722] In some embodiments, the composition comprises a combination of (i) a KRAS inhibitor and (ii) an ATR inhibitor as shown in Table 4. In some embodiments, the composition comprises combinations 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, 161-1 A combination of (i) a KRAS inhibitor and (ii) an ATR inhibitor found in 70, 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, the composition comprises (i) a KRAS inhibitor compound of formula (I) and (ii) cilazetine. In some embodiments, the composition comprises (i) a KRAS inhibitor of formula (II) and (ii) cilazetine. In some embodiments, the composition comprises (i) a KRAS inhibitor of formula (III) and (ii) cilazetine. In some embodiments, the composition comprises (i) a KRAS inhibitor of formula (IV) and (ii) cilaseti.

[0723] In some embodiments, the composition comprising a KRAS inhibitor and an ATR inhibitor may be in a physical state suitable for a suitable administration mode. 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 a pharmaceutically acceptable excipient, diluent, or carrier.

[0724] In some embodiments, this disclosure provides the use of the compositions described herein for manufacturing a medicament, such as a medicament for treating cancer.

[0725] This disclosure describes how the administration of both a KRAS inhibitor and an ATR inhibitor can be used to treat cancer. In some embodiments, the KRAS inhibitor and the ATR inhibitor are both in the same composition. However, in some embodiments, the KRAS inhibitor and the ATR inhibitor are in separate compositions, but in a kit, such that both the KRAS inhibitor and the ATR inhibitor can be administered to the same subject to treat a condition, such as cancer. In some embodiments, the kit includes (a) a first container containing a first composition containing a KRAS inhibitor, and (b) a second container containing a second composition containing an ATR inhibitor. In some embodiments, the kit also includes instructions for administering the KRAS inhibitor and the ATR inhibitor, including the administration mode, dosage, and dosing regimen.

[0726] In some implementations, the KRAS inhibitors in the kit are sotorasidub, adagraxidub, 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, compounds of formula (I), compounds of formula (II), compounds of formula (III), or compounds of formula (IV). In some implementations, the ATR inhibitor in the kit is M6620 / VX970 (bexostat), BAY-1895344 (erristat), RP-3500 (carmenstat), ATRN-119, SC0245, ATRN-212, LR-02, M4344 (gatistat), 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).

[0727] 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 oral dosage forms. In some embodiments, the dosage forms in the kit may be different; for example, the KRAS inhibitor may be an oral dosage form, and the ATR inhibitor may be an intravenous dosage form. In some embodiments, the first composition of the kit, the second composition of the kit, or both the first composition and the second composition of the kit are liquids. In some embodiments, the first composition of the kit, the second composition of the kit, or both the first composition and the second composition of the kit are solids. In some embodiments, the first composition of the kit, the second composition of the kit, or both the first composition and the second composition of the kit are solid oral dosage forms. In some embodiments, the first composition of the kit, the second composition of the kit, or both the first composition and the second composition of the kit further comprise pharmaceutically acceptable excipients, diluents, or carriers.

[0728] All references cited in this article, including patents, patent applications, papers, textbooks, and their cited references, as well as any references not cited therein, are incorporated herein by reference in their entirety.

[0729] Example

[0730] All pathogen-free animals used in the following studies were housed in a controlled pathogen-free environment with the following conditions: temperature (19°C–23°C), humidity (55% ± 10%), photoperiod (12-hour light / dark cycle), and air exchange. Animals were housed in individually ventilated cages with food and water provided freely.

[0731] The following test materials were used in the following preclinical and in vivo studies: the mediator (0.5% HPMC / 0.1% Tween 80), AZD4625 (0.5% HPMC / 0.1% Tween 80), the compound of formula IV (0.5% HPMC / 0.1% Tween 80), and AZD6738 (10% DMSO / 40% PG / 50% WFI). For monotherapy, the mediator and inhibitor were administered orally at doses of 0.05 mL / 10 g to 0.1 mL / 10 g. For combination therapy, AZD4625 or the compound of formula IV was administered 4 hours or 2 hours after administration of AZD6738 in the morning.

[0732] Tumors were measured three times weekly using calipers, and their volume was calculated using the ellipse formula (pi / 6 × width × width × length). Animal weight and tumor status were also recorded during the study. The subject mice continued the study until the tumor size used for the anti-tumor research reached 1.5 cm. 3 Furthermore, the tumor size used in the re-stimulation study reached 0.7 cm.3 Clinical signs were observed, or until the end of the study.

[0733] Example 1

[0734] Using KRAS G12C The antitumor activity of KRAS-mutant cancers, mediated by dual inhibition of KRAS and ATR, was determined in preclinical and in vivo studies of ATR inhibitors. The KRAS used... G12C The ATR inhibitor is AZD4625 (KRAS). G12C (covalent allosteric inhibitors) and AZD6738 (cilaseti, an ATP-competitive ATR inhibitor).

[0735] For this study, it will be engineered to express KRAS. G12C Mutant CT26 G12C Mouse colon cancer cells grew subcutaneously in BALB / c mice with intact immune systems. To prepare test mice, 5 × 10⁶ cells were used. 5 5 × 10 4 CT26 G12C (G12C clone P5E6) cells were subcutaneously implanted into the right abdomen of female BALB / c mice (Envigo UK, strain ID: HSD-162) or female naked Foxn1nu mice (Envigo UK, strain ID: HSD-069). Once formed, the average volume was approximately 0.2 cm³. 3 For tumors, test mice were randomly divided into relevant treatment groups and control groups, and treated with a vector control, AZD4625, or AZD6738 as monotherapy or combination therapy for 4 weeks. During the 7-day dosing, 7-day stop-drug regimen of the treatment period, AZD4625 was administered daily and AZD6738 was administered twice daily. Figure 1 A). Monitor tumor growth and body weight in animals during and after treatment. Mice were kept under investigation until the tumor size reached 1.5 cm. 3 Clinical signs were observed, or until the end of the study (day 54).

