Ras inhibitors in combination therapy for use in treating cancers

Abstract

The present invention relates to methods of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of a RAS inhibitor and other therapeutic agents.

Description

-1- Case 39447 Combination therapy for treating cancers FIELD OF THE INVENTION The RAS family of oncogenes, including KRAS, NRAS, and HRAS, are among the most frequently mutated genes in human cancers, playing a pivotal role in driving tumorigenesis and resistance to various therapies [1, 2]. These genes encode small GTPases that act as molecular 5 switches, regulating cell proliferation, differentiation, and survival through the RAS-RAF-MEK- ERK signaling pathway. Mutations in RAS genes, particularly in KRAS, lead to constitutive activation of these pathways, resulting in uncontrolled cell growth and cancer progression. RAS proteins are critical regulators of several cellular processes, including growth, differentiation, and survival. When functioning normally, RAS proteins cycle between an active 10 GTP-bound state and an inactive GDP-bound state, tightly controlling downstream signaling pathways. However, mutations in RAS genes, especially in KRAS, result in the protein being locked in its active form, continuously signaling for cell proliferation and survival. This aberrant signaling is a hallmark of many cancers, including colorectal cancer (CRC), pancreatic ductal adenocarcinoma (PDAC), non-small cell lung cancer (NSCLC), and others. 15 Despite their critical role in cancer, direct targeting of RAS proteins has been notoriously challenging due to their high affinity for GTP / GDP and the lack of suitable binding pockets for small molecules. There has been significant progress in the development of RAS inhibitors as monotherapies, however the need for combination therapies was recognized to enhance their 20 efficacy. Single-agent treatments often face limitations such as the development of resistance and incomplete inhibition of the signaling pathways. Cancer cells are highly adaptive and can activate alternative pathways to bypass the inhibited RAS signaling, leading to therapeutic resistance and disease progression. Therefore, combination therapies of RAS inhibitors with other therapeutic agents were designed and tested herein to meet unmet medical needs, including 25 targeting multiple pathways simultaneously to reduce the likelihood of resistance, achieve more robust and sustained responses, and potentially lead to better clinical outcomes.-2- SUMMARY OF THE INVENTION The present invention relates to methods of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of a RAS inhibitor and a second therapeutic agent, wherein the RAS inhibitor is a compound of 5 formula (I):wherein R1is 2-oxabicyclo[2.1.1]hexanyl, 3-oxabicyclo[3.1.0]hexanyl, 10 6-bicyclo[3.1.0]hexanyl substituted twice by halogen, 6-tricyclo[3.1.1.03,6]heptanyl, C3-7cycloalkyl substituted once, twice or three times by the substituents independently selected from C1-6alkyl, C1-6alkylpyridinyl, C1-6alkylpyrimidinyl, C1-6alkyltetrazolyl, C3-7cycloalkyl, haloC1-6alkyl, halogen, halophenyl, 15 hydroxy, phenyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl and thiazolyl, or tetrahydropyranyl; R2is 1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazinyl, 3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazinyl, 20 morpholinyl, or piperazinyl unsubstituted or substituted by substituents independently selected from C1-6alkoxyC1-6alkyl, C1-6alkyl, C3-7cycloalkyl, haloC1-6alkyl, hydroxyC1-6alkyl, morpholinylC1-6alkyl, oxetanyl, oxopyrrolidinylC1-6alkyl and tetrahydrofuranyloxyC1-6alkyl;-3- R3is H or halogen; M is C1-6alkylene or O; L is C1-6alkylene, hydroxyC1-6alkylene or haloC1-6alkylene; or a pharmaceutically acceptable salt thereof. 5 BRIEF DESCRIPTION OF THE FIGURE Figure 1. Effect of Compound 1 and Erlotinib combination therapy on NCI-H2122 NSCLC model in nude mice. Figure 2. Effect of Compound 1 and Cetuximab combination therapy on PDX CRC model in nude mice. 10 Figure 3. Effect of Compound 1 and anti-VEGF Aflibercept combination therapy on LU11693 NSCLC PDX in nude mice. Figure 4. Effect of Compound 1 and anti-VEGF Bevacizumab combination therapy on CR2528 CRC PDX in nude mice. (Individual tumor growth data for Compound 1 was administered QD, anti-VEGF administered BIW, or their combination over 21 days are depicted. 15 Dose levels are expressed as free-base equivalents.) Figure 5. Effect of Compound 1 and PI3K inhibitor (Inovalisib) combination therapy on NCI-H2122 NSCLC tumor xenografts in nude mice. Figure 6. Effect of Compound 1 and PI3K inhibitor (Inovalisib) combination therapy on LS180 CRC tumor xenografts in nude mice. 20 Figure 7. Effect of Compound 1 and SWII RAS G12C inhibitor (GDC-6036) combination therapy on NCI-H2122 NSCLC tumor xenografts in nude mice. Figure 8. Effect of Compound 1 and selective RAS(ON) KRAS G12C inhibitor (Compound 2) combination therapy on NCI-H2122 NSCLC tumor xenografts in nude mice. Figure 9. Effect of Compound 1 and YAP-TEAD inhibitor (IAG933) combination therapy 25 on NCI-H2122 NSCLC tumor xenografts in nude mice. Figure 10. Effect of Compound 1 and YAP-TEAD inhibitor (IAG933) combination therapy on MKN1 gastric adenosquamous carcinoma xenografts in nude mice. Figure 11. Effect of Compound 1 and FOLFOX combination therapy on CR2528 CRC PDX in nude mice. 30 Figure 12. Effect of Compound 1 and FOLFIRI combination therapy on CR2528 CRC PDX in nude mice. Figure 13. Effect of Compound 1 and FOLFIRINOX combination therapy on PA2410 PDAC PDX in nude mice.-4- Figure 14. Effect of Compound 1 and Gemcitabine / Paclitaxel combination therapy on PA2410 PDAC PDX in nude mice. Figure 15. Effect of Compound 1 and EGFR inhibitor Osimertinib combination therapy on HCI-H1975-Osimertinib induced resistant EGFR mutant NSCLC in nude mice. 5 Figure 16. Effect of Compound 1 and anti-EGFR Cetuximab combination therapy on RAS wildtype CRC PDX model. Figure 17. Effect of Compound 1 and BRAF inhibitor Encorafenib combination therapy on BRAFV600E CRC PDX model. Figure 18. Efficacy study testing Compound 1 in combination with checkpoint inhibitor 10 (anti-muPD-1) in the CT26 colon carcinoma model. Figure 19. Efficacy study testing Compound 1 in combination with EGFR-cMET bispecific antibody Amivantamab in the CR2528 CRC model Figure 20. Efficacy study testing Compound 1 in combination with PD-1-VEGF bispecific antibody Ivonescimab in the NCI-H441 NSCLC PBMC model 15 Figure 21. Efficacy study testing Compound 1 in combination with PD-1-CTLA-4 bispecific antibody Cadonilimab in the NCI-H441 NSCLC PBMC model Figure 22. Efficacy study testing Compound 1 in combination with an-PD-1 antibody Pembrolizumab in NSCLC NCI-H358 NSCLC CDX model Figure 23. Efficacy study testing Compound 1 in combination with anti-PD-1 antibody 20 Pembrolizumab in NCI-H441 NSCLC CDX model DETAILED DESCRIPTION OF THE INVENTION DEFINITIONS The term “C1-6alkyl” denotes a saturated, linear or branched chain alkyl group containing 1 25 to 6, particularly 1 to 4 carbon atoms, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl and the like. Particular “C1-6alkyl” groups are methyl, ethyl and n-propyl. The term “C1-6alkylene” denotes a linear saturated divalent hydrocarbon group of 1 to 6 carbon atoms or a divalent-branched saturated hydrocarbon group of 3 to 6 carbon atoms. Examples of C1-6alkylene groups include methylene, ethylene, propylene, 2-methylpropylene, 30 butylene, 2-ethylbutylene, pentylene, hexylene. The term “halogen” and “halo” are used interchangeably herein and denote fluoro, chloro, bromo, or iodo.-5- The term “haloC1-6alkyl” denotes a C1-6alkyl group wherein at least one of the hydrogen atoms of the C1-6alkyl group has been replaced by same or different halogen atoms, particularly fluoro atoms. Examples of haloalkyl include monofluoro-, difluoro- or trifluoro-methyl, -ethyl or -propyl, for example 3,3,3-trifluoropropyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, fluoromethyl, or 5 trifluoromethyl. The term “haloC1-6alkylene” denotes a C1-6alkylene group wherein at least one of the hydrogen atoms of the C1-6alkylene group has been replaced by same or different halogen atoms. The term “halophenyl” denotes a phenyl group wherein at least one of the hydrogen atoms of the phenyl group has been replaced by same or different halogen atoms. 10 The term “C3-7cycloalkyl” denotes a monovalent saturated monocyclic or bicyclic hydrocarbon group of 3 to 7 ring carbon atoms. Bicyclic means consisting of two saturated carbocycles having one or more carbon atoms in common. Examples for monocyclic cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. Examples for bicyclic cycloalkyl are bicyclo[1.1.0]butyl, bicyclo[2.2.1]heptanyl, bicyclo[1.1.1]pentanyl, or 15 bicyclo[2.2.2]octanyl. “BRAF-mutant CRC” refers to colorectal cancer (CRC) that harbors mutations in the BRAF gene. These mutations lead to the activation of the MAPK / ERK signaling pathway, which promotes cell proliferation and survival. Examples of BRAF mutations include, without being limited to, the V600E mutation, which is the most common and well-studied mutation in BRAF- 20 mutant CRC. Examples of BRAF inhibitors used in the treatment of BRAF-mutant CRC include, without being limited to, vemurafenib, dabrafenib, and encorafenib. “EGFR-mutant NSCLC” refers to non-small cell lung cancer (NSCLC) that harbors mutations in the epidermal growth factor receptor (EGFR) gene. These mutations lead to the activation of the EGFR signaling pathway, which promotes cell proliferation and survival. 25 Examples of EGFR mutations include, without being limited to, exon 19 deletions, L858R point mutations in exon 21, and T790M resistance mutations in exon 20. Agents targeting (e.g. inhibiting) EGFR relate to compounds which target (e.g. inhibit) one or more members of the epidermal growth factor receptor family (erbBl, erbB2, erbB3, erbB4) and include inhibitors of one or more members of the epidermal growth factor receptor (EGFR) 30 family kinases (either as single kinase inhibitor or as multi-kinase inhibitor) as well as antibodies binding to one or more members of the epidermal growth factor receptor (EGFR) family. Examples of small molecule epidermal growth factor receptor (EGFR) inhibitors include, without being limited to, erlotinib, gefitinib, afatinib, lapatinib, vandetanib (Zactima, also-6- inhibitor of VEGFR and RETR), BMS-690514 (also an inhibitor of VEGFR), neratinib (HKI- 272), varlitinib, AZD-8931, AC-480, AEE-788 (also inhibitor of VEGFR). Examples of antibodies against the epidermal growth factor receptor (EGFR) include the anti-ErbBl antibodies cetuximab, panitumumab or nimotuzumab, the anti-ErbB2 antibodies trastuzumab, 5 pertuzumab or ertumaxomab, and the anti-EGFR antibody zalutumumab. “RAS-mutant and amplified GASC” refers to gastric cancer (GASC) that harbors mutations in the RAS gene and / or amplification of the RAS gene. These genetic alterations lead to the activation of the RAS signaling pathway, which promotes cell proliferation and survival. Examples of therapeutic approaches targeting RAS-mutant and amplified GASC include, 10 without being limited to, MEK inhibitors such as trametinib and selumetinib. “RAS-mutant CRC” refers to colorectal cancer (CRC) that harbors mutations in the RAS gene, including hotspot mutations such as G12X, G13X, and Q61X in KRAS, NRAS, and HRAS. These mutations lead to the activation of the RAS signaling pathway, which promotes cell proliferation and survival. Examples of therapeutic approaches targeting RAS-mutant CRC15 include, without being limited to, platinum-based regimen or Irinotecan-based regimen or anti- VEGF(R) antibody, and emerging RAS inhibitors like sotorasib and adagrasib. “RAS-mutant NSCLC” refers to non-small cell lung cancer (NSCLC) that harbors mutations in the RAS gene, including hotspot mutations such as G12X, G13X, and Q61X in KRAS, NRAS, and HRAS. These mutations lead to the activation of the RAS signaling pathway, 20 which promotes cell proliferation and survival. Examples of therapeutic approaches targeting RAS-mutant NSCLC include, without being limited to, emerging RAS inhibitors like sotorasib and adagrasib. “RAS-mutant PDAC” refers to pancreatic ductal adenocarcinoma (PDAC) that harbors mutations in the RAS gene, including hotspot mutations such as G12X, G13X, and Q61X in 25 KRAS, NRAS, and HRAS. These mutations lead to the activation of the RAS signaling pathway, which promotes cell proliferation and survival. The standard of care (SOC) for PDAC typically includes chemotherapy regimens based on 5-fluorouracil (5-FU) or gemcitabine. “RAS-wildtype CRC” refers to colorectal cancer (CRC) that does not have mutations in the RAS family of genes, including KRAS and NRAS. This classification is important because 30 the presence or absence of RAS mutations can influence the effectiveness of certain targeted therapies, such as anti-EGFR (epidermal growth factor receptor) monoclonal antibodies. “RAS-mutant MM” refers to multiple myeloma (MM) that harbors mutations in RAS genes, including hotspot mutations such as G12X, G13X, and Q61S in KRAS, NRAS, and-7- HRAS. These mutations lead to the activation of the RAS signaling pathway, which promotes cell proliferation and survival. The standard of care (SOC) for Multiple Myeloma (MM) includes proteasome inhibitors such as Bortezomib (Velcade), Carfilzomib (Kyprolis), and Ixazomib (Ninlaro); immunomodulatory drugs like Lenalidomide (Revlimid), Thalidomide (Thalomid), 5 and Pomalidomide (Pomalyst); monoclonal antibodies such as Daratumumab (Darzalex), Elotuzumab (Empliciti), and Isatuximab; chemotherapy agents like Cyclophosphamide and Melphalan; corticosteroids like Dexamethasone and Prednisone; and targeted therapies such as Venetoclax and Selinexor (Xpovio). Stem cell transplant is also an option for eligible patients. “RAS-mutant AML” refers to acute myeloid leukemia (AML) that harbors mutations in 10 RAS genes, such as KRAS or NRAS. These mutations are commonly found in AML and are associated with the activation of the RAS / MAPK signaling pathway, which promotes cell proliferation, survival, and resistance to therapies. The standard of care for Multiple Myeloma (MM) includes proteasome inhibitors such as Bortezomib (Velcade), Carfilzomib (Kyprolis), and Ixazomib (Ninlaro); immunomodulatory drugs like Lenalidomide (Revlimid), Thalidomide 15 (Thalomid), and Pomalidomide (Pomalyst); monoclonal antibodies such as Daratumumab (Darzalex), Elotuzumab (Empliciti), and Isatuximab; chemotherapy agents like Cyclophosphamide, Melphalan, and Doxorubicin; corticosteroids like Dexamethasone and Prednisone; targeted therapies such as Venetoclax and Selinexor (Xpovio) for specific genetic subtypes; and stem cell transplantation for eligible patients, along with supportive care measures 20 such as Zoledronic Acid or Denosumab for bone health. “5-FU-based regimen” refers to a chemotherapy treatment plan that includes the drug 5- fluorouracil (5-FU) as a key component.5-FU is an antimetabolite that interferes with the synthesis of DNA and RNA, thereby inhibiting cancer cell growth and proliferation. A 5-FU- based regimen typically comprises several drugs used in combination to enhance therapeutic 25 efficacy and manage colorectal cancer. Common 5-FU-based regimens include FOLFOX (5-FU, leucovorin, and oxaliplatin), FOLFIRI (5-FU, leucovorin, and irinotecan), CAPOX (or XELOX, which combines capecitabine, an oral prodrug of 5-FU, with oxaliplatin), and FOLFOXIRI (5- FU, leucovorin, oxaliplatin, and irinotecan). These regimens are used to treat various stages of colorectal cancer, either as adjuvant therapy (post-surgery to eliminate residual cancer cells) or 30 for metastatic disease (to control cancer spread and improve survival). The choice of regimen depends on multiple factors, including the patient's overall health, cancer stage, and specific genetic characteristics of the tumor.-8- “Gemcitabine-based regimen” refers to a chemotherapy treatment plan that includes the drug gemcitabine as a key component. Gemcitabine is a nucleoside analog that interferes with DNA synthesis, thereby inhibiting cancer cell growth and inducing apoptosis. A gemcitabine- based regimen typically comprises gemcitabine in combination with other chemotherapeutic 5 agents to enhance therapeutic efficacy and manage various types of cancer. Common gemcitabine-based regimens include Gemcitabine and Cisplatin, often used to treat advanced or metastatic non-small cell lung cancer (NSCLC) and bladder cancer; Gemcitabine and Carboplatin, used for NSCLC and ovarian cancer; Gemcitabine and Paclitaxel, commonly used for metastatic breast cancer; and Gemcitabine and Nab-Paclitaxel, used for metastatic pancreatic 10 cancer. “Platinum-based regimen” refers to a chemotherapy treatment plan that includes a platinum-containing drug as a key component. Platinum-based drugs, such as cisplatin, carboplatin, and oxaliplatin, work by forming DNA crosslinks, which inhibit DNA replication and transcription, ultimately leading to cancer cell death. A platinum-based regimen typically 15 comprises a platinum drug in combination with other chemotherapeutic agents to enhance therapeutic efficacy and manage various types of cancer. Common platinum-based regimens include Cisplatin and Etoposide, often used to treat small cell lung cancer (SCLC) and testicular cancer; Carboplatin and Paclitaxel, commonly used for ovarian cancer, non-small cell lung cancer (NSCLC), and breast cancer; Oxaliplatin and 5-FU / Leucovorin (FOLFOX), used for 20 colorectal cancer; and Cisplatin and Gemcitabine, used for bladder cancer, NSCLC, and pancreatic cancer. “Irinotecan-based regimen” refers to a chemotherapy treatment plan that includes the drug irinotecan (“IRI”) as a key component. Irinotecan is a topoisomerase I inhibitor that prevents DNA unwinding and replication, leading to DNA damage and cancer cell death. An irinotecan- 25 based regimen typically comprises irinotecan in combination with other chemotherapeutic agents to enhance therapeutic efficacy and manage various types of cancer. Common irinotecan-based regimens include FOLFIRI, which includes irinotecan, 5-fluorouracil (5-FU), and leucovorin, and is commonly used to treat metastatic colorectal cancer; IRI and Cetuximab, which combines irinotecan with cetuximab, an anti-EGFR monoclonal antibody, for metastatic colorectal cancer, 30 particularly in patients with RAS-wildtype tumors; IRI and Bevacizumab, which combines irinotecan with bevacizumab, an anti-VEGF monoclonal antibody, to inhibit angiogenesis and tumor growth in metastatic colorectal cancer; and IRI and Capecitabine (XELIRI), which includes irinotecan and capecitabine, an oral prodrug of 5-FU, for metastatic colorectal cancer.-9- In some embodiments, angiogenesis inhibitors are agents targeting (e.g. inhibiting) vascular endothelial growth factor (VEGF) or VEGF receptor (VEGFR). Agents targeting (e.g. inhibiting) VEGF / VEGFR relate to compounds which target (e.g. inhibit) one or more members of the VEGF or VEGFR family (VEGFR1, VEGFR2, VEGFR3) and include inhibitors of any 5 vascular endothelial growth factor (VEGF) ligand (such as e.g. ligand antibodies or soluble receptors) as well as inhibitors of any VEGF receptor (VEGFR) (such as e.g. VEGFR tyrosin kinase inhibitors, VEGFR antagonists or receptor antibodies). Examples of small molecule VEGFR inhibitors include, without being limited to, sorafenib (Nexavar, also an inhibitor of Raf, PDGFR, Flt3, Kit and RETR), sunitinib (Sutent, also inhibitor of Kit, Flt3 and PDGFR), 10 pazopanib (GW-786034, also inhibitor of Kit and PDGFR), cediranib (Recentin, AZD-2171), axitinib (AG-013736, also inhibitor of PDGFR and Kit), vandetanib (Zactima, ZD-6474, also inhibitor of EGFR and Ret), vatalanib (also inhibitor of PDGFR and Kit), motesanib (AMG-706, also inhibitor of PDGFR and Kit), brivanib (also FGFR inhibitor), linifanib (ABT-869, also inhibitor of PDGFR, Flt3 and Kit), tivozanib (KRN-951, also inhibitor of PDGFR, Kit, and 15 MAP), BMS-690514 (also and inhibitor of EGFR and HER-2), E-7080 (also inhibitor of Kit and Kdr), regorafenib (BAY-73-4506, also inhibitor of Tek), fbretinib (XL-880, also inhibitor of Flt3, Kit and Met), telatinib (BAY-57-9352), MGCD-265 (also inhibitor of c-MET, Tie2 and Ron), dovitinib (also inhibitor of PDGFR, Flt3, Kit and FGFR), nintedanib (also inhibitor of FGFR and PDGFR), XL-184 (cabozantinib, also inhibitor of Met, Flt3, Ret, Tek and Kit). 20 Examples of biological entities inhibiting VEGF(R) include, without being limited to, anti- VEGF ligand antibodies such as bevacizumab (Avastin); soluble receptors such as aflibercept (VEGF-Trap); anti-VEGF receptor antibodies such as ramucirumab (IMC-1121b) or IMC-18Fl; VEGFR antagonists such as CT-322 or CDP-791. In some embodiments, the PD-1 inhibitor or PD-L1 inhibitor is an anti-PD-1 antibody. In 25 some embodiments, the anti-PD-1 antibody is selected from the group consisting of zimberelimab, pembrolizumab, nivolumab, cemiplimab, pidilizumab, MEDI0680, spartalizumab, tislelizumab, toripalimab, genolimzumab, camrelizumab, sintilimab, dostarlimab, sasanlimab, cetrelimab, serplulimab, balstilimab, prolgolimab, budigalimab, vopratelimab, AK-105, CS- 1003, BI-754091, LZM-009, Sym-021, BAT-1306, PD-1-PIK, tebotelimab (PD-l / LAG-3), RG-30 6139 (PD-l / LAG-3), FS-118 (LAG-3 / PD-L1), RO-7121661 (PD-l / TIM-3), RG7769 (PD-l / TIM- 3), TAK-252 (PD-1 / OX40L), PF-06936308 (PD-1 / CTLA4), PF-06801591, MGD-019 (PD- 1 / CTLA4), KN-046 (PD-1 / CTLA4), XmAb-20717 (PD-1 / CTLA4), AK-104 (CTLA4 / PD-1), and MEDI-5752 (CTLA4 / PD-1). In some embodiments, the anti-PD-1 antibody is-10- zimberelimab.

