Treatment methods involving KRAS G12C inhibitors and SHP2 inhibitors

Abstract

The present disclosure provides a method of treating a patient for cancer, comprising administering to a patient in need thereof an effective amount of a compound of the following formula: [Formula 1] TIFF2025509202000058.tif42128In formula, R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 , R 11 , R 12 In another aspect, the present invention provides a method of treating a patient suffering from atopic dermatitis, the method comprising administering a compound or a pharma- ceutically acceptable salt thereof, wherein A, B, and Y are as described herein, and a SHP2 inhibitor or a pharma- ceutically acceptable salt thereof.

Description

[Technical field]

[0001] The present disclosure relates to a method of treating a patient for cancer, comprising administering to a patient in need thereof an effective amount of a KRAS G12C inhibitor, or a pharma- ceutically acceptable salt thereof, together with an SHP2 inhibitor, or a pharma- ceutically acceptable salt thereof, to treat cancer, such as lung cancer, colorectal cancer, pancreatic cancer, bladder cancer, cervical cancer, endometrial cancer, ovarian cancer, bile duct cancer, or esophageal cancer. [Background technology]

[0002] Oncogenic KRas mutations have been identified in approximately 30% of human cancers and have been demonstrated to activate multiple downstream signaling pathways. Despite the prevalence of KRas mutations, it remains a challenging therapeutic target. (Cox,ADDrugging the Undruggable RAS:Mission Possible?Nat.Rev.Drug Disc.2014,13,828-851; Pylayeva-Gupta,y et al.RAS Oncogenes:Weaving a Tumorigenic Web.Nat.Rev.Cancer 2011,11,761-774).

[0003] WO 2015 / 054572 and WO 2016 / 164675 disclose certain quinazoline derivatives that can bind to KRAS G12C. WO 2016 / 044772 also discloses methods of using such quinazoline derivatives. WO 2020 / 0081282 discloses KRAS G12C inhibitors. WO 2018 / 206539 and WO 2020 / 178282 disclose certain heteroaryl compounds that can bind to KRAS G12C oncoprotein.

[0004] SHP2 inhibitors are also known in the art. WO 2019 / 167000 and WO 2020 / 022323 disclose certain SHP2 inhibitors.

[0005] WO 2018 / 013597, WO 2019 / 051084, and U.S. Patent Application Publication No. 2020 / 368238 each disclose certain SHP2 inhibitors in combination with a RAS inhibitor.

[0006] There remains a need to provide small molecule combinations of KRAS G12C inhibitors and SHP2 inhibitors. In particular, there is a need to provide more potent and orally deliverable KRAS G12C inhibitors and SHP2 inhibitors useful for the treatment of cancer. More particularly, there is a need to provide small molecule inhibitor combinations that specifically inhibit KRas GTP activity and SHP2 activity. There is also a need to provide small molecule KRAS G12C inhibitor and SHP2 inhibitor combinations that exhibit synergistic anti-proliferative and anti-tumor effects. Furthermore, it is desirable to provide KRAS G12C inhibitor and SHP2 inhibitor combinations that overcome the avoidance of KRAS inhibitory therapy. There is also a need to provide KRAS G12C inhibitor and SHP2 inhibitor combinations that exhibit increased efficacy with reduced or minimized adverse or undesirable effects. The present disclosure addresses one or more of these needs by providing KRAS G12C inhibitor and SHP2 inhibitor combinations, as well as methods and uses of the combinations.

[0007] The present disclosure provides a method of treating a patient for cancer, comprising administering to a patient in need thereof an effective amount of a compound of formula I,

[0008] [ka] During the ceremony, A is -OCH2-, -N(R6)CH2-, -OCH2CH2-, -N(R6)CH2CH2-, -CH2OCH2-, or -CH2N(R6)CH2-; B is -CH2- or -C(O)-; Y is -C(CN)- or -N-; R1 is -CN,

[0009] [ka] or a group of the formula

[0010] [ka] R2 is H, methyl, or -CH2CN; R3 and R5 are each independently H, halogen, -C 0~3 Alkyl-cyclopropyl, R 10 -C optionally substituted 1 to 3 times with 1~6 Alkyl or R 10 -OC optionally substituted 1 to 3 times with 1~6 is alkyl, R4 is H, halogen, or R 10 -C optionally substituted 1 to 3 times with 1~6 is alkyl, R6 is H or R 10 -C optionally substituted 1 to 3 times with 1~6 is alkyl, R7 is H, halogen, -NR 11 R 12 , -CH2NR 11 R 12 , R 10 Or R 13 -C optionally substituted 1 to 3 times with 1~6 Alkyl, -C 0~3 Alkylcyclopropyl, or R 10 Or R 13 -OC optionally substituted 1 to 3 times with 1~6 is alkyl, R8 is H, R 10 -C optionally substituted 1 to 3 times with 1~4 Alkyl or R 10 -C optionally substituted 1 to 3 times with 3~6 is cycloalkyl, R9 is H, halogen, -CN, -C 0~3 Alkyl-C 3~6 Cycloalkyl or R10 -C optionally substituted 1 to 3 times with 1~6 is alkyl, R 10 Each occurrence independently represents halogen, oxygen, hydroxy, -C 1~4 Alkyl or -OC 1~4 is alkyl, R 11 and R 12 are each independently H, -C 1~4 Alkyl or -C 1~4 Heteroalkyl, R 11 and R 12 may combine to form a heterocycloalkyl; R 13 But for each occurrence, -NC 1~4 is alkyl, a compound or a pharma- ceutically acceptable salt thereof, The method includes administering an effective amount of an SHP2 inhibitor or a pharma- ceutically acceptable salt thereof.

[0011] As used herein, the term halogen means fluoro (F), chloro (Cl), bromo (Br), or iodo (I). As used herein, the term alkyl means a saturated straight or branched chain monovalent hydrocarbon radical of 1 to 6 carbon atoms, e.g., "-C 1~6 "-C" refers to an alkyl group. Examples of alkyl include, but are not limited to, methyl, ethyl, propyl, 1-propyl, isopropyl, butyl, pentyl, and hexyl. As used herein, the term heteroalkyl refers to a saturated linear or branched monovalent hydrocarbon radical containing 2 to 5 carbon atoms and at least one heteroatom, e.g., "-C 1~4 As used herein, the term cycloalkyl refers to a saturated monovalent cyclic molecule having 3 to 6 carbon atoms, e.g., "-C 3~6Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. As used herein, the term cycloheteroalkyl refers to a saturated monovalent cyclic molecule having 2 to 5 carbon atoms and at least one heteroatom, e.g., "-C 3~6 Examples of cycloheteroalkyl groups include, but are not limited to, pyrrolidine, piperidine, imidazolidine, pyrazolidine, and piperazine.

[0012] If zero is indicated, e.g., -C 0~3 Alkyl-C 3~6 In the case of cycloalkyl, the alkyl component of the substituent may be absent, and thus, when R9 of formula I is a cyclopropyl group not preceded by an alkyl, the substituent may be -C as described for R9. 0~3 It would be described by an alkyl-cyclopropyl substituent (ie, the substituent would be --C.sub.0-cyclopropyl).

[0013] R 11 and R 12 With respect to these two groups, when the chemistry allows for the formation of a heterocycloalkyl, these two groups may be combined at the nitrogen to which they are attached. Examples of such heterocycloalkyl groups include, but are not limited to, piperidine, piperazine, and morpholine.

[0014] In embodiments, the disclosure provides a method of treating a patient for cancer, comprising administering to a patient in need thereof an effective amount of a compound of formula I, or a pharma- ceutically acceptable salt thereof, wherein the compound of formula I is a compound of formula Ia:

[0015] [ka] wherein R1, R2, R3, R4, R5, A, B, and Y are as defined above, or a pharma- ceutically acceptable salt thereof, and an effective amount of an SHP2 inhibitor or a pharma- ceutically acceptable salt thereof.

[0016] In an embodiment, in the compound of formula I or formula Ia, or a pharma- ceutically acceptable salt thereof, A is -OCH2-, -N(R6)CH2-, -OCH2CH2-, -N(R6)CH2CH2-. In a further embodiment, in the compound of formula I or formula Ia, or a pharma- ceutically acceptable salt thereof, A is -OCH2- or -OCH2CH2-. In yet a further embodiment, in the compound of formula I or formula Ia, or a pharma- ceutically acceptable salt thereof, A is -OCH2CH2-.

[0017] In a further embodiment, in the compound of Formula I or Formula Ia, or a pharma- ceutically acceptable salt thereof, B is -C(O)-.

[0018] In a further embodiment, in the compound of Formula I or Formula Ia, or a pharma- ceutically acceptable salt thereof, Y is -C(CN)-.

[0019] In a further embodiment, in the compound of Formula I or Formula Ia, or a pharma- ceutically acceptable salt thereof, Y is --N--.

