Methods of treatment comprising KRAS G12C inhibitors and SHP2 inhibitors

Abstract

The present disclosure provides a method of treating a cancer patient comprising administering to a patient in need thereof an effective amount of a compound of formula: # imgabs0 # wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, A, B, and Y are as described herein, or a pharmaceutically acceptable salt thereof, and an SHP2 inhibitor, or a pharmaceutically acceptable salt thereof.

Description

[0001] The present invention relates to a method for treating cancer patients, comprising administering an effective amount of a KRASG12C inhibitor or a pharmaceutically acceptable salt thereof and a SHP2 inhibitor or a pharmaceutically acceptable salt thereof to a patient in need thereof, so as to treat cancers such as lung cancer, colorectal cancer, pancreatic cancer, bladder cancer, cervical cancer, endometrial cancer, ovarian cancer, bile duct cancer or esophageal cancer.

[0002] Oncogenic KRAS mutations have been identified in approximately 30% of human cancers and have been shown to activate multiple downstream signaling pathways. Despite the prevalence of KRas mutations, it has been a difficult target for treatment. (Cox, ADDruggingtheUndruggableRAS:MissionPossible?Nat.Rev.DrugDisc.2014,13,828-851; Pylayeva-Gupta,y et al.,RASOncogenes:WeavingaTumorigenicWeb.Nat.Rev.Cancer2011,11,761-774).

[0003] WO2015 / 054572 and WO2016 / 164675 disclose certain quinazoline derivatives capable of binding to KRAS G12C. WO2016 / 044772 also discloses methods of using such quinazoline derivatives. WO2020 / 0081282 discloses KRASG12C inhibitors. WO2018 / 206539 and WO2020 / 178282 disclose certain heteroaryl compounds capable of binding 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 US 2020 / 368238 respectively disclose certain combinations of SHP2 inhibitors and RAS inhibitors.

[0006] There is still a need to provide small molecule combinations of KRAS G12C and SHP2 inhibitors. In particular, there is a need to provide more effective, orally deliverable KRAS G12C and SHP2 inhibitors for the treatment of cancer. More particularly, there is a need to provide a small molecule inhibitor combination that specifically inhibits KRas GTP and SHP2 activity. There is also a need to provide a small molecule KRAS G12C and SHP2 inhibitor combination that exhibits synergistic anti-proliferative and anti-tumor effects. In addition, there is a need to provide a KRAS G12C and SHP2 inhibitor combination that overcomes KRAS inhibition therapy escape (bypass). In addition, there is a need to provide a combination of KRAS G12C and SHP2 inhibitors that exhibit increased efficacy and reduce or minimize adverse or undesirable effects. The present disclosure addresses one or more of these needs by providing a combination of KRAS G12C and SHP2 inhibitors and methods and uses of the combination.

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

[0008]

[0009] in:

[0010] A is -OCH2-, -N(R6)CH2-, -OCH2CH2-, -N(R6)CH2CH2-, -CH2OCH2-, or -CH2N(R6)CH2-;

[0011] B is -CH2- or -C(O)-;

[0012] Y is -C(CN)- or -N-;

[0013] R1 is -CN, -C(O)C≡CR8, or a group of the formula

[0014]

[0015] R2 is H, methyl, or -CH2CN;

[0016] R3 and R5 are each independently H, halogen, -C 0-3 Alkyl-cyclopropyl, optionally substituted by R 10 Replace 1-3 times -C 1-6 alkyl, or optionally R 10 Replace 1-3 times -OC 1-6 alkyl;

[0017] R4 is H, halogen, or optionally replaced by R 10 Replace 1-3 times -C 1-6 alkyl;

[0018] R6 is H or optionally replaced by R 10 Replace 1-3 times -C 1-6 alkyl;

[0019] R7 is H, halogen, -NR 11 R 12 、-CH2NR 11 R 12 , optionally by R 10 or R 13 Replace 1-3 times -C 1-6 Alkyl, -C 0-3 Alkylcyclopropyl, or optionally R 10 or R 13 Replace 1-3 times -OC 1-6 alkyl;

[0020] R8 is H, optionally replaced by R 10 Replace 1-3 times -C 1-4 alkyl, or optionally R 10 Replace 1-3 times -C 3-6 Cycloalkyl;

[0021] R9 is H, halogen, -CN, -C 0-3 Alkyl-C 3-6 Cycloalkyl, or optionally R 10 Replace 1-3 times -C 1-6 alkyl;

[0022] R 10 Each occurrence is independently halogen, oxygen, hydroxyl, -C 1-4 Alkyl or -OC 1-4 alkyl;

[0023] R 11 and R 12 Each independently is H, -C 1-4 Alkyl or -C 1-4 Heteroalkyl, where R 11 and R 12 may combine to form a heterocycloalkyl group; and

[0024] R 13 Each occurrence is independently -NC 1-4 alkyl,

[0025] or a pharmaceutically acceptable salt thereof; and

[0026] An effective amount of a SHP2 inhibitor, or a pharmaceutically acceptable salt thereof.

[0027] As used herein, the term halogen refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I). As used herein, the term alkyl refers to a saturated straight or branched monovalent hydrocarbon group having one to six carbon atoms, such as "-C 1-6 Alkyl". 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 straight or branched monovalent hydrocarbon group having two to five carbon atoms and at least one heteroatom, such as "-C 1-4 As used herein, the term "cycloalkyl" refers to a saturated monovalent cyclic molecule having three to six carbon atoms, such as "-C 3-6 Cycloalkyl". Examples of cycloalkyl 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 two to five carbon atoms and at least one heteroatom, such as "-C 3-6 Examples of cycloheteroalkyl groups include, but are not limited to, pyrrolidine, piperidine, imidazolidine, pyrazolidine, and piperazine.

[0028] In the case of indicating zero, such as -C 0-3 Alkyl-C 3-6 The alkyl portion of the substituent may not be present. Thus, if R9 in Formula I is a cyclopropyl group without a preceding alkyl group, the substituent will be replaced by a -C 0-3 The substituent would not be described by an alkyl-cyclopropyl substituent (i.e., the substituent would be -C0-cyclopropyl).

[0029] For R 11 and R 12 , when chemical conditions permit, these two groups can combine with the nitrogen atom to which they are attached to form a heterocycloalkyl. Examples of the heterocycloalkyl include, but are not limited to, piperidine, piperazine and morpholine.

[0030] In one embodiment, the present disclosure provides a method of treating a cancer patient, comprising administering to a patient in need thereof an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I is a compound of Formula Ia:

[0031]

[0032] wherein R1, R2, R3, R4, R5, A, B, and Y are as defined above, or a pharmaceutically acceptable salt thereof; and an effective amount of a SHP2 inhibitor, or a pharmaceutically acceptable salt thereof.

[0033] In one embodiment, in the compound of Formula I or Ia or a pharmaceutically acceptable salt thereof, A is -OCH2-, -N(R6)CH2-, -OCH2CH2-, -N(R6)CH2CH2-. In a further embodiment, in the compound of Formula I or Ia or a pharmaceutically acceptable salt thereof, A is -OCH2- or -OCH2CH2-. In yet another further embodiment, in the compound of Formula I or Ia or a pharmaceutically acceptable salt thereof, A is -OCH2CH2-.

[0034] In a further embodiment, in the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, B is -C(O)-.

[0035] In a further embodiment, in the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, Y is -C(CN)-.