[0029] In some embodiments, the PD-1 inhibitor or PD-L1 inhibitor is an anti-PD- L1 antibody. In some embodiments, the PD-L1 inhibitor is selected from the group consisting of atezolizumab, avelumab, envafolimab, durvalumab, cosibelimab, lodapolimab, garivulimab, envafolimab, opucolimab, manelimab, CX-072, CBT-502, MSB-2311, SHR-1316, sugemalimab, 5 A167, STI-A1015, FAZ-053, BMS-936559, INCB086550, GEN-1046 (PD-L1 / 4-1BB), FPT-155 (CTLA4 / PD-L1 / CD28), bintrafusp alpha (M7824; PD-L1 / TGβ-EC domain), CA-170 (PD- L1 / VISTA), CDX-527 (CD27 / PD-L1), LY-3415244 (TIM-3 / PDL1), INBRX-105 (4- 1BB / PDL1), MAX10181 and GNS-1480 (PD-L1 / EGFR). Phosphoinositide 3-kinase (PI3K) inhibitors are a class of medicines that have been 10 developed to inhibit one or more of the phosphoinositide 3-kinase enzymes. These enzymes form part of the PI3K / AKT / mTOR pathway, which is a pathway involved in cell growth and survival, as well as several other processes that are frequently activated in many cancers. Examples of PI3K inhibitors include, without being limited to, alpelisib, idelalisib, alpelisib, leniolisib, duvelisib, copanlisib, umbralisib and inavolisib. 15 “YAP-TEAD inhibitor” refers to a class of medicines inhibiting the interaction between the transcription coactivator yes-associated protein 1 (YAP) and the transcription factor TEAD (TEA domain), with antineoplastic activity. Examples of YAP-TEAD inhibitor include, without being limited to, IAG933. PKMYT1 is a regulator of CDK1 phosphorylation and is a compelling therapeutic target 20 for the treatment of certain types of DNA damage response cancers due to its established synthetic lethal relationship with CCNE1 amplification. Examples of PKMYT1 inhibitor include, without being limited to, RP-6306. Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that exhibits high expression in various tumors and is associated with a poor prognosis. FAK activation promotes25 tumor growth, invasion, metastasis, and angiogenesis via both kinase-dependent and kinase- independent pathways. Examples of FAK inhibitor include, without being limited to, IN10018, defactinib, ifebemtinib, GSK2256098, conteltinib, and APG-2449. Polo-like kinase 1 (PLK1) is the principle member of the well conserved serine / threonine kinase family. PLK1 has a key role in the progression of mitosis and recent evidence suggest its 30 important involvement in regulating the G2 / M checkpoint, in DNA damage and replication stress response, and in cell death pathways. Examples of PLK1 inhibitor include, without being limited to, BI2536, volasertib, onvansertib, GSK461364, TAK960, and rigosertib.-11- "MEK / RAF inhibitor" refers to a type of targeted cancer therapy that blocks the activity of both MEK and RAF proteins, which are key components of the RAS / RAF / MEK / ERK signaling pathway. This pathway is crucial for cell division, differentiation, and survival, and its dysregulation is often implicated in various cancers. A specific MEK / RAF dual inhibitor is VS- 5 6766 (also known as CH5126766). VS-6766 is designed to block the aberrant signaling caused by mutations in the RAS or RAF genes, thereby inhibiting cancer cell growth and proliferation. VS-6766 employs a unique "clamp mechanism" that stabilizes the inactive forms of both MEK and RAF, preventing their activation and subsequent signaling through the pathway. This dual inhibition can be particularly effective in cancers where both MEK and RAF pathways are 10 dysregulated. "PD-1-CTLA-4 bispecific antibody" refers to an immunotherapy that simultaneously targets both PD-1 (programmed cell death protein-1) and CTLA-4 (cytotoxic T-lymphocyte- associated protein-4), two critical immune checkpoint proteins that suppress the immune response. Cancer cells often exploit these checkpoints to evade immune detection. By blocking 15 both PD-1 and CTLA-4, this therapy enhances T-cell activation and restores the immune system's ability to recognize and attack cancer cells. A notable example is Cadonilimab (AK104), which combines the benefits of PD-1 and CTLA-4 inhibition in a single molecule, potentially reducing immune suppression more effectively than monotherapies targeting either checkpoint alone. This dual-targeting approach improves T-cell activation and proliferation 20 while addressing redundant immune escape pathways, making it particularly effective in cancers where immune evasion is a key factor. “PD-1-VEGF bispecific antibody” is an immunotherapy designed to simultaneously target PD-1and VEGF (vascular endothelial growth factor), combining immune checkpoint inhibition with anti-angiogenesis. By blocking PD-1, it restores T-cell activity, enhancing the immune 25 system's ability to recognize and attack cancer cells, while targeting VEGF disrupts tumor angiogenesis, cutting off the blood supply critical for tumor growth and spread. A notable example is Ivonescimab (AK112), which enhances antitumor immunity while reducing tumor vascularization, providing a synergistic effect. This dual mechanism is particularly promising for tumors where both immune evasion and angiogenesis are key drivers of progression, offering a 30 potentially more effective therapeutic approach compared to targeting each pathway individually. “EGFR-cMET bispecific antibody” is a targeted therapy designed to simultaneously inhibit EGFR (epidermal growth factor receptor) and cMET (mesenchymal-epithelial transition factor),-12- two critical drivers of tumor growth, survival, and resistance to therapy. EGFR is frequently overexpressed or mutated in various cancers, promoting cell proliferation, while cMET is associated with tumor invasion, metastasis, and resistance to EGFR-targeted therapies. By blocking both pathways, an EGFR-cMET bispecific antibody aims to overcome pathway 5 redundancy and crosstalk, which often lead to treatment resistance. A notable example is Amivantamab (Rybrevant), approved for non-small cell lung cancer (NSCLC) with EGFR exon 20 insertion mutations. This therapy inhibits ligand binding and receptor activation for both EGFR and cMET, leading to reduced tumor cell proliferation and survival while enhancing receptor degradation. It is particularly effective in cancers driven by EGFR mutations and cMET 10 dysregulation. In some embodiments, the solid tumor is located in or arising from a tissue or organ selected from the group consisting of: • bone (e.g., adamantinoma, aneurysmal bone cysts, angiosarcoma, chondroblastoma, chondroma, chondromyxoid fibroma, chondrosarcoma, chordoma, dedifferentiated 15 chondrosarcoma, enchondroma, epithelioid hemangioendothelioma, fibrous dysplasia of the bone, giant cell tumor of bone, haemangiomas and related lesions, osteoblastoma, osteochondroma, osteosarcoma, osteoid osteoma, osteoma, periosteal chondroma, Desmoid tumor, Ewing sarcoma); • lips and oral cavity (e.g., odontogenic ameloblastoma, oral leukoplakia, oral squamous 20 cell carcinoma, primary oral mucosal melanoma); salivary glands (e.g., pleomorphic salivary gland adenoma, salivary gland adenoid cystic carcinoma, salivary gland mucoepidermoid carcinoma, salivary gland Warthin's tumors); • esophagus (e.g., Barrett's esophagus, dysplasia and adenocarcinoma); • gastrointestinal tract, including stomach (e.g., gastric adenocarcinoma, primary gastric 25 lymphoma, gastrointestinal stromal tumors (GISTs), metastatic deposits, gastric carcinoids, gastric sarcomas, neuroendocrine carcinoma, gastric primary squamous cell carcinoma, gastric adenoacanthomas), intestines and smooth muscle (e.g., intravenous leiomyomatosis), colon (e.g., colorectal adenocarcinoma), rectum, anus; • pancreas (e.g., serous neoplasms, including microcystic or macrocystic serous 30 cystadenoma, solid serous cystadenoma, Von Hippel-Landau (VHL)-associated serous cystic neoplasm, serous cystadenocarcinoma; mucinous cystic neoplasms (MCN), intraductal papillary mucinous neoplasms (IPMN), intraductal oncocytic papillary neoplasms (IOPN), intraductal tubular neoplasms, cystic acinar neoplasms, including acinar cell cystadenoma, acinar cell-13- cystadenocarcinoma, pancreatic adenocarcinoma, invasive pancreatic ductal adenocarcinomas, including tubular adenocarcinoma, adenosquamous carcinoma, colloid carcinoma, medullary carcinoma, hepatoid carcinoma, signet ring cell carcinoma, undifferentiated carcinoma, undifferentiated carcinoma with osteoclast-like giant cells, acinar cell carcinoma, neuroendocrine 5 neoplasms, neuroendocrine microadenoma, neuroendocrine tumors (NET), neuroendocrine carcinoma (NEC), including small cell or large cell NEC, insulinoma, gastrinoma, glucagonoma, serotonin-producing NET, somatostatinoma, VIPoma, solid-pseudopapillary neoplasms (SPN), pancreatoblastoma); • gall bladder (e.g., carcinoma of the gallbladder and extrahepatic bile ducts, intrahepatic 10 cholangiocarcinoma); • neuro-endocrine (e.g., adrenal cortical carcinoma, carcinoid tumors, phaeochromocytoma, pituitary adenomas); • thyroid (e.g., anaplastic (undifferentiated) carcinoma, medullary carcinoma, oncocytic tumors, papillary carcinoma, adenocarcinoma); 15 • liver (e.g., adenoma, combined hepatocellular and cholangiocarcinoma, fibrolamellar carcinoma, hepatoblastoma, hepatocellular carcinoma, mesenchymal, nested stromal epithelial tumor, undifferentiated carcinoma; hepatocellular carcinoma, intrahepatic cholangiocarcinoma, bile duct cystadenocarcinoma, epithelioid hemangioendothelioma, angiosarcoma, embryonal sarcoma, rhabdomyosarcoma, solitary fibrous tumor, teratoma, York sac tumor, carcinosarcoma, 20 rhabdoid tumor); • kidney (e.g., ALK-rearranged renal cell carcinoma, chromophobe renal cell carcinoma, clear cell renal cell carcinoma, clear cell sarcoma, metanephric adenoma, metanephric adenofibroma, mucinous tubular and spindle cell carcinoma, nephroma, nephroblastoma (Wilms tumor), papillary adenoma, papillary renal cell carcinoma, renal oncocytoma, renal cell 25 carcinoma, succinate dehydrogenase-deficient renal cell carcinoma, collecting duct carcinoma); • breast (e.g., invasive ductal carcinoma, including without limitation, acinic cell carcinoma, adenoid cystic carcinoma, apocrine carcinoma, cribriform carcinoma, glycogen- rich / clear cell, inflammatory carcinoma, lipid-rich carcinoma, medullary carcinoma, metaplastic carcinoma, micropapillary carcinoma, mucinous carcinoma, neuroendocrine carcinoma, 30 oncocytic carcinoma, papillary carcinoma, sebaceous carcinoma, secretory breast carcinoma, tubular carcinoma; lobular carcinoma, including without limitation, pleomorphic carcinoma, signet ring cell carcinoma); • peritoneum (e.g., mesothelioma; primary peritoneal cancer);-14- • female sex organ tissues, including ovary (e.g., choriocarcinoma, epithelial tumors, germ cell tumors, sex cord-stromal tumors), Fallopian tubes (e.g., serous adenocarcinoma, mucinous adenocarcinoma, endometrioid adenocarcinoma, clear cell adenocarcinoma, transitional cell carcinoma, squamous cell carcinoma, undifferentiated carcinoma, Müllerian tumors, 5 adenosarcoma, leiomyosarcoma, teratoma, germ cell tumors, choriocarcinoma, trophoblastic tumors), uterus (e.g., carcinoma of the cervix, endometrial polyps, endometrial hyperplasia, intraepithelial carcinoma (EIC), endometrial carcinoma (e.g., endometrioid carcinoma, serous carcinoma, clear cell carcinoma, mucinous carcinoma, squamous cell carcinoma, transitional carcinoma, small cell carcinoma, undifferentiated carcinoma, mesenchymal neoplasia), 10 leiomyoma (e.g., endometrial stromal nodule, leiomyosarcoma, endometrial stromal sarcoma (ESS), mesenchymal tumors), mixed epithelial and mesenchymal tumors (e.g., adenofibroma, carcinofibroma, adenosarcoma, carcinosarcoma (malignant mixed mesodermal sarcoma - MMMT)), endometrial stromal tumors, endometrial malignant mullerian mixed tumors, gestational trophoblastic tumors (partial hydatiform mole, complete hydatiform mole, invasive 15 hydatiform mole, placental site tumor)), vulva, vagina; • male sex organ tissues, including prostate, testis (e.g., germ cell tumors, spermatocytic seminoma), penis; • bladder (e.g., squamous cell carcinoma, urothelial carcinoma, bladder urothelial carcinoma); 20 • brain, (e.g., gliomas (e.g., astrocytomas, including non-infiltrating, low-grade, anaplastic, glioblastomas; oligodendrogliomas, ependymomas), meningiomas, gangliogliomas, schwannomas (neurilemmomas), craniopharyngiomas, chordomas, Non-Hodgkin lymphomas (NHLs), indolent non-Hodgkin’s lymphoma (iNHL), refractory iNHL, pituitary tumors; • eye (e.g., retinoma, retinoblastoma, ocular melanoma, posterior uveal melanoma, iris 25 hamartoma); • head and neck (e.g., nasopharyngeal carcinoma, Endolymphatic Sac Tumor (ELST), epidermoid carcinoma, laryngeal cancers including squamous cell carcinoma (SCC) (e.g., glottic carcinoma, supraglottic carcinoma, subglottic carcinoma, transglottic carcinoma), carcinoma in situ, verrucous, spindle cell and basaloid SCC, undifferentiated carcinoma, laryngeal 30 adenocarcinoma, adenoid cystic carcinoma, neuroendocrine carcinomas, laryngeal sarcoma), head and neck paragangliomas (e.g., carotid body, jugulotympanic, vagal); • thymus (e.g., thymoma); • heart (e.g., cardiac myxoma);-15- • lung (e.g., small cell carcinoma (SCLC), non-small cell lung carcinoma (NSCLC), including squamous cell carcinoma (SCC), adenocarcinoma and large cell carcinoma, carcinoids (typical or atypical), carcinosarcomas, pulmonary blastomas, giant cell carcinomas, spindle cell carcinomas, pleuropulmonary blastoma); 5 • central nervous system (CNS) (e.g., gliomas including astrocytic tumors (e.g., pilocytic astrocytoma, pilomyxoid astrocytoma, subependymal giant cell astrocytoma, pleomorphic xanthoastrocytoma, diffuse astrocytoma, fibrillary astrocytoma, gemistocytic astrocytoma, protoplasmic astrocytoma, anaplastic astrocytoma, glioblastoma (e.g., giant cell glioblastoma, gliosarcoma, glioblastoma multiforme) and gliomatosis cerebri), oligodendroglial tumors (e.g., 10 oligodendroglioma, anaplastic oligodendroglioma), oligoastrocytic tumors (e.g., oligoastrocytoma, anaplastic oligoastrocytoma), ependymal tumors (e.g., subependymom, myxopapillary ependymoma, ependymomas (e.g., cellular, papillary, clear cell, tanycytic), anaplastic ependymoma), optic nerve glioma, and non- gliomas (e.g., choroid plexus tumors, neuronal and mixed neuronal-glial tumors, pineal region tumors, embryonal tumors, 15 medulloblastoma, meningeal tumors, primary CNS lymphomas, germ cell tumors, Pituitary adenomas, cranial and paraspinal nerve tumors, stellar region tumors); neurofibroma, meningioma, peripheral nerve sheath tumors, peripheral neuroblastic tumors (including without limitation neuroblastoma, ganglioneuroblastoma, ganglioneuroma), trisomy 19 ependymoma); • neuroendocrine tissues (e.g., paraganglionic system including adrenal medulla 20 (pheochromocytomas) and extra-adrenal paraganglia ((extra-adrenal) paragangliomas); • skin (e.g., clear cell hidradenoma, cutaneous benign fibrous histiocytomas, cylindroma, hidradenoma, melanoma (including cutaneous melanoma, mucosal melanoma), pilomatricoma, Spitz tumors); and • soft tissues (e.g., aggressive angiomyxoma, alveolar rhabdomyosarcoma, alveolar soft 25 part sarcoma, angiofibroma, angiomatoid fibrous histiocytoma, synovial sarcoma, biphasic synovial sarcoma, clear cell sarcoma, dermatofibrosarcoma protuberans, desmoid-type fibromatosis, small round cell tumor, desmoplastic small round cell tumor, elastofibroma, embryonal rhabdomyosarcoma, Ewing's tumors / primitive neurectodermal tumors (PNET), extraskeletal myxoid chondrosarcoma, extraskeletal osteosarcoma, paraspinal sarcoma, 30 inflammatory myofibroblastic tumor, lipoblastoma, lipoma, chondroid lipoma, liposarcoma / malignant lipomatous tumors, liposarcoma, myxoid liposarcoma, fibromyxoid sarcoma, lymphangioleiomyoma, malignant myoepithelioma, malignant melanoma of soft parts, myoepithelial carcinoma, myoepithelioma, myxoinflammatory fibroblastic sarcoma,-16- undifferentiated sarcoma, pericytoma, rhabdomyosarcoma, non- rhabdomyosarcoma soft tissue sarcoma (NRSTS), soft tissue leiomyosarcoma, undifferentiated sarcoma, well-differentiated liposarcoma. In some embodiments, the hematological malignancies are located in or arise from a tissue 5 or organ selected from the group consisting of blood, bone marrow, lymph nodes, spleen, thymus, and other lymphoid or hematopoietic tissues. The hematological malignancies include, but are not limited to, various types of leukemia such as acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), acute promyelocytic leukemia (APL), chronic myelomonocytic leukemia 10 (CMML), hairy cell leukemia (HCL), large granular lymphocytic leukemia (LGLL), and mast cell leukemia (MCL); various types of lymphoma such as Hodgkin lymphoma (HL) and non- Hodgkin lymphomas (NHL) including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), Burkitt lymphoma (BL), peripheral T-cell lymphoma (PTCL), anaplastic large cell lymphoma (ALCL), 15 cutaneous T-cell lymphomas (CTCL) such as mycosis fungoides (MF) and Sézary syndrome (SS), small lymphocytic lymphoma (SLL), and Waldenström macroglobulinemia (WM); plasma cell neoplasms such as multiple myeloma (MM), plasmacytoma, monoclonal gammopathy of undetermined significance (MGUS), and primary amyloidosis (AL); myelodysplastic syndromes (MDS); myeloproliferative neoplasms (MPN) such as polycythemia vera (PV), essential 20 thrombocythemia (ET), primary myelofibrosis (PMF), chronic eosinophilic leukemia (CEL), and chronic neutrophilic leukemia (CNL); mast cell neoplasms such as systemic mastocytosis (SM), cutaneous mastocytosis (CM), mast cell leukemia (MCL), and mast cell sarcoma (MCS); as well as histiocytic and dendritic cell neoplasms such as Langerhans cell histiocytosis (LCH) and blastic plasmacytoid dendritic cell neoplasm (BPDCN). 25 As used herein, the term “subject” refers to any animal, including mammals such as mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, primates, and humans. In some embodiments, the patient is a human. In some embodiments, the subject has experienced and / or exhibited at least one symptom of the disease or disorder to be treated and / or prevented. The term “pharmaceutically acceptable salts” denotes salts which are not biologically or 30 otherwise undesirable. Pharmaceutically acceptable salts include both acid and base addition salts. The term “pharmaceutically acceptable acid addition salt” denotes those pharmaceutically acceptable salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid,-17- sulfuric acid, nitric acid, carbonic acid, phosphoric acid, and organic acids selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, maloneic acid, succinic acid, fumaric 5 acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, embonic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicyclic acid. The term “pharmaceutically acceptable base addition salt” denotes those pharmaceutically acceptable salts formed with an organic or inorganic base. Examples of acceptable inorganic 10 bases include sodium, potassium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Salts derived from pharmaceutically acceptable organic nontoxic bases includes salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, 15 ethanolamine, 2-diethylaminoethanol, trimethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperizine, piperidine, N-ethylpiperidine, and polyamine resins. The term “therapeutically effective amount” denotes an amount of a compound or 20 molecule of the present invention that, when administered to a subject, (i) treats or prevents the particular disease, condition or disorder, (ii) attenuates, ameliorates or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition or disorder described herein. The therapeutically effective amount will vary depending on the compound, the disease state being 25 treated, the severity of the disease treated, the age and relative health of the subject, the route and form of administration, the judgement of the attending medical or veterinary practitioner, and other factors. The term “pharmaceutical composition” denotes a mixture or solution comprising a therapeutically effective amount of an active pharmaceutical ingredient together with 30 pharmaceutically acceptable excipients to be administered to a mammal, e.g., a human in need thereof. The terms “pharmaceutically acceptable excipient”, “pharmaceutically acceptable carrier” and “therapeutically inert excipient” can be used interchangeably and denote any-18- pharmaceutically acceptable ingredient in a pharmaceutical composition having no therapeutic activity and being non-toxic to the subject administered, such as disintegrators, binders, fillers, solvents, buffers, tonicity agents, stabilizers, antioxidants, surfactants, carriers, diluents or lubricants used in formulating pharmaceutical products. 5 COMBINATION THERAPIES In one embodiment of the invention, provided herein is (i) a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of a RAS inhibitor and a second therapeutic agent, wherein the RAS inhibitor is a compound of formula (I): 10, wherein R1is 2-oxabicyclo[2.1.1]hexanyl, 3-oxabicyclo[3.1.0]hexanyl, 6-bicyclo[3.1.0]hexanyl substituted twice by halogen, 15 6-tricyclo[3.1.1.03,6]heptanyl, C3-7cycloalkyl substituted once, twice or three times by the substituents independently selected from C1-6alkyl, C1-6alkylpyridinyl, C1-6alkylpyrimidinyl, C1-6alkyltetrazolyl, C3-7cycloalkyl, haloC1-6alkyl, halogen, halophenyl, hydroxy, phenyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl and thiazolyl, 20 or tetrahydropyranyl; R2is 1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazinyl, 3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazinyl,-19- morpholinyl, or piperazinyl unsubstituted or substituted by substituents independently selected from C1-6alkoxyC1-6alkyl, C1-6alkyl, C3-7cycloalkyl, haloC1-6alkyl, hydroxyC1-6alkyl, morpholinylC1-6alkyl, oxetanyl, oxopyrrolidinylC1-6alkyl and 5 tetrahydrofuranyloxyC1-6alkyl; R3is H or halogen; M is C1-6alkylene or O; L is C1-6alkylene, hydroxyC1-6alkylene or haloC1-6alkylene; or a pharmaceutically acceptable salt thereof. 10 A further embodiment of present invention is (ii) the method according to (i), wherein theacceptable salt thereof. A further embodiment of present invention is (iii) the method according to (i) or (ii), wherein the cancer is selected from a group consisting of BRAF-mutant CRC, EGFR-mutant15 NSCLC, RAS-mutant and amplified GASC, RAS-mutant CRC, RAS-mutant NSCLC, RAS- mutant PDAC, RAS-mutant solid tumor, and RAS-wildtype CRC; wherein the solid tumor is selected from a group consisting of melanoma, SCLC, gastric cancer, esophageal cancer, gynecologic cancer, liver cancer, thyroid cancer, breast cancer, kidney cancer, head and neck cancer, and bladder cancer. 