[0020] In a further embodiment, in the compound of formula I or formula Ia, or a pharma- ceutically acceptable salt thereof, R1 is -CN,

[0021] [ka] In still further embodiments, in the compound of formula I or formula Ia, or a pharma- ceutically acceptable salt thereof, R1 is a group of the formula:

[0022] [ka]

[0023] In a further embodiment, in the compound of formula I or formula Ia, or a pharma- ceutically acceptable salt thereof, R2 is H or methyl. In yet a further embodiment, in the compound of formula I or formula Ia, or a pharma- ceutically acceptable salt thereof, R2 is H.

[0024] In a further embodiment, in the compound of formula I or formula Ia, or a pharma- ceutically acceptable salt thereof, R3 is H, halogen, methyl, methoxy, ethyl, isopropyl, or cyclopropyl.In yet a further embodiment, in the compound of formula I or formula Ia, or a pharma- ceutically acceptable salt thereof, R3 is halogen (preferably F or Cl).

[0025] In a further embodiment, in the compound of formula I or formula Ia, or a pharma- ceutically acceptable salt thereof, R4 is H or halogen. In yet a further embodiment, in the compound of formula I or formula Ia, or a pharma- ceutically acceptable salt thereof, R4 is H, F, or Cl.

[0026] In a further embodiment, in the compound of formula I or formula Ia, or a pharma- ceutically acceptable salt thereof, R5 is halogen (preferably Cl).

[0027] In a further embodiment, in the compound of formula I or formula Ia, or a pharma- ceutically acceptable salt thereof, R6 is H or CH3.

[0028] In a further embodiment, in the compound of formula I or formula Ia, or a pharma- ceutically acceptable salt thereof, R9 is H, F, Cl, -CH2F, -CF3, or -CH2OH. In yet a further embodiment, in the compound of formula I or formula Ia, or a pharma- ceutically acceptable salt thereof, R9 is H.

[0029] In a further embodiment, in the compound of formula I or formula Ia, or a pharma- ceutically acceptable salt thereof, R7 is H, -CHF2, -CH2F, -CH2OH, -CH2OCH3, -CH2N(CH3)2, or -CH2-morpholine. In yet a further embodiment, in the compound of formula I or formula Ia, or a pharma- ceutically acceptable salt thereof, R7 is H.

[0030] In still further embodiments, in the compound of formula I or formula Ia, or a pharma- ceutically acceptable salt thereof, R9 is H and R7 is H, -CHF2, -CH2F, -CH2OH, -CH2OCH3, -CH2N(CH3)2, or -CH2-morpholine.

[0031] In still further embodiments, in the compound of formula I or formula Ia, R9 is H, F, Cl, -CH2F, -CF3, or -CH2OH, and in the compound of formula I or formula Ia, or a pharma- ceutically acceptable salt thereof, R7 is H.

[0032] In still further embodiments, in the compound of formula I or formula Ia, or a pharma- ceutically acceptable salt thereof, both R7 and R9 are H.

[0033] In still further embodiments, in the compound of formula I or formula Ia, R1 is -CN, or

[0034] [ka] and in the compound of formula I or formula Ia, or a pharma- ceutically acceptable salt thereof, R8 is H, methyl, -CH2F, or -CH2OH.

[0035] In yet further embodiments, in the compound of formula I or formula Ia, R1 is a group of the formula:

[0036] [ka] In the compounds of formula I or formula Ia, or a pharma- ceutically acceptable salt thereof, both R7 and R9 are H.

[0037] In yet further embodiments, in the compound of formula I or formula Ia, R1 is a group of the formula:

[0038] [ka] In the compounds of formula I or formula Ia, R7 is tert-butyl, and in the compounds of formula I or formula Ia, or a pharma- ceutically acceptable salt thereof, R9 is --CN.

[0039] In still further embodiments, in the compound of Formula I or Formula Ia, A is -OCH2-, -N(R6)CH2-, -OCH2CH2-, -N(R6)CH2CH2-, and in the compound of Formula I or Formula Ia, or a pharma- ceutically acceptable salt thereof, B is -C(O)-.

[0040] In still further embodiments, in the compound of Formula I or Formula Ia, A is -OCH2- or -OCH2CH2-, and in the compound of Formula I or Formula Ia, or a pharma- ceutically acceptable salt thereof, B is -C(O)-.

[0041] In still further embodiments, in the compound of Formula I or Formula Ia, A is -OCH2CH2- and in the compound of Formula I or Formula Ia, or a pharma- ceutically acceptable salt thereof, B is -C(O)-.

[0042] In still further embodiments, in the compound of Formula I or Formula Ia, A is -OCH2-, -N(R6)CH2-, -OCH2CH2-, or -N(R6)CH2CH2-; in the compound of Formula I or Formula Ia, B is C(O); and in the compound of Formula I or Formula Ia, or a pharma- ceutically acceptable salt thereof, R2 is H or -CH3.

[0043] In still further embodiments, A is -OCH2- or -OCH2CH2-, in the compound of Formula I or Formula Ia, B is -C(O)-, and in the compound of Formula I or Formula Ia, or a pharma- ceutically acceptable salt thereof, R2 is H or methyl.

[0044] In still further embodiments, in the compound of formula I or formula Ia, A is -OCHCH-; in the compound of formula I or formula Ia, B is -C(O)-; and in the compound of formula I or formula Ia, or a pharma- ceutically acceptable salt thereof, R is H or methyl.

[0045] In still further embodiments, in the compound of formula I or formula Ia, A is -OCH2-, -N(R6)CH2-, -OCH2CH2-, -N(R6)CH2CH2-; in the compound of formula I or formula Ia, B is -C(O)-; and in the compound of formula I or formula Ia, or a pharma- ceutically acceptable salt thereof, R2 is H.

[0046] In still further embodiments, in the compound of Formula I or Formula Ia, A is -OCH2- or -OCH2CH2-; in the compound of Formula I or Formula Ia, B is -C(O)-; and in the compound of Formula I or Formula Ia, or a pharma- ceutically acceptable salt thereof, R2 is H.

[0047] In still further embodiments, in the compound of Formula I or Formula Ia, A is -OCHCH-; in the compound of Formula I or Formula Ia, B is -C(O)-; and in the compound of Formula I or Formula Ia, or a pharma- ceutically acceptable salt thereof, R is H.

[0048] In still further embodiments, in the compound of formula I or formula Ia, A is -OCH2CH2-, and in the compound of formula I or formula Ia, or a pharma- ceutically acceptable salt thereof, R2 is H or methyl.

[0049] In still further embodiments, in the compound of formula I or formula Ia, A is -OCH2CH2- and in the compound of formula I or formula Ia, or a pharma- ceutically acceptable salt thereof, R2 is H.

[0050] In yet a further embodiment, in the compound of formula I or formula Ia, B is -C(O)-, and in the compound of formula I or formula Ia, or a pharma- ceutically acceptable salt thereof, R2 is H or methyl.

[0051] In still further embodiments, in the compound of formula I or formula Ia, B is -C(O)- and in the compound of formula I or formula Ia, or a pharma- ceutically acceptable salt thereof, R2 is H.

[0052] In still further embodiments, in the compound of Formula I or Formula Ia, or a pharma- ceutically acceptable salt thereof, R3 and R5 are each independently selected from H, halogen, or methyl.

[0053] In still further embodiments, in the compound of formula I or formula Ia, or a pharma- ceutically acceptable salt thereof, R3 or R5 is halogen.

[0054] In still further embodiments, in the compound of formula I or formula Ia, or a pharma- ceutically acceptable salt thereof, R3 and R5 are halogen.

[0055] In still further embodiments, in the compound of Formula I or Formula Ia, or a pharma- ceutically acceptable salt thereof, R3 and R5 are each independently selected from F or Cl.

[0056] In yet a further embodiment, in the compound of formula I or formula Ia, Y is -C(CN)-, and in the compound of formula I or formula Ia, or a pharma- ceutically acceptable salt thereof, R4 is H or a halogen (preferably, F or Cl).

[0057] In yet a further embodiment, in the compound of formula I or formula Ia, Y is -N-, and in the compound of formula I or formula Ia, or a pharma- ceutically acceptable salt thereof, R4 is H or halogen (preferably F or Cl).

[0058] In yet a further embodiment, in the compound of Formula I or Formula Ia, Y is -C(CN)-; and in the compound of Formula I or Formula Ia, or a pharma- ceutically acceptable salt thereof, R3 and R5 are each independently selected from methyl or halogen.

[0059] In yet a further embodiment, in the compound of formula I or formula Ia, Y is -C(CN)-, and in the compound of formula I or formula Ia, or a pharma- ceutically acceptable salt thereof, R3 and R5 are each halogen (preferably F or Cl).

[0060] In yet further embodiments, in the compound of Formula I or Formula Ia, Y is -N-; and in the compound of Formula I or Formula Ia, or a pharma- ceutically acceptable salt thereof, R3 and R5 are each independently selected from methyl or halogen.

[0061] In yet a further embodiment, in the compound of formula I or formula Ia, Y is -N-, and in the compound of formula I or formula Ia, or a pharma- ceutically acceptable salt thereof, R3 and R5 are each halogen (preferably F or Cl).

