5,6,7,8-Tetrahydro-2,6-naphthyridine derivatives as cancer therapeutic agents

Abstract

The present invention relates to novel compounds as described herein, methods for preparing same, pharmaceutical compositions thereof, and methods of using same. In particular, the present invention relates to compounds of formula A or pharma- ceutically acceptable salts thereof, which are useful as inhibitors of KRAS protein and for the treatment, prevention and / or amelioration of diseases or disorders associated with KRAS, particularly cancer:

Description

[Technical field]

[0001] This application claims the benefit of priority to Indian Provisional Patent Application No. 202141057591, filed on December 10, 2021, which is incorporated herein by reference in its entirety.

[0002] FIELD OF THEINVENTION The present invention relates to novel compounds as described herein, methods for preparing same, pharmaceutical compositions thereof, and methods of using same. In particular, the present invention relates to compounds of formula A or pharma- ceutically acceptable salts thereof, which are useful as inhibitors of KRAS protein and for the treatment, prevention and / or amelioration of diseases or disorders associated with KRAS, particularly cancer: [Background technology]

[0003] Genes are found in the DNA of each cell in the human body, and they control how the cell functions, including how fast it grows, how often it divides, and how long it lives. Genes control how the cell functions by making proteins. Because proteins have specific functions and act as messengers for the cell, each gene must have precise instructions to make that protein. This allows the protein to function correctly for the cell. All cancers begin when one or more genes in a cell mutate. Mutations are changes that can produce abnormal proteins or prevent the formation of a protein. Abnormal proteins provide different information than normal proteins. This can cause the cell to grow uncontrollably and become cancerous.

[0004] Overall, researchers refer to two basic types of genetic mutations: (a) cancers that arise because of acquired mutations and factors that cause these mutations, including tobacco use, exposure to ultraviolet (UV) radiation, viruses, or age, called sporadic cancers, and (b) germline mutations, which are rarer and occur in sperm or egg cells. Because the mutations affect reproductive cells, they can be transmitted between generations. Cancers caused by germline mutations are called hereditary cancers and account for approximately 5% to 20% of all cancers.

[0005] Many of the genes that contribute to cancer development fall into the following broad categories:

[0006] DNA repair genes. These correct mistakes that occur when DNA is copied. Many of them act as tumor suppressor genes. BRCA1, BRCA2, and p53 are all DNA repair genes. In people with errors in DNA repair genes, the mistakes are not corrected and can lead to mutations. These mutations can eventually lead to cancer, especially when they occur in tumor suppressor genes or oncogenes.

[0007] Tumor suppressor genes. These are protective genes. Normally, they limit cell proliferation by monitoring how quickly cells divide into new cells, repairing mismatched DNA, and controlling cell death. When tumor suppressor genes mutate, cells can grow uncontrollably and eventually form tumors. Examples of tumor suppressor genes include BRCA1, BRCA2, and p53 or TP53.

[0008] Oncogenes. These turn healthy cells into cancer cells. Mutations in these genes are not known to be hereditary. Two of the most common oncogenes are HER2, a specialized protein that controls cancer growth and spread. They are found in some cancer cells, such as breast and ovarian cancer cells, and RAS, a gene in the RAS family that makes proteins involved in cell-to-cell signaling pathways, cell growth, and cell death.

[0009] One such mutation that has been reported is a mutation in the RAS family of genes. RAS is known to act as a molecular switch and is a monomeric globular protein associated with the cell membrane. RAS can bind either guanosine 5'-diphosphate (GDP) (known as the resting state or inactive state) or guanosine-5'-triphosphate (GTP) and convert GDP to GTP (known as the "switched on" state or active state). It is the growth-promoting stimulus that causes induction of RAS, which allows the active state of RAS to interact with and activate other proteins, resulting in the switch of GDP to GTP. This activation of RAS signals the cell to continue proliferation and differentiation.

[0010] Notably, the intrinsic ability to turn off RAS proteins by converting GTP back to GDP is very low; to turn off RAS, GTPase-activating proteins (GAPs) that interact with RAS and greatly accelerate the conversion of GTP to GDP are required. Any mutation in RAS that affects its ability to interact with GAPs or convert GTP back to GDP leads to prolonged activation of the protein and consequently prolonged and hyperactive RAS signaling, ultimately leading to cancer.

[0011] The RAS family is further divided into various members such as HRAS, KRAS, DIRAS1, DIRAS2, DIRAS3, ERAS, GEM, MRAS, NKIRAS1, NKIRAS2, NRAS, RALA, RALB, RAP1A, RAP1B, RAP2A, RAP2B, RAP2C, RASD1, RASD2, RASL10A, RASL10B, RASL11A, RASL11B, RASL12, REM1, REM2, RERG, RERGL, RRAD, RRAS, but the most notable RAS members associated with cancer are Harvey rat sarcoma viral oncogene homolog (HRAS), Kirsten rat sarcoma viral oncogene homolog (KRAS) and Neuroblastoma rat sarcoma viral oncogene homolog (NRAS).

[0012] Approximately 30% of all human tumors have been reported to harbor some mutations in the RAS genes, with the majority of mutations detected in the KRAS gene in approximately 25-30% of tumors, among the three members of the HRAS, KRAS, and NRAS families.

[0013] Mutations in the KRAS gene are more prevalent in pancreatic cancer, lung adenocarcinoma, colorectal cancer, gallbladder cancer, thyroid cancer, and cholangiocarcinoma. KRAS mutations are also found in approximately 25% of patients with NSCLC, and some studies have shown that KRAS mutations are a negative prognostic factor in NSCLC patients. Recently, KRAS mutations have been found to confer resistance to epidermal growth factor receptor (EGFR)-targeted therapy in colorectal cancer, and understanding the KRAS mutation status seems increasingly important before the use of tyrosine kinase inhibitors (TKIs).

[0014] The most common KRAS mutations are found at residues G12 and G13 and residue Q61 in its P-loop, with G12D being the most frequent mutation in the KRAS gene. G12D mutations have been reported to be the most widespread across cancers, mostly reported in pancreatic, colon and lung cancers.

[0015] Researchers have learned a lot about how cancer genes work. However, many cancers have not been linked to specific genes. Cancers are likely to involve multiple genetic mutations. In addition, some evidence suggests that genes interact with their environment. This further complicates understanding the role genes play in cancer. Researchers continue to study how genetic changes affect the development of cancer. This knowledge has led to improvements in cancer care, including early detection, risk reduction, use of targeted therapies, and survival.

[0016] Cancers in general are considered to have very few treatment options, especially when the cancer is unresectable because it is the result of metastasis. On the one hand, there have been some advances in treatment options, for example, the use of chemotherapy alone or in combination with radiation and / or surgery, but on the other hand, there have been considerable challenges in prognosis, especially for cancers such as lung, pancreatic, prostate, gastric, endometrial, ovarian, and colorectal cancers.

[0017] Thus, there exists an unmet medical need with regard to the treatment of such cancers, which the present invention aims to address. Summary of the Invention

[0018] The present invention relates to a compound of formula (A), or a pharma- ceutically acceptable salt thereof, or a composition thereof and a method of treatment therewith, and in particular, the present invention relates to a compound of formula (A) and a pharma- ceutically acceptable salt thereof that is useful in the treatment of RAS-mediated cancers.

[0019] In one embodiment of the present invention, a compound of structural formula (A) [ka] or a tautomer thereof, an isotope thereof, a prodrug thereof, an N-oxide thereof, a pharma- ceutically acceptable ester thereof, a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof, wherein: A1 is absent or independently substituted or unsubstituted C 1~4 Alkyl, substituted or unsubstituted C 2~4 Alkenyl, substituted or unsubstituted C 2~4 Alkynyl, substituted or unsubstituted C 3~10 Cycloalkyl, substituted or unsubstituted C 3~10 Heterocycloalkyl, -(CR b R c ) p -, O, S, -S (=O) p -, -C(=O)-, -NR x -, -CO-NR x -, and -NR x -CO-, A2 is absent or independently substituted or unsubstituted C 1~4 Alkyl, substituted or unsubstituted C 2~4 Alkenyl, substituted or unsubstituted C 2~4 Alkynyl, substituted or unsubstituted C 3~10 Cycloalkyl, substituted or unsubstituted C 3~10 Heterocycloalkyl, -(CR b R c ) p -, O, S, -S (=O) p -, -C(=O)-, -NR x -, -CO-NR x -, and -NR x -CO-, Cy 1 is selected from a cyclic group selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl; Cy 2is selected from cyclic groups selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl optionally substituted by G; G is a group capable of forming an interaction with aspartic acid at position 12 of the KRAS protein, R, at each occurrence, is independently: CN (cyano), COOH, CONH2, SO3H, C(=O)OR b , -C(=O)R b , -C(=S)R b , -C(=O)NR b R c , -C(=O)ONR b R c , -NR b R c , -NR b C(=O)NR b R c , -NR b S(=O)R c , -NR b S(=O)2R c , -NR b -OR c , =N-NR b R c , -NR b C(=O)OR c , -NR b C(=O)R c , -NR b C(=S)R c , -NR b C(=S)NR b R c , -SONR b R c , -SO2NR b R c , -OR b , -OR b C(=O)NR b R c , -OR b C(=O)OR c, -OC(=O)R b , -OC(=O)NR b R c , -R b NR c C(=O)R b , -R b OR c , -R b C(=O)OR c , -R b C(=O)NR b R c , -R b C(=O)R c , -R b OC(=O)R c , -SR b , -SOR c , -SO2R b , -CR b R c C(=O)R b , or -CR b R c C(=S)R z is selected from R 1 is, at each occurrence, independently selected from hydrogen, hydroxy, halogen, substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, C(═O)OR b , -C(=O)R b , -C(=S)R b , -C(=O)NR b R c , -C(=O)ONR b R c , -NR b R c , -NR b C(=O)NR b R c , -NRb S(=O)R c 、 -NR b S(=O)2R c 、 -NR b -OR c 、 =N-NR b R c 、 -NR b C(=O)OR c 、 -NR b C(=O)R c 、 -NR b C(=S)R c 、 -NR b C(=S)NR b R c 、 -SONR b R c 、 -SO2NR b R c 、 -OR b 、 -OR b C(=O)NR b R c 、 -OR b C(=O)OR c 、 -OC(=O)R b 、 -OC(=O)NR b R c 、 -R b NR c C(=O)R b 、 -R b OR c 、 -R b C(=O)OR c 、 -R b C(=O)NR b R c 、 -R b C(=O)R c 、 -R b OC(=O)R c 、 -SR b 、 -SOR c 、 -SO2R b 、 -CR b R c C(=O)R b 、 or -CR b R c C(=S)R z selected from R ais, at each occurrence, independently selected from hydrogen, hydroxy, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, -C(=O)OR b , -C(=O)R b , -C(=S)R b , -C(=O)NR b R c , -C(=O)ONR b R c , -NR b R c , -NR b -OR c , -NR b C(=O)NR b R c , -NR b S(=O)R c , -NR b S(=O)2R c , -NR b -OR c , =N-NR b R c , -NR b C(=O)OR c , -NR b C(=O)R c , -NR b C(=S)R c , -NR b C(=S)NR b R c , -SONR b R c , -SO2NR b R c , -OR b , -OR b C(=O)NR b R c , -OR b C(=O)OR c , -OC(=O)R b , -OC(=O)NR b R c , -R b NR c C(=O)R b , -R b OR c , -R b C(=O)OR c , -R b C(=O)NR b R c, -R b C(=O)R c , -R b OC(=O)R c , -SR b , -SOR c , -SO2R b , -CR b R c C(=O)R b , or -CR b R c C(=S)R z or any two R a may be taken together to form a substituted or unsubstituted, saturated or unsaturated 3- to 6-membered ring, which may optionally be the same or different, and which is selected from O, NR a or S; or any two R a Together, they form oxo (C=O) and imino (=NR b ), C=S(O) p or a substituted or unsubstituted, saturated or unsaturated 3- to 6-membered ring, which may optionally be the same or different, and may be selected from the group consisting of O, NR a or S, R b and R c is independently selected from, for each occurrence, hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclic ring, substituted heterocyclylalkyl ring, or substituted or unsubstituted amino, or R when attached to a common atom; b and R c any two of the above may be taken together to form (i) a substituted or unsubstituted, saturated or unsaturated 3- to 14-membered ring, which may optionally be the same or different, and which may be selected from O, NRx or S; or (ii) one or more heteroatoms selected from an oxo (=O) group, a thio (=S) group or an imino (=NR x ) group, R x and R z is independently hydrogen, hydroxy, cyano, halogen, -OR a , -COOR a , -S(=O) q -R a , -NR a R b , -C(=Z')-R a , substituted or unsubstituted alkyl groups, substituted or unsubstituted alkenyl groups, substituted or unsubstituted alkynyl groups, and substituted or unsubstituted cycloalkyl groups; Z' is selected from O or S; and and p is independently 0, 1, or 2 at each occurrence.

[0020] Formula (A), wherein A2 is absent or -CR b R c -, wherein R b and R c More preferred are compounds where each of is independently selected from hydrogen, substituted alkyl, or unsubstituted alkyl.

[0021] Formula (A), wherein A2 is absent or -CR b R c -, wherein R b is independently methyl or ethyl, and R c More preferred are compounds in which is hydrogen.

[0022] More preferred is a compound of formula (A) in which A2 is absent.

[0023] More preferred are compounds of formula (A) where R is cyano (CN).

[0024] In one embodiment of the present invention, a compound of formula (AI) [ka] or a tautomer thereof, an isotope thereof, a prodrug thereof, an N-oxide thereof, a pharma- ceutically acceptable ester thereof, a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof, wherein: A1 is absent or independently substituted or unsubstituted C 1~4 Alkyl, substituted or unsubstituted C 2~4 Alkenyl, substituted or unsubstituted C 2~4 Alkynyl, substituted or unsubstituted C 3~10 Cycloalkyl, substituted or unsubstituted C 3~10 Heterocycloalkyl, -(CR b R c ) p -, -O-, -S-, -S(=O) p -, -C(=O)-, -NR x -, -CO-NR x -, and -NR x -CO-, Cy 1 is selected from a cyclic group selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl; Cy 2 is selected from cyclic groups selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl optionally substituted by G; G is a group capable of forming an interaction with aspartic acid at position 12 of the KRAS protein, R 1 is, at each occurrence, independently selected from hydrogen, hydroxy, halogen, substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, C(═O)OR b , -C(=O)R b , -C(=S)R b , -C(=O)NR b R c , -C(=O)ONR b R c , -NR b R c , -NR b C(=O)NR b R c , -NR b S(=O)R c , -NR b S(=O)2R c , -NR b -OR c , =N-NR b R c , -NR b C(=O)OR c , -NR b C(=O)R c , -NR b C(=S)R c , -NR b C(=S)NR b R c , -SONR b R c , -SO2NR b R c , -OR b , -OR b C(=O)NR b R c, -OR b C(=O)OR c , -OC(=O)R b , -OC(=O)NR b R c , -R b NR c C(=O)R b , -R b OR c , -R b C(=O)OR c , -R b C(=O)NR b R c , -R b C(=O)R c , -R b OC(=O)R c , -SR b , -SOR c , -SO2R b , -CR b R c C(=O)R b , or -CR b R c C(=S)R z is selected from R a is, at each occurrence, independently selected from hydrogen, hydroxy, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, -C(=O)OR b , -C(=O)R b , -C(=S)R b , -C(=O)NR b R c , -C(=O)ONR b R c , -NR b R c , -NR b -OR c , -NR b C(=O)NR b R c , -NR b S(=O)R c , -NR b S(=O)2R c , -NR b -OR c , =N-NR b R c , -NR b C(=O)ORc , -NR b C(=O)R c , -NR b C(=S)R c , -NR b C(=S)NR b R c , -SONR b R c , -SO2NR b R c , -OR b , -OR b C(=O)NR b R c , -OR b C(=O)OR c , -OC(=O)R b , -OC(=O)NR b R c , -R b NR c C(=O)R b , -R b OR c , -R b C(=O)OR c , -R b C(=O)NR b R c , -R b C(=O)R c , -R b OC(=O)R c , -SR b , -SOR c , -SO2R b , -CR b R c C(=O)R b , or -CR b R c C(=S)R z or any two R a may be taken together to form a substituted or unsubstituted, saturated or unsaturated 3- to 6-membered ring, which may optionally be the same or different, and which is selected from O, NR a or S; or any two R a Together, they form oxo (C=O) and imino (=NR b ), C=S(O) por a substituted or unsubstituted, saturated or unsaturated 3- to 6-membered ring, which may optionally be the same or different, and may be selected from the group consisting of O, NR x or S, R b and R c is independently selected from, for each occurrence, hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclic ring, substituted heterocyclylalkyl ring, or substituted or unsubstituted amino, or R when attached to a common atom; b and R c any two of the above may be taken together to form (i) a substituted or unsubstituted, saturated or unsaturated 3- to 14-membered ring, which may optionally be the same or different, and which may be selected from O, NR x or S; or (ii) one or more heteroatoms selected from an oxo (=O) group, a thio (=S) group or an imino (=NR x ) groups, and p is independently 0, 1, or 2 at each occurrence.

[0025] Formula (A) or (AI), wherein Cy 2 More preferred are compounds in which the cyclic group is selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocyclyl, and substituted or unsubstituted heterocyclylalkyl.

[0026] Formula (A) or (AI), wherein Cy 2Further preferred are compounds in which is selected from cyclic groups selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocyclyl, and substituted or unsubstituted heterocyclylalkyl, each of which may be further substituted with a group G.

[0027] In one embodiment of the present invention, a compound represented by structural formula (A-II) [ka] or a tautomer thereof, an isotope thereof, a prodrug thereof, an N-oxide thereof, a pharma- ceutically acceptable ester thereof, a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof, wherein: A1 is absent or independently substituted or unsubstituted C 1~4 Alkyl, substituted or unsubstituted C 2~4 Alkenyl, substituted or unsubstituted C 2~4 Alkynyl, substituted or unsubstituted C 3~10 Cycloalkyl, substituted or unsubstituted C 3~10 Heterocycloalkyl, -(CR b R c ) p -, -O-, -S-, -S(=O) p -, -C(=O)-, -NR x -, -CO-NR x -, and -NR x -CO-, Cy 1 is selected from a cyclic group selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl; Cy 2 is a substituted or unsubstituted heterocyclyl, which is optionally substituted by G; G is a group capable of forming an interaction with aspartic acid at position 12 of the KRAS protein, R 1 is, at each occurrence, independently selected from hydrogen, hydroxy, halogen, substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, C(═O)OR b , -C(=O)R b , -C(=S)R b , -C(=O)NR b R c , -C(=O)ONR b R c , -NR b R c , -NR b C(=O)NR b R c , -NR b S(=O)R c , -NR b S(=O)2R c , -NR b -OR c , =N-NR b R c , -NR b C(=O)OR c , -NR b C(=O)R c , -NR b C(=S)R c , -NR b C(=S)NR b R c , -SONR b R c , -SO2NR b R c , -OR b , -OR b C(=O)NR b R c, -OR b C(=O)OR c , -OC(=O)R b , -OC(=O)NR b R c , -R b NR c C(=O)R b , -R b OR c , -R b C(=O)OR c , -R b C(=O)NR b R c , -R b C(=O)R c , -R b OC(=O)R c , -SR b , -SOR c , -SO2R b , -CR b R c C(=O)R b , or -CR b R c C(=S)R z is selected from R a is, at each occurrence, independently selected from hydrogen, hydroxy, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, -C(=O)OR b , -C(=O)R b , -C(=S)R b , -C(=O)NR b R c , -C(=O)ONR b R c , -NR b R c , -NR b -OR c , -NR b C(=O)NR b R c , -NR b S(=O)R c , -NR b S(=O)2R c , -NR b -OR c , =N-NR b R c , -NR b C(=O)ORc , -NR b C(=O)R c , -NR b C(=S)R c , -NR b C(=S)NR b R c , -SONR b R c , -SO2NR b R c , -OR b , -OR b C(=O)NR b R c , -OR b C(=O)OR c , -OC(=O)R b , -OC(=O)NR b R c , -R b NR c C(=O)R b , -R b OR c , -R b C(=O)OR c , -R b C(=O)NR b R c , -R b C(=O)R c , -R b OC(=O)R c , -SR b , -SOR c , -SO2R b , -CR b R c C(=O)R b , or -CR b R c C(=S)R z or any two R a may be taken together to form a substituted or unsubstituted, saturated or unsaturated 3- to 6-membered ring, which may optionally be the same or different, and which is selected from O, NR a or S; or any two R a Together, they form oxo (C=O) and imino (=NR b ), C=S(O) por a substituted or unsubstituted, saturated or unsaturated 3- to 6-membered ring, which may optionally be the same or different, and may be selected from the group consisting of O, NR x or S, R b and R c is independently selected from, for each occurrence, hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclic ring, substituted heterocyclylalkyl ring, or substituted or unsubstituted amino, or R when attached to a common atom; b and R c any two of the above may be taken together to form (i) a substituted or unsubstituted, saturated or unsaturated 3- to 14-membered ring, which may optionally be the same or different, and which may be selected from O, NR x or S; or (ii) one or more heteroatoms selected from an oxo (=O) group, a thio (=S) group or an imino (=NR x ) groups, and p is independently 0, 1, or 2 at each occurrence.

[0028] Formula (A), (AI) or (A-II), wherein Cy 2 is more preferably a compound selected from the following: [ka] In the formula, Cy 2 is replaced by one or more G's.

[0029] Formula (A), (AI) or (A-II), wherein A2-Cy 2 More preferably, -G is a compound selected from the following: [ka]

[0030] Formula (A), (AI) or (A-II), wherein A1 is (i) Not present or -CR b R c -, wherein R b and R c each is independently selected from hydrogen, or substituted or unsubstituted alkyl, and / or (ii) Not present or -CR b R c -, wherein R b is independently methyl or ethyl, and R c is hydrogen, and / or (iii) Absent or -CR b R c -, wherein R b is hydrogen and R c is hydrogen, and / or (iv) is absent, or is -CH2 or -(C=O), and / or any combination thereof; A2 is, (i) Not present or -CR b R c -, wherein R b and R c each is independently selected from hydrogen, substituted alkyl or unsubstituted alkyl, and / or (ii) Not present or -CR b R c -, wherein R b is independently methyl or ethyl, and R c is hydrogen, and / or (iii) absent, and / or any combination thereof; Cy 1 teeth, (i) a cyclic group selected from substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, and / or (ii) selected from substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl, and / or combinations thereof; Cy 2 teeth, (i) a cyclic group selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocyclyl, and substituted or unsubstituted heterocyclylalkyl; and / or (ii) a cyclic group selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocyclyl, and substituted or unsubstituted heterocyclylalkyl, and / or combinations thereof, each of which may be further substituted with a group G, where G is a group capable of forming an interaction with an aspartic acid at position 12 of the KRAS protein; R is cyano (CN), and R 1 teeth, (i) Hydrogen, halogens, OR b , S.R. b , -S(=O) p R b -, -C(=O)-R b , -NR b R c , -CO-NR b R c - and -NR b -CO-R c and / or (ii)-OR b and / or (iii)-NR b R c and / or (iv) substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, and / or (v) Further preferred are compounds selected from substituted or unsubstituted alkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, and substituted or unsubstituted heteroaryl, and / or combinations thereof.

[0031] Formula (A), (AI) or (A-II), wherein R, at each occurrence, is independently: CN (cyano), COOH, CONH2, SO3H, C(=O)OR b , -C(=O)R b , -C(=S)R b , -C(=O)NR b R c , -C(=O)ONR b R c , -NR b R c , -NR b C(=O)NR b R c , -NR b S(=O)R c , -NR b S(=O)2R c , -NR b -OR c , =N-NR b R c , -NR b C(=O)OR c , -NR b C(=O)R c , -NR b C(=S)R c , -NR b C(=S)NR b R c , -SONR b R c , -SO2NR b R c , -OR b , -OR b C(=O)NR b Rc , -OR b C(=O)OR c , -OC(=O)R b , -OC(=O)NR b R c , -R b NR c C(=O)R b , -R b OR c , -R b C(=O)OR c , -R b C(=O)NR b R c , -R b C(=O)R c , -R b OC(=O)R c , -SR b , -SOR c , -SO2R b , -CR b R c C(=O)R b , or -CR b R c C(=S)R z is selected from A1 is absent or a substituted or unsubstituted C 1~4 is alkyl, A2 is absent or a substituted or unsubstituted C 1~4 is alkyl, Cy 1 is selected from substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; Cy 2 is selected from substituted or unsubstituted heterocyclyl optionally substituted by G; G is a group capable of forming an interaction with aspartic acid at position 12 of the KRAS protein, R 1is, at each occurrence, independently selected from hydrogen, hydroxy, halogen, substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, C(═O)OR b , -C(=O)R b , -C(=S)R b , -C(=O)NR b R c , -C(=O)ONR b R c , -NR b R c , -NR b C(=O)NR b R c , -NR b S(=O)R c , -NR b S(=O)2R c , -NR b -OR c , =N-NR b R c , -NR b C(=O)OR c , -NR b C(=O)R c , -NR b C(=S)R c , -NR b C(=S)NR b R c , -SONR b R c , -SO2NR b R c , -OR b , -OR b C(=O)NR b R c , -OR b C(=O)OR c , -OC(=O)R b, -OC(=O)NR b R c , -R b NR c C(=O)R b , -R b OR c , -R b C(=O)OR c , -R b C(=O)NR b R c , -R b C(=O)R c , -R b OC(=O)R c , -SR b , -SOR c , -SO2R b , -CR b R c C(=O)R b , or -CR b R c C(=S)R z is selected from R a is, at each occurrence, independently selected from hydrogen, hydroxy, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, -C(=O)OR b , -C(=O)R b , -C(=S)R b , -C(=O)NR b R c , -C(=O)ONR b R c , -NR b R c , -NR b -OR c , -NR b C(=O)NR b R c , -NR b S(=O)R c , -NR b S(=O)2R c , -NR b -OR c , =N-NR b R c , -NR b C(=O)OR c , -NR b C(=O)R c , -NR bC(=S)R c , -NR b C(=S)NR b R c , -SONR b R c , -SO2NR b R c , -OR b , -OR b C(=O)NR b R c , -OR b C(=O)OR c , -OC(=O)R b , -OC(=O)NR b R c , -R b NR c C(=O)R b , -R b OR c , -R b C(=O)OR c , -R b C(=O)NR b R c , -R b C(=O)R c , -R b OC(=O)R c , -SR b , -SOR c , -SO2R b , -CR b R c C(=O)R b , or -CR b R c C(=S)R z or any two R a may be taken together to form a substituted or unsubstituted, saturated or unsaturated 3- to 6-membered ring, which may optionally be the same or different, and which is selected from O, NR a or S; or any two R a Together, they form oxo (C=O) and imino (=NR b ), C=S(O) p or a substituted or unsubstituted, saturated or unsaturated 3- to 6-membered ring, which may optionally be the same or different, and may be selected from the group consisting of O, NRx or S, R b and R c is independently selected from, for each occurrence, hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclic ring, substituted heterocyclylalkyl ring, or substituted or unsubstituted amino, or R when attached to a common atom; b and R c any two of the above may be taken together to form (i) a substituted or unsubstituted, saturated or unsaturated 3- to 14-membered ring, which may optionally be the same or different, and which may be selected from O, NR x or S; or (ii) one or more heteroatoms selected from an oxo (=O) group, a thio (=S) group or an imino (=NR x ) group, R x and R z is independently hydrogen, hydroxy, cyano, halogen, -OR a , -COOR a , -S(=O) q -R a , -NR a R b , -C(=Z')-R a , substituted or unsubstituted alkyl groups, substituted or unsubstituted alkenyl groups, substituted or unsubstituted alkynyl groups, and substituted or unsubstituted cycloalkyl groups; Z' is selected from O or S; and Further preferred are compounds wherein p is independently 0, 1, or 2 at each occurrence.

