Small molecules for cancer therapy

Abstract

The present application 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- ceutical 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: [Formula 1] TIFF2024538851000059.tif45158

Description

[Technical field]

[0001] This application claims the benefit of priority to Indian Provisional Patent Application No. 202141046053, filed on October 8, 2021, and U.S. Provisional Patent Application No. 63 / 308727, filed on February 10, 2022, the disclosures of both of which are incorporated herein by reference in their entireties.

[0002] The present application 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- ceutical 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 produce abnormal proteins or may prevent a protein from being formed. 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, such as 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 the most frequent mutation in the KRAS gene being G12C, which has been reported to be approximately 14-15% across various cancers, with the majority reported in lung and colon 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 substituted naphthyridine compound represented by 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 E; E is a group capable of forming a covalent bond, or an "electrophile" or "electrophilic moiety" capable of forming a covalent bond; 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 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 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 Rc 、 -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 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 may contain a heteroatom selected from O, NRa 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; x and R y 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 the group consisting of O, NR xor 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)qR 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 p is independently 0, 1, or 2 at each occurrence.

[0020] In one embodiment of the present invention, a substituted naphthyridine compound represented by structural 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 1is 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 E; E is a group capable of forming a covalent bond, or an "electrophile" or "electrophilic moiety" capable of forming a covalent bond; 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 bC(=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 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; x and R y 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 the group consisting of 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 ) groups, and p is independently 0, 1, or 2 at each occurrence.

[0021] In one embodiment of the present invention, a substituted naphthyridine 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 E; E is a group capable of forming a covalent bond, or an "electrophile" or "electrophilic moiety" capable of forming a covalent bond; 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 bC(=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 Rc , -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; x and R y 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 the group consisting of 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.

[0022] Formula (A), (AI) or (A-II), wherein A1 is absent or -CR b R c -, wherein R b and R c Further preferred are compounds wherein each of is independently selected from hydrogen or substituted or unsubstituted alkyl.

[0023] Formula (A), (AI) or (A-II), wherein A1 is absent or -CRb R c -, wherein R b is independently methyl or ethyl, and R c Further preferred are compounds wherein R is hydrogen.

[0024] Formula (A), (AI) or (A-II), wherein A1 is absent or -CR b R c -, wherein R b is hydrogen and R c Further preferred are compounds wherein:

[0025] Further preferred are compounds of formula (A), (AI) or (A-II), wherein A1 is absent, -CH2, or -(C=O).

[0026] Formula (A), (AI) or (A-II), wherein A2 is absent or -CR b R c -, wherein R b and R c Further preferred are compounds wherein each of is independently selected from hydrogen, substituted alkyl, or unsubstituted alkyl.

[0027] Formula (A), (AI) or (A-II), wherein A2 is absent or -CR b R c -, wherein R b is independently methyl or ethyl, and R c Further preferred are compounds wherein:

[0028] Further preferred are compounds of formula (A), (AI) or (A-II), wherein A2 is absent.

[0029] Formula (A), (AI) or (A-II), wherein Cy 1Further preferred are compounds wherein 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.

[0030] Formula (A), (AI) or (A-II), wherein Cy 1 Further preferred are compounds wherein is selected from a cyclic group selected from substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0031] Formula (A), (AI) or (A-II), wherein Cy 1 Further preferred are compounds wherein: [ka] JPEG2024538851000006.jpg79158

[0032] Formula (A), (AI) or (A-II), wherein Cy 2 Further preferred are compounds wherein is selected from a cyclic group selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocyclyl, and substituted or unsubstituted heterocyclylalkyl.

[0033] Formula (A), (AI) or (A-II), wherein Cy 2 Further preferred are compounds wherein is selected from a cyclic group 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 E.

[0034] Formula (A), (AI) or (A-II), wherein Cy 2 is selected from: [ka] Further preferred are compounds which are substituted with a group E capable of forming a covalent bond.

[0035] Further preferred are compounds of formula (A), (AI) or (A-II), wherein E is selected from: [ka]

[0036] Further preferred are compounds of formula (A), (AI) or (A-II), wherein E is selected from: [ka]

[0037] Formula (A), (AI) or (A-II), wherein A2-Cy 2 Further preferred are compounds, wherein -E is selected from the following: [ka]

[0038] Formula (A), (AI) or (A-II), wherein A2-Cy 2 Further preferred are compounds, wherein -E is selected from the following: [ka]

[0039] Further preferred are compounds of formula (A), (AI) or (A-II), wherein R is cyano (CN).

[0040] Formula (A), (AI) or (A-II), wherein R 1 is hydrogen, halogen, OR b , S.R. b , -S(=O)pRb -, -C(=O)-R b , -NR b R c , -CO-NR b R c -, and -NR b -CO-R c Further preferred is a compound selected from:

[0041] Formula (A), (AI) or (A-II), wherein R 1 -OR b Further preferred is a compound wherein

[0042] Formula (A), (AI) or (A-II), wherein R 1 -NR b R c Further preferred is a compound wherein

[0043] Formula (A), (AI) or (A-II), wherein R 1 Further 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.

[0044] Formula (A), (AI) or (A-II), wherein R 1 Further 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.

[0045] Formula (A), (AI) or (A-II), wherein R 1 Further preferred are compounds wherein: [ka] JPEG2024538851000013.jpg24158

[0046] Formula (A), (AI) or (A-II), wherein R a Further preferred are compounds where is hydrogen or substituted or unsubstituted alkyl.

[0047] Formula (A), (AI) or (A-II), wherein two R a Further preferred are compounds in which:

[0048] 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) Not present 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 -CRb 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) cyclic groups 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) 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 E, and / or combinations thereof; R is cyano (CN), and R 1 teeth, (i) Hydrogen, halogens, OR b , S.R. b , -S(=O)pR 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 Further preferred are compounds that are selected from (v) substituted or unsubstituted alkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, and substituted or unsubstituted heteroaryl, and / or combinations thereof.

[0049] 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 Rc , -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 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, which is optionally substituted by E; E is a group capable of forming a covalent bond, or an "electrophile" or "electrophilic moiety" capable of forming a covalent bond; 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 may optionally be 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; x and R y 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 the group consisting of 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)qR 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, at each occurrence, is independently 0, 1, or 2.

[0050] Formula (A), (AI) or (A-II), 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; 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 E; E is a group capable of forming a covalent bond, or an "electrophile" or "electrophilic moiety" capable of forming a covalent bond; 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 selected from 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; x and R y 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 the group consisting of 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)qR 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, at each occurrence, is independently 0, 1, or 2.

[0051] Formula (A), (AI) or (A-II), wherein Cy 1is 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-, 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 E; E is a group capable of forming a covalent bond, or an "electrophile" or "electrophilic moiety" capable of forming a covalent bond; 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)ORb 、-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 、-SORc , -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 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 may optionally be 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; x and R y 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 the group consisting of 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)qR 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, at each occurrence, is independently 0, 1, or 2.

[0052] Formula (A), (AI) or (A-II), wherein Cy 2 is a substituted or unsubstituted heterocyclyl, which is optionally substituted by E; E is a group capable of forming a covalent bond, or an "electrophile" or "electrophilic moiety" capable of forming a covalent bond; 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; 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 may optionally be 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;x and R y 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 the group consisting of 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)qR 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, at each occurrence, is independently 0, 1, or 2.

[0053] 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-, 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 E; E is a group capable of forming a covalent bond, or an "electrophile" or "electrophilic moiety" capable of forming a covalent bond; 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 , -NRb -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 may optionally be O, NR aor 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 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)qR 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, at each occurrence, is independently 0, 1, or 2.

[0054] In another embodiment of the present invention, a substituted naphthyridine compound represented by structural formula (A-III): [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 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 is selected from -NE or CH2-E, O or S; E is a group capable of forming a covalent bond, or an "electrophile" or "electrophilic moiety" capable of forming a covalent bond; R y is selected from hydrogen, halogen, substituted alkyl or unsubstituted alkyl; n is 0, 1, 2, 3, 4, 5, 6, 7, or 8.

[0055] Further preferred are compounds of formula (A-III), wherein A1 is absent or methyl.

[0056] Further preferred is a compound of formula (A-III), wherein A1 is absent.

[0057] Formula (A-III), wherein Cy 1 Further preferred are compounds wherein is selected from substituted or unsubstituted aryl.

[0058] Formula (A-III), wherein Cy 1Further preferred are compounds wherein is selected from phenyl or naphthalene, which may be substituted with halogen, hydroxy or substituted or unsubstituted alkyl.

[0059] Formula (A-III), wherein Cy 1 Further preferred are compounds wherein is selected from quinoline or quinazoline optionally substituted with halogen, hydroxy or substituted or unsubstituted alkyl.

[0060] Formula (A-III), wherein R 1 Further preferred are compounds in which is selected from hydrogen, halogen, [ka]

[0061] Formula (A-III), wherein X 1 Further preferred are compounds wherein:

[0062] Formula (A-III), wherein X 2 Further preferred are compounds wherein is selected from -NE or CH2-E or O, where E is selected from the following: [ka]

[0063] Formula (A-III), wherein X 2 Further preferred are compounds wherein is selected from -NE or CH2-E or O, where E is selected from the following: [ka]

[0064] Formula (A-III), wherein A1 is absent or methyl; Cy 1is selected from substituted or unsubstituted aryl; R 1 is selected from hydrogen, halogen, [ka] X 1 is N, and X 2 Further preferred are compounds wherein is selected from -NE or CH2-E or O, where E is selected from: [ka]

[0065] 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-(4-acryloylpiperazin-1-yl)-3-(1,1-dioxidothiomorpholino)-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, 2. 1-(4-acryloylpiperazin-1-yl)-6-(8-chloronaphthalen-1-yl)-3-morpholino-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, 3. 1-(4-acryloylpiperazin-1-yl)-3-(2-morpholinoethoxy)-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, 4. 1-(4-acryloylpiperazin-1-yl)-6-(8-chloronaphthalen-1-yl)-3-(2-orpholinoethoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, 5. 3-(4-acryloylpiperazin-1-yl)-1-(2,6-dimethylmorpholino)-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, 6. 3-(4-acryloylpiperazin-1-yl)-6-(8-chloronaphthalen-1-yl)-1-(2,6-dimethylmorpholino)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, 7. 3-(4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-1-(2,6-dimethylmorpholino)-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, 8. (S)-1-(4-acryloylpiperazin-1-yl)-6-(8-chloronaphthalen-1-yl)-3-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, 9. (S)-1-(4-acryloylpiperazin-1-yl)-6-(3-hydroxynaphthalen-1-yl)-3-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, 10. (S)-1-(4-(2-fluoroacryloyl)piperazin-1-yl)-3-((1-methylpyrrolidin-2-yl)methoxy)-6-(quinazolin-4-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, 11. (S)-6-(8-chloronaphthalen-1-yl)-3-((1-methylpyrrolidin-2-yl)methoxy)-1-(4-(vinylsulfonyl)piperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, 12. 6-(8-chloronaphthalen-1-yl)-1-(4-(2-fluoroacryloyl)-3-methylpiperazin-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, 13. 1-(4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-3-(2,6-dimethylmorpholino)-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, 14. 1-((S)-4-Acryloyl-3-(cyanomethyl)piperazin-1-yl)-3-(2,6-dimethylmorpholino)-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, 15. 1-((R)-4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-3-(2,6-dimethylmorpholino)-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, 16. 1-(4-acryloyl-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, 17. 1-((S)-4-Acryloyl-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, 18. 1-((R)-4-acryloyl-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, 19. 1-(4-acryloyl-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, 20. 1-(3-(cyanomethyl)-4-(2-fluoroacryloyl)piperazin-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, 21. (S)-1-(4-acryloylpiperazin-1-yl)-6-(isoquinolin-4-yl)-3-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, 22. (S)-1-(4-acryloylpiperazin-1-yl)-3-((1-methylpyrrolidin-2-yl)methoxy)-6-(quinolin-8-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, 23. 1-(4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-6-(8-chloronaphthalen-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, 24. 1-((R)-4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-6-(8-chloronaphthalen-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, 25. 1-((S)-4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-6-(8-chloronaphthalen-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, 26. 6-(8-chloronaphthalen-1-yl)-1-(3-(cyanomethyl)-4-(2-fluoroacryloyl)piperazin-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, 27. 6-(8-chloronaphthalen-1-yl)-1-((S)-3-(cyanomethyl)-4-(2-fluoroacryloyl)piperazin-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, 28. 6-(8-chloronaphthalen-1-yl)-1-((R)-3-(cyanomethyl)-4-(2-fluoroacryloyl)piperazin-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, 29. 1-(4-acryloylpiperazin-1-yl)-6-benzyl-3-chloro-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, 30. N-(1-(6-benzyl-3-chloro-4-cyano-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)piperidin-4-yl)acrylamide, 31. N-(1-(6-benzyl-4-cyano-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)piperidin-4-yl)acrylamide, 32. 1,3-Bis(4-acryloylpiperazin-1-yl)-6-benzyl-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, 33. 1-(4-acryloylpiperazin-1-yl)-6-benzyl-4-cyano-5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl acrylate, 34. 1-(4-acryloylpiperazin-1-yl)-6-benzyl-3-morpholino-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, 35. 1-(4-acryloylpiperazin-1-yl)-6-benzyl-3-(4-methylpiperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, 36. 1-(4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-6-benzyl-3-(4-methylpiperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, 37. 6-(1-naphthoyl)-1-(4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-3-(4-methylpiperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, 38. (S)-1-(4-acryloyl-2-methylpiperazin-1-yl)-6-benzyl-3-(4-methylpiperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, 39. (R)-1-(4-acryloyl-2-methylpiperazin-1-yl)-6-benzyl-3-(4-methylpiperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, 40. 1-(4-acryloylpiperazin-1-yl)-6-benzyl-3-hydroxy-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, 41. 1-(4-acryloylpiperazin-1-yl)-3-(4-methylpiperazin-1-yl)-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, 42. 1-(4-acryloylpiperazin-1-yl)-6-benzyl-3-(piperidin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, 43. 1-(4-acryloylpiperazin-1-yl)-6-benzyl-3-(2-fluoropyridin-4-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, 44. 1-(4-acryloylpiperazin-1-yl)-6-(naphthalen-1-yl)-3-(piperidin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, 45. 1-(4-acryloylpiperazin-1-yl)-6-benzyl-3-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, 46. ​​1,3-bis(4-acryloylpiperazin-1-yl)-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, 47. 1,3-Bis(4-acryloylpiperazin-1-yl)-6-(benzo[b]thiophen-4-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, 48. 1-(4-acryloylpiperazin-1-yl)-6-(naphthalen-1-yl)-3-(4-propionylpiperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, 49. 3-(4-acryloylpiperazin-1-yl)-6-(naphthalen-1-yl)-1-(4-propionylpiperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, 50. 1-(4-acryloylpiperazin-1-yl)-3-morpholino-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, 51. 3-(4-acetylpiperazin-1-yl)-1-(4-acryloylpiperazin-1-yl)-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, 52. 1-(4-acryloylpiperazin-1-yl)-3-(2,6-dimethylmorpholino)-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, 53. 1-(4-acryloylpiperazin-1-yl)-3-(4-(methylsulfonyl)piperazin-1-yl)-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, 54. 1-(4-acryloylpiperazin-1-yl)-3-(4-ethylpiperazin-1-yl)-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, 55. (S)-1-(4-acryloylpiperazin-1-yl)-3-((1-methylpyrrolidin-2-yl)methoxy)-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, 56. 1-(4-acryloylpiperazin-1-yl)-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, 57. 1-(4-(2-fluoroacryloyl)piperazin-1-yl)-6-(naphthalen-1-yl)-3-(4-propionylpiperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, and pharma- ceutically acceptable salts thereof.