[0062] In still further embodiments, in the compound of formula I or formula Ia, A is -OCH2-, -OCH2CH2-, -N(R6)CH2CH2-, -CH2OCH2-, or -CH2N(R6)CH2; in the compound of formula I or formula Ia, B is -CH2- or -C(O)-; in the compound of formula I or formula Ia, Y is -C(CN)- or -N-; in the compound of formula I or formula Ia, R1 is -CN,

[0063] [ka] or a group of the formula

[0064] [ka] In the compounds of formula I or formula Ia, R2 is H or methyl; in the compounds of formula I or formula Ia, R3 and R5 are each H, F, Cl, or methyl; R4 is H or F; in the compounds of formula I or formula Ia, R6 is H or methyl; in the compounds of formula I or formula Ia, R7 is H, -CHF2, -CH2F, -CH2OH, -CHOCH3, -CH2N(CH3)2, -CH2-morpholine, or tert-butyl; in the compounds of formula I or formula Ia, R8 is methyl, -CH2F, or -CH2OH; in the compounds of formula I or formula Ia, R9 is H, F, Cl, -CH2F, -CF3, -CH2OH, or CN, or a pharma- ceutically acceptable salt thereof.

[0065] In still further embodiments, in the compound of formula I or formula Ia, A is -OCH2- or -OCH2CH2-; in the compound of formula I or formula Ia, B is -CH2- or -C(O)-; in the compound of formula I or formula Ia, Y is -C(CN)- or -N-; in the compound of formula I or formula Ia, R2, R7, and R8 are each H; in the compound of formula I or formula Ia, R4 is H or halogen; and in the compound of formula I or formula Ia, R3 and R5 are each halogen; or a pharma- ceutically acceptable salt thereof.

[0066] The present disclosure provides a method of treating a patient for cancer, comprising administering to a patient in need thereof an effective amount of a compound of formula II,

[0067] [ka] In the formula, R is

[0068] [ka] and X is Cl or F; m is 1 or 2, or a pharma- ceutically acceptable salt thereof, and Further provided are methods comprising administering an SHP2 inhibitor or a pharma- ceutically acceptable salt thereof.

[0069] The present disclosure also provides a method of treating a patient for cancer, comprising administering to a patient in need thereof an effective amount of a compound of formula IIa,

[0070] [ka] In the formula, R is

[0071] [ka] and X is Cl or F; m is 1 or 2, or a pharma- ceutically acceptable salt thereof, and The method includes administering an SHP2 inhibitor or a pharma- ceutically acceptable salt thereof.

[0072] The present disclosure also provides a method of treating a patient for cancer, comprising administering to a patient in need thereof an effective amount of a compound of formula I, wherein the compound of formula I is formula Ib:

[0073] [ka] During the ceremony, A is -OCH2- or -OCH2CH2-, Y is -C(CN)- or -N-; R3 is Cl or F; When Y is C(CN), R4 is H or F; When Y is N, R4 is F, or a pharma- ceutically acceptable salt thereof, and an SHP2 inhibitor or a pharma- ceutically acceptable salt thereof.

[0074] Another way of describing the compounds of formula IIa is according to formula Ib, where A is:

[0075] [ka]

[0076] The present disclosure also provides a method of treating a patient for cancer, comprising administering to a patient in need thereof an effective amount of a compound of formula I or formula Ia, selected from any one of the following formulae III-VI:

[0077] [ka] or a pharma- ceutically acceptable salt thereof, and The method includes administering an SHP2 inhibitor or a pharma- ceutically acceptable salt thereof.

[0078] In another embodiment, the present disclosure provides a method of treating a patient for cancer, comprising administering to a patient in need thereof an effective amount of a compound of formula III.

[0079] [ka] or a pharma- ceutically acceptable salt thereof, and The method includes administering an SHP2 inhibitor or a pharma- ceutically acceptable salt thereof.

[0080] In another embodiment, the present disclosure provides a method of treating a patient for cancer, comprising administering to a patient in need thereof an effective amount of a compound of formula IV.

[0081] [ka] or a pharma- ceutically acceptable salt thereof, and The method includes administering an SHP2 inhibitor or a pharma- ceutically acceptable salt thereof.

[0082] In another embodiment, the present disclosure provides a method of treating a patient for cancer, comprising administering to a patient in need thereof an effective amount of a compound of formula V

[0083] [ka] or a pharma- ceutically acceptable salt thereof, and The method includes administering an SHP2 inhibitor or a pharma- ceutically acceptable salt thereof.

[0084] In another embodiment, the present disclosure provides a method of treating a patient for cancer, comprising administering to a patient in need thereof an effective amount of a compound of formula VI.

[0085] [ka] or a pharma- ceutically acceptable salt thereof, and The method includes administering an SHP2 inhibitor or a pharma- ceutically acceptable salt thereof.

[0086] In another embodiment, the methods comprising a compound according to any one of Formulas I-VI also include where the SHP2 inhibitor, or a pharma- ceutically acceptable salt thereof, is a type I SHP2 inhibitor or a type II SHP2 inhibitor. In another embodiment, the type I SHP2 inhibitor is PHPS1 or GS-493, or a pharma- ceutically acceptable salt thereof. In another embodiment, the type I SHP2 inhibitor is NSC-87877 or NSC-117199, or a pharma- ceutically acceptable salt thereof. In another embodiment, the type I SHP2 inhibitor is cefsulodin, or a pharma- ceutically acceptable salt thereof.

[0087] In another embodiment, the type II SHP2 inhibitor is JAB-3068 or JAB-3312, or a pharma- ceutically acceptable salt thereof. In another embodiment, the type II SHP2 inhibitor is RMC-4550 or RMC-4630, or a pharma- ceutically acceptable salt thereof. In another embodiment, the type II SHP2 inhibitor is SHP099, SHP244, SHP389, SHP394, or TN0155, or a pharma- ceutically acceptable salt thereof. In another embodiment, the type II SHP2 inhibitor is RG-6433 or RLY-1971, or a pharma- ceutically acceptable salt thereof.

[0088] In another embodiment, the SHP2 inhibitor is BBP-398, IACS-15509, or IACS-13909, or a pharma- ceutically acceptable salt thereof. In another embodiment, the SHP2 inhibitor is X37, or a pharma- ceutically acceptable salt thereof. In another embodiment, the SHP2 inhibitor is ERAS-601, or a pharma- ceutically acceptable salt thereof. In another embodiment, the SHP2 inhibitor is SH3809, or a pharma- ceutically acceptable salt thereof. In another embodiment, the SHP2 inhibitor is HBI-2376, or a pharma- ceutically acceptable salt thereof. In another embodiment, the SHP2 inhibitor is ETS-001, or a pharma- ceutically acceptable salt thereof. In another embodiment, the SHP2 inhibitor is PCC0208023, or a pharma- ceutically acceptable salt thereof.

[0089] In another embodiment, the disclosure provides a method of treating a patient for cancer, comprising administering to a patient in need thereof an effective amount of a compound according to any one of Formulas I-VI or a pharma- ceutically acceptable salt thereof, together with RMC-4630.

[0090] In another embodiment, the disclosure provides a method of treating a patient for cancer, comprising administering to a patient in need thereof an effective amount of a compound according to any one of Formulas I-VI or a pharma- ceutically acceptable salt thereof, together with JAB-3068.

[0091] In another embodiment, the disclosure provides a method of treating a patient for cancer, comprising administering to a patient in need thereof an effective amount of a compound according to any one of Formulas I-VI or a pharma- ceutically acceptable salt thereof, together with TN0155.

[0092] The disclosure also provides a method of treating a patient for cancer, comprising administering to a patient in need thereof an effective amount of a compound according to any one of Formulas I-VI, or a pharma- ceutically acceptable salt thereof, together with an SHP2 inhibitor, or a pharma- ceutically acceptable salt thereof.

[0093] In various embodiments, the cancer is lung cancer, colorectal cancer, pancreatic cancer, bladder cancer, cervical cancer, endometrial cancer, ovarian cancer, bile duct cancer, or esophageal cancer. In preferred embodiments, the cancer is non-small cell lung cancer, pancreatic cancer, or colorectal cancer. In even more preferred embodiments, the cancer is non-small cell lung cancer.

[0094] The disclosure also provides a method of treating a patient having cancer, comprising administering to a patient in need thereof an effective amount of a compound according to any one of Formulas I-VI or a pharma- ceutically acceptable salt thereof, together with an SHP2 inhibitor or a pharma- ceutically acceptable salt thereof, wherein the cancer has one or more cells that express a mutant KRas G12C protein with or without SHP2 dysregulation or overexpression. The disclosure also provides a method of treating cancer, comprising administering to a patient in need thereof an effective amount of a compound according to any one of Formulas I-VI or a pharma- ceutically acceptable salt thereof, and an SHP2 inhibitor compound or a pharma- ceutically acceptable salt thereof, wherein the cancer is non-small cell lung cancer, and one or more cells with or without SHP2 dysregulation or overexpression express a KRas G12C mutant protein. The disclosure also provides a method of treating cancer comprising administering to a patient in need thereof an effective amount of a compound according to any one of Formulas I-VI or a pharma- ceutically acceptable salt thereof and an SHP2 inhibitor compound or a pharma- ceutically acceptable salt thereof, wherein the cancer is colorectal cancer and one or more cells with or without SHP2 dysregulation or overexpression express a KRas G12C mutant protein.The disclosure also provides a method of treating cancer comprising administering to a patient in need thereof an effective amount of a compound according to any one of Formulas I-VI or a pharma- ceutically acceptable salt thereof and an SHP2 inhibitor compound or a pharma- ceutically acceptable salt thereof, wherein the cancer is pancreatic cancer and one or more cells with or without SHP2 dysregulation or overexpression express a KRas G12C mutant protein.