[0036] In a further embodiment, in the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, Y is -N-.

[0037] In a further embodiment, in the compound of formula I or Ia or a pharmaceutically acceptable salt thereof, R1 is -CN, -C(O)C≡CR8. In yet another further embodiment, in the compound of formula I or Ia or a pharmaceutically acceptable salt thereof, R1 is a group of the formula:

[0038]

[0039] In a further embodiment, in the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, R2 is H or methyl. In yet a further embodiment, in the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, R2 is H.

[0040] In a further embodiment, in a compound of Formula I or Ia or a pharmaceutically acceptable salt thereof, R3 is H, halogen, methyl, methoxy, ethyl, isopropyl or cyclopropyl. In yet a further embodiment, in a compound of Formula I or Ia or a pharmaceutically acceptable salt thereof, R3 is halogen (preferably F or Cl).

[0041] In a further embodiment, in the compound of Formula I or Ia or a pharmaceutically acceptable salt thereof, R4 is H or halogen. In yet a further embodiment, in the compound of Formula I or Ia or a pharmaceutically acceptable salt thereof, R4 is H, F, or Cl.

[0042] In a further embodiment, in the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, R5 is halogen (preferably Cl).

[0043] In further embodiments, in the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, R6 is H or CH3.

[0044] In a further embodiment, in the compound of Formula I or Ia or a pharmaceutically acceptable salt thereof, R9 is H, F, Cl, -CH2F, -CF3, or -CH2OH. In yet a further embodiment, in the compound of Formula I or Ia or a pharmaceutically acceptable salt thereof, R9 is H.

[0045] In a further embodiment, in a compound of Formula I or Ia or a pharmaceutically acceptable salt thereof, R is H, -CHF, -CHF, -CHOH, -CHOCH, -CHN(CH) or -CH-morpholine. In yet a further embodiment, in a compound of Formula I or Ia or a pharmaceutically acceptable salt thereof, R is H.

[0046] In yet a further embodiment, in a compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, R9 is H and R7 is H, -CHF2, -CH2F, -CH2OH, -CH2OCH3, -CH2N(CH3)2, or -CH2-morpholine.

[0047] In yet a further embodiment, in the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, R9 is H, F, Cl, -CH2F, -CF3, or -CH2OH, and in the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, R7 is H.

[0048] In yet a further embodiment, in the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, R7 and R9 are both H.

[0049] In yet a further embodiment, in the compound of Formula I or Ia or a pharmaceutically acceptable salt thereof, R1 is -CN, or -C(O)C≡CR8, and in the compound of Formula I or Ia or a pharmaceutically acceptable salt thereof, R8 is H, methyl, -CH2F, or -CH2OH.

[0050] In yet a further embodiment, in the compound of formula I or Ia, R1 is a group of the formula:

[0051]

[0052] And in the compound of Formula I or Ia or a pharmaceutically acceptable salt thereof, R7 and R9 are both H.

[0053] In yet a further embodiment, in the compound of formula I or Ia, R1 is a group of the formula:

[0054]

[0055] And in the compound of formula I or Ia or a pharmaceutically acceptable salt thereof, R7 is tert-butyl, and in the compound of formula I or Ia or a pharmaceutically acceptable salt thereof, R9 is -CN.

[0056] In yet a further embodiment, in the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, A is -OCH2-, -N(R6)CH2-, -OCH2CH2-, -N(R6)CH2CH2-, and in the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, B is -C(O)-.

[0057] In yet a further embodiment, in the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, A is -OCH2- or -OCH2CH2-, and in the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, B is -C(O)-.

[0058] In yet a further embodiment, in the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, A is -OCH2CH2-, and in the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, B is -C(O)-.

[0059] In yet a further embodiment, in the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, A is -OCH2-, -N(R6)CH2-, -OCH2CH2-, or -N(R6)CH2CH2-, in the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, B is C(O), and in the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, R2 is H or -CH3.

[0060] In yet a further embodiment, in the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, A is -OCH2- or -OCH2CH2-, B is -C(O)-, and in the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, R2 is H or methyl.

[0061] In yet a further embodiment, in the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, A is -OCH2CH2-, in the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, B is -C(O)-, and in the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, R2 is H or methyl.

[0062] In yet a further embodiment, in the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, A is -OCH2-, -N(R6)CH2-, -OCH2CH2-, -N(R6)CH2CH2-, in the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, B is -C(O)-, and in the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, R2 is H.

[0063] In yet a further embodiment, in the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, A is -OCH2- or -OCH2CH2-, in the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, B is -C(O)-, and in the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, R2 is H.

[0064] In yet a further embodiment, in the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, A is -OCH2CH2-, in the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, B is -C(O)-, and in the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, R2 is H.

[0065] In yet a further embodiment, in the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, A is -OCH2CH2-, and in the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, R2 is H or methyl.

[0066] In yet a further embodiment, in the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, A is -OCH2CH2-, and in the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, R2 is H.

[0067] In yet a further embodiment, in the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, B is -C(O)-, and in the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, R2 is H or methyl.

[0068] In yet a further embodiment, in the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, B is -C(O)-, and in the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, R2 is H.

[0069] In yet a further embodiment, in the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, R3 and R5 are each independently selected from H, halogen or methyl.

[0070] In yet a further embodiment, in the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, R3 or R5 is halogen.

[0071] In yet a further embodiment, in the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, R3 and R5 are halogen.

[0072] In yet a further embodiment, in the compound of Formula I or Ia or a pharmaceutically acceptable salt thereof, R3 and R5 are each independently selected from F or Cl.

[0073] In yet a further embodiment, in the compound of formula I or Ia or a pharmaceutically acceptable salt thereof, Y is -C(CN)-, and in the compound of formula I or Ia or a pharmaceutically acceptable salt thereof, R4 is H or halogen (preferably F or Cl).

[0074] In yet a further embodiment, in the compound of formula I or Ia or a pharmaceutically acceptable salt thereof, Y is -N-, and in the compound of formula I or Ia or a pharmaceutically acceptable salt thereof, R4 is H or halogen (preferably F or Cl).

[0075] In yet a further embodiment, in the compound of Formula I or Ia or a pharmaceutically acceptable salt thereof, Y is -C(CN)-, and in the compound of Formula I or Ia or a pharmaceutically acceptable salt thereof, R3 and R5 are each independently selected from methyl or halogen.

[0076] In yet a further embodiment, in the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, Y is -C(CN)-, and in the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, R3 and R5 are each halogen (preferably F or Cl).

[0077] In yet a further embodiment, in the compound of Formula I or Ia or a pharmaceutically acceptable salt thereof, Y is -N-, and in the compound of Formula I or Ia or a pharmaceutically acceptable salt thereof, R3 and R5 are each independently selected from methyl or halogen.

[0078] In yet a further embodiment, in the compound of Formula I or Ia or a pharmaceutically acceptable salt thereof, Y is -N-, and in the compound of Formula I or Ia or a pharmaceutically acceptable salt thereof, R3 and R5 are each halogen (preferably F or Cl).