20 A further embodiment of present invention is (iii) the method according to (i) or (ii), wherein the cancer is selected from a group consisting of BRAF-mutant CRC, EGFR-mutant NSCLC, RAS-mutant and amplified GASC, RAS-mutant CRC, RAS-mutant NSCLC, RAS- mutant PDAC, RAS-mutant solid tumor, RAS-mutant hematological malignancies, RAS-mutant Multiple Myeloma and RAS-wildtype CRC; wherein the solid tumor is selected from a group 25 consisting of melanoma, SCLC, gastric cancer, esophageal cancer, gynecologic cancer, liver cancer, thyroid cancer, breast cancer, kidney cancer, head and neck cancer, and bladder cancer.-20- A further embodiment of present invention is (iv) the method according to any one of (i) to (iii), wherein the cancer is selected from a group consisting of EGFR-mutant NSCLC, RAS- mutant CRC, RAS-mutant NSCLC, and RAS-mutant PDAC. A further embodiment of present invention is (v) the method according to any one of (i) to 5 (iv), wherein the second therapeutic agent is selected from a group consisting of 5-FU-based regimen, Gemcitabine-based regimen, anti-EGFR antibody, anti-PD-1 antibody, anti-PD-L1 antibody, anti-VEGF antibody, anti-VEGFR antibody, Bcl-2 family inhibitors, BRAF inhibitor, EGFR inhibitor, FAK inhibitor, Irinotecan-based regimen, KRAS G12D inhibitor, MEK / RAF inhibitor, PI3K inhibitor, PKMYT1 inhibitor, Platinum-based regimen, PLK1 inhibitor, RAS 10 G12C inhibitor, RAS G12V inhibitor, SHOC2 disruptor, SHP2 inhibitor, SOS1 inhibitor, and YAP-TEAD inhibitor. A further embodiment of present invention is (v) the method according to any one of (i) to (iv), wherein the second therapeutic agent is selected from a group consisting of 5-FU-based regimen, Gemcitabine-based regimen, anti-EGFR antibody, anti-PD-1 antibody, anti-PD-L1 15 antibody, anti-VEGF antibody, anti-VEGFR antibody, Bcl-2 family inhibitors, BRAF inhibitor, EGFR inhibitor, FAK inhibitor, Irinotecan-based regimen, KRAS G12D inhibitor, MEK / RAF inhibitor, PI3K inhibitor, PKMYT1 inhibitor, Platinum-based regimen, PLK1 inhibitor, RAS G12C inhibitor, RAS G12V inhibitor, SHOC2 disruptor, SHP2 inhibitor, SOS1 inhibitor, YAP- TEAD inhibitor, EGFR-cMET bispecific antibody, PD-1-VEGF bispecific antibody, PD-1- 20 CTLA-4 bispecific antibody, GSPT1 inhibitor, HER3 based antibody drug conjugates, B7H3 based antibody drug conjugates, cMET based antibody drug conjugates, TROP2 based antibody drug conjugates, proteasome inhibitor, Immunomodulatory Drugs (IMiDs), CD38 antibody and Corticosteroids. A further embodiment of present invention is (vi) the method according to any one of (i) 25 to (v), wherein the second therapeutic agent is selected from a group consisting of Aflibercept, Atezolizumab, Avutometinib, Bevacizumab, BI-1701963, Cetuximab, RAS G12C inhibitor, Defactinib, Encorafenib, Erlotinib, Irinotecan-based regimen, 5-FU-based regimen, Platinum- based regimen, GDC-1971, GDC-7035, gemcitabine and paclitaxel , IAG933, Ifebemtinib, Inovalisib, Navitoclax, Obatoclax, Onvansertib, Osimertinib, Pembrolizumab, RMP1-14, RP- 30 6306, and Venetoclax; wherein Platinum-based regimen is FOLFOX or CAPEOX; Irinotecan-based regimen is FOLFIRI; 5-FU-based regimen is FOLFIRINOX or NALIRIFOX;-21- RAS G12C inhibitor is Divarasib or(compound 2), or a pharmaceutically acceptable salt thereof. A further embodiment of present invention is (vi) the method according to any one of (i) to (v), wherein the second therapeutic agent is selected from a group consisting of Aflibercept, 5 Amivantamab, Atezolizumab, Avutometinib, Bevacizumab, BI-1701963, Cadonilimab, Cetuximab, RAS G12C inhibitor, Defactinib, Encorafenib, Erlotinib, Irinotecan-based regimen, Ivonescimab, 5-FU-based regimen, Platinum-based regimen, GDC-1971, GDC-7035, gemcitabine and paclitaxel , IAG933, Ifebemtinib, Inovalisib, MRT-2359, Navitoclax, Obatoclax, Onvansertib, Osimertinib, Pembrolizumab, RMP1-14, RP-6306, Patritumab 10 Deruxtecan, DS-7300, MGC018, Telisotuzumab Vedotin, Bortezomib, Carfilzomib, Ixazomib, Lenalidomide, Thalidomide, Pomalidomide, Daratumumab, Isatuximab, Dexamethasone, prednisone and Venetoclax; wherein Platinum-based regimen is FOLFOX or CAPEOX; Irinotecan-based regimen is FOLFIRI; 15 5-FU-based regimen is FOLFIRINOX or NALIRIFOX; RAS G12C inhibitor is Divarasib or(compound 2), or a pharmaceutically acceptable salt thereof. A further embodiment of present invention is (vii) the method according to any one of (i) to (vi), wherein the second therapeutic agent is selected from a group consisting of 5-FU-based-22- regimen, Gemcitabine-based regimen, anti-EGFR antibody, anti-VEGF antibody, anti-VEGFR antibody, EGFR inhibitor, Irinotecan-based regimen, PI3K inhibitor, Platinum-based regimen, and RAS G12C inhibitor. A further embodiment of present invention is (vii) the method according to any one of (i) 5 to (vi), wherein the second therapeutic agent is selected from a group consisting of 5-FU-based regimen, Gemcitabine-based regimen, anti-EGFR antibody, anti-VEGF antibody, anti-VEGFR antibody, EGFR inhibitor, Irinotecan-based regimen, PI3K inhibitor, Platinum-based regimen, RAS G12C inhibitor, EGFR-cMET bispecific antibody, PD-1-VEGF bispecific antibody and PD-1-CTLA-4 bispecific antibody. 10 A further embodiment of present invention is (viii) the method according to any one of (i) to (vii), wherein the second therapeutic agent is selected from a group consisting of Aflibercept, Bevacizumab, Cetuximab, Divarasib, Erlotinib, FOLFIRI, FOLFIRINOX, FOLFOX, gemcitabine and paclitaxel, Inovalisib, and Osimertinib. A further embodiment of present invention is (viii) the method according to any one of (i) 15 to (vii), wherein the second therapeutic agent is selected from a group consisting of Aflibercept, Bevacizumab, Cetuximab, Divarasib, Erlotinib, FOLFIRI, FOLFIRINOX, FOLFOX, gemcitabine and paclitaxel, Inovalisib, Osimertinib, Amivantamab, Ivonescimab and Cadonilimab. A further embodiment of present invention is (ix) the method according to any one of (i) 20 to (viii), wherein the method further comprises a third therapeutic agent. A further embodiment of present invention is (x) the method according to any one of (i) to (ix), wherein the second therapeutic agent is selected from a group consisting of Irinotecan-based regimen, MEK / RAF inhibitor, platinum-based chemotherapy, Platinum-based regimen, PLK1 inhibitor, and RAS G12C inhibitor; wherein the third therapeutic agent is selected from a group 25 consisting of anti-EGFR antibody, anti-PD-1 antibody, anti-PD-L1 antibody, anti-VEGF antibody, FAK inhibitor, and Irinotecan-based regimen. A further embodiment of present invention is (xi) the method according to any one of (i) to (x), wherein the second therapeutic agent is selected from a group consisting of Avutometinib, cisplatin and pemetrexed, carboplatin and pemetrexed, Compound 2, Divarasib, FOLFIRI, 30 FOLFOX, and Onvansertib. A further embodiment of present invention is (xii) the method according to any one of (i) to (xi), wherein the third therapeutic agent is selected from a group consisting of Atezolizumab, Bevacizumab, Cetuximab, Defactinib, FOLFIRI, Ifebemtinib, and Pembrolizumab.-23- Another embodiment of present invention is (xiii) the method of treating RAS-mutant NSCLC in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of EGFR inhibitor and Compound 1, or a pharmaceutically acceptable salt thereof. 5 Another embodiment of present invention is (xiii) the method of treating RAS-mutant NSCLC in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of Erlotinib and Compound 1, or a pharmaceutically acceptable salt thereof. Another embodiment of present invention is (xiv) the method of treating RAS-mutant 10 CRC in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of anti-EGFR antibody and Compound 1, or a pharmaceutically acceptable salt thereof. Another embodiment of present invention is (xiv) the method of treating RAS-mutant CRC in a subject in need thereof, comprising administering to the subject a therapeutically 15 effective amount of a combination of Cetuximab and Compound 1, or a pharmaceutically acceptable salt thereof. Another embodiment of present invention is (xv) the method of treating RAS-mutant NSCLC in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of anti-EGFR antibody / anti-VEGF antibody and Compound 20 1, or a pharmaceutically acceptable salt thereof. Another embodiment of present invention is (xv) the method of treating RAS-mutant NSCLC in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of Aflibercept and Compound 1, or a pharmaceutically acceptable salt thereof. 25 Another embodiment of present invention is (xvi) the method of treating RAS-mutant CRC in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of Bevacizumab and Compound 1, or a pharmaceutically acceptable salt thereof. Another embodiment of present invention is (xvii) the method of treating RAS-mutant 30 NSCLC or RAS-mutant CRC in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of PI3K inhibitor and Compound 1, or a pharmaceutically acceptable salt thereof.-24- Another embodiment of present invention is (xvii) the method of treating RAS-mutant NSCLC or RAS-mutant CRC in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of Inovalisib and Compound 1, or a pharmaceutically acceptable salt thereof. 5 Another embodiment of present invention is (xviii) the method of treating RAS-mutant NSCLC in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of RAS G12C inhibitor and Compound 1, or a pharmaceutically acceptable salt thereof. Another embodiment of present invention is (xviii) the method of treating RAS-mutant 10 NSCLC in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of Divarasib and Compound 1, or a pharmaceutically acceptable salt thereof. Another embodiment of present invention is (xix) the method of treating RAS-mutant NSCLC in a subject in need thereof, comprising administering to the subject a therapeutically 15 effective amount of a combination of Compound 2 and Compound 1, or a pharmaceutically acceptable salt thereof. Another embodiment of present invention is (xx) the method of treating RAS-mutant NSCLC or RAS-mutant and amplified GASC in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of YAP-TEAD 20 inhibitor and Compound 1, or a pharmaceutically acceptable salt thereof. Another embodiment of present invention is (xx) the method of treating RAS-mutant NSCLC or RAS-mutant and amplified GASC in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of IAG933 and Compound 1, or a pharmaceutically acceptable salt thereof. 25 Another embodiment of present invention is (xxi) the method of treating RAS-mutant CRC in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of Platinum-based regimen and Compound 1, or a pharmaceutically acceptable salt thereof. Another embodiment of present invention is (xxi) the method of treating RAS-mutant 30 CRC in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of FOLFOX and Compound 1, or a pharmaceutically acceptable salt thereof.-25- Another embodiment of present invention is (xxii) the method of treating RAS-mutant CRC in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of Irinotecan-based regimen and Compound 1, or a pharmaceutically acceptable salt thereof. 5 Another embodiment of present invention is (xxii) the method of treating RAS-mutant CRC in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of FOLFIRI and Compound 1, or a pharmaceutically acceptable salt thereof. Another embodiment of present invention is (xxiii) the method of treating RAS-mutant 10 PDAC in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of 5-FU-based regimen and Compound 1, or a pharmaceutically acceptable salt thereof. Another embodiment of present invention is (xxiii) the method of treating RAS-mutant PDAC in a subject in need thereof, comprising administering to the subject a therapeutically 15 effective amount of a combination of FOLFIRINOX and Compound 1, or a pharmaceutically acceptable salt thereof. Another embodiment of present invention is (xxiv) the method of treating RAS-mutant PDAC in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of Gemcitabine-based regimen and Compound 1, or a 20 pharmaceutically acceptable salt thereof. Another embodiment of present invention is (xxiv) the method of treating RAS-mutant PDAC in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of Gemcitabine and paclitaxel and Compound 1, or a pharmaceutically acceptable salt thereof. 25 Another embodiment of present invention is (xxv) the method of treating EGFR-mutant NSCLC in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of EGFR inhibitor and Compound 1, or a pharmaceutically acceptable salt thereof. Another embodiment of present invention is (xxv) the method of treating EGFR-mutant 30 NSCLC in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of Osimertinib and Compound 1, or a pharmaceutically acceptable salt thereof.-26- Another embodiment of present invention is (xxvi) the method of treating RAS-wildtype CRC in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of anti-EGFR antibody and Compound 1, or a pharmaceutically acceptable salt thereof. 5 Another embodiment of present invention is (xxvi) the method of treating RAS-wildtype CRC in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of Cetuximab and Compound 1, or a pharmaceutically acceptable salt thereof. Another embodiment of present invention is (xxvii) the method of treating BRAF-mutant 10 CRC in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of BRAF inhibitor and Compound 1, or a pharmaceutically acceptable salt thereof. Another embodiment of present invention is (xxvii) the method of treating BRAF-mutant CRC in a subject in need thereof, comprising administering to the subject a therapeutically 15 effective amount of a combination of Encorafenib and Compound 1, or a pharmaceutically acceptable salt thereof. Another embodiment of present invention is (xxviii) the method of treating RAS-mutant CRC in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of anti-PD-1 antibody and Compound 1, or a 20 pharmaceutically acceptable salt thereof. Another embodiment of present invention is (xxviii) the method of treating RAS-mutant CRC in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of RMP1-14 and Compound 1, or a pharmaceutically acceptable salt thereof. 25 Another embodiment of present invention is (xxix) the method of treating RAS-mutant CRC in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of EGFR-cMET bispecific antibody and Compound 1, or a pharmaceutically acceptable salt thereof. Another embodiment of present invention is (xxix) the method of treating RAS-mutant 30 CRC in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of Amivantamab and Compound 1, or a pharmaceutically acceptable salt thereof.-27- Another embodiment of present invention is (xxx) the method of treating RAS-mutant NSCLC in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of PD-1-VEGF bispecific antibody and Compound 1, or a pharmaceutically acceptable salt thereof. 5 Another embodiment of present invention is (xxx) the method of treating RAS-mutant NSCLC in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of Ivonescimab and Compound 1, or a pharmaceutically acceptable salt thereof. Another embodiment of present invention is (xxxi) the method of treating RAS-mutant 10 NSCLC in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of GSPT1 inhibitor and Compound 1, or a pharmaceutically acceptable salt thereof. Another embodiment of present invention is (xxxi) the method of treating RAS-mutant NSCLC in a subject in need thereof, comprising administering to the subject a therapeutically 15 effective amount of a combination of MRT-2359 and Compound 1, or a pharmaceutically acceptable salt thereof. Another embodiment of present invention is (xxxii) the method of treating RAS-mutant NSCLC in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of anti-PD-1 antibody and Compound 1, or a 20 pharmaceutically acceptable salt thereof. Another embodiment of present invention is (xxxii) the method of treating RAS-mutant NSCLC in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of Pembrolizumab and Compound 1, or a pharmaceutically acceptable salt thereof. 25 Another embodiment of present invention is (xxxiii) the use of the combination of a RAS inhibitor and a second therapeutic agent for treating cancer in a subject in need thereof, wherein the RAS inhibitor is a compound of formula (I), or a pharmaceutically acceptable salt thereof. A further embodiment of present invention is (xxxiv) the use according to (xxxiii), wherein the RAS inhibitor is compound 1, or a pharmaceutically acceptable salt thereof. 30 A further embodiment of present invention is (xxxv) the use according to (xxxiii) or (xxxiv), wherein the cancer is selected from a group consisting of BRAF-mutant CRC, EGFR- mutant NSCLC, RAS-mutant and amplified GASC, RAS-mutant CRC, RAS-mutant NSCLC, RAS-mutant PDAC, RAS-mutant solid tumor, RAS-mutant hematological malignancies, RAS--28- mutant Multiple Myeloma and RAS-wildtype CRC; wherein the solid tumor is selected from a group consisting of melanoma, SCLC, gastric cancer, esophageal cancer, gynecologic cancer, liver cancer, thyroid cancer, breast cancer, kidney cancer, head and neck cancer, and bladder cancer. 5 A further embodiment of present invention is (xxxvi) the use according to any one of (xxxiii) to (xxxv), wherein the cancer is selected from a group consisting of EGFR-mutant NSCLC, RAS-mutant CRC, RAS-mutant NSCLC, and RAS-mutant PDAC. A further embodiment of present invention is (xxxvii) the use according to any one of (xxxiii) to (xxxvi), wherein the second therapeutic agent is selected from a group consisting of 5-10 FU-based regimen, Gemcitabine-based regimen, anti-EGFR antibody, anti-VEGF antibody, anti- VEGFR antibody, EGFR inhibitor, Irinotecan-based regimen, PI3K inhibitor, Platinum-based regimen, and RAS G12C inhibitor. A further embodiment of present invention is (xxxvii) the use according to any one of (xxxiii) to (xxxvi), wherein the second therapeutic agent is selected from a group consisting of 5-15 FU-based regimen, Gemcitabine-based regimen, anti-EGFR antibody, anti-VEGF antibody, anti- VEGFR antibody, EGFR inhibitor, Irinotecan-based regimen, PI3K inhibitor, Platinum-based regimen, RAS G12C inhibitor, EGFR-cMET bispecific antibody, PD-1-VEGF bispecific antibody and PD-1-CTLA-4 bispecific antibody. A further embodiment of present invention is (xxxviii) the use according to any one of 20 (xxxiii) to (xxxvii), wherein the second therapeutic agent is selected from a group consisting of Aflibercept, Bevacizumab, Cetuximab, Divarasib, Erlotinib, FOLFIRI, FOLFIRINOX, FOLFOX, gemcitabine and paclitaxel, Inovalisib, and Osimertinib. A further embodiment of present invention is (xxxviii) the use according to any one of (xxxiii) to (xxxvii), wherein the second therapeutic agent is selected from a group consisting of 25 Aflibercept, Bevacizumab, Cetuximab, Divarasib, Erlotinib, FOLFIRI, FOLFIRINOX, FOLFOX, gemcitabine and paclitaxel, Inovalisib, Osimertinib, Amivantamab, Ivonescimab and Cadonilimab. Another embodiment of present invention is (xxxix) the use according to any one of (xxxiii) to (xxxviii), wherein the combination further comprises a third therapeutic agent. 30 A further embodiment of present invention is (xl) the use according to (xxxix), wherein the second therapeutic agent is selected from a group consisting of Irinotecan-based regimen, MEK / RAF inhibitor, platinum-based chemotherapy, Platinum-based regimen, PLK1 inhibitor, and RAS G12C inhibitor; wherein the third therapeutic agent is selected from a group consisting-29- of anti-EGFR antibody, anti-PD-1 antibody, anti-PD-L1 antibody, anti-VEGF antibody, FAK inhibitor, and Irinotecan-based regimen. A further embodiment of present invention is (xli) the use according to (xxxix) or (xl), wherein the second therapeutic agent is selected from a group consisting of Avutometinib, 5 cisplatin and pemetrexed, carboplatin and pemetrexed, Compound 2, Divarasib, FOLFIRI, FOLFOX, and Onvansertib; wherein the third therapeutic agent is selected from a group consisting of Atezolizumab, Bevacizumab, Cetuximab, Defactinib, FOLFIRI, Ifebemtinib, and Pembrolizumab. Another embodiment of present invention is (xlii) the use of a RAS inhibitor in the 10 manufacture of a medicament for treating cancer in a subject in need thereof, in combination with a second therapeutic agent, wherein the RAS inhibitor is a compound of formula (I), or a pharmaceutically acceptable salt thereof. A further embodiment of present invention is (xliii) the use according to (xlii), wherein the RAS inhibitor is compound 1, or a pharmaceutically acceptable salt thereof. 15 A further embodiment of present invention is (xliv) the use according to (xxii) or (xxiii), wherein the cancer is selected from a group consisting of BRAF-mutant CRC, EGFR-mutant NSCLC, RAS-mutant and amplified GASC, RAS-mutant CRC, RAS-mutant NSCLC, RAS- mutant PDAC, RAS-mutant solid tumor, and RAS-wildtype CRC; wherein the solid tumor is selected from a group consisting of melanoma, SCLC, gastric cancer, esophageal cancer, 20 gynecologic cancer, liver cancer, thyroid cancer, breast cancer, kidney cancer, head and neck cancer, and bladder cancer. A further embodiment of present invention is (xlv) the use according to any one of (xlii) to (xliv), wherein the cancer is selected from a group consisting of EGFR-mutant NSCLC, RAS- mutant CRC, RAS-mutant NSCLC, and RAS-mutant PDAC. 25 A further embodiment of present invention is (xlvi) the use according to any one of (xlii) to (xlv), wherein the second therapeutic agent is selected from a group consisting of 5-FU-based regimen, Gemcitabine-based regimen, anti-EGFR antibody, anti-VEGF antibody, anti-VEGFR antibody, EGFR inhibitor, Irinotecan-based regimen, PI3K inhibitor, Platinum-based regimen, and RAS G12C inhibitor. 