[0095] The disclosure also provides a method of treating cancer in a patient in need thereof, wherein the patient has a cancer determined to express a KRas G12C mutant protein and associated with SHP2 dysregulation or overexpression.

[0096] In another embodiment, the cancer is non-small cell lung cancer, and the cancer has one or more cells expressing KRas G12C mutant protein and / or with SHP2 dysregulation or overexpression. In another embodiment, the cancer is colorectal cancer, and the cancer has one or more cells expressing KRas G12C mutant protein and / or with SHP2 dysregulation or overexpression. In yet another embodiment, the cancer is mutant pancreatic cancer, and the cancer has one or more cells expressing KRas G12C mutant protein and / or with SHP2 dysregulation or overexpression. In another embodiment, the disclosure includes a method of treating cancers of other origins with KRas G12C mutant and / or SHP2 dysregulation or overexpression.

[0097] In yet another embodiment, the disclosure includes a method of treating cancer comprising administering to a patient in need thereof an effective amount of a compound according to any one of Formulas I-VI or a pharma- ceutically acceptable salt thereof, together with an SHP2 inhibitor or a pharma- ceutically acceptable salt thereof, wherein the cancer has one or more cells expressing a mutant KRas G12C protein or with SHP2 dysregulation or overexpression. In some embodiments, the patient has a cancer that is determined to have one or more cells expressing a KRas G12C mutant protein prior to administration of the compound or a pharma- ceutically acceptable salt thereof, or an SHP2 inhibitor or a pharma- ceutically acceptable salt thereof. In some embodiments, the patient has a cancer with a KRAS G12C mutation.

[0098] In yet another embodiment, the disclosure includes a method of treating cancer comprising administering to a patient in need thereof an effective amount of a compound according to any one of Formulas I-VI or a pharma- ceutically acceptable salt thereof together with an SHP2 inhibitor or a pharma- ceutically acceptable salt thereof, wherein the compound of the formula and the SHP2 inhibitor are provided to the patient in need thereof in a simultaneous or sequential combination. In some embodiments, the compound of the formula and the SHP2 inhibitor are provided to the patient in need thereof in a simultaneous combination. In some embodiments, the compound of the formula and the SHP2 inhibitor are provided to the patient in need thereof in a sequential combination. In some embodiments, the compound of the formula is provided to the patient in need thereof prior to the SHP2 inhibitor being provided to the patient in need thereof. In some embodiments, the SHP2 inhibitor is provided to the patient in need thereof prior to the compound of the formula being provided to the patient in need thereof.

[0099] In the methods described herein, the cancer can be lung cancer, colorectal cancer, pancreatic cancer, bladder cancer, cervical cancer, endometrial cancer, ovarian cancer, bile duct cancer, or esophageal cancer. In a preferred embodiment, the cancer is non-small cell lung cancer, pancreatic cancer, or colorectal cancer. In an even more preferred embodiment, the cancer is non-small cell lung cancer. In other embodiments, the cancer has one or more cancer cells that express mutant KRas G12C protein and / or have SHP2 dysregulation or overexpression. Preferably, the cancer is selected from KRas G12C mutant non-small cell lung cancer, KRas G12C mutant colorectal cancer, and KRas G12C mutant pancreatic cancer.

[0100] In embodiments, the disclosure provides a compound according to any one of formulas I-VI or a pharma- ceutically acceptable salt thereof for use in therapy in simultaneous, separate or sequential combination with an SHP2 inhibitor or a pharma- ceutically acceptable salt thereof. The disclosure also provides a compound according to any one of formulas I-VI or a pharma- ceutically acceptable salt thereof for use in the treatment of cancer in simultaneous, separate or sequential combination with an SHP2 inhibitor or a pharma- ceutically acceptable salt thereof. The disclosure also provides the use of a compound according to any one of formulas I-VI or a pharma- ceutically acceptable salt thereof in the manufacture of a medicament for the treatment of cancer in simultaneous, separate or sequential combination with an SHP2 inhibitor or a pharma- ceutically acceptable salt thereof.

[0101] As used herein, the term "KRas G12Ci" may refer to any compound according to any one of Formulas I-VI or a pharma- ceutically acceptable salt thereof.

[0102] The term "pharmaceutical acceptable salt" as used herein refers to a salt of a compound that is deemed acceptable for clinical and / or veterinary use. Examples of pharmaceutical acceptable salts and the general methodology for their preparation can be found in "Handbook of Pharmaceutical Salts: Properties, Selection and Use" P.Stahl, et al., 2nd Revised Edition, Wiley-VCH, 2011 and S.M.Berge, et al., "Pharmaceutical Salts", Journal of Pharmaceutical Sciences, 1977, 66(1), 1-19.

[0103] The pharmaceutical compositions of the present disclosure may be prepared using pharma- ceutically acceptable excipients. The term "pharmaceutical acceptable excipients" as used herein for pharmaceutical compositions refers to one or more carriers, diluents, and excipients that are compatible with other excipients of the composition or formulation and are not harmful to the patient. Examples of pharmaceutical compositions and processes for their preparation are described in "Remington: The Science and Practice of Pharmacy", Loyd, V., et al. Eds., 22 nd Ed., Mack Publishing Co., 2012. Non-limiting examples of pharma- ceutically acceptable carriers, diluents, and excipients include saline, water, starch, sugars, mannitol, and silica derivatives; binders such as carboxymethylcellulose, alginates, gelatin, and polyvinylpyrrolidone; kaolin and bentonite; and polyethyl glycols.

[0104] As used herein, the term "effective amount" refers to an amount that is an effective dose in treating disorders or diseases, such as cancerous lesions or abnormal cell proliferation and / or cell division progression. As a person skilled in the art, the attending physician can easily determine the effective amount by using conventional techniques and observing the results obtained under analogous circumstances.

[0105] The daily therapeutic dosage for a compound of formula I will usually fall within the range of about 1 mg / day or 2 times daily to 1000 mg / day or 2 times daily, more preferably 100 mg / day or 2 times daily to 900 mg / day or 2 times daily.

[0106] The daily therapeutic dosage for the SHP2 inhibitors, JAB-3068 or JAB-3312, RMC-4550 or RMC-4630, SHP099 or TN0155, RG-6433 or RLY-1971, BBP-398, IACS-15509 or IACS-13909, X37, ERAS-601, SH3809, HBI-2376, or ETS-001, typically falls within the range of about 0.1 to about 100 mg. For the SHP2 inhibitors JAB-3068 or JAB-3312, RMC-4550 or RMC-4630, SHP099 or TN0155, RG-6433 or RLY-1971, BBP-398, IACS-15509 or IACS-13909, X37, ERAS-601, SH3809, HBI-2376, or ETS-001, in some cases dosage levels below the lower limit of the range may be more than sufficient, while in other cases even higher doses may be used. For SHP2 inhibitors, JAB-3068 or JAB-3312, RMC-4550 or RMC-4630, SHP099 or TN0155, RG-6433 or RLY-1971, BBP-398, IACS-15509 or IACS-13909, X37, ERAS-601, SH3809, HBI-2376, or ETS-001, preferred dosages fall within the range of 1-80 mg, more preferably 1-50 mg, even more preferably 1-30 mg, and even more preferably 1-25 mg. Dosages may be administered once a day, twice a day, three times a day, or more. In one embodiment, TN0155 may be administered at a dosage of 20 mg per dose administered orally twice a day (BID). In one embodiment, the dosing regimen for TNO155 comprises two weeks of daily administration followed by one week without administration.

[0107] Factors to be considered in determining the effective amount or dose of a compound include: whether the compound or a salt thereof is administered, if used, the co-administration of other drugs, the type of patient being treated, the size, age, and general health of the patient; the extent or involvement or severity of the disorder, the response of the individual patient; the mode of administration; the bioavailability characteristics of the administered preparation; the selected dosing regimen and the use of other concomitant drugs.

[0108] The treating physician, veterinarian, or other medical professional will be able to determine the effective amount of the compound for treating the patient in need of treatment. Preferred pharmaceutical compositions can be formulated as tablets or capsules for oral administration, liquids for oral administration, or liquids for injection. The tablets, capsules, or liquids can contain an effective amount of the disclosed compound for treating a patient in need of cancer treatment.

[0109] As used herein, the terms "treating," "treat," or "treatment" include slowing, alleviating, or reversing the progression or severity of an existing symptom, disorder, or condition, which in particular can include slowing the growth of cancerous lesions or the progression of abnormal cell proliferation and / or cell division.