[0079] In yet a further embodiment, in the compound of formula I or Ia, A is -OCH2-, -OCH2CH2-, -N(R6)CH2CH2-, -CH2OCH2-, or -CH2N(R6)CH2; in the compound of formula I or Ia, B is -CH2- or -C(O)-; in the compound of formula I or Ia, Y is -C(CN)- or N-; in the compound of formula I or Ia, R1 is -CN, -C(O)C≡CR8, or a group of the formula:

[0080]

[0081] In the compound of formula I or Ia, R2 is H or methyl; in the compound of formula I or Ia, R3 and R5 are each H, F, Cl or methyl; R4 is H or F; in the compound of formula I or Ia, R6 is H or methyl; in the compound of formula I or Ia, R7 is H, -CHF2, -CH2F, -CH2OH, -CH2OCH3, -CH2N(CH3)2, -CH2-morpholine or tert-butyl; in the compound of formula I or Ia, R8 is methyl, -CH2F or -CH2OH; and in the compound of formula I or Ia, R9 is H, F, Cl, -CH2F, -CF3, -CH2OH or CN; or a pharmaceutically acceptable salt thereof.

[0082] In yet a further embodiment, in the compound of Formula I or Ia, A is -OCH2- or -OCH2CH2-; in the compound of Formula I or Ia, B is -CH2- or -C(O)-; in the compound of Formula I or Ia, Y is -C(CN)- or -N-; in the compound of Formula I or Ia, R2, R7 and R8 are each H; in the compound of Formula I or Ia, R4 is H or halogen; in the compound of Formula I or Ia, R3 and R5 are each halogen; or a pharmaceutically acceptable salt thereof.

[0083] The present disclosure also provides a method for treating a cancer patient, comprising administering to a patient in need thereof an effective amount of a compound of formula II:

[0084]

[0085] Where R is

[0086] X is Cl or F;

[0087] and m is 1 or 2;

[0088] or a pharmaceutically acceptable salt thereof, and

[0089] A SHP2 inhibitor, or a pharmaceutically acceptable salt thereof.

[0090] The present disclosure also provides a method of treating a cancer patient, comprising administering to a patient in need thereof an effective amount of a compound of Formula IIa:

[0091]

[0092] Where R is

[0093] X is Cl or F;

[0094] and m is 1 or 2;

[0095] or a pharmaceutically acceptable salt thereof, and

[0096] A SHP2 inhibitor, or a pharmaceutically acceptable salt thereof.

[0097] The present disclosure also provides a method for treating a cancer patient, comprising administering an effective amount of a compound of Formula I to a patient in need thereof, wherein the compound of Formula I is Formula Ib:

[0098]

[0099] in:

[0100] A is -OCH2- or -OCH2CH2-;

[0101] Y is -C(CN)- or -N-;

[0102] R3 is Cl or F;

[0103] When Y is C(CN), R4 is H or F; and

[0104] When Y is N, R4 is F;

[0105] or a pharmaceutically acceptable salt thereof; and

[0106] A SHP2 inhibitor, or a pharmaceutically acceptable salt thereof.

[0107] Another way to describe the compounds of formula IIa is to use formula Ib, where A is

[0108]

[0109] The present disclosure also provides a method for treating a cancer patient, comprising administering to a patient in need thereof an effective amount of a compound of Formula I or Ia, wherein Formula I or Ia is selected from any one of the following Formulas III-VI:

[0110]

[0111] or a pharmaceutically acceptable salt thereof, and

[0112] A SHP2 inhibitor, or a pharmaceutically acceptable salt thereof.

[0113] In another embodiment, the present disclosure provides a method of treating a cancer patient, comprising administering to a patient in need thereof an effective amount of a compound of formula III, wherein the compound of formula III is:

[0114]

[0115] or a pharmaceutically acceptable salt thereof, and

[0116] A SHP2 inhibitor, or a pharmaceutically acceptable salt thereof.

[0117] In another embodiment, the present disclosure provides a method of treating a cancer patient, comprising administering to a patient in need thereof an effective amount of a compound of formula IV, wherein the compound of formula IV is:

[0118]

[0119] or a pharmaceutically acceptable salt thereof, and

[0120] A SHP2 inhibitor, or a pharmaceutically acceptable salt thereof.

[0121] In another embodiment, the present disclosure provides a method of treating a cancer patient, comprising administering to a patient in need thereof an effective amount of a compound of Formula V, wherein the compound of Formula V is:

[0122]

[0123] or a pharmaceutically acceptable salt thereof, and

[0124] A SHP2 inhibitor, or a pharmaceutically acceptable salt thereof.

[0125] In another embodiment, the present disclosure provides a method of treating a cancer patient, comprising administering to a patient in need thereof an effective amount of a compound of Formula VI, wherein the compound of Formula VI is:

[0126]

[0127] or a pharmaceutically acceptable salt thereof, and

[0128] A SHP2 inhibitor, or a pharmaceutically acceptable salt thereof.

[0129] In another embodiment, the method comprising a compound according to any one of Formulas I-VI further comprises wherein the SHP2 inhibitor or a pharmaceutically 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 pharmaceutically acceptable salt thereof. In another embodiment, the Type I SHP2 inhibitor is NSC-87877 or NSC-117199 or a pharmaceutically acceptable salt thereof. In another embodiment, the Type I SHP2 inhibitor is Cefsulodin or a pharmaceutically acceptable salt thereof.

[0130] In another embodiment, the type II SHP2 inhibitor is JAB-3068 or JAB-3312, or a pharmaceutically acceptable salt thereof. In another embodiment, the type II SHP2 inhibitor is RMC-4550 or RMC-4630, or a pharmaceutically acceptable salt thereof. In another embodiment, the type II SHP2 inhibitor is SHP099, SHP244, SHP389, SHP394 or TN0155, or a pharmaceutically acceptable salt thereof. In another embodiment, the type II SHP2 inhibitor is RG-6433 or RLY-1971, or a pharmaceutically acceptable salt thereof.

[0131] In another embodiment, the SHP2 inhibitor is BBP-398, IACS-15509 or IACS-13909, or a pharmaceutically acceptable salt thereof. In another embodiment, the SHP2 inhibitor is X37, or a pharmaceutically acceptable salt thereof. In another embodiment, the SHP2 inhibitor is ERAS-601, or a pharmaceutically acceptable salt thereof. In another embodiment, the SHP2 inhibitor is SH3809, or a pharmaceutically acceptable salt thereof. In another embodiment, the SHP2 inhibitor is HBI-2376, or a pharmaceutically acceptable salt thereof. In another embodiment, the SHP2 inhibitor is ETS-001, or a pharmaceutically acceptable salt thereof. In another embodiment, the SHP2 inhibitor is PCC0208023, or a pharmaceutically acceptable salt thereof.

[0132] In another embodiment, the present disclosure provides a method of treating a cancer patient, comprising administering to a patient in need thereof an effective amount of a compound according to any one of Formulae I-VI or a pharmaceutically acceptable salt thereof and RMC-4630.

[0133] In another embodiment, the present disclosure provides a method of treating a cancer patient, comprising administering to a patient in need thereof an effective amount of a compound according to any one of Formulae I-VI or a pharmaceutically acceptable salt thereof and JAB-3068.

[0134] In another embodiment, the present disclosure provides a method of treating a cancer patient, comprising administering to a patient in need thereof an effective amount of a compound according to any one of Formulae I-VI or a pharmaceutically acceptable salt thereof and TN0155.

[0135] The present disclosure also provides a method of treating a cancer patient, comprising administering to a patient in need thereof an effective amount of a compound according to any one of Formulae I-VI, or a pharmaceutically acceptable salt thereof, and a SHP2 inhibitor, or a pharmaceutically acceptable salt thereof.