30 A further embodiment of present invention is (xlvi) the use according to any one of (xlii) to (xlv), wherein the second therapeutic agent is selected from a group consisting of 5-FU-based regimen, Gemcitabine-based regimen, anti-EGFR antibody, anti-VEGF antibody, anti-VEGFR antibody, EGFR inhibitor, Irinotecan-based regimen, PI3K inhibitor, Platinum-based regimen,-30- RAS G12C inhibitor, EGFR-cMET bispecific antibody, PD-1-VEGF bispecific antibody and PD-1-CTLA-4 bispecific antibody. A further embodiment of present invention is (xlvii) the use according to any one of (xlii) to (xlvi), wherein the second therapeutic agent is selected from a group consisting of Aflibercept, 5 Bevacizumab, Cetuximab, Divarasib, Erlotinib, FOLFIRI, FOLFIRINOX, FOLFOX, gemcitabine and paclitaxel, Inovalisib, and Osimertinib. A further embodiment of present invention is (xlvii) the use according to any one of (xlii) to (xlvi), wherein the second therapeutic agent is selected from a group consisting of Aflibercept, Bevacizumab, Cetuximab, Divarasib, Erlotinib, FOLFIRI, FOLFIRINOX, FOLFOX, 10 gemcitabine and paclitaxel, Inovalisib, Osimertinib, Amivantamab, Ivonescimab and Cadonilimab. Another embodiment of present invention is (xlviii) a pharmaceutical composition, comprising a therapeutically effective amount of a combination of a combination of a RAS inhibitor and a second therapeutic agent, wherein the RAS inhibitor is a compound of formula 15 (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. A further embodiment of present invention is (xlix) a pharmaceutical composition according to (xlviii), wherein the RAS inhibitor is compound 1, or a pharmaceutically acceptable salt thereof. A further embodiment of present invention is (l) a pharmaceutical composition according 20 to (xlviii) or (xlix), wherein the cancer is selected from a group consisting of EGFR-mutant NSCLC, RAS-mutant CRC, RAS-mutant NSCLC, and RAS-mutant PDAC. A further embodiment of present invention is (li) a pharmaceutical composition according to any one of (xlviii) to (l), wherein the second therapeutic agent is selected from a group consisting of 5-FU-based regimen, Gemcitabine-based regimen, anti-EGFR antibody, anti-VEGF 25 antibody, anti-VEGFR antibody, EGFR inhibitor, Irinotecan-based regimen, PI3K inhibitor, Platinum-based regimen, and RAS G12C inhibitor. A further embodiment of present invention is (li) a pharmaceutical composition according to any one of (xlviii) to (l), wherein the second therapeutic agent is selected from a group consisting of 5-FU-based regimen, Gemcitabine-based regimen, anti-EGFR antibody, anti-VEGF 30 antibody, anti-VEGFR antibody, EGFR inhibitor, Irinotecan-based regimen, PI3K inhibitor, Platinum-based regimen, RAS G12C inhibitor, EGFR-cMET bispecific antibody, PD-1-VEGF bispecific antibody and PD-1-CTLA-4 bispecific antibody.-31- A further embodiment of present invention is (lii) a pharmaceutical composition according to (xlviii) to (li), wherein the second therapeutic agent is selected from a group consisting of Aflibercept, Bevacizumab, Cetuximab, Divarasib, Erlotinib, FOLFIRI, FOLFIRINOX, FOLFOX, gemcitabine and paclitaxel, Inovalisib, and Osimertinib. 5 A further embodiment of present invention is (lii) a pharmaceutical composition according to (xlviii) to (li), wherein the second therapeutic agent is selected from a group consisting of Aflibercept, Bevacizumab, Cetuximab, Divarasib, Erlotinib, FOLFIRI, FOLFIRINOX, FOLFOX, gemcitabine and paclitaxel, Inovalisib, Osimertinib, Amivantamab, Ivonescimab and Cadonilimab. 10 A further embodiment of present invention is (liii) a pharmaceutical composition according to (xlviii) to (lii), wherein the composition further comprises a third therapeutic agent. A further embodiment of present invention is (liv) a pharmaceutical composition according to (xlix), wherein the second therapeutic agent is selected from a group consisting of Irinotecan-based regimen, MEK / RAF inhibitor, platinum-based chemotherapy, Platinum-based 15 regimen, PLK1 inhibitor, and RAS G12C inhibitor; wherein the third therapeutic agent is selected from a group consisting of anti-EGFR antibody, anti-PD-1 antibody, anti-PD-L1 antibody, anti-VEGF antibody, FAK inhibitor, and Irinotecan-based regimen. A further embodiment of present invention is (lv) a pharmaceutical composition according to (liii) or (liv), wherein the second therapeutic agent is selected from a group consisting of 20 Avutometinib, cisplatin and pemetrexed, carboplatin and pemetrexed, Compound 2, Divarasib, FOLFIRI, FOLFOX, and Onvansertib; wherein the third therapeutic agent is selected from a group consisting of Atezolizumab, Bevacizumab, Cetuximab, Defactinib, FOLFIRI, Ifebemtinib, and Pembrolizumab. Another embodiment of present invention is (lv) a kit comprising a pharmaceutical 25 composition of any one of (xlviii) to (lv). EXAMPLES The invention will be more fully understood by reference to the following examples. They should not, however, be construed as limiting the scope of the invention. 30 ABBREVIATIONS ADC Antibody drug conjugates AGA actionable oncogenic alterations-32- BRAF B-Raf Proto-Oncogene, Serine / Threonine Kinase CAPEOX Chemotherapy regimen consisting of Capecitabine and Oxaliplatin CRC Colorectal Cancer CMPI 2-Chloro-1-methylpyridinium iodide 5 CTLA-4 Cytotoxic T-Lymphocyte-Associated Protein 4 cMET Mesenchymal-epithelial transition factor EGFR Epidermal Growth Factor Receptor EtOAc or EA ethyl acetate FOLFOX Chemotherapy regimen consisting of Folinic Acid (leucovorin), 10 Fluorouracil (5-FU), and Oxaliplatin FOLFIRI Chemotherapy regimen consisting of Folinic Acid (leucovorin), Fluorouracil (5-FU), and Irinotecan FOLFIRINOX Chemotherapy regimen consisting of Folinic Acid (leucovorin), Fluorouracil (5-FU), Irinotecan, and Oxaliplatin 15 GC Gastric Cancer GnP Gemcitabine plus Nab-Paclitaxel HATU (1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate) HPLC high performance liquid chromatography 20 HOBt N-hydroxybenzotriazole KRAS Kirsten Rat Sarcoma Viral Oncogene Homolog MS (ESI) mass spectroscopy (electron spray ionization) NMR nuclear magnetic resonance NMM N-Methylmorpholine 25 NPLC Normal phase liquid chromatography NSCLC Non-Small Cell Lung Cancer PD-1 Programmed Cell Death Protein 1 PD-L1 Programmed Death-Ligand 1 PDAC Pancreatic Ductal Adenocarcinoma 30 Pd(dtbpf)Cl2[1,1′-Bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) PI3K Phosphoinositide 3-Kinase PKMYT1 Protein Kinase, Myosin Light Chain Kinase 1 SHOC2 Leucine-Rich Repeat Scaffold Protein SHOC2-33- SHP2 Src Homology Region 2 Domain-Containing Phosphatase-2 SOS1 Son of Sevenless Homolog 1 TGI tumor growth inhibition T4P 1,3,5,2,4,6-Trioxatriphosphorinane, 2,4,6-tributyl-, 2,4,6-trioxide 5 TBAF Tetrabutylammonium fluoride VEGF Vascular Endothelial Growth Factor YAP-TEAD Yes-Associated Protein - TEA Domain Family Member (a transcriptional regulator complex) FAK Focal Adhesion Kinase 10 MEK / RAF MEK (Mitogen-Activated Protein Kinase Kinase) and RAF (Rapidly Accelerated Fibrosarcoma) kinases PLK1 Polo-Like Kinase 1 Bcl-2 family Including BCL2 (B-cell lymphoma 2), BCL-XL (BCL2-like 1, MCL1 (Myeloid Cell Leukemia 1), BCL-W (BCL2-like 2) 15 QD Once a day QW Once a week BIW Twice a week PO Oral administration IP Intraperitoneal adminstration 20 Synthesis of Compound 1 (1r,2R,3S)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3- pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen- 25 7-yl]-2,3-dimethyl-cyclopropanecarboxamide-34-Compound 1 To a solution of (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,30,31- 5 tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaene- 8,14-dione (Intermediate E, 20 mg) and (1r,2S,3R)-2,3-dimethylcyclopropanecarboxylic acid (CAS 34669-51-7) ( 4.3 mg) in DMF (0.2 mL) were added DIEA (14 µL), HATU (18.5 mg) at 0 °C. After being stirred at 20 °C for 1 h, the reaction mixture was diluted with water (15 mL), extracted with EtOAc (15 mL, three times). The combined organic layer was washed with brine 10 (20 mL), dried over Na2SO4, filtered and concentrated in vacuo to get a residue. The residue was purified by prep-HPLC to afford compound 1 (7.3 mg) as a white solid. MS calc’d 837.4 (MH+), measured 837.4 (MH+).1H NMR (400 MHz, Methanol-d4) δ = 8.33 - 8.25 (m, 2H), 7.37 (s, 1H), 7.29 (s, 1H), 7.17 (d, J = 2.8 Hz, 1H), 5.72 - 5.64 (m, 1H), 4.47 (br s, 2H), 4.36 - 4.24 (m, 2H), 4.17 - 4.08 (m, 2H), 3.66 - 3.62 (m, 2H), 3.54 - 3.45 (m, 1H), 15 3.34 - 3.26 (m, 5H), 3.18 - 3.13 (m, 1H), 3.02 - 2.85 (m, 3H), 2.73 - 2.61 (m, 5H), 2.50 (br d, J = 14.3 Hz, 1H), 2.38 (s, 3H), 2.25 - 2.15 (m, 1H), 2.12 - 2.02 (m, 2H), 1.82 (br d, J = 13.3 Hz, 1H), 1.71 - 1.58 (m, 1H), 1.49 (dq, J = 3.6, 12.5 Hz, 1H), 1.36 - 1.31 (m, 3H), 1.30 - 1.21 (m, 2H), 1.08 - 0.94 (m, 8H), 0.86 - 0.81 (m, 3H), 0.46 - 0.40 (m, 3H). Intermediate E 20 (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]- 17,17-dimethyl-15-oxa-4-thia-9,21,30,31- 2,5 9,13 19,27 21,26 tetrazahexacyclo[23.3.1.1 .1 .0 .0 ]hentriaconta-1(28),2,5(31),19,25(29),26-hexaene- 8,14-dione-35-The compound was prepared according to the following scheme:5-36-Intermediate E Step 1: Preparation of benzyl 4-[5-[2-(6-bromo-1,2,3,4-tetrahydroquinolin-8- yl)ethynyl]-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (compound E1).-37- To a solution of benzyl 4-[5-ethynyl-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1- carboxylate (Intermediate Z, 26.1 g, 68.8 mmol) in DMF (400 mL) were added 6-bromo-8-iodo- 1,2,3,4-tetrahydroquinoline (Intermediate Y, 23.3 g, 68.8 mmol), TEA (47.9 mL, 343.9 mmol), CuI (1.3 g, 6.88 mmol) and Pd(PPh3)2Cl2 (4.8 g, 6.88 mmol). The reaction mixture was degassed 5 and purged with nitrogen for three times and then it was stirred at 25 °C for 12 hrs. After the reaction was completed, the reaction mixture was poured into water (1.4 L), and extracted with EtOAc (800 mL, three times). The combined organic layer was washed with brine (800 mL, four times), dried over Na2SO4, filtered and concentrated under vacuum to give a residue, which was purified by column chromatography to afford benzyl 4-[5-[2-(6-bromo-1,2,3,4- 10 tetrahydroquinolin-8-yl)ethynyl]-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (compound E1, 30.0 g) as a yellow solid. MS calc’d 589.2 (MH+), measured 589.2(MH+). Step 2: Preparation of benzyl 4-[5-(6-bromo-1-azatricyclo[6.3.1.04,12]dodeca- 2,4,6,8(12)-tetraen-2-yl)-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (compound E2). 15 To a solution of benzyl 4-[5-[2-(6-bromo-1,2,3,4-tetrahydroquinolin-8-yl)ethynyl]-6-[(1S)- 1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (compound E1, 27.0 g, 45.8 mmol) in DMF (270 mL) was added PdCl2 (1.6 g, 9.16 mmol) in one portion. The reaction mixture was degassed and purged with nitrogen for three times and then heated to 70 °C for 16 hrs. After being cooled to the room temperature, the mixture was poured into water (800 mL), and 20 extracted with EtOAc (300 mL, three times). The combined organic layer was washed with brine (300 mL, three times), dried over Na2SO4, filtered and concentrated under vacuum to give a residue, which was purified by column chromatography to afford benzyl 4-[5-(6-bromo-1- azatricyclo[6.3.1.04,12]dodeca-2,4,6,8(12)-tetraen-2-yl)-6-[(1S)-1-methoxyethyl]-3- pyridyl]piperazine-1-carboxylate (compound E2, 19.2 g) as a yellow solid. MS calc’d 589.2 25 (MH+), measured 589.2 (MH+). Step 3: Preparation of benzyl 4-[5-(6-bromo-3-formyl-1-azatricyclo[6.3.1.04,12]dodeca- 2,4,6,8(12)-tetraen-2-yl)-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (compound E3). Phosphorus oxychloride (30.4 mL, 325.69 mmol) was added into DMF (350 mL) dropwise 30 slowly at 0°C. After being stirred at 0 °C for 0.5 h, the reaction mixture was added with a solution of benzyl 4-[5-(6-bromo-1-azatricyclo[6.3.1.04,12]dodeca-2,4,6,8(12)-tetraen-2-yl)-6- [(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (compound E2, 19.2 g, 32.57 mmol) in DMF (150 mL) dropwise at 0 ºC. The reaction mixture was heated to 45 °C, and then stirred-38- for another 1 h. The reaction was quenched with sat. NaHCO3 aq. solution (1.5 L), extracted with EtOAc (500 mL, three times). The organic phase was washed with brine (500 mL, three times), dried over anhydrous Na2SO4, filtered and concentrated under vacuum to give a residue. The residue was purified by column chromatography to afford benzyl 4-[5-(6-bromo-3-formyl-1- 5 azatricyclo[6.3.1.04,12]dodeca-2,4,6,8(12)-tetraen-2-yl)-6-[(1S)-1-methoxyethyl]-3- pyridyl]piperazine-1-carboxylate (compound E3, 14.6 g) as a yellow solid. MS calc’d 616.9 (MH+), measured 617.2 (MH+). Step 4: Preparation of benzyl 4-[5-[6-bromo-3-(1-hydroxy-3-methoxy-2,2-dimethyl-3- 4,12 oxo-propyl)-1-azatricyclo[6.3.1.0 ]dodeca-2,4,6,8(12)-tetraen-2-yl]-6-[(1S)-1- 10 methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (compound E4) To a solution of methyl isobutyrate (13.4 g, 131.17 mmol) in THF (150 mL) was added LDA (65.58 mL, 131.17 mmol) dropwise at -70 °C under nitrogen atmosphere. After being stirred for 0.5 h, the reaction mixture was added with a solution of benzyl 4-[5-(6-bromo-3- formyl-1-azatricyclo[6.3.1.04,12]dodeca-2,4,6,8(12)-tetraen-2-yl)-6-[(1S)-1-methoxyethyl]-3- 15 pyridyl]piperazine-1-carboxylate (compound E3, 13.5 g, 21.86 mmol) in THF (50 mL) dropwise at -70 °C. The reaction mixture was then allowed warm up to room temperature and stirred for 1 h. After the reaction was completed, the mixture was quenched with sat. NH4Cl (600 mL) aqueous solution and extracted with EtOAc (200 mL, three times). The organic phase was washed with brine (500 mL), dried with anhydrous Na2SO4, filtered and concentrated under 20 vacuum to give a residue. The residue was purified by column chromatography to afford benzyl 4-[5-[6-bromo-3-(1-hydroxy-3-methoxy-2,2-dimethyl-3-oxo-propyl)-1- 4,12 azatricyclo[6.3.1.0 ]dodeca-2,4,6,8(12)-tetraen-2-yl]-6-[(1S)-1-methoxyethyl]-3- pyridyl]piperazine-1-carboxylate (compound E4, 14.01 g) as a yellow gum. MS calc’d 719.3 (MH+), measured 719.2 (MH+). 25 Step 5: Preparation of benzyl 4-[5-[6-bromo-3-(3-methoxy-2,2-dimethyl-3-oxo-propyl)- 1-azatricyclo[6.3.1.04,12]dodeca-2,4,6,8(12)-tetraen-2-yl]-6-[(1S)-1-methoxyethyl]-3- pyridyl]piperazine-1-carboxylate (compound E5) To a solution of benzyl 4-[5-[6-bromo-3-(1-hydroxy-3-methoxy-2,2-dimethyl-3-oxo- propyl)-1-azatricyclo[6.3.1.04,12]dodeca-2,4,6,8(12)-tetraen-2-yl]-6-[(1S)-1-methoxyethyl]-3- 30 pyridyl]piperazine-1-carboxylate (compound E4, 14.0 g, 19.45 mmol) and Et3SiH (18.1 g, 155.63 mmol) in DCM (280 mL) was added TFA (57.8 mL, 778.15 mmol) at 0 °C. After being stirred at 25°C for 12 hrs, the reaction mixture was concentrated under vacuum to give a residue, which was diluted with sat. NaHCO3aq. until pH=9 and extracted with EtOAc (300 mL, three-39- times). The combined organic layer was dried with anhydrous Na2SO4, filtered and concentrated under vacuum to give a residue. The residue was purified by column to afford benzyl 4-[5-[6- bromo-3-(3-methoxy-2,2-dimethyl-3-oxo-propyl)-1-azatricyclo[6.3.1.04,12]dodeca-2,4,6,8(12)- tetraen-2-yl]-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (compound E5, 14 g) 5 as a yellow gum. MS calc’d 703.2 (MH+), measured 703.2 (MH+). Step 6: Preparation of benzyl 4-[(5M)-5-[6-bromo-3-(3-hydroxy-2,2-dimethyl-propyl)- 1-azatricyclo[6.3.1.04,12]dodeca-2,4,6,8(12)-tetraen-2-yl]-6-[(1S)-1-methoxyethyl]-3- pyridyl]piperazine-1-carboxylate (compound E6) To a solution of benzyl 4-[5-[6-bromo-3-(3-methoxy-2,2-dimethyl-3-oxo-propyl)-1-10 azatricyclo[6.3.1.04,12]dodeca-2,4,6,8(12)-tetraen-2-yl]-6-[(1S)-1-methoxyethyl]-3- pyridyl]piperazine-1-carboxylate (compound E5, 14.0 g, 19.9 mmol) in THF (150 mL) was added lithium borohydride (99.48 mL, 198.96 mmol) dropwise under N2 at 0°C. After being stirred at 20 °C for 15 hrs, the reaction was quenched by sat. NH4Cl aq. (600 mL) at 0 °C and the resultant mixture was extracted with EtOAc (100mL, three times). The combined organic layer 15 was washed with brine (200 mL), dried over Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography to afford benzyl 4-[(5M)-5-[6- bromo-3-(3-hydroxy-2,2-dimethyl-propyl)-1-azatricyclo[6.3.1.04,12]dodeca-2,4,6,8(12)-tetraen-2- yl]-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (compound E6, 7 g, faster eluted) as a yellow solid. MS calc’d 675.3 (MH+), measured 675.2 (MH+). 20 Step 7: Preparation of benzyl 4-[(5M)-5-[3-(3-hydroxy-2,2-dimethyl-propyl)-6-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1-azatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2- yl]-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (compound E7) To a solution of benzyl 4-[(5M)-5-[6-bromo-3-(3-hydroxy-2,2-dimethyl-propyl)-1- azatricyclo[6.3.1.04,12]dodeca-2,4,6,8(12)-tetraen-2-yl]-6-[(1S)-1-methoxyethyl]-3- 25 pyridyl]piperazine-1-carboxylate (compound E6, 7.0 g, 10.36 mmol) and bis(pinacolato)diboron (3.95 g, 15.54 mmol) in toluene (140 mL) was added KOAc (2.56 g, 26.05 mmol) and Pd(dppf)Cl2(760.87 mg, 1.04 mmol). The mixture was degassed and purged with nitrogen for three times and stirred at 75 °C for 16 hrs. After being cooled to the room temperature, the reaction mixture was filtered and concentrated under vacuum to give a residue. The residue was30 purified by column chromatography to afford benzyl 4-[(5M)-5-[3-(3-hydroxy-2,2-dimethyl- propyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-azatricyclo[6.3.1.04,12]dodeca- 2,4(12),5,7-tetraen-2-yl]-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (compound E7, 7.3 g) as a yellow solid. MS calc’d 723.4 (MH+), measured 723.4 (MH+).-40- Step 8: Preparation of methyl (3S)-1-[(2S)-3-[4-[(2M)-2-[5-(4- benzyloxycarbonylpiperazin-1-yl)-2-[(1S)-1-methoxyethyl]-3-pyridyl]-3-(3-hydroxy-2,2- dimethyl-propyl)-1-azatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-6-yl]thiazol-2-yl]-2- (tert-butoxycarbonylamino)propanoyl]hexahydropyridazine-3-carboxylate (compound E8) 5 To a solution of benzyl 4-[(5M)-5-[3-(3-hydroxy-2,2-dimethyl-propyl)-6-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1-azatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl]- 6-[(1S -1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (compound E7, 6.8 g, 9.41 mmol) and methyl (3S)-1-[(2S)-3-(4-bromothiazol-2-yl)-2-(tert- butoxycarbonylamino)propanoyl]hexahydropyridazine-3-carboxylate (Intermediate B, 4.9 g, 10 10.35 mmol) in toluene (90 mL) / 1,4-dioxane (30 mL) / water (30 mL) was added K3PO4(5.0 g, 23.52 mmol) and Pd(dtbpf)Cl2 (613.2 mg, 0.94 mmol) in one portion. The mixture was degassed and purged with nitrogen for three times and then stirred at 70 °C for 15 hrs. After being cooled to room temperature, the reaction mixture was filtered, and the filtrate was concentrated under vacuum to give a residue. The residue was purified by column chromatography to afford methyl15 (3S)-1-[(2S)-3-[4-[(2M)-2-[5-(4-benzyloxycarbonylpiperazin-1-yl)-2-[(1S)-1-methoxyethyl]-3- pyridyl]-3-(3-hydroxy-2,2-dimethyl-propyl)-1-azatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen- 6-yl]thiazol-2-yl]-2-(tert-butoxycarbonylamino)propanoyl]hexahydropyridazine-3-carboxylate (compound E8, 8.1 g) as a yellow solid. MS calc’d 993.7 (MH+), measured 993.7 (MH+). Step 9: Preparation of (3S)-1-[(2S)-3-[4-[(2M)-2-[5-(4-benzyloxycarbonylpiperazin-1-20 yl)-2-[(1S)-1-methoxyethyl]-3-pyridyl]-3-(3-hydroxy-2,2-dimethyl-propyl)-1- azatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-6-yl]thiazol-2-yl]-2-(tert- butoxycarbonylamino)propanoyl]hexahydropyridazine-3-carboxylic acid (compound E9) To the mixture of methyl (3S)-1-[(2S)-3-[4-[(2M)-2-[5-(4-benzyloxycarbonylpiperazin-1- yl)-2-[(1S)-1-methoxyethyl]-3-pyridyl]-3-(3-hydroxy-2,2-dimethyl-propyl)-1-25 azatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-6-yl]thiazol-2-yl]-2-(tert- butoxycarbonylamino)propanoyl]hexahydropyridazine-3-carboxylate (compound E8, 8.1 g, 8.16 mmol) in DCE (160 mL) was added trimethyltin hydroxide (5.9 g, 32.62 mmol) in one portion. After being stirred at 60 °C for 16 hrs, the reaction mixture was poured into water (200 mL) and extracted with EtOAc (100 mL, three times). The combined organic layer was washed with brine 30 (200 mL), dried over anhydrous Na2SO4, and then filtered. The filtrate was concentrated under vacuum to afford (3S)-1-[(2S)-3-[4-[(2M)-2-[5-(4-benzyloxycarbonylpiperazin-1-yl)-2-[(1S)-1- methoxyethyl]-3-pyridyl]-3-(3-hydroxy-2,2-dimethyl-propyl)-1-azatricyclo[6.3.1.04,12]dodeca- 2,4(12),5,7-tetraen-6-yl]thiazol-2-yl]-2-(tert--41- butoxycarbonylamino)propanoyl]hexahydropyridazine-3-carboxylic acid (compound E9, 7.9 g) as a brown solid. MS calc’d 979.5 (MH+), measured 979.5 (MH+). Step 10: Preparation of benzyl 4-[(5M)-5-[(7S,13S)-7-(tert-butoxycarbonylamino)- 17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31- 5 tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen- 20-yl]-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (compound E10) To a solution of (3S)-1-[(2S)-3-[4-[(2M)-2-[5-(4-benzyloxycarbonylpiperazin-1-yl)-2-[(1S)- 1-methoxyethyl]-3-pyridyl]-3-(3-hydroxy-2,2-dimethyl-propyl)-1-azatricyclo[6.3.1.04,12]dodeca- 2,4(12),5,7-tetraen-6-yl]thiazol-2-yl]-2-(tert- 10 butoxycarbonylamino)propanoyl]hexahydropyridazine-3-carboxylic acid (compound E9, 6.8 g, 6.94 mmol) in DCM (700 mL) was added DIEA (24.2 mL, 138.89 mmol), EDCI (19.9 g, 104.17 mmol) and HOBt (2.4 g, 17.36 mmol) at 0°C. After being stirred at 30 °C for 15 hrs, the reaction mixture was poured into water (500 mL), and extracted with EtOAc (300 mL, three times). The combined organic layer was washed with brine (300 mL), dried over Na2SO4, and then filtered. 15 The filtrate was concentrated under vacuum to give a residue, which was purified by silica column to afford benzyl 4-[(5M)-5-[(7S,13S)-7-(tert-butoxycarbonylamino)-17,17-dimethyl- 8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28),2,5(31),19,25(29),26-hexaen-20-yl]-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1- carboxylate (compound E10, 5.6 g) as a yellow solid. MS calc’d 961.5 (MH+), measured 961.5 20 (MH+). Step 11: Preparation of tert-butyl N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen- 7-yl]carbamate (compound E11) 25 To a solution of benzyl 4-[(5M)-5-[(7S,13S)-7-(tert-butoxycarbonylamino)-17,17-dimethyl- 8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28),2,5(31),19,25(29),26-hexaen-20-yl]-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1- carboxylate (compound E10, 5.6 g, 5.83 mmol) and formaldehyde (1.9 g, 23.3 mmol) in methanol (150 mL) was added Pd(OH)2on activated carbon (3.0 g, 2.91 mmol) under nitrogen 30 atmosphere. The reaction mixture was degassed and purged with H2for three times and then it was stirred at 35 °C for 15 hrs under H2 (15psi). After being cooled to room temperature, the reaction mixture was filtered, and the filtrate was concentrated under vacuum to give a residue. EtOAc (50 mL) and water (50 mL) were added into the residue and the layers were separated.-42- The aqueous phase was extracted with EtOAc (50 mL, twice). The combined organic layer was washed with brine (60 mL), dried over Na2SO4, and then filtered. The filtrate was concentrated under vacuum to give tert-butyl N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31- 5 tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7- yl]carbamate (compound E11, 3.9 g) as a yellow solid which was used in the next step without further purification. MS calc’d 841.5 (MH+), measured 841.4 (MH+). Step 12: Preparation of (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,30,31-10 tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaene- 8,14-dione (Intermediate E) To a solution of tert-butyl N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7- 15 yl]carbamate (compound E11, 3.9 g, 4.6 mmol) in DCM (30 mL) was added TFA (15.0 mL) in one portion. After being stirred at 25°C for 1 h, the mixture was poured into water (100 mL) and extracted with EtOAc (200 mL). The organic phase was washed with water (50 mL, twice). The combined aqueous phase was basified with sat. NaHCO3 aq. until pH = 9 and extracted with EtOAc (100 mL, three times). The combined organic layer was washed with brine (200 mL),20 dried over anhydrous Na2SO4, filtered and concentrated under vacuum to afford (7S,13S)-7- amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17- dimethyl-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (Intermediate E, 2.95 g) as a yellow solid. MS calc’d 741.5 (MH+), measured 741.4 (MH+). 