[0736] Results: Compared with the control group, the treatment groups treated with AZD4625 or AZD6738 monotherapy initially showed delayed tumor growth and prolonged survival, but most tumors eventually recurred. Figure 1 B, “the medium”, “AZD4625”, and “AZD6738”. In contrast, the treatment group treated with the combination therapy of AZD4625 and AZD6738 showed complete tumor regression with a durable response after drug withdrawal; 9 out of 10 animals even maintained complete tumor regression during the study period after drug withdrawal. Figure 1Bm“AZD4625 + AZD6738”). All treatments were well tolerated with minimal impact on weight. Figure 1 C).

[0737] Example 2

[0738] Using KRAS G12C In a second in vivo study using an ATR inhibitor, the antitumor activity of KRAS-mutant cancers was determined through dual inhibition of KRAS and ATR. The KRAS used... G12C The ATR inhibitor is AZD4625 (KRAS). G12C Covalent allosteric inhibitors), compounds of formula IV (a second chemically different allosteric covalent KRAS) G12C (inhibitors) and AZD6738 (cilaseti, an ATP-competitive ATR inhibitor).

[0739] For this study, it will be engineered to express KRAS. G12C Mutant CT26 G12C Mouse colon cancer cells grew subcutaneously in BALB / c mice with intact immune systems. To prepare test mice, 5 × 10⁶ cells were used. 5 5 × 10 4 CT26 G12C (G12C clone P5E6) cells were subcutaneously implanted into the right abdomen of female BALB / c mice (Envigo UK, strain ID: HSD-162) or female naked Foxn1nu mice (Envigo UK, strain ID: HSD-069). Once formed, the average volume was approximately 0.2 cm³. 3 For tumors, test mice were randomly divided into relevant treatment groups and control groups, and treated with a mediator control, AZD4625, a compound of formula IV, or AZD6738 as monotherapy, or a combination of AZD4625 and AZD6738 or a compound of formula IV and AZD6738 for 4 weeks. During the 7-day dosing and 7-day stop-treatment regimen of the treatment period, AZD4625 and the compound of formula IV were administered daily, and AZD6738 was administered twice daily. Figure 2 A). Monitor tumor growth and body weight in animals during and after treatment. Mice were kept under investigation until the tumor size reached 1.5 cm. 3 Clinical signs were observed, or until the end of the study. Mice in the AZD4625 monotherapy and combination therapy groups were monitored until 65 days post-implantation, while mice in the compound IV monotherapy and combination therapy groups were monitored until 119 days post-implantation.

[0740] Results: The treatment group treated with monotherapy of the compound of formula IV initially showed similar tumor regression to the AZD4625 monotherapy group, but 8 out of 9 tumors relapsed after discontinuation of the drug. Figure 2 B, “Mediator”, “AZD4625”, “Formula IV Compound”, “AZD6738”. In contrast, the treatment group treated with the combination therapy of Formula IV compound and AZD6738 showed complete tumor regression with a durable response after drug withdrawal; 9 out of 9 animals even maintained tumor regression levels after drug withdrawal and during the subsequent 90-day monitoring period. Figure 2 B, "Compound of Formula IV + AZD6738"). In the AZD6738 and AZD4625 groups, 7 out of 9 mice showed a complete response, and these responses persisted in 5 mice when drug treatment was stopped. Figure 2 B, "AZD4625+AZD6738").

[0741] Example 3

[0742] Using KRAS G12C In subsequent in vivo studies (re-excitation studies) with ATR inhibitors, the long-term antitumor activity of KRAS-mutant cancers via dual inhibition of KRAS and ATR was determined. The KRAS used... G12C The ATR inhibitor is a compound of formula IV and AZD6738.

[0743] For re-excitation studies, 5×10 5 CT26 G12C (G12C clone P5E6) cells were subcutaneously implanted into the left ventral epigastric region of five mice. These mice showed a complete antitumor response to the combination therapy of compound IV and AZD6738. For the control group, 5 × 10⁻⁶ cells were implanted. 5 CT26 G12C (G12C clone P5E6) cells were implanted into the left ventral epigastric region of primordial female BALB / c mice. Figure 3 A). Monitor tumor implantation and growth for 4 weeks without drug treatment.

[0744] Results: As expected, CT26 was observed in the original control mice. G12C Tumor growth was observed, but no tumor growth was observed on either side of the abdomen in the re-challenged mouse group. Figure 3 B). Lesions were observed at the non-implantation site (lymph node) in one mouse in the re-stimulation group, but it could not be confirmed that the tumor originated from the implanted CT26. G12C Cells. This data indicates that, using KRAS G12C Mice treated with combination therapy with ATR inhibitors may have developed long-term anti-tumor immunity.

[0745] Example 4

[0746] Using CT26 G12C Xenotransplantation studies have identified the role of the adaptive immune system in driving antitumor activity through dual suppression of KRAS and ATR in KRAS-mutant cancers. These studies were conducted in nude mice lacking a thymus, thus preventing the generation of mature T cells.

[0747] Result: Using KRAS G12C CT26 was observed in nude mice with inhibitor monotherapy. G12C The tumor showed transient regression, but the depth and duration of the anti-tumor response were not as robust as in the immune-active BALB / c mice. Figure 4 A). In nude mice, KRAS G12C The combination therapy of inhibitor and AZD6738 showed a slightly better antitumor response than that of KRAS. G12C Antitumor response to inhibitor monotherapy ( Figure 4 A). However, compared with CT26 observed in immune-active BALB / c mice. G12C In contrast, there was no complete response to combination therapy in nude mice, despite deep and persistent tumor regression. Figure 4 A).

