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KR-20260066067-A - Combination therapy using KRAS modulators

KR20260066067AKR 20260066067 AKR20260066067 AKR 20260066067AKR-20260066067-A

Abstract

The present invention provides a method for treating cancer in a subject requiring cancer treatment, comprising the step of administering a therapeutically effective amount of a combination of an RTK-MAPK pathway inhibitor and a compound of formula (II) to the subject.

Inventors

  • 린 홍
  • 피트 카메론

Assignees

  • 콴타 테라퓨틱스, 인크.

Dates

Publication Date
20260512
Application Date
20240807
Priority Date
20230808

Claims (20)

  1. A method for treating cancer in a subject requiring cancer treatment, comprising the step of administering to the subject a therapeutically effective amount of a combination of an RTK-MAPK pathway inhibitor and a compound of the following formula (II) or a pharmaceutically acceptable salt thereof: In the above formula, M is selected from O, S, SO, SO2 , and NR3 ; R1 is selected from C3 - C12 carbon rings and 5- to 15-membered heterocyclic rings, each of which is a halogen, -B(OR 20 ) 2 , -OR 20 , -SR 20 , -S(O) 2 (R 20 ), -S(O) 2 N(R 20 ) 2 , -S(O)N(R 20 ) 2 , -S(O)R 20 (=NR 20 ), -NR 20 S(O) 2 R 20 , -C(O)N(R 20 ) 2 , -C(=NR 20 )N(R 20 ) 2 , -C(O)NR 20 OR 20 , -N(R 20 )C(O)R 20 , -N(R 20 )C(O)N(R 20 ) 2 , -N(R 20 )C(O)OR 20 , -N(R 20 ) 2 , -C(O)R 20 , -C(O)OR 20 , -OC(O)R 20 , -OC(O)N(R 20 ) 2 , -NO 2 , =O, =N(R 20 ), =NO(R 20 ), -CN, -NHCN, C 1-6 alkyl-N(R 20 ) 2 , C 1-6 aminoalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 cyanoalkyl, C 1-6 haloalkyl, C 1-6 alkyl-SO 2 R 20 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 -C 12 carbon ring and 5 to It is optionally substituted with one or more substituents independently selected from the 12-membered heteroring, wherein the C3 - C12 carbon ring and the 5- to 12-membered heteroring are each independently optionally substituted with one or more R1 * ; Each R 1* is a halogen, -B(OR 20 ) 2 , -OR 20 , -SR 20 , -S(O) 2 (R 20 ), -S(O) 2 N(R 20 ) 2 , -S(O)N(R 20 ) 2 , -S(O)R 20 (=NR 20 ), -NR 20 S(O) 2 R 20 , -C(O)N(R 20 ) 2 , -C(O)NR 20 OR 20 , -N(R 20 )C(O)R 20 , -N(R 20 )C(O)N(R 20 ) 2 , -N(R 20 )C(O)OR 20 , -N(R 20 ) 2 , -C(O)R 20 , Independently selected from -C(O)OR 20 , -OC(O)R 20 , -OC(O)N(R 20 ) 2 , -NO 2 , =O, =N(R 20 ), =NO(R 20 ), -CN, -NHCN, C 1-6 alkyl-N(R 20 ) 2 , C 1-6 aminoalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 cyanoalkyl, C 1-6 haloalkyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 3 -C 12 carbon rings; Y is selected from bond, O, S, and NR 5 ; R2 is selected from -LN( R21 ) 2 , -L- OR21 , heterocyclic, Cl - C6alkyl , -L-heterocyclic, -L-aryl, -L-heteroaryl, -L-cycloalkyl, -L-NHC(=NH) NH2 , -LC(O)N( R21 ) 2 , -LCl- C6haloalkyl , -L- NR21C (O)-aryl, -L-COOH, -L- NR21S (O) 2 ( R21 ), -LS(O) 2N ( R21 ) 2 , -LN( R21 )C(O)( OR21 ), -L-OC(O)N( R21 ) 2 , and -LC(=O) OCl - C6alkyl , wherein heterocyclic and -L-NR 21 The aryl portion of the C(O)-aryl, the heterocyclic portion of the -L-heterocyclic, and the cycloalkyl portion of the -L-cycloalkyl are each optionally substituted with one or more R6s , the aryl portion of the -L-aryl and the heteroaryl portion of the -L-heteroaryl are each optionally substituted with one or more R7s , and where Y is bond, O, or S, R2 is additionally selected from hydrogens; Each L is independently selected from Cl - C4 alkylenes optionally substituted with one or more substituents selected from hydroxy, Cl - C4 hydroxyalkyl, Cl- C4 alkyl, C3 - C6 carbon rings, or ternary to octary heterocyclic rings, wherein the C3 - C6 carbon rings and ternary to octary heterocyclic rings are optionally substituted with one or more substituents selected from halogen, -OH, -NO2 , =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl; Optionally, two