25 Intermediate Y 6-bromo-8-iodo-1,2,3,4-tetrahydroquinolineThe compound was prepared according to the following scheme:-43-To a solution of 6-bromo-1,2,3,4-tetrahydroquinoline (compound Y1, 40.0 g, 188.6 mmol) in DMF (1.3 L) was added NIS (42.4 g, 188.6 mmol) portion-wise at 0 °C. After being stirred for 2 h at 25 °C, the reaction mixture was poured into water (4 L) and extracted with EtOAc (2 L, 5 three times). The combined organic layer was washed with brine (2 L, three times), dried with anhydrous Na2SO4, filtered and concentrated under vacuum to give a residue. The residue was purified by reversed phase chromatography to give 6-bromo-8-iodo-1,2,3,4-tetrahydroquinoline (Intermediate Y, 37 g) as a brown gum. MS calc’d 337.9 (MH+), measured 338.0 (MH+). Intermediate Z 10 Benzyl 4-[5-ethynyl-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylateThe compound Z was prepared according to the following scheme:-44-Step 1: Preparation of benzyl 4-[5-bromo-6-[(1S)-1-methoxyethyl]-3- pyridyl]piperazine-1-carboxylate (compound A5) To a solution of 3-bromo-5-iodo-2-[(1S)-1-methoxyethyl]pyridine (compound A3, 660 mg, 5 1.9 mmol, CAS 2641451-76-3, PBWZ170, PharmaBlock (Nanjing) R&D Co. Ltd) and 1-Cbz- piperazine (compound A4, 425.1 mg, 1.9 mmol) in toluene (10 mL) were added cesium carbonate (1.6 g, 4.83 mmol), (R)-BINAP (60.1 mg, 0.1 mmol) and palladium (II) acetate (43.3 mg, 0.19 mmol). After being stirred at 100 °C for 12 hrs under N2 protection, the mixture was filtered and then the filtrate was concentrated under vacuum. The residue was purified by silica10 gel chromatography (EA / PE: 0-50%) to afford benzyl 4-[5-bromo-6-[(1S)-1-methoxyethyl]-3- pyridyl]piperazine-1-carboxylate (compound A5, 740 mg) as a yellow solid. MS calc’d 434.1 (MH+), measured 434.1 (MH+). Step 2: Preparation of benzyl 4-[6-[(1S)-1-methoxyethyl]-5-(2-trimethylsilylethynyl)-3- pyridyl]piperazine-1-carboxylate (compound Z1) 15 To a solution of benzyl 4-[5-bromo-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1- carboxylate (compound A5, 33.0 g, 75.98 mmol) in DMF (1 L) was added trimethylsilylacetylene (85.9 mL, 607.83 mmol), Pd(PPh3)2Cl2(5.3 g, 7.6 mmol), CuI (1.5 g, 7.6 mmol) and TEA (52.9 mL, 379.9 mmol) under a nitrogen atmosphere. The reaction mixture was degassed and purged with nitrogen for three times and then it was stirred at 100 °C for 12 hrs. 20 After the reaction was completed, the reaction mixture was cooled to room temperature, filtered and the filtrate was added with H2O (3 L). The reaction mixture was extracted with EtOAc (1 L, three times). The combined organic layer was washed with brine (3 L), dried over Na2SO4,-45- filtered and concentrated under vacuum to give a residue, which was purified by column chromatography to afford benzyl 4-[6-[(1S)-1-methoxyethyl]-5-(2-trimethylsilylethynyl)-3- pyridyl]piperazine-1-carboxylate (compound Z1, 21.0 g) as a yellow solid. MS calc’d 452.2 (MH+), measured 452.2 (MH+). 5 Step 3: Preparation of benzyl 4-[5-ethynyl-6-[(1S)-1-methoxyethyl]-3- pyridyl]piperazine-1-carboxylate (intermediate Z) To a solution of benzyl 4-[6-[(1S)-1-methoxyethyl]-5-(2-trimethylsilylethynyl)-3- pyridyl]piperazine-1-carboxylate (compound Z1, 31 g, 68.6 mmol) in Methanol (500 mL) was added potassium fluoride (8.1 g, 139.8 mmol) at 0 °C. The mixture was stirred at 20 °C for 1 h. 10 After the reaction was completed, the reaction mixture was concentrated under vacuum to give a residue, which was purified by column chromatography to afford benzyl 4-[5-ethynyl-6-[(1S)-1- methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (intermediate Z, 25 g) as a brown solid. MS calc’d 380.2 (MH+), measured 380.2 (MH+). Intermediate B 15 Methyl (3S)-1-[(2S)-3-(4-bromothiazol-2-yl)-2-(tert- butoxycarbonylamino)propanoyl]hexahydropyridazine-3-carboxylateThe intermediate B was prepared according to the following scheme:-46-B8 Intermediate B Step 1: Preparation of (4-bromothiazol-2-yl)methanol (compound B2) To a solution of 4-bromothiazole-2-carboxaldehyde (compound B1 ̧6.0 g, 31.25 mmol)in methanol (70 mL) was added sodium borohydride (1.7 g, 46.87 mmol) at 0 °C. The mixture 5 was stirred at 25 °C for 1 hour. The reaction was quenched with water (300 mL) at 0 °C and the reaction mixture was extracted by ethyl acetate (200 mL, three times). The combined organic phase was washed with brine (150 mL, twice), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under vacuum to afford (4-bromothiazol-2-yl)methanol (compound B2, 6g) as colorless oil. 10 Step 2: Preparation of 4-bromo-2-(bromomethyl)thiazole (compound B3) To a solution of (4-bromothiazol-2-yl)methanol (compound B2, 6.0 g, 30.92 mmol) in DCM (80 mL) was added CBr4 (15.4 g, 46.38 mmol) and triphenylphosphine (12.1 g, 46.38 mmol) at 0 °C. After being stirred at 25 °C for 1 hour, the mixture was filtered, and the filtrate-47- was concentrated under vacuum. The residue was purified by silica gel column, eluted with ethyl acetate in petroleum ether (0~10%) to afford 4-bromo-2-(bromomethyl)thiazole (compound B3, 6.0 g) as yellow oil. MS calc’d 255.9 (MH+), measured 255.9 (MH+). Step 3: Preparation of 4-bromo-2-[[(2S,5R)-5-isopropyl-3,6-dimethoxy-2,5- 5 dihydropyrazin-2-yl]methyl]thiazole (compound B5) To a mixture of (2R)-2-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (compound B4, 4.3 g, 23.45 mmol) in THF (60 mL) was added n-butyllithium (10 mL, 25.22 mmol, 2.5 M) at - 78 °C slowly. After addition, the mixture was stirred for 0.5 hour at -78 °C.4-bromo-2- (bromomethyl)thiazole (compound B3, 5.4 g, 21.02 mmol) was added into above mixture at - 10 78 °C which was stirred for another 1 hour. The reaction was quenched with saturated solution of NH4Cl (100 mL), and the reaction mixture was extracted with EtOAc (100 mL, twice). The combined organic layer was washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under vacuum. The residue was purified by reversed- phase chromatography to afford 4-bromo-2-[[(2S,5R)-5-isopropyl-3,6-dimethoxy-2,5- 15 dihydropyrazin-2-yl]methyl]thiazole (compound B5, 3.6 g) as yellow oil. MS calc’d 360 (MH+), measured 359.9 (MH+). Step 4: Preparation of methyl (2S)-2-amino-3-(4-bromothiazol-2-yl)propanoate (compound B6) To a solution of 4-bromo-2-[[(2S,5R)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazin-2- 20 yl]methyl]thiazole (compound B5, 3.6 g, 10 mmol) in ACN (20 mL) was added hydrochloric acid (66.6 mL, 0.3 M). The mixture was stirred at 25 °C for 2 hours. The mixture was basified by saturated solution of NaHCO3 until pH=8. The mixture was extracted with EtOAc (80 mL, six times). The combined organic layer was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under vacuum to afford methyl (2S)-2-amino-3-(4-bromothiazol-2- 25 yl)propanoate (compound B6, 3.1 g) as yellow oil. MS calc’d 264.9 (MH+), measured 264.9 (MH+). Step 5: Preparation of methyl (2S)-3-(4-bromothiazol-2-yl)-2-(tert- butoxycarbonylamino)propanoate (compound B7) To a solution of methyl (2S)-2-amino-3-(4-bromothiazol-2-yl)propanoate (compound B6, 30 3.1 g, 11.69 mmol) in DCM (40 mL) were added TEA (2.9 g, 29.23 mmol) and (Boc)2O (3.8 g, 17.54 mmol). After being stirred at 30 °C for 12 hours, the mixture was concentrated under vacuum. The residue was purified by silica gel column, eluted with ethyl acetate in petroleum ether (0~30%) to afford methyl (2S)-3-(4-bromothiazol-2-yl)-2-(tert--48- butoxycarbonylamino)propanoate (compound B7, 3.2 g) as yellow oil. MS calc’d 387(MNa+), measured 386.9 (MNa+). Step 6: Preparation of (2S)-3-(4-bromothiazol-2-yl)-2-(tert-butoxycarbonylamino)- propanoic acid (compound B8) 5 To a solution of methyl (2S)-3-(4-bromothiazol-2-yl)-2-(tert- butoxycarbonylamino)propanoate (compound B7, 3.2 g, 8.76 mmol) in THF (30 mL), methanol (2 mL) and water (10 mL) was added lithium hydroxide (0.4 mL, 43.81 mmol). After being stirred at 25 °C for 1 hour, the reaction mixture was acidified by 1 M solution of HCl until pH=5. The mixture was extracted with EtOAc (40 mL, twice). The combined organic layer was washed 10 with brine (100 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under vacuum to afford (2S)-3-(4-bromothiazol-2-yl)-2-(tert- butoxycarbonylamino)propanoic acid (compound B8, 3.1 g) as yellow oil. MS calc’d 373(MNa+), measured 372.9 (MNa+). Step 7: Preparation of methyl (3S)-1-[(2S)-3-(4-bromothiazol-2-yl)-2-(tert- 15 butoxycarbonylamino)propanoyl]hexahydropyridazine-3-carboxylate (Intermediate B) To a solution of (2S)-3-(4-bromothiazol-2-yl)-2-(tert-butoxycarbonylamino)propanoic acid (compound B8, 3.1 g, 8.83 mmol) in DCM (50 mL) was added methyl (3S)- hexahydropyridazine-3-carboxylate;hydrochloride (compound B9, 2.4 g, 13.24 mmol), EDCI (3.4 g, 17.65 mmol), 1-Hydroxybenzotriazole (238.5 mg, 1.77 mmol) and NMM (9.92 mL, 88.26 20 mmol) at 0 °C. After being stirred at 25 °C for 1 hour, the reaction mixture was diluted with water (60 mL) and extracted with EtOAc (60 mL, three times). The combined organic layer was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under vacuum. The residue was purified by silica gel column and eluted with ethyl acetate in petroleum ether (10~30%) to afford methyl (3S)-1-[(2S)-3-(4-bromothiazol-2-yl)-2- 25 (tert-butoxycarbonylamino)propanoyl]hexahydropyridazine-3-carboxylate (intermediate B, 2.4 g). MS calc’d 477(MH+), measured 476.9 (MH+). Synthesis of Compound 2 1-[4-(dimethylamino)-4-methyl-pent-2-ynoyl]-N-[(1S)-1-[[(6S,8S,14S)-22-ethyl-25-fluoro- (21M)-21-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-18,18-dimethyl-9,15-dioxo-5,16-dioxa-30 2,10,22,28-tetrazapentacyclo[18.5.2.12,6.110,14.023,27]nonacosa-1(26),20,23(27),24-tetraen-8- yl]carbamoyl]-2-methyl-propyl]-4-fluoro-N-methyl-piperidine-4-carboxamide-49-The compound was prepared according to the following scheme:Step 1: Preparation of tert-butyl N-[(1S)-1-[[(6S,8S,14S)-22-ethyl-25-fluoro-(21M)-21-5 [2-[(1S)-1-methoxyethyl]-3-pyridyl]-18,18-dimethyl-9,15-dioxo-5,16-dioxa-2,10,22,28- tetrazapentacyclo[18.5.2.12,6.110,14.023,27]nonacosa-1(26),20,23(27),24-tetraen-8- yl]carbamoyl]-2-methyl-propyl]-N-methyl-carbamate (compound 2a) To a mixture of (6S,8S,14S)-8-amino-22-ethyl-25-fluoro-(21M)-21-[2-[(1S)-1- methoxyethyl]-3-pyridyl]-18,18-dimethyl-5,16-dioxa-2,10,22,28--50- tetrazapentacyclo[18.5.2.12,6.110,14.023,27]nonacosa-1(26),20,23(27),24-tetraene-9,15-dione (intermediate F, 270.0 mg, 0.41 mmol) and (2S)-2-[tert-butoxycarbonyl(methyl)amino]-3- methyl-butanoic acid (191.9 mg, 0.83 mmol) in DMF (3 mL) were added DIEA (0.36 mL, 2.07 mmol) and T4P (597.9 mg, 0.83 mmol) at 0 °C. The mixture was stirred at 25 °C for 1h. The 5 mixture was concentrated under vacuum to get a residue, which was purified by reversed phase chromatography to afford tert-butyl N-[(1S)-1-[[(6S,8S,14S)-22-ethyl-25-fluoro-(21M)-21-[2- [(1S)-1-methoxyethyl]-3-pyridyl]-18,18-dimethyl-9,15-dioxo-5,16-dioxa-2,10,22,28- tetrazapentacyclo[18.5.2.12,6.110,14.023,27]nonacosa-1(26),20,23(27),24-tetraen-8-yl]carbamoyl]-2- methyl-propyl]-N-methyl-carbamate (compound 2a, 210.0 mg) as a brown solid. MS calc’d 10 864.5 (MH+), measured 864.5(MH+). Step 2: Preparation of (2S)-N-[(6S,8S,14S)-22-ethyl-25-fluoro-(21M)-21-[2-[(1S)-1- methoxyethyl]-3-pyridyl]-18,18-dimethyl-9,15-dioxo-5,16-dioxa-2,10,22,28- tetrazapentacyclo[18.5.2.12,6.110,14.023,27]nonacosa-1(26),20,23(27),24-tetraen-8-yl]-3-methyl- 2-(methylamino)butanamide (compound 2b) 15 To a solution of tert-butyl N-[(1S)-1-[[(6S,8S,14S)-22-ethyl-25-fluoro-(21M)-21-[2-[(1S)-1- methoxyethyl]-3-pyridyl]-18,18-dimethyl-9,15-dioxo-5,16-dioxa-2,10,22,28- tetrazapentacyclo[18.5.2.12,6.110,14.023,27]nonacosa-1(26),20,23(27),24-tetraen-8-yl]carbamoyl]-2- methyl-propyl]-N-methyl-carbamate (compound 2a, 210.0 mg, 0.24 mmol) in DCM (2 mL) was added TFA (1.0 mL, 12.98 mmol). The mixture was stirred at 25 °C for 1 h. After the reaction 20 completed, the mixture was concentrated under vacuum to remove most solvent, then poured into sat. NaHCO3 aq. (5 mL) and extracted with EtOAc (30 mL, five times). The combined organic layer was washed by brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to afford (2S)-N-[(6S,8S,14S)-22-ethyl-25-fluoro-(21M)-21-[2-[(1S)- 1-methoxyethyl]-3-pyridyl]-18,18-dimethyl-9,15-dioxo-5,16-dioxa-2,10,22,28-25 tetrazapentacyclo[18.5.2.12,6.110,14.023,27]nonacosa-1(26),20,23(27),24-tetraen-8-yl]-3-methyl-2- (methylamino)butanamide (compound 2b, 225.0 mg) as a brown solid. MS calc’d 764.4 (MH+), measured 764.4 (MH+). Step 3: Preparation of tert-butyl 4-[[(1S)-1-[[(6S,8S,14S)-22-ethyl-25-fluoro-21-[2- [(1S)-1-methoxyethyl]-3-pyridyl]-18,18-dimethyl-9,15-dioxo-5,16-dioxa-2,10,22,28-30 tetrazapentacyclo[18.5.2.12,6.110,14.023,27]nonacosa-1(26),20,23(27),24-tetraen-8- yl]carbamoyl]-2-methyl-propyl]-methyl-carbamoyl]-4-fluoro-piperidine-1-carboxylate (compound 2c)-51- To a solution of (2S)-N-[(6S,8S,14S)-22-ethyl-25-fluoro-(21M)-21-[2-[(1S)-1- methoxyethyl]-3-pyridyl]-18,18-dimethyl-9,15-dioxo-5,16-dioxa-2,10,22,28- tetrazapentacyclo[18.5.2.12,6.110,14.023,27]nonacosa-1(26),20,23(27),24-tetraen-8-yl]-3-methyl-2- (methylamino)butanamide (compound 2b, 200.0 mg, 0.26 mmol) in DMF (2.5 mL) were added 5 DIEA (0.5 mL, 2.62 mmol), 1-tert-butoxycarbonyl-4-fluoro-piperidine-4-carboxylic acid (194.2 mg, 0.79 mmol) and CMPI (200.6 mg, 0.79 mmol) at 0 °C. The mixture was stirred at 25 °C for 1 h. The mixture was poured into water (30 mL) and extracted with EtOAc (30 mL, three times). The combined organic layer was washed by brine (30 mL, twice), dried over Na2SO4, filtered and concentrated under vacuum to give a residue. The residue was purified by reversed phase10 chromatography to afford tert-butyl 4-[[(1S)-1-[[(6S,8S,14S)-22-ethyl-25-fluoro-21-[2-[(1S)-1- methoxyethyl]-3-pyridyl]-18,18-dimethyl-9,15-dioxo-5,16-dioxa-2,10,22,28- tetrazapentacyclo[18.5.2.12,6.110,14.023,27]nonacosa-1(26),20,23(27),24-tetraen-8-yl]carbamoyl]-2- methyl-propyl]-methyl-carbamoyl]-4-fluoro-piperidine-1-carboxylate (compound 2c, 200.0 mg) as yellow oil. MS calc’d 993.6 (MH+), measured 993.6 (MH+). 15 Step 4: Preparation of N-[(1S)-1-[[(6S,8S,14S)-22-ethyl-25-fluoro-(21M)-21-[2-[(1S)-1- methoxyethyl]-3-pyridyl]-18,18-dimethyl-9,15-dioxo-5,16-dioxa-2,10,22,28- tetrazapentacyclo[18.5.2.12,6.110,14.023,27]nonacosa-1(26),20,23(27),24-tetraen-8- yl]carbamoyl]-2-methyl-propyl]-4-fluoro-N-methyl-piperidine-4-carboxamide (compound 2d) 20 To a solution of tert-butyl 4-[[(1S)-1-[[(6S,8S,14S)-22-ethyl-25-fluoro-21-[2-[(1S)-1- methoxyethyl]-3-pyridyl]-18,18-dimethyl-9,15-dioxo-5,16-dioxa-2,10,22,28- tetrazapentacyclo[18.5.2.12,6.110,14.023,27]nonacosa-1(26),20,23(27),24-tetraen-8-yl]carbamoyl]-2- methyl-propyl]-methyl-carbamoyl]-4-fluoro-piperidine-1-carboxylate (compound 2c, 200.0 mg, 0.2 mmol) in DCM (2 mL) was added TFA (1.1 mL, 14.35 mmol) at 0°C. The mixture was 25 stirred at 25°C for 1 hour. After the reaction completed, the mixture was concentrated under vacuum to remove most solvent, then poured into sat. NaHCO3aq. (5 mL) and extracted with EtOAc (20 mL, three times). The combined organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to afford N-[(1S)-1- [[(6S,8S,14S)-22-ethyl-25-fluoro-(21M)-21-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-18,18-dimethyl-30 9,15-dioxo-5,16-dioxa-2,10,22,28-tetrazapentacyclo[18.5.2.12,6.110,14.023,27]nonacosa- 1(26),20,23(27),24-tetraen-8-yl]carbamoyl]-2-methyl-propyl]-4-fluoro-N-methyl-piperidine-4- carboxamide (compound 2d, 200.0 mg) as yellow oil. MS calc’d 893.5 (MH+), measured 893.5 (MH+).-52- Step 5: Preparation of 1-[4-(dimethylamino)-4-methyl-pent-2-ynoyl]-N-[(1S)-1- [[(6S,8S,14S)-22-ethyl-25-fluoro-(21M)-21-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-18,18- dimethyl-9,15-dioxo-5,16-dioxa-2,10,22,28- tetrazapentacyclo[18.5.2.12,6.110,14.023,27]nonacosa-1(26),20,23(27),24-tetraen-8- 5 yl]carbamoyl]-2-methyl-propyl]-4-fluoro-N-methyl-piperidine-4-carboxamide (Compound 2) To a mixture of N-[(1S)-1-[[(6S,8S,14S)-22-ethyl-25-fluoro-(21M)-21-[2-[(1S)-1- methoxyethyl]-3-pyridyl]-18,18-dimethyl-9,15-dioxo-5,16-dioxa-2,10,22,28- tetrazapentacyclo[18.5.2.12,6.110,14.023,27]nonacosa-1(26),20,23(27),24-tetraen-8-yl]carbamoyl]-2- 10 methyl-propyl]-4-fluoro-N-methyl-piperidine-4-carboxamide (compound 2d, 100.0 mg, 0.11 mmol) and 4-(dimethylamino)-4-methyl-pent-2-ynoic acid (intermediate I, 34.7 mg, 0.22 mmol,) in DMF (2 mL) were added DIEA (0.1 mL, 0.56 mmol) and T4P (161.4 mg, 0.22 mmol) at 0 °C. The mixture was stirred at 25 °C for 1h, then purified by Prep-HPLC to afford 1-[4- (dimethylamino)-4-methyl-pent-2-ynoyl]-N-[(1S)-1-[[(6S,8S,14S)-22-ethyl-25-fluoro-(21M)-21-15 [2-[(1S)-1-methoxyethyl]-3-pyridyl]-18,18-dimethyl-9,15-dioxo-5,16-dioxa-2,10,22,28- tetrazapentacyclo[18.5.2.12,6.110,14.023,27]nonacosa-1(26),20,23(27),24-tetraen-8-yl]carbamoyl]-2- methyl-propyl]-4-fluoro-N-methyl-piperidine-4-carboxamide (compound 2, 45.0 mg) as a yellow solid. MS calc’d 1030.6 (MH+), measured 1030.6 (MH+).1H NMR (400 MHz, METHANOL-d4) δ = 8.82 ( s, 1H), 8.25 - 8.13 (m, 1H), 7.75 - 7.65 (m, 1H), 7.33 - 7.23 (m, 2H), 5.74 - 5.64 (m, 20 1H), 4.65 - 4.60 (d, J = 10.8 Hz, 1H), 4.55 - 4.44 (m, 1H), 4.40 - 4.30 (m, 1H), 4.30 - 4.17 (m, 2H), 4.16 - 4.06 (m, 1H), 3.98 - 3.89 (m, 2H), 3.89 - 3.84 (m, 1H), 3.80 (dd, J = 4.0, 11.2 Hz, 2H), 3.65-3.55 (m, 2H), 3.50 - 3.37 (m, 1H), 3.26 - 3.18 (m, 4H), 3.16 (d, J = 5.2 Hz, 2H), 3.10 - 3.08 (m, 1H), 3.02 ( s, 5H), 2.98 - 2.94 (m, 1H), 2.84 - 2.76 (m, 1H), 2.71 - 2.58 (m, 1H), 2.38 - 2.25 (m, 2H), 2.23 - 2.03 (m, 5H), 1.99 - 1.85 (m, 3H), 1.80 (s, 6H), 1.75 - 1.56 (m, 4H), 1.51 - 25 1.39 (m, 5H), 1.11-1.01 (m, 3H), 1.00 - 0.89 (m, 6H), 0.85 (d, J = 6.4 Hz, 2H), 0.82 - 0.73 (m, 4H). Intermediate F (6S,8S,14S)-8-amino-22-ethyl-25-fluoro-(21M)-21-[2-[(1S)-1-methoxyethyl]-3-pyridyl]- 18,18-dimethyl-5,16-dioxa-2,10,22,28-tetrazapentacyclo[18.5.2.12,6.110,14.023,27]nonacosa- 30 1(26),20,23(27),24-tetraene-9,15-dione-53-The compound was prepared according to the following scheme:F6 intermediate FStep 1: Preparation of 2-[(1S)-1-methoxyethyl]-3-(4,4,5,5-tetramethyl-1,3,2- 5 dioxaborolan-2-yl)pyridine (compound F1) To a solution of 3-bromo-2-[(1S)-1-methoxyethyl]pyridine (compound A1, 46.0 g, 212.88 mmol) and bis(pinacolato)diboron (108.1 g, 425.77 mmol) in 2-methyltetrahydrofuran (1 L) were added potassium carbonate (88.3 g, 638.65 mmol), Pd(dppf)Cl2(15.6 g, 21.29 mmol) and pivalic acid (10.87 g, 106.44 mmol). Then the mixture was degassed and purged with N2(this-54- sequence was repeated three times). After being stirred at 80 °C for 3 hrs under N2, the reaction mixture was filtered, and the collected solid was washed with EtOAc (100 mL). The filtrate was poured into water (400 mL), extracted with EA (400 mL, three times).The combined organic layer was washed with brine (300 mL, twice), dried over Na2SO4, filtered, and concentrated 5 under vacuum to give the crude product which was purified by silica gel chromatography to afford 2-[(1S)-1-methoxyethyl]-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (compound F1, 75.0 g) as brown oil. MS calc’d 264.1 (MH+), measured 264.0 (MH+). Step 2: Preparation of [3-[5-bromo-6-fluoro-2-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-1H- indol-3-yl]-2,2-dimethyl-propoxy]-tert-butyl-diphenyl-silane (compound F2) 10 To a mixture of 2-[(1S)-1-methoxyethyl]-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyridine (compound F1, 18.0 g, 30.78 mmol) and [3-(5-bromo-6-fluoro-2-iodo-1H-indol-3- yl)-2,2-dimethyl-propoxy]-tert-butyl-diphenyl-silane (intermediate D, 20.5 g, 30.78 mmol) in 1,4-dioxane (200 mL) / water (70 mL) / toluene (70 mL) were added potassium phosphate (19.6 g, 92.35 mmol) and Pd(dppf)Cl2 (2.3 g, 3.08 mmol). The mixture was stirred at 70 °C for 16 hrs 15 under N2. After the reaction completed, the cooling reaction mixture was filtered, and the filtrate was concentrated under vacuum. The resultant mixture was extracted with EtOAc (200 mL, three times). The combined organic layer was washed with brine (100 mL, twice), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography to afford [3-[5-bromo-6-fluoro-2-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-1H-indol-3-yl]-2,2- 20 dimethyl-propoxy]-tert-butyl-diphenyl-silane (compound F2, 22.0 g) as a brown solid. MS calc’d 674.7 (MH+), measured 675.3 (MH+). Step 3: Preparation of [3-[5-bromo-1-ethyl-6-fluoro-(2M)-2-[2-[(1S)-1-methoxyethyl]- 3-pyridyl]indol-3-yl]-2,2-dimethyl-propoxy]-tert-butyl-diphenyl-silane (compound F3) To a solution of [3-[5-bromo-6-fluoro-2-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-1H-indol-3- 25 yl]-2,2-dimethyl-propoxy]-tert-butyl-diphenyl-silane (compound F2, 7 g, 10.39 mmol,) in toluene (20 mL) were added benzyl(triethyl)azanium;bromide (5.6 g, 20.78 mmol), molecular sieve (4Å) (7.5 g, 31.17 mmol) and KOH (1.2 g, 20.78 mmol). The reaction mixture was added with a solution of iodoethane (1.1 mL, 13.51 mmol) in toluene (2 mL). After being stirred at 25 °C for 6 hrs, the reaction mixture was filtered, and the filtrate was concentrated under vacuum to 30 give a residue. The residue was purified by NPLC (Column: Welch Ultimate XB-SiOH 250 mm × 100 mm × 10 µm, Hexane-EtOH) and concentrated to give [3-[5-bromo-1-ethyl-6-fluoro- (2M)-2-[2-[(1S)-1-methoxyethyl]-3-pyridyl]indol-3-yl]-2,2-dimethyl-propoxy]-tert-butyl--55- diphenyl-silane (compound F3, 7.0 g) as yellow oil. MS calc’d 702.8 (MH+), measured 703.2 (MH+). Step 4: Preparation of methyl (3S)-1-[(2S)-2-(benzyloxycarbonylamino)-3-[(2S)-4-[3- [3-[tert-butyl(diphenyl)silyl]oxy-2,2-dimethyl-propyl]-1-ethyl-6-fluoro-(2M)-2-[2-[(1S)-1- 5 methoxyethyl]-3-pyridyl]indol-5-yl]morpholin-2-yl]propanoyl]hexahydropyridazine-3- carboxylate (compound F4) To the mixture of [3-[5-bromo-1-ethyl-6-fluoro-(2M)-2-[2-[(1S)-1-methoxyethyl]-3- pyridyl]indol-3-yl]-2,2-dimethyl-propoxy]-tert-butyl-diphenyl-silane (compound F3, 2.1 g, 2.99 mmol) in 1,4-dioxane (20 mL) was added methyl (3S)-1-[(2S)-2-(benzyloxycarbonylamino)-3- 10 [(2S)-morpholin-2-yl]propanoyl]hexahydropyridazine-3-carboxylate (intermediate C, 1.6 g, 3.59 mmol), Pd-PESSI-IPent Cl (251.4 mg, 0.3 mmol) and cesium carbonate (2.9 g, 8.98 mmol). The mixture was stirred at 115 °C for 16 hrs. The cooling reaction mixture was added with EtOAc (40 mL), and water (40 mL) and layers were separated. The aqueous phase was extracted with EtOAc (30 mL, twice). The combined organic layer was washed with brine (50 mL), dried over15 Na2SO4, filtered, and purified by column chromatography to afford methyl (3S)-1-[(2S)-2- (benzyloxycarbonylamino)-3-[(2S)-4-[3-[3-[tert-butyl(diphenyl)silyl]oxy-2,2-dimethyl-propyl]- 1-ethyl-6-fluoro-(2M)-2-[2-[(1S)-1-methoxyethyl]-3-pyridyl]indol-5-yl]morpholin-2- yl]propanoyl]hexahydropyridazine-3-carboxylate (compound F4, 1.0 g) as a yellow solid. MS calc’d 1055.5 (MH+), measured 1055.6 (MH+). 