[0032] Formula (A), (AI) or (A-II), wherein A1 is absent or is substituted or unsubstituted alkyl; A2 is absent or independently substituted or unsubstituted C 1~4 Alkyl, substituted or unsubstituted C 2~4 Alkenyl, substituted or unsubstituted C 2~4 Alkynyl, substituted or unsubstituted C 3~10 Cycloalkyl, substituted or unsubstituted C 3~10 Heterocycloalkyl, -(CR b R c ) p -, -O-, -S-, -S(=O) p -, -C(=O)-, -NR x -, -CO-NR x -, and -NR x -CO-, Cy 1 is selected from a cyclic group selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl; Cy 2 is selected from cyclic groups selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl optionally substituted by G; G is a group capable of forming an interaction with aspartic acid at position 12 of the KRAS protein, R, at each occurrence, is independently: CN (cyano), COOH, CONH2, SO3H, C(=O)OR b , -C(=O)R b , -C(=S)R b , -C(=O)NRb R c 、-C(=O)ONR b R c 、-NR b R c 、-NR b C(=O)NR b R c 、-NR b S(=O)R c 、-NR b S(=O)2R c 、-NR b -OR c 、=N-NR b R c 、-NR b C(=O)OR c 、-NR b C(=O)R c 、-NR b C(=S)R c 、-NR b C(=S)NR b R c 、-SONR b R c 、-SO2NR b R c 、-OR b 、-OR b C(=O)NR b R c 、-OR b C(=O)OR c 、-OC(=O)R b 、-OC(=O)NR b R c 、-R b NR c C(=O)R b 、-R b OR c 、-R b C(=O)OR c 、-R b C(=O)NR b R c 、-R b C(=O)R c 、-R b OC(=O)R c 、-SR b 、-SOR c 、-SO2R b 、-CR b R cC(=O)R b , or -CR b R c C(=S)R z is selected from R 1 is, at each occurrence, independently selected from hydrogen, hydroxy, halogen, substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, C(═O)OR b , -C(=O)R b , -C(=S)R b , -C(=O)NR b R c , -C(=O)ONR b R c , -NR b R c , -NR b C(=O)NR b R c , -NR b S(=O)R c , -NR b S(=O)2R c , -NR b -OR c , =N-NR b R c , -NR b C(=O)OR c , -NR b C(=O)R c , -NR b C(=S)R c , -NR b C(=S)NR b R c , -SONR b R c , -SO2NR b R c , -OR b , -ORb C(=O)NR b R c , -OR b C(=O)OR c , -OC(=O)R b , -OC(=O)NR b R c , -R b NR c C(=O)R b , -R b OR c , -R b C(=O)OR c , -R b C(=O)NR b R c , -R b C(=O)R c , -R b OC(=O)R c , -SR b , -SOR c , -SO2R b , -CR b R c C(=O)R b , or -CR b R c C(=S)R z is selected from R a is, at each occurrence, independently selected from hydrogen, hydroxy, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, -C(=O)OR b , -C(=O)R b , -C(=S)R b , -C(=O)NR b R c , -C(=O)ONR b R c , -NR b R c , -NR b -OR c , -NR b C(=O)NR b R c , -NR b S(=O)R c , -NR b S(=O)2R c , -NR b -OR c , =N-NR bR c , -NR b C(=O)OR c , -NR b C(=O)R c , -NR b C(=S)R c , -NR b C(=S)NR b R c , -SONR b R c , -SO2NR b R c , -OR b , -OR b C(=O)NR b R c , -OR b C(=O)OR c , -OC(=O)R b , -OC(=O)NR b R c , -R b NR c C(=O)R b , -R b OR c , -R b C(=O)OR c , -R b C(=O)NR b R c , -R b C(=O)R c , -R b OC(=O)R c , -SR b , -SOR c , -SO2R b , -CR b R c C(=O)R b , or -CR b R c C(=S)R z or any two R a may be taken together to form a substituted or unsubstituted, saturated or unsaturated 3- to 6-membered ring, which may optionally be the same or different, and which is selected from O, NR a or S; or any two R a Together, they form oxo (C=O) and imino (=NRb ), C=S(O) p or a substituted or unsubstituted, saturated or unsaturated 3- to 6-membered ring, which may optionally be the same or different, and may be selected from the group consisting of O, NR x or S, R b and R c is independently selected from, for each occurrence, hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclic ring, substituted heterocyclylalkyl ring, or substituted or unsubstituted amino, or R when attached to a common atom; b and R c any two of the above may be taken together to form (i) a substituted or unsubstituted, saturated or unsaturated 3- to 14-membered ring, which may optionally be the same or different, and which may be selected from O, NR x or S; or (ii) one or more heteroatoms selected from an oxo (=O) group, a thio (=S) group or an imino (=NR x ) group, R x and R z is independently hydrogen, hydroxy, cyano, halogen, -OR a , -COOR a , -S(=O) q -R a , -NR a R b , -C(=Z')-R a , substituted or unsubstituted alkyl groups, substituted or unsubstituted alkenyl groups, substituted or unsubstituted alkynyl groups, and substituted or unsubstituted cycloalkyl groups; Z' is selected from O or S; and Further preferred are compounds wherein p is independently 0, 1, or 2 at each occurrence.

[0033] Formula (A), (AI) or (A-II), wherein Cy 1 is selected from substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; A1 is absent or independently substituted or unsubstituted C 1~4 Alkyl, substituted or unsubstituted C 2~4 Alkenyl, substituted or unsubstituted C 2~4 Alkynyl, substituted or unsubstituted C 3~10 Cycloalkyl, substituted or unsubstituted C 3~10 Heterocycloalkyl, -(CR b R c ) p -, -O-, -S-, -S(=O) p -, -C(=O)-, -NR x -, -CO-NR x -, and -NR x -CO-, A2 is absent or independently substituted or unsubstituted C 1~4 Alkyl, substituted or unsubstituted C 2~4 Alkenyl, substituted or unsubstituted C 2~4 Alkynyl, substituted or unsubstituted C 3~10 Cycloalkyl, substituted or unsubstituted C 3~10 Heterocycloalkyl, -(CR b R c ) p -, -O-, -S-, -S(=O) p -, -C(=O)-, -NR x -, -CO-NR x -, and -NR x -CO-, Cy 2is selected from cyclic groups selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl optionally substituted by G; G is a group capable of forming an interaction with aspartic acid at position 12 of the KRAS protein, R 1 is, at each occurrence, independently selected from hydrogen, hydroxy, halogen, substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, C(═O)OR b , -C(=O)R b , -C(=S)R b , -C(=O)NR b R c , -C(=O)ONR b R c , -NR b R c , -NR b C(=O)NR b R c , -NR b S(=O)R c , -NR b S(=O)2R c , -NR b -OR c , =N-NR b R c , -NR b C(=O)OR c , -NR b C(=O)R c, -NR b C(=S)R c , -NR b C(=S)NR b R c , -SONR b R c , -SO2NR b R c , -OR b , -OR b C(=O)NR b R c , -OR b C(=O)OR c , -OC(=O)R b , -OC(=O)NR b R c , -R b NR c C(=O)R b , -R b OR c , -R b C(=O)OR c , -R b C(=O)NR b R c , -R b C(=O)R c , -R b OC(=O)R c , -SR b , -SOR c , -SO2R b , -CR b R c C(=O)R b , or -CR b R c C(=S)R z is selected from R, at each occurrence, is independently: CN (cyano), COOH, CONH2, SO3H, C(=O)OR b , -C(=O)R b , -C(=S)R b , -C(=O)NR b R c , -C(=O)ONR b R c , -NR b R c , -NR b C(=O)NR b R c , -NRb S(=O)R c 、 -NR b S(=O)2R c 、 -NR b -OR c 、 =N-NR b R c 、 -NR b C(=O)OR c 、 -NR b C(=O)R c 、 -NR b C(=S)R c 、 -NR b C(=S)NR b R c 、 -SONR b R c 、 -SO2NR b R c 、 -OR b 、 -OR b C(=O)NR b R c 、 -OR b C(=O)OR c 、 -OC(=O)R b 、 -OC(=O)NR b R c 、 -R b NR c C(=O)R b 、 -R b OR c 、 -R b C(=O)OR c 、 -R b C(=O)NR b R c 、 -R b C(=O)R c 、 -R b OC(=O)R c 、 -SR b 、 -SOR c 、 -SO2R b 、 -CR b R c C(=O)R b 、 or -CR b R c C(=S)R z selected from R ais, at each occurrence, independently selected from hydrogen, hydroxy, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, -C(=O)OR b , -C(=O)R b , -C(=S)R b , -C(=O)NR b R c , -C(=O)ONR b R c , -NR b R c , -NR b -OR c , -NR b C(=O)NR b R c , -NR b S(=O)R c , -NR b S(=O)2R c , -NR b -OR c , =N-NR b R c , -NR b C(=O)OR c , -NR b C(=O)R c , -NR b C(=S)R c , -NR b C(=S)NR b R c , -SONR b R c , -SO2NR b R c , -OR b , -OR b C(=O)NR b R c , -OR b C(=O)OR c , -OC(=O)R b , -OC(=O)NR b R c , -R b NR c C(=O)R b , -R b OR c , -R b C(=O)OR c , -R b C(=O)NR b R c, -R b C(=O)R c , -R b OC(=O)R c , -SR b , -SOR c , -SO2R b , -CR b R c C(=O)R b , or -CR b R c C(=S)R z or any two R a may be taken together to form a substituted or unsubstituted, saturated or unsaturated 3- to 6-membered ring, which may optionally be the same or different, and which is selected from O, NR a or S; or any two R a Together, they form oxo (C=O) and imino (=NR b ), C=S(O) p or a substituted or unsubstituted, saturated or unsaturated 3- to 6-membered ring, which may optionally be the same or different, and may be selected from the group consisting of O, NR x or S, R b and R c is independently selected from, for each occurrence, hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclic ring, substituted heterocyclylalkyl ring, or substituted or unsubstituted amino, or R when attached to a common atom; b and R c any two of the above may be taken together to form (i) a substituted or unsubstituted, saturated or unsaturated 3- to 14-membered ring, which may optionally be the same or different, and which may be selected from O, NRx or S; or (ii) one or more heteroatoms selected from an oxo (=O) group, a thio (=S) group or an imino (=NR x ) group, R x and R z is independently hydrogen, hydroxy, cyano, halogen, -OR a , -COOR a , -S(=O) q -R a , -NR a R b , -C(=Z')-R a , substituted or unsubstituted alkyl groups, substituted or unsubstituted alkenyl groups, substituted or unsubstituted alkynyl groups, and substituted or unsubstituted cycloalkyl groups; Z' is selected from O or S; and Further preferred are compounds wherein p is independently 0, 1, or 2 at each occurrence.

[0034] Formula (A), (AI) or (A-II), wherein Cy 2 is a substituted or unsubstituted heterocyclyl, which is optionally substituted by G; G is a group capable of forming an interaction with aspartic acid at position 12 of the KRAS protein, A1 is absent or independently substituted or unsubstituted C 1~4 Alkyl, substituted or unsubstituted C 2~4 Alkenyl, substituted or unsubstituted C 2~4 Alkynyl, substituted or unsubstituted C 3~10 Cycloalkyl, substituted or unsubstituted C 3~10 Heterocycloalkyl, -(CR b R c ) p -, -O-, -S-, -S(=O) p -, -C(=O)-, -NR x -, -CO-NR x -, and -NR x -CO-, A2 is absent or independently substituted or unsubstituted C 1~4 Alkyl, substituted or unsubstituted C 2~4 Alkenyl, substituted or unsubstituted C 2~4 Alkynyl, substituted or unsubstituted C 3~10 Cycloalkyl, substituted or unsubstituted C 3~10 Heterocycloalkyl, -(CR b R c ) p -, -O-, -S-, -S(=O) p -, -C(=O)-, -NR x -, -CO-NR x -, and -NR x -CO-, Cy 1 is selected from a cyclic group selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl; R 1 is, at each occurrence, independently selected from hydrogen, hydroxy, halogen, substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, C(═O)OR b , -C(=O)R b , -C(=S)R b , -C(=O)NR b R c , -C(=O)ONR b R c , -NRb R c 、-NR b C(=O)NR b R c 、-NR b S(=O)R c 、-NR b S(=O)2R c 、-NR b -OR c 、=N-NR b R c 、-NR b C(=O)OR c 、-NR b C(=O)R c 、-NR b C(=S)R c 、-NR b C(=S)NR b R c 、-SONR b R c 、-SO2NR b R c 、-OR b 、-OR b C(=O)NR b R c 、-OR b C(=O)OR c 、-OC(=O)R b 、-OC(=O)NR b R c 、-R b NR c C(=O)R b 、-R b OR c 、-R b C(=O)OR c 、-R b C(=O)NR b R c 、-R b C(=O)R c 、-R b OC(=O)R c 、-SR b 、-SOR c 、-SO2R b 、-CR b R c C(=O)R b 、または-CR b R c C(=S)R zis selected from R, at each occurrence, is independently: CN (cyano), COOH, CONH2, SO3H, C(=O)OR b , -C(=O)R b , -C(=S)R b , -C(=O)NR b R c , -C(=O)ONR b R c , -NR b R c , -NR b C(=O)NR b R c , -NR b S(=O)R c , -NR b S(=O)2R c , -NR b -OR c , =N-NR b R c , -NR b C(=O)OR c , -NR b C(=O)R c , -NR b C(=S)R c , -NR b C(=S)NR b R c , -SONR b R c , -SO2NR b R c , -OR b , -OR b C(=O)NR b R c , -OR b C(=O)OR c , -OC(=O)R b , -OC(=O)NR b R c , -R b NR c C(=O)R b , -R b OR c , -R b C(=O)OR c , -R b C(=O)NR b R c , -R b C(=O)Rc , -R b OC(=O)R c , -SR b , -SOR c , -SO2R b , -CR b R c C(=O)R b , or -CR b R c C(=S)R z is selected from R a is, at each occurrence, independently selected from hydrogen, hydroxy, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, -C(=O)OR b , -C(=O)R b , -C(=S)R b , -C(=O)NR b R c , -C(=O)ONR b R c , -NR b R c , -NR b -OR c , -NR b C(=O)NR b R c , -NR b S(=O)R c , -NR b S(=O)2R c , -NR b -OR c , =N-NR b R c , -NR b C(=O)OR c , -NR b C(=O)R c , -NR b C(=S)R c , -NR b C(=S)NR b R c , -SONR b R c , -SO2NR b R c , -OR b , -OR b C(=O)NR b R c , -OR bC(=O)OR c , -OC(=O)R b , -OC(=O)NR b R c , -R b NR c C(=O)R b , -R b OR c , -R b C(=O)OR c , -R b C(=O)NR b R c , -R b C(=O)R c , -R b OC(=O)R c , -SR b , -SOR c , -SO2R b , -CR b R c C(=O)R b , or -CR b R c C(=S)R z or any two R a may be taken together to form a substituted or unsubstituted, saturated or unsaturated 3- to 6-membered ring, which may optionally be the same or different, and which is selected from O, NR a or S; or any two R a Together, they form oxo (C=O) and imino (=NR b ), C=S(O) p or a substituted or unsubstituted, saturated or unsaturated 3- to 6-membered ring, which may optionally be the same or different, and may be selected from the group consisting of O, NR x or S, R b and R cis independently selected from, for each occurrence, hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclic ring, substituted heterocyclylalkyl ring, or substituted or unsubstituted amino, or R when attached to a common atom; b and R c any two of the above may be taken together to form (i) a substituted or unsubstituted, saturated or unsaturated 3- to 14-membered ring, which may optionally be the same or different, and which may be selected from O, NR x or S; or (ii) one or more heteroatoms selected from an oxo (=O) group, a thio (=S) group or an imino (=NR x ) group, R x and R z is independently hydrogen, hydroxy, cyano, halogen, -OR a , -COOR a , -S(=O) q -R a , -NR a R b , -C(=Z')-R a , substituted or unsubstituted alkyl groups, substituted or unsubstituted alkenyl groups, substituted or unsubstituted alkynyl groups, and substituted or unsubstituted cycloalkyl groups; Z' is selected from O or S; and Further preferred are compounds wherein p is independently 0, 1, or 2 at each occurrence.

[0035] Formula (A), (AI) or (A-II), wherein R 1 is hydrogen, halogen, -NR b R c -OR b is selected from A1 is absent or independently substituted or unsubstituted C 1~4 Alkyl, substituted or unsubstituted C 2~4 Alkenyl, substituted or unsubstituted C 2~4 Alkynyl, substituted or unsubstituted C 3~10 Cycloalkyl, substituted or unsubstituted C 3~10 Heterocycloalkyl, -(CR b R c ) p -, -O-, -S-, -S(=O) p -, -C(=O)-, -NR x -, -CO-NR x -, and -NR x -CO-, A2 is absent or independently substituted or unsubstituted C 1~4 Alkyl, substituted or unsubstituted C 2~4 Alkenyl, substituted or unsubstituted C 2~4 Alkynyl, substituted or unsubstituted C 3~10 Cycloalkyl, substituted or unsubstituted C 3~10 Heterocycloalkyl, -(CR b R c ) p -, -O-, -S-, -S(=O) p -, -C(=O)-, -NR x -, -CO-NR x -, and -NR x -CO-, Cy 1 is selected from a cyclic group selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl; Cy 2is selected from cyclic groups selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl optionally substituted by G; G is a group capable of forming an interaction with aspartic acid at position 12 of the KRAS protein, R, at each occurrence, is independently: CN (cyano), COOH, CONH2, SO3H, C(=O)OR b , -C(=O)R b , -C(=S)R b , -C(=O)NR b R c , -C(=O)ONR b R c , -NR b R c , -NR b C(=O)NR b R c , -NR b S(=O)R c , -NR b S(=O)2R c , -NR b -OR c , =N-NR b R c , -NR b C(=O)OR c , -NR b C(=O)R c , -NR b C(=S)R c , -NR b C(=S)NR b R c , -SONR b R c , -SO2NR b R c , -OR b , -OR b C(=O)NR b R c , -OR b C(=O)OR c, -OC(=O)R b , -OC(=O)NR b R c , -R b NR c C(=O)R b , -R b OR c , -R b C(=O)OR c , -R b C(=O)NR b R c , -R b C(=O)R c , -R b OC(=O)R c , -SR b , -SOR c , -SO2R b , -CR b R c C(=O)R b , or -CR b R c C(=S)R z is selected from R a is, at each occurrence, independently selected from hydrogen, hydroxy, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, -C(=O)OR b , -C(=O)R b , -C(=S)R b , -C(=O)NR b R c , -C(=O)ONR b R c , -NR b R c , -NR b -OR c , -NR b C(=O)NR b R c , -NR b S(=O)R c , -NR b S(=O)2R c , -NR b -OR c , =N-NR b R c , -NR b C(=O)OR c , -NR b C(=O)Rc , -NR b C(=S)R c , -NR b C(=S)NR b R c , -SONR b R c , -SO2NR b R c , -OR b , -OR b C(=O)NR b R c , -OR b C(=O)OR c , -OC(=O)R b , -OC(=O)NR b R c , -R b NR c C(=O)R b , -R b OR c , -R b C(=O)OR c , -R b C(=O)NR b R c , -R b C(=O)R c , -R b OC(=O)R c , -SR b , -SOR c , -SO2R b , -CR b R c C(=O)R b , or -CR b R c C(=S)R z or any two R a may be taken together to form a substituted or unsubstituted, saturated or unsaturated 3- to 6-membered ring, which may optionally be the same or different, and which is selected from O, NR a or S; or any two R a Together, they form oxo (C=O) and imino (=NR b ), C=S(O) por a substituted or unsubstituted, saturated or unsaturated 3- to 6-membered ring, which may optionally be the same or different, and may be selected from the group consisting of O, NR x or S, R b and R c is independently selected at each occurrence from hydrogen, substituted alkyl or unsubstituted alkyl, or R b and R c The variables which are, together with the nitrogen to which they are attached, can form a substituted or unsubstituted heterocyclic ring; R x and R z is independently hydrogen, hydroxy, cyano, halogen, -OR a , -COOR a , -S(=O) q -R a , -NR a R b , -C(=Z')-R a , substituted or unsubstituted alkyl groups, substituted or unsubstituted alkenyl groups, substituted or unsubstituted alkynyl groups, and substituted or unsubstituted cycloalkyl groups; Z' is selected from O or S; and Further preferred are compounds wherein p is independently 0, 1, or 2 at each occurrence.

[0036] In another embodiment of the present invention, a compound represented by structural formula (A-IIIA), (A-IIIB) or (A-IIIC) [ka] or a tautomer thereof, an isotope thereof, a prodrug thereof, an N-oxide thereof, a pharma- ceutically acceptable ester thereof, a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof, wherein: A1 is absent or independently substituted or unsubstituted C 1~4 Alkyl, substituted or unsubstituted C 2~4 Alkenyl, substituted or unsubstituted C 2~4Alkynyl, substituted or unsubstituted C 3~10 Cycloalkyl, substituted or unsubstituted C 3~10 Heterocycloalkyl, -(CR b R c ) p -, -O-, -S-, -S(=O) p -, -C(=O)-, -NR x -, -CO-NR x -, and -NR x -CO-, Cy 1 is selected from a cyclic group selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl; X 1 is C or N, X 2 -NG or CR y R y - selected from G, O or S; G is a group capable of forming an interaction with aspartic acid at position 12 of the KRAS protein, R 1 is, at each occurrence, independently selected from hydrogen, hydroxy, halogen, substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, C(═O)OR b , -C(=O)R b , -C(=S)R b , -C(=O)NRb R c 、-C(=O)ONR b R c 、-NR b R c 、-NR b C(=O)NR b R c 、-NR b S(=O)R c 、-NR b S(=O)2R c 、-NR b -OR c 、=N-NR b R c 、-NR b C(=O)OR c 、-NR b C(=O)R c 、-NR b C(=S)R c 、-NR b C(=S)NR b R c 、-SONR b R c 、-SO2NR b R c 、-OR b 、-OR b C(=O)NR b R c 、-OR b C(=O)OR c 、-OC(=O)R b 、-OC(=O)NR b R c 、-R b NR c C(=O)R b 、-R b OR c 、-R b C(=O)OR c 、-R b C(=O)NR b R c 、-R b C(=O)R c 、-R b OC(=O)R c 、-SR b 、-SOR c 、-SO2R b 、-CR b R cC(=O)R b , or -CR b R c C(=S)R z is selected from R a is, at each occurrence, independently selected from hydrogen, hydroxy, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, -C(=O)OR b , -C(=O)R b , -C(=S)R b , -C(=O)NR b R c , -C(=O)ONR b R c , -NR b R c , -NR b -OR c , -NR b C(=O)NR b R c , -NR b S(=O)R c , -NR b S(=O)2R c , -NR b -OR c , =N-NR b R c , -NR b C(=O)OR c , -NR b C(=O)R c , -NR b C(=S)R c , -NR b C(=S)NR b R c , -SONR b R c , -SO2NR b R c , -OR b , -OR b C(=O)NR b R c , -OR b C(=O)OR c , -OC(=O)R b , -OC(=O)NR b R c , -R b NR c C(=O)R b , -Rb OR c , -R b C(=O)OR c , -R b C(=O)NR b R c , -R b C(=O)R c , -R b OC(=O)R c , -SR b , -SOR c , -SO2R b , -CR b R c C(=O)R b , or -CR b R c C(=S)R z or any two R a may be taken together to form a substituted or unsubstituted, saturated or unsaturated 3- to 6-membered ring, which may optionally be the same or different, and which is selected from O, NR a or S; or any two R a Together, they form oxo (C=O) and imino (=NR b ), C=S(O) p or a substituted or unsubstituted, saturated or unsaturated 3- to 6-membered ring, which may optionally be the same or different, and may be selected from the group consisting of O, NR x or S, R b and R c is independently selected from, for each occurrence, hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclic ring, substituted heterocyclylalkyl ring, or substituted or unsubstituted amino, or R when attached to a common atom;b and R c any two of the above may be taken together to form (i) a substituted or unsubstituted, saturated or unsaturated 3- to 14-membered ring, which may optionally be the same or different, and which may be selected from O, NR x or S; or (ii) one or more heteroatoms selected from an oxo (=O) group, a thio (=S) group or an imino (=NR x ) group, R y is, at each occurrence, independently selected from hydrogen, hydroxy, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, -C(=O)OR b , -C(=O)R b , -C(=S)R b , -C(=O)NR b R c , -C(=O)ONR b R c , -NR b R c , -NR b -OR c , -NR b C(=O)NR b R c , -NR b S(=O)R c , -NR b S(=O)2R c , -NR b -OR c , -NR b C(=O)OR c , -NR b C(=O)R c , -NR b C(=S)R c , -NR b C(=S)NR b R c , -SONR b R c , -SO2NR b R c , -OR b , -OR b C(=O)NR b R c , -OR b C(=O)OR c , -OC(=O)Rb , -OC(=O)NR b R c , -R b NR c C(=O)R b , -R b OR c , -R b C(=O)OR c , -R b C(=O)NR b R c , -R b C(=O)R c , -R b OC(=O)R c , -SR b , -SOR c , -SO2R b , -CR b R c C(=O)R b , or -CR b R c C(=S)R z or any two R a may be taken together to form a substituted or unsubstituted, saturated or unsaturated 3- to 6-membered ring, which may optionally be the same or different, and which is selected from O, NR a or S; or any two R a Together, they form oxo (C=O) and imino (=NR b ), C=S(O) p or a substituted or unsubstituted, saturated or unsaturated 3- to 6-membered ring, which may optionally be the same or different, and may be selected from the group consisting of O, NR x or S, n is 0, 1, 2, 3, 4, 5, 6, 7, or 8; p is independently 0, 1, or 2 at each occurrence.

[0037] Formula (A), (AI), (A-II), (A-IIIA), (A-IIIB) or (A-IIIC), wherein A1 is absent or -CR b R c-, wherein R b and R c More preferred are compounds where each of is independently selected from hydrogen or substituted or unsubstituted alkyl.

[0038] Formula (A), (AI), (A-II), (A-IIIA), (A-IIIB) or (A-IIIC), wherein A1 is absent or -CR b R c -, wherein R b is independently methyl or ethyl; R c More preferably, the compound is a compound in which R is hydrogen.

[0039] Formula (A), (AI), (A-II), (A-IIIA), (A-IIIB) or (A-IIIC), wherein A1 is absent or -CR b R c -, wherein R b is hydrogen and R c More preferably, the compound is a compound in which R is hydrogen.

[0040] Further preferred are compounds of formula (A), (AI), (A-II), (A-IIIA), (A-IIIB) or (A-IIIC), wherein A1 is absent, -CH2, or -(C=O).

[0041] Formula (A), (AI), (A-II), (A-IIIA), (A-IIIB) or (A-IIIC), wherein Cy 1 More preferred are compounds in which the cyclic group is selected from substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl.

[0042] Formula (A), (AI), (A-II), (A-IIIA), (A-IIIB) or (A-IIIC), wherein Cy 1Further preferred are compounds in which is selected from a cyclic group selected from substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0043] Formula (A), (AI), (A-II), (A-IIIA), (A-IIIB) or (A-IIIC), wherein Cy 1 More preferably, the compound is selected from the following: [ka] TIFF2025502625000008.tif101158 Formula (A), (AI), (A-II), (A-IIIA), (A-IIIB) or (A-IIIC), wherein G is hydrogen, -NH2, -NHR a , -NHOH, -COOH, -OH or -CHR a More preferred are compounds which are -OH, or -CH2-OH or amino acids.

[0044] Further preferred are compounds of formula (A), (AI), (A-II), (A-IIIA), (A-IIIB) or (A-IIIC), wherein G is hydrogen, D-valine or L-threonine.

[0045] Formula (A), (AI), (A-II), (A-IIIA), (A-IIIB) or (A-IIIC), wherein R 1 is hydrogen, halogen, OR b , S.R. b , -S(=O) p R b -, -C(=O)-R b , -NR b R c , -CO-NR b R c -, and -NR b -CO-R c Further preferred are compounds selected from:

[0046] Formula (A), (AI), (A-II), (A-IIIA), (A-IIIB) or (A-IIIC), wherein R 1 -OR b Further preferred is a compound in which

[0047] Formula (A), (AI), (A-II), (A-IIIA), (A-IIIB) or (A-IIIC), wherein R 1 -NR b R c Further preferred is a compound in which

[0048] Formula (A), (AI), (A-II), (A-IIIA), (A-IIIB) or (A-IIIC), wherein R 1 More preferred are compounds where is independently selected from substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl.

[0049] Formula (A), (AI), (A-II), (A-IIIA), (A-IIIB) or (A-IIIC), wherein R 1 More preferred are compounds where is independently selected from substituted or unsubstituted alkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, and substituted or unsubstituted heteroaryl.

[0050] Formula (A), (AI), (A-II), (A-IIIA), (A-IIIB) or (A-IIIC), wherein R 1 is further preferably a compound independently selected from the following: [ka] TIFF2025502625000010.tif30158

[0051] Formula (A), (AI), (A-II), (A-IIIA), (A-IIIB) or (A-IIIC), wherein R a More preferred are compounds where is hydrogen or substituted or unsubstituted alkyl.

[0052] Formula (A), (AI), (A-II), (A-IIIA), (A-IIIB) or (A-IIIC), wherein two R a However, compounds which form a C=O (oxo) group are more preferred.

[0053] Formula (A), (AI), (A-II), (A-IIIA), (A-IIIB) or (A-IIIC), wherein A1 is (i) Not present or -CR b R c -, wherein R b and R c each is independently selected from hydrogen, or substituted or unsubstituted alkyl, and / or (ii) Not present or -CR b R c -, wherein R b is independently methyl or ethyl, and R c is hydrogen, and / or (iii) Absent or -CR b R c -, wherein R b is hydrogen and R c is hydrogen, and / or (iv) is absent, or is -CH2 or -(C=O), and / or any combination thereof; Cy 1 teeth, (i) a cyclic group selected from substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, and / or (ii) a cyclic group selected from substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl, and / or combinations thereof; R 1 teeth, (vi) Hydrogen, halogen, OR b , S.R. b , -S(=O) p R b -, -C(=O)-R b , -NR b R c , -CO-NR b R c - and -NR b -CO-R c and / or (vii)-OR b and / or (viii)-NR b R c and / or (ix) substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, and / or (x) selected from substituted or unsubstituted alkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, and substituted or unsubstituted heteroaryl, and / or combinations thereof; X 1 is C or N, X 2 -NG or CR y R y - selected from G, O or S; G is a group capable of forming an interaction with the aspartic acid at position 12 of the KRAS protein, and R y is, at each occurrence, independently selected from hydrogen, hydroxy, halogen, substituted or unsubstituted alkyl, -NR b R c , -OR b , -SR b , SOR c , -SO2Rb or two R y may be taken together to form a substituted or unsubstituted saturated or unsaturated 3- to 6-membered ring, which may optionally be the same or different, and may be O, NR a or S.

