Combination therapy including an FGFR inhibitor and a KRAS inhibitor

Abstract

The present invention relates to a method of treating cancer by administering a compound that is a fibroblast growth factor receptor (FGFR) inhibitor in combination with a Kirsten rat sarcoma (KRAS) inhibitor.

Description

[Technical field]

[0001] The present invention relates to a method of treating cancer by administering a compound that is a fibroblast growth factor receptor (FGFR) inhibitor in combination with a Kirsten rat sarcoma (KRAS) inhibitor. [Background technology]

[0002] Ras proteins are part of a family of small GTPases that are activated by growth factors and various extracellular stimuli. The Ras family regulates intracellular signaling pathways involved in cell proliferation, migration, survival, and differentiation. Activation of RAS proteins at the cell membrane leads to the binding of key effectors and initiation of a cascade of intracellular signaling pathways, including the RAF and PI3K kinase pathways. While somatic mutations in RAS can result in uncontrolled cell proliferation and malignant transformation, activation of RAS proteins is tightly regulated in normal cells (Simanshu, D. et al. Cell 170.1 (2017): 17-33). The Ras family consists of three members: KRAS, NRAS, and HRAS. RAS-mutated cancers account for approximately 25% of human cancers. KRAS is the most frequently mutated isoform, accounting for 85% of all RAS mutations, while NRAS and HRAS are mutated in 12% and 3% of all RAS-mutated cancers, respectively (Simanshu, D. et al. Cell 170.1 (2017): 17-33). KRAS mutations are prevalent among the top three most lethal cancer types: pancreatic (97%), colorectal (44%), and lung (30%) (Cox, AD et al. Nat Rev Drug Discov (2014) 13: 828-51). The majority of RAS mutations occur at amino acid residues 12, 13, and 61. The frequency of specific mutations varies among RAS gene isoforms, with G12 and Q61 mutations predominating in KRAS and NRAS, respectively, while G12, G13, and Q61 mutations are most frequent in HRAS. Furthermore, the spectrum of mutations in RAS isoforms differs among cancer types. For example, KRAS G12D mutations are predominant in pancreatic cancer (51%), followed by colorectal adenocarcinoma (45%) and lung cancer (17%), while KRAS G12V mutations are associated with pancreatic cancer (30%), followed by colorectal adenocarcinoma (27%) and lung adenocarcinoma (23%) (Cox, AD et al. Nat Rev Drug Discov (2014) 13:828-51).In contrast, KRAS G12C mutations predominate in non-small cell lung cancer (NSCLC), including 11-16% of lung adenocarcinomas, and 2-5% of pancreatic and colorectal adenocarcinomas (Cox, AD et al. Nat. Rev. Drug Discov. (2014) 13:828-51). Genomic studies across hundreds of cancer cell lines have demonstrated that cancer cells harboring KRAS mutations are highly dependent on KRAS function for cell proliferation and survival (McDonald, R. et al. Cell 170 (2017):577-592). The role of mutant KRAS as an oncogenic driver is further supported by extensive in vivo experimental evidence showing that mutant KRAS is required for the development and maintenance of early tumors in animal models (Cox, AD et al. Nat Rev Drug Discov (2014) 13:828-51).

[0003] Fibroblast growth factor receptors (FGFRs) are receptor tyrosine kinases that bind to fibroblast growth factor (FGF) ligands. There are four FGFR proteins (FGFR1-4) that can bind to ligands and are involved in the control of many physiological processes, including tissue development, angiogenesis, wound healing, and metabolic regulation. Upon ligand binding, the receptor undergoes dimerization and phosphorylation, leading to stimulation of protein kinase activity and recruitment of many intracellular docking proteins. These interactions promote the activation of a series of intracellular signaling pathways, including Ras-MAPK, AKT-PI3K, and phospholipase C, which are important for cell growth, proliferation, and survival (Reviewed in Eswarakumar et al. Cytokine & Growth Factor Reviews (2005) 16(2):139-149).

[0004] Aberrant activation of this pathway, either by overexpression of FGF ligands or FGFRs, or by activating mutations in FGFRs, can lead to tumor initiation, progression, and resistance to conventional cancer treatments. Genetic alterations including gene amplification, chromosomal translocations, and somatic mutations leading to ligand-independent receptor activation have been described in human cancers. Large-scale DNA sequencing of thousands of tumor samples has revealed that components of the FGFR pathway are the most frequently mutated in human cancers.

[0005] Recently, the FDA approved the KRAS G12C inhibitor sotorasib for treating KRAS G12C-mutated non-small cell lung cancer (NSCLC). Potential resistance mechanisms of KRAS G12C-mutated tumors to KRAS G12C inhibitors are currently under investigation. Recently, several publications have reported that epithelial-mesenchymal transition (EMT) is responsible for intrinsic resistance to KRAS G12C inhibitors, and high expression of FGFR1 is associated with epithelial or mesenchymal cancer lines (see, for example, Adachi et al. Clinical Cancer Research, (2020) 26 (22): 5962-5973; Solanki et al. Clinical Cancer Research, (2021) 27 (9): 2533-2548; Kitai et al. Cancer Discovery, (2016) 6 (7): 754-69).

[0006] Inhibitors of FGFR are currently being developed for the treatment of cancer. For example, pemigatinib, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one, and other small molecule inhibitors of FGFR are disclosed in U.S. Pat. No. 9,611,267, as well as in U.S. Pat. Reported in patent publication numbers: 2012 / 0165305; 2014 / 0045814; 2013 / 0338134; 2014 / 0171405; 2014 / 0315902; 2016 / 0115164; 2016 / 0244448; 2016 / 0244449, 2016 / 0244450, 2019 / 0337948, and 2020 / 0002338.

[0007] There remains a need for new therapies for cancers with KRAS mutations while addressing potential drug resistance mechanisms such as mesenchymal phenotype and FGFR dysfunction, particularly FGFR1 dysfunction, etc. The present disclosure addresses this need, as well as other needs, using FGFR inhibitors, particularly FGFR1 inhibitors, in combination with KRAS inhibitors. Summary of the Invention

[0008] The present disclosure relates, inter alia, to a method of treating cancer in a patient, comprising administering to the patient: (i) an FGFR1 inhibitor; (ii) a KRAS inhibitor; and The method includes administering

[0009] The present application further provides a method of treating cancer in a patient, comprising administering to the patient an FGFR1 inhibitor and a KRAS inhibitor.

[0010] The present application also provides the use of an FGFR1 inhibitor and a KRAS inhibitor for the preparation of a medicament for the treatment of cancer.

[0011] The present application further provides an FGFR1 inhibitor and a KRAS inhibitor for use in any of the methods described herein.

[0012] The present disclosure further provides a method of treating cancer in a patient, comprising administering to the patient: (i) pemigatinib, or a pharma- ceutically acceptable salt thereof; (ii) sotorasib, or a pharma- ceutically acceptable salt thereof; and The method includes administering

[0013] The present application also provides the use of pemigatinib, or a pharma- ceutically acceptable salt thereof, and a KRAS inhibitor for the preparation of a medicament for the treatment of cancer.

[0014] The application further provides pemigatinib, or a pharma- ceutically acceptable salt thereof, and a KRAS inhibitor for use in any of the methods described herein.

[0015] The present application also provides the use of pemigatinib, or a pharma- ceutically acceptable salt thereof, and sotorasib, or a pharma- ceutically acceptable salt thereof, for the preparation of a medicament for the treatment of cancer.

[0016] The application further provides pemigatinib, or a pharma- ceutically acceptable salt thereof, and sotorasib, or a pharma- ceutically acceptable salt thereof, for use in any of the methods described herein. [Brief description of the drawings]

[0017] [Figure 1A] Western blots of FGFR1, pFRS2a, E-cadherin, vimentin, and beta-actin in the four indicated cell lines are shown. [Figure 1B] Western blots of pFRS2a and beta-actin in LU99 cell lysates subjected to the indicated treatments are shown. [Diagram 2]1 shows Western blots of pERK, pFRS2a, and beta-actin in LU99 cells treated with KRAS G12C inhibitor Compound 2 with or without pemigatinib or Compound 1 for 24 hours. [Diagram 3] Graph showing tumor volume in LU99 tumor-bearing mice administered (i) vehicle, (ii) 20 mg / kg AMG-510, (iii) 0.3 mg / kg pemigatinib, or (iv) a combination of AMG-510 and pemigatinib at 20 mg / kg and 0.3 mg / kg, respectively. [Figure 4] 1 is a graph showing inhibition of pERK in LU99 tumors in mice administered 20 mg / kg AMG-510, 0.3 mg / kg pemigatinib, or a combination of AMG-510 and pemigatinib at 20 mg / kg and 0.3 mg / kg, respectively. [Diagram 5] Western blot of pFRS2a and beta-actin in MRTX849-treated LU99 cell lysates is shown. [Figure 6] 1 shows Western blots of pERK, pFRS2a, and beta-actin in LU99 cells treated with the KRAS G12C inhibitor, MRTX849, with or without pemigatinib or Compound 1 for 24 hours. [Figure 7] Graph showing tumor volume in LU99 tumor-bearing mice administered (i) vehicle, (ii) 10 mg / kg MRTX849, (iii) 0.3 mg / kg pemigatinib, or (iv) a combination of MRTX849 and pemigatinib at 10 mg / kg and 0.3 mg / kg, respectively. [Figure 8] 1 is a graph showing inhibition of pERK in LU99 tumors in mice administered 10 mg / kg MRTX849, 0.3 mg / kg pemigatinib, or a combination of MRTX849 and pemigatinib at 10 mg / kg and 0.3 mg / kg, respectively. [Figure 9A] Western blots of knockdown experiments of FGFR1, FGFR2, FGFR3, and FGFR4 are shown. [Figure 9B]1 shows the inhibitory effect of siRNA knockdown of FGFR1 and FGFR4 in combination with compound 3 on LU99 cell proliferation after 120 hours. [Figure 9C] 1 shows the inhibitory effect of siRNA knockdown of FGFR1 and FGFR4 in combination with AMG510 on LU99 cell proliferation after 120 hours. [Figure 10A] Western blots of FGFR2 and FGFR3 knockdown experiments are shown. [Figure 10B] 1 shows the inhibitory effect of siRNA knockdown of FGFR1, FGFR2, and FGFR3 in combination with Compound 2 on LU99 cell proliferation after 120 hours. [Figure 10C] 1 shows the inhibitory effect of siRNA knockdown of FGFR1, FGFR2, and FGFR3 in combination with AMG510 on LU99 cell proliferation after 120 hours. [Figure 11A] To assess possible compensation of FGFR2, FGFR3, and FGFR4, Western blots of FGFR1, FGFR2, FGFR3, and FGFR4 after knockdown of FGR1 are shown. [Figure 11B] 1 shows the inhibitory effect of siRNA knockdown of FGFR1, FGFR2, FGFR3, and FGFR4 in combination with Compound 2 on LU99 cell proliferation after 120 hours. [Figure 12] Western blot analysis of FGFR1, pERK, and B-actin in MiaPaca2 KRAS G12C resistant clones. [Figure 13A] Western blots of knockdown experiments of FGFR1, FGFR2, FGFR3, and FGFR4 are shown. [Figure 13B] FIG. 1 shows the inhibitory effect of siRNA knockdown of single FGFR isoforms in combination with compound 5 on A427 cell proliferation after 120 hours. [Figure 13C] 1 shows the inhibitory effect of siRNA knockdown of multiple FGFR isoforms in combination with compound 5 on A427 cell proliferation after 120 hours. [Figure 13D]FIG. 1 shows the inhibitory effect of siRNA knockdown of single FGFR isoforms in combination with compound 6 on A427 cell proliferation after 120 hours. [Figure 13E] 1 shows the inhibitory effect of siRNA knockdown of multiple FGFR isoforms in combination with compound 6 on A427 cell proliferation after 120 hours. [Figure 13F] FIG. 1 shows the inhibitory effect of siRNA knockdown of single FGFR isoforms in combination with compound 7 on A427 cell proliferation after 120 hours. [Figure 13G] 1 shows the inhibitory effect of siRNA knockdown of multiple FGFR isoforms in combination with compound 7 on A427 cell proliferation after 120 hours. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0018] The present application provides, inter alia, a method of treating cancer in a patient comprising administering an FGFR1 inhibitor in combination with a KRAS inhibitor.

[0019] FGFR inhibitors Pemigatinib has the structure: [ka] No. 9,611,267, which is incorporated herein by reference in its entirety. Pemigatinib is further described in U.S. Publication Nos. 2019 / 0337948 and 2020 / 0002338, which are incorporated herein by reference in their entirety. Pemigatinib, as described herein, can inhibit the activity of FGFR1, FGFR2, and FGFR3 enzymes. For example, pemigatinib can be used to inhibit the activity of FGFR enzymes in cells, individuals, or patients in need of enzyme inhibition by administering an inhibitory amount of pemigatinib to the cells, individuals, or patients. As an FGFR inhibitor, pemigatinib is useful for treating a variety of diseases associated with abnormal expression or activity of FGFR enzymes or FGFR ligands.

[0020] TAS-120 (futibatinib) has the following structure: [ka] It is commercially available, i.e., from Selleck Chemicals (https: / / www.selleckchem.com / products / tas-120.html). TAS-120 is further described in Chem.Med.Chem.2019,14,494-500, which is incorporated herein by reference in its entirety. TAS-120, as described herein, can inhibit the activity of FGFR1, FGFR2, FGFR3, and FGFR4 enzymes.

[0021] Erdafitinib has the following structure: [ka] It is commercially available, i.e., from Selleck Chemicals (https: / / www.selleckchem.com / products / jnj-42756493-erdafitinib.html). Erdafitinib is further described in Mol. Cancer Ther. 2017, 16(6), 1010-1020, the entire contents of which are incorporated herein by reference. Erdafitinib, as described herein, can inhibit the activity of FGFR1, FGFR2, FGFR3, and FGFR4 enzymes.

[0022] BGJ398 (infigratinib) has the following structure: [ka] It is commercially available, i.e., from Selleck Chemicals (https: / / www.selleckchem.com / products / bgj398-nvp-bgj398.html). BGJ398 is further described in J.Med.Chem.2011,54,7066-7083, the entire contents of which are incorporated herein by reference. BGJ398 as described herein can inhibit the activity of FGFR1, FGFR2, and FGFR3 enzymes.

[0023] Compound 1, described herein, is capable of inhibiting the activity of FGFR2 and FGFR3 enzymes and is 40-fold more selective for inhibiting FGFR2 and FGFR3 over inhibiting FGFR1.

[0024] Compounds that inhibit FGFR may be useful for providing a means of preventing tumor growth or inducing apoptosis, particularly by inhibiting angiogenesis.The methods disclosed herein may be useful for treating or preventing proliferative disorders, such as cancer.In particular, tumors that have activating mutant forms of receptor tyrosine kinases or have upregulation of receptor tyrosine kinases may be particularly susceptible to the methods described herein.

[0025] KRAS inhibitors AMG-510 (sotorasib) has the following structure: [ka] It is commercially available, i.e., from Selleck Chemicals (https: / / www.selleckchem.com / products / amg510.html). AMG-510 is further described in J.Med.Chem.2020,63,52-65, the entire contents of which are incorporated herein by reference. AMG-510 as described herein can inhibit the activity of KRAS G12C mutant protein.

[0026] MRTX849 (adagrasib) has the following structure: [ka] It is commercially available, i.e., from Selleck Chemicals (https: / / www.selleckchem.com / products / mrtx849.html). MRTX849 is further described in J.Med. Chem. 2020,63,6679-6693, the entire contents of which are incorporated herein by reference. MRTX849 as described herein can inhibit the activity of KRAS G12C mutant protein.

[0027] 2-((2S,4S)-4-(4-(3-(dimethylamino)-3-methylazetidin-1-yl)-6-fluoro-7-(5-fluoroquinolin-8-yl)-8-(trifluoromethyl)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-((E)-4-methoxybut-2-enoyl)piperidin-2-yl)acetonitrile (compound 2) has the following structure: [ka] Compound 2 is disclosed in U.S. Provisional Application No. 63 / 219,274, the entirety of which is incorporated herein by reference. Compound 2 is also disclosed in U.S. Provisional Application No. 63 / 292,774 and No. 63 / 310,811, the entirety of which is incorporated herein by reference. Compound 2 described herein can inhibit the activity of KRAS G12C mutant protein.

[0028] 2-((2S,4S)-4-(4-(3-(dimethylamino)-3-methylazetidin-1-yl)-6-fluoro-7-(5-fluoroquinolin-8-yl)-8-(trifluoromethyl)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-((E)-4-fluorobut-2-enoyl)piperidin-2-yl)acetonitrile (compound 3) has the following structure: [ka] Compound 3, as described herein, is capable of inhibiting the activity of KRAS G12C mutant protein.

[0029] 2-((2S,4S)-1-Acryloyl-4-(8-chloro-7-(6-chloro-5-methyl-1H-indazol-4-yl)-4-(3-(dimethylamino)azetidin-1-yl)-6-fluoro-1H-pyrazolo[4,3-c]quinolin-1-yl)piperidin-2-yl)acetonitrile (compound 4) has the following structure: [ka] The present invention is disclosed in International Application Publication No. WO2021 / 211864 A1, the entire contents of which are incorporated herein by reference. Compound 4 described herein can inhibit the activity of KRAS G12C mutant protein.

[0030] 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-7-(7-fluoro-3-hydroxynaphthalen-1-yl)-2-methyl-4-(1H-1,2,4-triazol-1-yl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile (compound 5) has the following structure: [ka] The compound 5 described herein can inhibit the activity of KRAS G12D mutant protein.

[0031] 8-(2-((R)-1-acetylpyrrolidin-2-yl)-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-8-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-7-yl)-1,2,3,4-tetrahydronaphthalene-1-carbonitrile (compound 6) has the following structure: [ka] No. 63 / 368,124, the entire contents of which are incorporated herein by reference. Compound 6, as described herein, is capable of inhibiting the activity of KRAS G12D mutant protein.

[0032] 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-4-ethoxy-2-((4-ethyl-2-oxopiperazin-1-yl)methyl)-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile (compound 7) has the following structure: [ka]

[0033] Compound 7 described herein is capable of inhibiting the activity of KRAS G12D mutant protein.

[0034] Compounds of formula (I) [ka] or a pharma- ceutically acceptable salt thereof, Y is N or CH; R 1 is selected from Cl, CH3, CH2F, CHF2, and CF3; Cy 1 teeth, [Table 1] Selected from; R 2 is selected from F and Cl; R 3 teeth, [Table 2] Selected from; Cy 2 teeth, [Table 3] Selected from; However, the compound of formula (I) [Table 4] (other than) are disclosed in U.S. Provisional Application US63 / 219,274, the entire contents of which are incorporated herein by reference. The compounds of formula (I) described herein can inhibit the activity of KRAS G12C mutant protein.

[0035] Compounds of formula (II): [ka] or a pharma- ceutically acceptable salt thereof, R 1 is selected from Cl, CH3, CH2F, CHF2, and CF3; Cy 1 teeth, [Table 5] Selected from; R 2 is selected from F and Cl; R 3 teeth, [Table 6] Selected from; Cy 2 teeth, [Table 7] Selected from; However, the compound of formula (II) [Table 8] (other than) are disclosed in U.S. Provisional Application US63 / 261,982, the entire contents of which are incorporated herein by reference. The compounds of formula (II) described herein can inhibit the activity of KRAS G12C mutant protein.

[0036] Compounds of formula (III): [ka] or a pharma- ceutically acceptable salt thereof, Y is N or CR 6 and R 1 , H, C 1-3 Alkyl, C 1-3 Haloalkyl, cyclopropyl, halo, D, CN, and OR a1 C is selected from 1-3 Alkyl and cyclopropyl are each optionally represented by R g and is substituted by 1 or 2 substituents independently selected from: R 2 , H, C 1-3 Alkyl, C 1-3 haloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl-C 1-3 Alkylene, Phenyl-C 1-3 Alkylene, 5-6 membered heteroaryl-C 1-3 Alkylene, halo, D, CN, and OR a2 C is selected from 1-3 Alkyl, 4-6 membered heterocycloalkylphenyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl-C 1-3 Alkylene, Phenyl-C 1-3 Alkylene, 5-6 membered heteroaryl-C 1-3 Each alkylene is optionally represented by R gand is substituted by 1 or 2 substituents independently selected from: Cy 1 is C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 aryl, and 6-10 membered heteroaryl; the 4-10 membered heterocycloalkyl and the 6-10 membered heteroaryl each have at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S; the ring-forming carbon atoms of the 6-10 membered heteroaryl and the 4-10 membered heterocycloalkyl are optionally substituted by oxo to form a carbonyl group; C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl and 6- to 10-membered heteroaryl are each optionally represented by R 10 and is substituted with 1, 2, 3, or 4 substituents independently selected from R 3 , H, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C 3~6 Cycloalkyl-C 1-3 Alkylene, 4-6 membered heterocycloalkyl-C 1~3 Alkylene, Phenyl-C 1-3 Alkylene, 5-6 membered heteroaryl-C 1-3 Alkylene, Halo, D, CN, OR f3 , C(O)NR c3 R d3 , N.R. c3 R j3 , and N.R. c3 C(O)R b3 C is selected from 1-3 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C 3-6 Cycloalkyl-C 1-3 Alkylene, 4-6 membered heterocycloalkyl-C 1-3 Alkylene, Phenyl-C1-3 Alkylene and 5-6 membered heteroaryl-C 1-3 Each alkylene is optionally represented by R 30 and is substituted by 1, 2, or 3 substituents independently selected from: R 5 , H, C 1-3 Alkyl, C 1-3 Haloalkyl, cyclopropyl, halo, D, CN, and OR a5 C is selected from 1-3 Alkyl and cyclopropyl are each optionally represented by R g and is substituted by 1 or 2 substituents independently selected from: R 6 , H, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, 4-9 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C 3~6 Cycloalkyl-C 1-3 Alkylene, 4-6 membered heterocycloalkyl-C 1~3 Alkylene, Phenyl-C 1-3 Alkylene, 5-6 membered heteroaryl-C 1-3 Alkylene, Halo, D, CN, OR a6 , and C(O)NR c6 R d6 ; selected from the group consisting of C 1-3 Alkyl, C 3-6 Cycloalkyl, 4-9 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C 3-6 Cycloalkyl-C 1-3 Alkylene, 4-6 membered heterocycloalkyl-C 1-3 Alkylene, Phenyl-C 1-3 Alkylene and 5-6 membered heteroaryl-C 1-3 Each alkylene is optionally represented by R 60 and is substituted by 1 or 2 substituents independently selected from: R 7 , H, C 1-3 Alkyl, C 1-3Haloalkyl, cyclopropyl, halo, D, CN, and OR a7 C is selected from 1-3 Alkyl and cyclopropyl are each optionally represented by R g and is substituted by 1 or 2 substituents independently selected from: Cy 2 teeth, [Table 9] (n is 0, 1, or 2); Each R 10 is C 1-3 Alkyl, C 1-3 Haloalkyl, Halo, D, CN, OR a10 , C(O)R b10 , C(O)NR c10 R d10 , C(O)OR a10 , N.R. c10 R d10 , and S(O)2R b10 are independently selected from; Each R 20 is independent, C 1-3 Alkyl, C 1-3 Haloalkyl, Halo, D, CN, and OR a20 Selected from; Each R 30 is independent, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, halo, D, CN, OR a30 , C(O)R b30 , C(O)NR c30 R d30 , C(O)OR a30 , N.R. c30 R d30 , and S(O)2R b30 C is selected from 1-3 Alkyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl are each optionally represented by R 31and is substituted by 1 or 2 substituents independently selected from: Each R 31 is C 1-3 Alkyl, C 1-3 Haloalkyl, Halo, D, CN, OR a31 , C(O)R b31 , C(O)NR c31 R d31 , C(O)OR a31 , N.R. c31 R d31 , and S(O)2R b31 are independently selected from; Each R 33 is independently C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, 4-membered heterocycloalkyl, 6-membered heterocycloalkyl, phenyl, 5-6-membered heteroaryl, halo, D, CN, OR a30 , C(O)NR c30 R d30 , and N.R. c30 R d30 C is selected from 1-3 Alkyl, C 3-6 Cycloalkyl, 4-membered heterocycloalkyl, 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl are each optionally represented by R 31 and is substituted by 1 or 2 substituents independently selected from: Each R 60 is independent, C 1-3 Alkyl, C 1-3 Haloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl, halo, D, CN, OR a60 , C(O)R b60 , C(O)NR c60 R d60 , N.R. c60 C(O)R b60 , C(O)OR a60 , N.R. c60 C(O)OR a60 , N.R. c60 R d60 , N.R. c60 S(O)2R b60 , and S(O)2Rb60 C is selected from 1-3 Alkyl, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl are each optionally represented by R 61 and is substituted by 1 or 2 substituents independently selected from: Each R 61 is independent, C 1-3 Alkyl, C 1-3 Haloalkyl, Halo, D, CN, OR a61 , and N.R. c61 R d61 Selected from; R a1 , H, C 1-3 Alkyl, and C 1-3 haloalkyl; Each R a2 , H, C 1-3 Alkyl, and C 1-3 haloalkyl; Each R b3 , R c3 , and R d3 are independent of each other, H, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl; 1-3 Alkyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl are each optionally represented by R 30 or is substituted by 1, 2, or 3 substituents independently selected from: or R bonded to the same N atom c3 and R d3 and together with the N atom to which they are attached, optionally R 30 forming a 4-, 5-, or 6-membered heterocycloalkyl group substituted with 1, 2, or 3 substituents independently selected from: R j3 is C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl; 1-3 Alkyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl are each optionally represented by R 30 or is substituted by 1, 2, or 3 substituents independently selected from: or R bonded to the same N atom c3 and R j3 and together with the N atom to which they are attached, optionally R 30 forming a 4-, 5-, or 6-membered heterocycloalkyl group substituted with 1, 2, or 3 substituents independently selected from: R f3 is C 1-3 Haloalkyl, C 3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl; 1-3 Haloalkyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl are each optionally represented by R 30 or is substituted by one, two, or three substituents independently selected from R f3 teeth, [Table 10] (R x is H or C 1-2 is alkyl, R y is C 1-2 Is it alkyl; or R x and R y are selected from: R a5 , H, C 1-3 Alkyl, and C 1-3 haloalkyl; Each R a6 , Rc6 , and R d6 are independent of each other, H, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl; 1-3 Alkyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl are each optionally represented by R 60 and is substituted by 1 or 2 substituents independently selected from: R a7 , H, C 1-3 Alkyl, and C 1-3 haloalkyl; Each R a10 , R b10 , R c10 , and R d10 , H, C 1-3 Alkyl, and C 1-3 independently selected from haloalkyl; Each R a20 , H, C 1-3 Alkyl, and C 1-3 haloalkyl; R b20 NH2, C 1-3 Alkyl, and C 1-3 haloalkyl; Each R a30 , R b30 , R c30 , and R d30 , H, C 1-3 Alkyl, and C 1-3 independently selected from haloalkyl; Each R a31 , R b31 , R c31 , and R d31 , H, C 1-3 Alkyl, and C 1-3 independently selected from haloalkyl; Each R a60 , R b60 , R c60 , and Rd60 are independent of each other, H, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl; 1-3 Alkyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl are each optionally represented by R 61 or is substituted by 1 or 2 substituents independently selected from: or any R bonded to the same N atom c60 and R d60 together with the N atom to which they are attached, optionally R 61 forming a 4-, 5-, or 6-membered heterocycloalkyl group substituted with 1 or 2 substituents independently selected from: Each R a61 , R c61 , and R d61 , H, C 1-3 Alkyl, and C 1-3 independently selected from haloalkyl; Each R g are independently D, OH, CN, halo, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, Amino, C 1-3 Alkylamino and di(C 1-3 alkyl)amino; However, the compound of formula (III) is 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-4-ethoxy-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-1H-pyrrolo[3,2-c]quinolin-2-yl)-N,N-dimethylpropanamide) is disclosed in PCT Application No. PCT / US22 / 78048, which is incorporated herein by reference in its entirety. Compounds of formula (III) described herein can inhibit the activity of KRAS G12D mutant protein.

[0037] KRAS inhibitors are useful for treating various diseases associated with abnormal expression or activity of KRAS. Compounds that inhibit KRAS will be useful for preventing tumor growth or providing a means by inducing apoptosis or inhibiting angiogenesis. Thus, it is expected that the compounds of the present disclosure will prove useful for treating or preventing proliferative disorders such as cancer. In particular, tumors that have activating mutant forms of receptor tyrosine kinases or have upregulation of receptor tyrosine kinases may be particularly sensitive to inhibitors.

[0038] Provided herein is a method of treating cancer in a patient, comprising administering to the patient: (i) an FGFR1 inhibitor; (ii) a KRAS inhibitor; and The method comprises administering

[0039] In some embodiments, the FGFR1 inhibitor is selected from pemigatinib, futibatinib, erdafitinib, and infigratinib, or a pharmaceutically acceptable salt thereof. In some embodiments, the FGFR1 inhibitor is pemigatinib or a pharmaceutically acceptable salt thereof. In some embodiments, the FGFR1 inhibitor is futibatinib or a pharmaceutically acceptable salt thereof. In some embodiments, the FGFR1 inhibitor is erdafitinib or a pharmaceutically acceptable salt thereof. In some embodiments, the FGFR1 inhibitor is infigratinib or a pharmaceutically acceptable salt thereof. In some embodiments, the FGFR1 inhibitor further inhibits FGFR2, FGFR3, or a combination thereof.

[0040] In some embodiments, the KRAS inhibitor is a compound of formula (I): [ka] or a pharma- ceutically acceptable salt thereof, Y is N or CH; R1 is selected from Cl, CH3, CH2F, CHF2, and CF3; Cy 1 teeth, [Table 11] Selected from; R 2 is selected from F and Cl; R 3 teeth, [Table 12] Selected from; Cy 2 teeth, [Table 13] Selected from; However, the compound of formula (I) [Table 14] (other than).