[0110] As used herein, the term "patient" refers to a mammal in need of treatment. Preferably, the patient is a human in need of treatment for cancer, e.g., cancer with a KRas G12C mutation.

[0111] Individual isomers, enantiomers, diastereomers, and atropisomers can be separated or resolved at any convenient point in the synthesis of the compounds listed below by methods such as selective crystallization techniques or chiral chromatography (see, for example, J. Jacques, et al., "Enantiomers, Racemates, and Resolutions", John Wiley and Sons, Inc., 1981, and EL Eliel and SH Wilen, "Stereochemistry of Organic Compounds", Wiley-Interscience, 1994). The present disclosure includes certain compounds that are atropisomers and can exist in different conformations or as different rotamers. Atropisomers are compounds that exist in different conformations resulting from restricted rotation around a single bond. Atropisomers can be separated as separate chemical species if the energy barrier for rotation around a single bond is high enough and the interconversion rate is slow enough to separate the individual rotamers from each other. The present disclosure contemplates all isomers, enantiomers, diastereomers, and atropisomers that are disclosed herein or that may be made using the compounds disclosed herein.

[0112] Any compound according to any one of formulas I-VI can be easily converted to a pharma-ceutically acceptable salt and isolated as a pharma-ceutically acceptable salt. Salt formation can occur upon addition of a pharma-ceutically acceptable acid to form an acid addition salt. Salts can also be formed simultaneously upon deprotection of nitrogen or oxygen, i.e., upon removal of a protecting group. Examples of reactions and conditions for salt formation can be found in Gould, PL, "Salt selection for basic drugs," International Journal of Pharmaceutics, 33:201-217 (1986); Bastin, RJ, et al. "Salt Selection and Optimization Procedures for Pharmaceutical New Chemical Entities," Organic Process Research and Development, 4:427-435 (2000); and Berge, SM, et al., "Pharmaceutical Salts," Journal of Pharmaceutical Sciences, 66:1-19, (1977).

[0113] The compounds of the present disclosure or their salts may be prepared by various procedures, some of which are illustrated in the following preparations and examples. The specific synthetic steps of each of the described routes can be combined in different ways or combined with steps of different routes to prepare the compounds or salts of the present disclosure. The products of each step in the following preparations can be recovered by conventional methods, including extraction, evaporation, precipitation, chromatography, filtration, trituration, and crystallization.

[0114] Biological assays The following assays demonstrate that combinations of exemplary compounds described herein are inhibitors of KRas G12C and inhibit the growth of certain tumors in vitro and / or in vivo.

[0115] The statistical methods used for the in vivo model are listed below.

[0116] Tumor growth inhibition assay Tumor volume was log 10 Scale transformation was used to equalize variance across time and treatment. 10 Volumes and body weights were analyzed separately using a two-way repeated measures analysis of variance model (RM ANOVA) consisting of time, treatment, and the interaction between time and treatment using the MIXED procedure of the SAS software package (version 9.3). A spatial power covariance structure was used to model the correlation of observations over time for the same subject. Kenward-Roger (1997) denominator degrees of freedom (DDFM) calculations were used to test fixed effects. Tumor volumes and body weights of treatment groups were compared to the control group on the summarized days using post-hoc pairwise t-tests, with p-values ​​≦0.05 considered statistically significant. The MIXED procedure was also used separately for each treatment group to calculate least squares means (LS means) and standard errors for each time point for the purpose of inclusion in plots and summary tables.

[0117] Calculating Effectiveness Efficacy was calculated at the end of treatment if at least half of the original number of control group subjects remained in the study, otherwise efficacy was calculated at the most recent observation date before the end of treatment for which these conditions were met.

[0118] Delta T / C% Delta [T / C]% was defined as the ratio of the tumor volume change at time t from baseline in the control group to the tumor volume change at time t from baseline in the treatment group multiplied by 100, where t is the mean tumor volume change at time t from baseline in the treatment group. ベースライン and the change from baseline in the treatment group is greater than zero (Equation 1).

[0119]

number

[0120] Tumor regression % Percent regression was defined as the ratio of baseline tumor volume change from baseline in the treatment group to the baseline tumor volume at time t times 100, where t is the mean tumor volume change from baseline in the treatment group. ベースライン greater, and the change from baseline in the treatment group is less than or equal to zero (Equation 2)

[0121]

number

[0122] Tumor Growth Inhibition (TGI)% TGI% was defined as 100 minus delta T / C% or regression% when applicable (Equation 3)

[0123]

number

[0124] Combinatorial analysis The Bliss Independence method was used to estimate the combination treatment effect on tumor volume. Log 10 Tumor volume data were analyzed using RM ANOVA as previously described, but with an additional two-way interaction effect contrast estimate of the following form: TV0-TV1-TV2+TV1,2 In the formula, TV0, TV1, TV2, and TV 1,2 is the estimated log 10 Volume LS average.

[0125] If the combined effect is exactly additive, the contrast estimate is equal to 0. This is mathematically equivalent to the Bliss Independence method, where the tumor is theoretically assumed to reach zero (complete regression).

[0126] If the contrast estimate was significantly different from zero (p ≤ 0.05), the combination effect was greater than additive (synergistic) or less than additive (antagonistic) if the observed combination group mean volume was less than or greater than the expected additive response (EAR) volume.

[0127]

number

[0128] If interaction contrast tests and all pairwise comparisons versus combination groups were all statistically significant (p≦0.05) and the observed combination mean volume was less than the EAR volume, the combination effect was declared greater than additive (synergistic).

[0129] If the interaction contrast test was statistically significant (p ≤ 0.05) and the observed combined mean volume was greater than the EAR volume, the combined effect was declared to be less than additive (antagonistic), regardless of the pairwise comparison results.

[0130] If the interaction test was not statistically significant (p ≥ 0.05) but all pairwise comparisons for the combination groups were significant (p ≤ 0.05), the combination effect was declared to be additive, otherwise the combination effect was inconclusive (no effect).

[0131] Combination studies with KRas G12Ci and RMC-4550 The objective of this study was to evaluate the antitumor efficacy of the KRAS G12C mutant-selective inhibitor KRas G12Ci in combination with the SHP2 inhibitor RMC-4550 in human NSCLC tumor or PDX models, each harboring a KRAS G12C mutation, and in a human CRC xenograft model.

[0132] The combination of KRAS G12CI with another SHP2 inhibitor (RMC-4550) demonstrated strong synergy in multiple NSCLC xenograft and PDX models.

[0133] The study evaluated the combination efficacy of KRas G12Ci with the SHP2 inhibitor RMC-4550. The combination efficacy was evaluated in two lung cancer xenograft models (H358 and H1373), one lung cancer PDX model (EL3187), and one colorectal xenograft model (SW837). The combination of KRas G12Ci with the SHP2 inhibitor demonstrated synergy and significantly better antitumor efficacy than either monotherapy. Better antitumor activity and significant tumor regression were observed with the combination therapy in three lung cancer models (EL3187, H358, and H1373) and the colorectal cancer SW837 model.

[0134] Test items: KRas G12Ci: 10% NMP, 15% w / v PVP-VA 90% in PEG400 was administered by oral gavage (0.2 mL / animal). 10% NMP of the total vehicle volume was added to the pre-weighed test article. Mixing was performed until all test article was dissolved (no visible particles). QS was mixed with PVPVA / PEG400 vehicle. Weekly batches.

[0135] SHP2 (RMC-4550): 20% Captisol (w / v) in 25 mM phosphate buffer (pH 2.0-2.2) administered by oral gavage (0.2 mL / animal). A portion of vehicle (approximately 20%) was added to test article and mixed to wet. Minus a small amount, remaining vehicle was added and mixed. Sonicated probes on ice bath to reduce particle size. QS to final volume and mix. Weekly batches.

[0136] Cell lines used: H358, H1373, and SW837 cells.

[0137] Table 1: Experimental design [Table 1] a In the H358 combination treatment group, one animal was reported to be sacrificed due to moribundity 3 days after dosing. b In the H1373 vehicle group, two animals were sacrificed on day 17 of treatment and one animal was sacrificed on day 24 of treatment due to tumor burden. The remainder of the vehicle treatment group was sacrificed on day 24. c In the RMC-4550 treatment group, one animal was sacrificed on day 21 due to tumor burden. d In the EL3187 vehicle group, three animals were sacrificed on day 22 of treatment due to tumor burden. e In the H358 and SW837 studies, n=6 in the vehicle group. N / A; not applicable, n; number of animals per group.