[0748] Lower antitumor activity in nude mice translated into lower overall survival, with all test subjects withdrawing from the study within 2 days of treatment due to tumor volume or clinical signs. Figure 4 B). Therefore, this data indicates that using KRAS G12C The deep and durable antitumor activity observed in the inhibitor and AZD6738 is mediated by an adaptive immune response.

[0749] In mice with a complete immune system, KRAS G12C Combination therapy of inhibitors and AZD6738 for KRAS G12C Preclinical models of mutant cancer exhibited unexpected and potent antitumor activity. Complete tumor regression was observed with the combination therapy, and these regressions were durable after discontinuation of drug treatment. Mouse subjects showing a complete antitumor response to the combination therapy were also protected from tumor reactivation, indicating that a long-term memory response against the tumor has been induced. This data is also consistent with KRAS. G12C The deep and durable antitumor activity of the combination therapy of the inhibitor and AZD6738 is consistent with the hypothesis that it is mediated by an adaptive immune response.

[0750] Example 5

[0751] Using in vivo CT26 G12CAdditional anti-tumor studies have been conducted using the KRAS inhibitor adagraxibu (MTRX849) or sotorasibu (AMG510) in combination with the AZD6738 (cilacelte) ATR inhibitor.

[0752] As described in Examples 1 and 2, CT26 was subcutaneously grown in BALB / c mice with intact immune systems. G12C Mouse colon cancer cells. Mice were randomly assigned to treatment groups and control groups, and treated for 4 weeks with a medium control, adagrasibulin, sotorasibulin, or AZD6738 as a single or combination therapy. During the 7-day dosing, 7-day stop-treatment regimen of the treatment period, adagrasibulin or sotorasibulin was administered daily at the specified dose, and AZD6738 was administered twice daily. Figure 5 Tumor growth and body weight were monitored in the animals during and after treatment. The mice were kept under investigation until the tumor size reached 1.5 cm. 3 Clinical signs are observed, or until the end of the study.

[0753] Results: Compared with the mediator control group, the treatment groups treated with adagrasib or sotorasib monotherapy showed an initial delay in tumor growth ( Figure 5 A) and increased survival rate ( Figure 5 (B) However, most tumors recurred after drug withdrawal, and 0-10% of mice survived at the end of the study. AZD6738 monotherapy showed no or weak activity compared to the vector control group. In contrast, adagrasib and AZD6738 or sotorasib and AZD6738 combination therapy groups showed no activity compared to their respective KRAS groups. G12C Compared to the inhibitor monotherapy group, it showed improved and more durable tumor growth inhibition. Figure 5 A), and has a further extended survival rate ( Figure 5 B), 30%-50% of mice survived at the end of the study. All treatments were well tolerated compared to the vector control group, with minimal impact on body weight. Figure 5 C).

Claims

1. A method of treating cancer in a subject, the method comprising administering to the subject: a.KRAS inhibitors, and b. Ataxia-telangiectasia and Rad-3-related (ATR) inhibitors.

2. A KRAS inhibitor for use in treating a subject's cancer, wherein the treatment comprises administering the inhibitor to the subject alone, sequentially, or simultaneously: a. The KRAS inhibitors mentioned above, and b. ATR inhibitors.

3. An ATR inhibitor for use in treating a subject's cancer, wherein the treatment comprises administering the inhibitor to the subject alone, sequentially, or simultaneously: a.KRAS inhibitors, and b. The ATR inhibitor.

4. Use of a KRAS inhibitor or an ATR inhibitor in the manufacture of a medicament for the combined administration of the KRAS inhibitor and the ATR inhibitor for the treatment of a subject with cancer.

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

8. The method of claim 7, the inhibitor used, or the application thereof, wherein the small molecule KRAS inhibitor is sotoraraciab, adagraciab, 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.

9. The method of claim 7, the inhibitor for use, or the application thereof, wherein the small molecule KRAS inhibitor is a compound of formula (I): in: Ring A is selected from phenyl and bicyclic heteroaryl groups; R 1 Each time it appears, it is independently selected from C. 1-4 Alkyl, halogenated, hydroxyl, C 1-4 Alkoxy, C 1-3 fluoroalkyl, C 1-3 Fluoroalkoxy, cyano, and ethynyl groups; b is 0, 1, 2, or 3; Y is CH2 or CH2CH2; R 2 It is cyano, halogenated, C 1-4 Alkyl, C 1-4 Alkoxy or C 1-3 fluoroalkyl; R 3 Is it F, Me, Et, MeO, or C? 1-2 fluoroalkyl; R 4 It is H or Me; R 5 It is H or Me; R 6 It is H or CH2NMe2; Or its pharmaceutically acceptable salt, provided that Y is CH2 and R is a chemically acceptable salt. 2 It is Cl, R 3 It is F, ring A is phenyl, b is 2, R 1 When the groups are F and OH and each is located ortho to the biaryl bond, and when R 4 and R 6 When both are H, then R 5 It's me.

10. The method of claim 9, the inhibitor for use, or the application thereof, wherein the small molecule KRAS inhibitor has a structure 。 11. The method of claim 10, the inhibitor for use, or the application thereof, wherein ring A is selected from the group consisting of: The ring A thereon is attached to the remainder of the compound of formula (I) at any point on the rings listed above.