[0041] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is 2-((2S,4S)-4-(4-(3-(dimethylamino)-3-methylazetidin-1-yl)-6-fluoro-7-(5-fluoroquinolin-8-yl)-8-(trifluoromethyl)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-((E)-4-fluorobut-2-enoyl)piperidin-2-yl)acetonitrile; 2-((2S,4S)-4-(4-(3-(dimethylamino)-3-methylazetidin-1-yl)-6-fluoro-7-(2-methoxy-3-methylphenyl)-8-(trifluoromethyl)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-((E)-4-fluorobut-2-enoyl)piperidin-2-yl)acetonitrile; 2-((2S,4S)-4-(7-(3-chloro-2-methoxyphenyl)-4-(3-(dimethylamino)-3-methylazetidin-1-yl)-6-fluoro-8-(trifluoromethyl)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-((E)-4-fluorobut-2-enoyl)piperidin-2-yl)acetonitrile; 2-((2S,4S)-4-(6-fluoro-7-(5-fluoroquinolin-8-yl)-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-8-(trifluoromethyl)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-((E)-4-fluorobut-2-enoyl)piperidin-2-yl)acetonitrile; 1-(4-(6-fluoro-7-(5-fluoroquinolin-8-yl)-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-8-(trifluoromethyl)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)piperidin-1-yl)prop-2-en-1-one; 2-((2S,4S)-4-(4-(3-(dimethylamino)-3-methylazetidin-1-yl)-7-(2,3-dimethylphenyl)-6-fluoro-8-methyl-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-((E)-4-methoxybut-2-enoyl)piperidin-2-yl)acetonitrile; 2-((2S,4S)-4-(6-fluoro-8-methyl-7-(1-methyl-1H-indazol-6-yl)-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-((E)-4-fluorobut-2-enoyl)piperidin-2-yl)acetonitrile; 2-((2S,4S)-4-(6-fluoro-8-methyl-7-(6-methylpyridin-3-yl)-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-((E)-4-fluorobut-2-enoyl)piperidin-2-yl)acetonitrile; 2-((2S,4S)-4-(6-fluoro-8-methyl-7-(1-methyl-1H-indazol-3-yl)-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-((E)-4-methoxybut-2-enoyl)piperidin-2-yl)acetonitrile; 2-((2S,4S)-4-(6-fluoro-7-(4-fluorophenyl)-8-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-((E)-4-methoxybut-2-enoyl)piperidin-2-yl)acetonitrile; 8-(1-(1-acryloylpiperidin-4-yl)-6-fluoro-8-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-[1,2,3]triazolo[4,5-c]quinolin-7-yl)-1-naphthonitrile; 2-((2S,4S)-4-(7-(2-chloro-3-methylphenyl)-4-(3-(dimethylamino)-3-methylazetidin-1-yl)-6-fluoro-8-methyl-1H-imidazo[4,5-c]quinolin-1-yl)-1-((E)-4-fluorobut-2-enoyl)piperidin-2-yl)acetonitrile; 2-((2S,4S)-4-(7-(2-chloro-3-methylphenyl)-6-fluoro-8-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-imidazo[4,5-c]quinolin-1-yl)-1-(2-fluoroacryloyl)piperidin-2-yl)acetonitrile; 8-(1-((2R,4S)-1-acryloyl-2-methylpiperidin-4-yl)-6-fluoro-8-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-[1,2,3]triazolo[4,5-c]quinolin-7-yl)-1-naphthonitrile; 2-((2S,4S)-4-(7-(5,6-dimethyl-1H-indazol-4-yl)-4-(3-(ethyl(methyl)amino)azetidin-1-yl)-6-fluoro-8-methyl-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-(2-fluoroacryloyl)piperidin-2-yl)acetonitrile; 8-(6-fluoro-1-(1-((E)-4-fluorobut-2-enoyl)piperidin-4-yl)-8-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-[1,2,3]triazolo[4,5-c]quinolin-7-yl)-1-naphthonitrile; 8-(1-((2S,4S)-2-(cyanomethyl)-1-(2-fluoroacryloyl)piperidin-4-yl)-4-(3-(dimethylamino)-3-methylazetidin-1-yl)-6-fluoro-8-methyl-1H-[1,2,3]triazolo[4,5-c]quinolin-7-yl)-1-naphthonitrile; 2-((2S,4S)-4-(6,8-dichloro-4-(3-(dimethylamino)-3-methylazetidin-1-yl)-7-(5-fluoroquinolin-8-yl)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-((E)-4-methoxybut-2-enoyl)piperidin-2-yl)acetonitrile; 2-((2S,4S)-4-(6,8-dichloro-4-(3-(dimethylamino)-3-methylazetidin-1-yl)-7-(5-fluoroquinolin-8-yl)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-((E)-4-fluorobut-2-enoyl)piperidin-2-yl)acetonitrile; and 2-((2S,4S)-4-(4-(3-(dimethylamino)-3-methylazetidin-1-yl)-6-fluoro-7-(5-fluoroquinolin-8-yl)-8-(trifluoromethyl)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-((E)-4-methoxybut-2-enoyl)piperidin-2-yl)acetonitrile; or a pharma- ceutically acceptable salt thereof.

[0042] In an embodiment of Formula (I), or a pharma- ceutically acceptable salt thereof, Y is N or CH; R 1 is selected from Cl, CH3, CH2F, CHF2, and CF3; Cy 1 teeth, [Table 15] Selected from; R 2 is selected from F and Cl; R 3 teeth, [Table 16] Selected from; Cy 2 teeth, [Table 17] is selected from.

[0043] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is 2-((2S,4S)-4-(4-(3-(dimethylamino)-3-methylazetidin-1-yl)-6-fluoro-7-(5-fluoroquinolin-8-yl)-8-(trifluoromethyl)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-((E)-4-fluorobut-2-enoyl)piperidin-2-yl)acetonitrile; 2-((2S,4S)-4-(4-(3-(dimethylamino)-3-methylazetidin-1-yl)-6-fluoro-7-(2-methoxy-3-methylphenyl)-8-(trifluoromethyl)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-((E)-4-fluorobut-2-enoyl)piperidin-2-yl)acetonitrile; 2-((2S,4S)-4-(7-(3-chloro-2-methoxyphenyl)-4-(3-(dimethylamino)-3-methylazetidin-1-yl)-6-fluoro-8-(trifluoromethyl)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-((E)-4-fluorobut-2-enoyl)piperidin-2-yl)acetonitrile; 2-((2S,4S)-4-(6-fluoro-7-(5-fluoroquinolin-8-yl)-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-8-(trifluoromethyl)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-((E)-4-fluorobut-2-enoyl)piperidin-2-yl)acetonitrile; 1-(4-(6-fluoro-7-(5-fluoroquinolin-8-yl)-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-8-(trifluoromethyl)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)piperidin-1-yl)prop-2-en-1-one; 2-((2S,4S)-4-(6-fluoro-8-methyl-7-(1-methyl-1H-indazol-6-yl)-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-((E)-4-fluorobut-2-enoyl)piperidin-2-yl)acetonitrile; 2-((2S,4S)-4-(6-fluoro-8-methyl-7-(6-methylpyridin-3-yl)-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-((E)-4-fluorobut-2-enoyl)piperidin-2-yl)acetonitrile; 2-((2S,4S)-4-(6-fluoro-8-methyl-7-(1-methyl-1H-indazol-3-yl)-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-((E)-4-methoxybut-2-enoyl)piperidin-2-yl)acetonitrile; 2-((2S,4S)-4-(6-fluoro-7-(4-fluorophenyl)-8-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-((E)-4-methoxybut-2-enoyl)piperidin-2-yl)acetonitrile; 8-(1-(1-acryloylpiperidin-4-yl)-6-fluoro-8-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-[1,2,3]triazolo[4,5-c]quinolin-7-yl)-1-naphthonitrile; 8-(1-((2R,4S)-1-acryloyl-2-methylpiperidin-4-yl)-6-fluoro-8-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-[1,2,3]triazolo[4,5-c]quinolin-7-yl)-1-naphthonitrile; 2-((2S,4S)-4-(7-(5,6-dimethyl-1H-indazol-4-yl)-4-(3-(ethyl(methyl)amino)azetidin-1-yl)-6-fluoro-8-methyl-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-(2-fluoroacryloyl)piperidin-2-yl)acetonitrile; 8-(6-fluoro-1-(1-((E)-4-fluorobut-2-enoyl)piperidin-4-yl)-8-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-[1,2,3]triazolo[4,5-c]quinolin-7-yl)-1-naphthonitrile; 8-(1-((2S,4S)-2-(cyanomethyl)-1-(2-fluoroacryloyl)piperidin-4-yl)-4-(3-(dimethylamino)-3-methylazetidin-1-yl)-6-fluoro-8-methyl-1H-[1,2,3]triazolo[4,5-c]quinolin-7-yl)-1-naphthonitrile; 2-((2S,4S)-4-(6,8-dichloro-4-(3-(dimethylamino)-3-methylazetidin-1-yl)-7-(5-fluoroquinolin-8-yl)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-((E)-4-methoxybut-2-enoyl)piperidin-2-yl)acetonitrile; 2-((2S,4S)-4-(6,8-dichloro-4-(3-(dimethylamino)-3-methylazetidin-1-yl)-7-(5-fluoroquinolin-8-yl)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-((E)-4-fluorobut-2-enoyl)piperidin-2-yl)acetonitrile; and 2-((2S,4S)-4-(4-(3-(dimethylamino)-3-methylazetidin-1-yl)-6-fluoro-7-(5-fluoroquinolin-8-yl)-8-(trifluoromethyl)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-((E)-4-methoxybut-2-enoyl)piperidin-2-yl)acetonitrile; or a pharma- ceutically acceptable salt thereof.

[0044] In some embodiments, the KRAS inhibitor is a compound of formula (II): [ka] or a pharma- ceutically acceptable salt thereof, R1 is selected from Cl, CH3, CH2F, CHF2, and CF3; Cy 1 teeth, [Table 18] Selected from; R 2 is selected from F and Cl; R 3 teeth, [Table 19] Selected from; Cy 2 teeth, [Table 20] Selected from; However, the compound of formula (II) [Table 21] (other than).

[0045] In some embodiments, the compound of formula (II) or a pharma- ceutically acceptable salt thereof is 1-(1-((2S,4S)-1-(but-2-ynoyl)-2-(cyanomethyl)piperidin-4-yl)-8-chloro-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrazolo[4,3-c]quinolin-7-yl)isoquinoline-8-carbonitrile; 1-(8-chloro-1-((2S,4S)-2-(cyanomethyl)-1-((E)-4-methoxybut-2-enoyl)piperidin-4-yl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrazolo[4,3-c]quinolin-7-yl)isoquinoline-8-carbonitrile; 1-(8-chloro-1-((2S,4S)-2-(cyanomethyl)-1-(2-fluoroacryloyl)piperidin-4-yl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrazolo[4,3-c]quinolin-7-yl)isoquinoline-8-carbonitrile; 2-((2S,4S)-4-(8-chloro-7-(5,6-dimethyl-1H-indazol-4-yl)-4-(3-(ethyl(methyl)amino)azetidin-1-yl)-6-fluoro-1H-pyrazolo[4,3-c]quinolin-1-yl)-1-(2-fluoroacryloyl)piperidin-2-yl)acetonitrile; 8-(8-chloro-1-((2S,4S)-2-(cyanomethyl)-1-(2-fluoroacryloyl)piperidin-4-yl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrazolo[4,3-c]quinolin-7-yl)-1-naphthonitrile; 8-(8-chloro-1-((2S,4S)-2-(cyanomethyl)-1-((E)-4-methoxybut-2-enoyl)piperidin-4-yl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrazolo[4,3-c]quinolin-7-yl)-1-naphthonitrile; and 8-(1-((2S,4S)-1-(but-2-ynoyl)-2-(cyanomethyl)piperidin-4-yl)-6-fluoro-8-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrazolo[4,3-c]quinolin-7-yl)-1-naphthonitrile; or a pharma- ceutically acceptable salt thereof.

[0046] In an embodiment of Formula (II), or a pharma- ceutically acceptable salt thereof, R 1 is selected from Cl, CH2F, CHF2, and CF3; Cy 1 teeth, [Table 22] Selected from; R 2 is selected from F and Cl; R 3 teeth, [Table 23] Selected from; Cy 2 teeth, [Table 24] is selected from.

[0047] In another embodiment, the compound of formula (II) or a pharma- ceutically acceptable salt thereof is 1-(1-((2S,4S)-1-(but-2-ynoyl)-2-(cyanomethyl)piperidin-4-yl)-8-chloro-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrazolo[4,3-c]quinolin-7-yl)isoquinoline-8-carbonitrile; 1-(8-chloro-1-((2S,4S)-2-(cyanomethyl)-1-((E)-4-methoxybut-2-enoyl)piperidin-4-yl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrazolo[4,3-c]quinolin-7-yl)isoquinoline-8-carbonitrile; 1-(8-chloro-1-((2S,4S)-2-(cyanomethyl)-1-(2-fluoroacryloyl)piperidin-4-yl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrazolo[4,3-c]quinolin-7-yl)isoquinoline-8-carbonitrile; 2-((2S,4S)-4-(8-chloro-7-(5,6-dimethyl-1H-indazol-4-yl)-4-(3-(ethyl(methyl)amino)azetidin-1-yl)-6-fluoro-1H-pyrazolo[4,3-c]quinolin-1-yl)-1-(2-fluoroacryloyl)piperidin-2-yl)acetonitrile; 8-(8-chloro-1-((2S,4S)-2-(cyanomethyl)-1-(2-fluoroacryloyl)piperidin-4-yl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrazolo[4,3-c]quinolin-7-yl)-1-naphthonitrile; and 8-(8-chloro-1-((2S,4S)-2-(cyanomethyl)-1-((E)-4-methoxybut-2-enoyl)piperidin-4-yl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrazolo[4,3-c]quinolin-7-yl)-1-naphthonitrile; or a pharma- ceutically acceptable salt thereof.

[0048] In some embodiments, the KRAS inhibitor is a compound of formula (III): [ka] or a pharma- ceutically acceptable salt thereof, Y is N or CR 6 and R 1 , H, C 1-3 Alkyl, C 1-3 Haloalkyl, cyclopropyl, halo, D, CN, and OR a1 C is selected from 1-3 Alkyl and cyclopropyl are each optionally represented by R g and is substituted by 1 or 2 substituents independently selected from: R 2 , H, C 1-3 Alkyl, C 1-3 haloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl-C 1-3 Alkylene, Phenyl-C 1-3 Alkylene, 5-6 membered heteroaryl-C 1-3 Alkylene, halo, D, CN, and OR a2 C is selected from 1-3Alkyl, 4-6 membered heterocycloalkylphenyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl-C 1-3 Alkylene, Phenyl-C 1-3 Alkylene, 5-6 membered heteroaryl-C 1-3 Each alkylene is optionally represented by R g and is substituted by 1 or 2 substituents independently selected from: Cy 1 is C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 aryl, and 6-10 membered heteroaryl; the 4-10 membered heterocycloalkyl and the 6-10 membered heteroaryl each have at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S; the ring-forming carbon atoms of the 6-10 membered heteroaryl and the 4-10 membered heterocycloalkyl are optionally substituted by oxo to form a carbonyl group; C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl and 6- to 10-membered heteroaryl are each optionally represented by R 10 and is substituted with 1, 2, 3, or 4 substituents independently selected from R 3 , H, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C 3~6 Cycloalkyl-C 1-3 Alkylene, 4-6 membered heterocycloalkyl-C 1~3 Alkylene, Phenyl-C 1-3 Alkylene, 5-6 membered heteroaryl-C 1-3 Alkylene, Halo, D, CN, OR f3 , C(O)NR c3 R d3 , N.R. c3 R j3 , and N.R. c3 C(O)R b3 C is selected from1-3 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C 3-6 Cycloalkyl-C 1-3 Alkylene, 4-6 membered heterocycloalkyl-C 1-3 Alkylene, Phenyl-C 1-3 Alkylene and 5-6 membered heteroaryl-C 1-3 Each alkylene is optionally represented by R 30 and is substituted by 1, 2, or 3 substituents independently selected from: R 5 , H, C 1-3 Alkyl, C 1-3 Haloalkyl, cyclopropyl, halo, D, CN, and OR a5 C is selected from 1-3 Alkyl and cyclopropyl are each optionally represented by R g and is substituted by 1 or 2 substituents independently selected from: R 6 , H, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, 4-9 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C 3~6 Cycloalkyl-C 1-3 Alkylene, 4-6 membered heterocycloalkyl-C 1~3 Alkylene, Phenyl-C 1-3 Alkylene, 5-6 membered heteroaryl-C 1-3 Alkylene, Halo, D, CN, OR a6 , and C(O)NR c6 R d6 ; selected from the group consisting of C 1-3 Alkyl, C 3-6 Cycloalkyl, 4-9 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C 3-6 Cycloalkyl-C 1-3 Alkylene, 4-6 membered heterocycloalkyl-C 1-3 Alkylene, Phenyl-C 1-3 Alkylene and 5-6 membered heteroaryl-C1-3 Each alkylene is optionally represented by R 60 and is substituted by 1 or 2 substituents independently selected from: R 7 , H, C 1-3 Alkyl, C 1-3 Haloalkyl, cyclopropyl, halo, D, CN, and OR a7 C is selected from 1-3 Alkyl and cyclopropyl are each optionally represented by R g and is substituted by 1 or 2 substituents independently selected from: Cy 2 teeth, [Table 25] (n is 0, 1, or 2); Each R 10 is C 1-3 Alkyl, C 1-3 Haloalkyl, Halo, D, CN, OR a10 , C(O)R b10 , C(O)NR c10 R d10 , C(O)OR a10 , N.R. c10 R d10 , and S(O)2R b10 are independently selected from; Each R 20 is independent, C 1-3 Alkyl, C 1-3 Haloalkyl, Halo, D, CN, and OR a20 Selected from; Each R 30 is independent, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, halo, D, CN, OR a30 , C(O)R b30 , C(O)NR c30 R d30 , C(O)OR a30 , N.R. c30 R d30, and S(O)2R b30 C is selected from 1-3 Alkyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl are each optionally represented by R 31 and is substituted by 1 or 2 substituents independently selected from: Each R 31 is C 1-3 Alkyl, C 1-3 Haloalkyl, Halo, D, CN, OR a31 , C(O)R b31 , C(O)NR c31 R d31 , C(O)OR a31 , N.R. c31 R d31 , and S(O)2R b31 are independently selected from; Each R 33 is independently C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, 4-membered heterocycloalkyl, 6-membered heterocycloalkyl, phenyl, 5-6-membered heteroaryl, halo, D, CN, OR a30 , C(O)NR c30 R d30 , and N.R. c30 R d30 C is selected from 1-3 Alkyl, C 3-6 Cycloalkyl, 4-membered heterocycloalkyl, 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl are each optionally represented by R 31 and is substituted by 1 or 2 substituents independently selected from: Each R 60 is independent, C 1-3 Alkyl, C 1-3 Haloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl, halo, D, CN, OR a60 , C(O)R b60 , C(O)NR c60 R d60 , N.R. c60 C(O)Rb60 , C(O)OR a60 , N.R. c60 C(O)OR a60 , N.R. c60 R d60 , N.R. c60 S(O)2R b60 , and S(O)2R b60 C is selected from 1-3 Alkyl, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl are each optionally represented by R 61 and is substituted by 1 or 2 substituents independently selected from: Each R 61 is independent, C 1-3 Alkyl, C 1-3 Haloalkyl, Halo, D, CN, OR a61 , and N.R. c61 R d61 Selected from; R a1 , H, C 1-3 Alkyl, and C 1-3 haloalkyl; Each R a2 , H, C 1-3 Alkyl, and C 1-3 haloalkyl; Each R b3 , R c3 , and R d3 are independent of each other, H, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl; 1-3 Alkyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl are each optionally represented by R 30 or is substituted by 1, 2, or 3 substituents independently selected from: or R bonded to the same N atom c3 and R d3 and together with the N atom to which they are attached, optionally R 30forming a 4-, 5-, or 6-membered heterocycloalkyl group substituted with 1, 2, or 3 substituents independently selected from: R j3 is C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl; 1-3 Alkyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl are each optionally represented by R 30 or is substituted by 1, 2, or 3 substituents independently selected from: or R bonded to the same N atom c3 and R j3 and together with the N atom to which they are attached, optionally R 30 forming a 4-, 5-, or 6-membered heterocycloalkyl group substituted with 1, 2, or 3 substituents independently selected from: R f3 is C 1-3 Haloalkyl, C 3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl; 1-3 Haloalkyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl are each optionally represented by R 30 or is substituted by one, two, or three substituents independently selected from R f3 teeth, [Table 26] (R x is H or C 1-2 is alkyl, R y is C 1-2 Is it alkyl; or R x and R yare selected from: R a5 , H, C 1-3 Alkyl, and C 1-3 haloalkyl; Each R a6 , R c6 , and R d6 are independent of each other, H, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl; 1-3 Alkyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl are each optionally represented by R 60 and is substituted by 1 or 2 substituents independently selected from: R a7 , H, C 1-3 Alkyl, and C 1-3 haloalkyl; Each R a10 , R b10 , R c10 , and R d10 , H, C 1-3 Alkyl, and C 1-3 independently selected from haloalkyl; Each R a20 , H, C 1-3 Alkyl, and C 1-3 haloalkyl; R b20 NH2, C 1-3 Alkyl, and C 1-3 haloalkyl; Each R a30 , R b30 , R c30 , and R d30 , H, C 1-3 Alkyl, and C 1-3 independently selected from haloalkyl; Each R a31 , Rb31 , R c31 , and R d31 , H, C 1-3 Alkyl, and C 1-3 independently selected from haloalkyl; Each R a60 , R b60 , R c60 , and R d60 are independent of each other, H, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl; 1-3 Alkyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl are each optionally represented by R 61 or is substituted by 1 or 2 substituents independently selected from: or any R bonded to the same N atom c60 and R d60 together with the N atom to which they are attached, optionally R 61 forming a 4-, 5-, or 6-membered heterocycloalkyl group substituted with 1 or 2 substituents independently selected from: Each R a61 , R c61 , and R d61 , H, C 1-3 Alkyl, and C 1-3 independently selected from haloalkyl; Each R g are independently D, OH, CN, halo, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, Amino, C 1-3 Alkylamino and di(C 1-3 alkyl)amino; However, the compound of formula (III) is other than 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-4-ethoxy-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-1H-pyrrolo[3,2-c]quinolin-2-yl)-N,N-dimethylpropanamide).

[0049] In some embodiments, the compound of formula (III) is: 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(7-chloro-3-hydroxynaphthalen-1-yl)-6-fluoro-2-methyl-4-(1H-1,2,4-triazol-1-yl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(5,7-difluoro-1H-indol-3-yl)-6-fluoro-2-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-7-(6-fluoro-5-methyl-1H-indol-3-yl)-2-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile; 3-(2-(3-(azetidin-1-yl)-3-oxopropyl)-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile; 3-((1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-8-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-2-yl)methyl)oxazolidin-2-one; 8-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-2,8-dimethyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-7-yl)-1-naphthonitrile; 1-((2S,4S)-1-acetyl-2-(cyanomethyl)piperidin-4-yl)-7-(8-cyanonaphthalen-1-yl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrazolo[4,3-c]quinoline-8-carbonitrile; 8-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-8-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-2-((3-oxomorpholino)methyl)-1H-pyrrolo[3,2-c]quinolin-7-yl)-1-naphthonitrile; 3-(7-(benzo[b]thiophen-3-yl)-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-2-((2-oxopyrrolidin-1-yl)methyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-4-(((S)-1-(dimethylamino)propan-2-yl)oxy)-6-fluoro-7-(7-fluoronaphthalen-1-yl)-2-((2-oxopyrrolidin-1-yl)methyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile; 8-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-6-fluoro-2-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-7-yl)-1-naphthonitrile; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(2,3-dichloro-5-hydroxyphenyl)-6-fluoro-2-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-6-fluoro-4-((3-fluoro-1-methylazetidin-3-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)-1H-pyrrolo[3,2-c]quinolin-2-yl)-N,N-dimethylpropanamide; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-2-methyl-4-(5-methylpyrazin-2-yl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-7-(7-fluoronaphthalen-1-yl)-4-methyl-2-((4-methyl-2-oxopiperazin-1-yl)methyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(2,3-dichloro-5-hydroxyphenyl)-4-ethoxy-6-fluoro-2-((4-isopropyl-2-oxopiperazin-1-yl)methyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-4-(3-(dimethylamino)-3-methylazetidin-1-yl)-6-fluoro-7-(7-fluoronaphthalen-1-yl)-2-((3-oxomorpholino)methyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-4-ethoxy-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-2-(1-(3-oxomorpholino)ethyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile; 3-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-2-(pyridin-3-yl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile; 3-(2-(3-(azetidin-1-yl)-3-oxopropyl)-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(7,8-difluoronaphthalen-1-yl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile; 3-(2-(3-(azetidin-1-yl)-3-oxopropyl)-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(6,7-difluoronaphthalen-1-yl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-7-(7-fluoro-3-hydroxynaphthalen-1-yl)-2-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile; 1-(1-((2S,4S)-1-acetyl-2-(cyanomethyl)piperidin-4-yl)-8-chloro-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrazolo[4,3-c]quinolin-7-yl)isoquinoline-8-carbonitrile; 8-(1-((2S,4S)-1-acetyl-2-(cyanomethyl)piperidin-4-yl)-8-chloro-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-7-yl)-1-naphthonitrile; 8-(1-((2S,4S)-1-acetyl-2-(cyanomethyl)piperidin-4-yl)-8-chloro-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrazolo[4,3-c]quinolin-7-yl)-1-naphthonitrile; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-7-(7-fluoro-3-hydroxynaphthalen-1-yl)-2-methyl-4-(1H-1,2,4-triazol-1-yl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-7-(7-fluoronaphthalen-1-yl)-2-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile; (2R)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(1H-1,2,4-triazol-1-yl)-1H-pyrrolo[3,2-c]quinolin-2-yl)-N,N-dimethylpyrrolidine-1-carboxamide; Methyl (2R)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(2-chloro-3-methylphenyl)-8-(2-cyanoethyl)-6-fluoro-4-(1H-1,2,4-triazol-1-yl)-1H-pyrrolo[3,2-c]quinolin-2-yl)pyrrolidine-1-carboxylate; Methyl (1S,3R,5S)-3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-4-(6-(dimethylcarbamoyl)pyridin-3-yl)-6-fluoro-1H-pyrrolo[3,2-c]quinolin-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-2-(5-oxo-1,2,3,5-tetrahydroindolizin-3-yl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile; Methyl (2R)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-4-(6-(dimethylcarbamoyl)pyridin-3-yl)-6-fluoro-1H-pyrrolo[3,2-c]quinolin-2-yl)pyrrolidine-1-carboxylate; Methyl (2R)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(6-(methylcarbamoyl)pyridin-3-yl)-1H-pyrrolo[3,2-c]quinolin-2-yl)pyrrolidine-1-carboxylate; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(2-chloro-3-fluorophenyl)-2-((R)-1-(cyclopropanecarbonyl)pyrrolidin-2-yl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile; 8-(2-((R)-1-acetylpyrrolidin-2-yl)-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-8-methyl-4-(2-methylpyridin-4-yl)-1H-pyrrolo[3,2-c]quinolin-7-yl)-1,2,3,4-tetrahydronaphthalene-1-carbonitrile; 5-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(3-chloro-2-methylphenyl)-8-(2-cyanoethyl)-6-fluoro-2-((R)-1-(2-oxopyrazin-1(2H)-yl)ethyl)-1H-pyrrolo[3,2-c]quinolin-4-yl)-N-methylpicolinamide; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-7-(7-fluoronaphthalen-1-yl)-4-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-2-((R)-1-(2-oxopyrazin-1(2H)-yl)ethyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(3-chloro-2-methylphenyl)-6-fluoro-4-(5-methylpyrazin-2-yl)-2-((R)-1-(2-oxopyrazin-1(2H)-yl)ethyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile; Methyl (2R)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(5-fluoro-6-(methylcarbamoyl)pyridin-3-yl)-1H-pyrrolo[3,2-c]quinolin-2-yl)pyrrolidine-1-carboxylate; Methyl (2R)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1H-pyrrolo[3,2-c]quinolin-2-yl)pyrrolidine-1-carboxylate; Ethyl (2R)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1H-pyrrolo[3,2-c]quinolin-2-yl)pyrrolidine-1-carboxylate; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(2,3-dichlorophenyl)-2-((R)-1-(3,3-difluoroazetidine-1-carbonyl)pyrrolidin-2-yl)-6-fluoro-4-(methyl-d3)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(2,3-dichlorophenyl)-2-((R)-1-(3,3-difluoroazetidine-1-carbonyl)pyrrolidin-2-yl)-6-fluoro-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(3-chloro-2-methylphenyl)-6-fluoro-4-(5-methylpyrazin-2-yl)-2-((R)-1-(3-oxomorpholino)ethyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile; 5-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-6-fluoro-7-(7-fluoronaphthalen-1-yl)-2-((R)-1-(3-oxomorpholino)ethyl)-1H-pyrrolo[3,2-c]quinolin-4-yl)-N-methylpicolinamide; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-7-(7-fluoronaphthalen-1-yl)-4-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-2-((R)-1-(3-oxomorpholino)ethyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-7-(7-fluoronaphthalen-1-yl)-4-(5-methylpyrazin-2-yl)-2-((R)-1-(3-oxomorpholino)ethyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile; Methyl (1R,3R,5R)-3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-4-(6-(dimethylcarbamoyl)pyridin-3-yl)-6-fluoro-1H-pyrrolo[3,2-c]quinolin-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-2-((R)-1-(2-oxopyrazin-1(2H)-yl)ethyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile; Methyl (2R,4S)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1H-pyrrolo[3,2-c]quinolin-2-yl)-4-fluorpyrrolidine-1-carboxylate; Methyl (2R,5R)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1H-pyrrolo[3,2-c]quinolin-2-yl)-5-methylpyrrolidine-1-carboxylate; Methyl (2R)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-3-chloro-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1H-pyrrolo[3,2-c]quinolin-2-yl)pyrrolidine-1-carboxylate; 4-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((R)-1-(2-oxopyrazin-1(2H)-yl)ethyl)-1H-pyrrolo[3,2-c]quinolin-4-yl)-2-fluoro-N-methylbenzamide; Methyl ((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-2-yl)ethyl)carbamate; N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-2-yl)ethyl)-2,2-difluoroacetamide; N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-2-yl)ethyl)-2,2-difluoroacetamide; (2S)-N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-2-yl)ethyl)tetrahydrofuran-2-carboxamide; N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-2-yl)ethyl)cyclopropanesulfonamide; N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-2-yl)ethyl)thiazole-4-carboxamide; N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-2-yl)ethyl)-N-methylcyclopropanecarboxamide; N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(1-hydroxyethyl)-1H-pyrrolo[3,2-c]quinolin-2-yl)ethyl)-1-methylcyclopropane-1-carboxamide; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(1-hydroxyethyl)-2-((1R,3R,5R)-2-(1-methylcyclopropane-1-carbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((1R,3R,5R)-2-(1-fluorocyclopropane-1-carbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-4-(1-hydroxyethyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((1R,3R,5R)-2-(1-fluorocyclopropane-1-carbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-4-methyl-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile; N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(1-hydroxyethyl)-1H-pyrrolo[3,2-c]quinolin-2-yl)ethyl)-1-fluorocyclopropane-1-carboxamide; N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(1-hydroxyethyl)-1H-pyrrolo[3,2-c]quinolin-2-yl)ethyl)-1-fluorocyclobutane-1-carboxamide; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(3-chloro-2-methylphenyl)-2-(1-(2,6-dimethyl-3-oxo-2,3-dihydropyridazin-4-yl)ethyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile; N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-2-yl)ethyl)pyrimidine-4-carboxamide; N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-2-yl)ethyl)pyridazine-3-carboxamide; N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-2-yl)ethyl)-3,3-difluoroazetidine-1-carboxamide; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-2-((R)-1-((1-methyl-1H-pyrazol-4-yl)amino)ethyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile; 5-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((R)-1-(1-fluorocyclopropane-1-carbonyl)pyrrolidin-2-yl)-1H-pyrrolo[3,2-c]quinolin-4-yl)-N,N-dimethylpicolinamide; methyl (2R)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-4-(4-((dimethylamino)methyl)-2,3-difluorophenyl)-6-fluoro-1H-pyrrolo[3,2-c]quinolin-2-yl)pyrrolidine-1-carboxylate, or a pharma- ceutically acceptable salt thereof.

[0050] In some embodiments, the compound of formula (III) is: 3-(2-((R)-1-acetylpyrrolidin-2-yl)-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile; 4-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-6-fluoro-7-(7-fluoronaphthalen-1-yl)-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-2-yl)-N,N,1-trimethyl-1H -pyrazole-5-carboxamide; 3-(2-((R)-1-acetylpyrrolidin-2-yl)-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-3-chloro-7-(2,3-dichlorophenyl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile; and 8-(2-((R)-1-acetylpyrrolidin-2-yl)-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-8-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-7-yl)-1,2,3,4-tetrahydronaphthalene-1-carbonitrile, or a pharma- ceutically acceptable salt thereof.