[0054] Formula (A), (AI), (A-II), (A-IIIA), (A-IIIB) or (A-IIIC), wherein A1 is absent or a substituted or unsubstituted C 1~4 is alkyl, Cy 1 is selected from substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; X 1 is C or N, X 2 -NG or CR y R y - selected from G, O or S; G is a group capable of forming an interaction with aspartic acid at position 12 of the KRAS protein, R y is, at each occurrence, independently selected from hydrogen, hydroxy, halogen, substituted or unsubstituted alkyl, -NR b R c , -OR b , -SR b , SOR c , -SO2R b or two R y may be taken together to form a substituted or unsubstituted saturated or unsaturated 3- to 6-membered ring, which may optionally be the same or different, and O, NR a or S, R 1is, at each occurrence, independently selected from hydrogen, hydroxy, halogen, substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, C(═O)OR b , -C(=O)R b , -C(=S)R b , -C(=O)NR b R c , -C(=O)ONR b R c , -NR b R c , -NR b C(=O)NR b R c , -NR b S(=O)R c , -NR b S(=O)2R c , -NR b -OR c , =N-NR b R c , -NR b C(=O)OR c , -NR b C(=O)R c , -NR b C(=S)R c , -NR b C(=S)NR b R c , -SONR b R c , -SO2NR b R c , -OR b , -OR b C(=O)NR b R c , -OR b C(=O)OR c , -OC(=O)R b, -OC(=O)NR b R c , -R b NR c C(=O)R b , -R b OR c , -R b C(=O)OR c , -R b C(=O)NR b R c , -R b C(=O)R c , -R b OC(=O)R c , -SR b , -SOR c , -SO2R b , -CR b R c C(=O)R b , or -CR b R c C(=S)R z is selected from R a is, at each occurrence, independently selected from hydrogen, hydroxy, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, -C(=O)OR b , -C(=O)R b , -C(=S)R b , -C(=O)NR b R c , -C(=O)ONR b R c , -NR b R c , -NR b -OR c , -NR b C(=O)NR b R c , -NR b S(=O)R c , -NR b S(=O)2R c , -NR b -OR c , =N-NR b R c , -NR b C(=O)OR c , -NR b C(=O)R c , -NR bC(=S)R c , -NR b C(=S)NR b R c , -SONR b R c , -SO2NR b R c , -OR b , -OR b C(=O)NR b R c , -OR b C(=O)OR c , -OC(=O)R b , -OC(=O)NR b R c , -R b NR c C(=O)R b , -R b OR c , -R b C(=O)OR c , -R b C(=O)NR b R c , -R b C(=O)R c , -R b OC(=O)R c , -SR b , -SOR c , -SO2R b , -CR b R c C(=O)R b , or -CR b R c C(=S)R z or any two R a may be taken together to form a substituted or unsubstituted, saturated or unsaturated 3- to 6-membered ring, which may optionally be the same or different, and which is selected from O, NR a or S; or any two R a Together, they form oxo (C=O) and imino (=NR b ), C=S(O) p or a substituted or unsubstituted, saturated or unsaturated 3- to 6-membered ring, which may optionally be the same or different, and may be selected from the group consisting of O, NRx or S, R b and R c is independently selected from, for each occurrence, hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclic ring, substituted heterocyclylalkyl ring, or substituted or unsubstituted amino, or R when attached to a common atom; b and R c any two of the above may be taken together to form (i) a substituted or unsubstituted, saturated or unsaturated 3- to 14-membered ring, which may optionally be the same or different, and which may be selected from O, NR x or S; or (ii) one or more heteroatoms selected from an oxo (=O) group, a thio (=S) group or an imino (=NR x ) group, R x and R z is independently hydrogen, hydroxy, cyano, halogen, -OR a , -COOR a , -S(=O) q -R a , -NR a R b , -C(=Z')-R a , substituted or unsubstituted alkyl groups, substituted or unsubstituted alkenyl groups, substituted or unsubstituted alkynyl groups, and substituted or unsubstituted cycloalkyl groups; Z' is selected from O or S; and Further preferred are compounds wherein p is independently 0, 1, or 2 at each occurrence.

[0055] Formula (A), (AI), (A-II), (A-IIIA), (A-IIIB) or (A-IIIC), wherein A1 is absent or is substituted or unsubstituted alkyl; Cy 1 is selected from a cyclic group selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl; X 1 is C or N, X 2 -NG or CR y R y - selected from G, O or S; G is a group capable of forming an interaction with aspartic acid at position 12 of the KRAS protein, R y is, at each occurrence, independently selected from hydrogen, hydroxy, halogen, substituted or unsubstituted alkyl, -NR b R c , -OR b , -SR b , SOR c , -SO2R b or two R y may be taken together to form a substituted or unsubstituted saturated or unsaturated 3- to 6-membered ring, which may optionally be the same or different, and O, NR a or S, R 1is, at each occurrence, independently selected from hydrogen, hydroxy, halogen, substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, C(═O)OR b , -C(=O)R b , -C(=S)R b , -C(=O)NR b R c , -C(=O)ONR b R c , -NR b R c , -NR b C(=O)NR b R c , -NR b S(=O)R c , -NR b S(=O)2R c , -NR b -OR c , =N-NR b R c , -NR b C(=O)OR c , -NR b C(=O)R c , -NR b C(=S)R c , -NR b C(=S)NR b R c , -SONR b R c , -SO2NR b R c , -OR b , -OR b C(=O)NR b R c , -OR b C(=O)OR c , -OC(=O)R b, -OC(=O)NR b R c , -R b NR c C(=O)R b , -R b OR c , -R b C(=O)OR c , -R b C(=O)NR b R c , -R b C(=O)R c , -R b OC(=O)R c , -SR b , -SOR c , -SO2R b , -CR b R c C(=O)R b , or -CR b R c C(=S)R z is selected from R a is, at each occurrence, independently selected from hydrogen, hydroxy, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, -C(=O)OR b , -C(=O)R b , -C(=S)R b , -C(=O)NR b R c , -C(=O)ONR b R c , -NR b R c , -NR b -OR c , -NR b C(=O)NR b R c , -NR b S(=O)R c , -NR b S(=O)2R c , -NR b -OR c , =N-NR b R c , -NR b C(=O)OR c , -NR b C(=O)R c , -NR bC(=S)R c , -NR b C(=S)NR b R c , -SONR b R c , -SO2NR b R c , -OR b , -OR b C(=O)NR b R c , -OR b C(=O)OR c , -OC(=O)R b , -OC(=O)NR b R c , -R b NR c C(=O)R b , -R b OR c , -R b C(=O)OR c , -R b C(=O)NR b R c , -R b C(=O)R c , -R b OC(=O)R c , -SR b , -SOR c , -SO2R b , -CR b R c C(=O)R b , or -CR b R c C(=S)R z or any two R a may be taken together to form a substituted or unsubstituted, saturated or unsaturated 3- to 6-membered ring, which may optionally be the same or different, and which is selected from O, NR a or S; or any two R a Together, they form oxo (C=O) and imino (=NR b ), C=S(O) p or a substituted or unsubstituted, saturated or unsaturated 3- to 6-membered ring, which may optionally be the same or different, and may be selected from the group consisting of O, NRx or S, R b and R c is independently selected from, for each occurrence, hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclic ring, substituted heterocyclylalkyl ring, or substituted or unsubstituted amino, or R when attached to a common atom; b and R c any two of the above may be taken together to form (i) a substituted or unsubstituted, saturated or unsaturated 3- to 14-membered ring, which may optionally be the same or different, and which may be selected from O, NR x or S; or (ii) one or more heteroatoms selected from an oxo (=O) group, a thio (=S) group or an imino (=NR x ) group, R x and R z is independently hydrogen, hydroxy, cyano, halogen, -OR a , -COOR a , -S(=O) q -R a , -NR a R b , -C(=Z')-R a , substituted or unsubstituted alkyl groups, substituted or unsubstituted alkenyl groups, substituted or unsubstituted alkynyl groups, and substituted or unsubstituted cycloalkyl groups; Z' is selected from O or S; and Further preferred are compounds wherein p is independently 0, 1, or 2 at each occurrence.

[0056] Formula (A), (AI), (A-II), (A-IIIA), (A-IIIB) or (A-IIIC), wherein Cy 1 is selected from substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; A1 is absent or independently substituted or unsubstituted C 1~4 Alkyl, substituted or unsubstituted C 2~4 Alkenyl, substituted or unsubstituted C 2~4 Alkynyl, substituted or unsubstituted C 3~10 Cycloalkyl, substituted or unsubstituted C 3~10 Heterocycloalkyl, -(CR b R c ) p -, -O-, -S-, -S(=O) p -, -C(=O)-, -NR x -, -CO-NR x -, and -NR x -CO-, X 1 is C or N, X 2 -NG or CR y R y - selected from G, O or S; G is a group capable of forming an interaction with aspartic acid at position 12 of the KRAS protein, R y is, at each occurrence, independently selected from hydrogen, hydroxy, halogen, substituted or unsubstituted alkyl, -NR b R c , -OR b , -SR b , SOR c , -SO2R b or two R y may be taken together to form a substituted or unsubstituted saturated or unsaturated 3- to 6-membered ring, which may optionally be the same or different, and O, NR a or S, R 1is, at each occurrence, independently selected from hydrogen, hydroxy, halogen, substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, C(═O)OR b , -C(=O)R b , -C(=S)R b , -C(=O)NR b R c , -C(=O)ONR b R c , -NR b R c , -NR b C(=O)NR b R c , -NR b S(=O)R c , -NR b S(=O)2R c , -NR b -OR c , =N-NR b R c , -NR b C(=O)OR c , -NR b C(=O)R c , -NR b C(=S)R c , -NR b C(=S)NR b R c , -SONR b R c , -SO2NR b R c , -OR b , -OR b C(=O)NR b R c , -OR b C(=O)OR c , -OC(=O)R b, -OC(=O)NR b R c , -R b NR c C(=O)R b , -R b OR c , -R b C(=O)OR c , -R b C(=O)NR b R c , -R b C(=O)R c , -R b OC(=O)R c , -SR b , -SOR c , -SO2R b , -CR b R c C(=O)R b , or -CR b R c C(=S)R z is selected from R a is, at each occurrence, independently selected from hydrogen, hydroxy, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, -C(=O)OR b , -C(=O)R b , -C(=S)R b , -C(=O)NR b R c , -C(=O)ONR b R c , -NR b R c , -NR b -OR c , -NR b C(=O)NR b R c , -NR b S(=O)R c , -NR b S(=O)2R c , -NR b -OR c , =N-NR b R c , -NR b C(=O)OR c , -NR b C(=O)R c , -NR bC(=S)R c , -NR b C(=S)NR b R c , -SONR b R c , -SO2NR b R c , -OR b , -OR b C(=O)NR b R c , -OR b C(=O)OR c , -OC(=O)R b , -OC(=O)NR b R c , -R b NR c C(=O)R b , -R b OR c , -R b C(=O)OR c , -R b C(=O)NR b R c , -R b C(=O)R c , -R b OC(=O)R c , -SR b , -SOR c , -SO2R b , -CR b R c C(=O)R b , or -CR b R c C(=S)R z or any two R a may be taken together to form a substituted or unsubstituted, saturated or unsaturated 3- to 6-membered ring, which may optionally be the same or different, and which is selected from O, NR a or S; or any two R a Together, they form oxo (C=O) and imino (=NR b ), C=S(O) p or a substituted or unsubstituted, saturated or unsaturated 3- to 6-membered ring, which may optionally be the same or different, and may be selected from the group consisting of O, NRx or S, R b and R c is independently selected from, for each occurrence, hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclic ring, substituted heterocyclylalkyl ring, or substituted or unsubstituted amino, or R when attached to a common atom; b and R c any two of the above may be taken together to form (i) a substituted or unsubstituted, saturated or unsaturated 3- to 14-membered ring, which may optionally be the same or different, and which may be selected from O, NR x or S; or (ii) one or more heteroatoms selected from an oxo (=O) group, a thio (=S) group or an imino (=NR x ) group, R x and R z is independently hydrogen, hydroxy, cyano, halogen, -OR a , -COOR a , -S(=O) q -R a , -NR a R b , -C(=Z')-R a , substituted or unsubstituted alkyl groups, substituted or unsubstituted alkenyl groups, substituted or unsubstituted alkynyl groups, and substituted or unsubstituted cycloalkyl groups; Z' is selected from O or S; and Further preferred are compounds wherein p is independently 0, 1, or 2 at each occurrence.

[0057] Formula (A), (AI), (A-II), (A-IIIA), (A-IIIB) or (A-IIIC), wherein A1 is absent or independently substituted or unsubstituted C 1~4 Alkyl, substituted or unsubstituted C 2~4 Alkenyl, substituted or unsubstituted C 2~4 Alkynyl, substituted or unsubstituted C 3~10 Cycloalkyl, substituted or unsubstituted C 3~10 Heterocycloalkyl, -(CR b R c ) p -, -O-, -S-, -S(=O) p -, -C(=O)-, -NR x -, -CO-NR x -, and -NR x -CO-, Cy 1 is selected from a cyclic group selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl; X 1 is C or N, X 2 -NG or CR y R y - selected from G, O or S; G is a group capable of forming an interaction with aspartic acid at position 12 of the KRAS protein, R y is, at each occurrence, independently selected from hydrogen, hydroxy, halogen, substituted or unsubstituted alkyl, -NR b R c , -OR b , -SR b , SOR c , -SO2R b or two R ymay be taken together to form a substituted or unsubstituted saturated or unsaturated 3- to 6-membered ring, which may optionally be the same or different, and O, NR a or S, R 1 is, at each occurrence, independently selected from hydrogen, hydroxy, halogen, substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, C(═O)OR b , -C(=O)R b , -C(=S)R b , -C(=O)NR b R c , -C(=O)ONR b R c , -NR b R c , -NR b C(=O)NR b R c , -NR b S(=O)R c , -NR b S(=O)2R c , -NR b -OR c , =N-NR b R c , -NR b C(=O)OR c , -NR b C(=O)R c , -NR b C(=S)R c , -NR b C(=S)NR b R c , -SONR b R c , -SO2NR b R c, -OR b , -OR b C(=O)NR b R c , -OR b C(=O)OR c , -OC(=O)R b , -OC(=O)NR b R c , -R b NR c C(=O)R b , -R b OR c , -R b C(=O)OR c , -R b C(=O)NR b R c , -R b C(=O)R c , -R b OC(=O)R c , -SR b , -SOR c , -SO2R b , -CR b R c C(=O)R b , or -CR b R c C(=S)R z is selected from R a is, at each occurrence, independently selected from hydrogen, hydroxy, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, -C(=O)OR b , -C(=O)R b , -C(=S)R b , -C(=O)NR b R c , -C(=O)ONR b R c , -NR b R c , -NR b -OR c , -NR b C(=O)NR b R c , -NR b S(=O)R c , -NR b S(=O)2R c , -NR b -ORc , =N-NR b R c , -NR b C(=O)OR c , -NR b C(=O)R c , -NR b C(=S)R c , -NR b C(=S)NR b R c , -SONR b R c , -SO2NR b R c , -OR b , -OR b C(=O)NR b R c , -OR b C(=O)OR c , -OC(=O)R b , -OC(=O)NR b R c , -R b NR c C(=O)R b , -R b OR c , -R b C(=O)OR c , -R b C(=O)NR b R c , -R b C(=O)R c , -R b OC(=O)R c , -SR b , -SOR c , -SO2R b , -CR b R c C(=O)R b , or -CR b R c C(=S)R z or any two R a may be taken together to form a substituted or unsubstituted, saturated or unsaturated 3- to 6-membered ring, which may optionally be the same or different, and which is selected from O, NR a or S; or any two Ra Together, they form oxo (C=O) and imino (=NR b ), C=S(O) p or a substituted or unsubstituted, saturated or unsaturated 3- to 6-membered ring, which may optionally be the same or different, and may be selected from the group consisting of O, NR x or S, R b and R c is independently selected from, for each occurrence, hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclic ring, substituted heterocyclylalkyl ring, or substituted or unsubstituted amino, or R when attached to a common atom; b and R c any two of the above may be taken together to form (i) a substituted or unsubstituted, saturated or unsaturated 3- to 14-membered ring, which may optionally be the same or different, and which may be selected from O, NR x or S; or (ii) one or more heteroatoms selected from an oxo (=O) group, a thio (=S) group or an imino (=NR x ) group, R x and R z is independently hydrogen, hydroxy, cyano, halogen, -OR a , -COOR a , -S(=O) q -R a , -NR a R b , -C(=Z')-R a , substituted or unsubstituted alkyl groups, substituted or unsubstituted alkenyl groups, substituted or unsubstituted alkynyl groups, and substituted or unsubstituted cycloalkyl groups; Z' is selected from O or S; and Further preferred are compounds wherein p is independently 0, 1, or 2 at each occurrence.

[0058] Formula (A), (AI), (A-II), (A-IIIA), (A-IIIB) or (A-IIIC), wherein R 1 is hydrogen, halogen, -NR b R c -OR b is selected from A1 is absent or independently substituted or unsubstituted C 1~4 Alkyl, substituted or unsubstituted C 2~4 Alkenyl, substituted or unsubstituted C 2~4 Alkynyl, substituted or unsubstituted C 3~10 Cycloalkyl, substituted or unsubstituted C 3~10 Heterocycloalkyl, -(CR b R c ) p -, -O-, -S-, -S(=O) p -, -C(=O)-, -NR x -, -CO-NR x -, and -NR x -CO-, Cy 1 is selected from a cyclic group selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl; X 1 is C or N, X 2 -NG or CR y R y - selected from G, O or S; G is a group capable of forming an interaction with aspartic acid at position 12 of the KRAS protein, Ry is, at each occurrence, independently selected from hydrogen, hydroxy, halogen, substituted or unsubstituted alkyl, -NR b R c , -OR b , -SR b , SOR c , -SO2R b or two R y may be taken together to form a substituted or unsubstituted saturated or unsaturated 3- to 6-membered ring, which may optionally be the same or different, and O, NR a or S, R a is, at each occurrence, independently selected from hydrogen, hydroxy, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, -C(=O)OR b , -C(=O)R b , -C(=S)R b , -C(=O)NR b R c , -C(=O)ONR b R c , -NR b R c , -NR b -OR c , -NR b C(=O)NR b R c , -NR b S(=O)R c , -NR b S(=O)2R c , -NR b -OR c , =N-NR b R c , -NR b C(=O)OR c , -NR b C(=O)R c , -NR b C(=S)R c , -NR b C(=S)NR b R c , -SONR b R c , -SO2NR b R c , -OR b, -OR b C(=O)NR b R c , -OR b C(=O)OR c , -OC(=O)R b , -OC(=O)NR b R c , -R b NR c C(=O)R b , -R b OR c , -R b C(=O)OR c , -R b C(=O)NR b R c , -R b C(=O)R c , -R b OC(=O)R c , -SR b , -SOR c , -SO2R b , -CR b R c C(=O)R b , or -CR b R c C(=S)R z or any two R a may be taken together to form a substituted or unsubstituted, saturated or unsaturated 3- to 6-membered ring, which may optionally be the same or different, and which is selected from O, NR a or S; or any two R a Together, they form oxo (C=O) and imino (=NR b ), C=S(O) p or a substituted or unsubstituted, saturated or unsaturated 3- to 6-membered ring, which may optionally be the same or different, and may be selected from the group consisting of O, NR x or S, R b and R c is independently selected at each occurrence from hydrogen, substituted alkyl or unsubstituted alkyl, or R b and R cThe variables which are, together with the nitrogen to which they are attached, can form a substituted or unsubstituted heterocyclic ring; R x and R z is independently hydrogen, hydroxy, cyano, halogen, -OR a , -COOR a , -S(=O) q -R a , -NR a R b , -C(=Z')-R a , substituted or unsubstituted alkyl groups, substituted or unsubstituted alkenyl groups, substituted or unsubstituted alkynyl groups, and substituted or unsubstituted cycloalkyl groups; Z' is selected from O or S; and Further preferred are compounds wherein p is independently 0, 1, or 2 at each occurrence.

[0059] In another embodiment of the present invention, the substituted naphthyridine is represented by structural formula (A), (AI), (A-II), (A-IIIA), (A-IIIB) or (A-IIIC): A1 is absent or is substituted or unsubstituted alkyl; Cy 1 is selected from substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; R 1 is hydrogen, halogen, substituted or unsubstituted alkyl, -NR b R c -OR b is selected from R b and R c is independently selected at each occurrence from hydrogen, substituted alkyl or unsubstituted alkyl, or R b and R c The variables which are, together with the nitrogen to which they are attached, can form a substituted or unsubstituted heterocyclic ring; X 1 is C or N, X 2 -NG or CR y R y- selected from G, O or S; G is a group capable of forming an interaction with aspartic acid at position 12 of the KRAS protein, R y is selected from hydrogen, halogen, substituted or unsubstituted alkyl, and n is 0, 1, 2, 3, 4, 5, 6, 7, or 8.

[0060] Further preferred are compounds of formula (A), (AI), (A-II), (A-IIIA), (A-IIIB) or (A-IIIC), wherein A1 is absent or methyl.

[0061] Formula (A), (AI), (A-II), (A-IIIA), (A-IIIB) or (A-IIIC), wherein A 1 More preferably, it is an absent compound.

[0062] Formula (A), (AI), (A-II), (A-IIIA), (A-IIIB) or (A-IIIC), wherein Cy 1 More preferably, the compound is selected from substituted or unsubstituted aryl.

[0063] Formula (A), (AI), (A-II), (A-IIIA), (A-IIIB) or (A-IIIC), wherein Cy 1 Further preferred are compounds selected from phenyl or naphthalene which may be substituted with halogen, hydroxy or substituted or unsubstituted alkyl.

[0064] Formula (A), (AI), (A-II), (A-IIIA), (A-IIIB) or (A-IIIC), wherein Cy 1 Further preferred are compounds selected from quinoline or quinazoline which may be substituted with halogen, hydroxy or substituted or unsubstituted alkyl.

[0065] Formula (A), (AI), (A-II), (A-IIIA), (A-IIIB) or (A-IIIC), wherein R 1 is more preferably hydrogen, halogen, hydroxy, and a compound selected from the following: [ka]

[0066] Formula (A-IIIA), (A-IIIB) or (A-IIIC), wherein X 1 is more preferably N.

[0067] Formula (A-IIIA), (A-IIIB) or (A-IIIC), wherein X 2 is -NG or CR y R y -G or O, where G is hydrogen, -NH2, -NHR a , -NHOH, -COOH, -OH or -CHR a Further preferred are compounds selected from -OH, or -CH2-OH or amino acids.

[0068] Formula (A), (AI), (A-II), (A-IIIA), (A-IIIB) or (A-IIIC), wherein A 1 is absent or is methyl, Cy 1 is selected from substituted or unsubstituted aryl; R 1 is selected from hydrogen, halogen, hydroxy, and [ka] X 1 is N, and X 2 is -NG or CR y R y -G or O, where G is hydrogen, -NH2, -NHR a , -NHOH, -COOH, -OH or -CHRa Further preferred are compounds selected from -OH, or -CH2-OH or amino acids.

[0069] Formula (A), (AI), (A-II), (A-IIIA), (A-IIIB) or (A-IIIC), wherein A 2 -Cy 2 More preferably, -G is a compound selected from the following: [ka]

[0070] It should be understood that the scope of the present invention contemplates any permutation of each of the above disclosed embodiments, including permutation of the preferred embodiments, e.g., any permutation of the different variables described herein may be selected as part of the present invention and are therefore within the scope of the present invention.

[0071] Non-limiting representative compounds of the present invention are as listed herein below, and pharma-ceutically acceptable salts thereof, and the present invention should not be construed as being limited to these compounds. 1. 1-(3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(3-hydroxynaphthalen-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride; 2. tert-Butyl 4-(6-(8-chloronaphthalen-1-yl)-4-cyano-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-2-(cyanomethyl)piperazine-1-carboxylate; 3. 6-(8-chloronaphthalen-1-yl)-1-(3-(cyanomethyl)piperazin-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride; 4. (1R,5S)-8-(4-cyano-6-(3-hydroxynaphthalen-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate tert-butyl; 5. 1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-6-(3-hydroxynaphthalen-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride; 6. 1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-6-(3-hydroxynaphthalen-1-yl)-3-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile compound (containing 2,2,2-trifluoroacetaldehyde (1:1)); 7. 1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-6-(8-bromonaphthalen-1-yl)-3-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile compound (containing 2,2,2-trifluoroacetaldehyde (1:1)); 8. 1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-6-(8-ethynylnaphthalen-1-yl)-3-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile compound (containing 2,2,2-trifluoroacetaldehyde (1:1)); 9. 1-((1R,5S,8r)-3-azabicyclo[3.2.1]octan-8-yl)-6-(8-bromo-3-hydroxynaphthalen-1-yl)-3-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile; 10. 1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-6-(8-bromonaphthalen-1-yl)-3-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile; 11. 1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-6-(8-ethynylnaphthalen-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile; 12. 1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-6-(8-ethynylnaphthalen-1-yl)-3-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile; 13. 6-Benzyl-1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-((1-(morpholinomethyl)cyclopropyl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile; 14. 1-(3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(8-ethynyl-3-hydroxynaphthalen-1-yl)-3-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile; 15. 1-(3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(8-bromo-3-hydroxynaphthalen-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile; 16. 1-(3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(8-chloronaphthalen-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile; 17. 1-(3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(8-chloronaphthalen-1-yl)-3-(((2R)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile; 18. 6-Benzyl-1-(3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile; 19. 6-Benzyl-1-(3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(((2R)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile; 20. ((R)-1-(4-(6-benzyl-4-cyano-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)piperazin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate tert-butyl; 21. 1-(4-(D-valyl)piperazin-1-yl)-6-benzyl-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile; 22. ((2S,3R)-1-(4-(6-benzyl-4-cyano-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)piperazin-1-yl)-3-(benzyloxy)-1-oxobutan-2-yl)carbamate tert-butyl; 23. 6-benzyl-1-(4-(O-benzyl-L-threonyl)piperazin-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile; 24. 6-Benzyl-1-(3,8-diazabicyclo[3.2.1]octan-3-yl)-3-((1-(morpholinomethyl)cyclopropyl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile; 25. 1-(3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(((2R)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile; 26. 3-(1,1-dioxidothiomorpholino)-6-(naphthalen-1-yl)-1-(piperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride; 27. 6-(8-chloronaphthalen-1-yl)-3-morpholino-1-(piperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride; 28. 3-(2-morpholinoethoxy)-6-(naphthalen-1-yl)-1-(piperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride; 29. 6-(8-chloronaphthalen-1-yl)-3-(2-morpholinoethoxy)-1-(piperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride; 30. 1-(2,6-Dimethylmorpholino)-6-(naphthalen-1-yl)-3-(piperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride; 31. 6-(8-chloronaphthalen-1-yl)-1-(2,6-dimethylmorpholino)-3-(piperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride; 32. 3-(3-(cyanomethyl)piperazin-1-yl)-1-(2,6-dimethylmorpholino)-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride; 33. (S)-6-(8-chloronaphthalen-1-yl)-3-((1-methylpyrrolidin-2-yl)methoxy)-1-(piperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride; 34. (S)-6-(3-hydroxynaphthalen-1-yl)-3-((1-methylpyrrolidin-2-yl)methoxy)-1-(piperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride; 35. (S)-3-((1-methylpyrrolidin-2-yl)methoxy)-1-(piperazin-1-yl)-6-(quinazolin-4-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride; 36. 6-(8-chloronaphthalen-1-yl)-1-(3-methylpiperazin-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride; 37. 1-(3-(cyanomethyl)piperazin-1-yl)-3-(2,6-dimethylmorpholino)-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride; 38. 1-((S)-3-(cyanomethyl)piperazin-1-yl)-3-(2,6-dimethylmorpholino)-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride; 39. 1-((R)-3-(cyanomethyl)piperazin-1-yl)-3-(2,6-dimethylmorpholino)-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride; 40. 1-(3-(cyanomethyl)piperazin-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride; 41. 1-((S)-3-(cyanomethyl)piperazin-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride; 42. 1-((R)-3-(cyanomethyl)piperazin-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride; 43. 1-(3-(cyanomethyl)piperazin-1-yl)-6-(3-hydroxynaphthalen-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride; 44. (S)-6-(isoquinolin-4-yl)-3-((1-methylpyrrolidin-2-yl)methoxy)-1-(piperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride; 45. (S)-3-((1-methylpyrrolidin-2-yl)methoxy)-1-(piperazin-1-yl)-6-(quinolin-8-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride; 46. ​​6-(8-chloronaphthalen-1-yl)-1-(3-(cyanomethyl)piperazin-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride; 47. 6-(8-chloronaphthalen-1-yl)-1-((S)-3-(cyanomethyl)piperazin-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride; 48. 6-(8-chloronaphthalen-1-yl)-1-((S)-3-(cyanomethyl)piperazin-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride; 49. 6-Benzyl-3-chloro-1-(piperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride; 50. 1-(4-aminopiperidin-1-yl)-6-benzyl-3-chloro-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride; 51. 1-(4-aminopiperidin-1-yl)-6-benzyl-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride; 52. 6-Benzyl-1,3-di(piperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride; 53. 6-Benzyl-3-hydroxy-1-(piperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride; 54. 6-Benzyl-3-morpholino-1-(piperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride; 55. 6-Benzyl-3-(4-methylpiperazin-1-yl)-1-(piperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride; 56. 6-Benzyl-1-(3-(cyanomethyl)piperazin-1-yl)-3-(4-methylpiperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride; 57. 6-(1-naphthoyl)-1-(3-(cyanomethyl)piperazin-1-yl)-3-(4-methylpiperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride; 58.(S)-6-Benzyl-1-(2-methylpiperazin-1-yl)-3-(4-methylpiperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride; 59.(R)-6-Benzyl-1-(2-methylpiperazin-1-yl)-3-(4-methylpiperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride; 60. 3-(4-Methylpiperazin-1-yl)-6-(naphthalen-1-yl)-1-(piperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride; 61. 6-Benzyl-1-(piperazin-1-yl)-3-(piperidin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride; 62. 6-Benzyl-3-(2-fluoropyridin-4-yl)-1-(piperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile; 63. 6-(Naphthalen-1-yl)-1-(piperazin-1-yl)-3-(piperidin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride; 64. 6-Benzyl-3-((1-methylpyrrolidin-2-yl)methoxy)-1-(piperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride; 65. 6-(Naphthalen-1-yl)-1,3-di(piperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride; 66. 6-(Benzo[b]thiophen-4-yl)-1,3-di(piperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile dihydrochloride; 67. 3-Morpholino-6-(naphthalen-1-yl)-1-(piperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride; 68. 3-(4-acetylpiperazin-1-yl)-6-(naphthalen-1-yl)-1-(piperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride; 69. 3-(2,6-Dimethylmorpholino)-6-(naphthalen-1-yl)-1-(piperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride; 70. 3-(4-(methylsulfonyl)piperazin-1-yl)-6-(naphthalen-1-yl)-1-(piperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride; 71. 3-(4-ethylpiperazin-1-yl)-6-(naphthalen-1-yl)-1-(piperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride; 72. (S)-3-((1-methylpyrrolidin-2-yl)methoxy)-6-(naphthalen-1-yl)-1-(piperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride; 73. 6-(Naphthalen-1-yl)-1-(piperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride; 74. 6-(Naphthalen-1-yl)-1-(piperazin-1-yl)-3-(4-propionylpiperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride; and 75. 6-benzyl-1-((S)-2-methylpiperazin-1-yl)-3-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, and pharma- ceutically acceptable salts thereof. [Table 1] TIFF2025502625000015.tif207158TIFF2025502625000016.tif198158TIFF2025502625000017.tif202158JPEG2025502625000018.jpg35158

[0072] Non-limiting representative compounds of the present invention listed herein below, and pharma- ceutically acceptable salts thereof, are as follows: [Table 2] TIFF2025502625000020.tif217158TIFF2025502625000021.tif222158TIFF2025502625000022.tif117158

[0073] Another embodiment of the present invention is a composition comprising a compound of the present invention, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

[0074] Yet another embodiment of the present invention is a method of treating cancer in a subject in need thereof, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present invention, or a pharma- ceutically acceptable salt thereof, or a composition comprising a compound of the present invention, or a pharma- ceutically acceptable salt thereof.