12. The method, inhibitor, or use according to any one of claims 9 to 11, wherein R 4 It's H.

13. The method, inhibitor for use, or application according to any one of claims 9 to 12, wherein R 6 It's H.

14. The method of claim 9, the inhibitor for use, or the application thereof, wherein Y is CH2.

15. The method of claim 9, the inhibitor for use, or the application thereof, wherein Y is CH2CH2.

16. The method, inhibitor for use, or application according to any one of claims 9 to 15, wherein R 2 It is Cl.

17. The method, inhibitor, or use according to any one of claims 9 to 16, wherein R 3 It is F.

18. The method, inhibitor, or use according to any one of claims 9 to 17, wherein R 4 It is H and R 5 It's M.

19. The method of claim 9, the inhibitor for use, or the application thereof, wherein the small molecule KRAS inhibitor is selected from: 7-[(8aS)-10-acryloyl-6-chloro-4-fluoro-8,8a,9,10,11,12-hexahydropyrazino[2',1':3,4][1,4]oxazolo[5,6,7-de]quinazolin-5-yl]-6-methyl-2,3-dihydro-1H-isoindol-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]oxazolo[5,6,7-de]quinazolin-10(8H)-yl]propyl-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]oxazolo[5,6,7-de]quinazolin-10(8H)-yl]propyl-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]oxazolidinyl[5,6,7-de]quinazolin-5-yl]-6-methylquinazolin-4(3H)-one; 1-[(8aS)-6-chloro-4-fluoro-5-(5-methyl-1H-benzimidazol-4-yl)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazolo[5,6,7-de]quinazolin-10(8H)-yl]propyl-2-en-1-one; 8-[(8aS)-6-chloro-4-fluoro-10-(prop-2-enoyl)-8,8a,9,10,11,12-hexahydropyrazino[2',1':3,4][1,4]oxazolo[5,6,7-de]quinazolin-5-yl]isoquinolin-1(2H)-one; 1-[(8aS)-6-chloro-4-fluoro-5-(1H-indazol-3-yl)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazolo[5,6,7-de]quinazolin-10(8H)-yl]propyl-2-en-1-one; 1-[(8aS)-6-chloro-4-fluoro-5-(2-hydroxy-6-methylphenyl)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazolo[5,6,7-de]quinazolin-10(8H)-yl]propyl-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]oxazolo[5,6,7-de]quinazolin-10(8H)-yl]-4-(dimethylamino)but-2-en-1-one; 8-[(8aS)-6-chloro-4-fluoro-10-(prop-2-enoyl)-8,8a,9,10,11,12-hexahydropyrazino[2',1':3,4][1,4]oxazolo[5,6,7-de]quinazolin-5-yl]-7-methylisoquinolin-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]oxazolo[5,6,7-de]quinazolin-10(8H)-yl]propyl-2-en-1-one; 1-((8aS)-6-chloro-4-fluoro-5-(5-fluoro-1H-benzo[d]imidazol-4-yl)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazolo[5,6,7-de]quinazolin-10(8H)-yl)prop-2-en-1-one; 1-[(8aS)-6-chloro-4-fluoro-5-(5-fluoro-1H-indazol-4-yl)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazolo[5,6,7-de]quinazolin-10(8H)-yl]propyl-2-en-1-one; 1-((8aS)-6-chloro-4-fluoro-5-(5-fluoro-1-methyl-1H-benzo[d]imidazol-4-yl)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazolo[5,6,7-de]quinazolin-10(8H)-yl)prop-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]oxazolo[5,6,7-de]quinazolin-10(8H)-yl]propyl-2-en-1-one; 8-[(8aS)-6-chloro-4-fluoro-10-(prop-2-enoyl)-8,8a,9,10,11,12-hexahydropyrazino[2',1':3,4][1,4]oxazolo[5,6,7-de]quinazolin-5-yl]-7-fluoroisoquinolin-1(2H)-one; (2E)-1-[(8aS)-6-chloro-4-fluoro-5-(5-methyl-1H-indazol-4-yl)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazolo[5,6,7-de]quinazolin-10(8H)-yl]-4-(dimethylamino)but-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]oxazolidinone[4,3,2-de]quinazolin-8-yl]propyl-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]oxazolidinone[4,3,2-de]quinazolin-8-yl]propyl-2-en-1-one; 8-[3-chloro-1-fluoro-8-(prop-2-enoyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':5,6][1,5]oxazolidinyl[4,3,2-de]quinazolin-2-yl]-7-methylisoquinolin-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]oxazolidinone[4,3,2-de]quinazolin-8-yl]propyl-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]oxazolidinone[4,3,2-de]quinazolin-8-yl]prop-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]oxazolidinone[4,3,2-de]quinazolin-8-yl]prop-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]oxazolo[5,6,7-de]quinazolin-10(8H)-yl]propyl-2-en-1-one; 1-[(8aS,11R)-6-chloro-4-fluoro-11-methyl-5-(5-methyl-1H-benzimidazol-4-yl)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazolo[5,6,7-de]quinazolin-10(8H)-yl]propyl-2-en-1-one; 8-[(8aS,11R)-6-chloro-4-fluoro-11-methyl-10-(prop-2-enoyl)-8,8a,9,10,11,12-hexahydropyrazino[2',1':3,4][1,4]oxazolo[5,6,7-de]quinazolin-5-yl]-7-methylisoquinolin-1(2H)-one; (2E)-1-[(8aS,11R)-6-chloro-4-fluoro-11-methyl-5-(5-methyl-1H-benzimidazol-4-yl)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazolo[5,6,7-de]quinazolin-10(8H)-yl]-4-(dimethylamino)but-2-en-1-one; and (2E)-1-[(8aS,11R)-6-chloro-4-fluoro-11-methyl-5-(5-methyl-1H-indazol-4-yl)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazolo[5,6,7-de]quinazolin-10(8H)-yl]-4-(dimethylamino)but-2-en-1-one; Or its pharmaceutically acceptable salt.

20. The method of claim 7, the inhibitor for use, or the application thereof, wherein the small molecule KRAS inhibitor is a compound of formula (II): (II).