[0051] In an embodiment of the compound of formula (III), or a pharma- ceutically acceptable salt thereof, Y is N or CR 6 and R 1 is H; R 2 is C 1-3 Alkyl, C 1-3 selected from haloalkyl, halo, CN, and -CHCHCN; Cy 1 is C 6-10 aryl and 6-10 membered heteroaryl; the 6-10 membered heteroaryl has at least one ring-forming carbon atom and one ring-forming heteroatom independently selected from N and S; 6-10 Aryl and 6-10 membered heteroaryl are each optionally represented by R 10 and is substituted by 1, 2, or 3 substituents independently selected from: R 3 is C 1-3 Alkyl, C 1-3 haloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl, and OR f3 C is selected from 1-3 Alkyl, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl are each optionally represented by R 30 and is substituted by 1 or 2 substituents independently selected from: R 5 is H; R 6 , H, C 1-3 Alkyl, C 1-3 haloalkyl, 5-6 membered heteroaryl; 1-3 Alkyl and 5- to 6-membered heteroaryl are each optionally represented by R 60 and is substituted by 1 or 2 substituents independently selected from: R 7 is a halo; Cy 2 teeth, [Table 27] Selected from; Each R 10 is independent, C 1-3 Alkyl, C 1-3 Haloalkyl, Halo, CN, and OR a10 Selected from; Each R 30 is independent, C 1-3 Alkyl, C 1-3 Haloalkyl, 4-6 membered heterocycloalkyl, halo, and NR c30 R d30 C is selected from 1-3 Alkyl and 4- to 6-membered heterocycloalkyl are each optionally represented by R 31 and is substituted by 1 or 2 substituents independently selected from: Each R 31 is independent, C 1-3 Alkyl, C 1-3 Haloalkyl, halo, and NR c31 R d31 Selected from; R 33 is C 2-3 Alkyl, C 1-3 haloalkyl, 4-membered heterocycloalkyl, 6-membered heterocycloalkyl, halo, and CN; 2-3 Alkyl, 4-membered heterocycloalkyl, and 6-membered heterocycloalkyl are each optionally represented by R 31 and is substituted by 1 or 2 substituents independently selected from: Each R 60 is independent, C 1-3 Alkyl, C 1-3 Haloalkyl, 4-6 membered heterocycloalkyl, halo, and C(O)NR c60 R d60 C is selected from 1-3 Alkyl and 4- to 6-membered heterocycloalkyl are each optionally represented by R 61 and is substituted by 1 or 2 substituents independently selected from: Each R61 is independent, C 1-3 Alkyl, C 1-3 selected from haloalkyl, and halo; R f3 is C 1-3 is haloalkyl; or R f3 teeth, [Table 28] (R x is H or C 1-2 is alkyl, R y is C 1-2 alkyl; Each R a10 , H, C 1-3 Alkyl, and C 1-3 haloalkyl; R b20 is C 1-3 Alkyl, and C 1-3 haloalkyl; Each R c30 and R d30 , H, C 1-3 Alkyl, and C 1-3 independently selected from haloalkyl; Each R c31 and R d31 , H, C 1-3 Alkyl, and C 1-3 independently selected from haloalkyl; Each R c60 and R d60 are independent of each other, H, C 1-3 Alkyl, C 1-3 haloalkyl, and 4- to 6-membered heterocycloalkyl; 1-3 Alkyl and 4- to 6-membered heterocycloalkyl are each optionally represented by R 61 or is substituted by 1 or 2 substituents independently selected from: or any R bonded to the same N atom c60 and R d60 together with the N atom to which they are attached, optionally R 61Form a 4- or 5-membered heterocycloalkyl group substituted with 1 or 2 substituents independently selected from:

[0052] In some embodiments, the KRAS inhibitor is selected from sotorasib, adagrasib, compound 2, compound 3, and compound 4, or a pharmaceutically acceptable salt thereof. In some embodiments, the KRAS inhibitor is selected from sotorasib, compound 2, compound 3, and compound 4, or a pharmaceutically acceptable salt thereof. In some embodiments, the KRAS inhibitor is sotorasib or a pharmaceutically acceptable salt thereof. In some embodiments, the KRAS inhibitor is adagrasib or a pharmaceutically acceptable salt thereof. In some embodiments, the KRAS inhibitor is compound 2 or a pharmaceutically acceptable salt thereof. In some embodiments, the KRAS inhibitor is compound 3 or a pharmaceutically acceptable salt thereof. In some embodiments, the KRAS inhibitor is compound 4 or a pharmaceutically acceptable salt thereof. In some embodiments, the KRAS inhibitor is a KRAS G12C inhibitor.

[0053] In some embodiments, the KRAS inhibitor is selected from sotorasib, adagrasib, compound 2, compound 3, compound 4, compound 5, compound 6, and compound 7, or a pharmaceutically acceptable salt thereof. In some embodiments, the KRAS inhibitor is selected from sotorasib, compound 2, compound 3, compound 4, compound 5, compound 6, and compound 7, or a pharmaceutically acceptable salt thereof. In some embodiments, the KRAS inhibitor is selected from compound 5, compound 6, and compound 7, or a pharmaceutically acceptable salt thereof. In some embodiments, the KRAS inhibitor is compound 5, or a pharmaceutically acceptable salt thereof. In some embodiments, the KRAS inhibitor is compound 6, or a pharmaceutically acceptable salt thereof. In some embodiments, the KRAS inhibitor is compound 7, or a pharmaceutically acceptable salt thereof. In some embodiments, the KRAS inhibitor is a KRAS G12D inhibitor.

[0054] Provided herein is a method of treating cancer in a patient, comprising administering to the patient: (i) pemigatinib, or a pharma- ceutically acceptable salt thereof; (ii) administering to a subject a KRAS inhibitor, the KRAS inhibitor being a compound of formula (I): [ka] or a pharma- ceutically acceptable salt thereof, Y is N or CH; R 1 is selected from Cl, CH3, CH2F, CHF2, and CF3; Cy 1 teeth, [Table 29] Selected from; R 2 is selected from F and Cl; R 3 teeth, [Table 30] Selected from; Cy 2 teeth, [Table 31] is selected from However, the compound of formula (I) [Table 32] (other than that).

[0055] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is 2-((2S,4S)-4-(4-(3-(dimethylamino)-3-methylazetidin-1-yl)-6-fluoro-7-(5-fluoroquinolin-8-yl)-8-(trifluoromethyl)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-((E)-4-fluorobut-2-enoyl)piperidin-2-yl)acetonitrile; 2-((2S,4S)-4-(4-(3-(dimethylamino)-3-methylazetidin-1-yl)-6-fluoro-7-(2-methoxy-3-methylphenyl)-8-(trifluoromethyl)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-((E)-4-fluorobut-2-enoyl)piperidin-2-yl)acetonitrile; 2-((2S,4S)-4-(7-(3-chloro-2-methoxyphenyl)-4-(3-(dimethylamino)-3-methylazetidin-1-yl)-6-fluoro-8-(trifluoromethyl)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-((E)-4-fluorobut-2-enoyl)piperidin-2-yl)acetonitrile; 2-((2S,4S)-4-(6-fluoro-7-(5-fluoroquinolin-8-yl)-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-8-(trifluoromethyl)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-((E)-4-fluorobut-2-enoyl)piperidin-2-yl)acetonitrile; 1-(4-(6-fluoro-7-(5-fluoroquinolin-8-yl)-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-8-(trifluoromethyl)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)piperidin-1-yl)prop-2-en-1-one; 2-((2S,4S)-4-(4-(3-(dimethylamino)-3-methylazetidin-1-yl)-7-(2,3-dimethylphenyl)-6-fluoro-8-methyl-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-((E)-4-methoxybut-2-enoyl)piperidin-2-yl)acetonitrile; 2-((2S,4S)-4-(6-fluoro-8-methyl-7-(1-methyl-1H-indazol-6-yl)-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-((E)-4-fluorobut-2-enoyl)piperidin-2-yl)acetonitrile; 2-((2S,4S)-4-(6-fluoro-8-methyl-7-(6-methylpyridin-3-yl)-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-((E)-4-fluorobut-2-enoyl)piperidin-2-yl)acetonitrile; 2-((2S,4S)-4-(6-fluoro-8-methyl-7-(1-methyl-1H-indazol-3-yl)-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-((E)-4-methoxybut-2-enoyl)piperidin-2-yl)acetonitrile; 2-((2S,4S)-4-(6-fluoro-7-(4-fluorophenyl)-8-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-((E)-4-methoxybut-2-enoyl)piperidin-2-yl)acetonitrile; 8-(1-(1-acryloylpiperidin-4-yl)-6-fluoro-8-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-[1,2,3]triazolo[4,5-c]quinolin-7-yl)-1-naphthonitrile; 2-((2S,4S)-4-(7-(2-chloro-3-methylphenyl)-4-(3-(dimethylamino)-3-methylazetidin-1-yl)-6-fluoro-8-methyl-1H-imidazo[4,5-c]quinolin-1-yl)-1-((E)-4-fluorobut-2-enoyl)piperidin-2-yl)acetonitrile; 2-((2S,4S)-4-(7-(2-chloro-3-methylphenyl)-6-fluoro-8-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-imidazo[4,5-c]quinolin-1-yl)-1-(2-fluoroacryloyl)piperidin-2-yl)acetonitrile; 8-(1-((2R,4S)-1-acryloyl-2-methylpiperidin-4-yl)-6-fluoro-8-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-[1,2,3]triazolo[4,5-c]quinolin-7-yl)-1-naphthonitrile; 2-((2S,4S)-4-(7-(5,6-dimethyl-1H-indazol-4-yl)-4-(3-(ethyl(methyl)amino)azetidin-1-yl)-6-fluoro-8-methyl-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-(2-fluoroacryloyl)piperidin-2-yl)acetonitrile; 8-(6-fluoro-1-(1-((E)-4-fluorobut-2-enoyl)piperidin-4-yl)-8-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-[1,2,3]triazolo[4,5-c]quinolin-7-yl)-1-naphthonitrile; 8-(1-((2S,4S)-2-(cyanomethyl)-1-(2-fluoroacryloyl)piperidin-4-yl)-4-(3-(dimethylamino)-3-methylazetidin-1-yl)-6-fluoro-8-methyl-1H-[1,2,3]triazolo[4,5-c]quinolin-7-yl)-1-naphthonitrile; 2-((2S,4S)-4-(6,8-dichloro-4-(3-(dimethylamino)-3-methylazetidin-1-yl)-7-(5-fluoroquinolin-8-yl)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-((E)-4-methoxybut-2-enoyl)piperidin-2-yl)acetonitrile; 2-((2S,4S)-4-(6,8-dichloro-4-(3-(dimethylamino)-3-methylazetidin-1-yl)-7-(5-fluoroquinolin-8-yl)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-((E)-4-fluorobut-2-enoyl)piperidin-2-yl)acetonitrile; and 2-((2S,4S)-4-(4-(3-(dimethylamino)-3-methylazetidin-1-yl)-6-fluoro-7-(5-fluoroquinolin-8-yl)-8-(trifluoromethyl)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-((E)-4-methoxybut-2-enoyl)piperidin-2-yl)acetonitrile; or a pharma- ceutically acceptable salt thereof.

[0056] Provided herein is a method of treating cancer in a patient, comprising administering to the patient: (i) pemigatinib, or a pharma- ceutically acceptable salt thereof; (ii) administering to a subject a KRAS inhibitor, the KRAS inhibitor being a compound of formula (II): [ka] or a pharma- ceutically acceptable salt thereof, R 1 is selected from Cl, CH3, CH2F, CHF2, and CF3; Cy 1 teeth, [Table 33] Selected from; R 2 is selected from F and Cl; R 3 teeth, [Table 34] Selected from; Cy 2 teeth, [Table 35] is selected from However, the compound of formula (II) [Table 36] (other than that).

[0057] In some embodiments, the compound of formula (II) or a pharma- ceutically acceptable salt thereof is 1-(1-((2S,4S)-1-(but-2-ynoyl)-2-(cyanomethyl)piperidin-4-yl)-8-chloro-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrazolo[4,3-c]quinolin-7-yl)isoquinoline-8-carbonitrile; 1-(8-chloro-1-((2S,4S)-2-(cyanomethyl)-1-((E)-4-methoxybut-2-enoyl)piperidin-4-yl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrazolo[4,3-c]quinolin-7-yl)isoquinoline-8-carbonitrile; 1-(8-chloro-1-((2S,4S)-2-(cyanomethyl)-1-(2-fluoroacryloyl)piperidin-4-yl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrazolo[4,3-c]quinolin-7-yl)isoquinoline-8-carbonitrile; 2-((2S,4S)-4-(8-chloro-7-(5,6-dimethyl-1H-indazol-4-yl)-4-(3-(ethyl(methyl)amino)azetidin-1-yl)-6-fluoro-1H-pyrazolo[4,3-c]quinolin-1-yl)-1-(2-fluoroacryloyl)piperidin-2-yl)acetonitrile; 8-(8-chloro-1-((2S,4S)-2-(cyanomethyl)-1-(2-fluoroacryloyl)piperidin-4-yl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrazolo[4,3-c]quinolin-7-yl)-1-naphthonitrile; 8-(8-chloro-1-((2S,4S)-2-(cyanomethyl)-1-((E)-4-methoxybut-2-enoyl)piperidin-4-yl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrazolo[4,3-c]quinolin-7-yl)-1-naphthonitrile; and 8-(1-((2S,4S)-1-(but-2-ynoyl)-2-(cyanomethyl)piperidin-4-yl)-6-fluoro-8-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrazolo[4,3-c]quinolin-7-yl)-1-naphthonitrile; or a pharma- ceutically acceptable salt thereof.

[0058] Provided herein is a method of treating cancer in a patient, comprising administering to the patient: (i) pemigatinib, or a pharma- ceutically acceptable salt thereof; (ii) administering to a subject a KRAS inhibitor, the KRAS inhibitor being a compound of formula (III): [ka] or a pharma- ceutically acceptable salt thereof, Y is N or CR 6 and R 1 , H, C 1-3 Alkyl, C 1-3Haloalkyl, cyclopropyl, halo, D, CN, and OR a1 C is selected from 1-3 Alkyl and cyclopropyl are each optionally represented by R g and is substituted by 1 or 2 substituents independently selected from: R 2 , H, C 1-3 Alkyl, C 1-3 haloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl-C 1-3 Alkylene, Phenyl-C 1-3 Alkylene, 5-6 membered heteroaryl-C 1-3 Alkylene, halo, D, CN, and OR a2 C is selected from 1-3 Alkyl, 4-6 membered heterocycloalkylphenyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl-C 1-3 Alkylene, Phenyl-C 1-3 Alkylene, 5-6 membered heteroaryl-C 1-3 Each alkylene is optionally represented by R g and is substituted by 1 or 2 substituents independently selected from: Cy 1 is C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 aryl, and 6-10 membered heteroaryl; the 4-10 membered heterocycloalkyl and the 6-10 membered heteroaryl each have at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S; the ring-forming carbon atoms of the 6-10 membered heteroaryl and the 4-10 membered heterocycloalkyl are optionally substituted by oxo to form a carbonyl group; C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl and 6- to 10-membered heteroaryl are each optionally represented by R 10 and is substituted with 1, 2, 3, or 4 substituents independently selected from R3 , H, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C 3~6 Cycloalkyl-C 1-3 Alkylene, 4-6 membered heterocycloalkyl-C 1~3 Alkylene, Phenyl-C 1-3 Alkylene, 5-6 membered heteroaryl-C 1-3 Alkylene, Halo, D, CN, OR f3 , C(O)NR c3 R d3 , N.R. c3 R j3 , and N.R. c3 C(O)R b3 C is selected from 1-3 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C 3-6 Cycloalkyl-C 1-3 Alkylene, 4-6 membered heterocycloalkyl-C 1-3 Alkylene, Phenyl-C 1-3 Alkylene and 5-6 membered heteroaryl-C 1-3 Each alkylene is optionally represented by R 30 and is substituted by 1, 2, or 3 substituents independently selected from: R 5 , H, C 1-3 Alkyl, C 1-3 Haloalkyl, cyclopropyl, halo, D, CN, and OR a5 C is selected from 1-3 Alkyl and cyclopropyl are each optionally represented by R g and is substituted by 1 or 2 substituents independently selected from: R 6 , H, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, 4-9 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C 3~6 Cycloalkyl-C1-3 Alkylene, 4-6 membered heterocycloalkyl-C 1~3 Alkylene, Phenyl-C 1-3 Alkylene, 5-6 membered heteroaryl-C 1-3 Alkylene, Halo, D, CN, OR a6 , and C(O)NR c6 R d6 ; selected from the group consisting of C 1-3 Alkyl, C 3-6 Cycloalkyl, 4-9 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C 3-6 Cycloalkyl-C 1-3 Alkylene, 4-6 membered heterocycloalkyl-C 1-3 Alkylene, Phenyl-C 1-3 Alkylene and 5-6 membered heteroaryl-C 1-3 Each alkylene is optionally represented by R 60 and is substituted by 1 or 2 substituents independently selected from: R 7 , H, C 1-3 Alkyl, C 1-3 Haloalkyl, cyclopropyl, halo, D, CN, and OR a7 C is selected from 1-3 Alkyl and cyclopropyl are each optionally represented by R g and is substituted by 1 or 2 substituents independently selected from: Cy 2 teeth, [Table 37] (n is 0, 1, or 2); Each R 10 is C 1-3 Alkyl, C 1-3 Haloalkyl, Halo, D, CN, OR a10 , C(O)R b10 , C(O)NR c10 R d10 , C(O)OR a10 , N.R. c10 R d10 , and S(O)2R b10are independently selected from; Each R 20 is independent, C 1-3 Alkyl, C 1-3 Haloalkyl, Halo, D, CN, and OR a20 Selected from; Each R 30 is independent, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, halo, D, CN, OR a30 , C(O)R b30 , C(O)NR c30 R d30 , C(O)OR a30 , N.R. c30 R d30 , and S(O)2R b30 C is selected from 1-3 Alkyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl are each optionally represented by R 31 and is substituted by 1 or 2 substituents independently selected from: Each R 31 is C 1-3 Alkyl, C 1-3 Haloalkyl, Halo, D, CN, OR a31 , C(O)R b31 , C(O)NR c31 R d31 , C(O)OR a31 , N.R. c31 R d31 , and S(O)2R b31 are independently selected from; Each R 33 is independently C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, 4-membered heterocycloalkyl, 6-membered heterocycloalkyl, phenyl, 5-6-membered heteroaryl, halo, D, CN, OR a30 , C(O)NR c30 R d30 , and N.R. c30 Rd30 C is selected from 1-3 Alkyl, C 3-6 Cycloalkyl, 4-membered heterocycloalkyl, 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl are each optionally represented by R 31 and is substituted by 1 or 2 substituents independently selected from: Each R 60 is independent, C 1-3 Alkyl, C 1-3 Haloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl, halo, D, CN, OR a60 , C(O)R b60 , C(O)NR c60 R d60 , N.R. c60 C(O)R b60 , C(O)OR a60 , N.R. c60 C(O)OR a60 , N.R. c60 R d60 , N.R. c60 S(O)2R b60 , and S(O)2R b60 C is selected from 1-3 Alkyl, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl are each optionally represented by R 61 and is substituted by 1 or 2 substituents independently selected from: Each R 61 is independent, C 1-3 Alkyl, C 1-3 Haloalkyl, Halo, D, CN, OR a61 , and N.R. c61 R d61 Selected from; R a1 , H, C 1-3 Alkyl, and C 1-3 haloalkyl; Each R a2 , H, C 1-3 Alkyl, and C 1-3 haloalkyl; Each R b3 , R c3 , and Rd3 are independent of each other, H, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl; 1-3 Alkyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl are each optionally represented by R 30 or is substituted by 1, 2, or 3 substituents independently selected from: or R bonded to the same N atom c3 and R d3 and together with the N atom to which they are attached, optionally R 30 forming a 4-, 5-, or 6-membered heterocycloalkyl group substituted with 1, 2, or 3 substituents independently selected from: R j3 is C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl; 1-3 Alkyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl are each optionally represented by R 30 or is substituted by 1, 2, or 3 substituents independently selected from: or R bonded to the same N atom c3 and R j3 and together with the N atom to which they are attached, optionally R 30 forming a 4-, 5-, or 6-membered heterocycloalkyl group substituted with 1, 2, or 3 substituents independently selected from: R f3 is C 1-3 Haloalkyl, C 3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl; 1-3 Haloalkyl, C 3-6Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl are each optionally represented by R 30 or is substituted by one, two, or three substituents independently selected from R f3 teeth, [Table 38] (R x is H or C 1-2 is alkyl, R y is C 1-2 alkyl; or R x and R y are selected from: R a5 , H, C 1-3 Alkyl, and C 1-3 haloalkyl; Each R a6 , R c6 , and R d6 are independent of each other, H, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl; 1-3 Alkyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl are each optionally represented by R 60 and is substituted by 1 or 2 substituents independently selected from: R a7 , H, C 1-3 Alkyl, and C 1-3 haloalkyl; Each R a10 , R b10 , R c10 , and R d10 , H, C 1-3 Alkyl, and C 1-3 independently selected from haloalkyl; Each Ra20 , H, C 1-3 Alkyl, and C 1-3 haloalkyl; R b20 NH2, C 1-3 Alkyl, and C 1-3 haloalkyl; Each R a30 , R b30 , R c30 , and R d30 , H, C 1-3 Alkyl, and C 1-3 independently selected from haloalkyl; Each R a31 , R b31 , R c31 , and R d31 , H, C 1-3 Alkyl, and C 1-3 independently selected from haloalkyl; Each R a60 , R b60 , R c60 , and R d60 are independent of each other, H, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl; 1-3 Alkyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl are each optionally represented by R 61 or is substituted by 1 or 2 substituents independently selected from: or any R bonded to the same N atom c60 and R d60 together with the N atom to which they are attached, optionally R 61 forming a 4-, 5-, or 6-membered heterocycloalkyl group substituted with 1 or 2 substituents independently selected from: Each R a61 , R c61 , and R d61 , H, C 1-3 Alkyl, and C 1-3independently selected from haloalkyl; Each R g are independently D, OH, CN, halo, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, Amino, C 1-3 Alkylamino and di(C 1-3 alkyl)amino; However, the compound of formula (III) is other than 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-4-ethoxy-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-1H-pyrrolo[3,2-c]quinolin-2-yl)-N,N-dimethylpropanamide).

[0059] In some embodiments, the compound of formula (III) is: 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(7-chloro-3-hydroxynaphthalen-1-yl)-6-fluoro-2-methyl-4-(1H-1,2,4-triazol-1-yl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(5,7-difluoro-1H-indol-3-yl)-6-fluoro-2-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-7-(6-fluoro-5-methyl-1H-indol-3-yl)-2-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile; 3-(2-(3-(azetidin-1-yl)-3-oxopropyl)-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile; 3-((1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-8-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-2-yl)methyl)oxazolidin-2-one; 8-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-2,8-dimethyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-7-yl)-1-naphthonitrile; 1-((2S,4S)-1-acetyl-2-(cyanomethyl)piperidin-4-yl)-7-(8-cyanonaphthalen-1-yl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrazolo[4,3-c]quinoline-8-carbonitrile; 8-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-8-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-2-((3-oxomorpholino)methyl)-1H-pyrrolo[3,2-c]quinolin-7-yl)-1-naphthonitrile; 3-(7-(benzo[b]thiophen-3-yl)-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-2-((2-oxopyrrolidin-1-yl)methyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-4-(((S)-1-(dimethylamino)propan-2-yl)oxy)-6-fluoro-7-(7-fluoronaphthalen-1-yl)-2-((2-oxopyrrolidin-1-yl)methyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile; 8-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-6-fluoro-2-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-7-yl)-1-naphthonitrile; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(2,3-dichloro-5-hydroxyphenyl)-6-fluoro-2-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-6-fluoro-4-((3-fluoro-1-methylazetidin-3-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)-1H-pyrrolo[3,2-c]quinolin-2-yl)-N,N-dimethylpropanamide; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-2-methyl-4-(5-methylpyrazin-2-yl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-7-(7-fluoronaphthalen-1-yl)-4-methyl-2-((4-methyl-2-oxopiperazin-1-yl)methyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(2,3-dichloro-5-hydroxyphenyl)-4-ethoxy-6-fluoro-2-((4-isopropyl-2-oxopiperazin-1-yl)methyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-4-(3-(dimethylamino)-3-methylazetidin-1-yl)-6-fluoro-7-(7-fluoronaphthalen-1-yl)-2-((3-oxomorpholino)methyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-4-ethoxy-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-2-(1-(3-oxomorpholino)ethyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile; 3-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-2-(pyridin-3-yl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile; 3-(2-(3-(azetidin-1-yl)-3-oxopropyl)-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(7,8-difluoronaphthalen-1-yl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile; 3-(2-(3-(azetidin-1-yl)-3-oxopropyl)-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(6,7-difluoronaphthalen-1-yl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-7-(7-fluoro-3-hydroxynaphthalen-1-yl)-2-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile; 1-(1-((2S,4S)-1-acetyl-2-(cyanomethyl)piperidin-4-yl)-8-chloro-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrazolo[4,3-c]quinolin-7-yl)isoquinoline-8-carbonitrile; 8-(1-((2S,4S)-1-acetyl-2-(cyanomethyl)piperidin-4-yl)-8-chloro-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-7-yl)-1-naphthonitrile; 8-(1-((2S,4S)-1-acetyl-2-(cyanomethyl)piperidin-4-yl)-8-chloro-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrazolo[4,3-c]quinolin-7-yl)-1-naphthonitrile; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-7-(7-fluoro-3-hydroxynaphthalen-1-yl)-2-methyl-4-(1H-1,2,4-triazol-1-yl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-7-(7-fluoronaphthalen-1-yl)-2-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile; (2R)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(1H-1,2,4-triazol-1-yl)-1H-pyrrolo[3,2-c]quinolin-2-yl)-N,N-dimethylpyrrolidine-1-carboxamide; Methyl (2R)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(2-chloro-3-methylphenyl)-8-(2-cyanoethyl)-6-fluoro-4-(1H-1,2,4-triazol-1-yl)-1H-pyrrolo[3,2-c]quinolin-2-yl)pyrrolidine-1-carboxylate; Methyl (1S,3R,5S)-3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-4-(6-(dimethylcarbamoyl)pyridin-3-yl)-6-fluoro-1H-pyrrolo[3,2-c]quinolin-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-2-(5-oxo-1,2,3,5-tetrahydroindolizin-3-yl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile; Methyl (2R)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-4-(6-(dimethylcarbamoyl)pyridin-3-yl)-6-fluoro-1H-pyrrolo[3,2-c]quinolin-2-yl)pyrrolidine-1-carboxylate; Methyl (2R)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(6-(methylcarbamoyl)pyridin-3-yl)-1H-pyrrolo[3,2-c]quinolin-2-yl)pyrrolidine-1-carboxylate; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(2-chloro-3-fluorophenyl)-2-((R)-1-(cyclopropanecarbonyl)pyrrolidin-2-yl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile; 8-(2-((R)-1-acetylpyrrolidin-2-yl)-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-8-methyl-4-(2-methylpyridin-4-yl)-1H-pyrrolo[3,2-c]quinolin-7-yl)-1,2,3,4-tetrahydronaphthalene-1-carbonitrile; 5-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(3-chloro-2-methylphenyl)-8-(2-cyanoethyl)-6-fluoro-2-((R)-1-(2-oxopyrazin-1(2H)-yl)ethyl)-1H-pyrrolo[3,2-c]quinolin-4-yl)-N-methylpicolinamide; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-7-(7-fluoronaphthalen-1-yl)-4-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-2-((R)-1-(2-oxopyrazin-1(2H)-yl)ethyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(3-chloro-2-methylphenyl)-6-fluoro-4-(5-methylpyrazin-2-yl)-2-((R)-1-(2-oxopyrazin-1(2H)-yl)ethyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile; Methyl (2R)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(5-fluoro-6-(methylcarbamoyl)pyridin-3-yl)-1H-pyrrolo[3,2-c]quinolin-2-yl)pyrrolidine-1-carboxylate; Methyl (2R)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1H-pyrrolo[3,2-c]quinolin-2-yl)pyrrolidine-1-carboxylate; Ethyl (2R)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1H-pyrrolo[3,2-c]quinolin-2-yl)pyrrolidine-1-carboxylate; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(2,3-dichlorophenyl)-2-((R)-1-(3,3-difluoroazetidine-1-carbonyl)pyrrolidin-2-yl)-6-fluoro-4-(methyl-d3)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(2,3-dichlorophenyl)-2-((R)-1-(3,3-difluoroazetidine-1-carbonyl)pyrrolidin-2-yl)-6-fluoro-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(3-chloro-2-methylphenyl)-6-fluoro-4-(5-methylpyrazin-2-yl)-2-((R)-1-(3-oxomorpholino)ethyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile; 5-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-6-fluoro-7-(7-fluoronaphthalen-1-yl)-2-((R)-1-(3-oxomorpholino)ethyl)-1H-pyrrolo[3,2-c]quinolin-4-yl)-N-methylpicolinamide; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-7-(7-fluoronaphthalen-1-yl)-4-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-2-((R)-1-(3-oxomorpholino)ethyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-7-(7-fluoronaphthalen-1-yl)-4-(5-methylpyrazin-2-yl)-2-((R)-1-(3-oxomorpholino)ethyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile; Methyl (1R,3R,5R)-3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-4-(6-(dimethylcarbamoyl)pyridin-3-yl)-6-fluoro-1H-pyrrolo[3,2-c]quinolin-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-2-((R)-1-(2-oxopyrazin-1(2H)-yl)ethyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile; Methyl (2R,4S)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1H-pyrrolo[3,2-c]quinolin-2-yl)-4-fluorpyrrolidine-1-carboxylate; Methyl (2R,5R)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1H-pyrrolo[3,2-c]quinolin-2-yl)-5-methylpyrrolidine-1-carboxylate; Methyl (2R)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-3-chloro-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1H-pyrrolo[3,2-c]quinolin-2-yl)pyrrolidine-1-carboxylate; 4-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((R)-1-(2-oxopyrazin-1(2H)-yl)ethyl)-1H-pyrrolo[3,2-c]quinolin-4-yl)-2-fluoro-N-methylbenzamide; Methyl ((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-2-yl)ethyl)carbamate; N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-2-yl)ethyl)-2,2-difluoroacetamide; N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-2-yl)ethyl)-2,2-difluoroacetamide; (2S)-N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-2-yl)ethyl)tetrahydrofuran-2-carboxamide; N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-2-yl)ethyl)cyclopropanesulfonamide; N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-2-yl)ethyl)thiazole-4-carboxamide; N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-2-yl)ethyl)-N-methylcyclopropanecarboxamide; N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(1-hydroxyethyl)-1H-pyrrolo[3,2-c]quinolin-2-yl)ethyl)-1-methylcyclopropane-1-carboxamide; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(1-hydroxyethyl)-2-((1R,3R,5R)-2-(1-methylcyclopropane-1-carbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((1R,3R,5R)-2-(1-fluorocyclopropane-1-carbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-4-(1-hydroxyethyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((1R,3R,5R)-2-(1-fluorocyclopropane-1-carbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-4-methyl-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile; N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(1-hydroxyethyl)-1H-pyrrolo[3,2-c]quinolin-2-yl)ethyl)-1-fluorocyclopropane-1-carboxamide; N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(1-hydroxyethyl)-1H-pyrrolo[3,2-c]quinolin-2-yl)ethyl)-1-fluorocyclobutane-1-carboxamide; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(3-chloro-2-methylphenyl)-2-(1-(2,6-dimethyl-3-oxo-2,3-dihydropyridazin-4-yl)ethyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile; N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-2-yl)ethyl)pyrimidine-4-carboxamide; N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-2-yl)ethyl)pyridazine-3-carboxamide; N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-2-yl)ethyl)-3,3-difluoroazetidine-1-carboxamide; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-2-((R)-1-((1-methyl-1H-pyrazol-4-yl)amino)ethyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile; 5-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((R)-1-(1-fluorocyclopropane-1-carbonyl)pyrrolidin-2-yl)-1H-pyrrolo[3,2-c]quinolin-4-yl)-N,N-dimethylpicolinamide; and Methyl (2R)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-4-(4-((dimethylamino)methyl)-2,3-difluorophenyl)-6-fluoro-1H-pyrrolo[3,2-c]quinolin-2-yl)pyrrolidine-1-carboxylate; or a pharma- ceutically acceptable salt thereof.

[0060] In some embodiments, the compound of formula (III) is: 3-(2-((R)-1-acetylpyrrolidin-2-yl)-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile; 4-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-6-fluoro-7-(7-fluoronaphthalen-1-yl)-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-2-yl)-N,N,1-trimethyl-1H -pyrazole-5-carboxamide; 3-(2-((R)-1-acetylpyrrolidin-2-yl)-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-3-chloro-7-(2,3-dichlorophenyl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile; and 8-(2-((R)-1-acetylpyrrolidin-2-yl)-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-8-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-7-yl)-1,2,3,4-tetrahydronaphthalene-1-carbonitrile, or a pharma- ceutically acceptable salt thereof.