[0075] Without being bound by any particular theory, compounds are provided herein that can modulate (e.g., inhibit) one or more members of KRAS family, for example, one or more of KRAS mutants.More specifically, and without being bound by any particular theory, it is believed that compounds described herein can bind to KRAS G12D and function as covalent inhibitors of KRAS G12D.

[0076] Thus, in another embodiment, the present invention is a method of treating a KRAS mediated disorder, in particular a KRAS G12D mediated disorder, in a subject in need thereof, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present invention, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of the present invention, or a pharma- ceutically acceptable salt thereof.

[0077] Another embodiment of the invention is the use of a compound of the invention to treat cancer or a RAS-mediated disorder, particularly a KRAS G12D-mediated disorder, in a subject.

[0078] Another embodiment of the invention is the use of a compound of the invention for the manufacture of a medicament for treating cancer or a RAS-mediated disorder, particularly a KRAS G12D-mediated disorder, in a subject.

[0079] The compounds of the present invention, as well as pharma- ceutically acceptable salts and / or compositions thereof, are useful in the treatment of a variety of cancers, such as solid cancers, more particularly solid cancers with KRASG12 mutations. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0080] A description of an exemplary embodiment of the present invention follows. definition

[0081] The compounds of the present invention include those generally described above, and are further described by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For the purposes of the present invention, chemical elements are identified according to the Periodic Table of the Elements (CAS version, Handbook of Chemistry and Physics, 7 5th Ed.). In addition, the general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry", 5th Ed., Ed.: Smith, MB and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference.

[0082] Unless otherwise specified herein, the nomenclature used herein generally follows the examples and rules set forth in Nomenclature of Organic Chemistry, Sections A, B, C, D, E, F, and H, Pergamon Press, Oxford, 1979, which is incorporated herein by reference for its exemplary chemical structure names and rules for naming chemical structures. Optionally, compound names may be generated using the following chemical naming program: ACD / ChemSketch, version 5.09 / September 2001, Advanced Chemistry Development, Inc., Toronto, Canada.

[0083] The compounds of the present invention may have asymmetric centers, chiral axes, and chiral planes (e.g., as described in E.L. Eliel and S.H. Wilen, Stereo-chemistry of Carbon Compounds, John Wiley & Sons, New York, 1994, pages 1119-1190) and may occur as racemates, racemic mixtures, and as individual diastereomers or enantiomers, including all possible isomers, including optical isomers, and mixtures thereof, which are included in the present invention.

[0084] As used herein, the following definitions shall apply unless otherwise indicated. Furthermore, many of the groups defined herein may be substituted. The listing of substituents in the definitions is exemplary and should not be construed as limiting the substituents defined elsewhere herein.

[0085] The term "alkyl", unless otherwise specified, refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, unsaturated, having from one to eight carbon atoms and attached to the remainder of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, and 1,1-dimethylethyl (t-butyl). 1~3 The term "alkyl" refers to an alkyl group as defined above having up to three carbon atoms. 1~6 The term "alkyl" refers to an alkyl group, as defined above, having up to six carbon atoms. In appropriate circumstances, the term "alkyl" refers to a hydrocarbon chain radical as defined above that is divalent.

[0086] The term "alkenyl," unless otherwise specified, refers to an aliphatic hydrocarbon group containing one or more carbon-carbon double bonds and which may be straight or branched, having from about 2 to about 10 carbon atoms, e.g., ethenyl, 1-propenyl, 2-propenyl (allyl), iso-propenyl, 2-methyl-1-propenyl, 1-butenyl, and 2-butenyl. 2~6The term "alkenyl" refers to an alkenyl group, as defined above, having up to six carbon atoms. In appropriate circumstances, the term "alkenyl" refers to a hydrocarbon group as defined above that is divalent.

[0087] The term "alkynyl," unless otherwise specified, refers to a straight or branched chain hydrocarbyl radical having at least one carbon-carbon triple bond and having in the range of 2 up to 12 carbon atoms, with radicals having in the range of 2 up to 10 carbon atoms being preferred herein, e.g., ethynyl, propynyl, and butynyl. 2~6 The term "alkynyl" refers to an alkynyl group, as defined above, having up to six carbon atoms. In appropriate circumstances, the term "alkynyl" refers to a hydrocarbyl radical, as defined above, that is divalent.

[0088] The term "alkoxy" refers to an alkyl, cycloalkyl, or cycloalkylalkyl group, as defined above, attached to the remainder of the molecule through an oxygen linkage, unless otherwise specified. The term "substituted alkoxy" refers to an alkoxy group in which the alkyl moiety is substituted (i.e., -O-(substituted alkyl)). For example, "alkoxy" refers to an -O-alkyl group containing from 1 to 8 carbon atoms of a straight, branched, or cyclic configuration, and combinations thereof, attached to the parent structure through an oxygen atom. Examples include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, and cyclohexyloxy. In appropriate circumstances, the term "alkoxy" refers to the above groups that are divalent.

[0089] The term "cycloalkyl", unless otherwise specified, refers to a non-aromatic monocyclic or polycyclic ring system of about 3 to 12 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of polycyclic cycloalkyl groups include perhydronaphthyl, adamantyl, and norbornyl groups, bridged cyclic groups, and sprirobicyclic groups, such as sprio(4,4)non-2-yl. 3~6 The term "cycloalkyl" refers to a cycloalkyl group as defined above having up to 6 carbon atoms.

[0090] The term "cycloalkylalkyl," unless otherwise specified, refers to a cyclic ring-containing radical that contains in the range of about 3 up to 8 carbon atoms directly bonded to an alkyl group, which is then attached to the backbone structure at any carbon from the alkyl group, such as cyclopropylmethyl, cyclobutylethyl, and cyclopentylethyl.

[0091] The term "cycloalkenyl," unless otherwise specified, refers to a cyclic ring-containing radical containing in the range of about 3 up to 8 carbon atoms having at least one carbon-carbon double bond, such as cyclopropenyl, cyclobutenyl, and cyclopentenyl. The term "cycloalkenylalkyl" refers to a cycloalkenyl group directly bonded to an alkyl group which is then attached to the backbone structure at any carbon from the alkyl group.

[0092] The term "aryl", unless otherwise specified, refers to aromatic radicals having in the range of 6 up to 20 carbon atoms, such as phenyl, naphthyl, tetrahydronaphthyl, indanyl, and biphenyl.

[0093] The term "arylalkyl," unless otherwise specified, refers to an aryl group as defined above directly bonded to an alkyl group, for example, -CH2C6H5 and -C2H5C6H5.

[0094] Unless otherwise specified, the term "G" refers to a basic group capable of forming an interaction with an amino acid such as aspartic acid or a chemical moiety capable of forming an interaction with an amino acid such as aspartic acid, including the possibility that said interaction was a covalent bond formation, including a group that is an electrophile or electrophilic moiety capable of forming a covalent bond with an amino acid such as aspartic acid.

[0095] The term "heterocyclic ring", unless otherwise specified, refers to a non-aromatic 3- to 15-membered ring radical consisting of carbon atoms and at least one heteroatom selected from nitrogen, phosphorus, oxygen, and sulfur. For purposes of the present invention, a heterocyclic ring radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused, bridged, or spiro ring systems, and the nitrogen, phosphorus, carbon, oxygen, or sulfur atoms in the heterocyclic ring radical may be optionally oxidized to various oxidation states. In addition, the nitrogen atom may be optionally quaternized. The heterocyclic ring radical may be attached to the main chain structure at any heteroatom or carbon atom.

[0096] The term "heterocyclyl" refers to a heterocyclic ring radical, as defined above, unless otherwise specified. The heterocyclyl ring radical may be attached to the main chain structure at any heteroatom or carbon atom.

[0097] The term "heterocyclylalkyl," unless otherwise specified, refers to a heterocyclic ring radical as defined above directly bonded to an alkyl group. The heterocyclylalkyl radical may be attached to the main chain structure at any carbon atom within the alkyl group. Examples of such heterocycloalkyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl.

[0098] The term "heteroaryl," unless otherwise specified, refers to an optionally substituted 5-14 membered aromatic ring having as ring atoms one or more heteroatoms selected from N, O and S. Heteroaryl can be a monocyclic, bicyclic, or tricyclic ring system. Examples of such "heterocyclic ring" or "heteroaryl" radicals include, but are not limited to, oxazolyl, thiazolyl, imidazolyl, pyrrolyl, furanyl, pyridinyl, pyrimidinyl, pyrazinyl, benzofuranyl, indolyl, benzothiazolyl, benzoxazolyl, carbazolyl, quinolyl, isoquinolyl, azetidinyl, acridinyl, benzodioxolyl, benzodioxanyl, benzofuranyl, carbazolyl, cinnolinyl, dioxolanyl, indolizinyl, naphthyridinyl, perhydroazepinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, quinazolinyl, quinoxalinyl, tetrazoyl, tetrahydroisoquinolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperyl, Examples of heteroaryl ring radicals include aryl, 2-oxopyrrolidinyl, 2-oxoazepinyl, azepinyl, 4-piperidonyl, pyrrolidinyl, pyridazinyl, oxazolinyl, oxazolidinyl, triazolyl, indanyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolinyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, isoindolyl, indolinyl, isoindolinyl, octahydroindolyl, octahydroisoindolyl, decahydroisoquinolyl, benzimidazolyl, thiadiazolyl, benzopyranyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, dioxaphosphoranyl, oxadiazolyl, chromanyl, and isochromanyl. The heteroaryl ring radical may be attached to the backbone structure at any heteroatom or carbon atom. The term "substituted heteroaryl" also includes ring systems substituted with one or more oxide (-O-) substituents, such as pyridinyl N-oxides.

[0099] The term "heteroarylalkyl," unless otherwise specified, refers to a heteroaryl ring radical as defined above directly bonded to an alkyl group. The heteroarylalkyl radical may be attached to the main chain structure at any carbon atom from the alkyl group.

[0100] The term "cyclic ring" refers to a cyclic ring containing from 3 to 10 carbon atoms.

[0101] The term "substituted", unless otherwise specified, refers to the following substituents, which may be the same or different, and independently include hydrogen, hydroxy, halogen, carboxyl, cyano, nitro, oxo (=O), thio (=S), substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic ring, substituted heterocyclylalkyl ring, substituted or unsubstituted guanidine, -COOR x , -C(O)R x , -C(S)R x , -C(O)NR x R y , -C(O)ONR x R y , -NR y R z , -NR x CONR y R z , -N(R x )SOR y , -N(R x )SO2R y , -(=NN(R x )R y ), -NR x C(O)OR y , -NR x R y , -NR x C(O)R y -, -NR x C(S)Ry -, -NR x C(S)NR y R z , -SONR x R y -,-SO2NR x R y -, -OR x , -OR x C(O)NR y R z , -OR x C(O)OR y -,-OC(O)R x , -OC(O)NR x R y , -R x NR y C(O)R z , -R x OR y , -R x C(O)OR y , -R x C(O)NR y R z , -R x C(O)R x , -R x O.C.(O)R y , -SR x , -SOR x , -SO2R x and -ONO2, wherein R in each of the above groups is selected from x , R y and R z may be hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted amino, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic ring, or substituted heterocyclylalkyl ring, or R x , R y and R zAny two of the above may be taken together to form a substituted or unsubstituted, saturated or unsaturated 3- to 10-membered ring, which may be the same or different, and may be O, NR x (For example, R x is hydrogen or C 1~6 "Stable" refers to substitution with any one or any combination of substituents, which may include a heteroatom selected from alkyl, aryl ...

[0102] The term "halo", "halide" or alternatively "halogen" means fluoro, chloro, bromo, or iodo.

[0103] The terms "haloalkyl," "haloalkenyl," "haloalkynyl," and "haloalkoxy" include alkyl, alkenyl, alkynyl, and alkoxy structures that are substituted with one or more halo groups or combinations thereof. For example, the terms "fluoroalkyl" and "fluoroalkoxy" include haloalkyl and haloalkoxy groups, respectively, in which the halo is fluorine.

[0104] The term "amino acid" as used herein for the construction of a group is composed of an amino moiety (NH2) with or without a characteristic stereochemistry and an acid (-COOH) moiety, which may be optionally substituted, for example to form an amide or ester bond, or to carry a suitable protecting group, or may be optionally substituted with one or more amino acids as defined herein. More preferably, the amino acid is one in which the amino and acid moieties are located on the same carbon, or in other words, the amino moiety is in the alpha (α) position relative to a carboxyl group with or without a characteristic stereochemistry; the term amino acid also includes compounds in which the amino moiety is in the beta (β) position relative to a carboxyl group with or without a characteristic stereochemistry. For example, the list of amino acids includes, but is not limited to, alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine, including both D and L isomers. In addition, other amino acids are modified amino acids, which may be called non-protein amino acids or non-natural amino acids, and are naturally occurring or synthetically produced or commercially obtained, for example, due to chemical moieties with characteristic amino acids. In addition to the 20 amino acids of known natural origin, more than 300 other amino acids reported in the literature, which occur naturally or are chemically or biocatalytically synthesized, are intended to be included in the definition of the term amino acid.

[0105] The term "protecting group" or "PG" refers to a substituent used to block or protect a particular functionality. Other functional groups on the compound may remain reactive. For example, an "amino protecting group" is a substituent attached to an amino group that blocks or protects the amino functionality in the compound. Suitable amino protecting groups include, but are not limited to, acetyl, trifluoroacetyl, tert-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz), and 9-fluorenylmethylenoxycarbonyl (Fmoc). Similarly, a "hydroxy protecting group" refers to a substituent of a hydroxy group that blocks or protects the hydroxy functionality. Suitable hydroxy protecting groups include, but are not limited to, acetyl and silyl. A "carboxy protecting group" refers to a substituent of a carboxy group that blocks or protects the carboxy functionality. Suitable carboxy protecting groups include, but are not limited to, -CH2CH2SO2Ph, cyanoethyl, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrophenylsulfenyl)ethyl, 2-(diphenylphosphino)-ethyl, and nitroethyl. For a general description of protecting groups and their uses, see TW Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.

[0106] Some of the compounds described herein may contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined in terms of absolute stereochemistry as (R)- or (S)-. The chemical entities, pharmaceutical compositions, and methods of the present application are meant to include all such possible isomers, including racemic mixtures, optically pure forms, and intermediate mixtures. Non-limiting examples of intermediate mixtures include mixtures of isomers in ratios of 10:90, 13:87, 17:83, 20:80, or 22:78. Optically active (R) and (S) isomers can be prepared using chiral syntheses or chiral reagents, or separated using conventional techniques. When the compounds described herein contain olefinic double bonds or other geometrically asymmetric centers, unless otherwise specified, it is intended that the compounds include both E and Z geometric isomers.

[0107] The term "tautomer" refers to a compound characterized by relatively easy interconversion of equilibrium isomers. These isomers are intended to be encompassed by the present invention. "Tautomers" are structurally distinct isomers that are interconverted by tautomerism. "Tautomerism" is a form of isomerization and includes prototropic tautomerism or proton shift tautomerism, which is considered a subset of acid-base chemistry. "Prototropic tautomerism" or "proton shift tautomerism" involves the migration of a proton accompanied by a change in bond order, often swapping a single bond with an adjacent double bond. Where tautomerism is possible (e.g., in solution), a chemical equilibrium of tautomers may be reached. An example of tautomerism is keto-enol tautomerism. A specific example of keto-enol tautomerism is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerism is keto-enol tautomerism. A specific example of phenol-keto tautomerism is the interconversion of pyridin-4-ol and pyridin-4(1H)-one tautomers.

[0108] Unless otherwise stated, structures depicted herein are also intended to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure, such as the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E stereoisomers. Thus, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the compounds of the present application are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the present invention are within the scope of the invention.

[0109] Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, the replacement of hydrogen with deuterium or tritium, or the replacement of carbon with 13 C or 14 Compounds produced by substitution of C with condensed carbons are within the scope of the invention. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents according to the invention. For example, in the case of variable moiety R, (C1-C4) alkyl or -O-(C1-C4) alkyl can be suitably deuterated (e.g., -CD3, -OCD3).

[0110] The compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as tritium (3H), iodine-125 (125I), or carbon-14 (14C). All isotopic forms of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0111] The term "stereoisomers" is a general term for all isomers of individual molecules that differ only in the orientation of their atoms in space. This includes mirror image isomers (enantiomers), geometric (cis / trans) isomers, and isomers of compounds with more than one chiral center that are not mirror images of one another (diastereomers).

[0112] A "leaving group or atom" (Lg or lg) is any group or atom that, under reaction conditions, will cleave from the starting material, thus facilitating reaction at a particular site. Unless otherwise specified, suitable examples of such groups include halogen atoms and mesyloxy, p-nitrobenzenesulfonyloxy, and tosyloxy groups.

[0113] "Prodrug" is meant to refer to a compound that can be converted under physiological conditions or by solvation into a biologically active compound described herein (e.g., a compound of formula (A), (AI), (A-II), (A-IIIA), (A-IIIB) or (A-IIIC). Thus, the term "prodrug" refers to a precursor of a biologically active compound that is pharma- ceutically acceptable. In some embodiments, a prodrug is inactive when administered to a subject, but is converted to an active compound in vivo, for example, by hydrolysis. Prodrug compounds often offer advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam). A discussion of prodrugs is provided in Higuchi, T., et al., "Pro-drugs as Novel Delivery Systems," ACS Symposium Series, Vol. 14, and Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987; prodrug design is generally discussed in Hardma, et al. (Eds.), Goodman and Gilman's The Pharmacological Basis of Therapeutics, 9th ed., pp.11-16 (1996), all of which are fully incorporated herein by reference. The term "prodrug" is also meant to include any covalently bonded carrier that releases an active compound in vivo when the prodrug is administered to a mammalian subject. As described herein, prodrugs of active compounds are typically prepared by modifying functional groups present in the active compound such that the modifications are cleaved to the parent active compound, either by routine manipulation or in vivo.Prodrugs include compounds in which a hydroxy, amino, or mercapto group is bonded to any group that is cleaved to form a free hydroxy, amino, or mercapto group, respectively, when the prodrug of the active compound is administered to a mammalian subject. Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of hydroxy functional groups, or acetamide, formamide, and benzamide derivatives of amine functional groups in the active compound.

[0114] In some embodiments, the prodrugs include compounds of (A), (AI), (A-II), (A-IIIA), (A-IIIB) or (A-IIIC) having a phosphate, phosphoalkoxy ester or boronic ester substituent. Without being bound by theory, it is believed that such substituents are converted to hydroxyl groups under physiological conditions. Thus, embodiments include any of the compounds disclosed herein where the hydroxyl group is replaced with a phosphate, phosphoalkoxy ester or boronic ester group, e.g., a phosphate or phosphoalkoxy group. For example, in some embodiments, R 1 A hydroxyl group on the moiety is replaced with a phosphate, phosphoalkoxy ester, or boronic ester group, such as a phosphate or alkoxyphosphate group.

[0115] The term "ester" refers to a compound formed by the reaction between an acid and an alcohol by elimination of water. Esters may be represented by the general formula RCOOR'.

[0116] These prodrugs and esters are intended to be covered within the scope of the present invention.

[0117] In addition, the present invention also relates to the substitution of, for example, hydrogen with deuterium or tritium, or carbon with 13 C- or 14 Includes compounds that differ only in the presence of one or more isotopically enriched atoms, such as substitution with a C-enriched carbon.

[0118] When ranges are used herein with respect to physical properties, such as molecular weight, or chemical properties, such as chemical formula, it is intended that all combinations and subcombinations of ranges and specific embodiments thereof are included.

[0119] The term "about" when referring to a numerical value or numerical range means that the referenced number or numerical range is approximate within experimental variation (or within statistical experimental error), and thus the number or numerical range may vary, for example, by 1% to 15% of the stated number or numerical range.

[0120] The term "comprising" (and related terms such as "comprise" or "having" or "including") includes those embodiments, including, for example, embodiments of any composition, composition, method, or process that "consists of" or "consists essentially of" the recited features.

[0121] The following abbreviations and terms have the meanings indicated throughout, and the abbreviations used herein have their conventional meaning within the chemical and biological arts.

[0122] The term "cell proliferation" refers to the phenomenon in which cell number changes as a result of division. The term also encompasses cell proliferation in which cell morphology changes (e.g., increases in size) in concert with proliferation signals.

[0123] As used herein, "co-administration," "administered in combination with," and their grammatical equivalents include administration of two or more agents to an animal such that both agents and / or their metabolites are present in the animal at the same time. Co-administration includes administration at the same time in separate compositions, administration at different times in separate compositions, or administration in a composition in which both agents are present.

[0124] The term "effective amount" or "therapeutically effective amount" refers to an amount of a compound described herein that is sufficient to effect the intended application, including but not limited to disease treatment, as defined below. The therapeutically effective amount may vary depending on the intended application (in vitro or in vivo) or depending on the subject and disease state to be treated, such as the subject's weight and age, the severity of the disease state, the method of administration, etc., which can be readily determined by one of skill in the art. The term also applies to a dose that will induce a particular response in the target cells, such as, for example, a reduction in platelet adhesion and / or cell migration. The particular dose will vary depending on the particular compound selected, the dosing regimen to be followed, whether it is administered in combination with other compounds, the timing of administration, the tissue to which it is administered, and the physical delivery system that carries it. In one embodiment, the amount of the compound administered ranges from about 0.1 mg to 5 g, about 1 mg to 2.0 g, about 100 mg to 1.5 g, about 200 mg to 1.5 g, about 400 mg to 1.5 g, and about 400 mg to 1.0 g.

[0125] As used herein, "treatment", "treating" or "ameliorating" refers to an approach to obtain a beneficial or desired result, including but not limited to therapeutic benefit and / or preventive benefit. Therapeutic benefit refers to eradication or amelioration of the underlying disease being treated. Additionally, therapeutic benefit is also achieved by eradicating or ameliorating one or more of the physiological symptoms associated with the underlying disease, such that an improvement is observed in the patient, even though the patient may still be suffering from the underlying disease. For preventive benefit, the composition may be administered to a patient at risk of developing a particular disease, or to a patient who reports one or more of the physiological symptoms of the disease, but may not have been diagnosed with the disease. These terms are used interchangeably.

[0126] A "therapeutic benefit," as that term is used herein, encompasses the therapeutic and / or prophylactic benefits described above. A prophylactic benefit includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting or reversing the progression of a disease or condition, or any combination thereof.

[0127] As used herein, an amount of a compound effective to treat a disorder, or a "therapeutically effective amount," refers to an amount of a compound that, upon administration to a subject or cell in a single dose or multiple doses, is effective to cure, alleviate, relieve or ameliorate one or more symptoms of the disorder.

[0128] As used herein, an amount of a compound effective to prevent a disorder, or a "prophylactically effective amount" of a compound, refers to an amount effective to prevent or delay the onset or recurrence of a disorder or one or more symptoms of the disorder, upon administration to a subject in a single dose or multiple doses.

[0129] As used herein, the term "subject" or "patient" is intended to include humans and non-human animals. Exemplary human subjects include human patients with disorders, such as those described herein, or healthy subjects. The term "non-human animals" of the present invention includes all vertebrates, such as non-mammals (chickens, amphibians, reptiles, etc.), and mammals, such as non-human primates, domesticated animals and / or animals useful for agriculture, such as sheep, cows, pigs, etc., and companion animals (dogs, cats, horses, etc.).

[0130] The methods described herein can be useful for both human therapeutics and veterinary applications (eg, dogs, cats, cows, sheep, pigs, horses, goats, chickens, turkeys, ducks, and geese).

[0131] In some embodiments, the patient is a mammal, and in some embodiments, the patient is human.

[0132] "Radiation therapy" means exposing a patient to radiation emitters, such as, for example, alpha particle-emitting radionuclides (e.g., actinium and thorium radionuclides), low linear energy transfer (LET) radiation emitters (i.e., beta emitters), conversion electron emitters (e.g., strontium-89 and samarium-153-EDTMP), or high energy radiation, such as, but not limited to, x-rays, gamma rays, and neutrons, using common methods and compositions known to physicians.

[0133] The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes, but is not limited to, any and all non-toxic solvents, dispersants, excipients, adjuvants, fillers, salts, disintegrants, binders, lubricants, glidants, wetting agents, sustained release matrices, colorants / flavoring agents, carriers, buffers, stabilizers, solubilizers, or other materials that are mixed with the active ingredient to allow the formation of a pharmaceutical composition, i.e., the formation of a dosage form that can be administered to a patient, and combinations thereof. One example of such a carrier is a pharmaceutically acceptable oil typically used for parenteral administration. Pharmaceutically acceptable carriers are well known in the art.

[0134] It is understood that the substituents and substitution patterns of the compounds of the present invention can be selected by those skilled in the art to provide compounds that are chemically stable and can be easily synthesized by techniques known in the art, as well as the methods described below. In general, the term "substituted", whether preceded by the term "optionally", means that one or more hydrogens of the indicated moiety are replaced with suitable substituents. Unless otherwise indicated, an "optionally substituted (optionally substituted) group" can have a suitable substituent at each substitutable position of the group, and when multiple positions in any given structure may be substituted with multiple substituents selected from a specified group, the substituents may be the same or different at each position. Alternatively, an "optionally substituted (optionally substituted) group" can be unsubstituted.

[0135] The combination of substituents envisioned by the present invention is preferably one that results in the formation of a stable or chemically viable compound. When a substituent itself is substituted with multiple groups, it is understood that these multiple groups may be on the same or different carbon atoms, so long as a stable structure results. As used herein, the term "stable" refers to a compound that is substantially unchanged when subjected to conditions that allow for its production, detection, and, in certain embodiments, its recovery, purification, and use for one or more of the purposes disclosed herein.

[0136] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that is suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic reaction, etc., within the scope of sound medical judgment, and is commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, the relevant teachings of which are incorporated herein by reference in their entirety. The pharmaceutically acceptable salts of the compounds of the present invention include salts derived from suitable inorganic and organic acids, and bases compatible with the treatment of patients.

[0137] Examples of pharma- ceutically acceptable, non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric, hydrobromic, phosphoric, sulfuric, and perchloric acids, or with organic acids such as acetic, oxalic, maleic, tartaric, citric, succinic, or malonic acids, or by using other methods used in the art, such as ion exchange. Other pharma-ceutically acceptable acid addition salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, hydrogensulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, and the like. Examples of suitable salts include, but are not limited to, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, and valerate.

[0138] In some embodiments, exemplary inorganic acids that form suitable salts include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, as well as acid metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate. Exemplary organic acids that form suitable salts include monocarboxylic acids, dicarboxylic acids, and tricarboxylic acids. Illustrative of such acids are, for example, acetic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, salicylic acid, 2-phenoxybenzoic acid, p-toluenesulfonic acid, and other sulfonic acids such as methanesulfonic acid and 2-hydroxyethanesulfonic acid. Either mono- or di-acid salts can be formed, or such salts can exist in either hydrated, solvated, or substantially anhydrous form. In general, the acid addition salts of these compounds are more soluble in water and various hydrophilic organic solvents, and usually demonstrate higher melting points in comparison to their free base forms.

[0139] In some embodiments, acid addition salts of compounds of Formula (A), (AI), (A-II), (A-IIIA), (A-IIIB) or (A-IIIC) are most suitably formed from a pharma- ceutically acceptable acid and include, for example, acid addition salts formed with inorganic acids such as hydrochloric acid, sulfuric acid or phosphoric acid, and acid addition salts formed with organic acids such as succinic acid, maleic acid, acetic acid or fumaric acid.

[0140] Other pharmaceutically unacceptable salts, such as oxalates, may be used, for example, for laboratory use or for subsequent conversion to pharmaceutically acceptable acid addition salts, in the isolation of compounds of formula (A), (AI), (A-II), (A-IIIA), (A-IIIB) or (A-IIIC).Also included within the scope of the present invention are base addition salts (such as sodium, potassium and ammonium salts), solvates and hydrates of the compounds of the present invention.Conversion of a given compound salt to a desired compound salt is accomplished by applying standard techniques well known to those skilled in the art.