21. The method of claim 7, the inhibitor for use, or the application thereof, wherein the small molecule KRAS inhibitor is a compound of formula III: (III) in: A 1 It is a phenyl or bicyclic heteroaryl group; X 1 and Y 1 Connected via double bonds, and i) X 1 It is CR 17 And Y 1 It is CR 18 ,ii) X 1 It is N and Y 1 It is CR 18 , or iii) X 1 It is CR 17 And Y 1 It is N; or X 1 and Y 1 Together for C(O)NR 19 ;or X 1 and Y 1 Is it with Z 1 The adjacent ring atoms of the substituted aromatic ring fused with the optionally substituted 5- or 6-membered N-heterocycle, and X 1 and Y 1 Both are C or C and N; Z 1 It is O, NH, or NMe; R 10 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 It is H, F, Cl, CCH, CCMe, CN, Br, C1-C3 alkyl, C1-C3 fluoroalkyl, OMe, or OEt; R 13a and R 13b Together = O or R 13a and R 13b It is H; R 14 It is H or Me; R 15 It is H or Me; R 16 It is H or CH2NMe2; R 17 and R 18 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 deuterated alkyl), 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 carbon rings or heterocycles; or R 17 and R 18 They can combine to form optionally substituted 5- or 6-membered carbon rings or heterocycles; R 19 Selected from H, Me, Et, C3H7 and C1-C3 fluoroalkyl groups; Or its pharmaceutically acceptable salt.

22. The method of claim 21, the inhibitor used, or the said use, wherein i) X 1 It is CR 17 And Y 1 It is CR 18 ,ii) X 1 It is N and Y 1 It is CR 18 , or iii) X 1 It is CR 17 And Y 1 It is N.