[0061] Provided herein is a method of treating cancer in a patient, comprising administering to the patient: (i) an FGFR1 inhibitor selected from pemigatinib, futibatinib, erdafitinib, and infigratinib, or a pharma- ceutically acceptable salt thereof; (ii) a KRAS inhibitor selected from sotorasib, adagrasib, compound 2, compound 3, and compound 4, or a pharma- ceutically acceptable salt thereof.

[0062] Provided herein is a method of treating cancer in a patient, comprising administering to the patient: (i) an FGFR1 inhibitor selected from pemigatinib, futibatinib, erdafitinib, and infigratinib, or a pharma- ceutically acceptable salt thereof; (ii) a KRAS inhibitor selected from sotorasib, compound 2, compound 3, and compound 4, or a pharma- ceutically acceptable salt thereof.

[0063] Provided herein is a method of treating cancer in a patient, comprising administering to the patient: (i) an FGFR1 inhibitor selected from pemigatinib, futibatinib, erdafitinib, and infigratinib, or a pharma- ceutically acceptable salt thereof; (ii) a KRAS inhibitor selected from sotorasib, compound 2, compound 3, compound 4, compound 5, compound 6, and compound 7, or a pharma- ceutically acceptable salt thereof.

[0064] Provided herein is a method of treating cancer in a patient, comprising administering to the patient: (i) an FGFR1 inhibitor selected from pemigatinib, futibatinib, erdafitinib, and infigratinib, or a pharma- ceutically acceptable salt thereof; (ii) a KRAS inhibitor selected from Compound 5, Compound 6, and Compound 7, or a pharma- ceutically acceptable salt thereof.

[0065] In some embodiments, the FGFR1 inhibitor is pemigatinib or a pharmaceutically acceptable salt thereof.In some embodiments, the FGFR1 inhibitor is futibatinib or a pharmaceutically acceptable salt thereof.In some embodiments, the FGFR1 inhibitor is erdafitinib or a pharmaceutically acceptable salt thereof.In some embodiments, the FGFR1 inhibitor is infigratinib or a pharmaceutically acceptable salt thereof.

[0066] In some embodiments, the KRAS inhibitor is sotorasib or a pharma- ceutically acceptable salt thereof. In some embodiments, the KRAS inhibitor is adagrasib or a pharma- ceutically acceptable salt thereof. In some embodiments, the KRAS inhibitor is compound 2 or a pharma- ceutically acceptable salt thereof. In some embodiments, the KRAS inhibitor is compound 3 or a pharma- ceutically acceptable salt thereof. In some embodiments, the KRAS inhibitor is compound 4 or a pharma- ceutically acceptable salt thereof. In some embodiments, the KRAS inhibitor is compound 5 or a pharma- ceutically acceptable salt thereof. In some embodiments, the KRAS inhibitor is compound 6 or a pharma- ceutically acceptable salt thereof. In some embodiments, the KRAS inhibitor is compound 7 or a pharma- ceutically acceptable salt thereof.

[0067] Provided herein is a method of treating cancer in a patient, comprising administering to the patient: (i) pemigatinib, or a pharma- ceutically acceptable salt thereof; (ii) a KRAS inhibitor selected from sotorasib, adagrasib, compound 2, compound 3, and compound 4, or a pharma- ceutically acceptable salt thereof.

[0068] Provided herein is a method of treating cancer in a patient, comprising administering to the patient: (i) pemigatinib, or a pharma- ceutically acceptable salt thereof; (ii) a KRAS inhibitor selected from sotorasib, adagrasib, compound 2, compound 3, compound 4, compound 5, compound 6, and compound 7, or a pharma- ceutically acceptable salt thereof.

[0069] Provided herein is a method of treating cancer in a patient, comprising administering to the patient: (i) pemigatinib, or a pharma- ceutically acceptable salt thereof; (ii) a KRAS inhibitor selected from Compound 5, Compound 6, and Compound 7, or a pharma- ceutically acceptable salt thereof.

[0070] Provided herein is a method of treating cancer in a patient, comprising administering to the patient: (i) pemigatinib, or a pharma- ceutically acceptable salt thereof; (ii) a KRAS inhibitor selected from sotorasib, compound 2, compound 3, and compound 4, or a pharma- ceutically acceptable salt thereof.

[0071] In some embodiments, the KRAS inhibitor is sotorasib or a pharma- ceutically acceptable salt thereof. In some embodiments, the KRAS inhibitor is adagrasib or a pharma- ceutically acceptable salt thereof. In some embodiments, the KRAS inhibitor is compound 2 or a pharma- ceutically acceptable salt thereof. In some embodiments, the KRAS inhibitor is compound 3 or a pharma- ceutically acceptable salt thereof. In some embodiments, the KRAS inhibitor is compound 4 or a pharma- ceutically acceptable salt thereof. In some embodiments, the KRAS inhibitor is compound 5 or a pharma- ceutically acceptable salt thereof. In some embodiments, the KRAS inhibitor is compound 6 or a pharma- ceutically acceptable salt thereof. In some embodiments, the KRAS inhibitor is compound 7 or a pharma- ceutically acceptable salt thereof.

[0072] Provided herein is a method of treating cancer in a patient, comprising administering to the patient: (i) pemigatinib, or a pharma- ceutically acceptable salt thereof; (ii) sotorasib, or a pharma- ceutically acceptable salt thereof; and The method includes administering

[0073] Provided herein is a method of treating cancer in a patient, comprising administering to the patient: (i) pemigatinib, or a pharma- ceutically acceptable salt thereof; (ii) adagrasib, or a pharma- ceutically acceptable salt thereof; and The method includes administering

[0074] In vivo studies have demonstrated that the combination of an FGFR1 inhibitor, pemigatinib, and a KRAS inhibitor, sotrasib, at certain doses has a synergistic effect in the treatment of lung cancer (see, e.g., Examples E and F).

[0075] In some embodiments, pemigatinib, or a pharmaceutically acceptable salt thereof, and sotorasib, or a pharmaceutically acceptable salt thereof, are administered to a patient simultaneously. In some embodiments, pemigatinib, or a pharmaceutically acceptable salt thereof, and sotorasib, or a pharmaceutically acceptable salt thereof, are administered to a patient sequentially.

[0076] In some embodiments, pemigatinib or a pharmaceutically acceptable salt thereof and adagrasib or a pharmaceutically acceptable salt thereof are administered to a patient simultaneously. In some embodiments, pemigatinib or a pharmaceutically acceptable salt thereof and adagrasib or a pharmaceutically acceptable salt thereof are administered to a patient sequentially.

[0077] Pemigatinib and its pharmaceutically acceptable salts can be administered to a subject, for example a subject in need thereof, for example a human subject, by various methods. In many applications, the route of administration is oral. In some embodiments, pemigatinib or its pharmaceutically acceptable salts are administered as a pharmaceutical composition.

[0078] In some embodiments, pemigatinib is administered orally. In some embodiments, pemigatinib is administered once daily.

[0079] In some embodiments, pemigatinib is administered at a daily dose of about 1 mg to about 50 mg. In some embodiments, pemigatinib is administered at a daily dose of about 1 mg to about 20 mg. In some embodiments, pemigatinib is administered at a daily dose of about 1 mg to about 15 mg. In some embodiments, pemigatinib is administered at a daily dose of about 1 mg to about 10 mg. In some embodiments, pemigatinib is administered at a daily dose of about 1 mg to about 5 mg. In some embodiments, pemigatinib is administered at a daily dose of about 5 mg to about 20 mg. In some embodiments, pemigatinib is administered at a daily dose of about 5 mg to about 10 mg. In some embodiments, pemigatinib is administered at a daily dose of about 10 mg to about 15 mg. In some embodiments, pemigatinib is administered at a daily dose of about 10 mg. In some embodiments, pemigatinib is administered at a daily dose of about 2 mg. In some embodiments, pemigatinib is administered at a daily dose of about 4.5 mg. In some embodiments, pemigatinib is administered at a daily dose of about 9 mg. In some embodiments, pemigatinib is administered at a daily dose of about 13.5 mg.

[0080] In some embodiments, pemigatinib is administered at a daily dose of about 20 mg or less. In some embodiments, pemigatinib is administered at a daily dose of about 15 mg or less. In some embodiments, pemigatinib is administered at a daily dose of about 10 mg or less. In some embodiments, pemigatinib is administered at a daily dose of about 9 mg or less. In some embodiments, pemigatinib is administered at a daily dose of about 8 mg or less. In some embodiments, pemigatinib is administered at a daily dose of about 7 mg or less. In some embodiments, pemigatinib is administered at a daily dose of about 6 mg or less. In some embodiments, pemigatinib is administered at a daily dose of about 5 mg or less. In some embodiments, pemigatinib is administered at a daily dose of about 4 mg or less. In some embodiments, pemigatinib is administered at a daily dose of about 3 mg or less. In some embodiments, pemigatinib is administered at a daily dose of about 2 mg or less. In some embodiments, pemigatinib is administered in a daily dose of about 1 mg or less.

[0081] In some embodiments, pemigatinib is administered as a tablet. In some embodiments, the tablet contains about 0.5 mg to about 10 mg of pemigatinib. In some embodiments, the tablet contains about 0.5 mg to about 5 mg of pemigatinib. In some embodiments, the tablet contains about 2 mg, about 4.5 mg, about 9 mg, about 13.5 mg, or about 18 mg of pemigatinib. In some embodiments, the tablet contains about 0.5 mg of pemigatinib. In some embodiments, the tablet contains about 2 mg of pemigatinib. In some embodiments, the tablet contains about 4.5 mg of pemigatinib. In some embodiments, the tablet contains about 9 mg of pemigatinib. In some embodiments, the tablet contains about 13.5 mg of pemigatinib. In some embodiments, the tablet contains about 18 mg of pemigatinib.

[0082] Sotorasib and its pharmaceutically acceptable salts can be administered to a subject, e.g., a subject in need thereof, e.g., a human subject, by a variety of methods. In many applications, the route of administration is oral. In some embodiments, sotorasib or its pharmaceutically acceptable salts are administered as a pharmaceutical composition.

[0083] In some embodiments, sotorasib is administered orally. In some embodiments, sotorasib is administered once daily.

[0084] In some embodiments, sotorasib is administered at a daily dose of about 10 mg to about 2000 mg. In some embodiments, sotorasib is administered at a daily dose of about 10 mg to about 1500 mg. In some embodiments, sotorasib is administered at a daily dose of about 50 mg to about 1000 mg. In some embodiments, sotorasib is administered at a daily dose of about 50 mg to about 300 mg. In some embodiments, sotorasib is administered at a daily dose of about 100 mg to about 200 mg. In some embodiments, sotorasib is administered at a daily dose of about 100 mg to about 150 mg. In some embodiments, sotorasib is administered at a daily dose of about 110 mg to about 140 mg. In some embodiments, sotorasib is administered at a daily dose of about 120 mg to about 135 mg. In some embodiments, sotorasib is administered at a daily dose of about 133 mg. In some embodiments, sotorasib is administered in a daily dose of about 120 mg.

[0085] In some embodiments, sotorasib is administered at a daily dose of about 2000 mg or less. In some embodiments, sotorasib is administered at a daily dose of about 1200 mg or less. In some embodiments, sotorasib is administered at a daily dose of about 1080 mg or less. In some embodiments, sotorasib is administered at a daily dose of about 960 mg or less. In some embodiments, sotorasib is administered at a daily dose of about 840 mg or less. In some embodiments, sotorasib is administered at a daily dose of about 720 mg or less. In some embodiments, sotorasib is administered at a daily dose of about 600 mg or less. In some embodiments, sotorasib is administered at a daily dose of about 500 mg or less. In some embodiments, sotorasib is administered at a daily dose of about 480 mg or less. In some embodiments, sotorasib is administered at a daily dose of about 360 mg or less. In some embodiments, sotorasib is administered at a daily dose of about 240 mg or less. In some embodiments, sotorasib is administered in a daily dose of about 120 mg or less.

[0086] In some embodiments, sotorasib is administered as a tablet. In some embodiments, the tablet contains about 50 mg to about 1000 mg of sotorasib. In some embodiments, the tablet contains about 50 mg to about 150 mg of sotorasib. In some embodiments, the tablet contains about 60 mg, about 120 mg, about 240 mg, about 360 mg, or about 480 mg of sotorasib. In some embodiments, the tablet contains about 60 mg of sotorasib. In some embodiments, the tablet contains about 120 mg of sotorasib. In some embodiments, the tablet contains about 240 mg of sotorasib.

[0087] In some embodiments, pemigatinib or a pharmaceutically acceptable salt thereof and sotorasib or a pharmaceutically acceptable salt thereof are orally administered simultaneously at a daily dose of about 2 mg and 120 mg, respectively. In some embodiments, pemigatinib or a pharmaceutically acceptable salt thereof and sotorasib or a pharmaceutically acceptable salt thereof are orally administered sequentially at a daily dose of about 2 mg and 120 mg, respectively. In some embodiments, pemigatinib or a pharmaceutically acceptable salt thereof and sotorasib or a pharmaceutically acceptable salt thereof are each administered in the form of a tablet.

[0088] Adaglasib and its pharmaceutically acceptable salts can be administered to a subject, e.g., a subject in need thereof, e.g., a human subject, by a variety of methods. In many applications, the route of administration is oral. In some embodiments, adagrasib or its pharmaceutically acceptable salts are administered as a pharmaceutical composition.

[0089] In some embodiments, adagrasib is administered orally. In some embodiments, adagrasib is administered twice a day. In some embodiments, adagrasib is administered once a day.

[0090] In some embodiments, adagrasib is administered at a daily dose of about 10 mg to about 2000 mg. In some embodiments, adagrasib is administered at a daily dose of about 10 mg to about 1500 mg. In some embodiments, adagrasib is administered at a daily dose of about 50 mg to about 1500 mg. In some embodiments, adagrasib is administered at a daily dose of about 100 mg to about 1500 mg. In some embodiments, adagrasib is administered at a daily dose of about 500 mg to about 500 mg. In some embodiments, adagrasib is administered at a daily dose of about 1000 mg to about 1500 mg. In some embodiments, adagrasib is administered at a daily dose of about 50 mg to about 1200 mg. In some embodiments, adagrasib is administered at a daily dose of about 50 mg to about 1000 mg. In some embodiments, adagrasib is administered at a daily dose of about 50 mg to about 800 mg. In some embodiments, adagrasib is administered at a daily dose of about 100 mg to about 800 mg. In some embodiments, adagrasib is administered at a daily dose of about 200 mg to about 800 mg. In some embodiments, adagrasib is administered at a daily dose of about 500 mg to about 700 mg. In some embodiments, adagrasib is administered at a daily dose of about 50 mg to about 300 mg. In some embodiments, adagrasib is administered at a daily dose of about 100 mg to about 200 mg. In some embodiments, adagrasib is administered at a daily dose of about 100 mg to about 300 mg. In some embodiments, adagrasib is administered at a daily dose of about 150 mg to about 200 mg. In some embodiments, adagrasib is administered at a daily dose of about 150 mg. In some embodiments, adagrasib is administered at a daily dose of about 300 mg. In some embodiments, adagrasib is administered at a daily dose of about 450 mg. In some embodiments, adagrasib is administered at a daily dose of about 600 mg. In some embodiments, adagrasib is administered at a daily dose of about 750 mg. In some embodiments, adagrasib is administered at a daily dose of about 900 mg. In some embodiments, adagrasib is administered at a daily dose of about 1050 mg.In some embodiments, adagrasib is administered at a daily dose of about 1200 mg.

[0091] In some embodiments, adagrasib is administered at a daily dose of about 2000 mg or less. In some embodiments, adagrasib is administered at a daily dose of about 1500 mg or less. In some embodiments, adagrasib is administered at a daily dose of about 1350 mg or less. In some embodiments, adagrasib is administered at a daily dose of about 1200 mg or less. In some embodiments, adagrasib is administered at a daily dose of about 1050 mg or less. In some embodiments, adagrasib is administered at a daily dose of about 900 mg or less. In some embodiments, adagrasib is administered at a daily dose of about 750 mg or less. In some embodiments, adagrasib is administered at a daily dose of about 600 mg or less. In some embodiments, adagrasib is administered at a daily dose of about 450 mg or less. In some embodiments, adagrasib is administered at a daily dose of about 300 mg or less. In some embodiments, adagrasib is administered in a daily dose of about 150 mg or less.

[0092] In some embodiments, adagrasib is administered as a tablet. In some embodiments, the tablet contains about 50 mg to about 1200 mg of adagrasib. In some embodiments, the tablet contains about 50 mg to about 200 mg of adagrasib. In some embodiments, the tablet contains about 150 mg, about 300 mg, about 450 mg, or about 600 mg of adagrasib.

[0093] In some embodiments, pemigatinib or a pharmaceutically acceptable salt thereof and adagrasib or a pharmaceutically acceptable salt thereof are orally administered simultaneously at a daily dose of about 2 mg and 150 mg, respectively. In some embodiments, pemigatinib or a pharmaceutically acceptable salt thereof and adagrasib or a pharmaceutically acceptable salt thereof are orally administered simultaneously at a daily dose of about 2 mg and 300 mg, respectively. In some embodiments, pemigatinib or a pharmaceutically acceptable salt thereof and adagrasib or a pharmaceutically acceptable salt thereof are orally administered simultaneously at a daily dose of about 2 mg and 450 mg, respectively. In some embodiments, pemigatinib or a pharmaceutically acceptable salt thereof and adagrasib or a pharmaceutically acceptable salt thereof are orally administered simultaneously at a daily dose of about 2 mg and 600 mg, respectively. In some embodiments, pemigatinib or a pharmaceutically acceptable salt thereof and adagrasib or a pharmaceutically acceptable salt thereof are orally administered sequentially at daily doses of about 2 mg and 1200 mg, respectively. In some embodiments, pemigatinib or a pharmaceutically acceptable salt thereof and adagrasib or a pharmaceutically acceptable salt thereof are each administered in tablet form.

[0094] How to use Cancer types involving KRAS with G12C, G12D and G12V mutations include, but are not limited to, carcinomas (e.g., pancreatic, colorectal, lung (i.e., non-small cell lung), ovarian, bladder, stomach, esophagus, breast, head and neck, cervical, skin, thyroid); hematopoietic malignancies (e.g., multiple myeloma, acute myeloid leukemia, and myeloproliferative neoplasms), and other tumors (e.g., glioblastoma, sarcoma).

[0095] The methods disclosed herein are useful in the treatment of cancer.

[0096] In some embodiments, the cancer comprises one or more KRAS mutations. In some embodiments, the one or more KRAS mutations comprise a mutation selected from G12C, G12D, C12V, and combinations thereof. In some embodiments, the one or more KRAS mutations are G12C mutations. In some embodiments, the cancer further comprises high FGFR1 expression. In some embodiments, the cancer is associated with alterations in the MAPK signaling pathway. In some embodiments, the cancer is associated with dysregulation of the KRAS pathway. In some embodiments, the cancer is associated with dysregulation of the FGFR pathway. In some embodiments, the cancer comprises mesenchymal-like cells.

[0097] In some embodiments, the cancer is selected from carcinoma, pancreatic cancer, colorectal cancer, lung cancer, non-small cell lung cancer, ovarian cancer, bladder cancer, gastric cancer, esophageal cancer, breast cancer, head and neck cancer, cervical cancer, skin cancer, thyroid cancer, hematopoietic malignancies, multiple myeloma, acute myeloid leukemia, myeloproliferative neoplasms, tumors, glioblastoma, and sarcoma.

[0098] In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is non-small cell lung cancer. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is ovarian cancer.

[0099] In some embodiments, the cancer is bladder cancer, breast cancer (e.g., hormone R positive, triple negative), cervical cancer, colorectal cancer, cancer of the small intestine, colon cancer, rectal cancer, cancer of the anus, endometrial cancer, gastric cancer (e.g., gastrointestinal stromal tumors), head and neck cancer (e.g., cancer of the larynx, hypopharynx, nasopharynx, oropharynx, lip, mouth, head and neck squamous cell carcinoma), kidney cancer (e.g., renal cell carcinoma, urothelial carcinoma, sarcoma, Wilms' tumor), liver cancer (e.g., hepatocellular carcinoma, cholangiocarcinoma, hepatic angiosarcoma, hepatoblastoma), lung cancer (e.g., adenocarcinoma, small cell carcinoma, pulmonary arterial cancer, pulmonary arterial cancer, pulmonary sarcoma ... alveolar and non-small cell lung cancer, small cell and non-small cell carcinoma, bronchial carcinoma, bronchial adenoma, pleuropulmonary blastoma), ovarian cancer, prostate cancer, testicular cancer, uterine cancer, vulvar cancer, esophageal cancer, gallbladder cancer, pancreatic cancer (e.g., exocrine pancreatic cancer), gastric cancer, thyroid cancer, parathyroid cancer, neuroendocrine cancer (e.g., pheochromocytoma, Merkel cell carcinoma, neuroendocrine carcinoma), skin cancer (e.g., squamous cell carcinoma, Kaposi's sarcoma, Merkel cell skin cancer), or brain tumors (e.g., astrocytoma, medulloblastoma, ependymoma, neuroexocrine tumor, pineal tumor).

[0100] In some embodiments, the cancer is a leukemia or lymphoma, multiple myeloma, chronic lymphocytic lymphoma, adult T-cell leukemia, B-cell lymphoma, cutaneous T-cell lymphoma, acute myeloid leukemia, Hodgkin's lymphoma or non-Hodgkin's lymphoma, hematopoietic malignancies such as myeloproliferative neoplasms (e.g., 8p11 myeloproliferative syndrome, polycythemia, essential thrombocythemia, and primary myelofibrosis), myelodysplastic syndrome, chronic eosinophilic leukemia, Waldenstrom's macroglubulinemia, hairy cell lymphoma, chronic myelogenous lymphoma, acute lymphoblastic lymphoma, AIDS-related lymphoma, or Burkitt's lymphoma.

[0101] In certain embodiments, provided herein is a method of treating a myeloid / lymphoid tumor in a patient in need thereof. In certain embodiments, the myeloid / lymphoid tumor is 8p11 myeloproliferative syndrome. As used herein, the term "8p11 myeloproliferative syndrome" (EMS) is meant to refer to a myeloid / lymphoid tumor associated with eosinophilia and FGFR1 abnormality, or myeloid / lymphoid neoplasm with FGFR1 rearrangement (MLN). 8P11 myeloproliferative syndrome is reviewed in Jackson, Courtney C., et.al. Human Pathology, 2010, 41, 461-476. In certain embodiments, the myeloid / lymphoid tumor exhibits an 8p11 translocation. In certain embodiments, the 8p11 translocation is associated with FGFR1 activation. In certain embodiments, the patient has failed at least one previous treatment for a myeloid / lymphoid tumor (e.g., 8p11 myeloproliferative syndrome). In some embodiments, the previous treatment is surgery or radiation therapy. In some embodiments, the patient has a history of hepatitis. In some embodiments, the hepatitis is chronic hepatitis B or hepatitis C. In some embodiments, the patient does not have a history of hepatitis.

[0102] In certain embodiments, the cancer is bladder cancer (e.g., urothelial carcinoma, squamous cell carcinoma, adenocarcinoma). In certain embodiments, the bladder cancer is a luminal papillary subtype of bladder cancer.

[0103] In certain embodiments, the cancer is glioblastoma or lung cancer.

[0104] In certain embodiments, the liver cancer is cholangiocarcinoma (e.g., intrahepatic, hilar or perihilar, distal extrahepatic). As used herein, cholangiocarcinoma is the same as cholangiocarcinoma or cholangiocarcinoma. In certain embodiments, the cholangiocarcinoma is advanced or metastatic cholangiocarcinoma. In certain embodiments, the cholangiocarcinoma is surgically unresectable. In certain embodiments, the cholangiocarcinoma is intrahepatic. In certain embodiments, the cholangiocarcinoma is distal extrahepatic.

[0105] Other cancers treatable with the methods provided herein include eye tumors, glioblastoma, melanoma, rhabdomyosarcoma, lymphosarcoma, leiomyosarcoma, urothelial carcinoma (e.g., ureter, urethra, bladder, urachus), and osteosarcoma.

[0106] The methods of the disclosure are also useful for treating metastatic cancers, particularly those that express PD-L1.

[0107] In some embodiments, diseases and indications treatable using the methods of the present disclosure include, but are not limited to, hematological cancers, head and neck cancers, sarcoma, lung cancer, gastrointestinal cancer, genitourinary tract cancer, liver cancer, bone cancer, nervous system cancer, gynecological cancer, and skin cancer.

[0108] Exemplary hematological cancers treatable using the methods of the present disclosure include lymphomas and leukemias, such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), chronic myelogenous leukemia (CML), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), non-Hodgkin's lymphoma (relapsed or refractory NHL), and the like. including idiopathic myelofibrosis (PMF), follicular lymphoma (FL), Hodgkin's lymphoma, lymphoblastic lymphoma, myeloproliferative disorders (e.g., primary myelofibrosis (PMF), polycythemia vera (PV), essential thrombocytosis (ET)), myelodysplastic syndromes (MDS), T-cell acute lymphoblastic leukemia (T-ALL), multiple myeloma, cutaneous T-cell lymphoma, peripheral T-cell lymphoma, Waldenstrom's macroglobulinemia, hairy cell lymphoma, chronic myelogenous lymphoma, and Burkitt's lymphoma.

[0109] Exemplary sarcomas treatable using the methods of the present disclosure include chondrosarcoma, Ewing's sarcoma, osteosarcoma, rhabdomyosarcoma, angiosarcoma, fibrosarcoma, liposarcoma, myxoma, rhabdomyoma, rhabdomyosarcoma, fibroma, lipoma, hamartoma, and teratoma.

[0110] Exemplary lung cancers treatable using the methods of the present disclosure include non-small cell lung cancer (NSCLC), small cell lung cancer, bronchial carcinoma (squamous cell, small undifferentiated cell, large undifferentiated cell, adenocarcinoma), alveolar (bronchial) carcinoma, bronchial adenoma, chondromatous hamartoma, and mesothelioma.

[0111] Exemplary gastrointestinal cancers treatable using the methods of the present disclosure include cancer of the esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), cancer of the stomach (carcinoma, lymphoma, leiomyosarcoma), cancer of the pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vipoma), cancer of the small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), cancer of the large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma), colorectal cancer, and bile duct cancer (cholangiocarcinoma).

[0112] Exemplary genitourinary tract cancers treatable using the methods of the present disclosure include cancer of the kidney (adenocarcinoma, Wilms' tumor [nephroblastoma], renal cell carcinoma), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma, urothelial carcinoma), prostate (adenocarcinoma, sarcoma), and testicular cancer (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma).

[0113] Exemplary liver cancers treatable using the methods of the present disclosure include hepatocarcinoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, and hemangioma.

[0114] Exemplary bone cancers treatable using the methods of the present disclosure include, for example, osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (retinal cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteochondral exostosis), benign chondroma, chondroblastoma, chondromyxoid fibroma, osteoid osteoma, and giant cell tumor.

[0115] Exemplary nervous system cancers treatable using the methods of the present disclosure include cancers of the skull (osteoma, hemangioma, granuloma, xanthomas, osteitis deformans), cancers of the meninges (meningioma, meningeal sarcoma, gliomatosis), cancers of the brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma, glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), and cancers of the spinal cord (neurofibroma, meningioma, sarcoma), as well as neuroblastoma and Lhermitte-Duclos disease, tumors of the central nervous system (CNS), primary CNS lymphoma, and tumors of the spinal axis.

[0116] Exemplary gynecological cancers treatable using the methods of the present disclosure include cancer of the uterus (endometrial carcinoma), cancer of the cervix (cervical carcinoma, preneoplastic cervical dysplasia), cancer of the ovaries (ovarian carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-theca cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), cancer of the vulva (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), cancer of the vagina (clear cell carcinoma, squamous cell carcinoma, sarcoma botryoides (embryonal rhabdomyosarcoma), and cancer of the fallopian tubes (epithelial carcinoma).

[0117] Exemplary skin cancers that can be treated using the methods of the present disclosure include melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, Merkel cell skin cancer, lenticular dysplasia nevus, lipoma, hemangioma, dermatofibroma, and keloids.

[0118] Exemplary head and neck cancers treatable using the methods of the present disclosure include glioblastoma, melanoma, rhabdomyosarcoma, lymphosarcoma, osteosarcoma, squamous cell carcinoma, adenocarcinoma, oral cavity cancer, laryngeal cancer, nasopharyngeal cancer, nasal cavity and paranasal sinus cancer, thyroid and parathyroid cancer.

[0119] In some embodiments, the present disclosure provides methods for treating hepatocellular carcinoma in a patient in need thereof.In some embodiments, the present disclosure provides methods for treating rhabdomyosarcoma, esophageal cancer, breast cancer, or head and neck cancer in a patient in need thereof.

[0120] The methods described herein include the treatment of cancer, preferably solid tumors.

[0121] In some embodiments, the solid tumor is selected from skin cancer, lung cancer, lymphoma, sarcoma, bladder cancer, ureteral, urethral, ​​and urachal cancer, gastric cancer, cervical cancer, liver cancer, breast cancer, renal cancer, squamous cell carcinoma, colorectal cancer, endometrial cancer, anal cancer, and tumors with microsatellite instability high (MSI-H), mismatch repair deficient (dMMR), and / or DNA polymerase epsilon exonuclease domain mutation positive disease.

[0122] In some embodiments, the solid tumor is selected from cholangiocarcinoma, melanoma, non-small cell lung cancer, small cell lung carcinoma, Hodgkin's lymphoma, urothelial carcinoma, hepatocellular carcinoma, Merkel cell carcinoma, triple-negative breast cancer, renal cell carcinoma, squamous cell carcinoma of the head and neck, and colorectal carcinoma.

[0123] In some embodiments, the solid tumor is selected from sarcoma, head and neck cancer, melanoma, and non-small cell lung cancer. In some embodiments, the solid tumor is a sarcoma. In some embodiments, the solid tumor is head and neck cancer. In some embodiments, the solid tumor is a melanoma. In some embodiments, the solid tumor is non-small cell lung cancer.

[0124] As used herein, the term "individual" or "patient" refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, primates, and most preferably humans.

[0125] As used herein, the phrase "therapeutically effective amount" refers to that amount of an active compound or pharmaceutical agent that elicits the biological or pharmacological response desired by a researcher, veterinarian, physician, or other clinician in a tissue, system, animal, individual, or human.

[0126] As used herein, the term "treating" or "treatment" refers to one or more of: (1) inhibiting a disease, e.g., inhibiting a disease, condition, or disorder in an individual experiencing or exhibiting a pathology or symptom of the disease, condition, or disorder (i.e., preventing further progression of the pathology or symptom), and (2) ameliorating a disease, e.g., ameliorating a disease, condition, or disorder in an individual experiencing or exhibiting a pathology or symptom of the disease, condition, or disorder (i.e., reversing the condition or symptom), e.g., reducing the severity of the disease. In some embodiments, the term "treating" or "treatment" refers to inhibiting or ameliorating a disease.

[0127] In some embodiments, the compounds of the invention are useful for preventing or reducing the risk of developing any of the diseases mentioned herein; for example, preventing or reducing the risk of developing a disease, condition, or disorder in an individual who may have a predisposition to a disease, condition, or disorder, but who has not yet experienced or exhibited the symptoms or symptoms of the disease, condition, or disorder.

[0128] As used herein, the term "co-administration" or "simultaneous administration" refers to administration of pemigatinib and one or more additional drugs (e.g., sotrasib) at or near the same time. In some embodiments, the one or more additional drugs are adagrasib. For example, pemigatinib can be administered on the same day, within one week, or within one month as the one or more additional drugs. In some embodiments, the one or more additional drugs are administered during administration of pemigatinib.

[0129] As used herein, the term "treatment" refers to the administration of a compound suitable for the treatment of cancer. For example, treatment can refer to the administration of pemigatinib for the treatment of cancer.