[0141] "Anti-cancer agent", "anti-tumor agent" or "chemotherapeutic agent" refers to any agent useful in the treatment of a neoplastic condition. One class of anti-cancer agents includes chemotherapeutic agents. "Chemotherapy" refers to the administration of one or more chemotherapeutic and / or other agents to a cancer patient by various methods including intravenous, oral, intramuscular, intraperitoneal, intravesical, subcutaneous, transdermal, buccal or inhalation, or in the form of a suppository. The term "cell proliferation" refers to the phenomenon in which the number of cells changes as a result of division. This term also encompasses cell proliferation in which the structure of the cell changes (e.g., increases in size) in accordance with a proliferation signal.

[0142] The terms "selective inhibition" or "selectively inhibit" refer to the ability of an agent to preferentially reduce target signaling activity relative to off-target signaling activity, through a direct or indirect interaction with the target.

[0143] "Any" or "optionally" means that the subsequently described circumstance event may or may not occur, such that the description includes instances in which the event or circumstance occurs and instances in which it does not occur. For example, "optionally substituted (optionally substituted) aryl" means that the aryl radical may be substituted or unsubstituted, and the description includes both substituted and unsubstituted aryl radicals.

[0144] A "pharmaceutical composition" refers to a medium normally accepted in the art for the formulation of a compound of the invention and the delivery of a biologically active compound to a mammal, e.g., a human. Such a medium includes any pharma- ceutically acceptable carrier, diluent, or excipient thereof.

[0145] When introducing elements disclosed herein, the articles "a," "an," "the," and "said" are intended to mean that there are one or more elements. The terms "comprising," "having," and "including" are intended to be open-ended, meaning that there may be additional elements other than the listed elements.

[0146] For example, provided herein is a method for treating various cancers in mammals (including humans and non-humans), comprising administering to a patient in need thereof a compound of the present invention or a pharma- ceutically acceptable salt thereof.Such cancers include hematological malignancies (leukemia, lymphoma, myeloma, myelodysplastic syndromes and myeloproliferative disorders) and solid tumors (carcinomas of the oral cavity, gallbladder, prostate, breast, lung, colon, pancreas, kidney, ovary, etc., as well as sarcomas and osteosarcomas of soft tissues, and stromal tumors).

[0147] Pharmaceutical Compositions The present invention provides pharmaceutical compositions comprising one or more compounds of the present invention. The pharmaceutical compositions may comprise one or more additional active ingredients as described herein. The pharmaceutical compositions may be administered for any of the disorders described herein.

[0148] The subject pharmaceutical compositions are typically formulated to provide a therapeutically effective amount of the compound of the present invention as an active ingredient. If necessary, the pharmaceutical compositions contain the compound of the present invention as an active ingredient and one or more pharma- ceutically acceptable carriers or excipients, such as inert solid diluents and fillers, diluents including sterile aqueous solutions, and various organic solvents, penetration enhancers, solubilizers, and adjuvants.

[0149] A pharmaceutical composition can be administered alone or in combination with one or more other drugs, which are also typically administered in the form of a pharmaceutical composition. If necessary, the subject compound and the other drugs may be mixed into one preparation, or both components may be formulated into separate preparations and used in combination separately or simultaneously.

[0150] The methods include administering a compound of the present invention alone or in combination as described herein, in each case optionally including one or more suitable diluents, fillers, salts, disintegrants, binders, lubricants, glidants, wetting agents, sustained release matrices, colorants / flavors, carriers, excipients, buffers, stabilizers, solubilizers, and combinations thereof.

[0151] The preparation of various pharmaceutical compositions is known in the art and can be found, for example, in Anderson, Philip O.; Knoben, James E.; Troutman, William G, eds., Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill, 2002; Pratt and Taylor, eds., Principles of Drug Action, Third Edition, Churchill Livingston, New York, 1990; Katzung, ed., Basic and Clinical Pharmacology, Ninth Edition, McGraw Hill, 2003; Goodman and Gilman, eds., The Pharmacological Basis of Therapeutics, Tenth Edition, McGraw Hill, 2001; Remingtons Pharmaceutical Sciences, 20th Ed., Lippincott Williams & Wilkins., 2000; Martindale, The Extra Pharmacopoeia, Thirty-Second Edition (The Pharmaceutical Press, London, 1999), all of which are incorporated herein by reference in their entireties.

[0152] The compounds or pharmaceutical compositions of the present invention can be administered by any route that allows delivery of the compound to the site of action, such as, for example, oral route, intraduodenal route, parenteral injection (including intravenous, intraarterial, subcutaneous, intramuscular, intravascular, intraperitoneal, or infusion), local administration (e.g., transdermal administration), rectal administration, local delivery by catheter or stent, or by inhalation.The compounds can also be administered intraadiposally or intrathecally.

[0153] The composition can be administered in solid, semi-solid, liquid or gas form, or can be dry powder, such as lyophilized form.The pharmaceutical composition can be packaged in a form convenient for delivery, including solid dosage forms such as capsules, sachets, cachets, gelatin, paper, tablets, capsules, suppositories, pellets, pills, troches and lozenges.The type of packaging generally depends on the desired route of administration.Implantable sustained release formulations are also contemplated, as are transdermal formulations.

[0154] Treatment method In a further aspect, the present invention provides the use of a compound of the present invention, or a pharma- ceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of cancer. In some embodiments, the present invention provides the use of a compound of the present invention in the manufacture of a medicament for the treatment of either cancer and / or neoplastic disorders. In a further aspect, the present invention provides a compound of the present invention for use in the treatment of cancer. In some embodiments, the present invention provides a compound of the present invention for use in the treatment of cancer and / or neoplastic disorders.

[0155] The compounds or compositions described herein can be used to treat neoplastic disorders. A "neoplastic disorder" is a disease or disorder characterized by cells capable of autonomous growth or replication, such as, for example, an abnormal condition or condition characterized by proliferative cell proliferation. Exemplary neoplastic disorders include, but are not limited to, carcinomas, sarcomas, metastatic disorders, such as solid tumors of the oral cavity, gallbladder, prostate, breast, lung, colon, pancreas, kidney, ovary, and the like, as well as sarcomas and osteosarcomas of soft tissue, and stromal tumors, such as tumors arising from the prostate, brain, bone, colon, pancreas, lung, breast, ovary, and liver, hematopoietic neoplastic disorders, such as leukemia, lymphoma, myeloma, myelodysplastic syndrome, myeloproliferative syndrome, and other malignant plasma cell disorders, and metastatic tumors. Common cancers include, but are not limited to, breast cancer, prostate cancer, colon cancer, lung cancer, liver cancer, and pancreatic cancer. Treatment with the compound can be in an amount effective to ameliorate at least one symptom of a neoplastic disorder, eg, a reduction in cell proliferation, a reduction in tumor mass, etc.

[0156] The disclosed methods are useful in the prevention and treatment of cancer, including, for example, solid tumors, soft tissue tumors, and their metastases, as well as familial cancer syndromes, such as Li-Fraumeni syndrome, familial breast and ovarian cancer (BRCA1 or BRAC2 mutation) syndrome, and the like. The disclosed methods are also useful in the treatment of non-solid cancers. Examples of solid tumors include malignant tumors (e.g., sarcomas, adenocarcinomas, and carcinomas) of various organ systems, such as the lung, breast, lymphatic, gastrointestinal system (e.g., colon), and genitourinary tract (e.g., renal, urothelial, or testicular tumors), pharynx, prostate, and ovary. Exemplary adenocarcinomas include colorectal cancer, renal cell carcinoma, hepatic cancer, non-small cell carcinoma of the lung, and cancer of the small intestine.

[0157] Exemplary cancers include, but are not limited to, tumors that are carcinomas of the lung, prostate, breast, brain, skin, cervix, testis, etc. More specifically, cancers that may be treated by the compositions and methods of the present invention include, but are not limited to, tumor types such as astrocytic, breast, cervical, colorectal, endometrial, esophageal, gastric, head and neck, hepatocellular, pharyngeal, lung, oral, ovarian, prostate, and thyroid carcinomas and sarcomas. More specifically, these compounds can be used to treat: cardiac: sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma; lung: bronchogenic carcinoma (squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondroitin hamartoma, mesothelioma; gastrointestinal: Ductal system: Esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vipoma), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, smooth fibroids); genitourinary system: kidney (adenocarcinoma, Wilms' tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma); liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma , hepatocellular adenoma, hemangioma;biliary tract: gallbladder cancer, ampullary cancer, bile duct cancer;bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteochondral exostosis), benign chondroma, chondroblastoma, chondromyxoid fibroma, osteoid osteoma and giant cell tumor;Nervous system: skull (osteoma, hemangioma, granuloma, xanthomas, osteitis deformans), meninges (meningioma, meningeal sarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal neurofibroma, meningioma, glioma, sarcoma); gynecology: uterus (endometrial cancer), cervix (cervical cancer, preneoplastic cervical dysplasia), ovary (ovarian cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, carcinoma unclassified), granulosa-thecal cell tumor tumor), Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tube (carcinoma); blood system: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndromes), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma), skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic nevi, lipoma, hemangioma, dermatofibroma, keloid, psoriasis, and adrenal gland: neuroblastoma.;

[0158] More preferably, the present invention provides a method of inhibiting KRAS activity in a cell, the method comprising contacting a cell in which inhibition of KRAS activity is desired with an effective amount of a compound of Formula (A), (AI), (A-II), (A-IIIA), (A-IIIB) or (A-IIIC), a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition containing the compound or a pharma- ceutically acceptable salt thereof.

[0159] More preferably, the present invention provides a method for inhibiting KRAS G12D activity in a cell, the method comprising contacting a cell in which inhibition of KRAS G12D activity is desired with an effective amount of a compound of formula (A), (AI), (A-II), (A-IIIA), (A-IIIB) or (A-IIIC), a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition containing the compound or a pharma- ceutically acceptable salt thereof.

[0160] In one embodiment, a cell in which inhibition of KRAS G12D activity is desired is contacted with an effective amount of a compound of Formula (A), (AI), (A-II), (A-IIIA), (A-IIIB) or (A-IIIC) to negatively regulate the activity of KRAS G12D.

[0161] More preferably, a therapeutically effective amount of a pharma- ceutically acceptable salt or pharmaceutical composition containing a compound of formula (A), (AI), (A-II), (A-IIIA), (A-IIIB) or (A-IIIC) may be used.

[0162] The method described herein is designed to inhibit the undesirable cell proliferation caused by enhanced KRAS G12D activity in cells by negatively regulating the activity of KRAS G12D.Cells can be contacted with a single dose or multiple doses according to a specific treatment regimen to bring about the desired negative regulation of KRAS G12D.

[0163] More preferably, there is provided a method of treating cancer in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a compound of Formula (A), (AI), (A-II), (A-IIIA), (A-IIIB) or (A-IIIC), a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound or a pharma- ceutically acceptable salt thereof.

[0164] The compositions and methods provided herein can be used in the treatment of KRAS-associated cancer in patients in need thereof, and the method comprises administering to the patient a therapeutically effective amount of the compound of formula (A), (AI), (A-II), (A-IIIA), (A-IIIB) or (A-IIIC), its pharmaceutical acceptable salt, or the pharmaceutical composition comprising the compound or its pharmaceutical acceptable salt.In one embodiment, the KRAS G12D-associated cancer is lung cancer.

[0165] The compositions and methods provided herein can be used in the treatment of KRAS G12D-associated cancer in patients in need thereof, and the method comprises administering to the patient a therapeutically effective amount of the compound of formula (A), (AI), (A-II), (A-IIIA), (A-IIIB) or (A-IIIC), its pharmaceutical acceptable salt, or the pharmaceutical composition comprising the compound or its pharmaceutical acceptable salt.In one embodiment, the KRAS G12D-associated cancer is lung cancer.

[0166] The compositions and methods provided herein may be used to treat a wide range of cancers, including, but not limited to, tumors that are carcinomas of the lung, prostate, breast, brain, skin, cervix, testis, etc. More specifically, cancers that may be treated by the compositions and methods of the present invention include, but are not limited to, tumor types such as astrocytic, breast, cervical, colorectal, endometrial, esophageal, gastric, head and neck, hepatocellular, pharyngeal, lung, oral, ovarian, prostate, and thyroid carcinomas and sarcomas. More specifically, these compounds can be used to treat: cardiac: sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma; lung: bronchogenic carcinoma (squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondroitin hamartoma, mesothelioma; gastrointestinal: Ductal system: Esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vipoma), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, smooth fibroids); genitourinary system: kidney (adenocarcinoma, Wilms' tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma); liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma , hepatocellular adenoma, hemangioma;biliary tract: gallbladder cancer, ampullary cancer, bile duct cancer;bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteochondral exostosis), benign chondroma, chondroblastoma, chondromyxoid fibroma, osteoid osteoma and giant cell tumor;Nervous system: skull (osteoma, hemangioma, granuloma, xanthomas, osteitis deformans), meninges (meningioma, meningeal sarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal neurofibroma, meningioma, glioma, sarcoma); gynecology: uterus (endometrial cancer), cervix (cervical cancer, preneoplastic cervical dysplasia), ovary (ovarian cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, carcinoma unclassified), granulosa-thecal cell tumor tumor), Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tube (carcinoma); blood system: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndromes), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma), skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic nevi, lipoma, hemangioma, dermatofibroma, keloid, psoriasis, and adrenal gland: neuroblastoma.;

[0167] More preferably, the cancer is non-small cell lung cancer, colorectal cancer, or pancreatic cancer.

[0168] More preferably, the cancer is lung cancer or colorectal cancer.

[0169] More preferably, the cancer is pancreatic cancer.

[0170] The concentration and route of administration to patients can vary depending on the cancer to be treated.The compound, its pharmaceutically acceptable salt, and pharmaceutical compositions containing such compounds and salts can also be co-administered with other anti-tumor compounds, such as chemotherapy, or used in combination with other treatments, such as in combination with other targeted agents or radiation or surgical intervention, either as pre- or post-operative adjuvant.

[0171] The present invention further provides a compound of formula (A), (AI), (A-II), (A-IIIA), (A-IIIB) or (A-IIIC), or a pharma- ceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof, as defined herein, for use in therapy.

[0172] The present invention further provides a compound of formula (A), (AI), (A-II), (A-IIIA), (A-IIIB) or (A-IIIC), or a pharma- ceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof, as defined herein, for use in the treatment of cancer.

[0173] The present invention further provides a compound of Formula (A), (AI), (A-II), (A-IIIA), (A-IIIB) or (A-IIIC), or a pharma- ceutically acceptable salt or solvate thereof, for use in inhibiting KRAS G12D.

[0174] The present invention further provides a compound of formula (A), (AI), (A-II), (A-IIIA), (A-IIIB) or (A-IIIC), or a pharma- ceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof, as defined herein, for use in the treatment of a KRAS G12D-associated disease or disorder.

[0175] The present invention further provides the use of a compound of formula ((A), (AI), (A-II), (A-IIIA), (A-IIIB) or (A-IIIC), or a pharma- ceutically acceptable salt or solvate thereof, as defined herein, in the manufacture of a medicament for the treatment of cancer.

[0176] The present invention provides the use of a compound of formula (A), (AI), (A-II), (A-IIIA), (A-IIIB) or (A-IIIC), or a pharma- ceutically acceptable salt or solvate thereof, as defined herein, in the manufacture of a medicament for the inhibition of the activity of KRAS G12D.

[0177] The present invention provides the use of a compound of formula (A), (AI), (A-II), (A-IIIA), (A-IIIB) or (A-IIIC), or a pharma- ceutically acceptable salt or solvate thereof, as defined herein, in the manufacture of a medicament for the treatment of a KRAS G12D-associated disease or disorder.

[0178] The present invention relates to a method for treating cancer in a patient in need of treatment, the method comprising: (a) identifying the cancer as associated with a KRAS G12D mutation (e.g., a KRAS G12D-associated cancer) (e.g., identified using a regulatory approved, e.g., FDA approved, assay or kit); and (b) administering to the patient a therapeutically effective amount of a compound of Formula (A), (AI), (A-II), (A-IIIA), (A-IIIB) or (A-IIIC) or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0179] Metastasis of the aforementioned cancers can also be treated or prevented according to the methods described herein.

[0180] Combination therapy In some embodiments, the compounds described herein are administered together with an additional "second" therapeutic agent or treatment. The second therapeutic agent may be selected from any agent typically used in monotherapy to treat the indicated disease or condition. As used herein, the term "administered together" and related terms refer to simultaneous or sequential administration of a therapeutic agent according to the invention. For example, a compound of the present invention may be administered together with another therapeutic agent simultaneously or sequentially in separate unit dosage forms, or together in a single unit dosage form. Thus, the present invention provides a single unit dosage form comprising a compound of any of the formulas described herein, an additional therapeutic agent, and a pharma- ceutically acceptable carrier, adjuvant, or vehicle.

[0181] In one embodiment of the present invention, when a second therapeutic agent is administered to a subject, the effective amount of the compound of the present invention is less than its effective amount when the second therapeutic agent is not administered. In another embodiment, the effective amount of the compound of the second therapeutic agent is less than its effective amount when the compound of the present invention is not administered. In this way, the undesirable side effects associated with any agent at high doses can be minimized. Other potential advantages (including, but not limited to, improved dosing regimens and / or reduced drug costs) will be apparent to those skilled in the art. The additional agents may be administered separately from the compound of the present invention as part of a multiple dose regimen. Alternatively, these agents may be part of a single dosage form mixed together with the compound of the present invention in a single composition.

[0182] The compounds, their pharma- ceutically acceptable salts, and pharmaceutical compositions comprising such compounds and salts may also be co-administered with other anti-tumor compounds, such as, for example, chemotherapy, or used in combination with other treatments, such as in combination with other targeted agents or radiation or surgical intervention, either as a pre- or post-operative adjunct.

[0183] The compounds, pharma- ceutical acceptable salts thereof, and pharmaceutical compositions comprising such compounds may be administered to a subject in need thereof, either simultaneously or sequentially with at least one other anti-cancer agent, anti-inflammatory agent, immunosuppressant, steroid, nonsteroidal anti-inflammatory agent, antihistamine, analgesic agent, or a mixture thereof.

[0184] Processes for preparing the compounds of the present invention The compounds of the present invention can be prepared by the following general process. The processes provided herein can be similarly applied to synthesize all possible variations of the compounds of the present invention, in particular the compounds of formula (A) provided herein above with all intended variations or without any variations. Unless otherwise indicated, the R, R a , R 1 , A1, A2, Cy 1 , Cy 2Variable moieties such as, for example, R, R, and E are to be constructed as defined herein above with respect to the compounds of the invention, particularly compounds of formula (A).

[0185] Synthetic Scheme A: This schematic of a scheme is intended to provide a possible route for the preparation of compounds of formula (A). Scheme A [ka]

[0186] In the intermediate of formula (A1), Pg is a suitable protecting group that, when reacted with an intermediate of formula R-CH-CONH using a suitable base or reagent, gives an intermediate of formula (A2). The intermediate of formula (A2) can then be subjected to chlorination using POCl to give an intermediate of formula (A3), which is represented by the formula Lg-A2-Cy. 2 When reacted with intermediate f of formula (A4), Lg is a good leaving group and with the use of a suitable base, intermediates of formula (A4) are obtained. The intermediates of formula (A4) are then reacted with intermediate f of formula (A4) to obtain intermediates of formula (A4) 1 where Lg is a good leaving group and with the use of a suitable base, an intermediate of formula (A5) is obtained. The intermediate of formula (A5) is then deprotected and subsequently reacted with Lg-A1-Cy under suitable conditions, such as a Buchwald coupling or other suitable N-alkylation or N-arylation to give Lg-A1-Cy. 1 group to give the desired compound of formula (A). A. The scheme in Example 1 provides an exemplary use of Scheme A as follows. [ka] B. The following scheme provides yet another illustrative use of Scheme A for preparing compounds of the invention. [ka] C. The following scheme provides yet another illustrative use of Scheme A for preparing compounds of the invention. [ka]

[0187] Experimental details The examples and preparations provided below further describe and illustrate the compounds of the present invention and the methods of preparing such compounds. It should be understood that the scope of the present invention is not limited in any manner by the scope of the following examples and preparations. In the following examples, molecules with a single chiral center are present as racemic mixtures unless otherwise specified. Molecules with two or more chiral centers are present as racemic mixtures of diastereomers unless otherwise specified. Single enantiomers / diastereomers can be obtained by methods known to those skilled in the art.

[0188] Part A: Preparation of intermediates Intermediate A: 6-benzyl-1,3-dioxo-1,2,3,4,5,6,7,8-octahydro-2,6-naphthyridine-4-carbonitrile: Ethyl 1-benzyl-3-oxopiperidine-4-carboxylate (300 g, 1.14 mol) was added to a two-neck flask containing methanol (2250 ml) to which was added cyanoacetamide (96 g, 1.14 mol) followed by a solution of potassium hydroxide in methanol (79 g, 1.43 mol KOH in 1485 mL MeOH). The resulting mixture was stirred and heated to reflux for 16 hours. The reaction mixture was cooled to room temperature and the white solid was filtered off and washed with methanol (250 mL). The resulting white solid was dried under reduced pressure to obtain 430 g of KOH salt 6-benzyl-1,3-dioxo-1,2,3,4,5,6,7,8-octahydro-2,6-naphthyridine-4-carbonitrile. The KOH salt was heated to 92°C in 3000 ml of water, acidified with concentrated HCl, filtered, washed with 500 ml of water, and dried in an oven overnight. Then, well-dried intermediate 1 (230 g, salt-free) 6-benzyl-1,3-dioxo-1,2,3,4,5,6,7,8-octahydro-2,6-naphthyridine-4-carbonitrile was obtained. MS(m / z):282.20[M+H] + .

[0189] Intermediate B: 6-benzyl-1,3-dichloro-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile: Intermediate 1 (20 g, 0.071 mmol), tetramethylammonium chloride salt (9.3 g, 0.085 mol), and phosphorus oxychloride (7 mL, 0.71 mol) were placed in a sealed vessel and heated at 125 °C for 14 h. The reaction was cooled to room temperature, the vessel was slowly opened, and concentrated under reduced pressure. The concentrated residue was poured into crushed ice and stirred vigorously with a glass rod. A saturated solution of NaOH (~500 mL) was then slowly added to the cooled, diluted reaction mixture to make it alkaline (pH = 8-10). The solid precipitated, was filtered off, and dried in an oven overnight to give Intermediate 2 (17 g) as a pale green solid. MS (m / z): 318.20 [M+H] + .

[0190] Intermediate 1: Synthesis of (1R,5S)-3-(6-benzyl-3-chloro-4-cyano-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-butyl: To a solution of 6-benzyl-1,3-dichloro-5,6,7,8-tetrahydro-2,6-naphthyridin-4-carbonitrile in THF, (1R,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-butyl and DIPEA were added. The reaction mixture was heated at 60° C. for 12 hours. The reaction was poured into water and extracted with ethyl acetate (3x), the combined organic layers were dried under Na2SO4, evaporated under reduced pressure and the crude material was purified by column chromatography eluting with ethyl acetate:n-hexane (1:4) to give (1R,5S)-tert-butyl 3-(6-benzyl-3-chloro-4-cyano-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. Mass Spectrum: 495.1[m+1].

[0191] Intermediate 1A: (1R,5S)-8-(6-benzyl-3-chloro-4-cyano-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate tert-butyl: To a solution of 6-benzyl-1,3-dichloro-5,6,7,8-tetrahydro-2,6-naphthyridin-4-carbonitrile in THF was added (1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate tert-butyl and DIPEA. The reaction mixture was heated at 60° C. for 12 hours. The reaction was poured into water and extracted with ethyl acetate (3x), the combined organic layers were dried under Na2SO4, evaporated under reduced pressure and the crude material was purified by column chromatography eluting with ethyl acetate:n-hexane (1:4) to give (1R,5S)-tert-butyl 8-(6-benzyl-3-chloro-4-cyano-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate. Mass Spectrum: 495.0[m+1].

[0192] Intermediate 2: (1R,5S)-3-(6-benzyl-4-cyano-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-butyl: A solution of (S)-(1-methylpyrrolidin-2-yl)methanol in THF was cooled at 0° C. NaH was added in portions and (1R,5S)-3-(6-benzyl-3-chloro-4-cyano-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-butyl was dissolved in THF and added dropwise. The reaction mixture was heated at 60° C. for 12 hours. The reaction was poured into water and extracted with ethyl acetate (3x), the combined organic layers were dried over Na2SO4, evaporated under reduced pressure and the crude material was purified using column chromatography eluting with (1:10) methanol:DCM to give tert-butyl (1R,5S)-3-(6-benzyl-4-cyano-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. Mass Spec: 573.2 [m+1].

[0193] Intermediate 2A: (1R,5S)-tert-butyl 8-(6-benzyl-4-cyano-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate: A solution of (S)-(1-methylpyrrolidin-2-yl)methanol in THF was cooled at 0° C. NaH was added in portions and (1R,5S)-tert-butyl 8-(6-benzyl-3-chloro-4-cyano-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate dissolved in THF was added dropwise. The reaction mixture was heated at 60° C. for 12 hours. The reaction was poured into water and extracted with ethyl acetate (3x), the combined organic layers were dried over Na2SO4, evaporated under reduced pressure and the crude material was purified using column chromatography eluting with (1:10) methanol:DCM to give tert-butyl (1R,5S)-8-(6-benzyl-4-cyano-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate. Mass Spec: 573.4 [m+1]. A solution of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol in THF was cooled to 0° C. NaH was added in portions to prepare tert-butyl (1R,5S)-3-(6-benzyl-3-chloro-4-cyano-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)methanol.

[0194] Intermediate 3: (1R,5S)-3-(6-benzyl-4-cyano-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-butyl: A solution of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol in THF was cooled at 0° C. NaH was added in portions and tert-butyl (1R,5S)-3-(6-benzyl-3-chloro-4-cyano-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate dissolved in THF was added dropwise. The reaction mixture was heated at 60° C. for 12 h. The reaction was poured into water and extracted with ethyl acetate (3x), the combined organic layers were dried over Na2SO4, evaporated under reduced pressure and the crude material was purified using column chromatography eluting with (1:10) methanol:DCM to give tert-butyl (1R,5S)-3-(6-benzyl-4-cyano-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. Mass Spec: 617.3 [m+1].

[0195] Intermediate 3A: (1R,5S)-8-(6-benzyl-4-cyano-3-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate tert-butyl: A solution of (tetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol in THF was cooled at 0° C. NaH was added in portions and (1R,5S)-8-(6-benzyl-3-chloro-4-cyano-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate tert-butyl was dissolved in THF and added dropwise. The reaction mixture was heated at 60° C. for 12 hours. The reaction was poured into water and extracted with ethyl acetate (3x), the combined organic layers were dried under Na2SO4, evaporated under reduced pressure and the crude material was purified using column chromatography eluting with (1:10) methanol:DCM to give tert-butyl (1R,5S)-8-(6-benzyl-4-cyano-3-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate. Mass Spec: 599.3 [m+1].

[0196] Intermediate 4: (1R,5S)-3-(tert-butyl 6-benzyl-4-cyano-3-((1-(hydroxymethyl)cyclopropyl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate: A solution of cyclopropane-1,1-diyldimethanol in THF was cooled at 0° C. NaH was added in portions and (1R,5S)-3-(6-benzyl-3-chloro-4-cyano-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-butyl dissolved in THF was added dropwise. The reaction mixture was heated at 60° C. for 12 hours. The reaction was poured into water and extracted with ethyl acetate (3x), the combined organic layers were dried under Na2SO4, evaporated under reduced pressure and the crude material was purified using column chromatography eluting with 30% ethyl acetate:petroleum ether to give tert-butyl (1R,5S)-3-(6-benzyl-4-cyano-3-((1-(hydroxymethyl)cyclopropyl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. Mass Spec: 560.2[m+1].

[0197] Intermediate 4A: (1R,5S)-tert-butyl 8-(6-benzyl-4-cyano-3-((1-(hydroxymethyl)cyclopropyl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate: A solution of cyclopropane-1,1-diyldimethanol in THF was cooled at 0° C. NaH was added in portions and tert-butyl (1R,5S)-3-(6-benzyl-3-chloro-4-cyano-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate dissolved in THF was added dropwise. The reaction mixture was heated at 60° C. for 12 hours. The reaction was poured into water and extracted with ethyl acetate (3x), the combined organic layers were dried over Na2SO4, evaporated under reduced pressure and the crude material was purified using column chromatography eluting with 30% ethyl acetate:petroleum ether to give tert-butyl (1R,5S)-8-(6-benzyl-4-cyano-3-((1-(hydroxymethyl)cyclopropyl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate. Mass Spec: 560.3[m+1].

[0198] Intermediate 5: (1R,5S)-3-(6-benzyl-4-cyano-3-((1-(((methylsulfonyl)oxy)methyl)cyclopropyl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-butyl: A solution of (1R,5S)-3-(6-benzyl-4-cyano-3-((1-(hydroxymethyl)cyclopropyl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-butyl in DCM was cooled at 0° C. Triethylamine and methanesulfonyl chloride were added dropwise. The reaction mixture was stirred at room temperature for 2 hours. The reaction was poured into water and extracted with ethyl acetate (3x) and the combined organic layers were dried over Na2SO4 and evaporated under reduced pressure to give tert-butyl (1R,5S)-3-(6-benzyl-4-cyano-3-((1-(((methylsulfonyl)oxy)methyl)cyclopropyl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. Mass Spec: 638.5[m+1].

[0199] Intermediate 5A: (1R,5S)-tert-butyl 8-(6-benzyl-4-cyano-3-((1-(((methylsulfonyl)oxy)methyl)cyclopropyl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate: A solution of (1R,5S)-tert-butyl 8-(6-benzyl-4-cyano-3-((1-(hydroxymethyl)cyclopropyl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate in DCM was cooled at 0° C. Triethylamine and methanesulfonyl chloride were added dropwise. The reaction mixture was stirred at room temperature for 2 hours. The reaction was poured into water and extracted with ethyl acetate (3x) and the combined organic layers were dried over Na2SO4 and evaporated under reduced pressure to give tert-butyl (1R,5S)-8-(6-benzyl-4-cyano-3-((1-(((methylsulfonyl)oxy)methyl)cyclopropyl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate. Mass Spec: 638.6[m+1].