20 Step 5: Preparation of (3S)-1-[(2S)-2-(benzyloxycarbonylamino)-3-[(2S)-4-[1-ethyl-6- fluoro-3-(3-hydroxy-2,2-dimethyl-propyl)-(2M)-2-[2-[(1S)-1-methoxyethyl]-3-pyridyl]indol- 5-yl]morpholin-2-yl]propanoyl]hexahydropyridazine-3-carboxylic acid (compound F5) A solution of methyl (3S)-1-[(2S)-2-(benzyloxycarbonylamino)-3-[(2S)-4-[3-[3-[tert- butyl(diphenyl)silyl]oxy-2,2-dimethyl-propyl]-1-ethyl-6-fluoro-(2M)-2-[2-[(1S)-1-25 methoxyethyl]-3-pyridyl]indol-5-yl]morpholin-2-yl]propanoyl]hexahydropyridazine-3- carboxylate (compound F4, 1.0 g, 0.95 mmol) in TBAF (7.6 mL, 7.6 mmol, 1 M in THF) was stirred at 40 °C for 12 hrs. After the reaction completed, the mixture was concentrated under vacuum to remove most solvent. The residue was diluted with 1N HCl aqueous solution (15 mL) and extracted with EtOAc (50 mL, three times). The combined organic layer was washed by aq. 30 NH4Cl (30 mL, twice), brine (40 mL, twice), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a crude product. The crude product was purified by reversed phase chromatography to afford (3S)-1-[(2S)-2-(benzyloxycarbonylamino)-3-[(2S)-4-[1-ethyl-6- fluoro-3-(3-hydroxy-2,2-dimethyl-propyl)-(2M)-2-[2-[(1S)-1-methoxyethyl]-3-pyridyl]indol-5--56- yl]morpholin-2-yl]propanoyl]hexahydropyridazine-3-carboxylic acid (compound F5, 500.0 mg) as a yellow solid. MS calc’d 803.4 (MH+), measured 803.4(MH+). Step 6: Preparation of benzyl N-[(6S,8S,14S)-22-ethyl-25-fluoro-(21M)-21-[2-[(1S)-1- methoxyethyl]-3-pyridyl]-18,18-dimethyl-9,15-dioxo-5,16-dioxa-2,10,22,28- 5 tetrazapentacyclo[18.5.2.12,6.110,14.023,27]nonacosa-1(26),20,23(27),24-tetraen-8-yl]carbamate (compound F6) To a solution of (3S)-1-[(2S)-2-(benzyloxycarbonylamino)-3-[(2S)-4-[1-ethyl-6-fluoro-3-(3- hydroxy-2,2-dimethyl-propyl)-(2M)-2-[2-[(1S)-1-methoxyethyl]-3-pyridyl]indol-5-yl]morpholin- 2-yl]propanoyl]hexahydropyridazine-3-carboxylic acid (compound F5, 700.0 mg, 0.87 mmol) in10 DCM (70 mL) were added DIEA (1.1 g, 8.72 mmol), HATU (1.7 g, 4.36 mmol) and 1- methylimidazole (715.8 mg, 8.72 mmol) at 25 °C. After being stirred at rt for 1 h, the mixture was concentrated under vacuum and purified by reversed phase chromatography to give benzyl N-[(6S,8S,14S)-22-ethyl-25-fluoro-(21M)-21-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-18,18- dimethyl-9,15-dioxo-5,16-dioxa-2,10,22,28-tetrazapentacyclo[18.5.2.12,6.110,14.023,27]nonacosa- 15 1(26),20,23(27),24-tetraen-8-yl]carbamate (compound F6, 320.0 mg) as a light yellow solid. MS calc’d 785.5 (MH+), measured 785.4(MH+). Step 7: Preparation of (6S,8S,14S)-8-amino-22-ethyl-25-fluoro-(21M)-21-[2-[(1S)-1- methoxyethyl]-3-pyridyl]-18,18-dimethyl-5,16-dioxa-2,10,22,28- tetrazapentacyclo[18.5.2.12,6.110,14.023,27]nonacosa-1(26),20,23(27),24-tetraene-9,15-dione 20 (intermediate F) To a solution of benzyl N-[(6S,8S,14S)-22-ethyl-25-fluoro-(21M)-21-[2-[(1S)-1- methoxyethyl]-3-pyridyl]-18,18-dimethyl-9,15-dioxo-5,16-dioxa-2,10,22,28- tetrazapentacyclo[18.5.2.12,6.110,14.023,27]nonacosa-1(26),20,23(27),24-tetraen-8-yl]carbamate (compound F6, 300.0 mg, 0.38 mmol) in THF (3 mL) was added Pd(OH)2 on activated carbon 25 (200 mg). The mixture reaction was stirred at 25 °C for 2 hrs. The mixture was filtered and the filtrate was concentrated under vacuum to afford (6S,8S,14S)-8-amino-22-ethyl-25-fluoro- (21M)-21-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-18,18-dimethyl-5,16-dioxa-2,10,22,28- tetrazapentacyclo[18.5.2.12,6.110,14.023,27]nonacosa-1(26),20,23(27),24-tetraene-9,15-dione (intermediate F, 270.0 mg) as a yellow solid. MS calc’d 651.4 (MH+), measured 651.4 (MH+). 30 Intermediate I 4-(dimethylamino)-4-methyl-pent-2-ynoic acid-57-The compound was prepared according to the following scheme:I1 I2 intermediate IStep 1: Preparation of N,N,2-trimethylbut-3-yn-2-amine (compound I2) 5 A mixture of 3-chloro-3-methyl-1-butyne (20.0 g, 195.01 mmol) and dimethylamine (22.0 g, 195.01 mmol) was stirred at 25 °C for 12 hrs. After the reaction completed, the suspension was filtered. The collected solid was washed with ice-water (50 mL, three times) and dissolved in cold HCl (3 N, 10 mL). The acidic solution was extracted with methyl tert-butyl ether (50 mL, twice). The resulting aqueous phase was cooled at 0 °C and made strongly alkaline with cold 10 NH3.H2O. The yellow precipitate was collected, washed with NH3.H2O (50 mL, three times) and H2O (50 mL, three times). The collected solid was concentrated in vacuo to afford N,N,2- trimethylbut-3-yn-2-amine (compound I2, 4.0 g) as a yellow solid. MS calc’d 112.1 (MH+), measured 112.1 (MH+). Step 2: Preparation of 4-(dimethylamino)-4-methyl-pent-2-ynoic acid (intermediate I) 15 To a solution of N,N,2-trimethylbut-3-yn-2-amine (compound I2, 3.2 g, 28.78 mmol) in THF (120 mL) was added dropwise n-BuLi (12.7 mL, 31.66 mmol, 2M in hexane) at -70 °C. After being stirred at -70°C for 5 min, the reaction mixture was warmed to 0 °C and stirred for another 10 min. After being cooled to -70 °C, the reaction mixture was bubbled with carbon dioxide for 30 min. The reaction mixture was stirred at 0°C for 2 hrs. After the reaction 20 completed, the reaction mixture was carefully hydrolyzed at 0°C by water (40 mL). Two phases were separated, and the aqueous layer was acidified with pH to 1-2 with 6N HCl. The aqueous was concentrated under vacuum to afford 4-(dimethylamino)-4-methyl-pent-2-ynoic acid (intermediate I, 4.3 g) as a white solid, which was used in the next step without purification. MS calc’d 156.1 (MH+), measured 156.1 (MH+).1H NMR (400 MHz, DEUTERIUM OXIDE-D2O) δ 25 = 2.99 - 2.91 (m, 6H), 1.77 - 1.68 (m, 6H). Intermediate C-58- Methyl (3S)-1-[(2S)-2-(benzyloxycarbonylamino)-3-[(2S)-morpholin-2- yl]propanoyl]hexahydropyridazine-3-carboxylateThe compound was prepared according to the following scheme:5intermediate CStep 1: Preparation of (2S)-2-(benzyloxycarbonylamino)-3-[(2S)-4-tert- butoxycarbonylmorpholin-2-yl]propanoic acid (compound C2) To a solution of tert-butyl (2S)-2-[(2S)-2-(benzyloxycarbonylamino)-3-methoxy-3-oxo- propyl]morpholine-4-carboxylate (CAS: 2641824-60-2, 20.0 g, 47.34 mmol) in THF (250 10 mL) / water (50 mL) was added LiOH·H2O (4.0 g, 94.68 mmol) at 0°C. After being stirred at 25 °C for 1.5 hrs, the reaction mixture was acidified by citric acid aq. until pH=6. The mixture was extracted with EtOAc (200 mL, three times). The combined organic layer was washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under vacuum to afford (2S)-2-(benzyloxycarbonylamino)-3-[(2S)-4-tert--59- butoxycarbonylmorpholin-2-yl]propanoic acid (compound C2, 20.0 g) as a yellow solid. MS calc’d 409.2 (MH+), measured 409.2 (MH+). Step 2: Preparation of tert-butyl (2S)-2-[(2S)-2-(benzyloxycarbonylamino)-3-[(3S)-3- methoxycarbonylhexahydropyridazin-1-yl]-3-oxo-propyl]morpholine-4-carboxylate 5 (compound C3) To a mixture of (2S)-2-(benzyloxycarbonylamino)-3-[(2S)-4-tert- butoxycarbonylmorpholin-2-yl]propanoic acid (compound C2, 20.0 g, 48.97 mmol) and methyl (3S)-hexahydropyridazine-3-carboxylate;dihydrochloride (compound B9, 21.3 g, 97.93 mmol,) in DMF (300 mL) was added DIEA (42.6 mL, 244.83 mmol) and T4P (70.6 g, 97.93 mmol) at 10 0 °C. After being stirred at 25 °C for 0.5 h, the reaction mixture was poured into water (300 mL) and extracted with EtOAc (150 mL, three times). The combined organic layer was washed with brine (150 mL, three times), dried over anhydrous Na2SO4, filtered and concentrated under vacuum to get a residue. The residue was purified by silica gel chromatography to tert-butyl (2S)-2-[(2S)-2-(benzyloxycarbonylamino)-3-[(3S)-3-methoxycarbonylhexahydropyridazin-1-yl]- 15 3-oxo-propyl]morpholine-4-carboxylate (compound C3, 22.7 g) as yellow oil. MS calc’d 535.3 (MH+), measured 535.3 (MH+). Step 3: Preparation of methyl (3S)-1-[(2S)-2-(benzyloxycarbonylamino)-3-[(2S)- morpholin-2-yl]propanoyl]hexahydropyridazine-3-carboxylate (intermediate C) To a solution of tert-butyl (2S)-2-[(2S)-2-(benzyloxycarbonylamino)-3-[(3S)-3- 20 methoxycarbonylhexahydropyridazin-1-yl]-3-oxo-propyl]morpholine-4-carboxylate (compound C3, 5.0 g, 9.35 mmol) in DCM (20 mL) was added TFA (19.8 mL) at 0 °C. The mixture was stirred at 25°C for 1 hour. After the reaction was completed, the reaction mixture was concentrated under vacuum to give a residue. Sat. NaHCO3aq. (20 mL) was added, and the mixture was extracted with EtOAc (30 mL, three times). The combined organic layer was 25 washed with brine (60 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford methyl (3S)-1-[(2S)-2-(benzyloxycarbonylamino)-3-[(2S)-morpholin-2- yl]propanoyl]hexahydropyridazine-3-carboxylate (intermediate C, 4.0 g) as a brown solid. MS calc’d 435.2 (MH+), measured 435.2 (MH+). Intermediate D 30 [3-(5-bromo-6-fluoro-2-iodo-1H-indol-3-yl)-2,2-dimethyl-propoxy]-tert-butyl-diphenyl- silane-60-The compound was prepared according to the following scheme:Intermediate D Step 1: Preparation of 1-(5-bromo-6-fluoro-1H-indol-3-yl)-3-((tert-butyldiphenylsilyl) 5 oxy)-2,2-dimethylpropan-1-one (compound D3) To a mixture of 3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropanoyl chloride (compound D1, 35.0 g, 116.8 mmol) in DCM (400 mL) at 0 °C was added a solution of SnCl4 (97.2 mL, 121.5 mmol) slowly. After the mixture was stirred at -40 °C for 0.5 hour, 5-bromo-6- fluoro-1H-indole (compound D2, 25.0 g, 116.8 mmol) in DCM (200 mL) was added dropwise 10 and the mixture was stirred at -40 °C for another 15 min. After the reaction was completed, it was quenched with sat.NaHCO3 aq. (800 mL), and the reaction mixture was extracted with EtOAc (900 mL, twice). The combined organic layer was washed with brine (700 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was triturated in a mixed solvent (100 mL, Petroleum ether: Ethyl acetate = 8:1) and filtered. The collected solid was dried in-61- vacuo to afford 1-(5-bromo-6-fluoro-1H-indol-3-yl)-3-((tertbutyldiphenylsilyl)oxy)-2,2- dimethylpropan-1-one (compound D3, 50.0 g) as a yellow solid. MS calc’d 552.1 (MH+), measured 552.1 (MH+). Step 2: Preparation of [3-(5-bromo-6-fluoro-1H-indol-3-yl)-2,2-dimethyl-propoxy]- 5 tert-butyl-diphenyl-silane (compound D4) To a mixture of 1-(5-bromo-6-fluoro-1H-indol-3-yl)-3-((tertbutyldiphenylsilyl)oxy)-2,2- dimethylpropan-1-one (compound D3, 50.0 g, 90.49 mmol) in THF (600 mL) was added LiBH4 (48.4 mL, 193.49 mmol, 4 M in THF) dropwise at 0 °C. The mixture was stirred at 70 °C for 24 hrs under nitrogen atmosphere. After the reaction was completed, it was quenched by addition of 10 water (600 mL) at 0 °C slowly and the reaction mixture was extracted with EtOAc (600 mL, twice). The combined organic layer was washed with brine (600 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica column chromatography (EtOAc in PE = 20% ~ 33%) to afford [3-(5-bromo-6-fluoro-1H-indol-3-yl)-2,2-dimethyl- propoxy]-tert-butyl-diphenyl-silane (compound D4, 46.0 g) as a white solid. MS calc’d 538.1 15 (MH+), measured 538.2 (MH+). Step 3: Preparation of [3-(5-bromo-6-fluoro-2-iodo-1H-indol-3-yl)-2,2-dimethyl- propoxy]-tert-butyl-diphenyl-silane (intermediate D) To a mixture of [3-(5-bromo-6-fluoro-1H-indol-3-yl)-2,2-dimethyl-propoxy]-tert-butyl- diphenyl-silane (compound D4, 35.4 g, 65.73 mmol) and iodine (18.4 g, 72.3 mmol) in THF 20 (400 mL) was added silver trifluoromethanesulfonate (20.3 g, 78.88 mmol) at 0 °C. The mixture was stirred at 0 °C for 10 min. After the reaction was completed, it was quenched by sat. Na2SO3 aq. (400 mL) and EtOAc (400 mL) and the reaction mixture was filtered. The organic layer was washed with brine (100 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica column chromatography (EtOAc in PE = 0% ~ 2.5%) to afford [3-(5- 25 bromo-6-fluoro-2-iodo-1H-indol-3-yl)-2,2-dimethyl-propoxy]-tert-butyl-diphenyl-silane (intermediate D, 43.0 g) as a yellow solid. MS calc’d 664.0 (MH+), measured 664.1 (MH+). Biological Examples CDX (cell-derived xenograft) models 30 The objective of this study is to evaluate preclinically the in vivo therapeutic efficacy of test article in the treatment of subcutaneous cell derived xenograft model (NCI-H2122, LS180, KP-4,MKN-1, NCI-H1975-OSI ) , in female BALB / c nude mice.-62- Studies were conducted at Wuxi AppTec (Nantong, China) or Crownbio (Taicang, China). All mouse studies and procedures related to animal handling, care and treatment were conducted in compliance with all applicable regulations and guidelines of the relevant Institutional Animal Care and Use Committee (IACUC). Mice were maintained under pathogen-free conditions, and 5 food and water were provided ad libitum. Female BALB / c nude mice or at 6-8 weeks old from Vital River Co. or Gempharmatech Co were used for these studies. In order to generate subcutaneous xenograft tumors, each mouse was inoculated at the right flank with tumor cells in 0.2mL of PBS and 50% matrigel with 5×10^6 NCI-H2122 cells, or in 0.1 ml of PBS with 2×10^6 LS180 cells, or in 0.2mL of PBS and 10 50% matrigel 1×10^6 KP-4 cells, or in0.2mL PBS and 50% matrigel 10×10^6 MKN-1, or in 0.1mL of PBS with 5x10^6 NCI-H1975-OSI cells. Mouse health was monitored daily, and caliper measurements began when tumors were palpable. Tumor volume measurements were determined utilizing the formula 0.5 × L × W2 in which L refers to length and W refers to width of each tumor. When tumors reached an average tumor volume of approximately 200 mm3for 15 LS180, KP-4 and NCI-H1975-OSI, 350 mm^3 for NCI-H2122 and MKN-1, mice were randomized into treatment groups. Mice were treated with either vehicle or isotope control or compounds in indicated formulations and dose regimens. For efficacy studies, tumor volumes and body weights were measured 3 times per week. Study day on efficacy plots indicates the day after which treatment 20 was initiated. PDX (patient-derived xenograft) models The objective of this study is to evaluate preclinically the in vivo therapeutic efficacy of 25 test article in the treatment of subcutaneous PDX models (LU11693, CR2528, PA2410) in female BALB / c nude mice and LD1-0038-361928 model in Nu / Nu mice (Crl:NU-Foxn1nu) Studies were conducted at Crownbio (Taicang, China) or Lidi (Shanghai, China). All mouse studies and procedures related to animal handling, care and treatment were conducted in compliance with all applicable regulations and guidelines of the relevant Institutional Animal 30 Care and Use Committee (IACUC). Mice were maintained under pathogen-free conditions, and food and water were provided ad libitum. Female BALB / c nude mice or at 6-8 weeks old from Shanghai Lingchang Bio-Technology Co. Ltd. were used for these studies. Each mouse will be inoculated subcutaneously at the right flank with a primary human tumor xenograft model tumor fragment (2-3 mm in diameter) for-63- tumor development. Randomization will begin when the mean tumor size reaches approximately 250-300 mm³. Post-inoculation, animals will be monitored daily for morbidity, mortality, and effects on behavior, with body weights and tumor volumes measured twice per week. Tumor volumes will be calculated using the formula V = (L × W × W) / 2. Treatment will commence 5 after randomization (day 0) as per the study design. PBMC model The objective of this study is to evaluate preclinically the in vivo therapeutic efficacy of test article in the treatment of subcutaneous human PBMC model (NCI-H441, NCI-H358 ) , in 10 female severe immunodeficient mice. Studies were conducted at Nona Biosciences (Shanghai, China). All mouse studies and procedures related to animal handling, care and treatment were conducted in compliance with all applicable regulations and guidelines of the relevant Institutional Animal Care and Use Committee (IACUC). Mice were maintained under pathogen-free conditions, and food and water 15 were provided ad libitum. Female NPG mice or at 6-8 weeks old from Beijing Vitalstar Biotechnology Co. Ltd. were used for these studies. In order to generate subcutaneous tumors, each mouse was inoculated subcutaneously on the right front region with 5x10^6 NCI-H441 cells with Matrigel in 0.1 mL of PBS or 5x10^6 NCI-H358 cells with Matrigel in 0.1 mL of PBS for tumor development. Mouse 20 health was monitored daily, and caliper measurements began when tumors were palpable. Tumor volume measurements were determined utilizing the formula 0.5 × L × W2 in which L refers to length and W refers to width of each tumor. When tumors reached an average tumor volume of approximately 80 mm3 for NCI-H441 and 125 mm3 for NCI-H358, 5x10^6 PBMC was injected into each animal by i.v. route and then mice were randomized into treatment groups. 25 Mice were treated with either vehicle or isotope control or compounds in indicated formulations and dose regimens. For efficacy studies, tumor volumes and body weights were measured 2-3 times per week. Study day on efficacy plots indicates the day after which treatment was initiated. 30 Materials Formulations: Vehicle : DMSO : Solutol HS15 :water (10:10:80); Compound 1 : DMSO : Solutol HS15:water (10:10:80);-64- Compound 2 : DMSO : Solutol HS15 :water (10:10:80); Erlotinib: 0.5% MC (400 cp) + 0.2% Tween 80 in ddH2O IAG933: 95 % 50 mM acetate buffer pH 4:5 % PEG300, pH 4.8 Divarasib: 0.6% Methocel A15 LV PH~4 5 Inavolisib: 0.6% Methocel A15 LV / 0.2% Tween 80 Osimertinib: 1% DMSO+30% PEG300 + 69%ddH2O Encorafenib: 0.5% methylcellulose with 0.5% Tween 80 Irinotecan: 0.9% NaCl 10 Oxaliplatin: 0.9% NaCl Leucovorin: 0.9% NaCl 5-Fu: 0.9% NaCl Gemcitabine: 0.9% NaCl Paxtaxel: 0.9% NaCl 15 Isotype:0.9% NaCl Bevacizumab: 0.9% NaCl Cetuximab: 0.9% NaCl Aflibercept: 0.9% NaCl 20 Pembrolizumab: PBS (Phosphate-buffered saline) Amivantamab: PBS Cadonilimab: PBS Ivonescimab: PBS 25 Compounds: Table 1. compound information-65- 5 10Summary of experiment conditions and results Table 2. Summary of TGI following Compound 1 mono or combo therapy-66--67-Example 1 Efficacy study testing Compound 1 in combination with EGFR inhibitor (Erlotinib) or anti-EGFR antibody (Cetuximab) in NCI-H2122 NSCLC and CR2528 CRC KRAS mutant 5 models Erlotinib and Cetuximab are well known EGFR inhibitors as NSCLC and CRC therapies respectively. Combination efficacy of Compound 1 with erlotinib was evaluated in an NCI-H2122 NSCLC xenograft model. Single-agent Compound 1 resulted in near complete tumor stasis 10 (93 % TGI), whereas single-agent erlotinib resulted in 49% TGI. Improved anti-tumor efficacy (119% TGI) was observed with the combination of Compound 1 and erlotinib (see Figure 1). All treatments and combinations were tolerated based on minimal changes in body weight and overall animal condition. These data demonstrate the significantly improved antitumor activity via the combination of Compound 1 and erlotinib compared with each single agent in a KRAS 15 G12C mutant NSCLC tumor model. NSCLC (non-small cell lung cancer; PO: oral; QD: once daily. Fitted group tumor volumes are depicted after administration of Compound 1 dosed QD, erlotinib dosed QD, or in combination for 21 days. Dose levels are expressed as free-base equivalents. Combination efficacy of Compound 1 with Cetuximab was evaluated in patient-derived20 xenograft (PDX) CRC tumor model CR2528 harboring mutant KRAS G12C mutations. Single- agent Compound 1 resulted in 47% TGI), whereas single-agent Cetuximab resulted in 35% TGI.-68- Improved combination activity of Compound 1 and cetuximab compared with each single agent was observed, resulting in increased TGI of 80% . All treatments and combinations were tolerated based on minimal changes in body weight and overall animal condition. These data demonstrate the improved antitumor activity via the combination of Compound 1 and cetuximab 5 compared with each single agent in a KRAS G12C mutant CRC PDX tumor model. In summary, the results above have proven that combining RAS inhibitors with EGFR inhibitors or antibodies offers a strategic approach to target cancer by simultaneously inhibiting RAS-driven and EGFR-mediated pathways. This dual inhibition can enhance anti-tumor efficacy, particularly in NSCLC by combining with EGFR inhibitors like erlotinib, gefitinib, or 10 osimertinib, and in CRC by combining with cetuximab and panitumumab, potentially leading to better clinical outcomes, higher response rates, and longer progression-free survival. Example 2 Efficacy study testing Compound 1 in combination with anti-VEGF / VEGFR antibodies 15 (Aflibercept and Bevacizumab) in LU11693 NSCLC and CR2528 CRC KRAS mutant models VEGF-mediated angiogenesis, which reduces tumor blood supply and nutrient availability. Combination efficacy of Compound 1 with anti-VEGF mAb Aflibercept was evaluated in the LU11693 NSCLC PDX model. 20 Single-agent Compound 1 resulted in an overall group response of 55% TGI, whereas single-agent Aflibercept resulted in 64% TGI. The combination of Compound 1 and anti-VEGF Aflibercept resulted in stronger anti-tumor efficacy (83% TGI) relative to each single-agent (Figure 3). All treatments and combinations were tolerated based on minimal changes in body weight and overall animal condition. These data demonstrate the improved antitumor activity via 25 the combination of Compound 1 and anti-VEGF antibody compared with each single agent in a KRAS G12C mutant NSCLC PDX tumor model. The efficacy of combining Compound 1 with the anti-VEGF monoclonal antibody Bevacizumab was tested in the CR2528 CRC PDX model. Compound 1 as a single agent achieved 47% TGI, while Bevacizumab monotherapy resulted in a comparable 40% TGI. The 30 combination of Compound 1 and Bevacizumab showed enhanced anti-tumor efficacy, with a TGI of 67% (Figure 4). All treatment regimens were well-tolerated, as indicated by minimal changes in body weight and overall animal health. These data highlight the improved antitumor-69- activity via the combination of Compound 1 and anti-VEGF antibody compared with each single agent in a KRAS mutant CRC PDX tumor model. The above results indicate that combining RAS inhibitors with anti-VEGF therapy can enhance anti-tumor efficacy in NSCLC and CRC. This combination targets both the RAS 5 signaling pathway and VEGF-mediated angiogenesis, leading to more effective tumor growth inhibition, with potential to significantly improve patient outcomes in both NSCLC and CRC.. Example 3 Efficacy study testing Compound 1 in combination with PI3K inhibitor in NSCLC and CRC models 10 PI3K inhibitors block the PI3K / AKT / mTOR pathway, essential for cell growth and metabolism. Combination efficacy of Compound 1 with the PI3K inhibitor (Inovalisib) was evaluated in the NCI-H2122 NSCLC xenograft model (Figure 5). Single agent Compound 1 resulted in 83% TGI, whereas single agent Inovalisib demonstrated tumor growth delay with 52% TGI. Greatly improved anti-tumor efficacy was observed when Compound 1 was 15 administered in combination with Inovalisib, with TGI of 114%. All treatments and combinations were well tolerated with minimal changes in body weight. These data demonstrate the improved antitumor activity via the combination of Compound 1 and PI3K inhibitor compared with each single agent in a KRAS mutant NSCLC tumor model. The efficacy of combining Compound 1 with the PI3K inhibitor Inovalisib was assessed in 20 the LS180 CRC xenograft model (Figure 6). Compound 1 alone resulted in 24% TGI, while Inovalisib alone caused a tumor growth delay with 66% TGI. Notably, the combination of Compound 1 and Inovalisib showed improved anti-tumor efficacy, achieving a TGI of 83%. All treatments and combinations were well tolerated, with minimal changes in body weight. These data demonstrate the improved antitumor activity via the combination of Compound 1 and PI3K 25 inhibitor compared with each single agent in a KRAS mutant CRC tumor model, which could enhance anti-tumor efficacy and potentially improve response rates, progression-free survival, and overall survival in patients. Example 4 Efficacy study testing Compound 1 in combination with selective RAS G12C inhibitors in 30 NCI-H2122 NSCLC model RAS protein switches between an active GTP-bound state and an inactive GDP-bound state. There are selective RAS G12C inhibitors that directly inhibit the GTP-bound active form of RAS G12C, as well as inhibitors that target the GDP-bound inactive form.