[0130] As used herein, unless otherwise specified, the term "about" when used in connection with a numerical value or range of values ​​indicates that the value or range of values ​​may deviate to an extent that would be considered reasonable by one of ordinary skill in the art. Specifically, the term "about" as used in this context indicates that a numerical value or range of values ​​may vary by 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% of the stated value or range of values.

[0131] As used herein, the terms "cancer" and "carcinoma" are synonymous.

[0132] As used herein, the term "cell" is meant to refer to a cell that is in vitro, ex vivo, or in vivo. In some embodiments, an ex vivo cell may be part of a tissue sample excised from an organism, such as a mammal. In some embodiments, an in vitro cell may be a cell in cell culture. In some embodiments, an in vivo cell is a cell that lives within an organism, such as a mammal.

[0133] As used herein, the term "contacting" refers to bringing the indicated moieties together in an in vitro system or in vivo system. For example, "contacting" an FGFR enzyme with an FGFR1 inhibitor, such as pemigatinib, includes administering an FGFR1 inhibitor as described herein to an individual or patient, such as a human having an FGFR, as well as introducing the FGFR1 inhibitor into a sample, such as a cell preparation or purified preparation, that contains an FGFR enzyme. As a further example, "contacting" a KRAS with a KRAS inhibitor as described herein includes administering an KRAS inhibitor as described herein to an individual or patient, such as a human having KRAS, as well as introducing the KRAS inhibitor into a sample, such as a cell preparation or purified preparation, that contains an KRAS enzyme.

[0134] The phrase "pharmacologically acceptable" is used herein to refer to compounds, substances, compositions, and / or dosage forms that are suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problem or complication, within the scope of sound medical judgment, commensurate with a reasonable benefit / risk ratio.

[0135] As used herein, the phrase "pharmaceutically acceptable carrier or excipient" refers to a pharma- ceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, solvent, or encapsulating material. Excipients or carriers are generally safe, non-toxic, and not biologically or otherwise undesirable, and include excipients or carriers that are acceptable for veterinary use as well as human pharmaceutical use. In one embodiment, each component is "pharmaceutically acceptable" as defined herein. For example, Remington:The Science and Practice of Pharmacy,21st ed.;Lippincott Williams & Wilkins:Philadelphia,Pa.,2005;Handbook of Pharmaceutical Excipients,6th ed.;Rowe et al.,Eds.;The Pharmaceutical Press and the American Pharmaceutical Association:2009;Handbook of Pharmaceutical Additives,3rd ed.;Ash and Ash Eds.;Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd ed.; Gibson Ed.; CRC Press LLC: Boca Raton, Fla., 2009.

[0136] In some embodiments, a pharma- ceutically acceptable salt of the FGFR1 inhibitor disclosed herein is used in the methods and combination therapies described herein. In some embodiments, a pharma- ceutically acceptable salt of pemigatinib is used in the methods and combination therapies described herein. Salt forms of pemigatinib are described in U.S. Publication No. 2019 / 0337948. In some embodiments, a pharma- ceutically acceptable salt of the KRAS inhibitor disclosed herein is used in the methods and combination therapies described herein. In some embodiments, a pharma- ceutically acceptable salt of sotorasib is used in the methods and combination therapies described herein. In some embodiments, a pharma- ceutically acceptable salt of adagrasib is used in the methods and combination therapies described herein.

[0137] In some embodiments, solid forms (e.g., crystalline forms) of the FGFR1 inhibitors disclosed herein are used in the methods and combination therapies described herein. In some embodiments, solid forms (e.g., crystalline forms) of pemigatinib can also be used in the methods and combination therapies described herein. Solid forms of pemigatinib and methods for preparing solid forms of pemigatinib are described in U.S. Publication No. 2020 / 0002338. In some embodiments, solid forms (e.g., crystalline forms) of the KRAS inhibitors disclosed herein are used in the methods and combination therapies described herein. In some embodiments, solid forms (e.g., crystalline forms) of sotorasib can also be used in the methods and combination therapies described herein. In some embodiments, solid forms (e.g., crystalline forms) of adagrasib can also be used in the methods and combination therapies described herein.

[0138] Certain features of the invention that are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment (although it is intended that these embodiments be combined as if described in multiple dependent forms). Conversely, various features of the invention that are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

[0139] Combination therapy with additional drugs Also provided herein is a method of treating cancer in a patient, comprising administering to the patient: (i) pemigatinib, or a pharma- ceutically acceptable salt thereof; (ii) a KRAS inhibitor as described herein; and (iii) one or more additional therapeutic agents; and The method comprises administering

[0140] Also provided herein is a method of treating cancer in a patient, comprising administering to the patient: (i) pemigatinib, or a pharma- ceutically acceptable salt thereof; (ii) sotorasib, or a pharma- ceutically acceptable salt thereof; and (iii) one or more additional therapeutic agents; and The method comprises administering

[0141] Also provided herein is a method of treating cancer in a patient, comprising administering to the patient: (i) pemigatinib, or a pharma- ceutically acceptable salt thereof; (ii) adagrasib, or a pharma- ceutically acceptable salt thereof; and (iii) one or more additional therapeutic agents; and The method comprises administering

[0142] Exemplary additional therapeutic agents are provided below.

[0143] I. Cancer Therapy Cancer cell growth and survival can be affected by the dysfunction of multiple signaling pathways. Therefore, it is useful to combine different enzyme / protein / receptor inhibitors that show different selectivity in the target that the enzyme / protein / receptor inhibitor modulates the activity of the target to treat such conditions. Targeting more than one signaling pathway (or more than one biomolecule involved in a given signaling pathway) can reduce the possibility of drug resistance occurring in cell populations and / or reduce the toxicity of treatment.

[0144] One or more additional pharmaceutical agents, such as chemotherapeutic agents, anti-inflammatory agents, steroids, immunosuppressants, cancer immunotherapeutic agents, metabolic enzyme inhibitors, chemokine receptor inhibitors, and phosphatase inhibitors, as well as targeted therapies, such as Bcr-Abl, Flt-3, EGFR, HER2, JAK, c-MET, VEGFR, PDGFR, c-Kit, IGF-1R, RAF, FAK, CDK2, and CDK4 / 6 kinase inhibitors, such as those described in WO2006 / 056399, may be used in combination with the therapeutic methods and regimens of the present disclosure to treat cancer and / or solid tumors. Other agents, such as therapeutic antibodies, may be used in combination with the therapeutic methods and regimens of the present disclosure for the treatment of cancer and solid tumors. One or more additional pharmaceutical agents may be administered to the patient simultaneously or sequentially.

[0145] The therapeutic methods disclosed herein may be used in combination with one or more other enzyme / protein / receptor inhibitor therapies to treat diseases such as cancer and other diseases or disorders described herein. For example, the therapeutic methods and regimens disclosed herein may be combined with inhibitors of one or more of the following kinases for the treatment of cancer: Akt1, Akt2, Akt3, BCL2, CDK2, CDK4 / 6, TGF-βR, PKA, PKG, PKC, CaM-kinase, phosphorylase kinase, MEKK, ERK, MAPK, mTOR, EGFR, HER2, HER3, HER4, INS-R, IDH2, IGF-1R, IR-R, KRAS, PDGFαR, PDGFβR, PI3K (alpha, beta, gamma, delta, and and multiple or selectively), CSF1R, KIT, FLK-II, KDR / FLK-1, FLK-4, flt-1, FGFR1, FGFR2, FGFR3, FGFR4, c-Met, PARP, Ron, Sea, TRKA, TRKB, TRKC, TAM kinases (Axl, Mer, Tyro3), FLT3, VEGFR / Flt2, Flt4, EphA1, EphA2, EphA3, EphB2, EphB4, Tie2, Src, Fyn, Lck, Fgr, Btk, Fak, SYK, FRK, JAK, ABL, ALK, and B-Raf.Non-limiting examples of inhibitors that may be combined with the therapeutic methods and regimens of the present disclosure for the treatment of cancer include FGFR inhibitors (FGFR1, FGFR2, FGFR3, or FGFR4, e.g., INCB62079), EGFR inhibitors (also known as ErB-1 or HER-1: e.g., erlotinib, gefitinib, vandetanib, osimertinib, cetuximab, necitumumab, or panitumumab), VEGFR inhibitors or pathway blockers (e.g., bevacizumab, pazopanib, nib, sunitinib, sorafenib, axitinib, regorafenib, ponatinib, cabozantinib, vandetanib, ramucirumab, lenvatinib, ziv-aflibercept), PARP inhibitors (e.g., olaparib, rucaparib, veliparib, or niraparib), JAK inhibitors (JAK1 and / or JAK2, e.g., ruxolitinib, baricitinib, itacitinib (INCB39110)), LSD1 inhibitors (e.g., INCB59872 and INCB60003), TDO inhibitors , PI3K-delta inhibitors (e.g., INCB50465 and INCB50797), PI3K-gamma inhibitors such as PI3K-gamma selective inhibitors, Pim inhibitors (e.g., INCB53914), CSF1R inhibitors, TAM receptor tyrosine kinases (Tyro-3, Axl, and Mer), adenosine receptor antagonists (e.g., A2a / A2b receptor antagonists), HPK1 inhibitors, chemokine receptor inhibitors (e.g., CCR2 or CCR5 inhibitors), SHP1 / 2 phosphatase inhibitors (e.g., phosphatase inhibitors), and the like. phatase inhibitors, histone deacetylase inhibitors (HDACs) such as HDAC8 inhibitors, angiogenesis inhibitors, interleukin receptor inhibitors, bromo and extra-terminal family member inhibitors (e.g., bromodomain inhibitors or BET inhibitors, e.g., INCB54329 and INCB57643), c-MET inhibitors (e.g., capmatinib), anti-CD19 antibodies (e.g., tafasitamab), ALK2 inhibitors (e.g., INCB00928), or combinations thereof.

[0146] In some embodiments, the therapeutic methods described herein are combined with administration of a PI3Kδ inhibitor. In some embodiments, the therapeutic methods described herein are combined with administration of a JAK inhibitor. In some embodiments, the therapeutic methods described herein are combined with administration of a JAK1 or JAK2 inhibitor (e.g., baricitinib or ruxolitinib). In some embodiments, the therapeutic methods described herein are combined with administration of a JAK1 inhibitor. In some embodiments, the therapeutic methods described herein are combined with administration of a JAK1 inhibitor that is more selective than JAK2.

[0147] Exemplary antibodies that may be administered in combination therapy include, but are not limited to, trastuzumab (e.g., anti-HER2), ranibizumab (e.g., anti-VEGF-A), bevacizumab (Avastin™, e.g., anti-VEGF), panitumumab (e.g., anti-EGFR), cetuximab (e.g., anti-EGFR), Rituxan (e.g., anti-CD20), and antibodies directed against c-MET.

[0148] One or more of the following agents may be administered to the patient in combination with the therapeutic methods of the present disclosure, and are presented as a non-limiting list: cytostatics, cisplatin, doxorubicin, taxotere, taxol, etoposide, irinotecan, camptostar, topotecan, paclitaxel, docetaxel, epothilone, tamoxifen, 5-fluorouracil, methotrexate, temozolomide, cyclophosphamide, SCH66336, R115777, L778, 123, BMS214662, Iressa™ (gefitinib), Tarceva™ (erlotinib), antibodies against EGFR, intron, ara-C, adriamycin, cytoxan, gemcitabine, uracil mustard. , chlormethine, ifosfamide, melphalan, chlorambucil, pipobroman, triethylenemelamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, oxaliplatin, leucovirin, Eloxatin™ (oxaliplatin), pentostatin, vinblastine, vincristine, vindesine, bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, mithramycin, deoxycoformycin, mitomycin-C, L-asparaginase, teniposide 17. alpha-.- Ethinyl estradiol, diethylstilbestrol, testosterone, prednisone, fluoxymesterone, dromostanolone propionate, testolactone, megstrol acetate, methylprednisolone, methyltestosterone, prednisolone, triamcinolone, chlorotrianisene, hydroxyprogesterone, aminoglutethimide, estramustine, medroxyprogesterone acetate, leuprolide, flutamide, toremifene, goserelin, carboplatin, hydroxyurea, amsacrine, procarbazine, mitotane, mitoxantrone, levamisole, navelbene, anastrazole, letrazole, capecitabine, reloxafine, droloxafine, hexamethylmelamine, avastin, herceptin (trademark) Tuzumab), Bexar™ (tositumomab), Velcade™ (bortezomib), Zevalin™ (ibritumomab tiuxetan), Trisenox™ (arsenic trioxide), Xeloda™ (capecitabine), vinorelbine, porfimer, Erbitux™ (cetuximab), thiotepa, altretamine, melphalan, trastuzumab, Relosol, Fu Rubestrant, Exemestane, Ifosfomide, Rituximab, C225 (Cetuximab), Campath (Alemtuzumab), Clofarabine, Cladribine, Afidicolone, Rituxan, Sunitinib, Dasatinib, Tezacitabine, Sml1, Fludarabine, Pentostatin, Triapine, Didox, Trimidox, Amidox, 3-AP, and MDL-101,731.

[0149] The therapeutic methods and regimens of the present disclosure can also be used in combination with other methods of treating cancer, such as chemotherapy, radiation therapy, tumor-targeted therapy, adjuvant therapy, immunotherapy, or surgery. Examples of immunotherapy include cytokine therapy (e.g., interferon, GM-CSF, G-CSF, IL-2), CRS-207 immunotherapy, cancer vaccines, monoclonal antibodies, bispecific or multispecific antibodies, antibody-drug conjugates, adoptive T cell transfer, Toll receptor agonists, RIG-I agonists, oncolytic virus therapy, and immunomodulatory small molecules, including thalidomide or JAK1 / 2 inhibitors, PI3Kδ inhibitors, and the like. The compounds can be administered in combination with one or more anti-cancer drugs, such as chemotherapeutic agents. Examples of chemotherapeutic agents include abarelix, aldesleukin, alemtuzumab, alitretinoin, allopurinol, altretamine, anastrozole, arsenic trioxide, asparaginase, azacitidine, bevacizumab, bexarotene, baricitinib, bleomycin, bortezomib, intravenous busulfan, oral busulfan, calcitinone, capecitabine, carboplatin, carmustine, cetuximab, chlorambucil, cisplatin, cladribine, clofarabine, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, dalteparin sodium, dasatinib, daunorubicin, decitabine, denileukin, denileukin diftitox, dexrazoxane, docetaxel, doxorubicin, dromopropionate, Stanolone, eculizumab, epirubicin, erlotinib, epacadostat, estramustine, etoposide phosphate, etoposide, exemestane, fentanyl citrate, filgrastim, floxuridine, fludarabine, fluorouracil, fulvestrant, gefitinib, gemcitabine, gemtuzumab ozogamicin, goserelin acetate, histrelin acetate, ibritumomab tiuxetan, idarubicin, ifosfamide, imatinib mesylate, interferon alpha 2a, irinotecan, lapatinib ditosylate, lenalidomide, letrozole, leucovorin, leuprolide acetate, levamisole, lomustine, mechlorethamine, megestrol acetate, melphalan, mercaptopurine, methotrexate, methoxsalen,Mitomycin C, mitotane, mitoxantrone, nandrolone phenpropionate, nelarabine, nofetumomab, oxaliplatin, paclitaxel, pamidronate, panitumumab, pegaspargase, pegfilgrastim, pemetrexed disodium, pentostatin, pipobroman, plicamycin, procarbazine, quinacrine, rasburicase, rituximab, ruxolitinib, sorafenib The present invention may include any of the following: sunitinib, streptozocin, sunitinib, sunitinib maleate, tamoxifen, temozolomide, teniposide, testolactone, thalidomide, thioguanine, thiotepa, topotecan, toremifene, tositumomab, trastuzumab, tretinoin, uracil mustard, valrubicin, vinblastine, vincristine, vinorelbine, vorinostat, and zoledronate.

[0150] Additional examples of chemotherapeutic agents include proteosome inhibitors (eg, bortezomib), thalidomide, revlimid, and DNA damaging agents such as melphalan, doxorubicin, cyclophosphamide, vincristine, etoposide, carmustine, and the like.

[0151] Exemplary steroids include corticosteroids, such as dexamethasone or prednisone.

[0152] Exemplary Bcr-Abl inhibitors include imatinib mesylate (GLEEVAC™), nilotinib, dasatinib, bosutinib, and ponatinib, and pharmaceutically acceptable salts.Other suitable Bcr-Abl inhibitors include the genera and species of compounds disclosed in U.S. Patent No. 5,521,184, WO04 / 005281, and U.S. Serial No. 60 / 578,491, and pharmaceutically acceptable salts thereof.

[0153] Exemplary suitable Flt-3 inhibitors include midostaurin, lestaurtinib, linifanib, sunitinib, sunitinib maleate, sorafenib, quizartinib, crenolanib, pacritinib, tandutinib, PLX3397, and ASP2215, and pharmaceutically acceptable salts thereof. Other suitable Flt-3 inhibitors include compounds as disclosed in WO03 / 037347, WO03 / 099771, and WO04 / 046120, and pharmaceutically acceptable salts thereof.

[0154] Exemplary suitable RAF inhibitors include dabrafenib, sorafenib, and vemurafenib, and pharmaceutically acceptable salts thereof. Other exemplary suitable RAF inhibitors include compounds as disclosed in WO00 / 09495 and WO05 / 028444, and pharmaceutically acceptable salts thereof.

[0155] Examples of suitable FAK inhibitors include VS-4718, VS-5095, VS-6062, VS-6063, BI853520, and GSK2256098, and pharma- ceutically acceptable salts thereof. Other examples of suitable FAK inhibitors include compounds such as those disclosed in WO04 / 080980, WO04 / 056786, WO03 / 024967, WO01 / 064655, WO00 / 053595, and WO01 / 014402, and pharma- ceutically acceptable salts thereof.

[0156] Exemplary and suitable CDK4 / 6 inhibitors include palbociclib, ribociclib, trilaciclib, relociclib, and abemaciclib, and pharmaceutically acceptable salts thereof. Other exemplary and suitable CDK4 / 6 inhibitors include compounds as disclosed in WO09 / 085185, WO12 / 129344, WO11 / 101409, WO03 / 062236, WO10 / 075074, and WO12 / 061156, and pharmaceutically acceptable salts thereof.

[0157] The therapeutic methods and regimens of the present disclosure can further be used in combination with one or more other kinase inhibitors, including imatinib, particularly to treat patients who are resistant to imatinib or other kinase inhibitors.

[0158] In some embodiments, the therapeutic methods of the present disclosure may be used in combination with chemotherapeutic agents in the treatment of cancer, and may improve the response of treatment compared to the response to the chemotherapeutic agent alone, without exacerbating its toxic effects. In some embodiments, the therapeutic methods of the present disclosure may be used in combination with the chemotherapeutic agents provided herein. For example, additional pharmaceutical agents used in the treatment of multiple myeloma may include, but are not limited to, melphalan, melphalan + prednisone [MP], doxorubicin, dexamethasone, and Velcade (bortezomib). Further additional agents used in the treatment of multiple myeloma include Bcr-Abl, Flt-3, RAF, and FAK kinase inhibitors. In some embodiments, the agent is an alkylating agent, a proteasome inhibitor, a corticosteroid, or an immunomodulatory agent. Examples of alkylating agents include cyclophosphamide (CY), melphalan (MEL), and bendamustine. In some embodiments, the proteasome inhibitor is carfilzomib. In some embodiments, the corticosteroid is dexamethasone (DEX). In some embodiments, the immunomodulatory agent is lenalidomide (LEN) or pomalidomide (POM). An additive or synergistic effect is a desirable outcome of combining the therapeutic methods of the present disclosure with an additional agent.

[0159] The therapeutic methods of the disclosure may be combined with antibodies, or antigen-binding fragments thereof, that bind to human PD-1 or human PD-L1.

[0160] In some embodiments, a corticosteroid such as dexamethasone is administered to a patient in combination with the therapeutic methods of the present disclosure, where the dexamethasone is administered intermittently rather than continuously.

[0161] The therapeutic methods described herein may be combined with other immunogenic agents, such as cancerous cells, purified tumor antigens (including recombinant proteins, peptides, and carbohydrate molecules), cells, and cells transfected with genes encoding immune stimulating cytokines. Non-limiting examples of tumor vaccines that may be used include peptides of melanoma antigens, such as peptides of gp100, MAGE antigens, Trp-2, MARTI, and / or tyrosinase, or tumor cells transfected to express the cytokine GM-CSF.

[0162] The therapeutic methods described herein can be used in combination with vaccination protocols for the treatment of cancer. In some embodiments, tumor cells are transduced to express GM-CSF. In some embodiments, tumor vaccines include proteins from viruses implicated in human cancers, such as human papillomavirus (HPV), hepatitis viruses (HBV and HCV), and Kaposi's herpes sarcoma virus (KHSV). In some embodiments, the therapeutic methods and regimens of the present disclosure can be used in combination with tumor-specific antigens, such as heat shock proteins isolated from the tumor tissue itself. In some embodiments, the therapeutic methods described herein can be combined with dendritic cell immunization to activate a strong anti-tumor response.

[0163] The therapeutic methods and regimens of the present disclosure can be used in combination with bispecific macrocyclic peptides that target Fe alpha or Fe gamma receptor expressing effector cells to tumor cells. The therapeutic methods and regimens of the present disclosure can also be combined with macrocyclic peptides that activate the host's immune responsiveness.

[0164] In some further embodiments, the therapeutic methods of the present disclosure can be administered to patients before, during, and / or after bone marrow or stem cell transplantation in combination with other therapeutic agents. The therapeutic methods and regimens of the present disclosure can be used in combination with bone marrow transplantation for the treatment of various tumors of hematopoietic origin.

[0165] When more than one pharmaceutical agent is administered to a patient, they may be administered simultaneously, separately, sequentially, or in combination (e.g., in the case of more than two agents), as discussed in any embodiment above.

[0166] Methods for safely and effectively administering most of these chemotherapeutic agents are known to those skilled in the art. In addition, their administration is described in standard texts. For example, the administration of many chemotherapeutic agents is described in the "Physicians' Desk Reference" (PDR, e.g., 1996 edition, Medical Economics Company, Montvale, NJ), the disclosure of which is incorporated herein by reference in its entirety as if set forth herein.

[0167] II. Immune checkpoint therapy The therapeutic methods described herein may be used in combination with one or more immune checkpoint inhibitors to treat a disease, such as cancer or an infectious disease. Exemplary immune checkpoint inhibitors include inhibitors against immune checkpoint molecules such as CBL-B, CD20, CD28, CD40, CD70, CD122, CD96, CD73, CD47, CDK2, GITR, CSF1R, JAK, PI3K delta, PI3K gamma, TAM, arginase, HPK1, CD137 (also known as 4-1BB), ICOS, A2AR, B7-H3, B7-H4, BTLA, CTLA-4, LAG3, TIM3, TLR (TLR7 / 8), TIGIT, CD112R, VISTA, PD-1, PD-L1, and PD-L2. In some embodiments, the immune checkpoint molecule is a stimulatory checkpoint molecule selected from CD27, CD28, CD40, ICOS, OX40, GITR, and CD137. In some embodiments, the immune checkpoint molecule is an inhibitory checkpoint molecule selected from A2AR, B7-H3, B7-H4, BTLA, CTLA-4, IDO, KIR, LAG3, PD-1, TIM3, TIGIT, and VISTA. In some embodiments, the compounds provided herein can be used in combination with one or more agents selected from a KIR inhibitor, a TIGIT inhibitor, a LAIR1 inhibitor, a CD160 inhibitor, a 2B4 inhibitor, and a TGFR beta inhibitor.

[0168] In some embodiments, the therapeutic methods provided herein may be used in combination with one or more agonists of immune checkpoint molecules, such as OX40, CD27, GITR, and CD137 (also known as 4-1BB).

[0169] In some embodiments, the inhibitor of an immune checkpoint molecule is an anti-PD1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody.

[0170] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of PD-1 or PD-L1, such as an anti-PD-1 or anti-PD-L1 monoclonal antibody. In some embodiments, the anti-PD-1 or anti-PD-L1 antibody is selected from the group consisting of nivolumab, pembrolizumab, atezolizumab, durvalumab, avelumab, cemiplimab, atezolizumab, avelumab, tislelizumab, spartalizumab (PDR001), cetrelimab (JNJ-63723283), toripalimab (JS001), camrelizumab (SHR-1210), sintilimab (IBI308), AB122 (GLS-010), AMP-224, AMP-514 / MEDI- 0680, BMS936559, JTX-4014, BGB-108, SHR-1210, MEDI4736, FAZ053, BCD-100, KN035, CS1001, BAT1306, LZM009, AK105, HLX10, SHR-1316, CBT-502(TQB2450), A167(KL-A167), STI-A101(ZKAB001), CK-301, BGB-A333, MSB-2311, HLX20, TSR-042, or LY3300054.In some embodiments, the PD-1 or PD-L1 inhibitor is a PD-L1 inhibitor as described in U.S. Patent Nos. 7,488,802, 7,943,743, 8,008,449, 8,168,757, 8,217,149, or 10,308,644; U.S. Patent Publication Nos. 2017 / 0145025, 2017 / 0174671, 2017 / 01 No. 74679, No. 2017 / 0320875, No. 2017 / 0342060, No. 2017 / 0362253, No. 2018 / 0016260, No. 2018 / 005 No. 7486, No. 2018 / 0177784, No. 2018 / 0177870, No. 2018 / 0179179, No. 2018 / 0179201, No. 2018 / 01792 02, 2018 / 0273519, 2019 / 0040082, 2019 / 0062345, 2019 / 0071439, 2019 / 0127467, 2019 / 0144439, 2019 / 0202824, 2019 / 0225601, 2019 / 0300524, or 2019 / 034 or PCT Publication Nos. WO03042402, WO2008156712, WO2010089411, WO2010036959, WO2011066342, WO2011159877, WO2011082400, or WO2011161699, each of which is incorporated by reference in its entirety. In some embodiments, the inhibitor of PD-L1 is INCB086550.

[0171] In some embodiments, the antibody is an anti-PD-1 antibody, for example, an anti-PD-1 monoclonal antibody. In some embodiments, the anti-PD-1 antibody is nivolumab, retifanlimab, pembrolizumab, cemiplimab, spartalizumab, camrelizumab, cetrelimab, toripalimab, sintilimab, AB122, AMP-224, JTX-4014, BGB-108, BCD-100, BAT1306, LZM009, AK105, HLX10, or TSR-042. In some embodiments, the anti-PD-1 antibody is nivolumab, pembrolizumab, cemiplimab, spartalizumab, camrelizumab, cetrelimab, toripalimab, or sintilimab. In some embodiments, the anti-PD-1 antibody is pembrolizumab. In some embodiments, the anti-PD-1 antibody is nivolumab. In some embodiments, the anti-PD-1 monoclonal antibody is retifanlimab. In some embodiments, the anti-PD-1 antibody is cemiplimab. In some embodiments, the anti-PD-1 antibody is spartalizumab. In some embodiments, the anti-PD-1 antibody is camrelizumab. In some embodiments, the anti-PD-1 antibody is cetrelimab. In some embodiments, the anti-PD-1 antibody is toripalimab. In some embodiments, the anti-PD-1 antibody is sintilimab. In some embodiments, the anti-PD-1 antibody is AB122. In some embodiments, the anti-PD-1 antibody is AMP-224. In some embodiments, the anti-PD-1 antibody is JTX-4014. In some embodiments, the anti-PD-1 antibody is BGB-108. In some embodiments, the anti-PD-1 antibody is BCD-100. In some embodiments, the anti-PD-1 antibody is BAT1306. In some embodiments, the anti-PD-1 antibody is LZM009. In some embodiments, the anti-PD-1 antibody is AK105. In some embodiments, the anti-PD-1 antibody is HLX10. In some embodiments, the anti-PD-1 antibody is TSR-042. In some embodiments, the anti-PD-1 monoclonal antibody is nivolumab or pembrolizumab. In some embodiments, the anti-PD1 antibody is SHR-1210.Other anti-cancer agent(s) include antibody therapeutics, such as 4-1BB (e.g., urelumab, utomirumab). In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of PD-L1, such as an anti-PD-L1 monoclonal antibody. In some embodiments, the anti-PD-L1 monoclonal antibody is atezolizumab, avelumab, durvalumab, tislelizumab, BMS-935559, MEDI4736, atezolizumab (also known as MPDL3280A, RG7446), avelumab (MSB0010718C), FAZ053, KN035, CS1001, SHR-1316, CBT-502, A167, STI-A101, CK-301, BGB-A333, MSB-2311, HLX20, or LY3300054. In some embodiments, the anti-PD-L1 antibody is atezolizumab, avelumab, durvalumab, or tislelizumab. In some embodiments, the anti-PD-L1 antibody is atezolizumab. In some embodiments, the anti-PD-L1 antibody is avelumab. In some embodiments, the anti-PD-L1 antibody is durvalumab. In some embodiments, the anti-PD-L1 antibody is tislelizumab. In some embodiments, the anti-PD-L1 antibody is BMS-935559. In some embodiments, the anti-PD-L1 antibody is MEDI4736. In some embodiments, the anti-PD-L1 antibody is FAZ053. In some embodiments, the anti-PD-L1 antibody is KN035. In some embodiments, the anti-PD-L1 antibody is CS1001. In some embodiments, the anti-PD-L1 antibody is SHR-1316. In some embodiments, the anti-PD-L1 antibody is CBT-502. In some embodiments, the anti-PD-L1 antibody is A167. In some embodiments, the anti-PD-L1 antibody is STI-A101. In some embodiments, the anti-PD-L1 antibody is CK-301. In some embodiments, the anti-PD-L1 antibody is BGB-A333. In some embodiments, the anti-PD-L1 antibody is MSB-2311. In some embodiments, the anti-PD-L1 antibody is HLX20. In some embodiments, the anti-PD-L1 antibody is LY3300054.

[0172] In some embodiments, the inhibitor of an immune checkpoint molecule is a small molecule that binds to PD-L1, or a pharma- ceutically acceptable salt thereof. In some embodiments, the inhibitor of an immune checkpoint molecule is a small molecule that binds to and internalizes PD-L1, or a pharma- ceutically acceptable salt thereof. In some embodiments, the inhibitor of an immune checkpoint molecule is a compound selected from those in US2018 / 0179201, US2018 / 0179197, US2018 / 0179179, US2018 / 0179202, US2018 / 0177784, US2018 / 0177870, US Ser. No. 16 / 369,654 (filed Mar. 29, 2019), and US Ser. No. 62 / 688,164, each of which is incorporated herein by reference in its entirety, or a pharma- ceutically acceptable salt thereof.

[0173] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of KIR, TIGIT, LAIR1, CD160, 2B4, and TGFRbeta.

[0174] In some embodiments, the inhibitor is MCLA-145.

[0175] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of CTLA-4, such as an anti-CTLA-4 antibody. In some embodiments, the anti-CTLA-4 antibody is ipilimumab, tremelimumab, AGEN1884, or CP-675,206.

[0176] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of LAG3, such as an anti-LAG3 antibody. In some embodiments, the anti-LAG3 antibody is BMS-986016, LAG525, INCAGN2385, or eftiragimodo alpha (IMP321).

[0177] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of CD73. In some embodiments, the inhibitor of CD73 is oleclumab.

[0178] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of TIGIT. In some embodiments, the inhibitor of TIGIT is OMP-31M32.

[0179] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of VISTA. In some embodiments, the inhibitor of VISTA is JNJ-61610588 or CA-170.

[0180] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of B7-H3. In some embodiments, the inhibitor of B7-H3 is enoblituzumab, MGD009, or 8H9.

[0181] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of KIR. In some embodiments, the inhibitor of KIR is lirilumab or IPH4102.

[0182] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of A2aR. In some embodiments, the inhibitor of A2aR is CPI-444.

[0183] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of TGF-beta. In some embodiments, the inhibitor of TGF-beta is travedersen, galcertinib, or M7824.

[0184] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of PI3K-gamma. In some embodiments, the inhibitor of PI3K-gamma is IPI-549.

[0185] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of CD47. In some embodiments, the inhibitor of CD47 is Hu5F9-G4 or TTI-621.