[0200] Intermediate 6: (1R,5S)-3-(6-benzyl-4-cyano-3-((1-(morpholinomethyl)cyclopropyl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-butyl: A solution of (1R,5S)-3-(6-benzyl-4-cyano-3-((1-(((methylsulfonyl)oxy)methyl)cyclopropyl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-butyl in THF was cooled at 0° C. DIPEA and morpholine were added dropwise. The reaction mixture was heated at 60° C. for 12 hours. The reaction was poured into water and extracted with ethyl acetate (3x), the combined organic layers were dried under Na2SO4, evaporated under reduced pressure and the crude material was purified using column chromatography eluting with 1% MeOH:DCM to give tert-butyl (1R,5S)-3-(6-benzyl-4-cyano-3-((1-(morpholinomethyl)cyclopropyl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. Mass Spec: 629.6[m+1].

[0201] Intermediate 6A: (1R,5S)-8-(6-benzyl-4-cyano-3-((1-(morpholinomethyl)cyclopropyl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate tert-butyl: A solution of (1R,5S)-8-(6-benzyl-4-cyano-3-((1-(((methylsulfonyl)oxy)methyl)cyclopropyl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate tert-butyl in THF was cooled at 0° C. DIPEA and morpholine were added dropwise. The reaction mixture was heated at 60° C. for 12 hours. The reaction was poured into water and extracted with ethyl acetate (3x), the combined organic layers were dried over Na2SO4, evaporated under reduced pressure and the crude material was purified using column chromatography eluting with 1% MeOH:DCM to give (1R,5S)-tert-butyl 8-(6-benzyl-4-cyano-3-((1-(morpholinomethyl)cyclopropyl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate. Mass Spec: 629.4[m+1].

[0202] Intermediate 6B: tert-butyl 4-(4-cyano-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-2-(cyanomethyl)piperazine-1-carboxylate: Intermediate 5a was prepared in a similar manner as described herein above for Intermediate 5 using Intermediate 2 with some modifications and using the specified chemicals and reagents. It was used in the next step without analytical data being obtained.

[0203] Intermediate 7: (1R,5S)-3-(4-cyano-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-butyl: A solution of (1R,5S)-3-(6-benzyl-4-cyano-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-butyl in methanol was purged with nitrogen gas for 10 minutes. 10% Pd / c was added and a H2 bladder was placed over the reaction flask. The reaction mixture was stirred at room temperature for 12 hours. The reaction was filtered through a pad of Celite and the filtrate was evaporated under reduced pressure to give tert-butyl (1R,5S)-3-(4-cyano-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. Mass Spectrum: 483.1 [m+1].

[0204] Intermediate 7A: (1R,5S)-tert-butyl 8-(4-cyano-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate: A solution of (1R,5S)-8-(6-benzyl-4-cyano-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate tert-butyl in methanol was purged with nitrogen gas for 10 minutes. 10% Pd / c was added and a H2 bladder was placed over the reaction flask. The reaction mixture was stirred at room temperature for 12 hours. The reaction was filtered through a pad of Celite and the filtrate was evaporated under reduced pressure to give tert-butyl (1R,5S)-8-(4-cyano-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate. Mass Spectrum: 483.1 [m+1].

[0205] Intermediate 8: Synthesis of tert-butyl (1R,5S)-3-(4-cyano-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate: A solution of tert-butyl (1R,5S)-3-(4-cyano-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate in methanol was purged with nitrogen gas for 10 minutes. 10% Pd / c was added and a H2 bladder was placed over the reaction flask. The reaction mixture was stirred at room temperature for 12 hours. The reaction was filtered through a pad of Celite and the filtrate was evaporated under reduced pressure to give tert-butyl (1R,5S)-3-(4-cyano-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. Mass Spectrum: 527.3[m+1].

[0206] Intermediate 8A: (1R,5S)-tert-butyl 8-(4-cyano-3-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate: A solution of (1R,5S)-8-(6-benzyl-4-cyano-3-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate tert-butyl in methanol was purged with nitrogen gas for 10 minutes. 10% Pd / c was added and a H2 bladder was placed over the reaction flask. The reaction mixture was stirred at room temperature for 12 hours. The reaction was filtered through a pad of Celite and the filtrate was evaporated under reduced pressure to give tert-butyl (1R,5S)-8-(4-cyano-3-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate. Mass Spectrum: 509.4[m+1].

[0207] Intermediate 9: (1R,5S)-3-(6-(8-chloronaphthalen-1-yl)-4-cyano-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-butyl: To a solution of (1R,5S)-3-(4-cyano-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-butyl and 1-bromo-8-chloronaphthalene in toluene was added CsCO and purged with N gas for 10 minutes. To it, Xantphos and Pd2(dba)3 were added and purged again for 5 minutes. The reaction mixture was heated at 110° C. for 16 hours. The reaction mixture was diluted with water, extracted with ethyl acetate (3×50 ml) and the combined organic layers were washed with brine, dried over Na2SO4 and evaporated under reduced pressure. Purification using column chromatography eluting with 2% DCM-methanol gave tert-butyl (1R,5S)-3-(6-(8-chloronaphthalen-1-yl)-4-cyano-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. Mass Spectrometry: 644.1 [m+1].

[0208] Intermediate 10: (1R,5S)-3-(6-(8-chloronaphthalen-1-yl)-4-cyano-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-butyl: (1R,5S)- in toluene To a solution of tert-butyl 3-(4-cyano-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate and 1-bromo-8-chloronaphthalene was added Cs2CO3 and purged with N2 gas for 10 minutes. To it was added Xantphos and Pd2(dba)3 and purged again for 5 minutes. The reaction mixture was heated at 110°C for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (3x50ml) and the combined organic layers were washed with brine, dried over Na2SO4 and evaporated under reduced pressure. Purification by column chromatography eluting with 2% DCM-methanol gave tert-butyl (1R,5S)-3-(6-(8-chloronaphthalen-1-yl)-4-cyano-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. Mass Spectrum: 688.2 [M-1].

[0209] Intermediate 11: (1R,5S)-3-(4-cyano-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-butyl: (1R,5S) in toluene To a solution of tert-butyl-3-(4-cyano-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate and 4-bromonaphthalen-2-ol was added Cs2CO3 and purged with N2 gas for 10 minutes. To it was added Xantphos and Pd2(dba)3 and purged again for 5 minutes. The reaction mixture was heated at 110°C for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (3x50ml) and the combined organic layers were washed with brine, dried over Na2SO4 and evaporated under reduced pressure. Purification by column chromatography eluting with 2% DCM-methanol gave tert-butyl (1R,5S)-3-(4-cyano-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. Mass Spectrum: 669.5[M+1].

[0210] Intermediate 11A: (1R,5S)-8-(4-cyano-6-(3-hydroxynaphthalen-1-yl)-3-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid tert-Butyl: To a solution of tert-butyl (1R,5S)-8-(4-cyano-3-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate and 4-bromonaphthalen-2-ol in toluene was added Cs2CO3 and purged with N2 gas for 10 minutes. To it was added Xantphos and Pd2(dba)3 and purged again for 5 minutes. The reaction mixture was heated at 110°C for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (3x50ml) and the combined organic layers were washed with brine, dried over Na2SO4 and evaporated under reduced pressure. Purification by column chromatography eluting with 2% DCM-methanol gave tert-butyl (1R,5S)-8-(4-cyano-6-(3-hydroxynaphthalen-1-yl)-3-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate. Mass Spectrum: 651.3 [M+1].

[0211] Intermediate 12A: (1R,5S)-8-(4-cyano-3-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-(8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate tert-butyl: (1R,5S)- in toluene To a solution of tert-butyl 8-(4-cyano-3-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate and ((8-bromonaphthalen-1-yl)ethynyl)triisopropylsilane was added Cs2CO3 and purged with N2 gas for 10 minutes. To it was added Xantphos and Pd2(dba)3 and purged again for 5 minutes. The reaction mixture was heated at 110°C for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (3x50ml) and the combined organic layers were washed with brine, dried over Na2SO4 and evaporated under reduced pressure. Purification by column chromatography eluting with 2% DCM-methanol gave tert-butyl (1R,5S)-8-(4-cyano-3-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-(8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate. Mass Spectrum: 816.1 [M+1].

[0212] Intermediate 13A: (1R,5S)-8-(4-cyano-6-(3-hydroxy-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-3-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate tert-butyl: (1R,5S) in toluene To a solution of tert-butyl 8-(4-cyano-3-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate and 4-bromo-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol was added Cs2CO3 and purged with N2 gas for 10 minutes. To it was added Xantphos and Pd2(dba)3 and purged again for 5 minutes. The reaction mixture was heated at 110°C for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (3x50ml) and the combined organic layers were washed with brine, dried over Na2SO4 and evaporated under reduced pressure. Purification by column chromatography eluting with 2% DCM-methanol gave tert-butyl (1R,5S)-8-(4-cyano-6-(3-hydroxy-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-3-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate. Mass Spectrum: 832.1 [M-1].

[0213] Intermediate 14A: (1R,5S)-8-(4-cyano-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6-(8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate tert-butyl: (1R,5S)- in toluene To a solution of tert-butyl 8-(4-cyano-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate and ((8-bromonaphthalen-1-yl)ethynyl)triisopropylsilane was added Cs2CO3 and purged with N2 gas for 10 minutes. To it was added Xantphos and Pd2(dba)3 and purged again for 5 minutes. The reaction mixture was heated at 110°C for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (3x50ml) and the combined organic layers were washed with brine, dried over Na2SO4 and evaporated under reduced pressure. Purification by column chromatography eluting with 2% DCM-methanol gave tert-butyl (1R,5S)-8-(4-cyano-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6-(8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate. Mass Spectrum: 790.1 [M-1].

[0214] Intermediate 15A: (1R,5S)-tert-butyl 8-(6-(8-bromonaphthalen-1-yl)-4-cyano-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate: To a solution of (1R,5S)-tert-butyl 8-(4-cyano-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate and 1,8-dibromonaphthalene in toluene was added CsCO and purged with N gas for 10 minutes. To it, Xantphos and Pd2(dba)3 were added and purged again for 5 minutes. The reaction mixture was heated at 110° C. for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (3×50 ml) and the combined organic layers were washed with brine, dried over Na2SO4 and evaporated under reduced pressure. Purification using column chromatography eluting with 2% DCM-methanol gave tert-butyl (1R,5S)-8-(6-(8-bromonaphthalen-1-yl)-4-cyano-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate. Mass Spectrometry: 688.3 [M-1].

[0215] Intermediate 16A: (1R,5S)-tert-butyl 8-(6-(8-bromo-6-hydroxynaphthalen-1-yl)-4-cyano-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate: To a solution of tert-butyl 8-(4-cyano-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate and 4,5-dibromonaphthalen-2-ol in toluene was added CsCO and purged with N gas for 10 minutes. To it, Xantphos and Pd2(dba)3 were added and purged again for 5 minutes. The reaction mixture was heated at 110° C. for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (3×50 ml) and the combined organic layers were washed with brine, dried over Na2SO4 and evaporated under reduced pressure. Purification using column chromatography eluting with 2% DCM-methanol gave tert-butyl (1R,5S)-8-(6-(8-bromo-6-hydroxynaphthalen-1-yl)-4-cyano-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate. Mass Spectrometry: 704.2 [M-1].

[0216] Intermediate 17A: (1R,5S)-8-(4-cyano-6-(8-ethynylnaphthalen-1-yl)-3-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate tert-butyl ... in DMF To tert-butyl ano-3-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-(8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate was added CsF and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (3x50ml) and the combined organic layers were washed with brine, dried over Na2SO4 and evaporated under reduced pressure. Purification by column chromatography eluting with 3% DCM-methanol gave tert-butyl (1R,5S)-8-(4-cyano-6-(8-ethynylnaphthalen-1-yl)-3-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate. Mass Spectrum: 659.4 [M-1].

[0217] Intermediate 18A: (1R,5S)-8-(4-cyano-6-(8-ethynyl-3-hydroxynaphthalen-1-yl)-3-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate tert-butyl ... in DMF To tert-butyl ano-6-(3-hydroxy-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-3-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate was added CsF and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (3x50ml) and the combined organic layers were washed with brine, dried over Na2SO4 and evaporated under reduced pressure. Purification by column chromatography eluting with 3% DCM-methanol gave tert-butyl (1R,5S)-8-(4-cyano-6-(8-ethynyl-3-hydroxynaphthalen-1-yl)-3-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate. Mass Spectrum: 675.5 [M-1].

[0218] Intermediate 19A: (1R,5S)-8-(4-cyano-6-(8-ethynylnaphthalen-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate tert-butyl ... in DMF To tert-butyl ano-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6-(8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate was added CsF and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (3x50ml) and the combined organic layers were washed with brine, dried over Na2SO4 and evaporated under reduced pressure. Purification by column chromatography eluting with 3% DCM-methanol gave tert-butyl (1R,5S)-8-(4-cyano-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6-(8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate. Mass Spectrum: 633.2 [M-1].

[0219] Intermediate 20A: tert-butyl 3-(6-(3-(benzyloxy)naphthalen-1-yl)-4-cyano-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate: 3-(4-cyano-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate in toluene (10 ml) [3.2.1] tert-Butyl octane-8-carboxylate (0.5 g, 0.0010 mmol) was purged under nitrogen gas for 20 min, and 3-(benzyloxy)-1-bromonaphthalene (0.48 g, 0.0015 mmol), cesium carbonate (1.01 g, 0.0030 mmol) and Xantphos (0.12 g, 0.0020 mmol) were added over 10 min and stirred under nitrogen. The reaction mixture was then added with Pd2(dba)3 (0.094 g, 0.0001 mmol) and heated at 120° C. for 12 h. The reaction mixture was quenched with water, extracted with ethyl acetate, and the extract was evaporated under reduced pressure to give a crude residue which was purified by column chromatography using MeOH:DCM (5%) to give the desired product (0.22 g). MS(m / z):714.6[M+H] + .

[0220] Intermediate 21: tert-butyl 4-{6-benzyl-4-cyano-3-[(1-methylpyrrolidin-2-yl)methoxy]-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl}-3-methylpiperazine-1-carboxylate: To a solution of [(2S)-1-methylpyrrolidin-2-yl]methanol (0.1 g, 0.311 mmol) in tetrahydrofuran was added sodium hydride (0.622 mmol) in portions while purging with N2 gas. To this was added dropwise a solution of tert-butyl 4-(6-benzyl-3-chloro-4-cyano-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-3-methylpiperazine-1-carboxylate (0.207 mmol) in tetrahydrofuran and the reaction mixture was heated at 60° C. overnight and the reaction mixture was monitored by TLC. The reaction mixture was cooled to room temperature, poured into water and extracted with ethyl acetate (3x25ml). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give crude tert-butyl 4-{6-benzyl-4-cyano-3-[(1-methylpyrrolidin-2-yl)methoxy]-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl}-3-methylpiperazine-1-carboxylate, which was purified by column chromatography to give 0.02g of the title compound. MS(m / z): 562.2[M+H] + . [Table 3] TIFF2025502625000028.tif227158TIFF2025502625000029.tif38158

[0221] Part B - Preparation of compounds Example 1: 1-(3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(3-hydroxynaphthalen-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride: To a cooled solution of tert-butyl 3-(4-cyano-6-(3-hydroxynaphthalen-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.057 g) in dichloromethane (2 ml) was added dioxane:HCl (1 ml) and the reaction mixture was stirred at 0° C. for 1 hour. After completion of the reaction, it was evaporated under reduced pressure to give an oily compound, which was triturated with diethyl ether to give a solid as the HCl salt. MS(m / z): 554.37[M+H] + . 1 H-NMR (δppm, DMSOD6, 400MHz): 11.00(bs,1H),9.87(bs,1H),9.26(bs,1H),8.01-7.99(m ,1H),7.69-7.67(m,1H),7.42-7.36(m,1H),7.29-7.22(m,1H),6.92-6.89(m,1H),6.84-6 .83(m,1H),4.73-4.65(m,4H),3.89-3.86(m,2H),3.50(s,3H),3.40-3.35(m,1H),3.26-3 .09(m,5H),,2.90-2.25(m,4H),2.20-2.25(m,1H),2.15-2.05(m,6H),1.87-1.80(m,1H).

[0222] Example 2: tert-Butyl 4-(6-(8-chloronaphthalen-1-yl)-4-cyano-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-2-(cyanomethyl)piperazine-1-carboxylate: 4-(4-cyano-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro A solution of tert-butyl doro-2,6-naphthyridin-1-yl)-2-(cyanomethyl)piperazine-1-carboxylate (Intermediate 5a, 1 g, 0.002 mol), 1-bromo-8-chloronaphthalene (0.45 g, 0.004 mol), Xantphos (0.23 g, 0.0004 mol) and Cs2CO3 (1.96 g, 0.006 mol) in toluene (20 ml) was degassed with N2 for 20 min. Then Pd2(dba)3 (0.18 g, 0.0002 mol) was added to the above solution and the whole reaction mixture was stirred at 120 °C for 12 h. The reaction completion was confirmed by TLC using 5% MeOH in DCM and one drop of methanolic ammonia. After the reaction was completed, the mixture was poured into cold water (20 mL) and extracted with ethyl acetate (30 mL x 2). The organic layer was washed with brine solution (10 mL), dried over Na2SO4, and evaporated under reduced pressure to give a crude residue, which was purified by column chromatography (100-200 mesh silica gel) using 3% MeOH in DCM as the mobile phase. The pure fractions were collected and concentrated to give the desired product (0.7 g, 63%). 1H-NMR(δppm, CDCl3,400MHz):7.77-7.75(m,1H),7.66-7.62(m,1H),7.53-7.51(m,1H),7.48-7.42(m,1H) ),7.40-7.34(m,1H),7.28-7.18(m,1H),4.59-4.55(m,2H),4.43-4.30(m,2H),3.90-3.34(m,3H),3.32- 3.19(m,1H),3.19-3.11(m,1H),3.09-3.07(m,4H),3.06-3.05(m,1H),2.73-2.64(m,3H),2.54(s,3H),2 .3-2.31(m,1H),2.06-2.03(m,1H),1.85-1.81(m,5H),1.51(s,9H).MS(m / z):656.3(M+1).HPLC:99.16%

[0223] Example 3: 6-(8-chloronaphthalen-1-yl)-1-(3-(cyanomethyl)piperazin-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride: To a cooled solution of Example 2 (0.100 g) in dichloromethane (2 ml), dioxane:HCl (1 ml) was added and the reaction mixture was stirred at 0° C. for 1 hour. After completion of the reaction, it was evaporated under reduced pressure to give an oily compound which was triturated with diethyl ether to give a solid as the HCl salt. MS (m / z): 556 [M+H] + .

[0224] Example 4: (1R,5S)-tert-butyl 8-(4-cyano-6-(3-hydroxynaphthalen-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate: To a solution of (1R,5S)-tert-butyl 8-(4-cyano-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate and 4-bromonaphthalen-2-ol in toluene, CsCO was added and purged with N gas for 10 minutes. To it, Xantphos and Pd2(dba)3 were added and purged again for 5 minutes. The reaction mixture was heated at 110° C. for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (3×50 ml) and the combined organic layers were washed with brine, dried over Na2SO4 and evaporated under reduced pressure. Purification using column chromatography eluting with 2% DCM-methanol gave tert-butyl (1R,5S)-8-(4-cyano-6-(3-hydroxynaphthalen-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate. Mass Spectrometry: 625.3 [M-1].

[0225] Example 5: 1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-6-(3-hydroxynaphthalen-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride: A solution of (1R,5S)-8-(4-cyano-6-(3-hydroxynaphthalen-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate tert-butyl in DCM (ml) was cooled at 0° C. To this was added 4M HCl in dioxane (). The reaction mixture was stirred at room temperature for 1 hour. The reaction was evaporated under reduced pressure and the crude material was triturated with diethyl ether and dried under reduced pressure to give 1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-6-(3-hydroxynaphthalen-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride. 1 H NMR(MeOD 400MHz):9.81(s,1H),7.87-7.86(m,1H),7.76-7.71(m,1H),7.61-7.55(m,2H),7.42-7. 39(m,2H),4.85(s,2H),4.63-4.61(m,1H),4.58-4.45(m,2H),3.98-3.96(m,1H),3.87--3 .86(m,1H),3.76-3.72(m,1H),3.60-3.59(m,4H),3.27-3.25(m,2H),3.14(s,3H),2.76- 2.73(m,1H),2.44-2.36(m,2H),2.25-2.05(m,4H),1.16-1.14(m,4H).Mass spectrometry:525.2[m+1].

[0226] Example 6: 1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-6-(3-hydroxynaphthalen-1-yl)-3-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile TFA salt: A solution of (1R,5S)-8-(4-cyano-6-(3-hydroxynaphthalen-1-yl)-3-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate tert-butyl in DCM (ml) was cooled at 0° C. To this was added TFA. The reaction mixture was stirred at room temperature for 1 hour. The reaction was evaporated under reduced pressure and the crude was triturated with diethyl ether and dried under reduced pressure to give 1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-6-(3-hydroxynaphthalen-1-yl)-3-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile TFA salt. 1 H NMR(MeOD 400MHz):9.81(s,1H),7.87-7.86(m,1H),7.76-7.71(m,1H),7.61-7.55(m,2H),7.42-7.39(m,2H),5.69(s,2H),4.12-3.99(m,2H),3.97-3 .94(m,2H),3.79(s,1H),3.86-3.64(m,4H),3.52-3.48(m,4H),2.99-2.97(m,4H),1.19-1.18(m,6H),1.16-1.14(m,6H).Mass spectrometry: 551.3[m+1].

[0227] Example 7: 1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-6-(8-bromonaphthalen-1-yl)-3-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile TFA salt: A solution of (1R,5S)-8-(6-(8-bromonaphthalen-1-yl)-4-cyano-3-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate tert-butyl in DCM (ml) was cooled at 0° C. To this was added TFA. The reaction mixture was stirred at room temperature for 1 h. The reaction was evaporated under reduced pressure and the crude was triturated with diethyl ether and dried under reduced pressure to give 1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-6-(8-bromonaphthalen-1-yl)-3-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile TFA salt. 1 H NMR(MeOD 400MHz):7.91-7.89(m,1H),7.83-7.81(m,1H),7.75-7.73(m,1H),7.55-7 .51(m,1H),7.41-7.40(m,1H),7.33-7.29(m,1H),5.69(s,2H),4.12-3.99( m,2H),3.97-3.94(m,2H),3.79(s,1H),3.86-3.64(m,4H),3.52-3.48(m,4H ),2.99-2.97(m,4H),1.19-1.18(m,6H),1.16-1.14(m,6H).Mass spectrometry:61[m+1].

[0228] Example 8: 1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-6-(8-ethynylnaphthalen-1-yl)-3-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile TFA salt: A solution of (1R,5S)-8-(4-cyano-6-(8-ethynylnaphthalen-1-yl)-3-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate tert-butyl in DCM was cooled at 0° C. To this was added TFA. The reaction mixture was stirred at room temperature for 1 hour. The reaction was evaporated under reduced pressure and the crude was triturated with diethyl ether and dried under reduced pressure to give 1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-6-(8-ethynylnaphthalen-1-yl)-3-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile TFA salt. 1 H NMR(MeOD 400MHz):7.87-7.86(m,1H),7.75-7.73(m,1H),7.58-7.50(m,2H),7.41-7.36(m,2H),5.68(s,2H),4.12-3.98(m,2H),3.97-3.95(m, 2H),3.79(s,1H),3.86-3.65(m,4H),3.51-3.48(m,4H),2.98-2.97(m,4H),1.19-1.17(m,6H),1.16-1.14(m,6H).Mass spectrometry: 559.3[m+1].

[0229] Example 9: 1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-6-(8-bromo-3-hydroxynaphthalen-1-yl)-3-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride: A solution of (1R,5S)-8-(6-(8-bromo-3-hydroxynaphthalen-1-yl)-4-cyano-3-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate tert-butyl in DCM was cooled to 0° C. To this was added 4M HCl in dioxane. The reaction mixture was stirred at room temperature for 1 hour. The reaction was evaporated under reduced pressure and the crude was triturated with diethyl ether and dried under reduced pressure to give 1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-6-(8-bromo-3-hydroxynaphthalen-1-yl)-3-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride. 1 H NMR(MeOD 400MHz):9.81(s,1H),7.87-7.86(m,1H),7.76-7.71(m,1H),7.61-7.55(m,2H),7.42-7.39(m,1H),5.69(s,2H),4.12-3.99(m,2H),3.97-3 .94(m,2H),3.79(s,1H),3.86-3.64(m,4H),3.52-3.48(m,4H),2.99-2.97(m,4H),1.19-1.18(m,6H),1.16-1.14(m,6H).Mass spectrometry: 628.5[m+1].

[0230] Example 10: 1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-6-(8-bromonaphthalen-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride: A solution of (1R,5S)-8-(6-(8-bromonaphthalen-1-yl)-4-cyano-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate tert-butyl in DCM was cooled at 0° C. To this was added 4M HCl in dioxane. The reaction mixture was stirred at room temperature for 1 hour. The reaction was evaporated under reduced pressure and the crude material was triturated with diethyl ether and dried under reduced pressure to give 1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-6-(8-bromonaphthalen-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride. 1 H NMR(MeOD 400MHz):7.91-7.89(m,1H),7.83-7.81(m,1H),7.75-7.73(m,1H),7.55-7.51(m,1H),7.41-7. 40(m,1H),7.33-7.29(m,1H),4.85(s,2H),4.63-4.61(m,1H),4.58-4.45(m,2H),3.98-3.96(m, 1H),3.87--3.86(m,1H),3.76-3.72(m,1H),3.60-3.59(m,4H),3.27-3.25(m,2H),3.14(s,3H), 2.76-2.73(m,1H),2.44-2.36(m,2H),2.25-2.05(m,4H),1.16-1.14(m,4H).Mass spectrometry:588.3[m+1].

[0231] Example 11: 1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-6-(8-ethynylnaphthalen-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride: A solution of (1R,5S)-8-(4-cyano-6-(8-ethynylnaphthalen-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate tert-butyl in DCM was cooled at 0° C. To this was added 4M HCl in dioxane. The reaction mixture was stirred at room temperature for 1 hour. The reaction was evaporated under reduced pressure and the crude material was triturated with diethyl ether and dried under reduced pressure to give 1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-6-(8-ethynylnaphthalen-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride. 1 H NMR(MeOD 400MHz):7.87-7.86(m,1H),7.76-7.71(m,1H),7.61-7.55(m,2H),7.42-7.39(m,2H),4.89(s,2H),3.79(s,1H),3.76-3 .65(m,4H),3.51-3.48(m,6H),2.98-2.97(m,5H),2.79(s,3H),2.44-2.43(m,2H),1.17-1.14(m,6H).Mass spectrometry: 533.3[m+1].

[0232] Example 12: 1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-6-(8-ethynylnaphthalen-1-yl)-3-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride: A solution of (1R,5S)-8-(4-cyano-6-(8-ethynylnaphthalen-1-yl)-3-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate tert-butyl in DCM was cooled at 0° C. To this was added 4M HCl in dioxane. The reaction mixture was stirred at room temperature for 1 h. The reaction was evaporated under reduced pressure and the crude was triturated with diethyl ether and dried under reduced pressure to give 1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-6-(8-ethynylnaphthalen-1-yl)-3-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride. 1 H NMR(MeOD 400MHz):7.87-7.86(m,1H),7.75-7.73(m,1H),7.58-7.50(m,2H),7.41-7.36(m,2H),5.68(s,2H),4.12-3.98(m,2H),3.97-3.95(m, 2H),3.79(s,1H),3.86-3.65(m,4H),3.51-3.48(m,4H),2.98-2.97(m,4H),1.19-1.17(m,6H),1.16-1.14(m,6H).Mass spectrometry: 559.3[m+1].

[0233] Example 13: 6-benzyl-1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-((1-(morpholinomethyl)cyclopropyl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride: A solution of (1R,5S)-8-(6-benzyl-4-cyano-3-((1-(morpholinomethyl)cyclopropyl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate tert-butyl in DCM was cooled at 0° C. To this was added 4M HCl in dioxane. The reaction mixture was stirred at room temperature for 1 hour. The reaction was evaporated under reduced pressure and the crude material was triturated with diethyl ether and dried under reduced pressure to give 6-benzyl-1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-((1-(morpholinomethyl)cyclopropyl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride. 1 H NMR(MeOD 400MHz):7.66-7.55(m,5H),4.49(s,2H),3.89(s,2H),3.78(s,2H),3.74-3.65(m,4H),3.19-3.01(m,4H),2 .98-2.86(m,6H),2.39-2.35(m,4H),2.31(s,2H),1.17-1.15(m,4H),0.86-0.45(m,4H).Mass spectrometry: 529.3[m+1].

[0234] Example 14: 1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-6-(8-ethynyl-3-hydroxynaphthalen-1-yl)-3-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride: A solution of (1R,5S)-8-(4-cyano-6-(8-ethynyl-3-hydroxynaphthalen-1-yl)-3-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate tert-butyl in DCM was cooled to 0° C. To this was added 4M HCl in dioxane. The reaction mixture was stirred at room temperature for 1 hour. The reaction was evaporated under reduced pressure and the crude was triturated with diethyl ether and dried under reduced pressure to give 1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-6-(8-ethynyl-3-hydroxynaphthalen-1-yl)-3-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride. 1 H NMR(MeOD 400MHz):9.81(s,1H),7.87-7.86(m,1H),7.75-7.73(m,1H),7.58-7.50(m,2H),7.41-7.36(m,2H),5.68(s,2H),4.12-3.98(m,2H),3.97-3 .95(m,2H),3.79(s,1H),3.86-3.65(m,4H),3.51-3.48(m,4H),2.98-2.97(m,4H),1.19-1.17(m,6H),1.16-1.14(m,6H).Mass spectrometry: 576.1[m+1].