[0138] Mouse xenograft model Female athymic mice (Envigo RMS, Inc., Mount Comfort, Indiana) or NOD SCID gamma mice (The Jackson Laboratory, Bar Harbor, Maine) weighing 20-22 grams were used in the study. Animals were housed and provided with standard diet and water ad libitum. For H358, H1373, and SW837 xenograft tumor growth, 5 × 106 cells in a volume of 0.2 mL of Hanks' Balanced Salt solution (HBSS):Matrigel (Corning, Cat#354234) (1:1) were implanted subcutaneously into the right flank of each animal. H358 cells were implanted into NOD SCID gamma mice, and H1373 and SW837 cells were implanted into athymic mice. Tumor volumes were measured twice weekly using calipers. Tumors with a volume of 200-300 mm 3 Upon reaching tumor mass, mice were randomized based on tumor measurements and body weights using a multitask block randomization tool (n=5 / group). Treatment was initiated by oral gavage with either 0.2 mL vehicle, 10 mg / kg QD KRas G12Ci, 30 mg / kg QD RMC-4550, or a combination of 0.2 mL 10 mg / kg QD KRas G12Ci and 0.2 mL 30 mg / kg QD RMC-4550 for 28 days according to the experimental design shown in Table 1. In the H358 combination treatment group, one animal was sacrificed due to moribundity 6 days after dosing. In the H1373 model, two animals in the vehicle group were sacrificed due to tumor necrosis or tumor burden on day 17 and one on day 24 of treatment, respectively, and one animal in the RMC-4550 group was sacrificed due to tumor necrosis on day 21. Statistical analysis results were summarized at day 28 of treatment for the H358 and SW837 xenograft studies and at day 24 of treatment for the H1373 xenograft study. In the H358 and H1373 studies, tumor regrowth was monitored for an additional 10-18 days after the last dose.

[0139] EL3187 PDX model EL3187 tumor fragments were obtained from the Methodist Research Institute Biorepository. Frozen vials containing tumor fragments were thawed at 37°C in a water bath. The tumor fragments were transferred to a 50 mL Falcon tube, and then ice-cold DMEM medium was slowly added to bring the total volume to 35 mL. The tumor fragments were then centrifuged at 130×g for 2 min at 4°C, and the supernatant was aspirated. This washing step was repeated twice, and the tumor fragments were resuspended in 10 mL of DMEM. The tumor fragments were implanted subcutaneously into the right hind flank of female 6-8 week old (20-22 grams) athymic nude Foxn1nu feeder mice (from Envigo RMS, Inc., Mount Comfort, Indiana). When the tumor volume reached 800-1000 mm3, the animals were sacrificed and the tumors were harvested using aseptic technique. Fresh tumors passaged 4 times were cut into 10-15 mm3 fragments and placed in cold Gibco Hibernate Medium, then pooled tumor fragments were implanted subcutaneously into animals with a 10 g trocar needle. 24 days after implantation, when tumor size was approximately 250-350 mm3, mice were randomized according to the experimental design shown in Table 1 (n=5 / group). Groups were dosed by oral gavage with either 0.2 mL of vehicle, 3 mg / kg QD KRas G12Ci, 30 mg / kg QD RMC-4550, or a combination of 0.2 mL of 3 mg / kg QD KRas G12Ci and 0.2 mL of 30 mg / kg QD RMC-4550 for 28 days. Tumor volumes were measured twice weekly using calipers. Three of the five animals in the vehicle group were sacrificed due to tumor burden on day 46 post-implant (day 22 of treatment). Statistical analysis results for the EL3187 PDX study were summarized on day 22 of treatment. Tumor regrowth was monitored for an additional 30 days after the last dose.

[0140] Table 2: Tumor growth inhibitory activity of combination treatment with KRas G12Ci and the SHP2 inhibitor RMC-4550 in the H358 NSCLC xenograft model [Table 2] P values ​​were estimated from RM ANOVA post-hoc pairwise t-tests between vehicle and each treatment group. Statistical analysis results were summarized on day 28 of treatment, and p≦0.05 was considered statistically significant. n=number of animals per group included in statistical analysis on day 28. N / A; not applicable; PO; by mouth; QD; once daily; TGI; tumor growth inhibition; SE; standard error.

[0141] Table 3: Tumor growth inhibitory activity of combination treatment with KRas G12Ci and RMC-4550 in the H1373 NSCLC xenograft model [Table 3] P values ​​were estimated from RM ANOVA post-hoc pairwise t-tests between vehicle and each treatment group. Statistical analysis results were summarized on day 24 of treatment, and p≦0.05 was considered statistically significant. n = number of animals per group included in statistical analysis on day 24. N / A; not applicable, PO; by mouth, QD; once daily, TGI; tumor growth inhibition, SE; standard error.

[0142] Table 4: Tumor growth inhibitory activity of combination treatment with KRas G12Ci and RMC-4550 in the SW837 CRC xenograft model [Table 4] P values ​​were estimated from RM ANOVA post-hoc pairwise t-tests between vehicle and each treatment group. Statistical analysis results were summarized on day 28 of treatment, and p≦0.05 was considered statistically significant. n = number of animals per group included in statistical analysis on day 28. N / A; not applicable, PO; by mouth, QD; once daily, TGI; tumor growth inhibition, SE; standard error.

[0143] Table 5: Tumor growth inhibition activity of combination treatment with KRas G12Ci and RMC-4550 in EL3187 NSCLC PDX models [Table 5] P values ​​were estimated from RM ANOVA post-hoc pairwise t-tests between vehicle and each treatment group. Statistical analysis results were summarized on day 22 of treatment, and p≦0.05 was considered statistically significant. n = number of animals per group included in statistical analysis on day 22. N / A; not applicable, PO; by mouth, QD; once daily, TGI; tumor growth inhibition, SE; standard error.

[0144] Results and Discussion In this study, the antitumor activity of KRAS G12C inhibitors in combination with the SHP2 inhibitor RMC-4550 was evaluated in two NSCLC models (H358 and H1373), one NSCLC patient-derived xenograft (PDX) model (EL3187), and one CRC xenograft model (SW837). In the H358, H1373, and SW837 xenograft models, tumor-bearing mice were treated with either KRas G12Ci at 10 mg / kg once daily (QD), RMC-4550 at 30 mg / kg QD, or a combination of KRas G12Ci at 10 mg / kg QD and RMC-4550 at 30 mg / kg QD (Table 1). KRas G12Ci at 10 mg / kg QD was selected as a suboptimal dose based on preclinical efficacy studies when used as monotherapy in these models, whereas RMC-4550 at 30 mg / kg QD was selected according to publications in preclinical xenograft models.

[0145] In the H358 NSCLC xenograft model, treatment with either KRas G12Ci or RMC-4550 for 28 days resulted in a significant tumor growth inhibition (TGI) of 74.9% or 71.7%, respectively, whereas treatment with KRas G12Ci in combination with RMC-4550 for the same period resulted in a significant tumor regression (TR) of 65.1% (Table 2). The antitumor activity of the dual treatment combination was significantly greater than that of either agent alone, and the expected additive response (EAR) indicated that the combination treatment effect was synergistic in this model. Sustained tumor regression was maintained for approximately 10 days after cessation of treatment in the combination treatment group. No weight loss was observed in the animals in any of the treatment groups, while there was no significant difference in mean body weight between either of the compound treatment groups and the vehicle group on the 28th day of treatment (Table 2). In the combination treatment group, one animal was sacrificed due to moribundity 6 days after dosing.

[0146] In the H1373 NSCLC model, two animals in the vehicle group were sacrificed on the 17th day of treatment and one on the 24th day due to tumor necrosis or tumor burden, respectively, and one animal in the RMC-4550 group was sacrificed on the 21st day due to tumor necrosis. Data from the 24th day of treatment were selected for statistical analysis. In this model, 24 days of treatment with either KRas G12Ci or RMC-4550 resulted in a significant TGI of 98.5% or 80.2%, respectively, while the combination treatment resulted in a significant TR of 74% (Table 3). The antitumor activity of KRas G12Ci in combination with RMC-4550 was significantly greater than that of either agent alone, but the results of the combination interaction study showed an additive combination treatment effect. In the combination treatment group, tumor regression persisted for approximately 10 days after cessation of compound treatment. No weight loss was observed in the animals in any of the treatment groups, and there was no significant difference in mean body weight between any of the compound treatment groups and the vehicle group on the 24th day of treatment (Table 3).

[0147] In the SW837 CRC model, 28 days of treatment with either KRas G12Ci or RMC-4550 alone resulted in a significant TGI of 70.6% or 79.4%, respectively, whereas the combination treatment resulted in a significant TR of 34% (Table 4). Similar to the results above, the antitumor activity of the combination treatment was significantly greater than that of either agent alone, indicating that the combination treatment effect was additive. No weight loss was observed in animals in any of the treatment groups in this model, and there was no significant difference in the average body weight between the compound-treated and vehicle-treated groups on the 28th day of treatment (Table 4).

[0148] Using the EL3187 NSCLC PDX model, tumor-bearing mice were treated with either KRas G12Ci at 3 mg / kg QD, RMC-4550 at 30 mg / kg QD, or a combination of KRas G12Ci and RMC-4550 at these dosages (Table 1). KRas G12Ci at 3 mg / kg QD was selected as a suboptimal dose based on previous preclinical efficacy studies when used as monotherapy in this model. In this study, three of five animals in the vehicle group were sacrificed due to tumor burden on day 46 after implantation (day 22 of treatment). Data from day 22 of treatment were selected for statistical analysis. Treatment with either KRas G12Ci or RMC-4550 alone for 22 days resulted in a significant TGI of 84.8% or 73.4%, respectively, while the combination treatment resulted in a significant TR of 76.2 (Table 5). The antitumor activity of the combination was significantly greater than that of either single agent alone and that of EAR, indicating that the combination therapeutic effect was synergistic in this model. No significant animal weight loss was observed in any of the treatment groups over the treatment period.