[0136] 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 more preferred embodiments, the cancer is non-small cell lung cancer.

[0137] The present disclosure also provides a method for treating a cancer patient, comprising administering an effective amount of a compound according to any one of Formulas I-VI or a pharmaceutically acceptable salt thereof and a SHP2 inhibitor or a pharmaceutically acceptable salt thereof to a patient in need, wherein the cancer has one or more cells expressing a mutant KRas G12C protein, with or without SHP2 dysregulation or overexpression. The present disclosure also provides a method for treating cancer, comprising administering an effective amount of a compound according to any one of Formulas I-VI or a pharmaceutically acceptable salt thereof and a SHP2 inhibitor compound or a pharmaceutically acceptable salt thereof to a patient in need, wherein the cancer is non-small cell lung cancer, and wherein one or more cells with or without SHP2 dysregulation or overexpression express KRas G12C mutant protein. The present disclosure also provides a method for treating cancer, comprising administering an effective amount of a compound according to any one of Formulas I-VI or a pharmaceutically acceptable salt thereof, and a SHP2 inhibitor compound or a pharmaceutically acceptable salt thereof to a patient in need, wherein the cancer is colorectal cancer, and wherein one or more cells with or without SHP2 dysregulation or overexpression express KRas G12C mutant protein. The present disclosure also provides a method for treating cancer, comprising administering an effective amount of a compound according to any one of Formulas I-VI or a pharmaceutically acceptable salt thereof, and a SHP2 inhibitor compound or a pharmaceutically acceptable salt thereof to a patient in need thereof, wherein the cancer is pancreatic cancer, and wherein one or more cells with or without SHP2 dysregulation or overexpression express KRas G12C mutant protein.

[0138] The present disclosure also provides a method of treating cancer in a patient in need thereof, wherein the patient has a cancer determined to express KRas G12C mutant protein and dysregulated or overexpressed SHP2.

[0139] In another embodiment, the cancer is non-small cell lung cancer, wherein the cancer has one or more cells expressing KRas G12C mutant protein and / or SHP2 dysregulation or overexpression. In another embodiment, the cancer is colorectal cancer, wherein the cancer has one or more cells expressing KRas G12C mutant protein and / or SHP2 dysregulation or overexpression. In yet another embodiment, the cancer is mutant pancreatic cancer, wherein the cancer has one or more cells expressing KRasG12C mutant protein and / or SHP2 dysregulation or overexpression. In another embodiment, the present disclosure includes methods for treating cancers of other sources that carry KRas G12C mutants and / or SHP2 dysregulation or overexpression.

[0140] In yet another embodiment, the present disclosure includes a method of treating cancer, comprising administering an effective amount of a compound according to any one of Formulas I-VI or a pharmaceutically acceptable salt thereof and a SHP2 inhibitor or a pharmaceutically acceptable salt thereof to a patient in need thereof, wherein the cancer has one or more cells expressing a mutant KRas G12C protein or 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 administering the compound or a pharmaceutically acceptable salt thereof, or a SHP2 inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the patient has a cancer with a KRAS G12C mutation.

[0141] In yet another embodiment, the present 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 pharmaceutically acceptable salt thereof and a SHP2 inhibitor or a pharmaceutically acceptable salt thereof, wherein the compound of the general 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 general formula and the SHP2 inhibitor are provided to the patient in need thereof in a simultaneous combination. In some embodiments, the compound of the general formula and the SHP2 inhibitor are provided to the patient in need thereof in a sequential combination. In some embodiments, the compound of the general formula is provided to the patient in need thereof before the SHP2 inhibitor is provided to the patient in need thereof. In some embodiments, the SHP2 inhibitor is provided to the patient in need thereof before the compound of the general formula is provided to the patient in need thereof.

[0142] 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 a more preferred embodiment, the cancer is non-small cell lung cancer. In other embodiments, the cancer has one or more cancer cells expressing mutant KRas G12C protein and / or 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.

[0143] In one embodiment, the present disclosure provides a compound according to any one of Formulas I-VI or a pharmaceutically acceptable salt thereof, for simultaneous, separate or sequential combination with a SHP2 inhibitor or a pharmaceutically acceptable salt thereof for treatment. The present disclosure also provides a compound according to any one of Formulas I-VI or a pharmaceutically acceptable salt thereof, for simultaneous, separate or sequential combination with a SHP2 inhibitor or a pharmaceutically acceptable salt thereof for treating cancer. The present disclosure also provides the use of a compound according to any one of Formulas I-VI or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating cancer, wherein the medicament is combined with a SHP2 inhibitor or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially for the preparation of a medicament for treating cancer.

[0144] As used herein, the term "KRas G12Ci" may refer to a compound according to any one of Formulas I-VI, or a pharmaceutically acceptable salt thereof.

[0145] As used herein, the term "pharmaceutically acceptable salt" refers to salts of compounds that are considered useful for clinical and / or veterinary use. Examples of pharmaceutically acceptable salts and common methods for preparing them can be found in "Handbook of Pharmaceutical Salts: Properties, Selection and Use" P. Stahl et al., 2nd Edition Revised, Wiley-VCH, 2011 and SM Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Sciences, 1977, 66 (1), 1-19.

[0146] The pharmaceutical composition of the present disclosure can be prepared using pharmaceutically acceptable additives. As used herein, the term "pharmaceutically acceptable additives" of a pharmaceutical composition refers to one or more carriers, diluents and excipients, which are compatible with other additives in the composition or preparation and are harmless to the patient. Examples of pharmaceutical compositions and methods of preparing the same can be found in "Remington: The Science and Practice of Pharmacy", edited by Loyd, V. et al., 22nd edition, Mack Publishing Co., 2012. Non-limiting examples of pharmaceutically acceptable carriers, diluents and excipients include: saline, water, starch, sugar, mannitol and silicon dioxide derivatives; adhesives, such as carboxymethyl cellulose, alginate, gelatin and polyvinyl pyrrolidone; kaolin and bentonite; and polyethylene glycol.

[0147] As used herein, the term "effective amount" refers to a dosage effective in treating a disorder or disease, such as a cancerous lesion or the progression of abnormal cell growth and / or cell division. As a person skilled in the art, the attending physician can easily determine the effective amount by using conventional techniques and by observing the results obtained under similar circumstances.

[0148] The daily therapeutic dose of the compound of formula I is generally in the range of about 1 mg / day or bid to 1000 mg / day or bid, more preferably 100 mg / day or bid to 900 mg / day or bid.

[0149] The daily therapeutic dose of 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, SH 3809, HBI-2376 or ETS-001 is generally in the range of about 0.1 to about 100 mg. In some cases, dose levels below the lower end of this range may be adequate, while in other cases, 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, still larger doses may be employed. 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, the preferred dose is in the range of 1 to 80 mg; more preferably between 1 to 50 mg; more preferably between 1 to 30 mg; more preferably between 1 to 25 mg. The dose may be administered once, twice, three times or more per day. In one embodiment, TN0155 may be orally administered twice a day (BID) at a dose of 20 mg per dose. In one embodiment, the dosing regimen of TNO155 includes two weeks of daily administration followed by one week of no administration.

[0150] 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, whether other drugs are co-administered; the type of patient to be treated; the patient's size, age, and general health; the extent or stage of involvement and / or severity of the condition; the response of the individual patient; the mode of administration; the bioavailability characteristics of the administered formulation; the dosage regimen selected; and the use of other concomitant drugs.