[0066] More preferably, 1-(4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-6-(8-chloronaphthalen-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, 1-((R)-4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-6-(8-chloronaphthalen-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, The compound is selected from 1-((S)-4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-6-(8-chloronaphthalen-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, and pharma- ceutically acceptable salts thereof.

[0067] More preferably, The compound is 1-(4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-6-(8-chloronaphthalen-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, and pharma- ceutically acceptable salts thereof.

[0068] More preferably, The compound is 1-((R)-4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-6-(8-chloronaphthalen-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, and pharma- ceutically acceptable salts thereof.

[0069] More preferably, The compound is selected from 1-((S)-4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-6-(8-chloronaphthalen-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, and pharma- ceutically acceptable salts thereof.

[0070] More preferably, 6-(8-chloronaphthalen-1-yl)-1-(3-(cyanomethyl)-4-(2-fluoroacryloyl)piperazin-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, 6-(8-chloronaphthalen-1-yl)-1-((S)-3-(cyanomethyl)-4-(2-fluoroacryloyl)piperazin-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, The compound is selected from 6-(8-chloronaphthalen-1-yl)-1-((R)-3-(cyanomethyl)-4-(2-fluoroacryloyl)piperazin-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, and pharma- ceutically acceptable salts thereof.

[0071] More preferably, The compound is 6-(8-chloronaphthalen-1-yl)-1-(3-(cyanomethyl)-4-(2-fluoroacryloyl)piperazin-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, and pharma- ceutically acceptable salts thereof.

[0072] More preferably, The compound is 6-(8-chloronaphthalen-1-yl)-1-((S)-3-(cyanomethyl)-4-(2-fluoroacryloyl)piperazin-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, and pharma- ceutically acceptable salts thereof.

[0073] More preferably, The compound is 6-(8-chloronaphthalen-1-yl)-1-((R)-3-(cyanomethyl)-4-(2-fluoroacryloyl)piperazin-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, and pharma- ceutically acceptable salts thereof. [Table 1] JPEG2024538851000021.jpg188158JPEG2024538851000022.jpg187158JPEG2024538851000023.jpg34158Non-limiting representative compounds of the present invention, and pharma- ceutically acceptable salts thereof, listed herein below are as follows: [Table 2] JPEG2024538851000025.jpg185158JPEG2024538851000026.jpg163158

[0074] 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.

[0075] 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.

[0076] Without being bound by any particular theory, the present specification provides compounds that can modulate (e.g., inhibit) one or more members of KRAS family, for example, one or more of KRAS mutants.More specifically, without being bound by any particular theory, it is believed that the compounds described herein can bind to KRAS G12C and function as covalent inhibitors of KRAS G12C.

[0077] Thus, in another embodiment, the present invention is a method of treating a KRAS mediated disorder, in particular a KRAS G12C 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.

[0078] 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 G12C-mediated disorder, in a subject.

[0079] 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 G12C-mediated disorder, in a subject.

[0080] 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, including solid cancers, more particularly solid cancers with KRASG12 mutations. [Brief description of the drawings]

[0081] [Figure 1] FIG. 1A: Line graph showing the effect of Cpd A on KRASG12C mutant cell lines in a 2D cell viability assay.

[0082] FIG. 1B: Line graph showing the effect of Cpd A on KRASG12C mutant cell lines in a 3D cell viability assay.

[0083] FIG. 1C: Line graph showing the effect of Cpd A on the eCT26 cell line in a 3D cell viability assay.

[0084] FIG. 1D: Line graph showing the effect of Cpd A on the CO-04-0070 patient-derived cell line in a 3D cell viability assay.

[0085] FIG. 1E: A line graph showing the selectivity of Cpd A over non-KRASG12C cell lines in a 2D cell viability assay.

[0086] [Diagram 2] Figure 2: Line graph showing the antitumor effect of Cpd A on NCI-H358 xenografts. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0087] A description of exemplary embodiments of the present invention follows. Definitions

[0088] 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.). Furthermore, 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.

[0089] 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.

[0090] 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.

[0091] 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.

[0092] 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 alkyl groups, 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.

[0093] 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.

[0094] 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.

[0095] 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.

[0096] 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.

[0097] 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.

[0098] 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.

[0099] 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.

[0100] 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.

[0101] 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.

[0102] The term "heterocyclyl," unless otherwise specified, refers to a heterocyclic ring radical, as defined above. The heterocyclyl ring radical may be attached to the main chain structure at any heteroatom or carbon atom.

[0103] 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.

[0104] 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.

[0105] 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.

[0106] The term "cyclic ring" refers to a cyclic ring containing from 3 to 10 carbon atoms.

[0107] 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 ...

[0108] The term "halo", "halide" or alternatively "halogen" means fluoro, chloro, bromo, or iodo.

[0109] 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.

[0110] 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.

[0111] 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.

[0112] 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.

[0113] 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.

[0114] 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 3C or 4C. 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).

[0115] 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 contain isotopes of, for example, tritium ( 3 H), iodine-125( 125 I), or carbon-14 ( 14 C). All isotopic forms of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0116] 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).

[0117] An "electrophile" or "electrophilic moiety" is any moiety (e.g., a moiety having a lone pair of electrons, a negative charge, a partial negative charge, and / or an excess of electrons, e.g., an -SH group) that can react with a nucleophile. An electrophile typically contains an atom that is electron deficient or is electron deficient. In certain embodiments, an electrophile contains a positive or partial positive charge, has a resonance structure that contains a positive or partial positive charge, or is a moiety in which delocalization or polarization of electrons results in one or more atoms containing a positive or partial positive charge. In some embodiments, an electrophile contains a conjugated double bond, such as an α,β-unsaturated carbonyl or α,β-unsaturated thiocarbonyl compound.

[0118] 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.

[0119] "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., compounds of structures (A), (AI), (A-II) and (A-III)). 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 in 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., ... 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.

[0120] In some embodiments, the prodrugs include compounds of structures (A), (AI), (A-II), and (A-III) having phosphate, phosphoalkoxy ester, or boronic ester substituents. 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 in which 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.

[0121] 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'.

[0122] These prodrugs and esters are intended to be covered within the scope of the present invention.

[0123] In addition, the present invention also relates to the substitution of, for example, hydrogen with deuterium or tritium, or carbon with 13C -or 14C -Includes compounds that differ only in the presence of one or more isotopically enriched atoms, such as the substitution of -enriched carbon.

[0124] 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.

[0125] 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.

[0126] 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.

[0127] 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.

[0128] The term "cell proliferation" refers to the phenomenon whereby a cell number changes as a result of division. The term also encompasses cell proliferation where the cell morphology changes (e.g., increases in size) in concert with a proliferation signal.

[0129] 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 co-administration in separate compositions, administration at different times in separate compositions, or administration in a composition in which both agents are present.

[0130] 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 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 a target cell, 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.

[0131] 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.

[0132] 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.

[0133] 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.

[0134] 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.

[0135] 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.).

[0136] 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).

[0137] In some embodiments, the patient is a mammal, and in some embodiments, the patient is human.

[0138] "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.

[0139] 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.

[0140] 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.

[0141] 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.

[0142] 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.

[0143] 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.

[0144] 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.

[0145] In some embodiments, acid addition salts of compounds of formula A are most suitably formed from pharma- ceutically acceptable acids, 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.

[0146] 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 the compounds of formula (A), (AI), (A-II) and (A-III).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.

[0147] "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.

[0148] 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.

[0149] "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.

[0150] 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, including any pharma- ceutically acceptable carrier, diluent, or excipient thereof.

[0151] 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.

[0152] 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).

[0153] 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.

[0154] 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.

[0155] 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.

[0156] 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.

[0157] 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.

[0158] 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.

[0159] 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.

[0160] 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 a neoplastic disorder.

[0161] 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 symptom 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.

[0162] 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.

[0163] Exemplary cancers include, but are not limited to, tumors that are carcinomas of the lung, prostate, breast, brain, skin, cervical, testicular, 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: 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: Esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma); Stomach (carcinoma, lymph ... tumor, 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), prostate (adenoma, ductal adenocarcinoma, lymphoma, leukemia), Cancer, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma), liver: hepatoma (hepatocellular carcinoma), bile duct cancer, 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, bone chromoma ( osteochronforma) (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 (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 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.,

[0164] 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 Formulas (A), (AI), (A-II) and (A-III), a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition containing the compound or a pharma- ceutically acceptable salt thereof.

[0165] More preferably, the present invention provides a method for inhibiting KRAS G12C activity in a cell, the method comprising contacting a cell in which inhibition of KRAS G12C activity is desired with an effective amount of a compound of Formula (A), (AI), (A-II) and (A-III), a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition containing the compound or a pharma- ceutically acceptable salt thereof.

[0166] In one embodiment, a cell in which inhibition of KRAS G12C activity is desired is contacted with an effective amount of a compound of Formulas (A), (AI), (A-II) and (A-III) to negatively regulate the activity of KRAS G12C.

[0167] More preferably, a therapeutically effective amount of a pharma- ceutically acceptable salt or pharmaceutical composition containing a compound of formula (A), (AI), (A-II) and (A-III) may be used.

[0168] The method described herein is designed to inhibit the undesirable cell proliferation caused by enhanced KRAS G12C activity in cells by negatively regulating the activity of KRAS G12C.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 G12C.

[0169] 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 Formulas (A), (AI), (A-II) and (A-III), a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound or a pharma- ceutically acceptable salt thereof.

[0170] The compositions and methods provided herein can be used in the treatment of KRAS-related cancer in patients who need it, and the method includes administering to the patient a therapeutically effective amount of the compound of formula (A), (AI), (A-II) and (A-III), its pharmaceutical acceptable salt, or the pharmaceutical composition comprising the compound or its pharmaceutical acceptable salt.In one embodiment, the KRAS G12C-related cancer is lung cancer.