-70- Combination efficacy of Compound 1 with the Swith II GDP-bound G12C inhibitor (GDC-6036) was evaluated in the NCI-H2122 NSCLC xenograft model (Figure 7). Single-agent Compound 1 resulted in 83% TGI, whereas single-agent GDC6036 resulted in 67% TGI. Improved anti-tumor efficacy was observed with the combination of Compound 1 and GDC- 5 6036 (106 % TGI). Likewise, in the same NCI-H2122 model, combination efficacy of Compound 1 with the selective GTP-bound RAS G12C inhibitor Compound 2 was also evaluated (Figure 8). Single- agent Compound 1 resulted in 83% TGI, where Compound 2 single-agent resulted in 77% TGI. An improvement in anti-tumor efficacy was observed with the combination of Compound 1 and 10 Compound 2 (109% TGI). All treatments and combinations were tolerated based on minimal changes in body weight and overall animal condition. These data demonstrate the improved antitumor activity via the combination of Compound 1 and selective RAS G12C inhibitor compared with each single agent in a KRAS G12C mutant NSCLC tumor model These above results suggest that combining selective RAS inhibitors with pan RAS 15 inhibitors could enhance the antitumor activities potentially via preventing compensatory activation, and may improve response rates, survival, and reduce resistance, leading to more durable therapeutic effects in clinic. Example 5 Efficacy study testing Compound 1 in combination with YAP-TEAD inhibitor in NCI- 20 H2122 KRAS G12C NSCLC or MKN1 KRAS amplified gastric adenosquamous carcinoma model YAP / TEAD inhibitors counteract the compensatory activation of the Hippo pathway, which regulates cell growth, apoptosis, and stem cell renewal. The anti-tumor efficacy of combining Compound 1 with the YAP-TEAD inhibitor IAG933 was investigated using the NCI- 25 H2122 NSCLC xenograft model (Figure 9). Compound 1 alone induced 78% TGI, whereas IAG933 as a monotherapy has almost no tumor growth inhibition (6% TGI). Notably, the combination of Compound 1 and IAG933 resulted in improved anti-tumor effects (114 %TGI). In a separate study using the MKN1 wildtype KRAS amplified model, the combination efficacy of Compound 1 with the YAP-TEAD inhibitor IAG933 was evaluated (Figure 10). 30 Compound 1 alone achieved 52%TGI, whereas IAG alone exhibited minimal antitumor activity in this model (6%TGI). However, when Compound 1 was combined with IAG933, a significant enhancement in anti-tumor efficacy was observed, achieving a tumor regression with 140%TGI. All treatment regimens were well-tolerated, as indicated by minimal changes in body weight and-71- overall animal health. These data demonstrate the improved antitumor activity via the combination of Compound 1 and YAP-TEAD inhibitor compared with each single agent in a KRAS mutant or amplified tumor models. These data demonstrate the improved antitumor activity via the combination of Compound 5 1 and YAP-TEAD inhibitor compared with each single agent in a KRAS mutant NSCLC tumor model or KRAS amplified gastric adenosquamous carcinoma model, which could enhance anti- tumor efficacy and potentially improve response rates, progression-free survival, and overall survival in patients. Example 6 10 A combination of RAS inhibitor (Compound 1) with platinum-based regimen (including but not limited to FOLFOX or CAPEOX) or Irinotecan-based regimen (including but not limited to FOLFIRI) with or without EGFR or VEGF inhibitor in CRC FOLFOX or CAPEOX and FOLFIRI target rapidly dividing cells through different mechanisms of action. Fluorouracil (5-FU) inhibits thymidylate synthase, leading to DNA 15 damage and apoptosis, and folinic acid enhances the binding of 5-FU to its target enzyme, increasing its efficacy. Oxaliplatin (in FOLFOX) induces DNA cross-linking, while irinotecan (in FOLFIRI) inhibits topoisomerase I, both leading to further DNA damage and cell death. Efficacy study testing Compound 1 in combination with FOLFOX or FOLFIRI in the CR2528 CRC model 20 Combination of Compound 1 and FOLFOX (folinic acid, fluorouracil (5-FU), and oxaliplatin) or FOLFIRI (folinic acid, fluorouracil (5-FU), and irinotecan) was assessed in the CR2528 KRAS G12C mutant colorectal xenograft tumor model in BALB / c nude mice). Compound 1 was assessed alone or in combination with FOLFOX (oxaliplatin 3mpk, folinic acid 50mpk, 5-FU 25mpk) or FOLFIRI (irinotecan 12mpk, folinic acid 50mpk, 5-FU 25mpk) 25 QW via IP administration. All agents tested were active in driving anti-tumor response with Compound 1 treatment resulting in 53% TGI, FOLFOX resulting in 21% TGI, and FOLFIRI resulting in 37% TGI. The combination of Compound 1 with FOLFOX or FOLFIRI lead to improved anti-tumor efficacy with 62% or 72% TGI, respectively (Figure 11,12). All treatments were well tolerated with minimal body weight loss < 10%. These data demonstrate the improved 30 antitumor activity via the combination of Compound 1 and with platinum-based regimen (including but not limited to FOLFOX) or Irinotecan-based regimen (including but not limited to FOLFIRI) compared with each single agent in KRAS mutant CRC models, which could-72- enhance anti-tumor efficacy and potentially improve response rates, progression-free survival, and overall survival in patients. Example 7 A combination of RAS inhibitor (Compound 1) with 5-FU-based regimen including but not 5 limited to FOLFIRINOX or modified FOLFIRINOX, NALIRIFOX in PDAC FOLFIRINOX targets rapidly dividing cells through multiple mechanisms: fluorouracil inhibits thymidylate synthase, irinotecan inhibits topoisomerase I, and oxaliplatin induces DNA cross-linking. Efficacy study testing Compound 1 in combination with FOLFIRINOX in the PA2410 10 PDAC model The efficacy of combining Compound 1 with FOLFIRINOX (folinic acid, fluorouracil, irinotecan, and oxaliplatin) was assessed in the PA2410 KRAS G12D mutant pancreatic ductal adenocarcinoma (PDAC) xenograft model using BALB / c nude mice. Compound 1 was administered either alone or in combination with FOLFIRINOX (oxaliplatin 3 mpk, folinic acid 15 50 mpk, 5-FU(fluorouracil) 25 mpk, irinotecan 12 mpk) QW via IP administration. Both treatments demonstrated significant anti-tumor activity, with Compound 1 monotherapy achieving 49% TGI and FOLFIRINOX achieving 33% TGI. Remarkably, the combination of Compound 1 with FOLFIRINOX led to enhanced anti-tumor efficacy, with a TGI value of 79% (Figure 13). All treatment regimens were well tolerated, with minimal body weight loss 20 observed. These data demonstrate the improved antitumor activity via the combination of Compound 1 and with FOLFIRINOX compared with each single agent in KRAS mutant PDAC models. These results suggested combining RAS inhibitors with FOLFIRINOX, modified FOLFIRINOX or NALIRIFOX can enhance the antitumor activity, and potentially offering a 25 robust strategy for better clinical outcomes in PDAC patients. Example 8 A combination of RAS inhibitor (compound 1) with Gemcitabine-based regimen (including but not limited to Gemcitabine and Paclitaxel) in PDAC Gemcitabine inhibits DNA synthesis, leading to cell cycle arrest and apoptosis, while 30 paclitaxel stabilizes microtubules, preventing mitosis and inducing cell death. Efficacy study testing Compound 1 in combination with Gemcitabine and Paclitaxel in the PA2410 PDAC model-73- The combination of Compound 1 with gemcitabine and paclitaxel was assessed in PA2410 PDAC PDX model. Compound 1 was administered either alone or in combination with gemcitabine (100 mpk) and paclitaxel (10 mpk) QW via IP administration. Both treatments showed anti-tumor activity, with Compound 1 alone achieving 49% TGI and Gemcitabine- 5 Paclitaxel achieving 38% TGI. The combination of Compound 1 with gemcitabine and paclitaxel led to improved anti-tumor efficacy with 69%TGI (Figure 14). All treatments were well tolerated, with minimal body weight loss observed. These data demonstrate the improved antitumor activity via the combination of Compound 1 and with Gemcitabine and Paclitaxel compared with each single agent in KRAS mutant PDAC models. These data suggested that 10 combining RAS inhibitors with Gemcitabine-based regimen (including but not limited to Gemcitabine and Paclitaxel) in PDAC could enhance anti-tumor efficacy, and potentially improve response rates and progression-free survival, offering a robust strategy for better outcomes in PDAC patients. Example 9 15 A combination of RAS inhibitor (compound 1) with EGFR inhibitor, anti-EGFR antibody, BRAF inhibitor, in non-RAS AGA mutants in NSCLC and CRC The combination of Compound 1 with an EGFR inhibitor in EGFR-mutant NSCLC was tested in the osimertinib-resistant NCI-H1975-OsiR model (Figure 15). Compound 1 alone induced a TGI of 44%, whereas Osimertinib as a monotherapy led to a TGI of 72%. Notably, the 20 combination of Compound 1 and Osimertinib resulted in improved anti-tumor effects, with a TGI of 119%. In a separate study (Figure 16) using the CRC PDX model LD1-0038-361928 with KRAS WT and EGFR amplification, the combination efficacy of Compound 1 with the EGFR antibody Cetuximab was evaluated. Compound 1 at 30 mpk alone caused a TGI of 60%, and cetuximab 25 reached a TGI of 55%. However, when combined, a significant enhancement in anti-tumor efficacy was observed, achieving tumor stasis with a TGI of 87%. All treatment regimens were well-tolerated, as indicated by minimal changes in body weight and overall animal health. The combination of Compound 1 with the BRAF inhibitor Encorafenib was evaluated in a separate study (Figure 17). Compound 1 alone at 30 mpk achieved 31% TGI at D19, and 30 Encorafenib at 10 mpk caused 86% TGI. After combination, a significant anti-tumor effect was observed with tumor regression or 107% TGI at D19. All treatment regimens were well- tolerated, as indicated by minimal changes in body weight and overall animal health.-74- These above results suggested that combining Compound 1, which targets active RAS or GTP-bound RAS independent of specific RAS mutations, with EGFR-MAPK pathway inhibitors such as EGFR inhibitors / antibodies or BRAF inhibitors, could enhance the anti-tumor effect in cancers with active MAPK signaling and actionable oncogenic alterations (AGA). This includes 5 EGFR-mutated NSCLC, BRAF V600-mutated CRC, and MAPK-dependent RAS wild-type CRC. The combination more effectively disrupts the MAPK signaling cascade, leading to improved therapeutic outcomes. This strategy leverages complementary mechanisms to achieve a more robust and durable anti-tumor response. Example 10 10 A combination of RAS inhibitor (Compound 1) with anti-PD-1 antibody in CRC The efficacy of Compound 1 combined with an anti-mouse PD-1 monoclonal antibody (RMP1-14) was evaluated in a CT26 colon carcinoma model. Single-agent anti-PD-1 at 10 mpk BIW treatment showed minimal efficacy with a 23% TGI, while single-agent Compound 1 resulted in a 30% TGI. The combination of Compound 1 with anti-PD-1 demonstrated enhanced 15 anti-tumor efficacy, achieving a 51% TGI (Figure 18). All treatments and combinations were well-tolerated, as indicated by minimal changes in body weight and overall animal condition. These data demonstrate the combination efficacy of RAS inhibition via Compound 1 with anti- PD-1 inhibition in a KRAS G12D mutant syngeneic tumor model. This indicates the potential benefit of combining a RAS inhibitor (Compound 1) with an anti-PD-1 or anti-PD-L1 antibody, 20 with or without platinum-based chemotherapy, in CRC or other solid tumors. Example 11 Cell viability assay The purpose of this cellular assay was to determine the effects of test compounds on the25 proliferation of human cancer cell lines NCI-H358 (ATCC-CRL5807) cells, AGS (ATCC-CRL- 1739) cells, SW620 (ATCC-CCL-227) over a 3-day treatment period by quantifying the amount of NADPH present at endpoint using Cell Counting Kit-8. Cells were seeded at 5,000 cells / well (NCI-H358), 2,000 cells / well (AGS) 2,000 cells / well (SW620) in 96-well assay plates (Corning-3699) and incubated overnight. On the day 30 of the assay, diluted compounds were then added in a final concentration of 0.5% DMSO. After 72 hrs incubation, a tenth of the volume of cell counting kit 8(Dnjindo-CK04) was added into each well. Read the signal (OD450 minus OD650) using EnVision after 2 hrs incubation. IC50was determined by fitting a 4-parameter sigmoidal concentration response model.-75- Table 3. Activity of Examples and Compounds of present invention in KRAS Cell viability assayExample 12 5 KRAS-BRAF with CYPA (500 nM) interaction assay In this example, TR-FRET was also used to measure the compound or compound-CYPA dependent disruption of the KRAS G12C-BRAF complex. This protocol was also used to measure disruption of KRAS G12D or KRAS G12V binding to BRAF by a compound of the invention, respectively. In assay buffer containing 25mM HEPES PH=7.4 (4-(2-hydroxyethyl)- 10 1-piperazineethanesulfonic acid, Thermo, 15630080), 0.002% Tween20, 0.1% BSA, 100mM NaCl, 5mM MgCl2, 10 µM GMPPNP (Guanosine 5′-[β,γ-imido]triphosphate trisodium salt hydrate, Sigma, G0635), tagless CYPA, GMPPNP loaded 6His-KRAS proteins, and GST- BRAFRBDwere mixed in a well of a 384-well assay plate at final concentrations of 50 nM, 6.25 nM and 1nM, respectively. Compound was present in plate wells as a 16-point 3-fold dilution 15 series starting at a final concentration of 10 µM and incubated for 3 hours. A mixture of MAb Anti-6His-XL665 (Cisbio, 61HISXLB) and Mab anti-GST-TB cryptate (Cisbio, 61GSTTLB)was then added at a final concentration of 6.67 nM and 0.21 nM, respectively, and the plate was incubated for an additional 1.5 hours. TR-FRET signal was read on a PHERstar FSX microplate reader (Ex320 nm, Em 665 / 615 nm). Compounds that facilitate disruption of the 20 KRAS-BRAF complex were identified as those eliciting a decrease in the TR-FRET ratio relative to DMSO control wells. Table 4. Activity of Examples and Compounds of present invention in KRAS-BRAF with CYPA (500 nM) interaction assay25 Example 13-76- pERK inhibition assay This assay is to measure the ability of test compounds in inhibiting the phosphorylation of ERK, the downstream signaling of KRAS G12C in NCI-H358 cells, KRAS G12D in AGS cells, and KRAS G12V in SW620. NCI-H358 (ATCC-CRL5807) cells, AGS (ATCC-CRL- 5 1739) cells, SW620 (ATCC-CCL-227) cells were all grown and maintained using RPMI-1640 medium (Thermo Fisher Scientific) with 10% fetal bovine serum and 1% penicillin / streptomycin. On the day prior to compound addition, cells were plated in tissue culture-treated 96 well plates (Corning-3699) at a density of 30,000 cell / well, 20,000 cell / well, 30,000 cell / well for NCI-H358, AGS and SW620 respectively, and allowed for attachment 10 overnight. Diluted compounds were then added in a final concentration of 0.5% DMSO. After 4 hours of incubation, the medium was removed, 100 µL of 4% formaldehyde was added, and the assay plates were incubated at room temperature for 20 minutes. The plates were then washed once with phosphate buffered saline (PBS), and permeabilized with 100 µL of chilled methanol for 10 minutes. Non-specific antibody binding to the plates was blocked using 50 µL 1X BSA 15 blocking buffer (Thermo-37520, 10-fold dilution by Phosphate-Buffered Saline Tween (PBST) for at least 1 hour at room temperature. The amount of phosphor-ERK was determined using an antibody specific for phosphorylated form of ERK. Primary antibody (pERK, CST-4370, Cell Signaling Technology) was diluted 1:300 in blocking buffer, with 50 µL aliquoted to each well, and incubated overnight 20 at 4 ℃. Cells was washed five times for 5 minutes with PBST. Secondary antibody (HRP-linked anti-rabbit IgG, CST-7074, Cell Signaling Technology) was diluted 1:1000 in blocking buffer, and 50 µL was added to each well and incubated 1-2 hrs at room temperature. Cells was washed 5 times for 5 minutes with PBST, 100µL TMB ELISA substrate (abcam-ab171523) were added and gently shake for 20 minutes.50µL stop solution (abcam-ab171529) were added, and then 25 read the signal (OD450) by EnVision. IC50was determined by fitting a 4-parameter sigmoidal concentration response model. Table 5. Activity of Examples and Compounds of present invention in KRAS pERK inhibition assay30-77- Example 14 Efficacy study testing Compound 1 in combination with Amivantamab in the CR2528 CRC model 5 Amivantamab is an FDA-approved bispecific antibody targeting EGF and Met receptors and has been demonstrated to be linked to three mechanisms of action (MOA): immune cell- mediated killing, receptor internalization and degradation, and inhibition of ligand binding to both EGFR and Met receptors. The combination of Compound 1 with Amivantamab EGFR-cMET bispecific antibody 10 was tested in the CR2528 CRC PDX model. Compound 1 as a single agent achieved 28% TGI, while Amivantamab resulted in a comparable 27% TGI. The combination of Compound 1 and Amivantamab showed enhanced anti-tumor efficacy, with a TGI of 85% (Figure 19). All treatment regimens were well-tolerated, as indicated by minimal changes in body weight and overall animal health. These data highlight the improved antitumor activity via the combination 15 of Compound 1 and EGFR-cMET bispecific antibody compared with each single agent in a KRAS mutant CRC PDX tumor model. The above results indicate that combining RAS inhibitors with EGFR-cMET bispecific antibody can enhance anti-tumor efficacy in CRC. This combination targets both the RAS signaling pathway and blocks the oncogenic activity of EGFR while also blocking MET 20 signaling, the common mechanism of resistance of EGFR inhibition leading to more effective tumor growth inhibition, with potential to significantly improve outcomes in CRC patients. Example 15 Efficacy study testing Compound 1 in combination with Ivonescimab in the NCI-H441 25 NSCLC PBMC model Inhibiting vascular endothelial growth factor (VEGF) function can improve the efficacy of immunotherapy by modulating the tumor immune microenvironment. Ivonescimab is the first-in- class humanized IgG1 bispecific antibody targeting programmed death-1 (PD-1) and VEGF. The The combination of Compound 1 with Ivonescimab was tested in the NCI-H441 NSCLC model. 30 Compound 1 as a single agent achieved 49% TGI, while Ivonescimab resulted in a comparable 66% TGI. The combination of Compound 1 and Ivonescimab showed enhanced anti-tumor efficacy, with a TGI of 89% (Figure 20). All treatment regimens were well-tolerated, as indicated by minimal changes in body weight and overall animal health. These data highlight the-78- improved antitumor activity via the combination of Compound 1 and PD-1-VEGF bispecific antibody compared with each single agent in a KRAS mutant NSCLC tumor model. The above results indicate that combining Ivonescimab and Compound 1 exhibited a potential synergistic antitumor effect in preclinical NSCLC model. This combination targets both 5 the RAS signaling pathway and vascular endothelial growth factor (VEGF) showed promising antitumor activity and was safe in mice, suggesting a valuable potential new treatment option for this patient population. Example 16 10 Efficacy study testing Compound 1 in combination with Cadonilimab in the NCI-H441 NSCLC PBMC model The purpose of this study is to evaluate the PD-1-CTLA-4 bispecific antibody, Cadonilimab, in combination with Compound 1 for the treatment of NCI-H441 NSCLC cancer model. Single-agent Cadonilimab at 3 mpk after single dosing showed efficacy with a 37% TGI, 15 while single-agent Compound 1 resulted in a 49% TGI. The combination of Compound 1 with Cadonilimab demonstrated enhanced anti-tumor efficacy, achieving a 70% TGI (Figure 21). All treatments and combinations were well-tolerated, as indicated by minimal changes in body weight and overall animal condition. These data demonstrate the combination efficacy of RAS inhibition via Compound 1 with Cadonilimab inhibition in a KRAS G12V mutant NSCLC tumor 20 model. This indicates the potential benefit of combining a RAS inhibitor (Compound 1) with an PD-1-CTLA4 bispecific antibody, with or without platinum-based chemotherapy, in NSCLC or other solid tumors. Example 17 25 Efficacy study testing Compound 1 in combination with anti-PD-1 antibody Pembrolizumab in NSCLC models Combination efficacy of Compound 1 with the anti-PD-1 antibody (Pembrolizumab) was evaluated in the NCI-H358 NSCLC human PBMC model (Figure 22). Single agent Compound 1 resulted in 36% TGI, whereas single agent Keytruda demonstrated tumor growth delay with 35% 30 TGI. The improved anti-tumor efficacy was observed when Compound 1 was administered in combination with Pembrolizumab, with TGI of 68%. All treatments and combinations were well tolerated with minimal changes in body weight. These data demonstrate the improved antitumor-79- activity via the combination of Compound 1 and anti-PD-1 antibody compared with each single agent in a KRAS mutant NSCLC tumor model. The efficacy of combining Compound 1 with the anti-PD-1 antibody Pembrolizumab was assessed in the NCI-H441 human PBMC model (Figure 23). Compound 1 alone resulted in 53% 5 TGI, while Pembrolizumab alone caused a tumor growth delay with 23% TGI. Notably, the combination of Compound 1 and Pembrolizumab showed improved anti-tumor efficacy, achieving a TGI of 83%. All treatments and combinations were well tolerated, with minimal changes in body weight. These data demonstrate the improved antitumor activity via the combination of Compound 1 and anti-PD-1 antibody compared with each single agent in a 10 KRAS mutant NSCLC tumor model, which could enhance anti-tumor efficacy and potentially improve response rates, progression-free survival, and overall survival in patients.