[0186] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of CD73. In some embodiments, the inhibitor of CD73 is MEDI9447.

[0187] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of CD70. In some embodiments, the inhibitor of CD70 is cusatuzumab or BMS-936561.

[0188] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of TIM3, such as an anti-TIM3 antibody. In some embodiments, the anti-TIM3 antibody is INCAGN2390, MBG453, or TSR-022.

[0189] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of CD20, such as an anti-CD20 antibody. In some embodiments, the anti-CD20 antibody is obinutuzumab or rituximab.

[0190] In some embodiments, the agonist of an immune checkpoint molecule is an agonist of OX40, CD27, CD28, GITR, ICOS, CD40, TLR7 / 8, and CD137 (also known as 4-1BB).

[0191] In some embodiments, the agonist of CD137 is urelumab. In some embodiments, the agonist of CD137 is utomirumab.

[0192] In some embodiments, the agonist of the immune checkpoint molecule is an inhibitor of GITR. In some embodiments, the agonist of GITR is TRX518, MK-4166, INCAGN1876, MK-1248, AMG228, BMS-986156, GWN323, MEDI1873, or MEDI6469. In some embodiments, the agonist of the immune checkpoint molecule is an agonist of OX40, such as an OX40 agonist antibody or an OX40L fusion protein. In some embodiments, the anti-OX40 antibody is INCAGN01949, MEDI0562 (tavolimab), MOXR-0916, PF-04518600, GSK3174998, BMS-986178, or 9B12. In some embodiments, the OX40L fusion protein is MEDI6383.

[0193] In some embodiments, the agonist of the immune checkpoint molecule is an agonist of CD40. In some embodiments, the agonist of CD40 is CP-870893, ADC-1013, CDX-1140, SEA-CD40, RO7009789, JNJ-64457107, APX-005M, or Chi Lob 7 / 4.

[0194] In some embodiments, the agonist of the immune checkpoint molecule is an agonist of ICOS. In some embodiments, the agonist of ICOS is GSK-3359609, JTX-2011, or MEDI-570.

[0195] In some embodiments, the agonist of the immune checkpoint molecule is an agonist of CD28. In some embodiments, the agonist of CD28 is ceralizumab.

[0196] In some embodiments, the agonist of the immune checkpoint molecule is an agonist of CD27. In some embodiments, the agonist of CD27 is varlilumab.

[0197] In some embodiments, the agonist of the immune checkpoint molecule is an agonist of TLR7 / 8. In some embodiments, the agonist of TLR7 / 8 is MEDI9197.

[0198] The compounds of the present disclosure can be used in combination with bispecific antibodies. In some embodiments, one of the domains of the bispecific antibody targets PD-1, PD-L1, CTLA-4, GITR, OX40, TIM3, LAG3, CD137, ICOS, CD3, or TGFβ receptor. In some embodiments, the bispecific antibody binds to PD-1 and PD-L1. In some embodiments, the bispecific antibody that binds to PD-1 and PD-L1 is MCLA-136. In some embodiments, the bispecific antibody binds to PD-L1 and CTLA-4. In some embodiments, the bispecific antibody that binds to PD-L1 and CTLA-4 is AK104.

[0199] In some embodiments, the compounds of the present disclosure can be used in combination with one or more metabolic enzyme inhibitors.In some embodiments, the metabolic enzyme inhibitor is an inhibitor of IDO1, TDO, or arginase.Examples of IDO1 inhibitors include epacadostat, NLG919, BMS-986205, PF-06840003, IOM2983, RG-70099, and LY338196.Inhibitors of arginase inhibitors include INCB1158.

[0200] As provided throughout, the additional compounds, inhibitors, agents, etc. may be combined with the present compounds in a single or consecutive dosage form, or they may be administered simultaneously or sequentially as separate dosage forms.

[0201] Pharmaceutical Preparations and Dosage Forms When used as pharmaceuticals, the compounds described herein can be administered in the form of pharmaceutical compositions, which refers to a combination of the compounds described herein and at least one pharma- ceutically acceptable carrier. These compositions can be prepared by methods well known in the pharmaceutical arts and can be administered by various routes, depending on whether local or systemic treatment is desired and the area to be treated. Administration can be topical (including transmucosal, including ocular, as well as intranasal, intravaginal, and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal, intranasal, epithelial, and transdermal), ocular, oral, or parenteral. Methods of ocular delivery can include topical administration (eye drops), subconjunctival, periorbital, or intravitreal injection, or introduction by a balloon catheter or ocular insert surgically placed in the conjunctival sac. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal, or intramuscular injection or infusion, or intracranial, e.g., intrathecal or intraventricular administration. Parenteral administration can be in the form of a single bolus dose or, for example, by a continuous perfusion pump. Pharmaceutical compositions and formulations for topical administration can include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids, and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners, and the like may be necessary or desirable.

[0202] The present disclosure also includes pharmaceutical compositions containing FGFR1 inhibitors and / or KRAS inhibitors as active ingredients in combination with one or more pharma- ceutically acceptable carriers. In preparing the compositions described herein, the active ingredient is typically mixed with an excipient, diluted by an excipient, or enclosed in such a carrier, for example, in the form of a capsule, sachet, paper, or other container. When an excipient functions as a diluent, it can be a solid, semi-solid, or liquid material that acts as a vehicle, carrier, or medium for the active ingredient. Thus, the composition can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solid or liquid media), for example, ointments containing up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.

[0203] When preparing formulation, active compound can be pulverized to obtain suitable particle size before being combined with other components.If active compound is substantially insoluble, it can be pulverized to a particle size of less than 200 mesh.If active compound is substantially water-soluble, particle size can be adjusted by pulverization to obtain substantially uniform distribution in formulation, for example, about 40 mesh.

[0204] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methylcellulose.The formulation may further include lubricants such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preservatives such as methylbenzoate and propylhydroxybenzoate; sweeteners; and flavoring agents.The composition described herein may be formulated to provide quick, sustained, or delayed release of active ingredient after administration to a patient by using methods known in the art.

[0205] The compositions can be formulated in unit dosage form, each dosage containing about 1 to about 10 mg, or about 5 mg, of active ingredient. In some embodiments, the unit dosage form contains about 2 mg of active ingredient. In some embodiments, the unit dosage form contains about 1 mg of active ingredient. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.

[0206] The active compound can be effective over a wide dosage range and is generally administered in a pharmacologic effective amount. However, it will be understood that the amount of compound actually administered will usually be determined by the physician according to the relevant circumstances, including the condition being treated, the selected route of administration, the compound actually administered, the age, weight, and response of the individual patient, the severity of the patient's condition, etc.

[0207] To prepare solid compositions such as tablets, the primary active ingredient is mixed with pharmaceutical excipients to form a solid preformulation composition containing a homogeneous mixture of the active ingredient. When these preformulation compositions are referred to as homogeneous, the active ingredient is usually uniformly dispersed throughout the composition, so that the composition can be easily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules. This solid preformulation is then divided into unit dosage forms of the type described above, for example, containing 0.1 to about 500 mg of the active ingredient of the present disclosure.

[0208] In some embodiments, the active ingredient is pemigatinib. In some embodiments, pemigatinib is administered orally. In some embodiments, pemigatinib is administered once a day. In some embodiments, pemigatinib is administered in a daily dose of about 1 mg to about 20 mg. In some embodiments, pemigatinib is administered in a daily dose of about 1 mg to about 5 mg. In some embodiments, pemigatinib is administered in a daily dose of about 2 mg. In some embodiments, pemigatinib is administered as a tablet. In some embodiments, the tablet contains about 0.5 mg to about 10 mg of pemigatinib. In some embodiments, the tablet contains about 0.5 mg to about 5 mg of pemigatinib. In some embodiments, the tablet contains about 2 mg, about 4.5 mg, about 9 mg, about 13.5 mg, or about 18 mg of pemigatinib. In some embodiments, the tablet contains about 0.5 mg of pemigatinib. In some embodiments, the tablet contains about 2 mg of pemigatinib. In some embodiments, the tablet contains about 4.5 mg of pemigatinib. In some embodiments, the tablet contains about 9 mg of pemigatinib. In some embodiments, the tablet contains about 13.5 mg of pemigatinib. In some embodiments, the tablet contains about 18 mg of pemigatinib.

[0209] The tablet or pill of the present invention can be coated or otherwise compounded to provide a dosage form that provides the advantage of long-term action.For example, the tablet or pill can comprise an inner dose and an outer dose component, the latter being in the form of an envelope on a molded agent.The two components can be separated by an enteric layer that resists disintegration in the stomach and allows the inner component to pass intact into the duodenum or to be delayed in release.Various materials can be utilized as such enteric layers or coatings, including materials that include a number of polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0210] Liquid forms for oral or injectable administration into which the pemigatinib or compositions of the present invention may be incorporated include aqueous solutions, suitably flavored syrups, aqueous or oily suspensions, and flavored emulsions including edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.

[0211] Compositions for inhalation or insufflation include solutions and suspensions in pharma- ceutically acceptable aqueous or organic solvents, or mixtures thereof, as well as powders. Liquid or solid compositions may contain suitable pharma- ceutically acceptable excipients as described above. In some embodiments, the compositions are administered by oral or nasal respiratory route for local or systemic effect. Compositions may be nebulized by using inert gases. Nebulized solutions may be breathed directly from the nebulizing device, or the nebulizing device may be attached to a face mask tent or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered orally or nasally from a device that delivers the formulation in an appropriate manner.

[0212] The amount of compound or composition administered to a patient will vary depending on what is being administered, the purpose of the administration, such as prophylaxis or treatment, the condition of the patient, the method of administration, etc. In therapeutic applications, the compositions may be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. The effective dose will depend on the condition of the disease being treated, as well as the judgment of the attending clinician based on factors such as the severity of the disease, the age, weight, and general health of the patient.

[0213] The compositions administered to a patient may be in the form of pharmaceutical compositions described above. These compositions may be sterilized by conventional sterilization techniques or may be sterile filtered. Aqueous solutions may be packaged or lyophilized for use as is, although lyophilized preparations are combined with a sterile aqueous carrier prior to administration. The pH of the compound preparations will typically be 3-11, more preferably 5-9, and most preferably 7-8. It will be appreciated that the use of certain of the aforementioned excipients, carriers, or stabilizers will result in the formulation of pharmaceutical salts.

[0214] The therapeutic dose of pemigatinib may vary according to, for example, the particular application for which the treatment is being performed, the method of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of pemigatinib in a pharmaceutical composition may vary depending on many factors, including dosage amount, chemical properties (e.g., hydrophobicity), and route of administration. For example, pemigatinib may be provided in an aqueous physiological buffer solution containing about 0.1 to about 10% w / v of the compound for parenteral administration. Some typical dose ranges are about 1 μg / kg body weight to about 1 g / kg body weight per day. In some embodiments, the dose range is about 0.01 mg / kg body weight to about 100 mg / kg body weight per day. The dosage may depend on variables such as the type and extent of progression of the disease or disorder, the overall health of the particular patient, the relative biological effectiveness of the selected compound, the excipient formulation, and its route of administration. Effective doses may be extrapolated from dose-response curves derived from in vitro or animal model test systems.

[0215] Pemigatinib can also be formulated in combination with one or more additional active ingredients, which may include any medicinal agent such as an antiviral agent, a vaccine, an antibody, an immune enhancer, an immunosuppressant, an anti-inflammatory agent, and the like.

[0216] In some embodiments, the active ingredient is sotorasibe. Sotorasibe as described herein can be administered in the form of a pharmaceutical composition and at least one pharma- ceutical acceptable excipient. In some embodiments, the active ingredient is adagrasib. Adagasib as described herein can be administered in the form of a pharmaceutical composition and at least one pharma-ceutical acceptable excipient. These compositions can be prepared in a manner well known in the pharmaceutical art and can be administered by various routes, depending on whether local or systemic treatment is desired and on the area to be treated. Pharmaceutical compositions can be in various forms. These include, for example, liquid, semi-solid and solid dosage forms, such as liquid solutions (e.g., injectable and infusible solutions), dispersions or suspensions, tablets, pills, powders, liposomes and suppositories. The preferred form can depend on the intended mode of administration and therapeutic application. A typical composition for the medicament described herein is in the form of a tablet.

[0217] labeled compound Another aspect of the present disclosure relates to labeled FGFR1 inhibitors, KRAS inhibitors, or both described herein (e.g., radiolabeled, fluorescently labeled, isotopically labeled, etc.), which may be useful in both in vitro and in vivo assays as well as imaging techniques.

[0218] The present disclosure further includes isotopically labeled FGFR1 inhibitors, KRAS inhibitors, or both as described herein. An "isotopically labeled" or "radiolabeled" compound is an FGFR1 inhibitor, KRAS inhibitor, or both as described herein in which one or more atoms are replaced or substituted by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature (i.e., naturally occurring). Suitable radionuclides that can be incorporated into the compounds of the present disclosure include: 2 H (also written as D for deuterium), 3 H (also written as T for tritium), 11 C. 13 C. 14 C. 13 N,15 N, 15 O. 17 O. 18 O. 18 F, 35 S, 36 Cl, 82 Br, 75 Br, 76 Br, 77 Br, 123 I, 124 I, 125 I, and 131 These include, but are not limited to, I. For example, one or more hydrogen atoms in the compounds of the present disclosure can be replaced by a deuterium atom, optionally replaced by deuterium.

[0219] One or more constituent atoms of the FGFR1 inhibitor, the KRAS inhibitor, or both may be replaced or substituted with an isotope of the atom at natural or non-natural abundance. In some embodiments, the FGFR1 inhibitor, the KRAS inhibitor, or both may include at least one deuterium atom. For example, one or more hydrogen atoms in the compounds of the present disclosure may be replaced or substituted with deuterium. In some embodiments, the compounds include two or more deuterium atoms. In some embodiments, the compounds include 1-2, 1-3, 1-4, 1-5, or 1-6 deuterium atoms. In some embodiments, all hydrogen atoms in the compounds may be replaced or substituted with deuterium atoms.

[0220] Synthetic methods for incorporating isotopes into organic compounds are known in the art (Alan F. Thomas, Deuterium Labeling in Organic Chemistry (New York, NY, Appleton-Century-Crofts, 1971); Jens Atzrodt, Volker Derdau, Thorsten Fey, Jochen Zimmermann, The Renaissance of H / D Exchange, Angew. Chem. Int. Ed. 2007, 7744-7765; James R. Hanson, The Organic Chemistry of Isotopic Labelling, Royal Society of Chemistry, 2011). Isotopically labeled compounds can be used in a variety of studies, such as NMR spectroscopy, metabolic experiments, and / or assays.

[0221] Substitution with heavier isotopes, such as deuterium, can provide certain therapeutic advantages, such as increased in vivo half-life or reduced dosage requirements, due to greater metabolic stability, and therefore may be preferred in some cases (see, for example, A. Kerekes et.al. J. Med. Chem. 2011, 54, 201-210; R. Xu et.al. J. Label Compd. Radiopharm. 2015, 58, 308-312). In particular, substitution at one or more metabolic sites can provide one or more therapeutic advantages.

[0222] A "radiolabel" or "labeled compound" is understood to be a compound that incorporates at least one radionuclide. In some embodiments, the radionuclide is 3 H and 14 C. In some embodiments, the radionuclide is 11 C. 18 F, 75 Br, 76 Br, and 77 Br.

[0223] kit The present disclosure also includes pharmaceutical kits, useful for example in the treatment of cancer, which include one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of an FGFR1 inhibitor, a KRAS inhibitor, or any of its embodiments. As will be apparent to those skilled in the art, such kits can further include one or more of a variety of conventional pharmaceutical kit components, such as, for example, a container with one or more pharma-ceutically acceptable carriers, additional containers, etc. Instructions, either as a package insert or label, indicating the amount of components to be administered, administration guidelines, and / or guidelines for mixing the components, can also be included in the kit. EXAMPLES

[0224] The present invention will be described in more detail by specific examples. The following examples are provided for illustrative purposes and are not intended to limit the present invention in any manner. Those skilled in the art will easily recognize various non-critical parameters that can be changed or modified to produce essentially the same results.

[0225] Example A. Treatment of KRAS-G12C inhibitors in mesenchymal-like lung cancer cells increased FGFR downstream signaling FGFR1 and downstream activation marker pFRS2a protein levels, as well as markers of epithelial-like cells (E-cadherin) and mesenchymal-like cells (vimentin) in the indicated cell lines were examined.

[0226] Mesenchymal-like cells with low E-cadherin expression and high vimentin expression, including LU99, H1792, and SW1573, showed higher levels of FGFR1 and pFRS2a compared with H358, an epithelial-like cell line with high E-cadherin and low vimentin.

[0227] In LU99 cells, 50 nM of the KRAS G12C inhibitor (AMG510 or compound 2) increased pFRS2a protein levels, and pemigatinib, but not the FGFR2 / 3 inhibitor compound 1, inhibited pFRS2a levels in combination with the KRAS inhibitor.

[0228] FIG. 1A shows Western blots of FGFR1, pFRS2a, E-cadherin, vimentin, and beta-actin in the four indicated cell lines.

[0229] FIG. 1B is a Western blot of pFRS2a and beta-actin in LU99 cell lysates subjected to the indicated treatments.

[0230] method: Cells were seeded at 6x105 cells / well in Corning 6-well tissue culture treated plates in RPMI medium containing 10% FBS. After 48 hours, cells were harvested for Western blot (A) or treated with the indicated compounds for 90 hours at 37°C, 5% CO2. Cells were washed with PBS and lysed in 1x lysis buffer (Cell Signaling #9803) containing protease and phosphatase inhibitors. 25μg of total protein lysate was subjected to SDS-PAGE and immunoblot analysis using antibodies from Cell Signaling Technology.

[0231] In conclusion, mesenchymal-like cancer cells had enhanced FGFR1 signaling, and only KRAS G12C inhibition increased FGFR1 signaling. Combination of KRAS G12C inhibitor with the FGFR1 inhibitor pemigatinib, but not with the FGFR2 / 3 inhibitor compound 1, inhibited KRAS G12C inhibitor-induced upregulation of the FGFR1 pathway.

[0232] Example B. Combination of Compound 2 and pemigatinib, but not Compound 1, maximized inhibition of pERK signaling in LU99 cells. The MEK-ERK pathway is a major downstream signaling pathway for the survival and proliferation of KRAS G12C mutant cancer cells, therefore, we assessed the effects of treatment with KRAS G12C and FGFR inhibitors on phosphorylated ERK (pERK).

[0233] Prior to lysate harvest, LU99 cells were treated with 100 nM compound 2, pemigatinib, compound 1, or the indicated combinations with or without 1 ng / ml recombinant human FGF (rhFGF) for 24 hours. Both pERK and pFRS2a signaling were elevated after 1 ng / ml hrFGF treatment. pFRS2a was elevated after compound 2 treatment with or without rhFGF stimulation, and the combination of compound 2 and pemigatinib completely inhibited pERK signaling.

[0234] FIG. 2 shows Western blots of pERK, pFRS2a, and beta-actin in LU99 cells treated with the KRAS G12C inhibitor Compound 2, with or without pemigatinib or Compound 1, for 24 hours.

[0235] method: Cells were seeded at 6x105 cells / well in Corning 6-well tissue culture treated plates in RPMI medium containing 10% FBS. After 48 hours, cells were treated with the indicated compounds for 24 hours at 37°C, 5% CO2. At the end of the experiment, rhFGF-basic (R&D systems 233-FB) was added at 1 nG / ml for 15 minutes as indicated. Cells were washed with PBS and lysed in 1x lysis buffer (Cell Signaling #9803) containing protease and phosphatase inhibitors. 25 μg of total protein lysate was subjected to SDS-PAGE and immunoblot analysis using the following antibodies from Cell Signaling: pERK (#4370), phosphorylated FRS2a (#3861), and beta-actin (#12620).

[0236] In summary, in mesenchymal-like cells such as LU99, inhibition of KRAS G12C did not completely inhibit downstream pERK signaling, but combining a KRAS G12C inhibitor with an FGFR1 inhibitor achieved complete inhibition of the pERK pathway.

[0237] Example C. Mesenchymal-like cell lines show increased synergy with pemigatinib + G12C inhibition compared to epithelial-like cell lines The in vitro efficacy of combining the FGFR1 inhibitor pemigatinib with selected KRAS G12C inhibitors, AMG-510, compound 3, or compound 4, was evaluated in various cell lines and showed greater synergy in mesenchymal-like cell lines than that demonstrated in epithelial-like cell lines.

[0238] [Table 39]

[0239] method: Cells were seeded at a density of 500 cells / well in RPMI medium with 10% HI FBS in Greiner white clear bottom 384-well tissue culture treated plates containing a 10x10 combination matrix of compounds. Plates were incubated at 37°C, 5% CO2 for 5 days. On day 5, Cell Titer Glo reagent was added to the plates and ATP luminescence was detected using a Pherastar FSX reader. Synergy scores for combination effects were calculated using the Bliss score model: Bliss score = Yab-(Ya+Yb-(YaYb)) x 100, where Ya and Yb are monotherapies. A Bliss score >20 indicates strong synergy, and higher Bliss scores indicate higher levels of synergy.

[0240] In summary, in mesenchymal-like cells, but not in epithelial-like KRAS G12C mutant cells, the combination of the FGFR1 inhibitor pemigatinib with a KRAS G12C inhibitor (i.e., AMG-510, compound 3, or compound 4) synergistically inhibited cell proliferation.

[0241] Example D. Synergistic Effects Observed Between Cell Lines When Combining FGFR and KRAS G12C Inhibitors The in vitro efficacy of the KRAS G12 inhibitor compound 3 in combination with the FGFR inhibitors pemigatinib, compound 1, TAS-120, erdafitinib, or BGJ398 was evaluated in various cell lines and showed greater synergy in mesenchymal-like cell lines than in epithelial-like cell lines.

[0242] [Table 40]

[0243] method: Cells were seeded at a density of 500 cells / well in RPMI medium with 10% HI FBS in Greiner white clear bottom 384-well tissue culture treated plates containing a 10x10 combination matrix of compounds. Plates were incubated at 37°C, 5% CO2 for 5 days. On day 5, Cell Titer Glo reagent was added to the plates and ATP luminescence was detected using a Pherastar FSX reader. The synergy score of the combination effect is calculated using the Bliss score model: Bliss score = Yab-(Ya+Yb-(YaYb)) x 100, where Ya and Yb are monotherapies. A Bliss score of >20 indicates strong synergy, and a higher Bliss score indicates a higher level of synergy.

[0244] In summary, in mesenchymal-like cells, but not in epithelial-like KRAS G12C mutant cells, the combination of the FGFR1 inhibitor pemigatinib and a KRAS G12C inhibitor synergistically inhibited cell proliferation. Compound 1, an FGFR2 / 3 selective inhibitor, did not show synergistic effects with the KRAS G12C inhibitor in any cell line, indicating that pemigatinib acts primarily through the FGFR1 receptor.

[0245] Example E. The combined effect of pemigatinib and AMG510 promotes tumor growth control in vivo LU99 xenograft model The in vivo efficacy of the combination of the FGFR1 inhibitor pemigatinib and the KRAS G12C inhibitor AMG510 was evaluated in a LU99 lung cancer model (JCRB0080, JCRB) xenograft model (Figure 3) in 6-8 week old female NCr nude mice (Taconic). Pemigatinib and AMG510 were suspended in 5% N,N-dimethylacetamide (DMAC) + 50 mM citrate buffer (pH 3.0) in 0.5% methylcellulose for oral administration. Briefly, mice were inoculated with 1 × 10 IgG1 cells resuspended 1:1 in a solution of PBS and Matrigel (Corning Life Sciences, Tewksbury, Mass) into the left flank of the mice. 7 LU99 cells were inoculated into each mouse. On day 7, the mice reached an approximate average volume (approximately 212 mm 3 ) into four groups of 10 mice each. Starting on day 7, mice were administered (i) vehicle, (ii) 20 mg / kg AMG510, (iii) 0.3 mg / kg pemigatinib, or (iv) a combination of AMG510 and pemigatinib at 20 mg / kg and 0.3 mg / kg, respectively. Pemigatinib and AMG510 were administered orally once daily (QD) for 30 days during the study. All treatment groups showed statistically significant TGI (tumor growth inhibition) compared to vehicle-treated mice. Tumor growth inhibition was calculated as (1-(V T / V C )) × 100, where V T is the tumor volume of the treatment group on the last day of treatment, and V C is the tumor volume of the control group on the last day of treatment. The TGI of AMG510, pemigatinib, and the combination was 66%, 63%, and 93%, respectively. The TGI of the combination group was statistically different from the single agent groups. Statistics were determined using one-way ANOVA.

[0246] FIG. 3 is a graph showing tumor volume in LU99 tumor-bearing mice administered (i) vehicle, (ii) 20 mg / kg AMG510, (iii) 0.3 mg / kg pemigatinib, or (iv) a combination of AMG510 and pemigatinib at 20 mg / kg and 0.3 mg / kg, respectively.

[0247] In summary, the combination of AMG510 and pemigatinib achieved maximal efficacy compared to each single-agent treatment group in the LU99 xenograft model, i.e., the combination acted synergistically.

[0248] Example F. The combination of pemigatinib and AMG510 increases phosphorylated ERK inhibition in LU99 tumors compared to single agent treatment. LU99 in vivo pERK inhibition The pERK inhibitory effect of the combination of pemigatinib and AMG510 was evaluated in vivo in the LU99 lung cancer xenograft model in 6-8 week old NCr nude mice (Taconic). Pemigatinib and AMG510 were suspended in 5% N,N-dimethylacetamide (DMAC) + 50 mM citrate buffer (pH 3.0) in 0.5% methylcellulose for oral administration. Briefly, 1 × 10 IgG1 cells resuspended 1:1 in a solution of PBS and Matrigel (Corning Life Sciences, Tewksbury, Mass) were inoculated into the left flank of the mice. 7 LU99 cells were inoculated into the tumor. The tumor size was approximately 564 mm 3At 1 h after immunization, mice were administered a single dose of either (i) vehicle, (ii) 20 mg / kg AMG510, (iii) 0.3 mg / kg pemigatinib, or (iv) 20 mg / kg AMG510 and 0.3 mg / kg pemigatinib, and tumors were harvested 2 h after administration. Tumors were then processed and the levels of phosphorylated ERK compared to total ERK were assessed on tumor lysates by MSD (Mesoscale). Data show that mice administered the combination of AMG510 and pemigatinib showed statistically greater inhibition of pERK than AMG510 alone or pemigatinib alone. Percent inhibition was calculated relative to vehicle-treated mice and is presented as the ratio of phosphorylated ERK to total ERK. Statistics were determined using one-way ANOVA.

[0249] FIG. 4 is a graph showing inhibition of pERK in LU99 tumors in mice receiving 20 mg / kg AMG510, 0.3 mg / kg pemigatinib, or a combination of AMG510 and pemigatinib at 20 mg / kg and 0.3 mg / kg, respectively.

[0250] In summary, the combination of AMG510 and pemigatinib maximally inhibited pERK signaling in the LU99 xenograft model, which is consistent with previous in vitro results.

[0251] Example G. Treatment of Mesenchymal-Like Lung Cancer Cells with MRTX849 (Adagrasib) The protein levels of pFRS2a, a marker of FGFR1 downstream activation, were examined in the mesenchymal-like cell line LU99. In these cells, 50 nM of the KRAS G12C inhibitor (MRTX849) increased pFRS2a protein levels, and 0.5 μM of pemigatinib, but not the FGFR2 / 3 inhibitor Compound 1, inhibited pFRS2a levels in combination with the KRAS inhibitor.

[0252] FIG. 5 shows a Western blot of pFRS2 and beta-actin in MRTX849-treated LU99 cell lysates.

[0253] method: Cells were seeded at 6x105 cells / well in Corning 6-well tissue culture treated plates in RPMI medium containing 10% FBS. After 48 hours, cells were harvested for Western blot (A) or treated with the indicated compounds for 90 hours at 37°C, 5% CO2. Cells were washed with PBS and lysed in 1x lysis buffer (Cell Signaling #9803) containing protease and phosphatase inhibitors. 25μg of total protein lysate was subjected to SDS-PAGE and immunoblot analysis using antibodies from Cell Signaling Technology.

[0254] In conclusion, FGFR1 signaling was elevated in the mesenchymal-like cancer cell line Lu99, and only KRAS G12C inhibition increased FGFR1 signaling. The combination of the KRAS G12C inhibitor MRTX849 with the FGFR1 inhibitor pemigatinib, and to a lesser extent with the FGFR2 / 3 inhibitor compound 1, inhibited the KRAS G12C inhibitor-induced upregulation of the FGFR1 pathway.

[0255] Example H. Combination of MRTX849 and Pemigatinib for Inhibition of pERK Signaling in LU99 Cells The MEK-ERK pathway is a major downstream signaling pathway for the survival and proliferation of KRAS G12C mutant cancer cells, therefore, we assessed the effects of treatment with KRAS G12C and FGFR inhibitors on phosphorylated ERK (pERK).

[0256] Prior to lysate harvest, LU99 cells were treated with 100 nM MRTX849, 100 nM pemigatinib, compound 1, or the indicated combinations with or without 1 ng / ml recombinant human FGF (rhFGF) for 24 h. Both pERK and pFRS2a signaling were elevated after 1 ng / ml hrFGF treatment. pFRS2a was elevated after MRTX849 treatment with or without rhFGF stimulation, and the combination of MRTX849 and pemigatinib completely inhibited pERK signaling.

[0257] FIG. 6 shows Western blots of pERK, pFRS2a, and beta-actin in LU99 cells treated with the KRAS G12C inhibitor, MRTX849, with or without pemigatinib or Compound 1 for 24 hours.

[0258] method: Cells were seeded at 6x105 cells / well in Corning 6-well tissue culture treated plates in RPMI medium containing 10% FBS. After 48 hours, cells were treated with the indicated compounds for 24 hours at 37°C, 5% CO2. At the end of the experiment, rhFGF-basic (R&D systems 233-FB) was added at 1 nG / ml for 15 minutes as indicated. Cells were washed with PBS and lysed in 1x lysis buffer (Cell Signaling #9803) containing protease and phosphatase inhibitors. 25 μg of total protein lysate was subjected to SDS-PAGE and immunoblot analysis using the following antibodies from Cell Signaling: pERK (#4370), phosphorylated FRS2a (#3861), and beta-actin (#12620).

[0259] In summary, in mesenchymal-like cells such as LU99, inhibition of KRAS G12C did not completely inhibit downstream pERK signaling, but combining KRAS G12C with an FGFR1 inhibitor achieved complete inhibition of the pERK pathway.

[0260] Example I. Combination of MRTX849 with FGFR inhibitors in epithelial and mesenchymal-like cell lines The in vitro effects of the FGFR1 inhibitor pemigatinib and the FGFR2 / 3 inhibitor compound 1 in combination with the KRAS G12C inhibitor MRTX849 were evaluated in various cell lines.

[0261] [Table 41]

[0262] method: Cells were seeded at a density of 500 cells / well in RPMI medium with 10% HI FBS in Greiner white clear bottom 384-well tissue culture treated plates containing a 10x10 combination matrix of compounds. Plates were incubated at 37°C, 5% CO2 for 5 days. On day 5, Cell Titer Glo reagent was added to the plates and ATP luminescence was detected using a Pherastar FSX reader. Synergy scores for combination effects were calculated using the Bliss score model: Bliss score = Yab-(Ya+Yb-(YaYb)) x 100, where Ya and Yb are monotherapies. A Bliss score >20 indicates strong synergy, and higher Bliss scores indicate higher levels of synergy.

[0263] In summary, in mesenchymal-like cells, but not in epithelial-like KRAS G12C mutant cells, the combination of the FGFR1 inhibitor pemigatinib and the KRAS G12C inhibitor MRTX849 synergistically inhibited cell proliferation.