[0171] The compositions and methods provided herein can be used in the treatment of KRAS G12C-related 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) and (A-III), its pharmaceutical acceptable salt, or the pharmaceutical composition comprising the compound or its pharmaceutical acceptable salt.In one embodiment, the KRAS G12C-related cancer is lung cancer.

[0172] 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, cervical, testicular, 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: 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: Esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma); Stomach (carcinoma tumor, 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), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma), liver: hepatoma (hepatocellular carcinoma), bile duct cancer, 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 (meningiomas, meningeal sarcomas, 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, unclassified carcinoma), 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.,

[0173] More preferably, the cancer is non-small cell lung cancer, colorectal cancer, or pancreatic cancer.

[0174] More preferably, the cancer is lung cancer or colorectal cancer.

[0175] 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.

[0176] The present invention further provides a compound of formula (A), (AI), (A-II) and (A-III), or a pharma- ceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof, as defined herein, for use in therapy.

[0177] The present invention further provides a compound of Formula (A), (AI), (A-II) and (A-III), or a pharma- ceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof, as defined herein, for use in the treatment of cancer.

[0178] Further provided herein is a compound of Formula (A), (AI), (A-II) and (A-III), or a pharma- ceutically acceptable salt or solvate thereof, for use in the inhibition of KRAS G12C.

[0179] Further provided herein is a compound of formula (A), (AI), (A-II) and (A-III), 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 G12C-associated disease or disorder.

[0180] Further provided herein is the use of a compound of formula (A), (AI), (A-II) and (A-III), or a pharma- ceutically acceptable salt or solvate thereof, as defined herein, in the manufacture of a medicament for the treatment of cancer.

[0181] Further provided herein is the use of a compound of formula (A), (AI), (A-II) and (A-III), 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 G12C.

[0182] Further provided herein is the use of a compound of formula (A), (AI), (A-II) and (A-III), or a pharma- ceutically acceptable salt or solvate thereof, as defined herein, in the manufacture of a medicament for the treatment of a KRAS G12C-associated disease or disorder.

[0183] Further provided herein is a method for treating cancer in a patient in need thereof, the method comprising: (a) determining that the cancer is associated with a KRAS G12C mutation (e.g., a KRAS G12C-associated cancer) (e.g., determined using a regulatory agency 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) or (A-III) or a pharma- ceutical acceptable salt thereof, or a pharmaceutical composition thereof.

[0184] Metastasis of the aforementioned cancers can also be treated or prevented according to the methods described herein.

[0185] 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.

[0186] 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.

[0187] 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.

[0188] 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.

[0189] 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 applied to synthesize all possible forms of the compounds of the present invention, in particular the compounds of formula (A), (AI), (A-II) and (A-III) provided herein above with all intended variations or without any variations. Unless otherwise indicated, the R, R a , R 1 , A1, A2, Cy1 , Cy 2 Variable moieties such as, for example, C, D, E, F ... Synthetic Scheme A: This schematic of a scheme is intended to provide possible routes for the preparation of compounds of formula (A), (AI), (A-II), and (A-III). [ka]

[0190] In the intermediate of formula (A1), Pg is a suitable protecting group that, when reacted with an intermediate of formula R-CH2-CONH2 using a suitable base or reagent, gives an intermediate of formula (A2). The intermediate of formula (A2) can then be subjected to chlorination using POCl3 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 Bukward coupling or other suitable N-alkylation or N-arylation. 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]

[0191] 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.

[0192] Part A: Preparation of intermediates Intermediate 1: (Ethyl 1-benzyl-3-oxopiperidine-4-carboxylate) In a reaction flask, (26 g, 80.00 mmol) of ethyl 4-(benzyl(2-methoxy-2-oxoethyl)amino)butanoate and (11 g, 160 mmol) of sodium ethoxide were added to 260 mL of toluene, the reaction was heated to reflux for 5 hours, the reaction was completely completed by TLC monitoring of the raw material, the reaction solution was cooled to room temperature, 150 mL of water was added, and the reaction was extracted into the organic phase twice with 250 mL of ethyl acetate. The organic phase was washed with a certain amount of saturated brine solution, and the organic phase was distilled to obtain 14 g of an oily compound. MS(m / z): 262.24 [M+H] + .

[0193] Intermediate 2: 6-Benzyl-1,3-dioxo-1,2,3,4,5,6,7,8-octahydro-2,6-naphthyridine-4-carbonitrile: A two-neck flask equipped with a mechanical stirrer and a condenser was charged with intermediate 1 (14 g, 50.00 mmol) in methanol (105 ml). Cyanoacetamide (4.5 g, 50.00 mmol) was added, followed by a solution of potassium hydroxide in methanol (3.94 g, 50 mmol KOH in 50 mL MeOH). The resulting mixture was stirred and heated to reflux. After a few minutes, the product began to form as a white solid. The reaction mixture was refluxed for 4 hours and cooled to room temperature overnight. The white solid was collected and the filter cake was washed with methanol (300 mL). The white solid was transferred to a 1 L one-neck flask equipped with a mechanical stirrer with the aid of warm water (55° C., 250 ml). The resulting mixture was stirred and acidified to pH=6 with acetic acid. After stirring for 1 hour, the white solid was collected, washed with water, pressed well with a rubber dam, and air-dried overnight in a fume hood to give 10 g of the title compound. MS(m / z): 282.20 [M+H] + .

[0194] Intermediate 3: 6-benzyl-1,3-dichloro-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile:

[0195] Method I: Intermediate 2 (5 g, 10.00 mmol) and phosphorus oxychloride (20 mL). The vessel was sealed and heated at 180° C. for 4 h, and the reaction mixture was concentrated under reduced pressure. The residue was dissolved in dichloromethane (500 ml) and added to a 1 L 3-neck flask equipped with a mechanical stirrer containing ice (approximately 45 g). The resulting mixture was basified to pH=9-10 by adding approximately 50 mL of 20% aqueous sodium hydroxide. Additional ice was added to maintain the internal temperature below 30° C. during this addition. The mixture was stirred for 15 min and then filtered to remove gel-like particles. The organic layer was separated, washed with brine (50 mL), filtered through filter paper, and concentrated under reduced pressure. (1.5 g) as an oil solidified on standing. MS (m / z): 318.20 [M+H] + .

[0196] Method II: Intermediate 2 (20 g mg, 0.071 mol, salt free), tetramethylammonium chloride (9.3 g, 0.085 mol), and phosphorus oxychloride (67 mL, 0.71 mol) were taken in a 500 mL sealed vessel and heated at 120 °C for 8 h. The reaction was cooled to room temperature and the vessel was opened slowly. The reaction mixture was poured slowly into ice and the reaction mixture was stirred for 30 min. Then a saturated solution of NaOH was added slowly to the cooled and diluted reaction mixture to make it alkaline (pH = 8-10) and the temperature was maintained below 40 °C. A brown solid was formed which was filtered on a filter flask and dried for 2 h to give Intermediate 3 (14 g). 1H-NMR(δppm, CDCl3,400MHz):7.36-7.30(m,5H),3.81(s,2H),3.75(s,2H),2 .84-2.82(d,2H,J=5.2Hz),2.80-2.78(d,2H,J=5.2Hz).MS(m / z):318.20[M+H] + .

[0197] Intermediate 4A: Benzyl-4-cyano-5,6,7,8-tetrahydro-2,6-naphthyridine-1,3-diyl bis(trifluoromethanesulfonate): Intermediate 2 (5 grams, 0.01 moles) and 2,6 lutidine (5.9 grams, 0.055 moles) were dissolved in DCM (200 ml) and cooled to 0° C. under nitrogen, then Triflic Anhydride (10 grams, 0.035) in DCM (25 ml) was added dropwise over 20 minutes. The reaction was allowed to warm gradually to 25° C. over 2 hours. The reaction mixture was concentrated in vacuo, the resulting oil was dissolved in ethyl acetate, the organic layer was washed three times with 10% KHSO4 followed by brine, and the organic layer was concentrated in vacuo. The resulting solid was purified by column chromatography (100-200 mesh silica gel, 0-40% ethyl acetate-hexane) to give intermediate 4 (3.2 gm). 1H-NMR (δppm, CDCl3, 400 MHz): 7.35 (m, 5H), 3.91 (s, 2H), 3.79 (s, 2H), 2.91 (t, 2H), 2.83 (m, 2H). MS (m / z): 545 [M+H]+ .

[0198] Intermediate 5: tert-Butyl (1-(6-benzyl-3-chloro-4-cyano-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)piperidin-4-yl)carbamate: tert-Butyl piperidin-4-ylcarbamate (0.5g, 16mmol) was dissolved in DMF (5ml), followed by addition of potassium carbonate (0.54g, 30mmol) in the reaction mixture and stirred at room temperature for 10 minutes. Intermediate 3 (0.5g, 10mmol) was added in the reaction mixture and the reaction was heated at 80°C for 20 minutes. The reaction was completed by TLC, and the reaction was poured into water and ethyl acetate and separated. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give an oily (0.3g) compound, which was used in the next step without analytical data.

[0199] Intermediate 5A: tert-Butyl 4-(6-benzyl-4-cyano-3-(((trifluoromethyl)sulfonyl)oxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)piperazine-1-carboxylate: To a solution of tert-butyl piperazine-1-carboxylate (0.46 gm, 0.001 mol) in THF (30 ml) was added DIPEA (1.2 ml, 0.03 mol) and stirred. A solution of intermediate 4A (1.5 gm, 0.001 mol) in THF (10 ml) was added dropwise to the reaction mixture and stirred at room temperature for 2 hours. The reaction mixture was quenched with water and extracted with ethyl acetate. The separated organic layer was washed with brine and subsequently dried over sodium sulfate. The organic layer was concentrated under reduced pressure to give a crude residue which was purified by column chromatography using ethyl acetate:hexane (25%) to give intermediate 5A (1.25 gm). 1H-NMR(δppm, CDCl3,400MHz):7.36-7.35(m,4H),7.32-7.30(m,1H),3.82(s,2H),3.72 (s,2H),3.52-3.51(m,4H),3.43-3.41(m,4H),2.68-2.63(m,4H).MS(m / z):582.50[M+H] + .

[0200] Intermediate 5B: tert-Butyl 4-(6-benzyl-4-cyano-3-(((trifluoromethyl)sulfonyl)oxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)piperazine-1-carboxylate: 2-(piperazin-2-yl)acetonitrile (0.920 gm, 0.0073 mol) and DIEPA (1.37 ml, 0.0073 mol) were dissolved in DCM (40 ml) and cooled to 0° C. under nitrogen atmosphere. To the reaction mixture was added Intermediate 4A (2.7 gm, 0.0049 mol) in DCM (10 ml) dropwise. The reaction was stirred at room temperature for 12 hours. To the above reaction mixture was added a solution of (BOC)2O in DCM (10 ml) dropwise at room temperature and stirred for further 12 hours. The reaction mixture was quenched with water and the organic layer was separated, washed with brine and concentrated in vacuo to give an oily residue which was purified by column chromatography (100-200 mesh silica gel) using 30% ethyl acetate:hexane to give Intermediate 9B (1.7 gm) as a white solid. 1H-NMR (δppm, CDCl3,400MHz):7.38-7.33(m,5H),4.62-4.60(m,1H),4.06(bs,1H),3.99-3.82(m,1H),3.76-3.67(m, 5H),3.35-3.34(m,1H),3.24-3.23(m,1H),2.83-2.71(m,5H),2.58-2.55(m,1H),1.48(s,9H).MS(m / z):621.22[M+H] + .

[0201] Intermediate 5C: tert-Butyl 4-(6-benzyl-3-chloro-4-cyano-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-2-(cyanomethyl)piperazine-1-carboxylate: 2-(piperazin-2-yl)acetonitrile (29.48 g, 0.23 mol) was added in 1,4-dioxane (1000 ml) to a 3 liter 4-neck RBF, followed by DIPEA (144 mL, 0.75 mol) in the above suspension and stirred at 0° C. for 10 min. Intermediate 3 (50 g, 0.15 mol) was added to the reaction mixture and stirred at 55° C. for 12 h. After a new polar spot was formed, the reaction mixture was cooled to room temperature and Boc anhydride (98 mL, 0.45 mol) was added to it and stirred at 55° C. for 2 h. After the reaction was completed, the reaction mixture was poured into cold water and extracted with ethyl acetate (1 L x 2). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give a crude residue. The crude was purified by column chromatography using 20-50% EtOAc in pet ether as the mobile phase. The pure fractions were collected and concentrated under reduced pressure to give intermediate 5C (40 g) as a white solid. 1H-NMR (δppm, CDCl3,400MHz):7.35-7.34(m,4H),7.31-7.29(m,1H),4.59(bs,1H),3.90(bs,1H),3.83-3.6 8(m,6H),3.27-3.23(m,2H),2.99-2.92(m,1H),2.81-2.69(m,5H),2.67-2.65(m,1H).MS(m / z):507.2[M+H] + .