[0235] Example 15: 1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-6-(8-bromo-3-hydroxynaphthalen-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride: A solution of (1R,5S)-8-(6-(8-bromo-3-hydroxynaphthalen-1-yl)-4-cyano-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate tert-butyl in DCM was cooled at 0° C. To this was added 4M HCl in dioxane. The reaction mixture was stirred at room temperature for 1 h. The reaction was evaporated under reduced pressure and the crude was triturated with diethyl ether and dried under reduced pressure to give 1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-6-(8-bromo-3-hydroxynaphthalen-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride. 1 H NMR(MeOD 400MHz):9.81(s,1H),7.87-7.86(m,1H),7.76-7.71(m,1H),7.61-7.55(m,2H),7.42-7.39(m,1H),4.99(s,2H),3.98-3 .65(m,4H),3.51-3.48(m,6H),2.98-2.97(m,5H),2.79(s,3H),2.44-2.43(m,2H),1.17-1.14(m,6H).Mass spectrometry: 604.2[m+1].

[0236] Example 16: 1-(3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(8-chloronaphthalen-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride: A solution of tert-butyl 3-(6-(8-chloronaphthalen-1-yl)-4-cyano-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate in DCM was cooled at 0° C. To this was added 4M HCl in dioxane. The reaction mixture was stirred at room temperature for 1 hour. The reaction was evaporated under reduced pressure and the crude material was triturated with diethyl ether and dried under reduced pressure to give 1-(3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(8-chloronaphthalen-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride. 1 H NMR(MeOD 400MHz):7.87-7.86(m,1H),7.75-7.73(m,1H),7.58-7.50(m,2H),7.41-7.36(m ,2H),4.58(s,2H),3.89-3.86(m,2H),3.65-3.62(m,2H),3.46-3.31(m,4H),3.26 -3.03(m,2H),2.98-2.96(m,1H),2.86-2.84(m,2H),2.56-2.53(m,2H),2.44(s, 3H),2.39-2.26(m,3H),1.18-1.16(m,3H),1.14-1.12(m,3H).Mass spectrometry: 542.7[m+1].

[0237] Example 17: 1-(3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(8-chloronaphthalen-1-yl)-3-(((2R)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride: A solution of tert-butyl 3-(6-(8-chloronaphthalen-1-yl)-4-cyano-3-(((2R)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate in DCM was cooled at 0° C. To this was added 4M HCl in dioxane. The reaction mixture was stirred at room temperature for 1 hour. The reaction was evaporated under reduced pressure and the crude was triturated with diethyl ether and dried under reduced pressure to give 1-(3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(8-chloronaphthalen-1-yl)-3-(((2R)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride. 1 H NMR(MeOD 400MHz):7.88-7.85(m,1H),7.74-7.72(m,1H),7.57-7.50(m,2H),7.42-7. 36(m,2H),5.68-5.54(m,1H),4.85(m,4H),4.67-4.59(m,2H),4.19(s,2H),4 .05-3.94(m,4H),3.51-3.48(m,3H),2.98-2.97(m,2H),2.74-2.61(m,2H), 2.44-2.43(m,3H),2.39-2.26(m,3H),1.17-1.15(m,2H).Mass spectrometry: 586.9[m+1].

[0238] Example 18: 6-benzyl-1-(3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride: A solution of tert-butyl 3-(6-benzyl-4-cyano-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate in DCM was cooled at 0° C. To this was added 4M HCl in dioxane. The reaction mixture was stirred at room temperature for 1 hour. The reaction was evaporated under reduced pressure and the crude material was triturated with diethyl ether and dried under reduced pressure to give 6-benzyl-1-(3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride. 1 H NMR(MeOD 400MHz):7.66-7.55(m,5H),4.59(s,2H),3.86(s,2H),3.65-3.64(m,2H),3.51-3.48(m,4H),2.98-2.97(m,2H),2.89-2.86(m,1H) ),2.84-2.82(m,2H),2.65-2.63(m,2H),2.56(s,3H),2.39-2.26(m,3H),1.18-1.16(m,3H),1.14-1.12(m,3H).Mass spectrometry:473.1[m+1].

[0239] Example 19: 6-benzyl-1-(3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(((2R)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride: A solution of tert-butyl 3-(6-benzyl-4-cyano-3-(((2R)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate in DCM was cooled at 0° C. To this was added 4M HCl in dioxane. The reaction mixture was stirred at room temperature for 1 hour. The reaction was evaporated under reduced pressure and the crude material was triturated with diethyl ether and dried under reduced pressure to give 6-benzyl-1-(3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(((2R)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride. 1 H NMR(MeOD 400MHz):7.66-7.55(m,5H),4.59(s,2H),4.56-4.51(m,2H),4.40(s,2H),4.19(s,2H),4.05-3.94(m,4H),3.75(s,2H),3.50-3 .47(m,3H),2.98-2.97(m,2H),2.73-2.60(m,3H),2.45-2.44(m,3H),2.37-2.25(m,4H),1.16-1.15(m,2H).Mass spectrometry: 516.9[m+1].

[0240] Example 20: tert-Butyl ((R)-1-(4-(6-benzyl-4-cyano-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)piperazin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate: A solution of (S)-6-benzyl-3-((1-methylpyrrolidin-2-yl)methoxy)-1-(piperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridin-4-carbonitrile hydrochloride in THF (ml) was cooled at 0° C. To this was added DIPEA and (tert-butoxycarbonyl)-D-valine and stirred for 15 minutes. HOBT and DCC were added and the reaction mixture was stirred at room temperature for 16 hours. The reaction was poured into water and extracted with ethyl acetate (3x), the combined organic layers were dried over Na2SO4, evaporated under reduced pressure and the crude material was purified using column chromatography eluting with (1:10) methanol:DCM to give tert-butyl ((R)-1-(4-(6-benzyl-4-cyano-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)piperazin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate. Mass Spec: 646.4 [m+1].

[0241] Example 21: 1-(4-(D-valyl)piperazin-1-yl)-6-benzyl-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride: A solution of ((R)-1-(4-(6-benzyl-4-cyano-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-1-yl)piperazin-1-yl)-3-methyl-1-oxobutan-2-yl)tert-butyl carbamate in DCM was cooled at 0° C. To this was added 4M HCl in dioxane. The reaction mixture was stirred at room temperature for 1 hour. The reaction was evaporated under reduced pressure and the crude material was triturated with diethyl ether and dried under reduced pressure to give 1-(4-(D-valyl)piperazin-1-yl)-6-benzyl-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride. 1 H NMR(MeOD 400MHz):7.66-7.55(m,5H),4.84(s,2H),3.89(s,2H),3.86-3.82(m,4H),3.79-3.75(m,2H),3.65-3.61(m,3H),2.96(m,2H) ),2.85-2.79(m,3H),2.45-2.44(m,2H),2.39(s,3H),2.21(m,1H),1.16-1.13(m,4H),1.01-0.99(m,6H).Mass spectrometry:547.0[m+1].

[0242] Example 22: ((2S,3R)-1-(4-(6-benzyl-4-cyano-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)piperazin-1-yl)-3-(benzyloxy)-1-oxobutan-2-yl)tert-butyl carbamate: A solution of (S)-6-benzyl-3-((1-methylpyrrolidin-2-yl)methoxy)-1-(piperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridin-4-carbonitrile hydrochloride in THF (ml) was cooled at 0° C. To this was added DIPEA and O-benzyl-N-(tert-butoxycarbonyl)-L-threonine and stirred for 15 minutes. HOBT and DCC were added and the reaction mixture was stirred at room temperature for 16 hours. The reaction was poured into water, extracted with ethyl acetate (3x), the combined organic layers were dried under Na2SO4, evaporated under reduced pressure and the crude material was purified using column chromatography eluting with (1:10) methanol:DCM to give tert-butyl ((2S,3R)-1-(4-(6-benzyl-4-cyano-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)piperazin-1-yl)-3-(benzyloxy)-1-oxobutan-2-yl)carbamate. Mass Spec: 738.6 [m+1].

[0243] Example 23: 6-benzyl-1-(4-(O-benzyl-L-threonyl)piperazin-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride: A solution of ((2S,3R)-1-(4-(6-benzyl-4-cyano-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-1-yl)piperazin-1-yl)-3-(benzyloxy)-1-oxobutan-2-yl)tert-butylcarbamate in DCM was cooled at 0° C. To this was added 4M HCl in dioxane. The reaction mixture was stirred at room temperature for 1 hour. The reaction was evaporated under reduced pressure and the crude material was triturated with diethyl ether and dried under reduced pressure to give 6-benzyl-1-(4-(O-benzyl-L-threonyl)piperazin-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride. 1 H NMR(MeOD 400MHz):7.81-7.79(m,5H),7.66-7.61(m,5H),4.84(s,2H),4.69(s,2 H),3.89(s,2H),3.86-3.82(m,4H),3.81-3.80(m,2H),3.79-3.75(m,4H ),3.65-3.63(m,3H),2.97(m,2H),2.85-2.79(m,3H),2.45-2.44(m,2H) ,2.38(s,3H),1.16-1.13(m,4H),1.01-0.99(m,3H).Mass spectrometry:638.0[m+1].

[0244] Example 24: 6-benzyl-1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-((1-(morpholinomethyl)cyclopropyl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride: A solution of (1R,5S)-3-(6-benzyl-4-cyano-3-((1-(morpholinomethyl)cyclopropyl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-butyl in DCM was cooled at 0° C. To this was added 4M HCl in dioxane. The reaction mixture was stirred at room temperature for 1 hour. The reaction was evaporated under reduced pressure and the crude material was triturated with diethyl ether and dried under reduced pressure to give 6-benzyl-1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-((1-(morpholinomethyl)cyclopropyl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride. 1 H NMR(MeOD 400MHz):7.66-7.55(m,5H),4.59(s,2H),4.51(s,2H),4.41(s,2H),4.15(s,2H),4.01-3.89(s,4H),3.81-3.78(m,3H),3 .66(s,3H),3.17-3.47(m,4H),2.12(m,3H),1.36-1.32(m,2H),1.16-1.13(m,2H),0.97-0.92(m,4H).Mass spectrometry: 529.1[m+1].

[0245] Example 25: 1-(3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(((2R)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride: A solution of 3-(4-cyano-3-(((2R)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-butyl in DCM was cooled at 0° C. To this was added 4M HCl in dioxane (). The reaction mixture was stirred at room temperature for 1 h. The reaction was evaporated under reduced pressure and the crude was triturated with diethyl ether and dried under reduced pressure to give 1-(3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(((2R)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride. 1 H NMR(MeOD 400MHz):8.05-8.03(m,1H),7.65-7.63(m,1H),7.39-7.23(m,2H),7.10-7.08(m ,1H),6.81(s,1H),5.68-5.55(m,1H),4.85(s,2H),4.67-4.59(m,2H),4.40(s,2H) ),4.18(s,2H),4.05-3.95(m,4H),3.50-3.47(m,3H),2.98(m,2H),2.73-2.60(m, 2H),2.45-2.44(m,3H),2.38-2.25(m,4H),1.16-1.15(m,2H).Mass spectrometry: 569.8[m+1].

[0246] Examples 26-74: The above examples were synthesized using the respective intermediates disclosed in International Application No. PCT / IB2022 / 059630 by treating a solution of the respective intermediate in dichloromethane or methanol with trifluoroacetic acid (TFA) or HCl in dioxane at 0° C. for 1-2 hours. Reaction completion was confirmed by TLC using methanol:DCM (5%) and a drop of methanolic ammonia. The solvent was evaporated under reduced pressure to give the respective individual compounds. Characterization data is reported in Table 4 below: [Table 4] TIFF2025502625000031.tif244158TIFF2025502625000032.tif239158TIFF2025502625000033.tif239158TIFF2025502625000034.tif28158

[0247] Example 75: 6-benzyl-1-((S)-2-methylpiperazin-1-yl)-3-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride: To a cooled solution of intermediate 21 (0.015 g) in dichloromethane (2 ml), dioxane:HCl (1 ml) was added and the reaction mixture was stirred at 0° C. for 1 h. After completion of the reaction, it was evaporated under reduced pressure to give an oily compound, which was triturated with diethyl ether to give a solid as the HCl salt. MS (m / z): 462.20 [M+H] + .

[0248] Part C: Biological activity The biological and / or pharmacological properties of the compounds of the invention can be confirmed by various assays. The biological and / or pharmacological assays which can be carried out with the compounds according to the invention and / or their pharma- ceutically acceptable salts are exemplified below.

[0249] Test 1: In vitro cell proliferation assay in HPAC and AGS cell lines Growth inhibition assays were performed using 10% FBS supplemented medium. Cells will be seeded at a concentration of 2,000-3,000 cells / well in 96-well plates. Test compounds will be added 24 hours later at concentrations ranging from 0.1-30uM. Proliferation is assessed using a CCK-8 kit to measure reduction at 0 hours (before addition of test compound) and 72-96 hours after addition of test compound. Absorbance is read at wavelengths of 450nm-600nm on a BIO-RAD iMark microplate reader or any equivalent microplate reader. Data will be analyzed and the percentage inhibition by test compound compared to control will be calculated accordingly. [Table 5]

[0250] Test 2: In vitro cell proliferation assay in KRASG12 cell line Growth inhibition assays were performed using 10% FBS supplemented medium. Cells were seeded at the desired concentration of 1,000-2,000 cells / well in well plates with the desired number of wells. Test compounds were added 24 hours later at the desired concentration range. Proliferation was assessed using Cell Titer-Glo (CTG, Cell Signaling) to measure reduction at 0 hours (before test compound addition) and 3 days (2D) or 7 days (3D) after addition of test compounds. Absorbance was read at a pre-determined wavelength, e.g., 450 nm, on a BIO-RAD iMark microplate reader or any equivalent microplate reader. Data was analyzed and percent inhibition and / or IC50 for each test compound was calculated accordingly. [Table 6]

[0251] Test 3: Nucleotide exchange assay An HTRF-based nucleotide exchange assay to detect GTP binding to K-Ras Human KRAS G12D protein (corresponding to amino acids 2-169) was mixed with a-GST-Tb antibody (1.5x solution), and 10uL of this solution was added to the reaction well. Then, the compounds (10 concentrations at 3x or optimal multiplication factor for serial dilutions with starting concentrations of approximately 300uM, 100uM, or 50uM, respectively, or other optimal concentrations) were placed into the reaction well using an ultrasonic dispenser (Echo, Labcyte) and incubated with Kras / aGST-Tb antibody for 1 hour at room temperature. After 1 h of incubation, 5 μL of SOS1 / GTP solution (SOS1- (corresponding to amino acids 564-1049) and GDP-DY-647P1 prepared using reaction buffer-20 mM Hepes, pH 7.4, 150 mM NaCl, 5 mM MgCl2, 1 mM DTT, 0.05% BSA, 0.0025% NP40) were added to the reaction wells to initiate the exchange reaction. HTRF-based SOS1-mediated GDP to GTP exchange was measured with a microplate reader PEHRAstar (BMG Labtech) at an excitation wavelength of 337 nm and emission wavelengths of 665 and 620 nm. Non-SOS1 reactions or the highest control compound concentration were used as blanks to calculate % inhibition and / or determine IC50 using a sigmoidal dose-response (variable slope) equation. [Table 7]

[0252] Study 4: Biomarker evaluation in HPAC and AGS cells using Western blotting Protein lysates were prepared using RIPA lysis buffer, which represents both control and test samples. In the present invention, protein lysates were prepared using HPAC cells and AGS cells treated with representative examples of the present invention over time using a 9-point concentration response to measure the regulation of pERK. Total protein was estimated by Bradford method and absorbance was measured at 595 nm using a Bio-Rad imark reader. The isolated total protein was separated by 10% SDS PAGE electrophoresis and transferred to nitrocellulose membrane. After transfer, the membrane was blocked with 5% BSA prepared in PBST (0.1% tween-20) at room temperature for 1 hour, and washed with 1×PBS and PBST. The membrane was then probed with rabbit monoclonal primary antibodies such as pERK (MA5-15173), ERK (MA5-15134), etc., procured from Invitrogen™, ThermoFisher Scientific, USA. Primary antibodies (1:2000 dilution) were prepared in a solution of 5% BSA, 0.1% tween-20 overnight at 4°C. After incubation with primary antibody membranes, they were washed 3 times with 1xPBS and PBST, followed by incubation with goat anti-rabbit secondary IgG HRP conjugate (Invitrogen™) (1:10000 dilution, prepared in 3% skim milk, 0.1% tween-20) for 1 hour at room temperature. After incubation, blots were washed and developed using G-biosciences femto LUCENT™ PLUS-HRP Chemiluminescent reagent on a Bio-Rad Chemidoc™ Imager system. Resulting bands on the blots were quantified using Image J software. Results: Representative compounds tested showed dose- and time-dependent regulation of pERK, a downstream biomarker indicative of KRAS signaling.

[0253] Test 5: RAS selectivity by nucleotide exchange assay HTRF-based nucleotide exchange assay to detect GTP binding to Ras proteins (H, N and K): A series of human RAS proteins, including KRASG12S, KRAS G12R, KRAS G12C, KRAS G13D, KRASQ61H, KRASWT, NRASWT, and HRASWT, were used to test the selection of compounds of the present invention. In the test, each protein was mixed with a-GST Tb antibody (1.5x solution), and 10uL of this solution was added to the reaction well. Then, the compounds (10 concentrations at 3x or optimal multiplication factor for serial dilutions with starting concentrations of about 300uM or 100μM or 50uM, respectively, or other optimal concentrations) were delivered to the reaction well using an ultrasonic dispenser (Echo, Labcyte), and incubated with each ras / aGST-Tb antibody at room temperature for 1 hour. After 1 h of incubation, 5 μL of SOS1 / GTP solution (SOS1- (corresponding to amino acids 564-1049) and GDP-DY-647P1 prepared using reaction buffer-20 mM Hepes, pH 7.4, 150 mM NaCl, 5 mM MgCl2, 1 mM DTT, 0.05% BSA, 0.0025% NP40) were added to the reaction wells to initiate the exchange reaction. HTRF-based SOS1-mediated GDP to GTP exchange was measured with a microplate reader PEHRAstar (BMG Labtech) at an excitation wavelength of 337 nm and emission wavelengths of 665 and 620 nm. Non-SOS1 reactions or the highest control compound concentration were used as blanks to calculate % inhibition and / or determine IC50 using the sigmoidal dose-response (variable slope) equation.

[0254] Results: Representative compounds tested showed a high degree of selectivity for KRASG12D over other RAS proteins tested, with selectivity ranging from 1500 to over 10,000-fold over the entire panel of proteins tested.

[0255] The present invention has been described with the aid of functional building blocks that illustrate the implementation of specific functions and their relationships. For convenience of description, the boundaries of these functional building blocks have been arbitrarily defined in this specification. Alternative boundaries may be defined as long as the specific functions and their relationships are appropriately implemented.

[0256] The foregoing description of the specific embodiments will fully reveal the general nature of the present invention, so that others can easily modify and / or adapt such specific embodiments to various applications by applying knowledge possessed by those skilled in the art without departing from the general concept of the present invention and without undue experimentation. Such adaptations and modifications are therefore intended to be within the meaning and range of equivalents to the disclosed embodiments, based on the teaching and guidance presented herein. It should be understood that the words or terms in this specification are for the purpose of description and not limitation, as the words or terms in this specification would be interpreted by one of ordinary skill in the art in light of the teaching and guidance.

Claims

1. Compound of formula (A): 【Chemistry 1】 or a tautomer thereof, an isotope thereof, a prodrug thereof, an N-oxide thereof, a pharma- ceutically acceptable ester thereof, a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof, wherein: A １ is absent or, independently, a substituted or unsubstituted C １～４ Alkyl, substituted or unsubstituted C ２～４ Alkenyl, substituted or unsubstituted C ２～４ Alkynyl, substituted or unsubstituted C ３～１０ Cycloalkyl, substituted or unsubstituted C ３～１０ Heterocycloalkyl, -(CR ｂ R ｃ ) ｐ -, O, S, -S (=O) ｐ -, -C(=O)-, -NR ｘ --CO-NR ｘ - and -NR ｘ -CO-, A ２ is absent or, independently, a substituted or unsubstituted C １～４ Alkyl, substituted or unsubstituted C ２～４ Alkenyl, substituted or unsubstituted C ２～４ Alkynyl, substituted or unsubstituted C ３～１０ Cycloalkyl, substituted or unsubstituted C ３～１０ Heterocycloalkyl, -(CR ｂ R ｃ ) ｐ -, O, S, -S (=O) ｐ -, -C(=O)-, -NR ｘ --CO-NR ｘ - and -NR ｘ -CO-, Cy １ is selected from a cyclic group selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl; Cy ２ is selected from cyclic groups selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl optionally substituted by G; G is a group capable of forming an interaction with the aspartic acid at position 12 of the KRAS protein, R is, independently for each occurrence, CN (cyano), COOH, CONH ２ , SO ３ H, C(=O)OR ｂ , -C(=O)R ｂ , -C(=S)R ｂ , -C(=O)NR ｂ R ｃ , -C(=O)ONR ｂ R ｃ , -NR ｂ R ｃ , -NR ｂ C(=O)NR ｂ R ｃ , -NR ｂ S(=O)R ｃ , -NR ｂ S(=O) ２ R ｃ , -NR ｂ -OR ｃ , =N-NR ｂ R ｃ , -NR ｂ C(=O)OR ｃ , -NR ｂ C(=O)R ｃ , -NR ｂ C(=S)R ｃ , -NR ｂ C(=S)NR ｂ R ｃ , -SONR ｂ R ｃ , -SO ２ NR ｂ R ｃ , -OR ｂ , -OR ｂ C(=O)NR ｂ R ｃ , -OR ｂ C(=O)OR ｃ , -OC(=O)R ｂ , -OC(=O)NR ｂ R ｃ , -R ｂ NR ｃ C(=O)R ｂ , -R ｂ OR ｃ , -R ｂ C(=O)OR ｃ , -R ｂ C(=O)NR ｂ R ｃ , -R ｂ C(=O)R ｃ , -R ｂ O.C.(=O)R ｃ , -SR ｂ , -SOR ｃ , -SO ２ R ｂ , -CR ｂ R ｃ C(=O)R ｂ , or -CR ｂ R ｃ C(=S)R ｚ is selected from R １ is, at each occurrence, independently selected from hydrogen, hydroxy, halogen, substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, C(═O)OR ｂ , -C(=O)R ｂ , -C(=S)R ｂ , -C(=O)NR ｂ R ｃ , -C(=O)ONR ｂ R ｃ , -NR ｂ R ｃ , -NR ｂ C(=O)NR ｂ R ｃ , -NR ｂ S(=O)R ｃ , -NR ｂ S (=O) ２ R ｃ , -NR ｂ -OR ｃ , =N-NR ｂ R ｃ , -NR ｂ C(=O)OR ｃ , -NR ｂ C(=O)R ｃ , -NR ｂ C(=S)R ｃ , -NR ｂ C(=S)NR ｂ R ｃ , -SONR ｂ R ｃ , -SO ２ N.R. ｂ R ｃ , -OR ｂ , -OR ｂ C(=O)NR ｂ R ｃ , -OR ｂ C(=O)OR ｃ , -OC(=O)R ｂ , -OC(=O)NR ｂ R ｃ , -R ｂ N.R. ｃ C(=O)R ｂ , -R ｂ OR ｃ , -R ｂ C(=O)OR ｃ , -R ｂ C(=O)NR ｂ R ｃ , -R ｂ C(=O)R ｃ , -R ｂ O.C.(=O)R ｃ , -SR ｂ , -SOR ｃ , -SO ２ R ｂ , -CR ｂ R ｃ C(=O)R ｂ , or -CR ｂ R ｃ C(=S)R ｚ is selected from R ａ is independently at each occurrence hydrogen, hydroxy, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, -C(=O)OR ｂ , -C(=O)R ｂ , -C(=S)R ｂ , -C(=O)NR ｂ R ｃ , -C(=O)ONR ｂ R ｃ , -NR ｂ R ｃ , -NR ｂ -OR ｃ , -NR ｂ C(=O)NR ｂ R ｃ , -NR ｂ S(=O)R ｃ , -NR ｂ S (=O) ２ R ｃ , -NR ｂ -OR ｃ , =N-NR ｂ R ｃ , -NR ｂ C(=O)OR ｃ , -NR ｂ C(=O)R ｃ , -NR ｂ C(=S)R ｃ , -NR ｂ C(=S)NR ｂ R ｃ , -SONR ｂ R ｃ , -SO ２ N.R. ｂ R ｃ , -OR ｂ , -OR ｂ C(=O)NR ｂ R ｃ , -OR ｂ C(=O)OR ｃ , -OC(=O)R ｂ , -OC(=O)NR ｂ R ｃ , -R ｂ N.R. ｃ C(=O)R ｂ , -R ｂ OR ｃ , -R ｂ C(=O)OR ｃ , -R ｂ C(=O)NR ｂ R ｃ , -R ｂ C(=O)R ｃ , -R ｂ O.C.(=O)R ｃ , -SR ｂ , -SOR ｃ , -SO ２ R ｂ , -CR ｂ R ｃ C(=O)R ｂ , or -CR ｂ R ｃ C(=S)R ｚ or any two R ａ may be taken together to form a substituted or unsubstituted, saturated or unsaturated 3- to 6-membered ring, which may optionally be the same or different, and O, NR ａ or S; or any two R ａ Together, they form oxo (C=O), imino (=NR ｂ ), C=S(O) ｐ or a substituted or unsubstituted, saturated or unsaturated 3- to 6-membered ring, which may optionally be the same or different, and which may be selected from O, NR ａ or S, R ｂ and R ｃ is independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclic ring, substituted heterocyclylalkyl ring, or substituted or unsubstituted amino, or R when attached to a common atom. ｂ and R ｃ Any two of the above may be taken together to form (i) a substituted or unsubstituted, saturated or unsaturated 3- to 14-membered ring, which may optionally be the same or different, and which are optionally selected from O, NR ｘ or S; or (ii) one or more heteroatoms selected from an oxo (=O) group, a thio (=S) group, or an imino (=NR ｘ ) group, R ｘ and R ｚ is independently selected for each occurrence hydrogen, hydroxy, cyano, halogen, -OR ａ , -COOR ａ , -S(=O) ｑ -R ａ , -NR ａ R ｂ , -C(=Z')-R ａ , substituted or unsubstituted alkyl groups, substituted or unsubstituted alkenyl groups, substituted or unsubstituted alkynyl groups, and substituted or unsubstituted cycloalkyl groups; Z' is selected from O or S; and A compound wherein p at each occurrence is independently 0, 1, or 2.

2. A ２ teeth, (i) -CR ｂ R ｃ -, wherein R ｂ and R ｃ each is independently selected from hydrogen, substituted alkyl or unsubstituted alkyl; (ii) -CR ｂ R ｃ -, wherein R ｂ is independently methyl or ethyl, and R ｃ is hydrogen, or (iii) The compound of claim 1, which is absent.