[0149] Taken together, these studies show that the dual-agent therapeutic combination of KRas G12Ci and the SHP2 inhibitor RMC-4550 demonstrated significantly higher antitumor activity than either single agent in multiple KRAS G12C tumor xenograft models. Dual-agent combination treatment showed additive effects in one NSCLC xenograft model (H1373) and one CRC xenograft model (SW837), and synergistic effects in the NSCLC H358 xenograft model and the EL3187 PDX model. Furthermore, with the exception of one death reported early after initiation of combination treatment in the H358 model, the combination treatment was well tolerated across models, suggesting that it may represent a safe and effective therapeutic agent for the treatment of cancer patients in the clinic.

[0150] KRas G12Ci, TNO155, and the combination of KRas G12Ci and TNO155 were investigated in a panel of cancer cell lines harboring the KRASG12C mutation, as shown in Table 6. Each cell line used in the study was seeded in a 384-well plate one day before treatment was added. The treatment time was 72 hours. After the treatment time had elapsed, 50ul of CellTiter Glo was added to each well. After waiting 15 minutes, the plate was read using EnVision. The resulting data was used to calculate the Abl IC50.

[0151] Table 6: Combination data of KRas G12Ci and SHP2 (TNO155) [Table 6]

[0152] The combination demonstrated strong synergy and efficacy. Combination treatment demonstrated additive effects in multiple cell lines (NCI-H1373, EI-3187, NCI-H358, LU99, NCI-H1792, and SW1573) and synergistic effects in other cell lines (HCC44, SW756, and NCI-H23). Combinations of KRas G12Ci with each of TNO155 and RMC-4550 exhibited similar synergy and efficacy in in vitro studies.

Claims

1. A method of treating a patient for cancer comprising administering to a patient in need thereof an effective amount of a compound of the following formula: 【Chemistry 1】 During the ceremony, A, -OCH ２ -、-N(R ６ )CH ２ -、-OCH ２ CH ２ -、-N(R ６ )CH ２ CH ２ -、-CH ２ OCH ２ - CH ２ N(R) ６ )CH ２ - B is -CH ２ - or -C(O)-, Y is -C(CN)- or -N-; R １ が、-CN、 【Chemistry 2】 or a group of the formula 【Chemistry 3】 R ２ is H, methyl, or -CH ２ CN, R ３ and R ５ each independently represents H, halogen, or -C ０～３ Alkyl-cyclopropyl, R １０ -C optionally substituted 1 to 3 times with １～６ Alkyl, or R １０ -OC optionally substituted 1 to 3 times １～６ is alkyl, R ４ is H, halogen, or R １０ -C optionally substituted 1 to 3 times with １～６ is alkyl, R ６ is H or R １０ -C optionally substituted 1 to 3 times with １～６ is alkyl, R ７ is H, halogen, -NR １１ R １２ , -CH ２ N.R. １１ R １２ , R １０ Or R １３ -C optionally substituted 1 to 3 times with １～６ Alkyl, -C ０～３ alkylcyclopropyl, or R １０ Or R １３ -OC optionally substituted 1 to 3 times １～６ is alkyl, R ８ But, H, R １０ -C optionally substituted 1 to 3 times with １～４ Alkyl, or R １０ -C optionally substituted 1 to 3 times with ３～６ is cycloalkyl, R ９ H, halogen, -CN, -C ０～３ Alkyl-C ３～６ Cycloalkyl, or R １０ -C optionally substituted 1 to 3 times with １～６ is alkyl, R １０ is independently selected from each occurrence of halogen, oxygen, hydroxy, -C １～４ Alkyl, or -O-C １～４ is alkyl, R １１ and R １２ each independently represents H, -C １～４ Alkyl, or -C １～４ Heteroalkyl, R １１ and R １２ may combine to form a heterocycloalkyl; R １３ is independently for each occurrence -N-C １～４ is alkyl, a compound or a pharma- ceutically acceptable salt thereof, A method comprising administering an effective amount of an SHP2 inhibitor or a pharma- ceutically acceptable salt thereof.

2. A compound of the following formula for use in simultaneous, separate or sequential combination therapy with an SHP2 inhibitor or a pharma- ceutically acceptable salt thereof: 【Chemistry 4】 During the ceremony, A, -OCH ２ -、-N(R ６ )CH ２ -、-OCH ２ CH ２ -、-N(R ６ )CH ２ CH ２ -、-CH ２ OCH ２ - CH ２ N(R) ６ )CH ２ - B is -CH ２ - or -C(O)-, Y is -C(CN)- or -N-; R １ が、-CN、 【Chemistry 5】 or a group of the formula 【Chemistry 6】 R ２ is H, methyl, or -CH ２ CN, R ３ and R ５ each independently represents H, halogen, or -C ０～３ Alkyl-cyclopropyl, R １０ -C optionally substituted 1 to 3 times with １～６ Alkyl, or R １０ -OC optionally substituted 1 to 3 times １～６ is alkyl, R ４ is H, halogen, or R １０ -C optionally substituted 1 to 3 times with １～６ is alkyl, R ６ is H or R １０ -C optionally substituted 1 to 3 times with １～６ is alkyl, R ７ is H, halogen, -NR １１ R １２ , -CH ２ N.R. １１ R １２ , R １０ Or R １３ -C optionally substituted 1 to 3 times with １～６ Alkyl, -C ０～３ alkylcyclopropyl, or R １０ Or R １３ -OC optionally substituted 1 to 3 times １～６ is alkyl, R ８ But, H, R １０ -C optionally substituted 1 to 3 times with １～４ Alkyl, or R １０ -C optionally substituted 1 to 3 times with ３～６ is cycloalkyl, R ９ H, halogen, -CN, -C ０～３ Alkyl-C ３～６ Cycloalkyl, or R １０ -C optionally substituted 1 to 3 times with １～６ is alkyl, R １０ is independently selected from each occurrence of halogen, oxygen, hydroxy, -C １～４ Alkyl, or -O-C １～４ is alkyl, R １１ and R １２ each independently represents H, -C １～４ Alkyl, or -C １～４ Heteroalkyl, R １１ and R １２ may combine to form a heterocycloalkyl; R １３ is independently for each occurrence -N-C １～４ is alkyl, A compound or a pharma- ceutically acceptable salt thereof.

3. 2. A compound of the following formula for use in the treatment of cancer in simultaneous, separate or sequential combination with a SHP2 inhibitor or a pharma- ceutically acceptable salt thereof: 【Chemistry 7】 During the ceremony, A, -OCH ２ -、-N(R ６ )CH ２ -、-OCH ２ CH ２ -、-N(R ６ )CH ２ CH ２ -、-CH ２ OCH ２ - CH ２ N(R) ６ )CH ２ - B is -CH ２ - or -C(O)-, Y is -C(CN)- or -N-; R １ が、-CN、 【Chemistry 8】 or a group of the formula 【Chemistry 9】 R ２ is H, methyl, or -CH ２ CN, R ３ and R ５ each independently represents H, halogen, or -C ０～３ Alkyl-cyclopropyl, R １０ -C optionally substituted 1 to 3 times with １～６ Alkyl, or R １０ -OC optionally substituted 1 to 3 times １～６ is alkyl, R ４ is H, halogen, or R １０ -C optionally substituted 1 to 3 times with １～６ is alkyl, R ６ is H or R １０ -C optionally substituted 1 to 3 times with １～６ is alkyl, R ７ is H, halogen, -NR １１ R １２ , -CH ２ N.R. １１ R １２ , R １０ Or R １３ -C optionally substituted 1 to 3 times with １～６ Alkyl, -C ０～３ alkylcyclopropyl, or R １０ Or R １３ -OC optionally substituted 1 to 3 times １～６ is alkyl, R ８ But, H, R １０ -C optionally substituted 1 to 3 times with １～４ Alkyl, or R １０ -C optionally substituted 1 to 3 times with ３～６ is cycloalkyl, R ９ H, halogen, -CN, -C ０～３ Alkyl-C ３～６ Cycloalkyl, or R １０ -C optionally substituted 1 to 3 times with １～６ is alkyl, R １０ is independently selected from each occurrence of halogen, oxygen, hydroxy, -C １～４ Alkyl, or -O-C １～４ is alkyl, R １１ and R １２ each independently represents H, -C １～４ Alkyl, or -C １～４ Heteroalkyl, R １１ and R １２ may combine to form a heterocycloalkyl; R １３ is independently for each occurrence -N-C １～４ is alkyl, A compound or a pharma- ceutically acceptable salt thereof.