[0151] The treating physician, veterinarian or other medical personnel will be able to determine the effective amount of the compound for treating a patient in need. Preferred pharmaceutical compositions can be prepared as tablets or capsules for oral administration, solutions for oral administration or injectable solutions. Tablets, capsules or solutions can include an effective amount of a compound of the present disclosure for treating a patient in need of cancer treatment.

[0152] As used herein, the term "treating" includes slowing, reducing or reversing the progression or severity of an existing symptom, disorder, condition, which may include specifically slowing the growth of cancerous lesions or the progression of abnormal cell growth and / or cell division.

[0153] 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, such as a cancer carrying a KRas G12C mutant.

[0154] Individual isomers, enantiomers, diastereomers and atropisomers can be separated or resolved at any convenient point in the synthesis of the following compounds, 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 Elliel 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 different rotational isomers. Atropisomers are a class of compounds that exist in different conformations that are caused by restricted rotation about a single bond. If the energy barrier to rotation about a single bond is high enough and the rate of interconversion is slow enough to allow the individual rotational isomers to be separated from each other, the atropisomers can be separated into separate chemical species. The present disclosure encompasses all isomers, enantiomers, diastereomers, and atropisomers disclosed herein or that can be prepared using the compounds disclosed herein.

[0155] Any compound of any of Formulas I-VI is readily converted to a pharmaceutically acceptable salt and can be isolated as a pharmaceutically acceptable salt. Salt formation can occur when a pharmaceutically acceptable acid is added to form an acid addition salt. Salts can also be formed simultaneously with nitrogen or oxygen deprotection, i.e., removal of protecting groups. Examples, 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).

[0156] Compounds of the present disclosure or their salts can be prepared by a variety of methods, some of which are described in the preparation examples and examples below. The specific synthesis steps of each approach can be combined in different ways, or combined with the steps of different approaches to prepare compounds or salts of the present disclosure. The products of each step in the preparation below can be recovered by conventional methods, including extraction, evaporation, precipitation, chromatography, filtration, grinding and crystallization.

[0157] Bioassay

[0158] The following assays demonstrate that combinations of exemplary compounds described herein are inhibitors of KRas G12C and can inhibit the growth of certain tumors in vitro and / or in vivo.

[0159] The statistical methods used for the in vivo model are listed below.

[0160] Tumor growth inhibition assay

[0161] Tumor volume was converted to log 10 Levels were adjusted to equalize differences between time and treatment. Log10 volume and body weight 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). The correlation of observations in the same individual over time was modeled using a Spacial Power covariance structure. Fixed effect tests were performed using the Kenward-Roger (1997) denominator degrees of freedom (DDFM) calculation. Post-hoc paired t tests were used to compare tumor volume and body weight between the treatment group and the control group on the summary day, and p values ​​≤ 0.05 were considered statistically significant. The MIXED procedure was also used for each treatment group to calculate the least squares mean (LS mean) and standard error at each time point for plotting and inclusion in the summary table.

[0162] Power calculation

[0163] If at least half of the initial subjects in the control group were still in the study, efficacy was calculated at the end of treatment. Otherwise, efficacy was calculated at the most recent observation day before the end of treatment when these conditions were met.

[0164] % Delta T / C

[0165] % Delta [T / C] is defined as 100 times the ratio of the change in tumor volume from baseline in the treatment group at time t to the change in tumor volume from baseline in the control group at time t, where t is greater than t 基线 , and the change from baseline in the treatment group is greater than zero (Equation 1)

[0166]

[0167] in,

[0168] TV t,X is the tumor volume of group X at time t, t>t 基线

[0169] ΔT t =TV t,治疗 –TV 基线 ,ΔT t >0

[0170] ΔC t =TV t,对照 –TV 基线 , ΔC t >0

[0171] TV 基线 All tumors in t 基线 The total average value of .

[0172] % Tumor Regression

[0173] % regression was defined as 100 times the ratio of the change in tumor volume from baseline in the treatment group to the baseline tumor volume at time t, where t is greater than t 基线 , and the change from baseline in the treatment group is less than or equal to zero (Equation 2)

[0174]

[0175] % Tumor Growth Inhibition (TGI)

[0176] %TGI is defined as 100 minus % variable T / C or % regression, as applicable (Equation 3)

[0177]

[0178] Combination Analysis

[0179] The effect of combination therapy on tumor volume was estimated using the Bliss independence method. Log variability of the control group, combination group, and their respective single-drug treatment groups was analyzed using RM ANOVA as described previously. 10 Tumor volume data, but with the addition of two-way interaction effect contrast estimates of the following form:

[0180] TV0-TV1-TV2+TV 1，2

[0181] Among them, TV0, TV1, TV2 and TV 1,2 is the estimated log of the control group (0), each single drug treatment group (1 or 2), and the combination treatment group (1,2) 10 Volume LS mean.

[0182] If the combined effect is completely additive, the contrast estimate equals 0. This approach is mathematically equivalent to the Bliss independence method, assuming that the tumor can theoretically reach zero (complete elimination).

[0183] If the contrast estimate is significantly different from zero (p≤0.05), then the combination effect is greater than (synergistic) or less than (antagonistic) additive if the observed combination group mean volume is less than or greater than the expected additive response (EAR) volume.

[0184]

[0185] If the interaction contrast test and all pairwise comparisons were statistically significant (p≤0.05) relative to the combination group, and the observed combined mean volume was less than the EAR volume, the combination effect was declared greater than additive (synergistic).

[0186] 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 less than additive (antagonistic) regardless of the pairwise comparison results.

[0187] If the interaction test was not statistically significant (p ≥ 0.05), but all pairwise comparisons were significant relative to the combined group (p ≤ 0.05), the combined effect was declared additive, otherwise the combined effect was indeterminate (no effect).

[0188] Combination study of KRas G12Ci and RMC-4550

[0189] The aim of this study was to evaluate the antitumor efficacy of the KRAS G12C mutation-selective inhibitor KRas G12Ci in combination with the SHP2 inhibitor RMC-4550 in human NSCLC tumor or PDX models and human CRC xenograft models, all bearing the KRAS G12C mutation.

[0190] The combination of KRAS G12CI with another SHP2 inhibitor (RMC-4550) showed strong synergy in multiple NSCLC xenograft and PDX models.

[0191] A study evaluated the combination of KRas G12Ci and 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 and the SHP2 inhibitor showed synergistic effects and significantly better antitumor effects than monotherapy. In three lung cancer models (EL3187, H358, and H1373) and the colorectal cancer SW837 model, the combination treatment had better antitumor activity and significant tumor regression.

[0192] Test product:

[0193] KRas G12Ci: 10% NMP, 90% 15% w / v PVP-VA in PEG400, administered by oral gavage (0.2 mL / animal). Add 10% of the total vehicle volume of NMP to pre-weighed test article. Mix until all test article is dissolved (no visible particles). QS with PVPVA / PEG400 vehicle and mix. Batch weekly.

[0194] SHP2 (RMC-4550): 20% Captisol (w / v) in 25 mM phosphate buffer (pH 2.0 to 2.2) administered by oral gavage (0.2 mL / animal). A portion of the vehicle (approximately 20%) was added to the test article and mixed until wet. The remaining vehicle (minus a small volume) was added and mixed. The probe was sonicated in an ice bath to reduce particle size. QS to final volume and mixed. Batches were made weekly.