[0202] Intermediate 5D: tert-butyl 4-(6-benzyl-4-cyano-3-(((trifluoromethyl)sulfonyl)oxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-2-methylpiperazine-1-carboxylate: Prepared using the process as described above for Intermediate 5A using 3-methyl piperazine-1-carboxylate (1.21 gm, 0.0065 mmol) and Intermediate 4 (3.0 gm, 0.0055 mol) to give Intermediate 5D (2.22 gm). MS (m / z): 596.24 [M+H] + ..

[0203] Intermediate 5E: 6-benzyl-4-cyano-1-(2,6-dimethylmorpholino)-5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl trifluoromethanesulfonate: Prepared using the process as described above for Intermediate 5A using 2,6-dimethylmorpholine (1.25 gm, 0.00688 mmol) and Intermediate 4 (2.5 gm, 0.0045 mmol) to give Intermediate 5E (1.8 gm). MS (m / z): 510.95 [M+H] + .

[0204] Intermediate 5F: (R)-tert-butyl 4-(6-benzyl-4-cyano-3-(((trifluoromethyl)sulfonyl)oxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-3-methylpiperazine-1-carboxylate: Prepared using the process as described above for Intermediate 5A using (R) tert-butyl 3-methylpiperazine-1-carboxylate (1.21 gm, 0.0065 mmol) and Intermediate 4A (3.0 gm, 0.0055 mol) to give Intermediate 5F (2.22 gm). MS (m / z): 596.24 [M+H] + .

[0205] Intermediate 5G: (S)-tert-butyl 4-(6-benzyl-4-cyano-3-(((trifluoromethyl)sulfonyl)oxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-3-methylpiperazine-1-carboxylate: Prepared using the process as described above for Intermediate 5A using (S) tert-butyl 3-methylpiperazine-1-carboxylate (1.21 gm, 0.0065 mmol) and Intermediate 4A (3.0 gm, 0.0055 mol) to give Intermediate 5G (2.22 gm). MS (m / z): 596.24 [M+H] + .

[0206] Intermediate 5H: tert-butyl 4-(6-benzyl-3-chloro-4-cyano-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)piperazine-1-carboxylate: Prepared using the process as described above for Intermediate 5A using N-Boc piperazine (1.1 gm) and Intermediate 3 (2.5 gm) to give Intermediate 5H (1.85 gm). 496.21 [M+H] + .

[0207] Intermediate 6: 1-(4-aminopiperidin-1-yl)-6-benzyl-3-chloro-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile: To a solution of intermediate 5 (0.5 g) dissolved in dioxane:HCl (10 ml), the reaction mixture was stirred for 1 hour at 0° C. After the reaction was complete, it was evaporated under reduced pressure to give an oily compound, which was dissolved in diethyl ether to give a solid, which was used directly in the next step without analytical data.

[0208] Intermediate 6A1: Bert-Butyl 4-(6-benzyl-4-cyano-3-hydroxy-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)piperazine-1-carboxylate: Intermediate 5A (1.0 gm, 0.0018 mmol) was dissolved in THF (20 ml) and the reaction mixture was stirred at room temperature, followed by addition of 10% NaOH (5 ml) and stirring the mixture for 30 minutes. The reaction mixture was extracted with ethyl acetate. The combined THF and ethyl acetate layers were dried over sodium sulfate and concentrated under vacuum to give Intermediate 6A1 (0.8 gm) as a white solid. MS (m / z): 450.12 [M+H] + .

[0209] Intermediate 6A2: tert-Butyl 4-(6-benzyl-4-cyano-3-hydroxy-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-2-(cyanomethyl)piperazine-1-carboxylate: Intermediate 5B (1.0 gm, 0.0018 mmol) was dissolved in THF (20 ml) and the reaction mixture was stirred at room temperature, followed by addition of 10% NaOH (5 ml) and stirring the mixture for 30 minutes. The reaction mixture was extracted with ethyl acetate. The combined THF and ethyl acetate layers were dried over sodium sulfate and concentrated under vacuum to obtain Intermediate 6A2 (0.8 gm) as a brown solid. 1H-NMR(400MHz)(CDCl3):7.30-7.22(m,5H),4.41(bs,1H),4.13-4.11(m,1H),3.75(bs,1H),3.62(bs,2H) ,3.51-3.47(m,2H),3.33-3.22(m,3H),2.68(bs,2H),2.44-2.39(m,5H),1.43(s,9H).MS:m / Z;489.2(M+1).

[0210] Intermediate 6B: tert-Butyl 4-(6-benzyl-4-cyano-3-morpholino-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)piperazine-1-carboxylate: K2CO3 (0.29 gm, 0.0021 mol) was added to a solution of morpholine (0.112 ml, 0.0012 mol) in N-methylpyrrolidone (NMP, 4 ml) and stirred at room temperature. Intermediate 5A (0.5 gm, 0.00086 mol) in NMP was added dropwise to the reaction mixture followed by heating at 60° C. for 2 hours. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated under vacuum to give a crude residue which was purified by column chromatography using ethyl acetate:hexane (25%) to give Intermediate 6B (0.4 gm). 1H-NMR (δppm, CDCl3,400MHz):7.38-7.34(m,4H),7.30-7.7.29(m,1H),3.81-3.79(m,4H),3.76(s,2H),3.70(s, 2H),3.61-3.58(m,4H),3.51-3.47(m,4H).3.28-3.26(m,4H),2.58(bs,4H),1.47(s,9H).MS(m / z):519.22[M+H] + .

[0211] Intermediate 6C: tert-butyl 4-(6-benzyl-4-cyano-3-(1,1-dioxidethiomorpholino)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)piperazine-1-carboxylate: Prepared using thiomorpholine 1,1 dioxide (0.52 gm, 0.0051 mmol) and Intermediate 5B (1.5 gm, 0.0025 mol) using the process as described above for Intermediate 6B to give a white solid Intermediate 6C was obtained as (1.25gm).1H-NMR (δppm, CDCl3,400MHz):7.38-7.32(m,4H),7.31-7.30(m,1H),4.12-4.10(m,4H),3.7 6(m,4H),3.52-3.50(m,4H),3.28-3.25(m,4H),3.18-3.16(m,4H),2.78(bs,4H),1.47(s,9H).MS(m / z):567.20[M+H] + .

[0212] Intermediate 6D: tert-Butyl 4-(6-benzyl-4-cyano-3-(4-methylpiperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)piperazine-1-carboxylate: To a solution of N-methylpiperazine (0.63 ml, 0.005 mol) in NMP (30 ml) was added DIPEA (2.0 ml, 0.01 mol) and stirred at room temperature. Intermediate 5A (2.2 gm, 0.003 mol) in NMP was added dropwise to the reaction mixture and heated at 60° C. for 2 hours. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated under vacuum to give a crude residue which was purified by column chromatography using ethyl acetate:hexane (25%) to give Intermediate 6D (1.0 gm). 1H-NMR (δppm, CDCl3,400MHz):7.38-7.32(m,4H),7.29-7.28(m,1H),3.76(s,2H),3.70(s,2H),3.50-3.49(m,4H),3.39 -3.36(m,4H),3.27-3.23(m,4H).2.84(s,3H),2.55-2.53(4H),2.39-2.35(2H),2.02-2.01(2H).MS(m / z):532.50[M+H] + .

[0213] Intermediate 6E: tert-butyl 4-(6-benzyl-4-cyano-3-(2-fluoropyridin-4-yl)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)piperazine-1-carboxylate: To a solution of intermediate 5A (1.5 gm, 0.0025 mol) and 3-fluoro 4-pyridineboronic acid (0.38 g, 0.0027 mol) in dioxane:H2O, K2CO3 (0.71 g, 0.0051 mol) was added and purged with N2 gas for 15 minutes. Tetrakis (0.13 g, 0.00012 mol) was added and purged again with N2 gas for 5 minutes, and the reaction mixture was heated at 110° C. for 2 hours. The reaction mixture was cooled to room temperature, quenched with ice cold water and extracted with EtOAc (3×50 ml), the EtOAc layer was dried over Na2SO4 and concentrated under vacuum to give the crude residue which was purified by column chromatography eluting with 30% EA in hexane to give intermediate 6E (0.2 gm) as a white solid. 1H-NMR (δppm, CDCl3,400MHz):8.35-8.34(m,1H),7.75-7.74(m,1H),7.45(s,1H),7.38-7.35(m,4H),7.32-7.30(m,1H), 3.89(s,2H),3.76(s,2H),3.56(bs,4H),3.39(bs,4H),2.76(bs,2H),2.69-2.68(m,2H),1.48(s,9H).MS(m / z):527[M+H] - .

[0214] Intermediate 6F: tert-butyl 4-(6-benzyl-4-cyano-3-(piperidin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)piperazine-1-carboxylate. Prepared using the process as described above for intermediate 6D using piperidine (0.63 mL, 0.005 mol) and intermediate 5A (2.2 gm, 0.003 mol) to give intermediate 6F (1.0 gm). 1H-NMR (δppm, CDCl3,400MHz):7.38-7.35(m,4H),7.34-7.32(m,1H),3.75(s,2H),3.69(s,2H),3.58-3.51(m, 4H),3.49-3.48(m,4H),3.26-3.24(m,4H),2.57(bs,4H),1.69-1.64(bs,6H),1.47(s,9H).MS(m / z):517[M+H] + .

[0215] Intermediate 6G: tert-Butyl 4-(6-benzyl-4-cyano-3-(2,6-dimethylmorpholino)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)piperazine-1-carboxylate: Prepared using 2,6 dimorpholine (0.112 ml, 0.0012 mol) and Intermediate 5A (0.5 gm, 0.00086 mol) using the process as described above for Intermediate 6C to give Intermediate 6G (0.4 gm). 1H-NMR (δppm, CDCl3,400MHz):7.36-7.35(m,5H),4.11-4.08(m,2H),3.76-3.70(m,6H),3.51-3.48(m,4H),3.2 6-3.24(m,4H),2.69-2.67(m,2H),2.58(bs,4H),1.48(s,9H),1.29(s,3H),1.20(s,3H).MS(m / z):547.72[M+H] + .

[0216] Intermediate 6H: tert-Butyl 4-(6-benzyl-4-cyano-3-(4-propionylpiperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)piperazine-1-carboxylate: To a solution of piperazine (0.33 gm, 0.0028 mmol) in THF (15), DIPEA (1.29 ml, 0.0075 mmol) was added and stirred at room temperature. Intermediate 5A (1.5 gm, 0.00258 mmol) in THF was added dropwise to the reaction mixture and heated at 80° C. for 2 hours. The reaction mixture was cooled at 0° C. and propionyl chloride (0.46 ml, 0.005 mmol) was added dropwise over 10 minutes and the reaction mixture was stirred for 1 hour. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated under vacuum to give a crude residue which was purified by column chromatography using ethyl acetate:hexane (25%) to give intermediate 6H (1.2 gm). 1H-NMR (δppm, CDCl3, 400 MHz): 7.38-7.26 (m, 5H), 3.76 (s, 2H), 3.70 (s, 4H), 3.55-3.54 (bs, 10H), 3.32-3.27 (m, 4H), 2.60 (bs, 4H), 2.40-2.30 (q, 2H), 1.47 (s, 9H), 1.90-1.54 (t, 3H). MS (m / z): 574.16 (M+H). + .

[0217] Intermediate 6I: 4-(6-benzyl-4-cyano-3-(4-(methylsulfonyl)piperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)piperazine-1-butyl carboxylate: To a solution of piperazine (0.33 gm, 0.0028 mmol) in THF (15 ml), DIPEA (1.29 ml, 0.0075 mmol) was added and stirred at room temperature. To the above reaction mixture, 4-(6-benzyl-4-cyano-3-(((trifluoromethyl)sulfonyl)oxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)piperazine-1-tert-butyl carboxylate (1.5 gm, 0.00258 mmol) in THF was added dropwise at the same temperature and heated at 80° C. for 2 hours. The reaction mixture was cooled at 0° C. and methanesulfonyl chloride (0.32 ml, 0.005 mmol) was added dropwise to the reaction mixture over 10 minutes and stirred for 1 hour. The reaction mixture was quenched with water, extracted with ethyl acetate, the organic layer was washed with brine, dried over sodium sulfate and subsequently evaporated to give the crude product which was purified by column chromatography using ethyl acetate:hexane (25%) to give the desired compound (1.2 gm). 1H-NMR(δppm, CDCl3,400MHz):7.38-7.26(m,5H),3.76(s,2H),3.70(s,4H),3.55-3.54(bs,10H),3.32 -3.27(m,4H),2.60(bs,4H),2.40-2.30(q,2H),1.47(s,9H),1.90-1.54(t,3H).MS(m / z):574.16(M+H) + .