4. In the manufacture of a medicament for the treatment of cancer in simultaneous, separate or sequential combination with an SHP2 inhibitor or a pharma- ceutically acceptable salt thereof, a compound of the following formula: 【Chemistry 10】 During the ceremony, A, -OCH ２ -、-N(R ６ )CH ２ -、-OCH ２ CH ２ -、-N(R ６ )CH ２ CH ２ -、-CH ２ OCH ２ - CH ２ N(R) ６ )CH ２ - B is -CH ２ - or -C(O)-, Y is -C(CN)- or -N-; R １ が、-CN、 【Chemistry 11】 or a group of the formula 【Chemistry 12】 R ２ is H, methyl, or -CH ２ CN, R ３ and R ５ each independently represents H, halogen, or -C ０～３ Alkyl-cyclopropyl, R １０ -C optionally substituted 1 to 3 times with １～６ Alkyl, or R １０ -OC optionally substituted 1 to 3 times １～６ is alkyl, R ４ is H, halogen, or R １０ -C optionally substituted 1 to 3 times with １～６ is alkyl, R ６ is H or R １０ -C optionally substituted 1 to 3 times with １～６ is alkyl, R ７ is H, halogen, -NR １１ R １２ , -CH ２ N.R. １１ R １２ , R １０ Or R １３ -C optionally substituted 1 to 3 times with １～６ Alkyl, -C ０～３ alkylcyclopropyl, or R １０ Or R １３ -OC optionally substituted 1 to 3 times １～６ is alkyl, R ８ But, H, R １０ -C optionally substituted 1 to 3 times with １～４ Alkyl, or R １０ -C optionally substituted 1 to 3 times with ３～６ is cycloalkyl, R ９ H, halogen, -CN, -C ０～３ Alkyl-C ３～６ Cycloalkyl, or R １０ -C optionally substituted 1 to 3 times with １～６ is alkyl, R １０ is independently selected from each occurrence of halogen, oxygen, hydroxy, -C １～４ Alkyl, or -O-C １～４ is alkyl, R １１ and R １２ each independently represents H, -C １～４ Alkyl, or -C １～４ Heteroalkyl, R １１ and R １２ may combine to form a heterocycloalkyl; R １３ is independently for each occurrence -N-C １～４ is alkyl, Use of a compound or a pharma- ceutically acceptable salt thereof.

5. A is -OCH ２ CH ２ - or a pharma- ceutically acceptable salt thereof.

6. 6. The method, compound or use according to any one of claims 1 to 5, wherein B is -C(O)- or a pharma- ceutically acceptable salt thereof.

7. Y is -C(CN)- or a pharma- ceutically acceptable salt thereof. 、 The method, compound or use according to any one of claims 1 to 6.

8. Y is -N- or a pharma- ceutically acceptable salt thereof. 、 The method, compound or use according to any one of claims 1 to 6.

9. R １ is the basis of the formula 【Chemistry 13】 In the formula, R ７ The method, compound or use according to any one of claims 1 to 8, wherein is a compound or a pharma- ceutically acceptable salt thereof, wherein: is H, F, Cl, methyl, ethoxy, ethyl, isopropyl, or cyclopropyl.

10. R １ is the basis of the formula 【Chemistry 14】 In the formula, R ９ H, F, Cl, -CHF ２ , -CF ３ , or -CH ２ 9. The method, compound or use according to any one of claims 1 to 8, wherein the compound is OH or a pharma- ceutically acceptable salt thereof.

11. R １ が、-CN、 【Chemistry 15】 9. The method, compound or use according to any one of claims 1 to 8, wherein the compound is:

12. R ２ The method, compound or use according to any one of claims 1 to 11, wherein is H or methyl, or a pharma- ceutically acceptable salt thereof.

13. R ３ The method, compound or use according to any one of claims 1 to 12, wherein is a compound or a pharma- ceutically acceptable salt thereof, wherein: is H, F, Cl, methyl, methoxy, ethyl, isopropyl, or cyclopropyl.

14. R ４ The method, compound or use according to any one of claims 1 to 13, wherein is H, F, or Cl, or a pharma- ceutically acceptable salt thereof.

15. R ５ H, -CHF ２ , -CH ２ F, -CH ２ OH or -CH ２ OCH ３ 15. The method, compound or use according to any one of claims 1 to 14, wherein said compound is:

16. The compound is of the formula: 【Chemistry 16】 The method, compound or use according to any one of claims 1 to 15, which is a compound or a pharma- ceutically acceptable salt thereof.

17. The compound is of the formula: 【Chemistry 17】 In the formula, R is 【Chemistry 18】 and X is Cl or F; m is 1 or 2; The method, compound or use according to any one of claims 1 to 16, which is a compound or a pharma- ceutically acceptable salt thereof.

18. The compound is of the formula: 【Chemistry 19】 In the formula, R is 【Chemistry 20】 and X is Cl or F; m is 1 or 2; 18. The method, compound or use according to any one of claims 1 to 17, which is a compound or a pharma- ceutically acceptable salt thereof.

19. The compound is of the formula: 【Chemistry 21】 During the ceremony, A is -OCH ２ -or-OCH ２ CH ２ - and Y is C(CN) or N; R ３ is Cl or F, When Y is C(CN), R ４ is H or F, When Y is N, R ４ But F.

18. The method, compound or use according to any one of claims 1 to 17, which is a compound or a pharma- ceutically acceptable salt thereof.

20. A, 【Chemical 22】 20. The method, compound or use according to any one of claims 1 to 19, wherein

21. The compound is 【Chemistry 23】 or a pharma- ceutically acceptable salt thereof; 21. The method, compound or use according to any one of claims 1 to 20.

22. The compound is 【Chemistry 24】 22. The method, compound or use according to any one of claims 1 to 21, wherein

23. 23. The method, compound, or use of any one of claims 1 to 22, wherein the SHP2 inhibitor is a compound selected from the group consisting of a type I SHP2 inhibitor, a type II SHP2 inhibitor, BBP-398, IACS-15509 or IACS-13909, X37, ERAS-601, SH3809, HBI-2376, ETS-001, or PCC0208023, or a pharma- ceutically acceptable salt thereof.

24. 24. The method, compound, or use according to any one of claims 1 to 23, wherein the type I SHP2 inhibitor is PHPS1, or a compound selected from the group consisting of GS-493, NSC-87877 or NSC-117199, cefsulodin, or a pharma- ceutically acceptable salt thereof.

25. 24. The method, compound or use of any one of claims 1 to 23, wherein the type II SHP2 inhibitor is a compound selected from the group consisting of JAB-3068 or JAB-3312, RMC-4550 or RMC-4630, SHP099, SHP244, SHP389, SHP394, or TN0155, RG-6433, or RLY-1971, or a pharma- ceutically acceptable salt thereof.

26. 26. The method, compound, or use of any one of claims 1 to 25, wherein the type II SHP2 inhibitor is a compound selected from the group consisting of JAB-3068, RMC-4630, TN0155, or RLY-1971, or a pharma- ceutically acceptable salt thereof.

27. 27. The method, compound or use of any one of claims 1 to 26, wherein said cancer is selected from the group consisting of lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, bile duct cancer, and colorectal cancer.

28. 28. The method, compound or use of any one of claims 1 to 27, wherein the cancer is non-small cell lung cancer and one or more cells express KRas G12C mutant protein with or without SHP2 dysregulation or overexpression.

29. 28. The method, compound or use of any one of claims 1 to 27, wherein the cancer is colorectal cancer and one or more cells, with or without SHP2 dysregulation or overexpression, express KRas G12C mutant protein.

30. 28. The method, compound or use of any one of claims 1 to 27, wherein the cancer is pancreatic cancer and one or more cells, with or without SHP2 dysregulation or overexpression, express KRas G12C mutant protein.

31. 28. The method, compound or use of any one of claims 1 to 27, wherein the patient has a cancer with a KRAS G12C mutation.

32. 32. The method, compound or use of any one of claims 1 to 31, wherein said patient has a cancer determined to have one or more cells expressing said KRas G12C mutant protein prior to administration of said compound or a pharma- ceutically acceptable salt thereof, or said SHP2 inhibitor or a pharma- ceutically acceptable salt thereof.

33. 33. The method, compound or use of any one of claims 1 to 32, wherein said compound of said formula and said SHP2 inhibitor are provided in simultaneous combination or sequential combination to said patient in need thereof.

34. 34. The method, compound or use of any one of claims 1 to 33, wherein said compound of said formula and said SHP2 inhibitor are provided in combination simultaneously to said patient in need thereof.

35. 34. The method, compound or use of any one of claims 1 to 33, wherein said compound of said formula and said SHP2 inhibitor are provided in sequential combination to said patient in need thereof.

36. 36. The method, compound or use of any one of claims 1 to 35, wherein said compound of said formula is provided to said patient in need thereof followed by said SHP2 inhibitor being provided to said patient in need thereof.

37. 36. The method, compound or use of any one of claims 1 to 35, wherein said SHP2 inhibitor is provided to said patient in need thereof followed by said compound of said formula being provided to said patient in need thereof.

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