23. The method according to claim 21 or 22, the inhibitor for use, or the application, wherein Z 1 It is O.

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

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

26. The method, inhibitor, or use according to any one of claims 21 to 25, wherein R 16 It's H.

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

28. The method of claim 21, the inhibitor used, or the application thereof, wherein the small molecule KRAS inhibitor is selected from: (12aS)-2-Acryloyl-10-chloro-9-(5-methyl-1H-indazol-4-yl)-1,2,3,4,12,12a-hexahydro-6H-benzo[f]pyrazino[2,1-c][1,4]oxazine-6-one; 1-((12aS)-10-chloro-9-(5-methyl-1H-indazol-4-yl)-3,4,12,12a-tetrahydro-6H-benzo[f]pyrazino[2,1-c][1,4]oxazolidin-2(1H)-yl)prop-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]benzoxazine-2(1H)-yl]propyl-2-en-1-one; (12aR)-10-chloro-9-(2-fluoro-6-hydroxyphenyl)-7-hydroxy-2-(prop-2-enoyl)-1,2,3,4,12,12a-hexahydro-6H-pyrazino[2,1-c][1,4]benzoxazine-6-one; (12aR)-10-chloro-9-(5-methyl-1H-indazol-4-yl)-2-(prop-2-enoyl)-1,2,3,4,12,12a-hexahydro-6H-pyrazino[2,1-c][1,4]benzoxazine-6-one; 1-((12aR)-10-chloro-9-(5-methyl-1H-indazol-4-yl)-3,4,12,12a-tetrahydro-6H-benzo[f]pyrazino[2,1-c][1,4]oxazine-2(1H)-yl)prop-2-en-1-one; (12aR)-10-chloro-8-fluoro-9-(2-fluoro-6-hydroxyphenyl)-2-(prop-2-enoyl)-1,2,3,4,12,12a-hexahydro-6H-pyrazino[2,1-c][1,4]benzoxazine-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]benzoxazine-2(1H)-yl]propyl-2-en-1-one; 1-[(12aR)-10-chloro-9-(2-fluoro-6-hydroxyphenyl)-7-(1H-imidazol-1-yl)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazono-2(1H)-yl]propyl-2-en-1-one; (12aR)-10-chloro-9-(2-fluoro-6-hydroxyphenyl)-2-(prop-2-enoyl)-1,2,3,4,12,12a-hexahydro-6H-pyrazino[2,1-c][1,4]benzoxazine-7-carboxynitrile; 1-[(12aR)-10-chloro-9-(2-fluoro-6-hydroxyphenyl)-7-(1H-pyrazol-1-yl)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazono-2(1H)-yl]propyl-2-en-1-one; 1-((12aR)-10-chloro-8-fluoro-9-(5-methyl-1H-benzo[d]imidazol-4-yl)-3,4,12,12a-tetrahydro-6H-benzo[f]pyrazino[2,1-c][1,4]oxazine-2(1H)-yl)prop-2-en-1-one; (12aR)-8,10-dichloro-9-(2-fluoro-6-hydroxyphenyl)-2-(prop-2-enoyl)-1,2,3,4,12,12a-hexahydro-6H-pyrazino[2,1-c][1,4]benzoxazine-6-one; (12aR)-10-chloro-9-(2-fluoro-6-hydroxyphenyl)-2-(prop-2-enoyl)-1,2,3,4,12,12a-hexahydro-6H-pyrazino[2,1-c][1,4]benzoxazine-8-carboxynitrile; (12aR)-10-chloro-9-(2-fluoro-6-hydroxyphenyl)-8-methyl-2-(prop-2-enoyl)-1,2,3,4,12,12a-hexahydro-6H-pyrazino[2,1-c][1,4]benzoxazine-6-one; 1-[(12aR)-8,10-dichloro-9-(2-fluoro-6-hydroxyphenyl)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazine-2(1H)-yl]propyl-2-en-1-one; 8-[(12aR)-10-chloro-8-fluoro-2-(prop-2-enoyl)-1,2,3,4,12,12a-hexahydro-6H-pyrazino[2,1-c][1,4]benzoxazine-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]benzoxazine-2(1H)-yl]propyl-2-en-1-one; (12aS)-10-chloro-9-(5-methyl-1H-indazol-4-yl)-2-(prop-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]benzoxazine-2(1H)-yl]propyl-2-en-1-one; (12aS)-10-chloro-11-methyl-9-(5-methyl-1H-indazol-4-yl)-2-(prop-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]benzoxazine-2(1H)-yl]propyl-2-en-1-one; (12aR)-10-chloro-9-(2-hydroxy-6-methylphenyl)-2-(prop-2-enoyl)-1,2,3,4,12,12a-hexahydro-6H-pyrazino[2,1-c][1,4]benzoxazine-8-carboxynitrile; 1-[(12aR)-9-(2-chloro-6-hydroxyphenyl)-8,10-difluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazine-2(1H)-yl]propyl-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]benzoxazine-2(1H)-yl]propyl-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]benzoxazine-2(1H)-yl]propyl-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]benzoxazine-2(1H)-yl]propyl-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]benzoxazine-2(1H)-yl]propyl-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]benzoxazine-2(1H)-yl]propyl-2-en-1-one; (12aR)-9-(2-chloro-6-hydroxyphenyl)-10-fluoro-2-(prop-2-enoyl)-1,2,3,4,12,12a-hexahydro-6H-pyrazino[2,1-c][1,4]benzoxazine-8-carboxynitrile; (12aR)-10-chloro-9-(2-chloro-6-hydroxyphenyl)-2-(prop-2-enoyl)-1,2,3,4,12,12a-hexahydro-6H-pyrazino[2,1-c][1,4]benzoxazine-8-carboxynitrile; 1-[(12aR)-9-(2-bromo-6-hydroxyphenyl)-8,10-difluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazine-2(1H)-yl]propyl-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]benzoxazine-2(1H)-yl]propyl-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]benzoxazine-2(1H)-yl]propyl-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]benzoxazine-2(1H)-yl]propyl-2-en-1-one; (6aR)-4-chloro-3-(2-fluoro-6-hydroxyphenyl)-2-methyl-8-(prop-2-enoyl)-2,6,6a,7,8,9,10,12-octahydro-1H-pyrazino[2,1-c]pyrido[3,4-f][1,4]oxazine-1-one; 1-[(6aR)-1,4-dichloro-3-(2-fluoro-6-hydroxyphenyl)-6a,7,9,10-tetrahydro-12H-pyrazino[2,1-c]pyridino[3,4-f][1,4]oxazine-8(6H)-yl]propyl-2-en-1-one; (6aR)-4-chloro-3-(2-fluoro-6-hydroxyphenyl)-8-(prop-2-enoyl)-2,6,6a,7,8,9,10,12-octahydro-1H-pyrazino[2,1-c]pyrido[3,4-f][1,4]oxazine-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]oxazolo-10(8H)-yl]propyl-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]oxazolo[7,6-g]indazole-9(7H)-yl]propyl-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]oxazadiazino[7,6-g]indazole-9(7H)-yl]propyl-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]benzoxazine-2(1H)-yl]prop-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]benzoxazine-2(1H)-yl]prop-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]oxazine-2(1H)-yl)prop-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]benzoxazine-9(7H)-yl]propyl-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]benzoxazine-2(1H)-yl]propyl-2-en-1-one; 1-[(12aR)-9-(2-chloro-6-hydroxyphenyl)-10-fluoro-8-(prop-1-yn-1-yl)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazine-2(1H)-yl]prop-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]pyridino[2,3-f][1,4]oxazine-8(6H)-yl]prop-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]benzoxazine-2(1H)-yl]propyl-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]benzoxazine-2(1H)-yl]propyl-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]benzoxazine-2(1H)-yl]propyl-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]benzoxazine-2(1H)-yl]prop-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]benzoxazine-2(1H)-yl]propyl-2-en-1-one; 1-[(12aR)-9-(2-chloro-6-hydroxyphenyl)-8-(cyclopropoxy)-10-fluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazine-2(1H)-yl]propyl-2-en-1-one; 1-((12aR)-9-(2-chloro-6-hydroxyphenyl)-8-(3-(dimethylamino)prop-1-yn-1-yl)-10-fluoro-3,4,12,12a-tetrahydro-6H-benzo[f]pyrazino[2,1-c][1,4]oxazine-2(1H)-yl)prop-2-en-1-one; 1-[(12aR)-9-(2-chloro-6-hydroxyphenyl)-10-fluoro-8-[(pyridin-4-yl)methoxy]-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazono-2(1H)-yl]propyl-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]benzoxazine-2(1H)-yl]propyl-2-en-1-one; 1-[(12aR)-9-(2-chloro-6-hydroxyphenyl)-10-fluoro-8-[2-(piperidin-1-yl)ethoxy]-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazine-2(1H)-yl]propyl-2-en-1-one; 1-[(12aR)-10-chloro-9-(2-chloro-6-hydroxyphenyl)-8-(prop-1-yn-1-yl)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazine-2(1H)-yl]prop-2-en-1-one; 1-[(6aR)-4-chloro-3-(2-chloro-6-hydroxyphenyl)-2-[( 2 [H3)methoxy]-6a,7,9,10-tetrahydro-12H-pyrazino[2,1-c]pyridino[2,3-f][1,4]oxazine-8(6H)-yl]propyl-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]benzoxazine-2(1H)-yl]propyl-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]benzoxazono-2(1H)-yl]propyl-2-en-1-one; 1-[(6aR)-4-chloro-3-(2-chloro-6-hydroxyphenyl)-1-(prop-1-yn-1-yl)-6a,7,9,10-tetrahydro-12H-pyrazino[2,1-c]pyridino[3,4-f][1,4]oxazine-8(6H)-yl]prop-2-en-1-one; and 1-((6aR)-4-chloro-3-(2-chloro-6-hydroxyphenyl)-1-ethynyl-6a,7,9,10-tetrahydro-12H-pyrazino[2,1-c]pyridino[3,4-f][1,4]oxazine-8(6H)-yl)prop-2-en-1-one; Or its pharmaceutically acceptable salt.