[0218] Intermediate 6J: tert-butyl 4-(3-(4-acetylpiperazin-1-yl)-6-benzyl-4-cyano-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)piperazine-1-carboxylate: To a solution of piperazine (0.33 gm, 0.0028 mmol) in THF (15), DIPEA (1.29 ml, 0.0075 mmol) was added and stirred at room temperature. To the above reaction mixture, tert-butyl 4-(6-benzyl-4-cyano-3-(((trifluoromethyl)sulfonyl)oxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)piperazine-1-carboxylate (1.5 gm, 0.00258 mmol) in THF was added dropwise at the same temperature and it was heated at 80° C. for 2 hours. Completion of the reaction was checked by TLC using ethyl acetate and hexane (30%). The reaction mixture was cooled at 0° C. and acetyl chloride (0.22 ml, 0.005 mmol) was added dropwise to the reaction mixture over 10 minutes and the reaction mixture was stirred for 1 hour. The reaction mixture was poured into water and ethyl acetate and the separated organic layer was washed with brine. The organic layer was dried over sodium sulfate and evaporated to give the crude product. The crude was purified by column chromatography using ethyl acetate:hexane (25%) to give intermediate 6J (1.0 gm). 1H-NMR (δppm, CDCl3,400MHz):7.38-7.32(m,4H),7.30-7.28(m,1H),3.76-3.70(m,6H),3.60(s,4H),3.56-3.5 4(m,2H),3.51-3.49(m,4H),3.28-3.26(m,4H),2.59(bs,4H),2.13(s,3H),1.47(s,9H).MS(m / z):560.12(M+H) + .

[0219] Intermediate 7: 1-(4-aminopiperidin-1-yl)-6-benzyl-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile: To a solution of tert-butyl (1-(6-benzyl-3-chloro-4-cyano-5,6,7,8-tetrahydro-2,6-naphthyridine-1-yl)piperidin-4-yl)carbamate (0.35 g), in methanol (10 ml), triethylamine (20 ul) and Pd / C (0.35 g) were dissolved and the reaction mixture was stirred at room temperature for 12 hours. After completion of the reaction, it was filtered over celite and the mixture was evaporated to give an oily compound (0.25 gm) which was used directly in the next step without analytical data.

[0220] Intermediate 7A: tert-butyl 4-(6-benzyl-4-cyano-3-(2,6-dimethylmorpholino)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-2-(cyanomethyl)piperazine-1-carboxylate. Prepared using the process as described above for Intermediate 6C using 2,6 dimorpholine (0.953 ml, 0.0051 mmol) and Intermediate 5C (3 gm, 0.0051 mmol) to give Intermediate 7A (2.6 gm). 1H-NMR (δppm, CDCl3,400MHz):7.38-7.34(m,4H),7.30-7.28(m,1H),4.68(m,2H),4.13-4.07(m,3H),3.84-3.76(m,4H),3.67-3.61(m, 4H),3.13-3.08(m,2H),2.77-26(m,3H),2.65-2.64(m,3H),2.48(m,2H),1.48(s,9H),1.29(s,3H),1.20(s,3H).MS(m / z):586.29[M+H] + .

[0221] Intermediate 7B: tert-butyl 4-(6-benzyl-4-cyano-1-(2,6-dimethylmorpholino)-5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)piperazine-1-carboxylate: Prepared using tert-butyl piperazine-1-carboxylate (0.74 gm, 4.02 mmol) and Intermediate 5C (1.37 gm, 2.68 mmol) using the process as described above for Intermediate 6C to obtain Intermediate 7B (1.2 gm). 1H-NMR (400MHz): δ7.34(m,4H),7.30(m,1H),4.22-4.17(q,2H),3.64(s,2H),3.20(t,2H),2.81-2.76(m 1H),2.60-2.58(t,2H),2.40-2.31(m,2H).,1.26(q,3H).MS(m / z):547.3(M+1).

[0222] Intermediate 7C: tert-butyl 4-(6-benzyl-4-cyano-1-(2,6-dimethylmorpholino)-5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)-2-(cyanomethyl)piperazine-1-carboxylate: Prepared using the process as described above for Intermediate 7B using 2-(piperazin-2-yl)acetonitrile dihydrochloride (1.6 gm, 13.1 mmol) and Intermediate 5E (4.4 gm, 8.6 mmol) to give Intermediate 7C (2.3 gm, 45.71%). MS (m / z): 547.3 (M+1).

[0223] Intermediate 7D: 4,4'-(6-benzyl-4-cyano-5,6,7,8-tetrahydro-2,6-naphthyridine-1,3-diyl)bis(piperazine-1-carboxylate) di-tert-butyl: To a solution of tert-butyl piperazine-1-carboxylate (0.9 gm, 0.002 mol) in THF (30 ml) was added DIPEA (1.2 ml, 0.03 mol) and stirred at room temperature. Intermediate 5A (1.5 gm, 0.001 mol) in THF (10 ml) was added dropwise to the reaction mixture and heated to 80° C. for 2 hours. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuum to give a crude residue which was purified by column chromatography using ethyl acetate:hexane (25%) to give Intermediate 7D (1.25 gm). MS(m / z):618.22[M+H] + .

[0224] Intermediate 7E: (R)-tert-butyl 4-(6-benzyl-4-cyano-3-(4-methylpiperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-3-methylpiperazine-1-carboxylate: Prepared using the process as described above for Intermediate 5F using 1-methylpiperazine (0.30 mL, 0.0027 mmol) (1.1 gm, 0.0018 mmol) to give Intermediate 7E (0.9 gm). MS (m / z): 546.23 (M+H). + .

[0225] Intermediate 7F: (S)-tert-butyl 4-(6-benzyl-4-cyano-3-(4-methylpiperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-3-methylpiperazine-1-carboxylate: Prepared using the process as described above for Intermediate 5A using 1-methylpiperazine (0.30 mL, 0.0027 mmol) and Intermediate 5G (1.1 gm, 0.0018 mmol) to give Intermediate 7F as a white solid (0.5 gm). MS (m / z): 546.23 (M+H). + .

[0226] Intermediate 7G: tert-butyl 4-(6-benzyl-4-cyano-3-(4-methylpiperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-2-(cyanomethyl)piperazine-1-carboxylate: Prepared using the process as described above for Intermediate 5C using 1-methylpiperazine (0.30 ml, 0.0027 mol) (0.9 g, 0.0018 mmol) to give Intermediate 7G (0.9 gm). 71.35 (M+H) + .

[0227] Intermediate 8: tert-Butyl 4-(6-benzyl-4-cyano-3-(2-morpholinoethoxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)piperazine-1-carboxylate: To a solution of intermediate 5A (1.6 gm, 0.0035 mmol) in DMSO (20 mL), NaH (60% in mineral oil) (213 mg, 0.0089 mmol) was added and stirred at 0° C. for 20 min. 4 (2-chloroethylmorpholine hydrochloride) (1.3 gm, 0.0071 mmol) was added slowly and the reaction mixture was stirred at 80° C. for 3 h. The reaction mixture was quenched with cold water (50 mL) and extracted with ethyl acetate (30 mL×2). The combined organic layers were washed with brine solution (30 mL), dried over Na2SO4 and evaporated under reduced pressure to give the crude product which was purified by column chromatography using ethyl acetate and petroleum ether (50%) to give intermediate 8 (1 gm) as a white solid. 1H-NMR (400 MHz): δ 7.37-7.34 (m, 4H), 7.32-7.30 (m, 1H), 4.49-4.46 (m, 4H), 3.77 (s, 2H), 3.73-3.69 (m, 6H), 3.51-3.50 (bs 4H), 3.29 (bs, 4H), 2.81-2.86 (m, 2H). 2.60 (bs, 8H), 1.47 (s, 9H). MS (m / z): 563.18 (M+1). + .

[0228] Intermediate 9A: tert-Butyl 4-(6-benzyl-4-cyano-3-((methylsulfonyl)oxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)piperazine-1-carboxylate: To a solution of intermediate 6A1 (2.1 gm, 0.0043 mol) in DCM (30 mL) was added TEA (1.5 mL, 0.0107 mol) at 0° C. Then to the above solution was slowly added a solution of methanesulphonyl chloride (0.5 mL, 0.0064 mol) in DCM (12 mL) and the reaction mixture was stirred at room temperature for 2 hours. The reaction completion was confirmed by TLC using 40% ethyl acetate and hexane as mobile phase. The reaction mixture was quenched into cold water and the organic layer was separated. The aqueous layer was extracted with additional DCM (20 mL×2) and the combined organic layer was washed with brine solution (20 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure and temperature (30-35°C) to give a crude residue which was purified by column chromatography (100-200 mesh silica gel) using 20-40% ethyl acetate in hexane as the mobile phase. The pure fractions were collected and concentrated to give intermediate 9A (1.72 gm, 70.72%) as an off-white solid which was used in the next reaction.

[0229] Intermediate 9B: tert-butyl 4-(6-benzyl-4-cyano-3-((methylsulfonyl)oxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-2-(cyanomethyl)piperazine-1-carboxylate: Prepared using the process as described above for Intermediate 9A. 1H-NMR(400MHz)(CDCl3):7.36-7.26(m,5H),4.62(bs,1H),4.13-4.09(m,1H),3.90-3.81(m,2H),3.78-3.67(m,4H),3. 44(s,3H),2.29-3.25(m,2H),3.05-2.98(m,1H),2.79-2.68(m,5H),2.61-2.58(m,1H)1.50(s,9H).MS:m / Z;567.2(M+1).

[0230] Intermediate 10A: (tert-butyl 4-(6-benzyl-4-cyano-3-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)piperazine-1-carboxylate: In a 100 mL pressure vessel, a suspension of Intermediate 5A (2.5 gm, 4.3 mmol), 1-methylpyrrolidine (0.99 gm, 8.6 mmol), Cs2CO3 (4.2 gm, 12.9 mmol), and ras BINAP (0.53 gm, 0.86 mmol) in toluene (38 mL) was purged with N2 gas for 20 minutes. To the above reaction mixture, Pd(OAc)2 (0.096 gm, 0.43 mmol) was added and stirred at 120° C. for 3 hours. The reaction mixture was quenched with cold water (40 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with brine solution (30 mL), dried over Na2SO4 and evaporated under reduced pressure to give the crude product, which was purified by column chromatography using ethyl acetate and petroleum ether (30-100%) to give intermediate 10A (1.2 gm, 50.93%). 1H-NMR (400 MHz): δ 7.38-7.26 (m, 5H), 4.32-4.23 (m, 2H), 3.78 (bs ,2H),3.70(bs,2H),3.52-3.43(m,4H),3.31-3.28(m,4H),3.11-3.07(m,1H),2.70-2.66(m,1H),2.60(bs,4H), 2.50(s,3H),2.31-2.29(m,1H),2.06-2.01(m,1H),1.81-1.77(m,3H),1.48(s,9H).MS(m / z):547.3(M+1),HPLC Purity: 83.95%.

[0231] Intermediate 10B: tert-butyl 4-(6-benzyl-4-cyano-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-2-(cyanomethyl)piperazine-1-carboxylate:

[0232] Method A: Prepared using the process as described above for intermediate 10A. 1H-NMR (400 MHz) (CDCl3): 7.37-7.29 (m, 5H), 4.62 (bs, 2H), 4.33-4.21 (m, 1H), 3.90-3.62 (m, 8H), 3.48-3.39 (m, 2H), 3.20-3.12 (m, 2H), 2.92-2.51 (m, 9H), 2.37-2.24 (m, 2H), 2.20-2.05 (m, 1H), 2.00-1.89 (m, 2H) 1.50 (s, 9H). MS: m / Z; 586.3 (M+1).

[0233] Method B: In a 500 mL sealed tube, (S)-(1-methylpyrrolidin-2-yl)methanol (6.2 gm, 0.054 mol) was added followed by dry THF (150 ml) and the reaction mixture was stirred at 0° C. To the reaction mixture was added NaH (60%) (1.74 gm, 0.072 mol) and the reaction was stirred at the same temperature under nitrogen for 30 minutes. Intermediate 5 (18.5 g, 0.036 mol) was dissolved in dry THF (120 mL) and added dropwise to the reaction mixture and stirred at 85° C. for 12 hours. After completion of the reaction, the reaction mixture was poured into saturated ammonium chloride solution (200 mL) and extracted with ethyl acetate (500 mL×2). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give a crude residue. The crude was purified by column chromatography using 3% DCM:methanol as the mobile phase. The pure fractions were collected and concentrated under reduced pressure to give intermediate 6 (14 g) as a pale yellow solid. 1H-NMR (δ ppm, CDCl3, 400 MHz): 7.37-7.32 (m, 4H), 7.31-7.29 (m, 1H), 4.31 (bs, 1H), 3.90 (bs, 1H), 3.67 (bs, 1H), 3.65-3.55 (m, 1H), 3.48-3.44 (m, 1H), 3.18-3.14 (m, 2H), 2.85-2.82 (m, 6H). 2.63 (s, 3H), 2.45 (m, 1H), 2.03-1.99 (m, 1H), 1.78. 1.75 (m, 6H), 1.50 (s, 9H), MS (m / z): 586.34 [M+H] + .