[0264] Example J. Testing the in vivo tumor growth suppression effect of the combination of pemigatinib and MRTX849 LU99 xenograft model The in vivo efficacy of the FGFR1 inhibitor pemigatinib in combination with the KRAS G12C inhibitor MRTX849 (adagrasib) was evaluated in a LU99 lung cancer xenograft model (JCRB0080, JCRB) in 6- to 8-week-old female NCr nude mice (Taconic). Pemigatinib was suspended in 5% N,N-dimethylacetamide (DMAC) + 50 mM citrate buffer (pH 3.0) in 0.5% methylcellulose, and MRTX849 was suspended in 10% Captisol + 50 mM citrate buffer (pH 2.5), both for oral administration. Briefly, mice were inoculated with 1 × 10 mAbs resuspended 1:1 in a solution of PBS and Matrigel (Corning Life Sciences, Tewksbury, Mass) into the left flank of the mice. 7LU99 cells were inoculated into each mouse. When the tumors reached an appropriate size (approximately day 7), the mice were randomized into groups of 10 based on the approximate tumor volume. From there, the mice were administered (i) vehicle, (ii) 10 mg / kg MRTX849, (ii) 30 mg / kg MRTX849, (iii) 0.3 mg / kg pemigatinib, (iv) a combination of 10 mg / kg MRTX849 and 0.3 mg / kg pemigatinib, or (v) a combination of 30 mg / kg MRTX849 and 0.3 mg / kg pemigatinib. Pemigatinib and MRTX849 were administered orally once daily (QD) for the duration of the study. The primary endpoint of the study was tumor growth inhibition (TGI). TGI is calculated as (1-(V T / V C )) × 100, where V T is the tumor volume of the treatment group on the last day of treatment, and V C is the tumor volume of the control group on the last day of treatment. Statistical relationships were tested using one-way analysis of variance.

[0265] FIG. 7 is a graph showing tumor volume in LU99 tumor-bearing mice administered (i) vehicle, (ii) 10 mg / kg MRTX849, (iii) 0.3 mg / kg pemigatinib, or (iv) a combination of MRTX849 and pemigatinib at 10 mg / kg and 0.3 mg / kg, respectively.

[0266] In summary, the combination of MRTX849 and pemigatinib achieved maximal efficacy compared with each single-agent treatment group in the LU99 xenograft model.

[0267] Example K. Study of the Effect of Combining Pemigatinib and MRTX849 on Phospho-ERK Inhibition in LU99 Tumors Compared to Single Agent Treatment LU99 in vivo pERK inhibition The pERK inhibitory effect of pemigatinib in combination with MRTX849 (adagrasib) was evaluated in vivo in the LU99 lung cancer xenograft model in 6-8 week old NCr nude mice (Taconic). Pemigatinib was suspended in 5% N,N-dimethylacetamide (DMAC) + 50 mM citrate buffer (pH 3.0) in 0.5% methylcellulose, and MRTX849 was suspended in 10% Captisol + 50 mM citrate buffer (pH 2.5), both for oral administration. Briefly, mice were inoculated with 1 × 10 mAbs resuspended 1:1 in a solution of PBS and Matrigel (Corning Life Sciences, Tewksbury, Mass) into the left flank of the mice. 7 LU99 cells were inoculated into the tumor. 3 At 1 h after administration, mice were administered a single dose of (i) vehicle, (ii) 10 mg / kg MRTX849, (iii) 0.3 mg / kg pemigatinib, or (iv) a combination of 10 mg / kg MRTX849 and 0.3 mg / kg pemigatinib. Tumors were harvested 2 h after administration. Tumors were then processed and the levels of phosphorylated ERK compared to total ERK on tumor lysates were assessed using MSD (Mesoscale). Percent inhibition was calculated compared to vehicle-treated mice. Data are presented as the ratio of phosphorylated ERK to total ERK. Statistical relationships were tested using one-way ANOVA.

[0268] FIG. 8 is a graph showing inhibition of pERK in LU99 tumors in mice administered 10 mg / kg MRTX849, 0.3 mg / kg pemigatinib, or the combination of MRTX849 and pemigatinib at 10 mg / kg and 0.3 mg / kg, respectively.

[0269] In summary, the combination of MRTX849 and pemigatinib maximally inhibited pERK signaling in the LU99 xenograft model, which is consistent with previous in vitro results.

[0270] Example L. Combination of siRNA FGFR isoform knockdown and KRAS G12C inhibitor reduced in vitro cell proliferation of LU99 cells. To further evaluate the mechanism of action of the KRAS / FGFR combination, multiple siRNA FGFR knockdown experiments were performed in LU99 cells, which were then treated with the KRAS G12C inhibitors Compound 2, Compound 3, or AMG510. Knockdown efficiency was assessed by Western blot, and the effect was measured by cell proliferation inhibition. In the first experiment (Figure 9), knockdown of FGFR1 and FGFR4 was achieved (Figure 9A). Addition of either Compound 3 (Figure 9B) or AMG510 (Figure 9C) resulted in a higher inhibition of proliferation than in the absence of FGFR1 or FGFR4.

[0271] In follow-up experiments, in addition to FGFR1 knockdown, FGFR2 and FGFR3 knockdown was achieved (Figure 10A). As in the previous example, addition of either compound 2 (Figure 10B) or AMG-510 (Figure 10C) resulted in greater inhibition of proliferation than in the absence of FGFR1, FGFR2, or FGFR3.

[0272] Finally, we knocked down all isoforms of FGFR to some extent and assessed their effect on proliferation (Figure 11A). As previously observed, the addition of compound 2 (Figure 11B) resulted in a higher inhibition of proliferation, especially in the absence of FGFR1 and FGFR2.

[0273] In summary, the combination of a KRAS G12C inhibitor after knockdown of an FGFR isoform resulted in higher inhibition of LU99 in vitro proliferation, very similar to the effect of combining a KRAS G12C inhibitor with an FGFR inhibitor.

[0274] method: Lyophilized siRNA pools or individual ones (Dharmacon ON-TARGET and siRNA from Horizon Discovery) were reconstituted by combining 1x siRNA buffer (200 μL) with lyophilized siRNA (20 nmol) or by combining 1x siRNA buffer (100 μL) with lyophilized siRNA (10 nmol). Dharmafect Reagent 1 was prepared at a 1:200 dilution in 1x siRNA. One tube of diluted reagent was prepared for each siRNA dilution. To each tube, the appropriate siRNA was added at a 1:400 dilution to Dharmafect Reagent 1. The prepared siRNA reagent (25 μL per well) was added to the appropriate number of wells of a 96-well clear-bottom Greiner plate and incubated at room temperature for 30 minutes.

[0275] To seed the 96-well plates, 2000 LU99 cells were prepared per well in 100 μL of medium. The prepared cells (100 μL per well) were added to each well of the 96-well plate and incubated for 48 hours.

[0276] Compound plates were prepared with 3-fold dilutions at a compound starting concentration of 5 mM. After 48 hours of transfection incubation, the appropriate compounds were added to the 96-well plate at 3-fold dilutions (11-point dose-response curves) with a final starting concentration of 5 μM. After compound addition, the 96-well plate was incubated at 37°C for 120 hours. After this time, Cell Titer Glo reagent was reconstituted and 100 μL of reagent was added per well. The plate was tapped and luminescence was read on a Pherastar microplate reader.

[0277] For Western blot analysis, LU99 cells (5 × 10 5Cells) were seeded into plates containing siRNA and incubated for 48 hours. Cells were trypsinized and washed, and an appropriate volume of 1x Cell Signaling Technology lysis buffer supplemented with 1x protease / phosphatase inhibitors was prepared for lysis. Lysates were subjected to Western blot analysis using antibodies against FGFR1 (CST #9740S), FGFR2 (Abcam #ab109372), FGFR3 (Abcam #ab133644), FGFR4 (CST #8562S), vimentin (CST #5741S), and GAPDH (CST #5174S).

[0278] FIG. 9A shows Western blots of knockdown experiments of FGFR1, FGFR2, FGFR3, and FGFR4.

[0279] FIG. 9B shows the inhibitory effect of siRNA knockdown of FGFR1 and FGFR4 in combination with compound 3 on LU99 cell proliferation after 120 hours.

[0280] FIG. 9C shows the inhibitory effect of siRNA knockdown of FGFR1 and FGFR4 in combination with AMG510 on LU99 cell proliferation after 120 hours.

[0281] FIG. 10A shows Western blots of FGFR2 and FGFR3 knockdown experiments.

[0282] FIG. 10B shows the inhibitory effect of siRNA knockdown of FGFR1, FGFR2, and FGFR3 in combination with Compound 2 on LU99 cell proliferation after 120 hours.

[0283] FIG. 10C shows the inhibitory effect of siRNA knockdown of FGFR1, FGFR2, and FGFR3 in combination with AMG510 on LU99 cell proliferation after 120 hours.

[0284] FIG. 11A shows Western blots of FGFR1, FGFR2, FGFR3, and FGFR4 after knockdown of FGR1 to assess possible compensation of FGFR2, FGFR3, and FGFR4.

[0285] FIG. 11B shows the inhibitory effect of siRNA knockdown of FGFR1, FGFR2, FGFR3, and FGFR4 in combination with Compound 2 on LU99 cell proliferation after 120 hours.

[0286] Example M. Combination of KRAS G12C inhibition with pemigatinib overcomes resistance in MiaPaca2 KRAS G12C-resistant clones The in vitro efficacy of the KRAS G12 inhibitor AMG510 in combination with the FGFR inhibitors pemigatinib and compound 1 was evaluated in MiaPaca2 KRAS G12C-resistant clones, which were generated by culturing cells in increasing concentrations of AMG510 followed by limiting dilution. The KRAS G12C-resistant clones showed increased expression of FGFR1 and activated its signaling pathway compared to control MiaPaca2 cells (Figure 12). MiaPaca2 KRAS G12C-resistant clones showed greater synergy (Bliss score) when the KRAS G12C inhibitor was added to the FGFR1 inhibitor pemigatinib compared to compound 1 in a 5-day Cell Titer Glo assay (Table 4). Furthermore, KRAS G12C resistance rendered MiaPaca2 cells sensitive to the combination, with greater synergy (Bliss score) seen at lower pemigatinib concentrations (Table 5).

[0287] [Table 42] [Table 43-1] [Table 43-2]

[0288] In summary, the combination of a KRAS G12C inhibitor and pemigatinib was effective in overcoming resistance to KRAS G12C inhibitors.

[0289] method: For Western blot analysis, cells were seeded at 6x105 cells / well in Corning 6-well tissue culture treated plates in RPMI medium containing 10% FBS. After 48 hours, cells were harvested for Western blot (A) or treated with the indicated compounds for 90 hours at 37°C, 5% CO2. Cells were washed with PBS and lysed in 1x lysis buffer (Cell Signaling #9803) containing protease and phosphatase inhibitors. A portion of the total protein lysate (25μg) was subjected to SDS-PAGE and immunoblot analysis using antibodies from Cell Signaling Technology.

[0290] To generate G12C-resistant clones, MiaPaca2 parental cells were cultured with increasing concentrations of AMG510 (up to 1 μM) over time. Surviving cells were re-fed weekly with fresh medium containing AMG510. Once AMG510-resistant cells grew at a normal rate in the presence of 1 μM AMG510, they were cloned by limiting dilution. Eight clones were selected for passaging and further experiments.

[0291] For synergy experiments, cells were seeded at a density of 500 cells / well in RPMI medium with 10% HI FBS in Greiner white clear bottom 384-well tissue culture treated plates containing a 10x10 combination matrix of compounds. Plates were incubated at 37°C and 5% CO2 for 5 days. On day 5, Cell Titer Glo reagent was added to the plates and ATP luminescence was detected using a Pherastar FSX reader. Synergy scores for combination effects were calculated using the Bliss score model: Bliss score = Yab-(Ya+Yb-(YaYb)) x 100, where Ya and Yb are monotherapies. A Bliss score of >20 indicates strong synergy, and higher Bliss scores indicate higher levels of synergy.

[0292] FIG. 12 shows Western blot analysis of FGFR1, pERK, and B-actin in MiaPaca2 KRAS G12C resistant clones.

[0293] Example N. Combination of siRNA FGFR isoform knockdown and KRAS G12D inhibitors reduced in vitro cell proliferation of A427 cells. To further evaluate the mechanism of action of KRAS / FGFR combinations, siRNA FGFR knockdown experiments were performed in A427 cells, followed by treatment with KRAS G12D inhibitors Compound 5, Compound 6, and Compound 7. Knockdown efficiency was assessed by Western blot (Figure 13A), and the effect was measured by cell growth inhibition (Figure 13B-G). First, the effect of single FGFR isoform knockdown in combination with KRAS G12D inhibitors Compound 5 (Figure 13B), Compound 6 (Figure 13D), and Compound 7 (Figure 13F) was evaluated. The data show that the best combination effect was achieved when knocking down the FGFR1 isoform from A427 cells, which showed higher growth inhibition compared to the control and knockdown of the remaining isoforms. Furthermore, combining FGFR1 knockdown with knockdown of additional FGFR isoforms further enhanced the effect of KRAS G12D inhibitors (Figures 13C, E, and G).

[0294] In summary, knockdown of FGFR isoforms followed by the combination of a KRAS G12D inhibitor led to stronger inhibition of A427 in vitro proliferation.

[0295] method: Lyophilized siRNA pools or individual ones (Dharmacon ON-TARGET plus siRNA from Horizon Discovery) were reconstituted by combining 1x siRNA buffer (200 μL) with lyophilized siRNA (20 nmol) or by combining 1x siRNA buffer (100 μL) with lyophilized siRNA (10 nmol). Dharmafect Reagent 1 was prepared at a 1:200 dilution in 1x siRNA×. One tube of diluted reagent was prepared for each siRNA dilution. To each tube, the appropriate siRNA was added at a 1:400 dilution to Dharmafect Reagent 1. The prepared siRNA reagent (25 μL per well) was added to the appropriate number of wells of a 96-well clear-bottom Greiner plate and incubated at room temperature for 30 minutes.

[0296] To seed the 96-well plates, 2000 A427 cells were prepared per well in 100 μL of medium. The prepared cells (100 μL per well) were added to each well of the 96-well plate and incubated for 48 hours.

[0297] Compound plates were prepared with 3-fold dilutions at a compound starting concentration of 5 mM. After 48 hours of transfection incubation, the appropriate compounds were added to the 96-well plate at 3-fold dilutions (11-point dose-response curves) with a final starting concentration of 5 μM. After compound addition, the 96-well plate was incubated at 37°C for 120 hours. After this time, Cell Titer Glo reagent was reconstituted and 100 μL of reagent was added per well. The plate was tapped and luminescence was read on a Pherastar microplate reader.

[0298] For Western blot analysis, A427 cells (5 × 10 5 Cells) were seeded into plates containing siRNA and incubated for 48 hours. Cells were trypsinized and washed, and an appropriate volume of 1x Cell Signaling Technology lysis buffer supplemented with 1x protease / phosphatase inhibitors was prepared for lysis. Lysates were subjected to Western blot analysis using antibodies against FGFR1 (CST #9740S), FGFR2 (Abcam #ab109372), FGFR3 (Abcam #ab133644), FGFR4 (CST #8562S), vimentin (CST #5741S), and GAPDH (CST #5174S).

[0299] FIG. 13A shows Western blots of knockdown experiments of FGFR1, FGFR2, FGFR3, and FGFR4.

[0300] FIG. 13B shows the inhibitory effect of siRNA knockdown of single FGFR isoforms in combination with compound 5 on A427 cell proliferation after 120 hours.

[0301] FIG. 13C shows the inhibitory effect of siRNA knockdown of multiple FGFR isoforms in combination with compound 5 on A427 cell proliferation after 120 hours.

[0302] FIG. 13D shows the inhibitory effect of siRNA knockdown of single FGFR isoforms in combination with compound 6 on A427 cell proliferation after 120 hours.

[0303] FIG. 13E shows the inhibitory effect of siRNA knockdown of multiple FGFR isoforms in combination with compound 6 on A427 cell proliferation after 120 hours.

[0304] FIG. 13F shows the inhibitory effect of siRNA knockdown of single FGFR isoforms in combination with compound 7 on A427 cell proliferation after 120 hours.

[0305] FIG. 13G shows the inhibitory effect of siRNA knockdown of multiple FGFR isoforms in combination with compound 7 on A427 cell proliferation after 120 hours.

[0306] In addition to those described herein, various modifications of the present invention will become apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference, including all patents, patent applications, and publications cited in this application, is hereby incorporated by reference in its entirety.

Claims

1. (i) an FGFR1 inhibitor; (ii) a KRAS inhibitor; 1. A combination pharmaceutical for the treatment of cancer in a patient, comprising: (i) an FGFR1 inhibitor and (ii) a KRAS inhibitor, wherein the combination pharmaceutical is administered to the patient simultaneously, separately, sequentially, or in combination.

2. 2. The pharmaceutical combination of claim 1, wherein the FGFR1 inhibitor is selected from pemigatinib, futibatinib, erdafitinib, and infigratinib, and pharmaceutically acceptable salts thereof.

3. The pharmaceutical combination according to claim 1, wherein the FGFR1 inhibitor is pemigatinib or a pharmaceutically acceptable salt thereof.

4. The pharmaceutical combination according to claim 1, wherein the FGFR1 inhibitor is futibatinib or a pharmaceutically acceptable salt thereof.

5. The pharmaceutical combination according to claim 1, wherein the FGFR1 inhibitor is erdafitinib or a pharmaceutically acceptable salt thereof.

6. The pharmaceutical combination according to claim 1, wherein the FGFR1 inhibitor is infigratinib or a pharmaceutically acceptable salt thereof.

7. 2. The pharmaceutical combination of claim 1, wherein the FGFR1 inhibitor further inhibits FGFR2, FGFR3, or a combination thereof.

8. The KRAS inhibitor is a compound of formula (I): 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, Y is N or CH; R １ is Cl, CH ３ , C.H. ２ F, CHF ２ , and CF ３ Selected from: Cy １ teeth, Table 1 Selected from: R ２ is selected from F and Cl; R ３ teeth, Table 2 Selected from: Cy ２ teeth, Table 3 is selected from However, the compound of formula (I) Table 4 other than The pharmaceutical combination according to claim 1, wherein

9. The compound of formula (I) or a pharmaceutically acceptable salt thereof is 2-((2S,4S)-4-(4-(3-(dimethylamino)-3-methylazetidin-1-yl)-6-fluoro-7-(5-fluoroquinolin-8-yl)-8-(trifluoromethyl)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-((E)-4-fluorobut-2-enoyl)piperidin-2-yl)acetonitrile; 2-((2S,4S)-4-(4-(3-(dimethylamino)-3-methylazetidin-1-yl)-6-fluoro-7-(2-methoxy-3-methylphenyl)-8-(trifluoromethyl)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-((E)-4-fluorobut-2-enoyl)piperidin-2-yl)acetonitrile; 2-((2S,4S)-4-(7-(3-chloro-2-methoxyphenyl)-4-(3-(dimethylamino)-3-methylazetidin-1-yl)-6-fluoro-8-(trifluoromethyl)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-((E)-4-fluorobut-2-enoyl)piperidin-2-yl)acetonitrile; 2-((2S,4S)-4-(6-fluoro-7-(5-fluoroquinolin-8-yl)-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-8-(trifluoromethyl)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-((E)-4-fluorobut-2-enoyl)piperidin-2-yl)acetonitrile; 1-(4-(6-fluoro-7-(5-fluoroquinolin-8-yl)-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-8-(trifluoromethyl)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)piperidin-1-yl)prop-2-en-1-one; 2-((2S,4S)-4-(4-(3-(dimethylamino)-3-methylazetidin-1-yl)-7-(2,3-dimethylphenyl)-6-fluoro-8-methyl-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-((E)-4-methoxybut-2-enoyl)piperidin-2-yl)acetonitrile; 2-((2S,4S)-4-(6-fluoro-8-methyl-7-(1-methyl-1H-indazol-6-yl)-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-((E)-4-fluorobut-2-enoyl)piperidin-2-yl)acetonitrile; 2-((2S,4S)-4-(6-fluoro-8-methyl-7-(6-methylpyridin-3-yl)-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-((E)-4-fluorobut-2-enoyl)piperidin-2-yl)acetonitrile; 2-((2S,4S)-4-(6-fluoro-8-methyl-7-(1-methyl-1H-indazol-3-yl)-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-((E)-4-methoxybut-2-enoyl)piperidin-2-yl)acetonitrile; 2-((2S,4S)-4-(6-fluoro-7-(4-fluorophenyl)-8-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-((E)-4-methoxybut-2-enoyl)piperidin-2-yl)acetonitrile; 8-(1-(1-acryloylpiperidin-4-yl)-6-fluoro-8-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-[1,2,3]triazolo[4,5-c]quinolin-7-yl)-1-naphthonitrile; 2-((2S,4S)-4-(7-(2-chloro-3-methylphenyl)-4-(3-(dimethylamino)-3-methylazetidin-1-yl)-6-fluoro-8-methyl-1H-imidazo[4,5-c]quinolin-1-yl)-1-((E)-4-fluorobut-2-enoyl)piperidin-2-yl)acetonitrile; 2-((2S,4S)-4-(7-(2-chloro-3-methylphenyl)-6-fluoro-8-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-imidazo[4,5-c]quinolin-1-yl)-1-(2-fluoroacryloyl)piperidin-2-yl)acetonitrile; 8-(1-((2R,4S)-1-acryloyl-2-methylpiperidin-4-yl)-6-fluoro-8-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-[1,2,3]triazolo[4,5-c]quinolin-7-yl)-1-naphthonitrile; 2-((2S,4S)-4-(7-(5,6-dimethyl-1H-indazol-4-yl)-4-(3-(ethyl(methyl)amino)azetidin-1-yl)-6-fluoro-8-methyl-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-(2-fluoroacryloyl)piperidin-2-yl)acetonitrile; 8-(6-fluoro-1-(1-((E)-4-fluorobut-2-enoyl)piperidin-4-yl)-8-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-[1,2,3]triazolo[4,5-c]quinolin-7-yl)-1-naphthonitrile; 8-(1-((2S,4S)-2-(cyanomethyl)-1-(2-fluoroacryloyl)piperidin-4-yl)-4-(3-(dimethylamino)-3-methylazetidin-1-yl)-6-fluoro-8-methyl-1H-[1,2,3]triazolo[4,5-c]quinolin-7-yl)-1-naphthonitrile; 2-((2S,4S)-4-(6,8-dichloro-4-(3-(dimethylamino)-3-methylazetidin-1-yl)-7-(5-fluoroquinolin-8-yl)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-((E)-4-methoxybut-2-enoyl)piperidin-2-yl)acetonitrile; 2-((2S,4S)-4-(6,8-dichloro-4-(3-(dimethylamino)-3-methylazetidin-1-yl)-7-(5-fluoroquinolin-8-yl)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-((E)-4-fluorobut-2-enoyl)piperidin-2-yl)acetonitrile; and 2-((2S,4S)-4-(4-(3-(dimethylamino)-3-methylazetidin-1-yl)-6-fluoro-7-(5-fluoroquinolin-8-yl)-8-(trifluoromethyl)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-((E)-4-methoxybut-2-enoyl)piperidin-2-yl)acetonitrile; 9. The pharmaceutical combination according to claim 8, which is selected from:

10. The KRAS inhibitor is a compound of formula (II): 【Chemistry 2】 or a pharmaceutically acceptable salt thereof, R １ is Cl, CH ３ , C.H. ２ F, CHF ２ , and CF ３ Selected from: Cy １ teeth, Table 5 R ２ is selected from F and Cl; R ３ teeth, Table 6 Selected from: Cy ２ teeth, Table 7 is selected from However, the compound of formula (II) Table 8 The pharmaceutical combination according to claim 1, wherein

11. The compound of formula (II) or a pharmaceutically acceptable salt thereof is 1-(1-((2S,4S)-1-(but-2-ynoyl)-2-(cyanomethyl)piperidin-4-yl)-8-chloro-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrazolo[4,3-c]quinolin-7-yl)isoquinoline-8-carbonitrile; 1-(8-chloro-1-((2S,4S)-2-(cyanomethyl)-1-((E)-4-methoxybut-2-enoyl)piperidin-4-yl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrazolo[4,3-c]quinolin-7-yl)isoquinoline-8-carbonitrile; 1-(8-chloro-1-((2S,4S)-2-(cyanomethyl)-1-(2-fluoroacryloyl)piperidin-4-yl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrazolo[4,3-c]quinolin-7-yl)isoquinoline-8-carbonitrile; 2-((2S,4S)-4-(8-chloro-7-(5,6-dimethyl-1H-indazol-4-yl)-4-(3-(ethyl(methyl)amino)azetidin-1-yl)-6-fluoro-1H-pyrazolo[4,3-c]quinolin-1-yl)-1-(2-fluoroacryloyl)piperidin-2-yl)acetonitrile; 8-(8-chloro-1-((2S,4S)-2-(cyanomethyl)-1-(2-fluoroacryloyl)piperidin-4-yl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrazolo[4,3-c]quinolin-7-yl)-1-naphthonitrile; 8-(8-chloro-1-((2S,4S)-2-(cyanomethyl)-1-((E)-4-methoxybut-2-enoyl)piperidin-4-yl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrazolo[4,3-c]quinolin-7-yl)-1-naphthonitrile; and 8-(1-((2S,4S)-1-(but-2-ynoyl)-2-(cyanomethyl)piperidin-4-yl)-6-fluoro-8-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrazolo[4,3-c]quinolin-7-yl)-1-naphthonitrile; 11. The pharmaceutical combination according to claim 10, selected from:

12. The KRAS inhibitor is a compound of formula (III): 【Transformation 3】 or a pharmaceutically acceptable salt thereof, Y is N or CR ６ and R １ is H, C １－３ Alkyl, C １－３ Haloalkyl, cyclopropyl, halo, D, CN, and OR ａ１ C １－３ Alkyl and cyclopropyl are each optionally represented by R ｇ and is substituted by one or two substituents independently selected from: R ２ is H, C １－３ Alkyl, C １－３ haloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, 4- to 6-membered heterocycloalkyl-C １－３ Alkylene, phenyl-C １－３ Alkylene, 5-6 membered heteroaryl-C １－３ Alkylene, halo, D, CN, and OR ａ２ C １－３ alkyl, 4- to 6-membered heterocycloalkylphenyl, 5- to 6-membered heteroaryl, 4- to 6-membered heterocycloalkyl-C １－３ Alkylene, phenyl-C １－３ Alkylene, 5-6 membered heteroaryl-C １－３ Each alkylene is optionally ｇ and is substituted by one or two substituents independently selected from: Cy １ is C ３－１０ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl, and 6- to 10-membered heteroaryl; the 4- to 10-membered heterocycloalkyl and the 6- to 10-membered heteroaryl each have at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S; the ring-forming carbon atoms of the 6- to 10-membered heteroaryl and the 4- to 10-membered heterocycloalkyl are optionally substituted by oxo to form a carbonyl group; C ３－１０ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ The aryl and 6- to 10-membered heteroaryl are each optionally represented by R １０ substituted with 1, 2, 3, or 4 substituents independently selected from R ３ is H, C １－３ Alkyl, C １－３ Haloalkyl, C ３－６ cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, C ３～６ Cycloalkyl-C １－３ Alkylene, 4- to 6-membered heterocycloalkyl-C １～３ Alkylene, phenyl-C １－３ Alkylene, 5-6 membered heteroaryl-C １－３ Alkylene, Halo, D, CN, OR ｆ３ , C(O)NR ｃ３ R ｄ３ , N.R. ｃ３ R ｊ３ , and N.R. ｃ３ C(O)R ｂ３ C １－３ Alkyl, C ３－６ cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, C ３－６ Cycloalkyl-C １－３ Alkylene, 4- to 6-membered heterocycloalkyl-C １－３ Alkylene, phenyl-C １－３ Alkylene, and 5- to 6-membered heteroaryl-C １－３ Each alkylene is optionally ３０ substituted by 1, 2, or 3 substituents independently selected from R ５ is H, C １－３ Alkyl, C １－３ Haloalkyl, cyclopropyl, halo, D, CN, and OR ａ５ C １－３ Alkyl and cyclopropyl are each optionally represented by R ｇ and is substituted by one or two substituents independently selected from: R ６ is H, C １－３ Alkyl, C １－３ Haloalkyl, C ３－６ cycloalkyl, 4- to 9-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, C ３～６ Cycloalkyl-C １－３ Alkylene, 4- to 6-membered heterocycloalkyl-C １～３ Alkylene, phenyl-C １－３ Alkylene, 5-6 membered heteroaryl-C １－３ Alkylene, Halo, D, CN, OR ａ６ , and C(O)NR ｃ６ R ｄ６ C is selected from １－３ Alkyl, C ３－６ cycloalkyl, 4- to 9-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, C ３－６ Cycloalkyl-C １－３ Alkylene, 4- to 6-membered heterocycloalkyl-C １－３ Alkylene, phenyl-C １－３ Alkylene, and 5- to 6-membered heteroaryl-C １－３ Each alkylene is optionally ６０ and is substituted by one or two substituents independently selected from: R ７ is H, C １－３ Alkyl, C １－３ Haloalkyl, cyclopropyl, halo, D, CN, and OR ａ７ C １－３ Alkyl and cyclopropyl are each optionally represented by R ｇ and is substituted by one or two substituents independently selected from: Cy ２ teeth, Table 9 (n is 0, 1, or 2); Each R １０ is C １－３ Alkyl, C １－３ Haloalkyl, Halo, D, CN, OR ａ１０ , C(O)R ｂ１０ , C(O)NR ｃ１０ R ｄ１０ , C(O)OR ａ１０ , N.R. ｃ１０ R ｄ１０ , and S(O) ２ R ｂ１０ are independently selected from Each R ２０ is independent, C １－３ Alkyl, C １－３ Haloalkyl, halo, D, CN, and OR ａ２０ Selected from: Each R ３０ is independent, C １－３ Alkyl, C １－３ Haloalkyl, C ３－６ cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, halo, D, CN, OR ａ３０ , C(O)R ｂ３０ , C(O)NR ｃ３０ R ｄ３０ , C(O)OR ａ３０ , N.R. ｃ３０ R ｄ３０ , and S(O) ２ R ｂ３０ C １－３ Alkyl, C ３－６ Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl are each optionally selected from R ３１ and is substituted by one or two substituents independently selected from: Each R ３１ is C １－３ Alkyl, C １－３ Haloalkyl, Halo, D, CN, OR ａ３１ , C(O)R ｂ３１ , C(O)NR ｃ３１ R ｄ３１ , C(O)OR ａ３１ , N.R. ｃ３１ R ｄ３１ , and S(O) ２ R ｂ３１ are independently selected from Each R ３３ is independently C １－３ Alkyl, C １－３ Haloalkyl, C ３－６ Cycloalkyl, 4-membered heterocycloalkyl, 6-membered heterocycloalkyl, phenyl, 5-6-membered heteroaryl, halo, D, CN, OR ａ３０ , C(O)NR ｃ３０ R ｄ３０ , and N.R. ｃ３０ R ｄ３０ C １－３ Alkyl, C ３－６ Cycloalkyl, 4-membered heterocycloalkyl, 6-membered heterocycloalkyl, phenyl, and 5-6-membered heteroaryl are each optionally selected from R ３１ and is substituted by one or two substituents independently selected from: Each R ６０ is independent, C １－３ Alkyl, C １－３ haloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl, halo, D, CN, OR ａ６０ , C(O)R ｂ６０ , C(O)NR ｃ６０ R ｄ６０ , N.R. ｃ６０ C(O)R ｂ６０ , C(O)OR ａ６０ , N.R. ｃ６０ C(O)OR ａ６０ , N.R. ｃ６０ R ｄ６０ , N.R. ｃ６０ S (O) ２ R ｂ６０ , and S(O) ２ R ｂ６０ C １－３ Alkyl, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl are each optionally represented by R ６１ and is substituted by one or two substituents independently selected from: Each R ６１ is independent, C １－３ Alkyl, C １－３ Haloalkyl, Halo, D, CN, OR ａ６１ , and N.R. ｃ６１ R ｄ６１ Selected from: R ａ１ is H, C １－３ Alkyl, and C １－３ haloalkyl; Each R ａ２ is H, C １－３ Alkyl, and C １－３ haloalkyl; Each R ｂ３ , R ｃ３ , and R ｄ３ are independently H, C １－３ Alkyl, C １－３ Haloalkyl, C ３－６ cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl; １－３ Alkyl, C ３－６ Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl are each optionally selected from R ３０ or substituted by 1, 2, or 3 substituents independently selected from or R bonded to the same N atom ｃ３ and R ｄ３ and together with the N atom to which they are attached, optionally R ３０ forming a 4-, 5-, or 6-membered heterocycloalkyl group substituted with 1, 2, or 3 substituents independently selected from: R ｊ３ is C １－３ Alkyl, C １－３ Haloalkyl, C ３－６ cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl; １－３ Alkyl, C ３－６ Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl are each optionally selected from R ３０ or substituted by 1, 2, or 3 substituents independently selected from or R bonded to the same N atom ｃ３ and R ｊ３ and together with the N atom to which they are attached, optionally R ３０ forming a 4-, 5-, or 6-membered heterocycloalkyl group substituted with 1, 2, or 3 substituents independently selected from: R ｆ３ is C １－３ Haloalkyl, C ３－６ cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl; １－３ Haloalkyl, C ３－６ Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl are each optionally selected from R ３０ or is substituted by one, two, or three substituents independently selected from R ｆ３ teeth, Table 10 (R ｘ is H or C １－２ alkyl, and R ｙ is C １－２ Is alkyl; or R ｘ and R ｙ are selected from: R ａ５ is H, C １－３ Alkyl, and C １－３ haloalkyl; Each R ａ６ , R ｃ６ , and R ｄ６ are independently H, C １－３ Alkyl, C １－３ Haloalkyl, C ３－６ cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl; １－３ Alkyl, C ３－６ Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl are each optionally selected from R ６０ and is substituted by one or two substituents independently selected from: R ａ７ is H, C １－３ Alkyl, and C １－３ haloalkyl; Each R ａ１０ , R ｂ１０ , R ｃ１０ , and R ｄ１０ is H, C １－３ Alkyl, and C １－３ independently selected from haloalkyl; Each R ａ２０ is H, C １－３ Alkyl, and C １－３ haloalkyl; R ｂ２０ is NH ２ , C １－３ Alkyl, and C １－３ haloalkyl; Each R ａ３０ , R ｂ３０ , R ｃ３０ , and R ｄ３０ is H, C １－３ Alkyl, and C １－３ independently selected from haloalkyl; Each R ａ３１ , R ｂ３１ , R ｃ３１ , and R ｄ３１ is H, C １－３ Alkyl, and C １－３ independently selected from haloalkyl; Each R ａ６０ , R ｂ６０ , R ｃ６０ , and R ｄ６０ are independently H, C １－３ Alkyl, C １－３ Haloalkyl, C ３－６ cycloalkyl, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl; １－３ Alkyl, C ３－６ Cycloalkyl, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl are each optionally represented by R ６１ or is substituted by one or two substituents independently selected from: or any R bonded to the same N atom ｃ６０ and R ｄ６０ together with the N atom to which they are attached, optionally R ６１ forming a 4-, 5-, or 6-membered heterocycloalkyl group substituted with 1 or 2 substituents independently selected from: Each R ａ６１ , R ｃ６１ , and R ｄ６１ is H, C １－３ Alkyl, and C １－３ independently selected from haloalkyl; Each R ｇ are independently D, OH, CN, halo, C １－３ Alkyl, C １－３ Haloalkyl, C １－３ Alkoxy, C １－３ Haloalkoxy, Amino, C １－３ Alkylamino, and di(C １－３ alkyl)amino; However, the compound of formula (III) other than 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-4-ethoxy-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-1H-pyrrolo[3,2-c]quinolin-2-yl)-N,N-dimethylpropanamide), The pharmaceutical combination of claim 1.