29. The method of claim 7, the inhibitor for use, or the application thereof, wherein the small molecule KRAS inhibitor is a compound of formula (IV): (IV)。 30. The method, inhibitor for use, or application according to any one of claims 1 to 29, wherein the ATR inhibitor is an antibody.

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

32. The method of claim 31, the inhibitor used, or the application thereof, wherein the small molecule ATR inhibitor is M6620 / VX970 (bexostatet), BAY-1895344 (erristatet), RP-3500 (carmenstatet), ATRN-119, SC0245, ATRN-212, LR-02, M4344 (gatistatet), M1774, ATG-018, ART0380, BG-129, JS-123, BKT-300, AZ-20, VE-821, AZD-559, or IMP9064.

33. The method of claim 31, the inhibitor used, or the application thereof, wherein the small molecule ATR inhibitor is a compound of formula (V): (V) in: R 21 Selected from morpholin-4-yl and 3-methylmorpholin-4-yl; R 22 yes , , or n is 0 or 1; R 22A R 22C R 22E and R 22F Each can be either hydrogen or methyl; R 22B and R 22D Each can be either hydrogen or methyl; R 22G Selected from -NHR 27 and –NHCOR 28 ; R 22H It is fluorine; R 23 It is methyl; R 24 and R 25 Each is independently hydrogen or methyl, or R 24 and R 25 Together with the atoms to which they are attached, they form ring A. 2 ; Ring A 2 It is C 3-6 Cycloalkyl or saturated 4-6 membered heterocycles containing a heteroatom selected from O and N; R 26 It is hydrogen; R 27 It is hydrogen or methyl; and R 28 It is methyl. Or its pharmaceutically acceptable salt.

34. The method of claim 33, the inhibitor used, or the application thereof, wherein R 24 and R 25 Together with the atoms to which they are attached, they form ring A. 2 And ring A 2 It is C 3-6 Cycloalkyl or saturated 4-6 heterocycles containing a heteroatom selected from O and N.

35. The method of claim 33 or 34, the inhibitor for use, or the application thereof, wherein ring A 2 It is a cyclopropyl, tetrahydropyranyl, or piperidinyl ring.

36. The method, inhibitor, or use according to any one of claims 33 to 35, wherein R 22A It is hydrogen; R 22B It is hydrogen; R 22C It is hydrogen; R 22D It is hydrogen; R 22E It is hydrogen; and R 22F It is hydrogen.

37. The method, inhibitor, or use according to any one of claims 33 to 36, wherein R 21 It is morpholino-4-yl.

38. The method, inhibitor, or use according to any one of claims 33 to 36, wherein R 21 It is 3-methylmorpholino-4-yl.

39. The method of claim 33, the inhibitor for use, or the application thereof, wherein the compound of formula (V) is a compound of formula (Va): (And) Or its pharmaceutically acceptable salt.

40. The method of claim 39, the inhibitor used, or the application thereof, wherein: Ring A 2 It is a cyclopropyl ring; R 22 yes , , or ; n is 0 or 1; R 22A It is hydrogen; R 22B It is hydrogen; R 22C It is hydrogen; R 22D It is hydrogen; R 22E It is hydrogen; R 22F It is hydrogen; R 22G Yes - NHR 27 ; R 22H It is fluorine; R 23 It is methyl; R 26 It is hydrogen; and R 27 It is hydrogen or methyl. Or its pharmaceutically acceptable salt.