3. The compound according to any one of claims 1 to 2, wherein R is cyano (CN).

4. Compound of formula (A-I): 【Chemistry 2】 or a tautomer thereof, an isotope thereof, a prodrug thereof, an N-oxide thereof, a pharma- ceutically acceptable ester thereof, a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof, wherein: A １ is absent or, independently, a substituted or unsubstituted C １～４ Alkyl, substituted or unsubstituted C ２～４ Alkenyl, substituted or unsubstituted C ２～４ Alkynyl, substituted or unsubstituted C ３～１０ Cycloalkyl, substituted or unsubstituted C ３～１０ Heterocycloalkyl, -(CR ｂ R ｃ ) ｐ -, -O-, -S-, -S (=O) ｐ -, -C(=O)-, -NR ｘ --CO-NR ｘ - and -NR ｘ -CO-, Cy １ is selected from a cyclic group selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl; Cy ２ is selected from cyclic groups selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl optionally substituted by G; G is a group capable of forming an interaction with the aspartic acid at position 12 of the KRAS protein, R １ is, at each occurrence, independently selected from hydrogen, hydroxy, halogen, substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, C(═O)OR ｂ , -C(=O)R ｂ , -C(=S)R ｂ , -C(=O)NR ｂ R ｃ , -C(=O)ONR ｂ R ｃ , -NR ｂ R ｃ , -NR ｂ C(=O)NR ｂ R ｃ , -NR ｂ S(=O)R ｃ , -NR ｂ S (=O) ２ R ｃ , -NR ｂ -OR ｃ , =N-NR ｂ R ｃ , -NR ｂ C(=O)OR ｃ , -NR ｂ C(=O)R ｃ , -NR ｂ C(=S)R ｃ , -NR ｂ C(=S)NR ｂ R ｃ , -SONR ｂ R ｃ , -SO ２ N.R. ｂ R ｃ , -OR ｂ , -OR ｂ C(=O)NR ｂ R ｃ , -OR ｂ C(=O)OR ｃ , -OC(=O)R ｂ , -OC(=O)NR ｂ R ｃ , -R ｂ N.R. ｃ C(=O)R ｂ , -R ｂ OR ｃ , -R ｂ C(=O)OR ｃ , -R ｂ C(=O)NR ｂ R ｃ , -R ｂ C(=O)R ｃ , -R ｂ O.C.(=O)R ｃ , -SR ｂ , -SOR ｃ , -SO ２ R ｂ , -CR ｂ R ｃ C(=O)R ｂ , or -CR ｂ R ｃ C(=S)R ｚ is selected from R ａ is independently at each occurrence hydrogen, hydroxy, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, -C(=O)OR ｂ , -C(=O)R ｂ , -C(=S)R ｂ , -C(=O)NR ｂ R ｃ , -C(=O)ONR ｂ R ｃ , -NR ｂ R ｃ , -NR ｂ -OR ｃ , -NR ｂ C(=O)NR ｂ R ｃ , -NR ｂ S(=O)R ｃ , -NR ｂ S (=O) ２ R ｃ , -NR ｂ -OR ｃ , =N-NR ｂ R ｃ , -NR ｂ C(=O)OR ｃ , -NR ｂ C(=O)R ｃ , -NR ｂ C(=S)R ｃ , -NR ｂ C(=S)NR ｂ R ｃ , -SONR ｂ R ｃ , -SO ２ N.R. ｂ R ｃ , -OR ｂ , -OR ｂ C(=O)NR ｂ R ｃ , -OR ｂ C(=O)OR ｃ , -OC(=O)R ｂ , -OC(=O)NR ｂ R ｃ , -R ｂ N.R. ｃ C(=O)R ｂ , -R ｂ OR ｃ , -R ｂ C(=O)OR ｃ , -R ｂ C(=O)NR ｂ R ｃ , -R ｂ C(=O)R ｃ , -R ｂ O.C.(=O)R ｃ , -SR ｂ , -SOR ｃ , -SO ２ R ｂ , -CR ｂ R ｃ C(=O)R ｂ , or -CR ｂ R ｃ C(=S)R ｚ or any two R ａ may be taken together to form a substituted or unsubstituted, saturated or unsaturated 3- to 6-membered ring, which may optionally be the same or different, and O, NR ａ or S; or any two R ａ Together, they form oxo (C=O), imino (=NR ｂ ), C=S(O) ｐ or a substituted or unsubstituted, saturated or unsaturated 3- to 6-membered ring, which may optionally be the same or different, and which may be selected from O, NR ｘ or S, R ｂ and R ｃ is independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclic ring, substituted heterocyclylalkyl ring, or substituted or unsubstituted amino, or R when attached to a common atom. ｂ and R ｃ Any two of the above may be taken together to form (i) a substituted or unsubstituted, saturated or unsaturated 3- to 14-membered ring, which may optionally be the same or different, and which are optionally selected from O, NR ｘ or S; or (ii) one or more heteroatoms selected from an oxo (=O) group, a thio (=S) group, or an imino (=NR ｘ ) groups, and A compound wherein p at each occurrence is independently 0, 1, or 2.

5. Cy ２ is selected from cyclic groups selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocyclyl, and substituted or unsubstituted heterocyclylalkyl, each of which is optionally further substituted with a group G.

6. Compound of formula (A-II): 【Chemistry 3】 or a tautomer thereof, an isotope thereof, a prodrug thereof, an N-oxide thereof, a pharma- ceutically acceptable ester thereof, a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof, wherein: A １ is absent or, independently, a substituted or unsubstituted C １～４ Alkyl, substituted or unsubstituted C ２～４ Alkenyl, substituted or unsubstituted C ２～４ Alkynyl, substituted or unsubstituted C ３～１０ Cycloalkyl, substituted or unsubstituted C ３～１０ Heterocycloalkyl, -(CR ｂ R ｃ ) ｐ -, -O-, -S-, -S (=O) ｐ -, -C(=O)-, -NR ｘ --CO-NR ｘ - and -NR ｘ -CO-, Cy １ is selected from a cyclic group selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl; Cy ２ is a substituted or unsubstituted heterocyclyl, which is optionally substituted by G; G is a group capable of forming an interaction with the aspartic acid at position 12 of the KRAS protein, R １ is, at each occurrence, independently selected from hydrogen, hydroxy, halogen, substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, C(═O)OR ｂ , -C(=O)R ｂ , -C(=S)R ｂ , -C(=O)NR ｂ R ｃ , -C(=O)ONR ｂ R ｃ , -NR ｂ R ｃ , -NR ｂ C(=O)NR ｂ R ｃ , -NR ｂ S(=O)R ｃ , -NR ｂ S (=O) ２ R ｃ , -NR ｂ -OR ｃ , =N-NR ｂ R ｃ , -NR ｂ C(=O)OR ｃ , -NR ｂ C(=O)R ｃ , -NR ｂ C(=S)R ｃ , -NR ｂ C(=S)NR ｂ R ｃ , -SONR ｂ R ｃ , -SO ２ N.R. ｂ R ｃ , -OR ｂ , -OR ｂ C(=O)NR ｂ R ｃ , -OR ｂ C(=O)OR ｃ , -OC(=O)R ｂ , -OC(=O)NR ｂ R ｃ , -R ｂ N.R. ｃ C(=O)R ｂ , -R ｂ OR ｃ , -R ｂ C(=O)OR ｃ , -R ｂ C(=O)NR ｂ R ｃ , -R ｂ C(=O)R ｃ , -R ｂ O.C.(=O)R ｃ , -SR ｂ , -SOR ｃ , -SO ２ R ｂ , -CR ｂ R ｃ C(=O)R ｂ , or -CR ｂ R ｃ C(=S)R ｚ is selected from R ａ is independently at each occurrence hydrogen, hydroxy, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, -C(=O)OR ｂ , -C(=O)R ｂ , -C(=S)R ｂ , -C(=O)NR ｂ R ｃ , -C(=O)ONR ｂ R ｃ , -NR ｂ R ｃ , -NR ｂ -OR ｃ , -NR ｂ C(=O)NR ｂ R ｃ , -NR ｂ S(=O)R ｃ , -NR ｂ S (=O) ２ R ｃ , -NR ｂ -OR ｃ , =N-NR ｂ R ｃ , -NR ｂ C(=O)OR ｃ , -NR ｂ C(=O)R ｃ , -NR ｂ C(=S)R ｃ , -NR ｂ C(=S)NR ｂ R ｃ , -SONR ｂ R ｃ , -SO ２ N.R. ｂ R ｃ , -OR ｂ , -OR ｂ C(=O)NR ｂ R ｃ , -OR ｂ C(=O)OR ｃ , -OC(=O)R ｂ , -OC(=O)NR ｂ R ｃ , -R ｂ N.R. ｃ C(=O)R ｂ , -R ｂ OR ｃ , -R ｂ C(=O)OR ｃ , -R ｂ C(=O)NR ｂ R ｃ , -R ｂ C(=O)R ｃ , -R ｂ O.C.(=O)R ｃ , -SR ｂ , -SOR ｃ , -SO ２ R ｂ , -CR ｂ R ｃ C(=O)R ｂ , or -CR ｂ R ｃ C(=S)R ｚ or any two R ａ may be taken together to form a substituted or unsubstituted, saturated or unsaturated 3- to 6-membered ring, which may optionally be the same or different, and O, NR ａ or S; or any two R ａ Together, they form oxo (C=O), imino (=NR ｂ ), C=S(O) ｐ or a substituted or unsubstituted, saturated or unsaturated 3- to 6-membered ring, which may optionally be the same or different, and which may be selected from O, NR ｘ or S, R ｂ and R ｃ is independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclic ring, substituted heterocyclylalkyl ring, or substituted or unsubstituted amino, or R when attached to a common atom. ｂ and R ｃ Any two of the above may be taken together to form (i) a substituted or unsubstituted, saturated or unsaturated 3- to 14-membered ring, which may optionally be the same or different, and which are optionally selected from O, NR ｘ or S; or (ii) one or more heteroatoms selected from an oxo (=O) group, a thio (=S) group, or an imino (=NR ｘ ) groups, and A compound wherein p at each occurrence is independently 0, 1, or 2.

7. Cy ２ The compound according to any one of claims 1 to 6, wherein is selected from the following: 【Chemistry 4】 In the formula, Cy ２ is replaced with one or more G's.

8. A ２ -Cy ２ The compound according to any one of claims 1 to 7, wherein -G is selected from the following: 【Chemistry 5】

9. Formula (A-IIIA), (A-IIIB) or (A-IIIC): 【Chemistry 6】 or a tautomer, an isotope, a prodrug, an N-oxide, a pharma- ceutically acceptable ester, a pharma- ceutically acceptable salt, or a stereoisomer thereof, wherein A １ is absent or, independently, a substituted or unsubstituted C １～４ Alkyl, substituted or unsubstituted C ２～４ Alkenyl, substituted or unsubstituted C ２～４ Alkynyl, substituted or unsubstituted C ３～１０ Cycloalkyl, substituted or unsubstituted C ３～１０ Heterocycloalkyl, -(CR ｂ R ｃ ) ｐ -, -O-, -S-, -S (=O) ｐ -, -C(=O)-, -NR ｘ --CO-NR ｘ - and -NR ｘ -CO-, Cy １ is selected from a cyclic group selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl; X １ is C or N, X ２ is -NG or CR ｙ R ｙ - selected from G, O or S, G is a group capable of forming an interaction with the aspartic acid at position 12 of the KRAS protein, R １ is, at each occurrence, independently selected from hydrogen, hydroxy, halogen, substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, C(═O)OR ｂ , -C(=O)R ｂ , -C(=S)R ｂ , -C(=O)NR ｂ R ｃ , -C(=O)ONR ｂ R ｃ , -NR ｂ R ｃ , -NR ｂ C(=O)NR ｂ R ｃ , -NR ｂ S(=O)R ｃ , -NR ｂ S (=O) ２ R ｃ , -NR ｂ -OR ｃ , =N-NR ｂ R ｃ , -NR ｂ C(=O)OR ｃ , -NR ｂ C(=O)R ｃ , -NR ｂ C(=S)R ｃ , -NR ｂ C(=S)NR ｂ R ｃ , -SONR ｂ R ｃ , -SO ２ N.R. ｂ R ｃ , -OR ｂ , -OR ｂ C(=O)NR ｂ R ｃ , -OR ｂ C(=O)OR ｃ , -OC(=O)R ｂ , -OC(=O)NR ｂ R ｃ , -R ｂ N.R. ｃ C(=O)R ｂ , -R ｂ OR ｃ , -R ｂ C(=O)OR ｃ , -R ｂ C(=O)NR ｂ R ｃ , -R ｂ C(=O)R ｃ , -R ｂ O.C.(=O)R ｃ , -SR ｂ , -SOR ｃ , -SO ２ R ｂ , -CR ｂ R ｃ C(=O)R ｂ , or -CR ｂ R ｃ C(=S)R ｚ is selected from R ａ is independently at each occurrence hydrogen, hydroxy, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, -C(=O)OR ｂ , -C(=O)R ｂ , -C(=S)R ｂ , -C(=O)NR ｂ R ｃ , -C(=O)ONR ｂ R ｃ , -NR ｂ R ｃ , -NR ｂ -OR ｃ , -NR ｂ C(=O)NR ｂ R ｃ , -NR ｂ S(=O)R ｃ , -NR ｂ S (=O) ２ R ｃ , -NR ｂ -OR ｃ , =N-NR ｂ R ｃ , -NR ｂ C(=O)OR ｃ , -NR ｂ C(=O)R ｃ , -NR ｂ C(=S)R ｃ , -NR ｂ C(=S)NR ｂ R ｃ , -SONR ｂ R ｃ , -SO ２ N.R. ｂ R ｃ , -OR ｂ , -OR ｂ C(=O)NR ｂ R ｃ , -OR ｂ C(=O)OR ｃ , -OC(=O)R ｂ , -OC(=O)NR ｂ R ｃ , -R ｂ N.R. ｃ C(=O)R ｂ , -R ｂ OR ｃ , -R ｂ C(=O)OR ｃ , -R ｂ C(=O)NR ｂ R ｃ , -R ｂ C(=O)R ｃ , -R ｂ O.C.(=O)R ｃ , -SR ｂ , -SOR ｃ , -SO ２ R ｂ , -CR ｂ R ｃ C(=O)R ｂ , or -CR ｂ R ｃ C(=S)R ｚ or any two R ａ may be taken together to form a substituted or unsubstituted, saturated or unsaturated 3- to 6-membered ring, which may optionally be the same or different, and O, NR ａ or S; or any two R ａ Together, they form oxo (C=O), imino (=NR ｂ ), C=S(O) ｐ or a substituted or unsubstituted, saturated or unsaturated 3- to 6-membered ring, which may optionally be the same or different, and which may be selected from O, NR ｘ or S, R ｂ and R ｃ is independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclic ring, substituted heterocyclylalkyl ring, or substituted or unsubstituted amino, or R when attached to a common atom. ｂ and R ｃ Any two of the above may be taken together to form (i) a substituted or unsubstituted, saturated or unsaturated 3- to 14-membered ring, which may optionally be the same or different, and which are optionally selected from O, NR ｘ or S; or (ii) one or more heteroatoms selected from an oxo (=O) group, a thio (=S) group, or an imino (=NR ｘ ) group, R ｙ is independently at each occurrence hydrogen, hydroxy, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, -C(=O)OR ｂ , -C(=O)R ｂ , -C(=S)R ｂ , -C(=O)NR ｂ R ｃ , -C(=O)ONR ｂ R ｃ , -NR ｂ R ｃ , -NR ｂ -OR ｃ , -NR ｂ C(=O)NR ｂ R ｃ , -NR ｂ S(=O)R ｃ , -NR ｂ S (=O) ２ R ｃ , -NR ｂ -OR ｃ , -NR ｂ C(=O)OR ｃ , -NR ｂ C(=O)R ｃ , -NR ｂ C(=S)R ｃ , -NR ｂ C(=S)NR ｂ R ｃ , -SONR ｂ R ｃ , -SO ２ N.R. ｂ R ｃ , -OR ｂ , -OR ｂ C(=O)NR ｂ R ｃ , -OR ｂ C(=O)OR ｃ , -OC(=O)R ｂ , -OC(=O)NR ｂ R ｃ , -R ｂ N.R. ｃ C(=O)R ｂ , -R ｂ OR ｃ , -R ｂ C(=O)OR ｃ , -R ｂ C(=O)NR ｂ R ｃ , -R ｂ C(=O)R ｃ , -R ｂ O.C.(=O)R ｃ , -SR ｂ , -SOR ｃ , -SO ２ R ｂ , -CR ｂ R ｃ C(=O)R ｂ , or -CR ｂ R ｃ C(=S)R ｚ or any two R ａ may be taken together to form a substituted or unsubstituted, saturated or unsaturated 3- to 6-membered ring, which may optionally be the same or different, and O, NR ａ or S; or any two R ａ Together, they form oxo (C=O), imino (=NR ｂ ), C=S(O) ｐ or a substituted or unsubstituted, saturated or unsaturated 3- to 6-membered ring, which may optionally be the same or different, and which may be selected from O, NR ｘ or S, n is 0, 1, 2, 3, 4, 5, 6, 7, or 8; A compound wherein p at each occurrence is independently 0, 1, or 2.

10. A １ is absent or -CR ｂ R ｃ -, wherein R ｂ and R ｃ The compound of any one of claims 1 to 9, wherein each of is independently selected from hydrogen, or substituted or unsubstituted alkyl.

11. A １ is absent or -CR ｂ R ｃ -, where R ｂ is independently methyl or ethyl; R ｃ The compound according to any one of claims 1 to 10, wherein is hydrogen.

12. A １ is absent or -CR ｂ R ｃ -, where R ｂ is hydrogen, R ｃ The compound according to any one of claims 1 to 11, wherein is hydrogen.

13. A １ is absent or -CH ２ or -(C=O).

14. Cy １ is selected from a cyclic group selected from substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl.

15. Cy １ is selected from a cyclic group selected from substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl.

16. Cy １ The compound according to any one of claims 1 to 15, wherein is selected from the following: 【Chemistry 7】 【change】

17. G is hydrogen, -NH ２ , -NHR ａ , —NHOH, —COOH, —OH or —CHR ａ -OH, or -CH ２ The compound according to any one of claims 1 to 16, which is -OH or an amino acid.

18. The compound according to any one of claims 1 to 17, wherein G is hydrogen, D-valine or L-threonine.

19. R １ is hydrogen, halogen, OR ｂ , S-R ｂ , -S(=O) ｐ R ｂ -, -C(=O)-R ｂ , -NR ｂ R ｃ , —CO—NR ｂ R ｃ - and -NR ｂ -C-O-R ｃ The compound according to any one of claims 1 to 18, selected from:

20. R １ is -O-R ｂ The compound according to any one of claims 1 to 19,

21. R １ is -NR ｂ R ｃ The compound according to any one of claims 1 to 20,

22. R １ is independently selected from substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl.

23. R １ is independently selected from substituted or unsubstituted alkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, and substituted or unsubstituted heteroaryl.

24. R １ The compound according to any one of claims 1 to 23, wherein: 【Chemistry 8】 【change】

25. R ａ The compound of any one of claims 1 to 24, wherein is hydrogen or substituted or unsubstituted alkyl.

26. Two Rs bonded to the same carbon atom ａ The compound according to any one of claims 1 to 25, wherein forms a C=O (oxo) group.

27. A １ is absent or is a substituted or unsubstituted alkyl; Cy １ is selected from substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; R １ is hydrogen, halogen, substituted or unsubstituted alkyl, -NR ｂ R ｃ or -OR ｂ is selected from R ｂ and R ｃ is independently selected at each occurrence from hydrogen, substituted alkyl or unsubstituted alkyl, or R ｂ and R ｃ The variables which are, together with the nitrogen to which they are attached, can form a substituted or unsubstituted heterocyclic ring; X １ is C or N, X ２ is -NG or CH ２ - selected from G, O or S, G is a group capable of forming an interaction with the aspartic acid at position 12 of the KRAS protein, R ｙ is selected from hydrogen, halogen, substituted or unsubstituted alkyl, and 27. The compound of any one of claims 1 to 26, wherein n is 0, 1, 2, 3, 4, 5, 6, 7, or 8.

28. A １ The compound according to any one of claims 1 to 27, wherein is methyl.

29. A １ The compound according to any one of claims 1 to 28, wherein is absent.

30. Cy １ The compound of any one of claims 1 to 29, wherein is selected from substituted or unsubstituted aryl.

31. Cy １ A compound according to any one of claims 1 to 30, wherein is selected from phenyl or naphthalene, optionally substituted with halogen, hydroxy or substituted or unsubstituted alkyl.

32. Cy １ A compound according to any one of claims 1 to 31, wherein is selected from quinoline or quinazoline optionally substituted with halogen, hydroxy or substituted or unsubstituted alkyl.

33. R １ The compound according to any one of claims 1 to 32, wherein is selected from hydrogen, halogen, hydroxy, or: 【Chemistry 9】

34. X １ The compound according to any one of claims 1 to 33, wherein is N.

35. X ２ is -NG or CR ｙ R ｙ -G or O, where G is hydrogen, -NH ２ , -NHR ａ , —NHOH, —COOH, —OH or —CHR ａ -OH or -CH ２ —OH or an amino acid; R ｙ The compound according to any one of claims 1 to 34, wherein is hydrogen.

36. A １ is absent or is methyl, Cy １ is selected from substituted or unsubstituted aryl; R １ is selected from hydrogen, halogen, hydroxy, or 【Chemistry 10】 X １ is N, and X ２ is -NG or CR ｙ R ｙ -G or O, where G is hydrogen, -NH ２ , -NHR ａ , —NHOH, —COOH, —OH or —CHR ａ -OH or -CH ２ The compound according to any one of claims 1 to 35, which is selected from -OH or an amino acid.

37. A ２ -Cy ２ The compound according to any one of claims 1 to 36, wherein -G is selected from the following: 【Chemistry 11】

38. 1-(3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(3-hydroxynaphthalen-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride; tert-butyl 4-(6-(8-chloronaphthalen-1-yl)-4-cyano-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-2-(cyanomethyl)piperazine-1-carboxylate; 6-(8-chloronaphthalen-1-yl)-1-(3-(cyanomethyl)piperazin-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride; (1R,5S)-8-(4-cyano-6-(3-hydroxynaphthalen-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate tert-butyl; 1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-6-(3-hydroxynaphthalen-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride; 1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-6-(3-hydroxynaphthalen-1-yl)-3-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile compound (containing 2,2,2-trifluoroacetaldehyde (1:1)); 1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-6-(8-bromonaphthalen-1-yl)-3-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile compound (containing 2,2,2-trifluoroacetaldehyde (1:1)); 1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-6-(8-ethynylnaphthalen-1-yl)-3-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile compound (containing 2,2,2-trifluoroacetaldehyde (1:1)); 1-((1R,5S,8r)-3-azabicyclo[3.2.1]octan-8-yl)-6-(8-bromo-3-hydroxynaphthalen-1-yl)-3-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile; 1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-6-(8-bromonaphthalen-1-yl)-3-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile; 1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-6-(8-ethynylnaphthalen-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile; 1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-6-(8-ethynylnaphthalen-1-yl)-3-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile; 6-benzyl-1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-((1-(morpholinomethyl)cyclopropyl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile; 1-(3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(8-ethynyl-3-hydroxynaphthalen-1-yl)-3-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile; 1-(3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(8-bromo-3-hydroxynaphthalen-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile; 1-(3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(8-chloronaphthalen-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile; 1-(3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(8-chloronaphthalen-1-yl)-3-(((2R)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile; 6-benzyl-1-(3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile; 6-benzyl-1-(3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(((2R)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile; ((R)-1-(4-(6-benzyl-4-cyano-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)piperazin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate tert-butyl; 1-(4-(D-valyl)piperazin-1-yl)-6-benzyl-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile; ((2S,3R)-1-(4-(6-benzyl-4-cyano-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)piperazin-1-yl)-3-(benzyloxy)-1-oxobutan-2-yl)carbamate tert-butyl; 6-benzyl-1-(4-(O-benzyl-L-threonyl)piperazin-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile; 6-benzyl-1-(3,8-diazabicyclo[3.2.1]octan-3-yl)-3-((1-(morpholinomethyl)cyclopropyl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile; 1-(3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(((2R)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-(3-hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile; 3-(1,1-dioxidothiomorpholino)-6-(naphthalen-1-yl)-1-(piperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride; 6-(8-chloronaphthalen-1-yl)-3-morpholino-1-(piperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride; 3-(2-morpholinoethoxy)-6-(naphthalen-1-yl)-1-(piperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride; 6-(8-chloronaphthalen-1-yl)-3-(2-morpholinoethoxy)-1-(piperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride; 1-(2,6-dimethylmorpholino)-6-(naphthalen-1-yl)-3-(piperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride; 6-(8-chloronaphthalen-1-yl)-1-(2,6-dimethylmorpholino)-3-(piperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride; 3-(3-(cyanomethyl)piperazin-1-yl)-1-(2,6-dimethylmorpholino)-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride; (S)-6-(8-chloronaphthalen-1-yl)-3-((1-methylpyrrolidin-2-yl)methoxy)-1-(piperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride; (S)-6-(3-hydroxynaphthalen-1-yl)-3-((1-methylpyrrolidin-2-yl)methoxy)-1-(piperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride; (S)-3-((1-methylpyrrolidin-2-yl)methoxy)-1-(piperazin-1-yl)-6-(quinazolin-4-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride; 6-(8-chloronaphthalen-1-yl)-1-(3-methylpiperazin-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride; 1-(3-(cyanomethyl)piperazin-1-yl)-3-(2,6-dimethylmorpholino)-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride; 1-((S)-3-(cyanomethyl)piperazin-1-yl)-3-(2,6-dimethylmorpholino)-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride; 1-((R)-3-(cyanomethyl)piperazin-1-yl)-3-(2,6-dimethylmorpholino)-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride; 1-(3-(cyanomethyl)piperazin-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride; 1-((S)-3-(cyanomethyl)piperazin-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride; 1-((R)-3-(cyanomethyl)piperazin-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride; 1-(3-(cyanomethyl)piperazin-1-yl)-6-(3-hydroxynaphthalen-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride; (S)-6-(isoquinolin-4-yl)-3-((1-methylpyrrolidin-2-yl)methoxy)-1-(piperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride; (S)-3-((1-methylpyrrolidin-2-yl)methoxy)-1-(piperazin-1-yl)-6-(quinolin-8-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride; 6-(8-chloronaphthalen-1-yl)-1-(3-(cyanomethyl)piperazin-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride; 6-(8-chloronaphthalen-1-yl)-1-((S)-3-(cyanomethyl)piperazin-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride; 6-(8-chloronaphthalen-1-yl)-1-((S)-3-(cyanomethyl)piperazin-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride; 6-benzyl-3-chloro-1-(piperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride; 1-(4-aminopiperidin-1-yl)-6-benzyl-3-chloro-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride; 1-(4-aminopiperidin-1-yl)-6-benzyl-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride; 6-benzyl-1,3-di(piperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride; 6-benzyl-3-hydroxy-1-(piperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride; 6-benzyl-3-morpholino-1-(piperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride; 6-benzyl-3-(4-methylpiperazin-1-yl)-1-(piperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride; 6-benzyl-1-(3-(cyanomethyl)piperazin-1-yl)-3-(4-methylpiperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride; 6-(1-naphthoyl)-1-(3-(cyanomethyl)piperazin-1-yl)-3-(4-methylpiperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride; (S)-6-benzyl-1-(2-methylpiperazin-1-yl)-3-(4-methylpiperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride; (R)-6-benzyl-1-(2-methylpiperazin-1-yl)-3-(4-methylpiperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride; 3-(4-methylpiperazin-1-yl)-6-(naphthalen-1-yl)-1-(piperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride; 6-benzyl-1-(piperazin-1-yl)-3-(piperidin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride; 6-benzyl-3-(2-fluoropyridin-4-yl)-1-(piperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile; 6-(naphthalen-1-yl)-1-(piperazin-1-yl)-3-(piperidin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride; 6-benzyl-3-((1-methylpyrrolidin-2-yl)methoxy)-1-(piperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride; 6-(naphthalen-1-yl)-1,3-di(piperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride; 6-(benzo[b]thiophen-4-yl)-1,3-di(piperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile dihydrochloride; 3-morpholino-6-(naphthalen-1-yl)-1-(piperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride; 3-(4-acetylpiperazin-1-yl)-6-(naphthalen-1-yl)-1-(piperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride; 3-(2,6-dimethylmorpholino)-6-(naphthalen-1-yl)-1-(piperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride; 3-(4-(methylsulfonyl)piperazin-1-yl)-6-(naphthalen-1-yl)-1-(piperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride; 3-(4-ethylpiperazin-1-yl)-6-(naphthalen-1-yl)-1-(piperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride; (S)-3-((1-methylpyrrolidin-2-yl)methoxy)-6-(naphthalen-1-yl)-1-(piperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride; 6-(naphthalen-1-yl)-1-(piperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride; 6-(naphthalen-1-yl)-1-(piperazin-1-yl)-3-(4-propionylpiperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride; and 6-benzyl-1-((S)-2-methylpiperazin-1-yl)-3-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, and pharma- ceutically acceptable salts thereof.

39. 40. A pharmaceutical composition comprising a compound according to claims 1-38, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

40. 40. A method of treating cancer in a subject in need thereof, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to claims 1-38, or a pharma- ceutically acceptable salt thereof, or a composition comprising a compound according to claims 1-38, or a pharma- ceutically acceptable salt thereof.

41. 41. The method of claim 40, further comprising the step of simultaneously or sequentially administering to a subject in need thereof at least one other anti-cancer agent, anti-inflammatory agent, immunosuppressant, steroid, non-steroidal anti-inflammatory agent, antihistamine, analgesic agent, or a mixture thereof.

42. A method of treating a KRAS mediated disorder, in particular a KRAS G12D mediated disorder, in a subject in need of such treatment, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to claims 1 to 38, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound according to claims 1 to 38, or a pharma- ceutically acceptable salt thereof.

43. 40. Use of a compound according to claims 1 to 38 for treating cancer or a RAS-mediated disorder, in particular a KRAS G12D-mediated cancer or disorder, in a subject.

44. 40. Use of a compound according to claims 1 to 38 for the manufacture of a medicament for treating cancer or a RAS mediated disorder, particularly a KRAS G12D mediated cancer or disorder, in a subject.

45. A method for treating various cancers, including solid cancers, more particularly solid cancers having a KRASG12 mutation, comprising administering to a subject a compound according to claims 1 to 38, or a pharma- ceutically acceptable salt and / or composition thereof.

46. Cancers include: heart: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; lung: bronchogenic carcinoma (squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondroitin hamartoma, mesothelioma; gastrointestinal system: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vipoma), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); genitourinary system: kidney (adenocarcinoma, Wilms' tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma) cancer), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma); liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; biliary tract: gallbladder cancer, ampullary cancer, bile duct cancer; bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma ( reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochromoma (osteochondral exostosis), benign chondroma, chondroblastoma, chondromyxoid fibroma, osteoid osteoma and giant cell tumor; nervous system: skull (osteoma, hemangioma, granuloma, xanthomas, osteitis deformans), meninges (meningiomas, meningeal sarcomas, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pineal tumor), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma);Gynecology: Uterus (endometrial cancer), Cervix (cervical cancer, preneoplastic cervical dysplasia), Ovaries (ovarian cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), Granulosa-thecal cell tumor 46. ​​The method according to claim 40, wherein the tumor is selected from the following: vulva (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tube (carcinoma); blood system: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndromes), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic nevi, lipoma, hemangioma, dermatofibroma, keloid, psoriasis, and adrenal gland: neuroblastoma;

47. The method of claims 40 to 46, wherein the cancer is lung cancer, pancreatic cancer, or colorectal cancer.

48. 48. The method of claim 47, wherein the cancer is lung cancer.

49. 48. The method of claim 47, wherein the cancer is non-small cell lung cancer.

50. 48. The method of claim 47, wherein the cancer is pancreatic cancer.

51. 48. The method of claim 47, wherein the cancer is colorectal cancer.

Images