13. The KRAS inhibitor is 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(7-chloro-3-hydroxynaphthalen-1-yl)-6-fluoro-2-methyl-4-(1H-1,2,4-triazol-1-yl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(5,7-difluoro-1H-indol-3-yl)-6-fluoro-2-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-7-(6-fluoro-5-methyl-1H-indol-3-yl)-2-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile; 3-(2-(3-(azetidin-1-yl)-3-oxopropyl)-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile; 3-((1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-8-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-2-yl)methyl)oxazolidin-2-one; 8-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-2,8-dimethyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-7-yl)-1-naphthonitrile; 1-((2S,4S)-1-acetyl-2-(cyanomethyl)piperidin-4-yl)-7-(8-cyanonaphthalen-1-yl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrazolo[4,3-c]quinoline-8-carbonitrile; 8-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-8-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-2-((3-oxomorpholino)methyl)-1H-pyrrolo[3,2-c]quinolin-7-yl)-1-naphthonitrile; 3-(7-(benzo[b]thiophen-3-yl)-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-2-((2-oxopyrrolidin-1-yl)methyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-4-(((S)-1-(dimethylamino)propan-2-yl)oxy)-6-fluoro-7-(7-fluoronaphthalen-1-yl)-2-((2-oxopyrrolidin-1-yl)methyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile; 8-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-6-fluoro-2-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-7-yl)-1-naphthonitrile; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(2,3-dichloro-5-hydroxyphenyl)-6-fluoro-2-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-6-fluoro-4-((3-fluoro-1-methylazetidin-3-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)-1H-pyrrolo[3,2-c]quinolin-2-yl)-N,N-dimethylpropanamide; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-2-methyl-4-(5-methylpyrazin-2-yl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-7-(7-fluoronaphthalen-1-yl)-4-methyl-2-((4-methyl-2-oxopiperazin-1-yl)methyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(2,3-dichloro-5-hydroxyphenyl)-4-ethoxy-6-fluoro-2-((4-isopropyl-2-oxopiperazin-1-yl)methyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-4-(3-(dimethylamino)-3-methylazetidin-1-yl)-6-fluoro-7-(7-fluoronaphthalen-1-yl)-2-((3-oxomorpholino)methyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-4-ethoxy-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-2-(1-(3-oxomorpholino)ethyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile; 3-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-2-(pyridin-3-yl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile; 3-(2-(3-(azetidin-1-yl)-3-oxopropyl)-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(7,8-difluoronaphthalen-1-yl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile; 3-(2-(3-(azetidin-1-yl)-3-oxopropyl)-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(6,7-difluoronaphthalen-1-yl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-7-(7-fluoro-3-hydroxynaphthalen-1-yl)-2-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile; 1-(1-((2S,4S)-1-acetyl-2-(cyanomethyl)piperidin-4-yl)-8-chloro-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrazolo[4,3-c]quinolin-7-yl)isoquinoline-8-carbonitrile; 8-(1-((2S,4S)-1-acetyl-2-(cyanomethyl)piperidin-4-yl)-8-chloro-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-7-yl)-1-naphthonitrile; 8-(1-((2S,4S)-1-acetyl-2-(cyanomethyl)piperidin-4-yl)-8-chloro-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrazolo[4,3-c]quinolin-7-yl)-1-naphthonitrile; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-7-(7-fluoro-3-hydroxynaphthalen-1-yl)-2-methyl-4-(1H-1,2,4-triazol-1-yl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-7-(7-fluoronaphthalen-1-yl)-2-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile; (2R)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(1H-1,2,4-triazol-1-yl)-1H-pyrrolo[3,2-c]quinolin-2-yl)-N,N-dimethylpyrrolidine-1-carboxamide; Methyl (2R)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(2-chloro-3-methylphenyl)-8-(2-cyanoethyl)-6-fluoro-4-(1H-1,2,4-triazol-1-yl)-1H-pyrrolo[3,2-c]quinolin-2-yl)pyrrolidine-1-carboxylate; Methyl (1S,3R,5S)-3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-4-(6-(dimethylcarbamoyl)pyridin-3-yl)-6-fluoro-1H-pyrrolo[3,2-c]quinolin-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-2-(5-oxo-1,2,3,5-tetrahydroindolizin-3-yl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile; Methyl (2R)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-4-(6-(dimethylcarbamoyl)pyridin-3-yl)-6-fluoro-1H-pyrrolo[3,2-c]quinolin-2-yl)pyrrolidine-1-carboxylate; Methyl (2R)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(6-(methylcarbamoyl)pyridin-3-yl)-1H-pyrrolo[3,2-c]quinolin-2-yl)pyrrolidine-1-carboxylate; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(2-chloro-3-fluorophenyl)-2-((R)-1-(cyclopropanecarbonyl)pyrrolidin-2-yl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile; 8-(2-((R)-1-acetylpyrrolidin-2-yl)-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-8-methyl-4-(2-methylpyridin-4-yl)-1H-pyrrolo[3,2-c]quinolin-7-yl)-1,2,3,4-tetrahydronaphthalene-1-carbonitrile; 5-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(3-chloro-2-methylphenyl)-8-(2-cyanoethyl)-6-fluoro-2-((R)-1-(2-oxopyrazin-1(2H)-yl)ethyl)-1H-pyrrolo[3,2-c]quinolin-4-yl)-N-methylpicolinamide; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-7-(7-fluoronaphthalen-1-yl)-4-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-2-((R)-1-(2-oxopyrazin-1(2H)-yl)ethyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(3-chloro-2-methylphenyl)-6-fluoro-4-(5-methylpyrazin-2-yl)-2-((R)-1-(2-oxopyrazin-1(2H)-yl)ethyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile; Methyl (2R)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(5-fluoro-6-(methylcarbamoyl)pyridin-3-yl)-1H-pyrrolo[3,2-c]quinolin-2-yl)pyrrolidine-1-carboxylate; Methyl (2R)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1H-pyrrolo[3,2-c]quinolin-2-yl)pyrrolidine-1-carboxylate; Ethyl (2R)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1H-pyrrolo[3,2-c]quinolin-2-yl)pyrrolidine-1-carboxylate; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(2,3-dichlorophenyl)-2-((R)-1-(3,3-difluoroazetidine-1-carbonyl)pyrrolidin-2-yl)-6-fluoro-4-(methyl-d3)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(2,3-dichlorophenyl)-2-((R)-1-(3,3-difluoroazetidine-1-carbonyl)pyrrolidin-2-yl)-6-fluoro-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(3-chloro-2-methylphenyl)-6-fluoro-4-(5-methylpyrazin-2-yl)-2-((R)-1-(3-oxomorpholino)ethyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile; 5-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-6-fluoro-7-(7-fluoronaphthalen-1-yl)-2-((R)-1-(3-oxomorpholino)ethyl)-1H-pyrrolo[3,2-c]quinolin-4-yl)-N-methylpicolinamide; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-7-(7-fluoronaphthalen-1-yl)-4-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-2-((R)-1-(3-oxomorpholino)ethyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-7-(7-fluoronaphthalen-1-yl)-4-(5-methylpyrazin-2-yl)-2-((R)-1-(3-oxomorpholino)ethyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile; Methyl (1R,3R,5R)-3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-4-(6-(dimethylcarbamoyl)pyridin-3-yl)-6-fluoro-1H-pyrrolo[3,2-c]quinolin-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-2-((R)-1-(2-oxopyrazin-1(2H)-yl)ethyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile; Methyl (2R,4S)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1H-pyrrolo[3,2-c]quinolin-2-yl)-4-fluoripyrrolidine-1-carboxylate; Methyl (2R,5R)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1H-pyrrolo[3,2-c]quinolin-2-yl)-5-methylpyrrolidine-1-carboxylate; Methyl (2R)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-3-chloro-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1H-pyrrolo[3,2-c]quinolin-2-yl)pyrrolidine-1-carboxylate; 4-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((R)-1-(2-oxopyrazin-1(2H)-yl)ethyl)-1H-pyrrolo[3,2-c]quinolin-4-yl)-2-fluoro-N-methylbenzamide; Methyl ((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-2-yl)ethyl)carbamate; N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-2-yl)ethyl)-2,2-difluoroacetamide; N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-2-yl)ethyl)-2,2-difluoroacetamide; (2S)—N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-2-yl)ethyl)tetrahydrofuran-2-carboxamide; N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-2-yl)ethyl)cyclopropanesulfonamide; N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-2-yl)ethyl)thiazole-4-carboxamide; N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-2-yl)ethyl)-N-methylcyclopropanecarboxamide; N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(1-hydroxyethyl)-1H-pyrrolo[3,2-c]quinolin-2-yl)ethyl)-1-methylcyclopropane-1-carboxamide; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(1-hydroxyethyl)-2-((1R,3R,5R)-2-(1-methylcyclopropane-1-carbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((1R,3R,5R)-2-(1-fluorocyclopropane-1-carbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-4-(1-hydroxyethyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((1R,3R,5R)-2-(1-fluorocyclopropane-1-carbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-4-methyl-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile; N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(1-hydroxyethyl)-1H-pyrrolo[3,2-c]quinolin-2-yl)ethyl)-1-fluorocyclopropane-1-carboxamide; N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(1-hydroxyethyl)-1H-pyrrolo[3,2-c]quinolin-2-yl)ethyl)-1-fluorocyclobutane-1-carboxamide; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(3-chloro-2-methylphenyl)-2-(1-(2,6-dimethyl-3-oxo-2,3-dihydropyridazin-4-yl)ethyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile; N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-2-yl)ethyl)pyrimidine-4-carboxamide; N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-2-yl)ethyl)pyridazine-3-carboxamide; N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-2-yl)ethyl)-3,3-difluoroazetidine-1-carboxamide; 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-2-((R)-1-((1-methyl-1H-pyrazol-4-yl)amino)ethyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile; 5-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((R)-1-(1-fluorocyclopropane-1-carbonyl)pyrrolidin-2-yl)-1H-pyrrolo[3,2-c]quinolin-4-yl)-N,N-dimethylpicolinamide; and methyl (2R)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-4-(4-((dimethylamino)methyl)-2,3-difluorophenyl)-6-fluoro-1H-pyrrolo[3,2-c]quinolin-2-yl)pyrrolidine-1-carboxylate, 13. The pharmaceutical combination according to claim 12, selected from:

14. The KRAS inhibitor is selected from the group consisting of sotrasib, adagrasib, and compound 2: 【Chemistry 4】 Compound 3: 【Transformation 5】 and Compound 4: 【Transformation 6】 2. The pharmaceutical combination according to claim 1, selected from:

15. The KRAS inhibitor is sotorasib, compound 2: 【Transformation 7】 Compound 3: 【Transformation 8】 and Compound 4: 【Chemistry 9】 2. The pharmaceutical combination according to claim 1, selected from:

16. The KRAS inhibitor is compound 5: 【Chemistry 10】 Compound 6: 【Chemistry 11】 and Compound 7: 【Chemistry 12】 2. The pharmaceutical combination according to claim 1, selected from:

17. The pharmaceutical combination of claim 1, wherein the KRAS inhibitor is sotorasib or a pharmaceutically acceptable salt thereof.

18. 2. The pharmaceutical combination of claim 1, wherein the KRAS inhibitor is adagrasib or a pharmaceutically acceptable salt thereof.

19. The KRAS inhibitor is Compound 2: 【Chemistry 13】 2. The pharmaceutical combination of claim 1, which is:

20. The KRAS inhibitor is compound 3: 【Chemistry 14】 2. The pharmaceutical combination of claim 1, which is:

21. The KRAS inhibitor is compound 4: 【Chemistry 15】 2. The pharmaceutical combination of claim 1, which is:

22. The pharmaceutical combination of claim 1 , wherein the KRAS inhibitor is a KRAS G12C inhibitor.

23. The pharmaceutical combination of claim 1, wherein the KRAS inhibitor is a KRAS G12D inhibitor.

24. (i) pemigatinib or a pharmaceutically acceptable salt thereof; (ii) a KRAS inhibitor; 1. A pharmaceutical combination for the treatment of cancer in a patient, comprising: said patient is administered (i) pemigatinib or a pharmaceutically acceptable salt thereof and (ii) a KRAS inhibitor simultaneously, separately, sequentially, or in combination; KRAS inhibitors include compounds of formula (I): 【Chemistry 16】 or a pharmaceutically acceptable salt thereof, Y is N or CH; R １ is Cl, CH ３ , C.H. ２ F, CHF ２ , and CF ３ Selected from: Cy １ teeth, Table 11 Selected from: R ２ is selected from F and Cl; R ３ teeth, Table 12 Selected from: Cy ２ teeth, Table 13 is selected from However, the compound of formula (I) Table 14 other than The combination drug,

25. The compound of formula (I) or a pharmaceutically acceptable salt thereof is 2-((2S,4S)-4-(4-(3-(dimethylamino)-3-methylazetidin-1-yl)-6-fluoro-7-(5-fluoroquinolin-8-yl)-8-(trifluoromethyl)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-((E)-4-fluorobut-2-enoyl)piperidin-2-yl)acetonitrile; 2-((2S,4S)-4-(4-(3-(dimethylamino)-3-methylazetidin-1-yl)-6-fluoro-7-(2-methoxy-3-methylphenyl)-8-(trifluoromethyl)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-((E)-4-fluorobut-2-enoyl)piperidin-2-yl)acetonitrile; 2-((2S,4S)-4-(7-(3-chloro-2-methoxyphenyl)-4-(3-(dimethylamino)-3-methylazetidin-1-yl)-6-fluoro-8-(trifluoromethyl)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-((E)-4-fluorobut-2-enoyl)piperidin-2-yl)acetonitrile; 2-((2S,4S)-4-(6-fluoro-7-(5-fluoroquinolin-8-yl)-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-8-(trifluoromethyl)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-((E)-4-fluorobut-2-enoyl)piperidin-2-yl)acetonitrile; 1-(4-(6-fluoro-7-(5-fluoroquinolin-8-yl)-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-8-(trifluoromethyl)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)piperidin-1-yl)prop-2-en-1-one; 2-((2S,4S)-4-(4-(3-(dimethylamino)-3-methylazetidin-1-yl)-7-(2,3-dimethylphenyl)-6-fluoro-8-methyl-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-((E)-4-methoxybut-2-enoyl)piperidin-2-yl)acetonitrile; 2-((2S,4S)-4-(6-fluoro-8-methyl-7-(1-methyl-1H-indazol-6-yl)-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-((E)-4-fluorobut-2-enoyl)piperidin-2-yl)acetonitrile; 2-((2S,4S)-4-(6-fluoro-8-methyl-7-(6-methylpyridin-3-yl)-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-((E)-4-fluorobut-2-enoyl)piperidin-2-yl)acetonitrile; 2-((2S,4S)-4-(6-fluoro-8-methyl-7-(1-methyl-1H-indazol-3-yl)-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-((E)-4-methoxybut-2-enoyl)piperidin-2-yl)acetonitrile; 2-((2S,4S)-4-(6-fluoro-7-(4-fluorophenyl)-8-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-((E)-4-methoxybut-2-enoyl)piperidin-2-yl)acetonitrile; 8-(1-(1-acryloylpiperidin-4-yl)-6-fluoro-8-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-[1,2,3]triazolo[4,5-c]quinolin-7-yl)-1-naphthonitrile; 2-((2S,4S)-4-(7-(2-chloro-3-methylphenyl)-4-(3-(dimethylamino)-3-methylazetidin-1-yl)-6-fluoro-8-methyl-1H-imidazo[4,5-c]quinolin-1-yl)-1-((E)-4-fluorobut-2-enoyl)piperidin-2-yl)acetonitrile; 2-((2S,4S)-4-(7-(2-chloro-3-methylphenyl)-6-fluoro-8-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-imidazo[4,5-c]quinolin-1-yl)-1-(2-fluoroacryloyl)piperidin-2-yl)acetonitrile; 8-(1-((2R,4S)-1-acryloyl-2-methylpiperidin-4-yl)-6-fluoro-8-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-[1,2,3]triazolo[4,5-c]quinolin-7-yl)-1-naphthonitrile; 2-((2S,4S)-4-(7-(5,6-dimethyl-1H-indazol-4-yl)-4-(3-(ethyl(methyl)amino)azetidin-1-yl)-6-fluoro-8-methyl-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-(2-fluoroacryloyl)piperidin-2-yl)acetonitrile; 8-(6-fluoro-1-(1-((E)-4-fluorobut-2-enoyl)piperidin-4-yl)-8-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-[1,2,3]triazolo[4,5-c]quinolin-7-yl)-1-naphthonitrile; 8-(1-((2S,4S)-2-(cyanomethyl)-1-(2-fluoroacryloyl)piperidin-4-yl)-4-(3-(dimethylamino)-3-methylazetidin-1-yl)-6-fluoro-8-methyl-1H-[1,2,3]triazolo[4,5-c]quinolin-7-yl)-1-naphthonitrile; 2-((2S,4S)-4-(6,8-dichloro-4-(3-(dimethylamino)-3-methylazetidin-1-yl)-7-(5-fluoroquinolin-8-yl)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-((E)-4-methoxybut-2-enoyl)piperidin-2-yl)acetonitrile; 2-((2S,4S)-4-(6,8-dichloro-4-(3-(dimethylamino)-3-methylazetidin-1-yl)-7-(5-fluoroquinolin-8-yl)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-((E)-4-fluorobut-2-enoyl)piperidin-2-yl)acetonitrile; and 2-((2S,4S)-4-(4-(3-(dimethylamino)-3-methylazetidin-1-yl)-6-fluoro-7-(5-fluoroquinolin-8-yl)-8-(trifluoromethyl)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-((E)-4-methoxybut-2-enoyl)piperidin-2-yl)acetonitrile; 25. The pharmaceutical combination according to claim 24, selected from:

26. (i) pemigatinib or a pharmaceutically acceptable salt thereof; (ii) a KRAS inhibitor; 1. A pharmaceutical combination for the treatment of cancer in a patient, comprising: said patient is administered (i) pemigatinib or a pharmaceutically acceptable salt thereof and (ii) a KRAS inhibitor simultaneously, separately, sequentially, or in combination; The KRAS inhibitor is a compound of formula (II): 【Chemistry 17】 or a pharmaceutically acceptable salt thereof, R １ is Cl, CH ３ , C.H. ２ F, CHF ２ , and CF ３ Selected from: Cy １ teeth, Table 15 Selected from: R ２ is selected from F and Cl; R ３ teeth, Table 16 Selected from: Cy ２ teeth, Table 17 is selected from However, the compound of formula (II) Table 18 The combination drug, wherein the compound is other than

27. The compound of formula (II) or a pharmaceutically acceptable salt thereof is 1-(1-((2S,4S)-1-(but-2-ynoyl)-2-(cyanomethyl)piperidin-4-yl)-8-chloro-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrazolo[4,3-c]quinolin-7-yl)isoquinoline-8-carbonitrile; 1-(8-chloro-1-((2S,4S)-2-(cyanomethyl)-1-((E)-4-methoxybut-2-enoyl)piperidin-4-yl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrazolo[4,3-c]quinolin-7-yl)isoquinoline-8-carbonitrile; 1-(8-chloro-1-((2S,4S)-2-(cyanomethyl)-1-(2-fluoroacryloyl)piperidin-4-yl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrazolo[4,3-c]quinolin-7-yl)isoquinoline-8-carbonitrile; 2-((2S,4S)-4-(8-chloro-7-(5,6-dimethyl-1H-indazol-4-yl)-4-(3-(ethyl(methyl)amino)azetidin-1-yl)-6-fluoro-1H-pyrazolo[4,3-c]quinolin-1-yl)-1-(2-fluoroacryloyl)piperidin-2-yl)acetonitrile; 8-(8-chloro-1-((2S,4S)-2-(cyanomethyl)-1-(2-fluoroacryloyl)piperidin-4-yl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrazolo[4,3-c]quinolin-7-yl)-1-naphthonitrile; 8-(8-chloro-1-((2S,4S)-2-(cyanomethyl)-1-((E)-4-methoxybut-2-enoyl)piperidin-4-yl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrazolo[4,3-c]quinolin-7-yl)-1-naphthonitrile; and 8-(1-((2S,4S)-1-(but-2-ynoyl)-2-(cyanomethyl)piperidin-4-yl)-6-fluoro-8-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrazolo[4,3-c]quinolin-7-yl)-1-naphthonitrile; 27. The pharmaceutical combination of claim 26, selected from:

28. (i) an FGFR1 inhibitor selected from pemigatinib, futibatinib, erdafitinib, and infigratinib, and pharmaceutically acceptable salts thereof; (ii) sotorasib, adagrasib, compound 2: [Chemistry 18] Compound 3: 【Chemistry 19】 and Compound 4: 【Chemistry 20】 and a KRAS inhibitor selected from the group consisting of:

1. A pharmaceutical combination for the treatment of cancer in a patient, comprising: (i) an FGFR1 inhibitor and (ii) a KRAS inhibitor, administered to said patient simultaneously, separately, sequentially, or in combination.

29. 29. The pharmaceutical combination of claim 28, wherein the FGFR1 inhibitor is pemigatinib or a pharmaceutically acceptable salt thereof.

30. The pharmaceutical combination of claim 28, wherein the FGFR1 inhibitor is futibatinib or a pharmaceutically acceptable salt thereof.

31. 29. The pharmaceutical combination of claim 28, wherein the FGFR1 inhibitor is erdafitinib or a pharmaceutically acceptable salt thereof.

32. 29. The pharmaceutical combination of claim 28, wherein the FGFR1 inhibitor is infigratinib or a pharmaceutically acceptable salt thereof.

33. 29. The pharmaceutical combination of claim 28, wherein the KRAS inhibitor is sotorasib or a pharmaceutically acceptable salt thereof.

34. 29. The pharmaceutical combination of claim 28, wherein the KRAS inhibitor is adagrasib or a pharmaceutically acceptable salt thereof.

35. 29. The pharmaceutical combination of claim 28, wherein the KRAS inhibitor is Compound 2 or a pharmaceutically acceptable salt thereof.

36. 29. The pharmaceutical combination of claim 28, wherein the KRAS inhibitor is compound 3 or a pharmaceutically acceptable salt thereof.

37. 29. The pharmaceutical combination of claim 28, wherein the KRAS inhibitor is compound 4 or a pharmaceutically acceptable salt thereof.

38. (i) pemigatinib or a pharmaceutically acceptable salt thereof; (ii) sotorasib, adagrasib, compound 2: 【Chemistry 21】 Compound 3: 【Chemistry 22】 and Compound 4: 【Chemistry 23】 and a KRAS inhibitor selected from the group consisting of:

1. A pharmaceutical combination for the treatment of cancer in a patient, comprising: (i) pemigatinib or a pharmaceutically acceptable salt thereof; and (ii) a KRAS inhibitor, administered to the patient simultaneously, separately, sequentially, or in combination.

39. 39. The pharmaceutical combination of claim 38, wherein the KRAS inhibitor is sotorasib or a pharmaceutically acceptable salt thereof.

40. 39. The pharmaceutical combination of claim 38, wherein the KRAS inhibitor is adagrasib or a pharmaceutically acceptable salt thereof.

41. 39. The pharmaceutical combination of claim 38, wherein the KRAS inhibitor is Compound 2 or a pharmaceutically acceptable salt thereof.

42. 39. The pharmaceutical combination of claim 38, wherein the KRAS inhibitor is compound 3 or a pharmaceutically acceptable salt thereof.

43. 39. The pharmaceutical combination of claim 38, wherein the KRAS inhibitor is compound 4 or a pharmaceutically acceptable salt thereof.

44. (i) pemigatinib or a pharmaceutically acceptable salt thereof; (ii) sotorasib, or a pharmaceutically acceptable salt thereof; 1. A pharmaceutical combination for treating cancer in a patient, comprising: (i) pemigatinib or a pharmaceutically acceptable salt thereof; and (ii) sotorasib or a pharmaceutically acceptable salt thereof, administered to the patient simultaneously, separately, sequentially, or in combination.

45. 45. The pharmaceutical combination of claim 44, wherein pemigatinib or a pharmaceutically acceptable salt thereof and sotorasib or a pharmaceutically acceptable salt thereof are administered simultaneously.

46. The pharmaceutical combination of claim 44, wherein pemigatinib or a pharmaceutically acceptable salt thereof and sotorasib or a pharmaceutically acceptable salt thereof are administered sequentially.

47. 45. The pharmaceutical combination of claim 44, wherein pemigatinib or a pharmaceutically acceptable salt thereof is administered orally.

48. 48. The pharmaceutical combination of claim 47, wherein pemigatinib or a pharmaceutically acceptable salt thereof is administered in the form of a tablet.

49. 45. The pharmaceutical combination of claim 44, wherein pemigatinib or a pharmaceutically acceptable salt thereof is administered in a daily dose of about 1 mg to about 10 mg.

50. 45. The pharmaceutical combination of claim 44, wherein pemigatinib or a pharmaceutically acceptable salt thereof is administered in a daily dose of about 1 mg to about 5 mg.

51. 45. The pharmaceutical combination of claim 44, wherein pemigatinib or a pharmaceutically acceptable salt thereof is administered in a daily dose of about 2 mg.

52. 45. The pharmaceutical combination of claim 44, wherein sotorasib or a pharmaceutically acceptable salt thereof is administered orally.

53. 53. The pharmaceutical combination of claim 52, wherein sotorasib or a pharmaceutically acceptable salt thereof is administered in the form of a tablet.

54. 45. The pharmaceutical combination of claim 44, wherein sotorasib or a pharmaceutically acceptable salt thereof is administered in a daily dose of about 50 mg to about 300 mg.

55. 45. The pharmaceutical combination of claim 44, wherein sotorasib or a pharmaceutically acceptable salt thereof is administered in a daily dose of about 100 mg to about 200 mg.

56. 45. The pharmaceutical combination of claim 44, wherein sotorasib or a pharmaceutically acceptable salt thereof is administered in a daily dose of about 133 mg.

57. 45. The pharmaceutical combination of claim 44, wherein sotorasib or a pharmaceutically acceptable salt thereof is administered in a daily dose of about 120 mg.

58. 45. The pharmaceutical combination of claim 44, wherein pemigatinib or a pharmaceutically acceptable salt thereof and sotorasib or a pharmaceutically acceptable salt thereof are administered orally simultaneously in daily doses of about 2 mg and 120 mg, respectively.

59. 45. The pharmaceutical combination of claim 44, wherein pemigatinib, or a pharmaceutically acceptable salt thereof, and sotorasib, or a pharmaceutically acceptable salt thereof, are orally administered sequentially in daily doses of about 2 mg and 120 mg, respectively.

60. 59. The pharmaceutical combination of claim 58, wherein pemigatinib or a pharmaceutically acceptable salt thereof and sotorasib or a pharmaceutically acceptable salt thereof are each administered in the form of a tablet.

61. The pharmaceutical combination of any one of claims 1 to 60, further comprising administering one or more additional therapeutic agents.

62. 62. The pharmaceutical combination of claim 61, comprising administering one additional therapeutic agent.

63. The pharmaceutical combination of claim 62, wherein the additional therapeutic agent is an inhibitor of PD-1 or PD-L1.

64. The pharmaceutical combination of any one of claims 1 to 60, wherein the cancer comprises one or more KRAS mutations.

65. 65. The pharmaceutical combination of claim 64, wherein the one or more KRAS mutations comprise a mutation selected from G12C, G12D, C12V, and combinations thereof.

66. 65. The pharmaceutical combination of claim 64, wherein the cancer further comprises high FGFR1 expression.

67. 61. The pharmaceutical combination of any one of claims 1 to 60, wherein the cancer is selected from carcinoma, pancreatic cancer, colorectal cancer, lung cancer, non-small cell lung cancer, ovarian cancer, bladder cancer, gastric cancer, esophageal cancer, breast cancer, head and neck cancer, cervical cancer, skin cancer, thyroid cancer, hematopoietic malignancies, multiple myeloma, acute myeloid leukemia, myeloproliferative neoplasms, tumors, glioblastoma, and sarcoma.

68. The combination pharmaceutical of any one of claims 1 to 60, wherein the cancer is lung cancer.

69. 69. The pharmaceutical combination of claim 68, wherein the cancer is non-small cell lung cancer.

70. The pharmaceutical combination of any one of claims 1 to 60, wherein the cancer is colorectal cancer.

71. The combination pharmaceutical of any one of claims 1 to 60, wherein the cancer is pancreatic cancer.

72. The pharmaceutical combination of any one of claims 1 to 60, wherein the cancer is ovarian cancer.

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