41. The method of claim 31, the inhibitor for use, or the application thereof, wherein the small molecule ATR inhibitor is selected from any of the following: 4-{4-[(3R)-3-methylmorpholin-4-yl]-6-[((R)-S-methylsulfonylimino)methyl]pyrimidin-2-yl}-1H-pyrrolo[2,3-b]pyridine; 4-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((S)-S-methylsulfonylimino)cyclopropyl]pyrimidin-2-yl}-1H-pyrrolo[2,3-b]pyridine; 4-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((R)-S-methylsulfonylimino)cyclopropyl]pyrimidin-2-yl}-1H-pyrrolo[2,3-b]pyridine; N-Methyl-1-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((R)-S-methylsulfonylimino)cyclopropyl]pyrimidin-2-yl}-1H-benzimidazole-2-amine; N-Methyl-1-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((S)-S-methylsulfonylimino)cyclopropyl]pyrimidin-2-yl}-1H-benzimidazole-2-amine; 4-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((R)-S-methylsulfonylimino)cyclopropyl]pyrimidin-2-yl}-1H-indole; 4-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((S)-S-methylsulfonylimino)cyclopropyl]pyrimidin-2-yl}-1H-indole; 1-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((R)-S-methylsulfonylimino)cyclopropyl]pyrimidin-2-yl}-1H-benzimidazol-2-amine; 1-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((S)-S-methylsulfonylimino)cyclopropyl]pyrimidin-2-yl}-1H-benzimidazol-2-amine; 4-Fluoro-N-methyl-1-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((R)-S-methylsulfonylimino)cyclopropyl]pyrimidin-2-yl}-1H-benzimidazol-2-amine; 4-Fluoro-N-methyl-1-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((S)-S-methylsulfonylimino)cyclopropyl]pyrimidin-2-yl}-1H-benzimidazol-2-amine; 4-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-(S-methylsulfonylimino)cyclopropyl]pyrimidin-2-yl}-1H-pyrrolo[2,3-c]pyridine; N-Methyl-1-{4-[1-methyl-1-((S)-S-methylsulfonylimino)ethyl]-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-2-yl}-1H-benzimidazole-2-amine; N-Methyl-1-{4-[1-methyl-1-((R)-S-methylsulfonylimino)ethyl]-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-2-yl}-1H-benzimidazol-2-amine; N-Methyl-1-{4-[(3R)-3-methylmorpholin-4-yl]-6-[4-((S)-S-methylsulfonylimino)tetrahydro-2H-pyran-4-yl]pyrimidin-2-yl}-1H-benzimidazol-2-amine; N-Methyl-1-{4-[(3R)-3-methylmorpholin-4-yl]-6-[4-((R)-S-methylsulfonylimino)tetrahydro-2H-pyran-4-yl]pyrimidin-2-yl}-1H-benzimidazol-2-amine; 4-{4-[(3R)-3-methylmorpholin-4-yl]-6-[4-((S)-S-methylsulfonylimino)tetrahydro-2H-pyran-4-yl]pyrimidin-2-yl}-1H-indole; 4-Fluoro-N-methyl-1-{4-[1-methyl-1-((S)-S-methylsulfonylimino)ethyl]-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-2-yl}-1H-benzimidazol-2-amine; 4-Fluoro-N-methyl-1-{4-[1-methyl-1-((R)-S-methylsulfonylimino)ethyl]-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-2-yl}-1H-benzimidazol-2-amine; 6-Fluoro-N-methyl-1-{4-[1-methyl-1-((R)-S-methylsulfonylimino)ethyl]-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-2-yl}-1H-benzimidazol-2-amine; 5-Fluoro-N-methyl-1-{4-[1-methyl-1-((R)-S-methylsulfonylimino)ethyl]-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-2-yl}-1H-benzimidazol-2-amine; 5-Fluoro-N-methyl-1-{4-[1-methyl-1-((S)-S-methylsulfonylimino)ethyl]-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-2-yl}-1H-benzimidazol-2-amine; 6-Fluoro-N-methyl-1-{4-[1-methyl-1-((S)-S-methylsulfonylimino)ethyl]-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-2-yl}-1H-benzimidazol-2-amine; 6-Fluoro-N-methyl-1-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((R)-S-methylsulfonylimino)cyclopropyl]pyrimidin-2-yl}-1H-benzimidazol-2-amine; 5-Fluoro-N-methyl-1-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((R)-S-methylsulfonylimino)cyclopropyl]pyrimidin-2-yl}-1H-benzimidazol-2-amine; 5-Fluoro-N-methyl-1-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((S)-S-methylsulfonylimino)cyclopropyl]pyrimidin-2-yl}-1H-benzimidazol-2-amine; and 6-Fluoro-N-methyl-1-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((S)-S-methylsulfonylimino)cyclopropyl]pyrimidin-2-yl}-1H-benzimidazol-2-amine; Or its pharmaceutically acceptable salt.

42. The method of claim 31, the inhibitor used, or the application thereof, wherein the small molecule ATR inhibitor is a compound of formula (VI) (cilaceltetracycline): (WE), Or its pharmaceutically acceptable salt.

43. 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 (i) KRAS inhibitor and (ii) ATR inhibitor are one of the following combinations: 。 44. The method according to claim 1, the inhibitor for use according to claim 2 or claim 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 cilasetraceti.

45. The method according to claim 1, the inhibitor for use according to claim 2 or claim 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 cilasetraceti.

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

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

49. The method of claim 47, the inhibitor for use, or the application thereof, wherein the KRAS mutation is a mutation at codon 12.

50. The method of claim 47, the inhibitor for use, or the application thereof, wherein the KRAS mutation is a G12C mutation.

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

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

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

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

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

56. A method of treating a subject in need, the method comprising administering a composition comprising: a.KRAS inhibitors, and b. ATR inhibitors, The subjects mentioned above suffer from conditions mediated by KRAS, NRAS, or HRAS G12C mutations.

57. A composition comprising: a.KRAS inhibitors, and b. ATR inhibitors.

58. The composition according to claim 57, wherein the KRAS inhibitor is sotoraraciab, adagraciab, Ly3537982, GDC-6036, D-1553, JDQ443, BI1823911, GFH925, D35-001, JAB-21822, HBI-2438, YL-15293, GEC255, IBI351, RMC-6291, or MK-10.

84. MRTX1133, HRS-4642, RMC-9805, JAB-2200, Vrtx153, ERAS-4, ASP3082, RMC-0708, RMC-8839, RMC-6291, JAB-23400, TEB-17231, QTX3046, compounds of formula (I), compounds of formula (II), compounds of formula (III), or compounds of formula (IV).

59. The composition according to claim 57 or 58, wherein the ATR inhibitor is M6620 / VX970 (bexostat), BAY-1895344 (erristat), RP-3500 (carmenstat), ATRN-119, SC0245, ATRN-212, LR-02, M4344 (gatistat), 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 a solid.

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

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 the composition of any one of claims 57 to 63 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament, optionally in the treatment of cancer.

65. A kit comprising: a. A first container, the first container containing a first composition containing a KRAS inhibitor, and b. A second container containing a second composition containing an ATR inhibitor.

66. The kit according to claim 65, wherein the KRAS inhibitor is sotoraraxib, adagraxib, Ly3537982, GDC-6036, D-1553, JDQ443, BI1823911, GFH925, D35-001, JAB-21822, HBI-2438, YL-15293, GEC255, IBI351, RMC-6291, or MK-10.

84. MRTX1133, HRS-4642, RMC-9805, JAB-2200, Vrtx153, ERAS-4, ASP3082, RMC-0708, RMC-8839, RMC-6291, JAB-23400, TEB-17231, QTX3046, compounds of formula (I), compounds of formula (II), compounds of formula (III), or compounds of formula (IV).

67. The kit according to claim 65 or 66, wherein the ATR inhibitor is M6620 / VX970 (bexostat), BAY-1895344 (erristat), RP-3500 (carmenstat), ATRN-119, SC0245, ATRN-212, LR-02, M4344 (gatistat), 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 solids.

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 a 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 composition and the second composition further comprise a pharmaceutically acceptable excipient, diluent, or carrier.

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