Claims

-80- CLAIMS 1. A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of a RAS inhibitor and a second therapeutic agent, wherein the RAS inhibitor is a compound of formula (I): 5wherein R1is 2-oxabicyclo[2.1.1]hexanyl, 3-oxabicyclo[3.1.0]hexanyl, 6-bicyclo[3.1.0]hexanyl substituted twice by halogen, 10 6-tricyclo[3.1.1.03,6]heptanyl, C3-7cycloalkyl substituted once, twice or three times by the substituents independently selected from C1-6alkyl, C1-6alkylpyridinyl, C1-6alkylpyrimidinyl, C1-6alkyltetrazolyl, C3-7cycloalkyl, haloC1-6alkyl, halogen, halophenyl, hydroxy, phenyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl and thiazolyl, 15 or tetrahydropyranyl; R2is 1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazinyl, 3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazinyl, morpholinyl, or 20 piperazinyl unsubstituted or substituted by substituents independently selected from C1-6alkoxyC1-6alkyl, C1-6alkyl, C3-7cycloalkyl, haloC1-6alkyl, hydroxyC1-6alkyl, morpholinylC1-6alkyl, oxetanyl, oxopyrrolidinylC1-6alkyl and tetrahydrofuranyloxyC1-6alkyl; R3is H or halogen; 25 M is C1-6alkylene or O;-81- L is C1-6alkylene, hydroxyC1-6alkylene or haloC1-6alkylene; or a pharmaceutically acceptable salt thereof.

2. The method according to claim 1, wherein the RAS inhibitor is5 (compound 1), or a pharmaceutically acceptable salt thereof.

3. The method according to claim 1 or 2, wherein the cancer is selected from a group consisting of BRAF-mutant CRC, EGFR-mutant NSCLC, RAS-mutant and amplified GASC, RAS-mutant 10 CRC, RAS-mutant NSCLC, RAS-mutant PDAC, RAS-mutant solid tumor, RAS-mutant hematological malignancies, RAS-mutant Multiple Myeloma and RAS-wildtype CRC; wherein the solid tumor is selected from a group consisting of melanoma, SCLC, gastric cancer, esophageal cancer, gynecologic cancer, liver cancer, thyroid cancer, breast cancer, kidney cancer, head and neck cancer, and bladder cancer. 15 4. The method according to any one of claims 1 to 3, wherein the cancer is selected from a group consisting of EGFR-mutant NSCLC, RAS-mutant CRC, RAS-mutant NSCLC, and RAS- mutant PDAC. 20 5. The method according to any one of claims 1 to 4, wherein the second therapeutic agent is selected from a group consisting of 5-FU-based regimen, Gemcitabine-based regimen, anti- EGFR antibody, anti-PD-1 antibody, anti-PD-L1 antibody, anti-VEGF antibody, anti-VEGFR antibody, Bcl-2 family inhibitors, BRAF inhibitor, EGFR inhibitor, FAK inhibitor, Irinotecan- based regimen, KRAS G12D inhibitor, MEK / RAF inhibitor, PI3K inhibitor, PKMYT1 inhibitor, 25 Platinum-based regimen, PLK1 inhibitor, RAS G12C inhibitor, RAS G12V inhibitor, SHOC2 disruptor, SHP2 inhibitor, SOS1 inhibitor, YAP-TEAD inhibitor, EGFR-cMET bispecific-82- antibody, PD-1-VEGF bispecific antibody, PD-1-CTLA-4 bispecific antibody, GSPT1 inhibitor, HER3 based antibody drug conjugates, B7H3 based antibody drug conjugates, cMET based antibody drug conjugates, TROP2 based antibody drug conjugates, proteasome inhibitor, Immunomodulatory Drugs (IMiDs), CD38 antibody and Corticosteroids. 5 6. The method according to any one of claims 1 to 5, wherein the second therapeutic agent is selected from a group consisting of Aflibercept, Amivantamab, Atezolizumab, Avutometinib, Bevacizumab, BI-1701963, Cadonilimab, Cetuximab, RAS G12C inhibitor, Defactinib, Encorafenib, Erlotinib, Irinotecan-based regimen, Ivonescimab, 5-FU-based regimen, Platinum- 10 based regimen, GDC-1971, GDC-7035, gemcitabine and paclitaxel , IAG933, Ifebemtinib, Inovalisib, MRT-2359, Navitoclax, Obatoclax, Onvansertib, Osimertinib, Pembrolizumab, RMP1-14, RP-6306, Patritumab Deruxtecan, DS-7300, MGC018, Telisotuzumab Vedotin, Bortezomib, Carfilzomib, Ixazomib, Lenalidomide, Thalidomide, Pomalidomide, Daratumumab, Isatuximab, Dexamethasone, prednisone and Venetoclax; wherein 15 Platinum-based regimen is FOLFOX or CAPEOX; Irinotecan-based regimen is FOLFIRI; 5-FU-based regimen is FOLFIRINOX or NALIRIFOX; RAS G12C inhibitor is Divarasib or(compound 2), or a pharmaceutically acceptable salt thereof. 20 7. The method according to any one of claims 1 to 5, wherein the second therapeutic agent is selected from a group consisting of 5-FU-based regimen, Gemcitabine-based regimen, anti- EGFR antibody, anti-VEGF antibody, anti-VEGFR antibody, EGFR inhibitor, Irinotecan-based regimen, PI3K inhibitor, Platinum-based regimen, RAS G12C inhibitor, EGFR-cMET bispecific 25 antibody, PD-1-VEGF bispecific antibody and PD-1-CTLA-4 bispecific antibody.-83- 8. The method according to claim 7, wherein the second therapeutic agent is selected from a group consisting of Aflibercept, Bevacizumab, Cetuximab, Divarasib, Erlotinib, FOLFIRI, FOLFIRINOX, FOLFOX, gemcitabine and paclitaxel, Inovalisib, Osimertinib, Amivantamab, 5 Ivonescimab and Cadonilimab.

9. The method according to any one of claims 1 to 4, wherein the method further comprises a third therapeutic agent. 10 10. The method according to claim 9, wherein the second therapeutic agent is selected from a group consisting of Irinotecan-based regimen, MEK / RAF inhibitor, platinum-based chemotherapy, Platinum-based regimen, PLK1 inhibitor, and RAS G12C inhibitor; wherein the third therapeutic agent is selected from a group consisting of anti-EGFR antibody, anti-PD-1 antibody, anti-PD-L1 antibody, anti-VEGF antibody, FAK inhibitor, and Irinotecan-based 15 regimen.

11. The method according to claim 9 or 10, wherein the second therapeutic agent is selected from a group consisting of Avutometinib, cisplatin and pemetrexed, carboplatin and pemetrexed, Compound 2, Divarasib, FOLFIRI, FOLFOX, and Onvansertib. 20 12. The method according to any one of claims 9 to 11, wherein the third therapeutic agent is selected from a group consisting of Atezolizumab, Bevacizumab, Cetuximab, Defactinib, FOLFIRI, Ifebemtinib, and Pembrolizumab. 25 13. A method of treating RAS-mutant NSCLC in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of Erlotinib and Compound 1, or a pharmaceutically acceptable salt thereof.

14. A method of treating RAS-mutant CRC in a subject in need thereof, comprising 30 administering to the subject a therapeutically effective amount of a combination of Cetuximab and Compound 1, or a pharmaceutically acceptable salt thereof.-84- 15. A method of treating RAS-mutant NSCLC in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of Aflibercept and Compound 1, or a pharmaceutically acceptable salt thereof. 5 16. A method of treating RAS-mutant CRC in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of Bevacizumab and Compound 1, or a pharmaceutically acceptable salt thereof.

17. A method of treating RAS-mutant NSCLC or RAS-mutant CRC in a subject in need thereof, 10 comprising administering to the subject a therapeutically effective amount of a combination of Inovalisib and Compound 1, or a pharmaceutically acceptable salt thereof.

18. A method of treating RAS-mutant NSCLC in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of Divarasib and 15 Compound 1, or a pharmaceutically acceptable salt thereof.

19. A method of treating RAS-mutant NSCLC in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of Compound 2 and Compound 1, or a pharmaceutically acceptable salt thereof. 20 20. A method of treating RAS-mutant NSCLC or RAS-mutant and amplified GASC in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of IAG933 and Compound 1, or a pharmaceutically acceptable salt thereof. 25 21. A method of treating RAS-mutant CRC in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of FOLFOX and Compound 1, or a pharmaceutically acceptable salt thereof.

22. A method of treating RAS-mutant CRC in a subject in need thereof, comprising 30 administering to the subject a therapeutically effective amount of a combination of FOLFIRI and Compound 1, or a pharmaceutically acceptable salt thereof.-85- 23. A method of treating RAS-mutant PDAC in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of FOLFIRINOX and Compound 1, or a pharmaceutically acceptable salt thereof. 5 24. A method of treating RAS-mutant PDAC in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of Gemcitabine and paclitaxel and Compound 1, or a pharmaceutically acceptable salt thereof.

25. A method of treating EGFR-mutant NSCLC in a subject in need thereof, comprising 10 administering to the subject a therapeutically effective amount of a combination of Osimertinib and Compound 1, or a pharmaceutically acceptable salt thereof.

26. A method of treating RAS-wildtype CRC in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of Cetuximab 15 and Compound 1, or a pharmaceutically acceptable salt thereof.

27. A method of treating BRAF-mutant CRC in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of Encorafenib and Compound 1, or a pharmaceutically acceptable salt thereof. 20 28. A method of treating RAS-mutant CRC in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of RMP1-14 and Compound 1, or a pharmaceutically acceptable salt thereof. 25 29. A method of treating RAS-mutant CRC in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of Amivantamab and Compound 1, or a pharmaceutically acceptable salt thereof.

30. A method of treating RAS-mutant NSCLC in a subject in need thereof, comprising 30 administering to the subject a therapeutically effective amount of a combination of Ivonescimab and Compound 1, or a pharmaceutically acceptable salt thereof.-86- 31. A method of treating RAS-mutant NSCLC in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of MRT-2359 and Compound 1, or a pharmaceutically acceptable salt thereof. 5 32. A method of treating RAS-mutant NSCLC in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of Pembrolizumab and Compound 1, or a pharmaceutically acceptable salt thereof.

33. Use of the combination of a RAS inhibitor and a second therapeutic agent for treating cancer 10 in a subject in need thereof, wherein the RAS inhibitor is a compound of formula (I), or a pharmaceutically acceptable salt thereof.

34. The use of claim 33, wherein the RAS inhibitor is compound 1, or a pharmaceutically acceptable salt thereof. 15 35. The use of claim 33 or 34, wherein the cancer is selected from a group consisting of BRAF- mutant CRC, EGFR-mutant NSCLC, RAS-mutant and amplified GASC, RAS-mutant CRC, RAS-mutant NSCLC, RAS-mutant PDAC, RAS-mutant solid tumor, RAS-mutant hematological malignancies, RAS-mutant Multiple Myeloma and RAS-wildtype CRC; wherein the solid tumor 20 is selected from a group consisting of melanoma, SCLC, gastric cancer, esophageal cancer, gynecologic cancer, liver cancer, thyroid cancer, breast cancer, kidney cancer, head and neck cancer, and bladder cancer.

36. The use of any one of claims 33 to 35, wherein the cancer is selected from a group consisting 25 of EGFR-mutant NSCLC, RAS-mutant CRC, RAS-mutant NSCLC, and RAS-mutant PDAC.

37. The use of any one of claims 33 to 36, wherein the second therapeutic agent is selected from a group consisting of 5-FU-based regimen, Gemcitabine-based regimen, anti-EGFR antibody, anti-VEGF antibody, anti-VEGFR antibody, EGFR inhibitor, Irinotecan-based regimen, PI3K30 inhibitor, Platinum-based regimen, RAS G12C inhibitor, EGFR-cMET bispecific antibody, PD- 1-VEGF bispecific antibody and PD-1-CTLA-4 bispecific antibody.-87- 38. The use of any one of claims 33 to 37, wherein the second therapeutic agent is selected from a group consisting of Aflibercept, Bevacizumab, Cetuximab, Divarasib, Erlotinib, FOLFIRI, FOLFIRINOX, FOLFOX, gemcitabine and paclitaxel, Inovalisib, Osimertinib, Amivantamab, Ivonescimab and Cadonilimab. 5 39. The use of any one of claims 33 to 38, wherein the combination further comprises a third therapeutic agent.

40. The use of claim 39, wherein the second therapeutic agent is selected from a group consisting10 of Irinotecan-based regimen, MEK / RAF inhibitor, platinum-based chemotherapy, Platinum- based regimen, PLK1 inhibitor, and RAS G12C inhibitor; wherein the third therapeutic agent is selected from a group consisting of anti-EGFR antibody, anti-PD-1 antibody, anti-PD-L1 antibody, anti-VEGF antibody, FAK inhibitor, and Irinotecan-based regimen. 15 41. The use of claim 39 or 40, wherein the second therapeutic agent is selected from a group consisting of Avutometinib, cisplatin and pemetrexed, carboplatin and pemetrexed, Compound 2, Divarasib, FOLFIRI, FOLFOX, and Onvansertib; wherein the third therapeutic agent is selected from a group consisting of Atezolizumab, Bevacizumab, Cetuximab, Defactinib, FOLFIRI, Ifebemtinib, and Pembrolizumab. 20 42. Use of a RAS inhibitor in the manufacture of a medicament for treating cancer in a subject in need thereof, in combination with a second therapeutic agent, wherein the RAS inhibitor is a compound of formula (I), or a pharmaceutically acceptable salt thereof.

43. The use of claim 42, wherein the RAS inhibitor is compound 1, or a pharmaceutically 25 acceptable salt thereof.

44. The use of any one of claim 42 or 43, wherein the cancer is selected from a group consisting of BRAF-mutant CRC, EGFR-mutant NSCLC, RAS-mutant and amplified GASC, RAS-mutant CRC, RAS-mutant NSCLC, RAS-mutant PDAC, RAS-mutant solid tumor, and RAS-wildtype 30 CRC; wherein the solid tumor is selected from a group consisting of melanoma, SCLC, gastric cancer, esophageal cancer, gynecologic cancer, liver cancer, thyroid cancer, breast cancer, kidney cancer, head and neck cancer, and bladder cancer.-88- 45. The use of any one of claims 42 to 44, wherein the cancer is selected from a group consisting of EGFR-mutant NSCLC, RAS-mutant CRC, RAS-mutant NSCLC, and RAS-mutant PDAC.

46. The use of any one of claims 42 to 45, wherein the second therapeutic agent is selected from 5 a group consisting of 5-FU-based regimen, Gemcitabine-based regimen, anti-EGFR antibody, anti-VEGF antibody, anti-VEGFR antibody, EGFR inhibitor, Irinotecan-based regimen, PI3K inhibitor, Platinum-based regimen, RAS G12C inhibitor, EGFR-cMET bispecific antibody, PD- 1-VEGF bispecific antibody and PD-1-CTLA-4 bispecific antibody. 10 47. The use of any one of claims 42 to 46, wherein the second therapeutic agent is selected from a group consisting of Aflibercept, Bevacizumab, Cetuximab, Divarasib, Erlotinib, FOLFIRI, FOLFIRINOX, FOLFOX, gemcitabine and paclitaxel, Inovalisib, Osimertinib, Amivantamab, Ivonescimab and Cadonilimab. 15 48. A pharmaceutical composition, comprising a therapeutically effective amount of a combination of a combination of a RAS inhibitor and a second therapeutic agent, wherein the RAS inhibitor is a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. 20 49. The pharmaceutical composition of claim 48, wherein the RAS inhibitor is compound 1, or a pharmaceutically acceptable salt thereof.

50. The pharmaceutical composition of claim 48 or 49, wherein the cancer is selected from a group consisting of EGFR-mutant NSCLC, RAS-mutant CRC, RAS-mutant NSCLC, and RAS- 25 mutant PDAC.

51. The pharmaceutical composition of any one of claims 48 to 50, wherein the second therapeutic agent is selected from a group consisting of 5-FU-based regimen, Gemcitabine-based regimen, anti-EGFR antibody, anti-VEGF antibody, anti-VEGFR antibody, EGFR inhibitor,30 Irinotecan-based regimen, PI3K inhibitor, Platinum-based regimen, RAS G12C inhibitor, EGFR- cMET bispecific antibody, PD-1-VEGF bispecific antibody and PD-1-CTLA-4 bispecific antibody.-89- 52. The pharmaceutical composition of any one of claims 48 to 51, wherein the second therapeutic agent is selected from a group consisting of Aflibercept, Bevacizumab, Cetuximab, Divarasib, Erlotinib, FOLFIRI, FOLFIRINOX, FOLFOX, gemcitabine and paclitaxel, Inovalisib, Osimertinib, Amivantamab, Ivonescimab and Cadonilimab. 5 53. The pharmaceutical composition of any one of claims 48 to 52, wherein the composition further comprises a third therapeutic agent.

54. The pharmaceutical composition of claim 53, wherein the second therapeutic agent is10 selected from a group consisting of Irinotecan-based regimen, MEK / RAF inhibitor, platinum- based chemotherapy, Platinum-based regimen, PLK1 inhibitor, and RAS G12C inhibitor; wherein the third therapeutic agent is selected from a group consisting of anti-EGFR antibody, anti-PD-1 antibody, anti-PD-L1 antibody, anti-VEGF antibody, FAK inhibitor, and Irinotecan- based regimen. 15 55. The pharmaceutical composition of claim 53 or 54, wherein the second therapeutic agent is selected from a group consisting of Avutometinib, cisplatin and pemetrexed, carboplatin and pemetrexed, Compound 2, Divarasib, FOLFIRI, FOLFOX, and Onvansertib; wherein the third therapeutic agent is selected from a group consisting of Atezolizumab, Bevacizumab, 20 Cetuximab, Defactinib, FOLFIRI, Ifebemtinib, and Pembrolizumab.

56. A kit comprising a pharmaceutical composition of any one of claims 48 to 55.

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