[0195] Cell lines used: H358, H1373 and SW837 cells.

[0196] Table 1: Experimental design

[0197]

[0198] aIn the H358 combination treatment group, one animal was reported to be sacrificed due to moribund 3 days after dosing.

[0199] b In the H1373 vehicle group, two animals were sacrificed on treatment day 17 and one animal was sacrificed on treatment day 24 due to tumor burden; the remaining animals in the vehicle-treated group were sacrificed on day 24.

[0200] c In the RMC-4550-treated group, one animal was sacrificed on day 21 due to tumor burden.

[0201] d In the EL3187 vehicle group, three animals were sacrificed on treatment day 22 due to tumor burden.

[0202] e In the H358 and SW837 studies, n=6 for the vehicle group.

[0203] N / A, not applicable; n, number of animals in each group.

[0204] Mouse xenograft model

[0205] Female athymic nude mice (Envigo RMS, Inc., Mount Comfort, Indiana) or NOD SCIDγ mice (The Jackson Laboratory, Bar Harbor, Maine) weighing 20-22 g were used in the study. The animals were housed and had free access to a standard diet and water. For the growth of H358, H1373, and SW837 xenograft tumors, 5 × 10 6 0.2 mL Hanks' balanced salt solution (HBSS): Matrigel (Corning, Cat#354234) (1:1) per cell. H358 cells were implanted into NOD SCIDγ mice, and H1373 and SW837 cells were implanted into athymic nude mice. Tumor volume was measured twice a week using a caliper. When the tumor volume reached 200-300 mm 3At the time of administration, mice were randomly divided into groups (n=5 per group) according to tumor measurements and body weight using a multitasking block randomization tool. According to the experimental design shown in Table 1, 0.2 mL of vehicle, KRas G12Ci 10 mg / kg QD, RMC-4550 30 mg / kg QD, or a combination of 0.2 mL KRas G12Ci 10 mg / kg QD and 0.2 mL RMC-4550 30 mg / kg QD were orally administered (gavage) to start treatment for 28 days. 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 on the 17th day of treatment and one animal on the 24th day due to tumor necrosis or tumor burden, respectively; one animal in the RMC-4550 group was sacrificed on the 21st day due to tumor necrosis. Statistical analysis results were summarized at treatment day 28 for the H358 and SW837 xenograft studies and at treatment day 24 for the H1373 xenograft studies. Tumor regrowth was also monitored for 10-18 days after the last dose in the H358 and H1373 studies.

[0206] EL3187 PDX Model

[0207] EL3187 tumor fragments were obtained from the Methodist Research Institute Biorepository. Frozen vials containing tumor fragments were thawed in a 37°C water bath. The tumor fragments were transferred to a 50 mL Falcon tube and ice-cold DMEM medium was slowly added to a total volume of 35 mL. The tumor fragments were then centrifuged at 130 × g for 2 minutes at 4°C and the supernatant was aspirated. This washing step was repeated twice and the tumor fragments were resuspended in 10 mL DMEM. The tumor fragments were subcutaneously implanted into the right posterior flank of female 6-8 week old (20-22 g) athymic nude Foxn1nu fed mice (from Envigo RMS, Inc., Mount Comfort, Indiana). When the tumor volume reached 800-1000 mm 3 At 4 s, animals were sacrificed and tumors were harvested using sterile techniques. Fresh tumors (passage 4) were cut into 10-15 mm 3 The fragments were separated and placed in cold Gibco Hibernate medium, and then the pooled tumor fragments were implanted subcutaneously into the animals using a 10 g trocar. On day 24 after implantation, when the tumor size was approximately 250-350 mm 3At 4 pm, mice were randomized into groups (n=5 per group) according to the experimental design shown in Table 1. Groups of mice were administered 0.2 mL of vehicle, KRas G12Ci 3 mg / kg QD, RMC-4550 30 mg / kg QD, or a combination of 0.2 mL of KRas G12Ci 3 mg / kg QD and 0.2 mL of RMC-4550 30 mg / kg QD by oral gavage for 28 days. Tumor volume was measured using a caliper twice a week. Three of the five animals in the vehicle group were sacrificed due to tumor burden on day 46 after implantation (day 22 of treatment). The statistical analysis results of the EL3187 PDX study were summarized on day 22 of treatment. Tumor regrowth was monitored for another 30 days after the last dose.

[0208] Table 2: Tumor growth inhibitory activity of KRas G12Ci combined with SHP2 inhibitor RMC-4550 in the H358 NSCLC xenograft model

[0209]

[0210] P values ​​were estimated based on RM ANOVA post hoc paired t-tests between the vehicle group and each treatment group. Statistical analysis Results were summarized at treatment day 28, and p ≤ 0.05 was considered statistically significant. n = number of animals included in each group in the statistical analysis at day 28; N / A, not applicable; PO, oral; QD, once daily; TGI, tumor growth inhibition; SE, standard error.

[0211] Table 3: Tumor growth inhibitory activity of KRas G12Ci combined with RMC-4550 in the H1373 NSCLC xenograft model

[0212]

[0213] P values ​​were estimated based on RM ANOVA post hoc paired t-tests between the vehicle group and each treatment group.Statistical analysis Results were pooled at treatment day 24, and p≤0.05 was considered statistically significant.

[0214] n = number of animals per group included in statistical analysis at day 24; N / A, not applicable; PO, oral; QD, once daily; TGI, tumor growth inhibition; SE, standard error.

[0215] Table 4: Tumor growth inhibitory activity of KRas G12Ci combined with RMC-4550 in the SW837 CRC xenograft model

[0216]

[0217] P values ​​were estimated based on RM ANOVA post hoc paired t-tests between the vehicle group and each treatment group.Statistical analysis Results were pooled at treatment day 28, and p≤0.05 was considered statistically significant.

[0218] n = number of animals per group included in statistical analysis at day 28; N / A, not applicable; PO, oral; QD, once daily; TGI, tumor growth inhibition; SE, standard error.

[0219] Table 5: Tumor growth inhibitory activity of KRas G12Ci combined with RMC-4550 in the EL3187 NSCLC PDX model

[0220]

[0221] P values ​​were estimated based on RM ANOVA post hoc paired t-tests between the vehicle group and each treatment group.Statistical analysis Results were pooled at treatment day 22, and p≤0.05 was considered statistically significant.

[0222] n = number of animals per group included in statistical analysis at day 22; N / A, not applicable; PO, oral; QD, once daily; TGI, tumor growth inhibition; SE, standard error.

[0223] Results and Discussion

[0224] In this study, the antitumor activity of the KRAS G12C inhibitor 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 KRasG12Ci 10 mg / kg once daily (QD), RMC-4550 30 mg / kg QD, or a combination of KRasG12Ci 10 mg / kg QD and RMC-4550 30 mg / kg QD (Table 1). KRas G12Ci at 10 mg / kg QD was selected as a suboptimal dose based on preclinical efficacy studies as monotherapy in these models, while RMC-4550 at 30 mg / kg QD was selected based on publication in preclinical xenograft models.