[0234] Intermediate 11: tert-Butyl 4-(4-cyano-3-morpholino-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)piperazine-1-carboxylate: In a 100 mL two-neck RBF, Intermediate 6B (0.9 gm, 1.59 mmol) in ethanol (18 mL) was purged with N2 gas for 20 minutes followed by addition of Pd(OH)2 / C (20%, 0.27 gm, 0.3 / w). The reaction mixture was stirred at 50° C. under H2 atmosphere for 3 hours. Reaction completion was confirmed by TLC using MeOH:DCM (5%). After completion of the reaction, the mixture was filtered through a bed of celite under inert atmosphere and the filtrate was evaporated under reduced pressure to give a crude residue which was purified by column chromatography using 5% MeOH in DCM as the mobile phase. Pure fractions were collected and concentrated to give the desired product (0.4 gm, 52.78%). 1H-NMR (400 MHz): δ 4.15-4.13 (m, 4H)), 3.55-3.53 (m, 4H), 3.29-3.26 (m, 4H), 3.19-3.17 (m, 4H), 3.14-3.10 (m, 2H), 3.09-3.06 (m 2H), 2.64-2.62 (m, 2H), 2.07 (s, 1H), 1.49 (s, 9H). MS (m / z): 477.2 (M+1).

[0235] Intermediate 12: tert-Butyl 4-(4-cyano-3-(1,1-dioxidothiomorpholino)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)piperazine-1-carboxylate: Prepared using Intermediate 6C (0.9 gm, 0.0015 mmol) using the process as described above for Intermediate 11 to give Intermediate 12 as a white solid. (0.6gm).1H-NMR(δppm,CDCl3,400MHz):4.15-4.12(m,5H),3.55-3.53(m,4H),3.29 -3.26(m,4H),3.19-3.14(m,4H),3.11-3.09(m,2H),3.07-3.05(m,2H),2.64-2.61(m 1H),1.48(s,9H).MS(m / z):478.02[M+H] + .

[0236] Intermediate 13: tert-Butyl 4-(4-cyano-3-(2-morpholinoethoxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)piperazine-1-carboxylate: Prepared using intermediate 8 (1.0 gm, 0.0017 mmol) using the process as described above for intermediate 11 to obtain intermediate 13 (0.3 gm). 1H-NMR(δppm, CDCl3,400MHz):4.49-4.46(t,2H),4.11(s,4H),3.73-3.71(t ,4H),3.54-3.52(t,4H),3.30-3.81(m,4H),3.01-2.99(m,2H),2.91-2.78(m 2H),2.61-2.59(m,4H),2.50(bs,2H),1.48(s,9H).MS(m / z):473.56[M+H] + .

[0237] Intermediate 14: tert-butyl 4-(4-cyano-3-(2,6-dimethylmorpholino)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-2-(cyanomethyl)piperazine-1-carboxylate: Prepared using Intermediate 7A (2.6 gm, 0.0044 mmol) using the process as described above for Intermediate 11 to give Intermediate 14 as a white solid (2.2 gm). 1H-NMR(δppm, CDCl3,400MHz):4.15-4.11(m,4H),3.98(s,4H),3.75-3.72(m ,2H),3.54-3.51(m,4H),3.26-3.24(m,4H),3.02-3.01(m,2H),2.68-2.51(m 2H),1.48(s,9H),1.29(s,3H),1.20(s,3H).MS(m / z):457.12[M+H] + .

[0238] Intermediate 15: (tert-butyl 4-(4-cyano-1-(2,6-dimethylmorpholino)-5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)piperazine-1-carboxylate): Prepared using the process as described above for Intermediate 11 using Intermediate 7A (1.2 gm, 2.19 mmol) to give Intermediate 15 (0.4 gm, 40%). 1H-NMR(400MHz):δ4.15(s,2H)),3.76-3.72(m,8H),3.60-3.56(m,4H),2.09-3.06(m,2H),2 .66-2.60(m,4H),2.04(s,1H),1.48(s,9H),1.24(s,3H),1.22(s,3H).MS(m / z):457.3(M+1).

[0239] Intermediate 16: (tert-butyl 4-(4-cyano-1-(2,6-dimethylmorpholino)-5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)-2-(cyanomethyl)piperazine-1-carboxylate): Prepared using Intermediate 7B (2.3 gm, 3.91 mmol) using the process as described above for Intermediate 11 to give Intermediate 16 (0.9 gm, 46.46%). MS: m / z; 496.3 (M+1).

[0240] Intermediate 17: (tert-butyl 4-(4-cyano-3-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)piperazine-1-carboxylate): Prepared using Intermediate 10A (1.2 gm, 2.19 mmol) using the process as described above for Intermediate 11 to give Intermediate 17 (0.32 gm, 32.37%). MS (m / z): 457.2 (M+1).

[0241] Intermediate 18: 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: In a 500 mL two-necked RBF, intermediate 10B (10 gm, 0.017 mol) in ethanol (200 mL) was degassed with N2 for 20 minutes. To the above solution, ammonia in methanol solution (12 mL) was then added, followed by 6 gm of Pd(OH)2 / C (20%). The entire reaction mixture was stirred at 70° C. for 24 hours under H2 gas atmosphere. Reaction completion was confirmed by TLC using 5% MeOH in DCM and one drop of ammonia in methanol solution. After completion of reaction, the mixture was filtered through a bed of celite under inert atmosphere and the filtrate was evaporated under reduced pressure to give the desired product, intermediate 17 (7.3 gm) as a pale yellow solid. 1H-NMR(400MHz)(CDCl3):4.81-4.78(m,1H),4.61(bs,1H),4.49-4.44(m,1H),4.14-4.04(m,3H),3.85-3.79(m,1H),3.67-3.64(m,1H) ),3.56-3.54(m,1H),3.36-3.18(m,5H),2.96-2.92(m,6H),2.71-2.61(m,2H),2.32-1.97(m,5H),1.51(s,9H).MS(m / z):496.3(M+1).

[0242] Intermediate 18A: 4,4'-(4-cyano-5,6,7,8-tetrahydro-2,6-naphthyridine-1,3-diyl)bis(piperazine-1-carboxylate) di-tert-butyl: A solution of Intermediate 7D (1.0 gm, 0.001 mol) in ethanol was purged with nitrogen gas for 20 minutes, after which 5 drops of acetic acid were added followed by Pd2(OH)2 (0.3 gm) and the reaction mixture was heated at 50°C for 12 hours. The reaction mixture was filtered on a celite pad and the filtrate was evaporated under reduced pressure to give the crude product. The crude was purified by column chromatography using methanol:DCM (10%) to give Intermediate 26 (0.4 gm) as a white solid. 1H-NMR(δppm, CDCl3,400MHz):4.14(s,2H),3.59-3.52(m,12H),3.28-3.25(m, 4H),3.04-3.01(m,2H),2.57-2.51(m,2H),1.43(s,18H).MS(m / z):528.25[M+H] + .

[0243] Intermediate 18B: tert-butyl 4-(4-cyano-3-(4-methylpiperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)piperazine-1-carboxylate: Prepared using Intermediate 6D (1.0 gm, 0.001 mol) using the process as described above for Intermediate 18A to give Intermediate 18B as a white solid (0.4 gm). 1H-NMR(δppm, CDCl3,400MHz):4.08(s,2H),3.69-3.67(m,4H),3.53-3.48(m,4H),3.28-3.27(m,4H), 3.00-2.98(m,2H),2.60-2.58(m,4H),2.55-2.53(m,2H),2.37(s,3H),1.48(s,9H).MS(m / z):442[M+H] + .

[0244] Intermediate 18C: tert-butyl 4-(4-cyano-3-(piperidin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)piperazine-1-carboxylate: Prepared using Intermediate 6F (0.6 gm, 0.0011 mol) using the process as described above for Intermediate 18A to give Intermediate 18C as a white solid (0.4 gm). MS (m / z): 428.45 [M+H] + .

[0245] Intermediate 18D: tert-butyl 4-(4-cyano-3-(2,6-dimethylmorpholino)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)piperazine-1-carboxylate: Prepared using the process as described above for Intermediate 18A using Intermediate 6G (0.8 gm, 0.0018 mmol) to give Intermediate 18D (0.6 gm). 1H-NMR(δppm, CDCl3,400MHz):4.15-4.11(m,4H),3.98(s,4H),3.75-3.72(m ,2H),3.54-3.51(m,4H),3.26-3.24(m,4H),3.02-3.01(m,2H),2.68-2.51(m 2H),1.48(s,9H),1.29(s,3H),1.20(s,3H).MS(m / z):457.12[M+H] + .

[0246] Intermediate 18E: tert-butyl 4-(4-cyano-3-(4-propionylpiperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)piperazine-1-carboxylate: Prepared using Intermediate 6H (1.0 gm, 0.0017 mmol) using the process as described above for Intermediate 18A to give Intermediate 18E (0.6 gm) as a white solid. MS (m / z): 484.12 [M+H] + .

[0247] Intermediate 18F: tert-butyl 4-(4-cyano-3-(4-methylsulfonyl)piperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)piperazine-1-carboxylate: Prepared using Intermediate 6I (1.0 gm, 0.0017 mmol) using the process as described above for Intermediate 18A to give Intermediate 18F (0.6 gm) as a white solid. 1H-NMR(δppm, CDCl3,400MHz):4.113(s,2H),3.68-3.66(m,4H),3.54-3.5 1(m,4H),3.37-3.35(m,4H),3.29-3.27(m,4H),3.06-3.03(m,2H),2.83(s 3H),2.61-2.58(m,2H),1.48(s,9H).MS(m / z):506.20[M+H] + .

[0248] Intermediate 18G: tert-butyl 4-(3-(4-acetylpiperazin-1-yl)-4-cyano-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)piperazine-1-carboxylate: Prepared using Intermediate 6J (0.8 gm, 0.0017 mmol) using the process as described above for Intermediate 26 to give Intermediate 18G (0.6 gm) as a white solid. 1H-NMR(δppm, CDCl3,400MHz):4.11(s,2H),3.75-3.74(m,2H),3.64-3.59(m ,6H),3.58-3.52(m,4H),3.29-3.27(m,4H),3.04-3.03(m,2H),2.58-2.56(m 2H),2.13(s,3H),1.48(s,9H).MS(m / z):470.12[M+H] + .

[0249] Intermediate 18H: tert-butyl 4-(4-cyano-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)piperazine-1-carboxylate: Prepared using intermediate 5H (0.7 gm, 0.0015 mol) using the process as described above for intermediate 11 to give intermediate 18H (0.4 gm). 344.20 [M+H] + .

[0250] Intermediate 19A: tert-Butyl 4-(6-(8-chloronaphthalen-1-yl)-4-cyano-3-morpholino-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)piperazine-1-carboxylate: To a solution of intermediate 11 (0.4 g, 0.00075 mmol) in 1,4-dioxane (10 ml) purged under nitrogen gas for 20 minutes, 1-bromo-8-bromonaphthalene (0.3 gm, 0.0015 mmol), sodium tert.butoxide (0.29 gm, 0.0030 mmol), and r-BINAP (0.093 gm, 0.00015 mmol) were added over 10 minutes and stirred under nitrogen atmosphere. To the reaction mixture was then added Pd2(dba)3 (0.068 gm, 0.000075 mmol) and heated at 130° C. for 16 h. The reaction mixture was filtered through a pad of Celite and the filtrate was evaporated under reduced pressure to give a crude residue which was purified by column chromatography using MeOH:DCM (5%) to give intermediate 19A. 1H-NMR(δppm, CDCl3,400MHz):7.77-7.75(m,1H),7.64-7.62(m,1H),7.53-7 .51(m,1H),7.46-7.42(m,1H),7.31-7.32(m,1H),7.23-7.21(m,1H),4.58-4 .53(m,1H),3.87-3.81(m,1H),3.64-3.62(m,4H),3.59-3.54(m,4H),3.52-3 .49(m,2H),3.23-3.22(m,2H),3.15-3.05(m,2H),2.60(bs,2H)1.49(s,9H).