substituents on the same carbon atom of L come together to form a C3 - C6 carbon ring or a ternary to octary heteroring, wherein the C3 - C6 carbon ring and the ternary to octary heteroring are each optionally substituted with one or more substituents selected from halogen, -OH, -NO2 , =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, and C1-6 haloalkyl; R3 is selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkyl-N( R20 ) 2 , C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkoxyalkyl, C3-12 carbon ring, and ternary to 12-membered heterocyclic rings, wherein the C3-12 carbon ring and the ternary to 12-membered heterocyclic rings are each halogen, -OH, -CN, -NO2, -NH2, -N(C1-6 alkyl)2 , C1-10 alkyl , -C1-10 haloalkyl, -OC1-10 alkyl, oxo, C3-12 carbon ring, and ternary to Randomly substituted with one or more substituents independently selected from a 12-membered heterocyclic ring; n is selected from 0 to 2; Each R4 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, oxo, hydroxyl, halogen, C3-12 carbon ring, and ternary to 12-membered heterocyclic rings, wherein C1 - C6 alkyl, C3-12 carbon ring, and ternary to 12-membered heterocyclic rings are each optionally substituted with one or more substituents independently selected from cyano, halogen, -OR5 , and -N( R5 ) 2 ; Each R5 is independently selected from hydrogen or C1 - C6 alkyl; Each R6 is a halogen, hydroxy, Cl -C3 hydroxyalkyl, Cl - C3 alkyl, oxo, Cl - C3 haloalkyl, Cl - C3 alkoxy, cyano, = CH2 , =NO- Cl - C3 alkyl, Cl -C3 aminoalkyl , -N( R5 )S(O) 2 ( R5 ), -Q-phenyl, -Q -phenylSO2F, -NHC(O)phenyl, -NHC(O)phenylSO2F, Cl - C3 alkyl -substituted pyrazolyl, tert-butyldimethylsilyloxyCH2-, -N(R5)2, (Cl-C3 alkoxy)Cl-C3 alkyl- , ( Cl - C3 alkyl )C(= O ), oxo, ( Cl - C3 Haloalkyl)C(=O)-, -SO₂F , ( C₁ - C₃alkoxy ) Cl- C₃alkoxy , -CH₂OC (O)N( R₅ ) ₂ , -CH₂NHC(O)OC₁ - C₆alkyl, -CH₂NHC (O)N( R₅ ) ₂ , -CH₂NHC(O) C₁- C₆alkyl , -CH₂ ( pyrazolyl ), -CH₂NHSO₂C₁ -C₆alkyl, -CH₂OC ( O )heterocyclic, -OC(O) N ( R₅ ) ₂ , -OC (O)NH( C₁ -C₃alkyl)O( Cl - C₃alkyl ), -OC(O)NH ( C₁ - C₃alkyl )O( Cl - C₃alkyl )phenyl( C₁ - C₃ Independently selected from alkyl)N( CH3 ) 2 , -OC(O)NH( C1 - C3alkyl )O( C1 -C3alkyl )phenyl, -OC(O)heterocyclic, -OC1- C3alkyl , and -CH2 heterocyclic, wherein the phenyl of -NHC(O)phenyl and -OC(O)NH( C1 - C3alkyl )( C1 - C3alkyl )phenyl is optionally substituted with one or more substituents selected from -C(O)H and OH, respectively, and the alkyl of -OC1 - C3alkyl is optionally substituted with a substituent selected from heterocyclic, oxo, and hydroxy; and the heterocyclic of -CH2 heterocyclic is optionally substituted with an oxo; Each Q is independently selected from the combination, S, and O; Each R7 is independently selected from halogen, hydroxy, HC(=O)-, Cl - C4 alkyl, Cl - C4 alkoxy, Cl - C4 haloalkyl, Cl - C4 hydroxyalkyl, or -N( R5 ) 2 ; Each R 20 is hydrogen; and is independently selected from C 1-6 alkyl, C 3-12 carbon ring, and ternary to 12-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO 2 , -NH 2 , -N(C 1-6 alkyl) 2 , C 1-10 alkyl, -C 1-10 haloalkyl, -OC 1-10 alkyl, oxo, =NH, C 3-12 carbon ring, and ternary to 12-membered heterocyclic rings; Each R 21 is hydrogen; and is independently selected from C 1-6 alkyl, C 3-12 carbon ring, and ternary to 12-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO 2 , -NH 2 , -N(C 1-6 alkyl) 2 , C 1-10 alkyl, -C 1-10 haloalkyl, -OC 1-10 alkyl, oxo, C 3-12 carbon ring, and ternary to 12-membered heterocyclic rings; B is selected from heterocyclic rings and carbon rings, where heterocyclic rings and carbon rings are, respectively, halogen, cyano, hydroxy, =O, -NO₂ , Cl - C₄alkyl , C₆aminoalkyl , -SC₆ -C₃alkyl, C₂ -C₄alkenyl, C₂ - C₄alkynyl , C₂ - C₄hydroxyalkynyl , C₁ - C₃cyanoalkyl, triazolyl , Cl-C₃haloalkyl, -OC₆ -C₃haloalkyl, -SC₆ - C₃haloalkyl, C₁- C₃alkoxy , Cl - C₃hydroxyalkyl , -CH₂C (=O)N( R₅ ) ₂ , -C₃ - C₄alkynyl ( NR₅ ) ₂ , -N ( R₅ ) ₂ , ( C₁ - C₃ It is optionally substituted with one or more substituents independently selected from alkoxy)halo-C l -C 3 alkyl-, C 1-6 alkyl-N(R 20 ) 2 , C 3 -C 12 carbon ring and 5- to 12 heterocyclic rings, wherein the C 3 -C 12 carbon ring and 5- to 12 heterocyclic rings are each optionally substituted with one or more substituents selected from halogen, -OH, -NO 2 , -NH 2 , =O, =S, -CN, C 1-6 alkyl-N(R 20 ) 2 , C 1-6 aminoalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 haloalkyl.
  2. In paragraph 1, the combination is a method that exhibits synergy.
  3. A method according to claim 1 or 2, wherein a therapeutically effective amount of a combination of an RTK-MAPK pathway inhibitor and a compound or salt of formula (II) results in an increase in overall survival, an increase in progression-free survival, an increase in tumor growth regression, an increase in tumor growth inhibition, an increase in disease stability, or any combination thereof, compared to treatment with the compound or salt of formula (II) alone in the subject.
  4. A method according to any one of claims 1 to 3, wherein the therapeutically effective amount of the compound or salt of formula (II) in the combination is about 0.01 to 100 mg/kg/day.
  5. A method according to any one of claims 1 to 4, wherein the therapeutically effective amount of the compound or salt of formula (II) in the combination is about 0.1 to 50 mg/kg/day.
  6. A method according to any one of claims 1 to 5, wherein the therapeutically effective amount of the RTK-MAPK pathway inhibitor in the combination is about 0.01 to 100 mg/kg/day.
  7. A method according to any one of claims 1 to 6, wherein the therapeutically effective amount of the RTK-MAPK pathway inhibitor in the combination is about 0.1 to 50 mg/kg/day.
  8. A method according to any one of claims 1 to 7, wherein the RTK-MAPK pathway inhibitor and the compound or salt of formula (II) are administered on different days.
  9. A method according to any one of claims 1 to 8, wherein the compound or salt of formula (II) is administered at the maximum tolerated dose.
  10. A method according to any one of claims 1 to 9, wherein the RTK-MAPK pathway inhibitor is administered at the maximum tolerated dose.
  11. A method according to any one of claims 1 to 10, wherein the RTK-MAPK pathway inhibitor and the compound or salt of formula (II) are each administered at the maximum tolerated dose.
  12. A method according to any one of claims 1 to 11, wherein the RTK-MAPK pathway inhibitor is a RAF-MEK-ERK pathway inhibitor.
  13. A method according to any one of claims 1 to 11, wherein the RTK-MAPK pathway inhibitor is an ERBB family inhibitor.
  14. A method according to any one of claims 1 to 13, wherein the inhibitor is selected from the group consisting of apatinib, dacomitinib, poziotinib, erlotinib, gefitinib, safitinib, taloxotinib, and cetuximab.
  15. A method in which, in any one of paragraphs 1 to 14, the inhibitor is cetuximab.
  16. A method according to any one of claims 1 to 15, wherein the RTK-MAPK pathway inhibitor is an epidermal growth factor receptor (EGFR) inhibitor.
  17. A method according to any one of claims 1 to 11, wherein the RTK-MAPK pathway inhibitor is an SHP-2 inhibitor.
  18. In paragraph 17, the SHP-2 inhibitor is SHP-099 (6-(4-amino-4-methylpiperidin-l-yl)-3-(2,3-dichlorophenyl)pyrazine-2-amine dihydrochloride); RMC-4550 (3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-6-(2,3-dichlorophenyl)-5-methylpyrazine-2-yl)methanol), RMC-4360 or TNO155 (Novartis).
  19. In paragraph 17, the method in which the SHP-2 inhibitor is RMC-4550.
  20. In paragraph 17, the method in which the SHP-2 inhibitor is RMC-4360.