[0225] In the H358 NSCLC xenograft model, treatment with KRas G12Ci or RMC-4550 for 28 days resulted in significant tumor growth inhibition (TGI) of 74.9% or 71.7%, respectively, while treatment with KRas G12Ci in combination with RMC-4550 for the same period resulted in significant tumor regression (TR) of 65.1% (Table 2). The antitumor activity of the dual treatment combination was significantly higher than that of either active agent alone, and the expected additive response (EAR) indicated that the combination treatment effect was synergistic in this model. Tumors continued to regress for approximately 10 days after cessation of treatment in the combination treatment group. Although no animal weight loss was observed in any treatment group, and there was no significant difference in mean body weight between any compound treatment group and the vehicle group on day 28 of treatment (Table 2), one animal in the combination treatment group was sacrificed due to moribundity 6 days after dosing.

[0226] In the H1373 NSCLC model, two animals in the vehicle group were sacrificed on days 17 and 24 of treatment, respectively, due to tumor necrosis or tumor burden; one animal in the RMC-4550 group was also sacrificed on day 21 due to tumor necrosis. Data from day 24 of treatment were selected for statistical analysis. In this model, treatment with KRas G12Ci or RMC-4550 for 24 days resulted in significant TGI of 98.5% or 80.2%, respectively, while the combination treatment resulted in a significant TR of 74% (Table 3). Although the antitumor activity of KRas G12Ci in combination with RMC-4550 was significantly higher than that of either active agent alone, the results of the combination interaction test indicated that the combination treatment effect was additive. Tumor regression in the combination treatment group continued for approximately 10 days after cessation of compound treatment. No animal weight loss was observed in any treatment group, and there was no significant difference in mean body weight between any compound treatment group and the vehicle group on day 24 of treatment (Table 3).

[0227] In the SW837 CRC model, treatment with KRas G12Ci or RMC-4550 alone for 28 days resulted in a significant TGI of 70.6% or 79.4%, respectively, while the combination treatment resulted in a significant TR of 34% (Table 4). Similar to the above results, the antitumor activity of the combination treatment was significantly higher than that of either active agent alone, and the combination treatment effect appeared to be additive. No animal weight loss was observed in any treatment group in this model, and there was no significant difference in mean body weight between the compound-treated and vehicle-treated groups on day 28 of treatment (Table 4).

[0228] Using the EL3187 NSCLC PDX model, tumor-bearing mice were treated with KRas G12Ci 3mg / kg QD, RMC-4550 30mg / kg QD, or a combination dose of KRas G12 Ci and RMC-4550 (Table 1). Based on previous preclinical efficacy studies when used as a monotherapy in this model, 3mg / kg QD of KRas G12Ci was selected as the suboptimal dose. In this study, three of the five animals in the vehicle group were sacrificed on day 46 after implantation (day 22 of treatment) due to tumor burden. Data from day 22 of treatment were selected for statistical analysis. Treatment with KRas G12Ci or RMC-4550 alone for 22 days resulted in significant TGI of 84.8% or 73.4%, respectively, while the combination treatment resulted in a significant TR of 76.2 (Table 5). The anti-tumor activity of the combination was significantly higher than that of any one active agent alone, and the EAR indicated that the combination treatment was synergistic in this model. During the treatment, no significant weight loss was observed in any of the treatment groups.

[0229] Overall, these studies showed that the dual-drug combination of KRasG12Ci and the SHP2 inhibitor RMC-4550 exhibited significantly higher antitumor activity than single agents in multiple KRAS G12C-driven tumor xenograft models. The dual-drug combination 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. In addition, with the exception of one early death reported in the H358 model after the start of the combination treatment, the combination treatment was well tolerated in all models, indicating that it may be a safe and effective treatment for clinical cancer patients.

[0230] As shown in Table 6, KRas G12Ci, TNO155, and the combination of KRas G12Ci and TNO155 were studied in a panel of cancer cell lines with KRas G12C mutations. Each cell line used for the study was seeded in a 384-well plate one day before the addition of treatment. The treatment time was 72 hours. After the treatment time was reached, 50ul CellTiter Glo was added to each well. After waiting for 15 minutes, the plate was read using EnVision. The resulting data was used to calculate the Abl IC50.

[0231] Table 6: KRas G12Ci and SHP2 (TNO155) combination data

[0232]

[0233] The combination showed strong synergy and efficacy. The combination treatment showed 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). In in vitro studies, the combination of KRas G12Ci with each of TNO155 and RMC-4550 showed similar synergy and efficacy.

Claims

1. A method for treating a cancer patient, comprising administering to a patient in need thereof an effective amount of a compound of the formula: in: 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, -C(O)C≡CR8, or a group of the formula R2 is H, methyl, or -CH2CN; R3 and R5 are each independently H, halogen, -C 0-3 Alkyl-cyclopropyl, optionally substituted by R 10 Replace 1-3 times -C 1-6 alkyl, or optionally R 10 Replace 1-3 times -OC 1-6 alkyl; R4 is H, halogen, or optionally replaced by R 10 Replace 1-3 times -C 1-6 alkyl; R6 is H or optionally replaced by R 10 Replace 1-3 times -C 1-6 alkyl; R7 is H, halogen, -NR 11 R 12 、-CH2NR 11 R 12 , optionally by R 10 or R 13 Replace 1-3 times -C 1-6 Alkyl, -C 0-3 Alkylcyclopropyl, or optionally R 10 or R 13 Replace 1-3 times -OC 1-6 alkyl; R8 is H, optionally replaced by R 10 Replace 1-3 times -C 1-4 alkyl, or optionally R 10 Replace 1-3 times -C 3-6 Cycloalkyl; R9 is H, halogen, -CN, -C 0-3 Alkyl-C 3-6 Cycloalkyl, or optionally R 10 Replace 1-3 times -C 1-6 alkyl; R 10 Each occurrence is independently halogen, oxygen, hydroxyl, -C 1-4 Alkyl or -OC 1-4 alkyl; R 11 and R 12 Each independently is H, -C 1-4 Alkyl or -C 1-4 Heteroalkyl, where R 11 and R 12 may combine to form a heterocycloalkyl group; and R 13 Each occurrence is independently -NC 1-4 alkyl, or a pharmaceutically acceptable salt thereof; and An effective amount of a SHP2 inhibitor, or a pharmaceutically acceptable salt thereof.

2. Compounds of the formula: in: 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, -C(O)C≡CR8, or a group of the formula R2 is H, methyl, or -CH2CN; R3 and R5 are each independently H, halogen, -C 0-3 Alkyl-cyclopropyl, optionally substituted by R 10 Replace 1-3 times -C 1-6 alkyl, or optionally R 10 Replace 1-3 times -OC 1-6 alkyl; R4 is H, halogen, or optionally replaced by R 10 Replace 1-3 times -C 1-6 alkyl; R6 is H or optionally replaced by R 10 Replace 1-3 times -C 1-6 alkyl; R7 is H, halogen, -NR 11 R 12 、-CH2NR 11 R 12 , optionally by R 10 or R 13 Replace 1-3 times -C 1-6 Alkyl, -C 0-3 Alkylcyclopropyl, or optionally R 10 or R 13 Replace 1-3 times -OC 1-6 alkyl; R8 is H, optionally replaced by R 10 Replace 1-3 times -C 1-4 alkyl, or optionally R 10 Replace 1-3 times -C 3-6 Cycloalkyl; R9 is H, halogen, -CN, -C 0-3 Alkyl-C 3-6 Cycloalkyl, or optionally R 10 Replace 1-3 times -C 1-6 alkyl; R 10 Each occurrence is independently halogen, oxygen, hydroxyl, -C 1-4 Alkyl or -OC 1-4 alkyl; R 11 and R 12 Each independently is H, -C 1-4 Alkyl or -C 1-4 Heteroalkyl, where R 11 and R 12 may combine to form a heterocycloalkyl group; and R 13 Each occurrence is independently -NC 1-4 alkyl, or a pharmaceutically acceptable salt thereof, for simultaneous, separate or sequential combination with a SHP2 inhibitor or a pharmaceutically acceptable salt thereof for treatment.