[0251] Intermediate 19B: tert-butyl 4-(4-cyano-3-(1,1-dioxidothiomorpholino)-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)piperazine-1-carboxylate: Prepared using Intermediate 12 using the process as described above for Intermediate 19A to give Intermediate 19B as a white solid (0.22 gm, 43.45%). 1H-NMR(400MHz): δ8.20-8.18(m,1H)),7.89-7.87(m,1H),7.64(d,J=8.0Hz,1H),7.53-7.50(m,2H),7.46-7.43(m,1H),7.19(d,J=6.8Hz,1 H),4.40(bs,2H),4.18-4.15(m,4H),3.60-3.58(m,4H),3.36(bs,6H),3.22-3.19(m,4H),2.88(bs,2H),1.50(s,9H).MS(m / z):603.2(M+1).

[0252] Intermediate 19C: tert-Butyl 4-(4-cyano-3-(2,6-dimethylmorpholino)-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-2-(cyanomethyl)piperazine-1-carboxylate: Intermediate 14 (1 g, 0.0020 mmol), 1-Bromonapthene (0.59 ml, 0.00 4mmol), Cesium carbonate (1.97gm, 0.0066mmol), Ruphos (0.18gm, 0.0004mmol) and Pd2(dba)3 (0.184gm, 0.000022mmol) were used to prepare intermediate 19C (0.9gm) as white marketable product using the process as described above for intermediate 19A at 110°C for 3 hours in toluene as solvent. 1H-NMR (δppm, CDCl3, 400MHz): 8.19-8.17(m,1H), 7.88-7.85(m,1H), 7.64-7.61(m,1H), 7.51-7.49(m,2H), 7.44-7.7.42(m,1H), 7.19-7.17(m,1H), 4.41(bs,1H), 4. 40(bs,1H),4.17-4.11(m,3H),3.80-3.73(m,4H),3.70(bs,1H),2.25(bs,3H),2.8 9-2.79(m,5H),2.75-2.69(m,3H),1.52(s,9H),1.29(s,6H).MS(m / z):622.22[M+H] + .

[0253] Intermediate 19D: tert-Butyl 4-(4-cyano-3-(2-morpholinoethoxy)-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)piperazine-1-carboxylate: Mixture of Intermediate 13 (0.3 gm, 0.00063 mmol), 1-bromonaphthalene (0.18 mL, 0.001271 mmol), Ruphos (0 Intermediate 19A was prepared using Cs2CO3 (0.06 gm, 0.00012 mmol), Cs2CO3 (0.13 gm, 0.00031 mmol) and Pd2(dba)3 (0.058 gm, 0.000063 mmol) at 110° C. for 4 hours using toluene as solvent to give Intermediate 19D as a white solid (0.25 gm, 18.17%). 1H-NMR (400MHz): δ8.20-8.17(m,1H),7.88-7.86(m,1H),7.64-7.62(m,1H),7.52-7.50(m,2H),7.48-7.43(m,1H),7.18-7.17(m,1H),4.54 (bs,2H),4.41(bs,2H),3.75(bs,4H),3.58-3.57(bs,4H),3.38(bs,5H),2.85(bs,4H),2.64(bs,4H),1.49(s,9H).MS(m / z):599.21(M+1).

[0254] Intermediate 19E: tert-Butyl 4-(6-(8-chloronaphthalen-1-yl)-4-cyano-3-(2-morpholinoethoxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)piperazine-1-carboxylate. Prepared using intermediate 13 (0.3 gm, 0.00063 mmol), 1-bromo-8-chloronaphthalene (0.36 mg, 0.001271 mmol), Ruphos (0.06 gm, 0.00012 mmol), Cs2CO3 (0.13 gm, 0.00031 mmol) and Pd2(dba)3 (0.058 gm, 0.000063 mmol) using the process as described above for intermediate 19A at 110° C. for 4 hours using toluene as solvent to give intermediate 19E as a white solid (0.25 gm, 18.17%). 1H-NMR (400MHz): δ7.78-7.75(m,1H),7.65-7.63(m,1H),7.54-7.52(m,1H),7.4 7-7.23(m,1H),7.36-7.32(m,1H),7.24-7.23(m,1H),4.60-4.48(m,3H),3.94-3. 74(m,1H),3.64-3.61(m,4H),3.54-3.52(m,2H),3.49-3.44(m,5H),3.28-3.26(m ,2H),3.24-3.12(m,2H),2.80-2.52(m,4H),1.49(s,9H).MS(m / z):634.20(M+1).

[0255] Intermediate 19F: (4-(4-cyano-1-(2,6-dimethylmorpholino)-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)piperazine-1-carboxylate) tert-butyl: Prepared using Intermediate 16 (0.4 gm, 0.88 mmol), 1-Bromonaphthalene (0.25 mL, 1.75 mmol), Xantphos (0.1 gm, 0.17 mmol), CsCO (0.86 gm, 2.63 mmol) and Pd(dba) using the process as described above for Intermediate 19A at 110° C. for 4 hours in toluene as solvent to obtain Intermediate 19E (0.32 gm, 63.7%). 1H-NMR (400MHz): δ8.22-8.20(m,1H),7.88-7.86(m,1H),7.64-7.62(m,1H),7.5 2-7.50(m,2H),7.46-7.42(m,1H),7.20-7.18(m,1H),4.38(bs,2H)),3.79-3.78( m,2H),3.69-3.68(m,2H),3.59-3.58(m,8H),3.38-25(m,2H),2.88-2.79(m,2H), 2.72-2.62(m,2H),1.42(s,9H),1.28(s,3H),1.26(s,3H).MS(m / z):583.3(M+1).

[0256] Intermediate 19G: (tert-Butyl 4-(4-cyano-1-(2,6-dimethylmorpholino)-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)-2-(cyanomethyl)piperazine-1-carboxylate): Prepared using Intermediate 16 (0.88 gm, 1.78 mmol), 1-Bromonaphthalene (0.53 mL, 3.56 mmol), Xantphos (0.2 gm, 0.36 mmol), CsCO (1.72 gm, 5.34 mmol) and Pd(dba) (0.16 gm, 0.18 mmol) at 110° C. for 4 hours using toluene as solvent to obtain Intermediate 19F as a white solid (0.2 gm, 18.17%). MS(m / z):622.3(M+1).

[0257] Intermediate 19H: (tert-Butyl 4-(4-cyano-3-((1-methylpyrrolidin-2-yl)methoxy)-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)piperazine-1-carboxylate): Prepared using Intermediate 17 (0.32 gm, 0.71 mmol), 1-Bromonaphthalene (0.21 mL, 1.42 mmol), RuPhos (0.066 gm, 0.14 mmol), CsCO (0.7 gm, 2.13 mmol) and Pd(dba) (0.064 gm, 0.071 mmol) using the process as described above for Intermediate 19A at 110° C. for 3 hours in toluene as solvent to obtain Intermediate 19G (0.2 gm, 48.31%). 1H-NMR (400MHz): δ8.20-8.18(m,1H),7.88-7.85(m,1H),7.64-7.62(m,1H),7.53-7.4 8(m,2H),7.46-7.41(m,1H),7.19-7.17(m,1H),4.40-3.70(m,4H),3.67(bs,4H),3.30 -3.12(m,5H),3.11-2.87(m,1H),2.75(bs,2H),2.73-2.54(m,1H),2.53(s,3H),2.31- 2.08(m,1H),2.07-2.01(m,1H),1.87-1.68(m,4H),1.42(s,9H).MS(m / z):583.3(M+1).

[0258] Intermediate 19I: 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: In a 500 mL sealed tube, Intermediate 18 (7 gm, 0.014 mol), 1-bromo-8-chloronaphthalene (5.01 gm, 0.027 mol), Xantphos (1.6 gm, 0.002 mol) and CsCO (13.8 gm, 0.042 mol) in toluene (140 mL) were degassed with N for 20 minutes. Then Pd2(dba)3 (1.3 gm, 0.0014 mol) was added to the above solution and the entire reaction mixture was stirred at 120°C for 12 hours. Reaction completion was confirmed by TLC using 5% MeOH in DCM and one drop of ammonia in methanol solution. After completion of reaction, 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 get the crude residue, which was purified by column chromatography (100-200 mesh silica gel) using 3% MeOH in DCM as mobile phase. Pure fractions were collected and concentrated to give intermediate 19I (7.26 gm) as the desired product. 1H-NMR(400MHz)(CDCl3):7.77-7.75(m,1H),7.66-7.62(m,1H),7.53-7.51(m,1H),7.48-7.42(m,1H), 7.40-7.32(m,1H),7.28-7.18(m,1H),4.59-4.55(m,2H),4.34-4.30(m,2H),3.90-3.77(m,1H),3.60-3. 55(m,2H),3.34-3.31(m,1H),3.19-3.13(m,1H),3.09-3.03(m,4H),2.73-2.64(m,3H),2.53(s,3H),2.3 3-2.31(m,1H),2.06-2.03(m,1H),1.85-1.78(m,5H),1.51(s,9H).MS(m / z):656.3(M+1).HPLC:99.01%.

[0259] Intermediate 19J: tert-butyl 4-(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)-2-(cyanomethyl)piperazine-1-carboxylate: Intermediate 18 (1.4 gm, 0.0028 mol), 3-(benzyloxy)-1-bromonaphthalene (1.77 gm, 0.0056 Prepared using the process as described above for Intermediate 19A using Cs2CO3 (2.7 gm, 0.0084 mol), Xantphos (0.32 gm, 0.00056 mol), Cs2CO3 (2.7 gm, 0.0084 mol), toluene (20 mL), and Pd2(dba)3 (0.26 gm, 0.00028 mol) to give the desired product, Intermediate 19J (1 gm, 49.06%). MS (m / z): 728.5 (M+1). HPLC: 80.75%.

[0260] Intermediate 19K: 4,4'-(4-cyano-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-1,3-diyl)bis(piperazine-1-carboxylate) di-tert-butyl: To a solution of Intermediate 18A (0.4 g, 0.00075 mmol) in 1,4-dioxane (10 ml) purged under nitrogen gas for 20 minutes, 1-Bromonapthene (0.22 ml, 0.0015 mmol), sodium tert.butoxide (0.29 gm, 0.0030 mmol), and r-BINAP (0.093 gm, 0.00015 mmol) were added over 10 minutes and stirred under nitrogen atmosphere. To the reaction mixture was then added Pd2(dba)3 (0.068 gm, 0.000075 mmol) and heated at 130° C. for 16 hours. The reaction mixture was filtered through a pad of Celite and the filtrate was evaporated under reduced pressure to give a crude residue which was purified by column chromatography using MeOH:DCM (5%) to give intermediate 19K (0.34 gm). 1H-NMR (δppm, CDCl3,400MHz):8.21-8.18(m,1H),7.87-7.85(m,1H),7.61-7.52(m,1H),7.51-7.49(m,2H),7.47-7.63(m, 1H),7.26-7.19(m,1H),4.38(s,2H),3.62-3.56(m,13H),3.53(bs,5H),2.85(bs,2H),1.49(s,18H).MS(m / z):554.37[M+H] + .

[0261] Intermediate 19L B: 4,4'-(6-(benzo[b]thiophen-4-yl)-4-cyano-5,6,7,8-tetrahydro-2,6-naphthyridine-1,3-diyl)bis(piperazine-1-carboxylate) di-tert-butyl: Prepared using the process as described above for Intermediate 19K using Intermediate 18A (0.4 g, 0.00075 mmol) and 4-bromobenzo[b]thiophene (0.31 ml, 0.0015 mmol). Obtained 19L of body (0.3gm).1H-NMR (δppm, CDCl3,400MHz):7.62-7.59(m,1H),7.45-7.44(m,2H),7.32-7.26(m,1H),6.99-6.97 (m,1H),4.41(s,2H),3.62-3.55(m,11H),3.45-3.32(m,7H),2.82-2.79(bs,2H),1.49(s,18H).MS(m / z):660.12[M+H] + .

[0262] Intermediate 19M: tert-Butyl 4-(4-cyano-3-(4-methylpiperazin-1-yl))-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)piperazine-1-carboxylate: Prepared as above for Intermediate 19K using Intermediate 18B (0.4 g, 0.009 mmol), 1-Bromonapthene (0.26 ml, 0.0018 mol), sodium tert.butoxide (0.348 gm, 0.0036 mol), r-BINAP (0.112 gm, 0.00018 mol), and Pd2(dba)3 (0.083 gm, 0.00009 mol). The intermediate 19M was obtained (0.34 gm) using the following process. 1H-NMR (δppm, CDCl3, 400 MHz): 8.21-8.19 (m, 1H), 7.787-7.85 (m, 1H), 7.62-7.60 (m, 1H), 7.52-747 (m, 2H), 7.45-7.41 (m, 1H), 7.19-7 .17(m,1H),4.38(s,2H),3.72-3.69(m,4H),3.58-3.55(m,4H),3.55(bs,5H),3.21(s, 1H),2.84(bs,2H),2.57-2.55(m,4H),2.35(s,3H),1.49(s,9H).MS(m / z):568.10[M+H] + .