Description

Combination therapy using KRAS modulators Cross-reference This application claims the benefit of U.S. Provisional Patent Application No. 63/518,177 filed on August 8, 2023, the entire contents of which are incorporated herein by reference. Background of the Invention KRAS (Kirsten Rat Sarcoma 2 Viral Oncogene Homolog), a small GTPase protein, is a member of the Ras family of cellular signaling switches that regulate the growth and survival of normal and cancer cells (see, e.g., Cully, M. and J. Downward, SnapShot: Ras Signaling. Cell, 2008. 133(7): p. 1292-1292 e1). KRAS mutations cause approximately 25% of human cancers through the abnormal regulation of the mitogen-activated protein kinase (MAPK) signaling cascade and other effector pathways (see, e.g., Stephen, A.G., et al., Dragging ras back in the ring. Cancer Cell, 2014. 25(3): p. 272-81). Although Ras has been recognized as a cancer target for about 40 years, Ras-induced cancers remain one of the most difficult cancers to treat due to their refractory nature to conventional targeted therapies. Ras, encoded by three major genes known as KRAS, NRAS, and HRAS, has the highest mutation rate among all oncogenes. All oncogeneic Ras mutations induce a transition to accumulate in an active GTP-bound state. The most commonly found Ras mutation across human tumor types is KRAS G12D (see, e.g., The AACR Project GENIE Consortium. Cancer Discovery, 2017. 7(8): p. 818-831. Dataset Version 4). Activating mutations at codon 12 inhibit the function of small GTPases in hydrolyzing GTP. This impaired regulation is essential for initiating and maintaining tumor progression. Despite extensive efforts, small molecules that block effector binding or restore GTPase-activating protein (GAP) sensitivity have not yet been identified; however, some small molecules have been discovered that block the interaction between Ras and SOS, a guanine nucleotide exchange factor (GEF) that activates Ras in the plasma membrane. It has been clinically demonstrated that the KRAS G12C mutation, the most common in lung adenocarcinoma, can be directly inhibited through covalent modification using small molecule inhibitors that anchor the protein to an inactive GDP-bound state. The KRAS G12D mutation significantly slows the intrinsic rate of GTP hydrolysis compared to G12C, consequently inducing more constitutive activation. Therefore, despite the existence of similar binding sites in the GDP state, pharmacologically targeting the inactive state appears unlikely to yield similar results for G12D. Furthermore, while cysteine present at the activating mutation site is suitable for covalent chemical reactions, aspartate does not provide a general medicinal chemical approach for selective covalent modification. To potentially exploit the property of KRAS G12D and other mutant variants to accumulate in a GTP-bound state as a vulnerability for selectively inhibiting cancer cells while preserving normal Ras function, a strategy in which small molecule inhibitors bind to the GTP state and stabilize a form unsuitable for oncogenic signaling interactions with effector proteins is highly attractive. Furthermore, it has been shown that only constitutive activation of Raf, MEK, and ERK kinases in the MAPK cascade downstream of Ras can bypass the requirement of Ras proteins in proliferation signaling (see, e.g., Drosten, M., et al., Genetic analysis of Ras signaling pathways in cell proliferation, migration and survival. EMBO J, 2010. 29(6): p. 1091-104). As all evidence suggests that MAPK signaling is essential for the growth effects of Ras in cancer, selectively inhibiting KRAS mutations in this pathway is considered an important functional indicator of the potential clinical benefit of new therapies. The compounds disclosed herein are potent inhibitors of KRas signaling and exhibit monotherapy activity to inhibit the in vitro proliferation of cell lines possessing KRas mutations or other KRas-activating genetic variants; however, the relative efficacy and/or observed maximum effect of specific KRas inhibitors may vary among KRas mutant cell lines. Although the causes for the range of efficacy and observed maximum effect are not fully understood, specific cell lines appear to possess different intrinsic resistance to mechanisms of action that bind to specific structural states of the KRAS protein. Therefore, there is a need to develop alternative approaches to maximize the efficacy, potency, therapeutic index, and/or clinical benefit of KRas inhibitors in vitro and in vivo. Due to known feedback loops in the Ras signaling pathway, upstream inhibition of RTK signaling or downstream inhibition of MAPK signaling may be required to completely block KRas mutant activity in the presence of KRas inhibitors. In one aspect, the present disclosure provides a method for treating cancer in a subject requiring cancer treatment, comprising the step of administering to the subject a therapeutically effective amount of a c