3. Compounds of the formula: in: 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, -C(O)C≡CR8, or a group of the formula R2 is H, methyl, or -CH2CN; R3 and R5 are each independently H, halogen, -C 0-3 Alkyl-cyclopropyl, optionally substituted by R 10 Replace 1-3 times -C 1-6 alkyl, or optionally R 10 Replace 1-3 times -OC 1-6 alkyl; R4 is H, halogen, or optionally replaced by R 10 Replace 1-3 times -C 1-6 alkyl; R6 is H or optionally replaced by R 10 Replace 1-3 times -C 1-6 alkyl; R7 is H, halogen, -NR 11 R 12 、-CH2NR 11 R 12 , optionally by R 10 or R 13 Replace 1-3 times -C 1-6 Alkyl, -C 0-3 Alkylcyclopropyl, or optionally R 10 or R 13 Replace 1-3 times -OC 1-6 alkyl; R8 is H, optionally replaced by R 10 Replace 1-3 times -C 1-4 alkyl, or optionally R 10 Replace 1-3 times -C 3-6 Cycloalkyl; R9 is H, halogen, -CN, -C 0-3 Alkyl-C 3-6 Cycloalkyl, or optionally R 10 Replace 1-3 times -C 1-6 alkyl; R 10 Each occurrence is independently halogen, oxygen, hydroxyl, -C 1-4 Alkyl or -OC 1-4 alkyl; R 11 and R 12 Each independently is H, -C 1-4 Alkyl or -C 1-4 Heteroalkyl, where R 11 and R 12 may combine to form a heterocycloalkyl group; and R 13 Each occurrence is independently -NC 1-4 alkyl, or a pharmaceutically acceptable salt thereof, for simultaneous, separate or sequential combination with a SHP2 inhibitor or a pharmaceutically acceptable salt thereof for treating cancer.

4. Use of a compound of the following formula or a pharmaceutically acceptable salt thereof in the preparation of a medicament for simultaneous, separate or sequential combination with a SHP2 inhibitor or a pharmaceutically acceptable salt thereof for the treatment of cancer: in: 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, -C(O)C≡CR8, or a group of the formula R2 is H, methyl, or -CH2CN; R3 and R5 are each independently H, halogen, -C 0-3 Alkyl-cyclopropyl, optionally substituted by R 10 Replace 1-3 times -C 1-6 alkyl, or optionally R 10 Replace 1-3 times -OC 1-6 alkyl; R4 is H, halogen, or optionally replaced by R 10 Replace 1-3 times -C 1-6 alkyl; R6 is H or optionally replaced by R 10 Replace 1-3 times -C 1-6 alkyl; R7 is H, halogen, -NR 11 R 12 、-CH2NR 11 R 12 , optionally by R 10 or R 13 Replace 1-3 times -C 1-6 Alkyl, -C 0-3 Alkylcyclopropyl, or optionally R 10 or R 13 Replace 1-3 times -OC 1-6 alkyl; R8 is H, optionally replaced by R 10 Replace 1-3 times -C 1-4 alkyl, or optionally R 10 Replace 1-3 times -C 3-6 Cycloalkyl; R9 is H, halogen, -CN, -C 0-3 Alkyl-C 3-6 Cycloalkyl, or optionally R 10 Replace 1-3 times -C 1-6 alkyl; R 10 Each occurrence is independently halogen, oxygen, hydroxyl, -C 1-4 Alkyl or -OC 1-4 alkyl; R 11 and R 12 Each independently is H, -C 1-4 Alkyl or -C 1-4 Heteroalkyl, where R 11 and R 12 may combine to form a heterocycloalkyl group; and R 13 Each occurrence is independently -NC 1-4 alkyl.

5. The method, compound or use according to any one of claims 1 to 4, wherein A is -OCH2CH2-, or a pharmaceutically acceptable salt thereof.

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

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

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

9. A method, compound or use according to any one of claims 1 to 8, wherein R1 is a radical of the formula And wherein R7 is H, F, Cl, methyl, ethoxy, ethyl, isopropyl or cyclopropyl, or a pharmaceutically acceptable salt thereof.

10. A method, compound or use according to any one of claims 1 to 8, wherein R1 is a group of the formula And wherein R9 is H, F, Cl, -CHF2, -CF3 or -CH2OH, or a pharmaceutically acceptable salt thereof.

11. The method, compound or use according to any one of claims 1 to 8, wherein R1 is -CN, -C(O)C≡CR8, or a pharmaceutically acceptable salt thereof.

12. The method, compound or use according to any one of claims 1 to 11, wherein R2 is H or methyl, or a pharmaceutically acceptable salt thereof.

13. The method, compound or use according to any one of claims 1 to 12, wherein R3 is H, F, Cl, methyl, methoxy, ethyl, isopropyl or cyclopropyl, or a pharmaceutically acceptable salt thereof.

14. The method, compound or use according to any one of claims 1 to 13, wherein R4 is H, F or Cl, or a pharmaceutically acceptable salt thereof.

15. The method, compound or use according to any one of claims 1 to 14, wherein R5 is H, -CHF2, -CH2F, -CH2OH or -CH2OCH3, or a pharmaceutically acceptable salt thereof.

16. The method, compound or use according to any one of claims 1 to 15, wherein the compound is of the formula: or a pharmaceutically acceptable salt thereof.

17. A method, compound or use according to any one of claims 1 to 16, wherein the compound is of the formula: Where R is X is Cl or F; and m is 1 or 2, or a pharmaceutically acceptable salt thereof.

18. The method, compound or use according to any one of claims 1 to 17, wherein the compound is of the formula: Where R is X is Cl or F; and m is 1 or 2, or a pharmaceutically acceptable salt thereof.

19. The method, compound or use according to any one of claims 1 to 17, wherein the compound is of the formula: in: A is -OCH2- is -OCH2CH2-; Y is C(CN) or N; R3 is Cl or F; When Y is C(CN), R4 is H or F; and When Y is N, R4 is F, or a pharmaceutically acceptable salt thereof.

20. The method, compound or use according to any one of claims 1 to 19, wherein A is 21. The method, compound or use according to any one of claims 1 to 20, wherein the compound is: or a pharmaceutically acceptable salt thereof.

22. The method, compound or use according to any one of claims 1 to 21, wherein the compound is:

23. The method, compound or use according to any one of claims 1 to 22, wherein the SHP2 inhibitor is selected from 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 pharmaceutically acceptable salt thereof.

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

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

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

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

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

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

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

31. The method, compound or use according to any one of claims 1-27, wherein the patient has a cancer having a KRASG12C mutation.

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

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

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

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

36. The method, compound or use according to any one of claims 1 to 35, wherein the compound of the formula is provided to a patient in need thereof prior to providing the SHP2 inhibitor to the patient in need thereof.

37. The method, compound or use according to any one of claims 1 to 35, wherein the SHP2 inhibitor is provided to a patient in need thereof prior to providing the compound of formula to a patient in need thereof.

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