[0263] Intermediate 19N: tert-Butyl 4-(4-cyano-6-(naphthalen-1-yl)-3-(piperidin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)piperazine-1-carboxylate: Prepared using the process as described above for Intermediate 19K using Intermediate 18C (0.27 g, 0.0006 mmol), 1-Bromonapthene (0.18 ml, 0.0018 mol), Sodium tert.butoxide (0.243 gm, 0.00025 mol), r-BINAP (0.078 gm, 0.00016 mol), and Pd2(dba)3 (0.057 gm, 0.000063 mmol) to give Intermediate 19N as a white solid (0.34 gm). 1H-NMR (δppm, CDCl3,400MHz):8.22-8.19(m,1H),7.78-7.84(m,1H),7.62-7.60(m,1H),7.51-7.48(m,2H),7.45-7.41(m,1H),7.19-7.17( m,1H),4.37(bs,2H),3.63-3.62(m,4H),3.58-3.55(m,4H),3.33(bs,6H),2.80(bs,2H),1.49(s,9H),1.23(bs,6H).MS(m / z):553.10[M+H] + .

[0264] Intermediate 19O: tert-Butyl 4-(4-cyano-3-(2,6-dimethylmorpholino)-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)piperazine-1-carboxylate: Prepared using the process as described above for intermediate 19K using intermediate 18D (0.5 g, 0.0010 mmol), 1-Bromonapthene (0.25 ml, 0.0020 mmol), sodium tert.butoxide (0.38 gm, 0.004 mmol), r-BINAP (0.12 gm, 0.0002 mmol), and Pd2(dba)3 (0.09 gm, 0.00001 mmol) to obtain intermediate 19O (0.4 gm). 1H-NMR(δppm, CDCl3,400MHz):8.21-8.19(m,1H),7.87-7.85(m,1H),7.62-7.6 0(m,1H),7.51-7.49(m,2H),7.45-7.41(m,1H),7.26-7.17(m,1H),4.38(s,2H) ,4.17-4.14(m,2H),3.80-3.72(m,2H),3.69-3.57(m,4H),3.56-3.33(m,6H),2 .89(bs,2H),2.74-2.68(m,1H)1.54(s,9H),1.25(s,6H).MS(m / z):584.12[M+H] + .

[0265] Intermediate 19P: tert-Butyl 4-(4-cyano-6-(naphthalen-1-yl)-3-(4-propionylpiperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)piperazine-1-carboxylate: Prepared using the process as described above for Intermediate 19K using Intermediate 18E (0.5 g, 0.0010 mmol), 1-Bromonapthene (0.25 ml, 0.0020 mmol), Sodium tert.butoxide (0.38 gm, 0.004 mmol), r-BINAP (0.12 gm, 0.0002 mmol), and Pd2(dba)3 (0.09 gm, 0.00001 mmol) to obtain Intermediate 19P (0.4 gm). 1H-NMR (δppm, CDCl3, 400MHz):8.21-8.18(m,1H),7.87-7.85(m,1H),7.63-7. 61(m,1H),7.51-7.49(m,2H),7.48-7.43(m,1H),7.19-7.7(m,1H),4.41(s,2H) ),3.82(s,2H),3.62-3.61(m,10H),3.50-3.41(m,6H),2.64(bs,2H),2.50-2. 48(q,2H),1.48(s,9H),1.30-1.25(t,3H)1.25(s,6H).MS(m / z):610.34[M+H] + .

[0266] Intermediate 19Q: tert-Butyl 4-(4-cyano-3-(4-(methylsulfonyl)piperazin-1-yl)-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)piperazine-1-carboxylate: Intermediate 18F (0.6 g, 0.0011 mmol), 1-Bromonapthene (0.5 ml, Prepared using the process as described above for intermediate 19K using Pd2(dba)3 (0.11 gm, 0.000011 mmol), sodium tert.butoxide (0.42 gm, 0.0044 mmol), r-BINAP (0.13 gm, 0.00022 mmol), and Pd2(dba)3 (0.11 gm, 0.000011 mmol) to give intermediate 19Q (0.4 gm) as a white solid. 1H-NMR (δppm, CDCl3,400MHz):8.20-8.18(m,1H),7.88-7.85(m,1H),7.63-7.53(m,1H),7.51-7.49(m,2H),7.45-7.43(m,1H),7.19-7.1 7(m,1H),4.39(bs,2H),3.71-3.69(m,4H),3.59-3.56(m,4H),3.48(bs,1H),3.40-3.37(m,9H),2.87(bs,2H),2.82(s,3H),1.48(s,9H).

[0267] Intermediate 19R: tert-Butyl 4-(3-(4-acetylpiperazin-1-yl)-4-cyano-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)piperazine-1-carboxylate: Prepared using the process as described above for Intermediate 19K using Intermediate 18G (0.6 g, 0.0011 mmol), 1-Bromonapthene (0.5 ml, 0.0022 mmol), Sodium tert.butoxide (0.42 gm, 0.0044 mmol), r-BINAP (0.13 gm, 0.00022 mmol), and Pd2(dba)3 (0.11 gm, 0.000011 mmol) to give Intermediate 19R (0.4 gm) as white marketable product. 1H-NMR (δppm, CDCl3,400MHz):8.22-8.18(m,1H),7.87-7.85(m,1H),7.63-7.61(m,1H),7.51-7.49(m,2H),7.45-7.2(m,1H),7.19-7.17( m,1H),4.34(bs,2H),3.78-3.75(m,2H),3.65-3.56(m,11H),3.35(bs,5H),2.68(bs,2H),2.14(s,3H),1.48(s,9H).MS(m / z):596.20[M+H] + .

[0268] Intermediate 19S: tert-butyl 4-(6-(8-chloronaphthalen-1-yl)-4-cyano-1-(2,6-dimethylmorpholino)-5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)piperazine-1-carboxylate: Prepared using the process as described above for intermediate 19K using intermediate 15 (0.6 g, 0.00131 mol), 1-bromo-8-chloronaphthalene (0.47 g, 0.0019 mol), sodium tert.butoxide (0.44 gm, 0.0039 mol), r-BINAP (0.13 gm, 0.00013 mol), and Pd2(dba)3 (0.11 gm, 0.000013 mol) to give intermediate 19S (0.4 gm). 618.29 [M+H] + .

[0269] Intermediate 19T: (S)-tert-butyl 4-(6-(8-chloronaphthalen-1-yl)-4-cyano-3-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)piperazine-1-carboxylate: Prepared using the process as described above for Intermediate 19K using Intermediate 15 (0.6 g, 0.00131 mol), 1-bromo-8-chloronaphthalene (0.47 g, 0.0019 mol), sodium tert.butoxide (0.44 gm, 0.0039 mol), r-BINAP (0.13 gm, 0.00013 mol), and Pd2(dba)3 (0.11 gm, 0.000013 mol) to give Intermediate 19S (0.35 g). 618.29[M+H] + .

[0270] Intermediate 19U: (S)-tert-butyl 4-(4-cyano-6-(3-hydroxynaphthalen-1-yl)-3-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)piperazine-1-carboxylate: Prepared using the process as described above for intermediate 19K using intermediate 17 (0.6 g, 0.00131 mol), 3 hydroxy-1-bromonaphthalene (0.43 g, 0.0019 mol), sodium tert.butoxide (0.44 g, 0.0039 mol), r-BINAP (0.13 g, 0.00013 mol), and Pd2(dba)3 (0.11 gm, 0.000013 mol) to give intermediate 19U (0.38 g). 599.33[M+H] + .

[0271] Intermediate 19V: (S)-tert-butyl 4-(4-cyano-3-((1-methylpyrrolidin-2-yl)methoxy)-6-(quinazolin-4-yl)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)piperazine-1-carboxylate: Prepared using the process as described above for Intermediate 19K using Intermediate 17 (0.6 g, 0.0013 mol), 4-bromoquinazoline (0.41 g, 0.0019 mol), sodium tert.butoxide (0.44 gm, 0.0039 mol), r-BINAP (0.13 gm, 0.00019 mol), and Pd2(dba)3 (0.11 gm, 0.000013 mol) to give Intermediate 19V as an off-white solid (0.28 gm). 585.33[M+H] + .

[0272] Intermediate 19W: (S)-tert-butyl 4-(4-cyano-3-((1-methylpyrrolidin-2-yl)methoxy)-6-(quinolin-4-yl)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)piperazine-1-carboxylate: Prepared using the process as described above for Intermediate 19K using Intermediate 17 (0.6 g, 0.0013 mol), 4-bromoquinoline (0.4 g, 0.0019 mol), sodium tert.butoxide (0.44 gm, 0.0039 mol), r-BINAP (0.13 gm, 0.00013 mol), and Pd2(dba)3 (0.11 gm, 0.000013 mol) to give Intermediate 19W as an off-white solid (0.39 g). 584.50[M+H] + .

[0273] Intermediate 19X: (S)-tert-butyl 4-(4-cyano-6-(isoquinolin-1-yl)-3-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)piperazine-1-carboxylate: Prepared using the process as described above for Intermediate 19K using Intermediate 17 (0.6 g, 0.0013 mol), 1-bromoisoquinoline (0.4 g, 0.0019 mol), sodium tert.butoxide (0.44 gm, 0.0039 mol), r-BINAP (0.13 gm, 0.00013 mol), and Pd2(dba)3 (0.11 gm, 0.000013 mol) to give Intermediate 19W (0.39 g) as an off-white solid. 584.30[M+H] + .

[0274] Intermediate 19Y: (S)-tert-butyl 4-(4-cyano-3-((1-methylpyrrolidin-2-yl)methoxy)-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)piperazine-1-carboxylate: Prepared using the process as described above for Intermediate 19K using Intermediate 17 (0.6 g, 0.0013 mol), 1-bromonaphthalene (0.4 g, 0.0019 mol), sodium tert.butoxide (0.44 gm, 0.0039 mol), r-BINAP (0.13 gm, 0.00013 mol), and Pd2(dba)3 (0.11 gm, 0.000013 mol) to give Intermediate 19Y (0.41 gm) as an off-white solid. 583.20[M+H] + .

[0275] Intermediate 19Z: tert-butyl 4-(4-cyano-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)-2-(cyanomethyl)piperazine-1-carboxylate: Prepared using the process as described above for intermediate 19K using intermediate 18 (0.6 g, 0.0012 mol), 1-bromonaphthalene (0.37 g, 0.00018 mol), sodium tert.butoxide (0.4 gm, 0.0036 mol), r-BINAP (0.075 g, 0.00012 mmol), and Pd2(dba)3 (0.11 gm, 0.000012 mol) to obtain intermediate 19Z (0.36 gm). 622.35[M+H] + .

[0276] Intermediate 20: tert-Butyl 4-(4-cyano-3-morpholino-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)piperazine-1-carboxylate: Prepared using the process as described above for intermediate 19K using intermediate 11 (0.5 g, 0.001 mol), 1-bromonaphthalene (0.36 g, 0.0017 mol), sodium tert.butoxide (0.39 g, 0.0035 mol), r-BINAP (0.072 g, 0.0001 mol), and Pd2(dba)3 (0.11 gm, 0.00001 mol) to give intermediate 20 (about 0.4 gm). 555.28 [M+H] + .

[0277] Intermediate 20A: tert-butyl 4-(4-cyano-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)piperazine-1-carboxylate: Prepared using the process as described above for intermediate 19K using intermediate 18H (0.5 g, 0.0014 mol), 1-bromonaphthalene (0.45 g, 0.0021 mol), sodium tert.butoxide (0.48 gm, 0.0043 mol), r-BINAP (0.09 g, 0.00014 mol), and Pd2(dba)3 (0.13 gm, 0.000014 mol) to give intermediate 20A (0.38 gm). 470.25 [M+H] + .

[0278] General procedure for deprotection (Method 20) To the desired solution of intermediates 19A-19Z, 20 and 20A (amounts as above) in DCM in a single neck RBF was added trifluoroacetic acid (TFA) in HCl or dioxane over 1-2 hours at 0° C. The reaction was complete by TLC using methanol:DCM (5%) and one drop of ammonia in methanol. The solvent was removed under reduced pressure to give the crude solid of the deprotected compound, which was used in the next step without any purification or characterization. [Table 3] JPEG2024538851000032.jpg195158JPEG2024538851000033.jpg196158JPEG2024538851000034.jpg66158

[0279] Part B - Preparation of compounds Example 1: 1-(4-Acryloylpiperazin-1-yl)-3-(1,1-dioxidothiomorpholino)-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile: In a 100 mL single neck RBF, to the deprotected intermediate from method 20 (0.2 gm, 0.39 mmol) in DCM (5 mL) was added DIEPA (0.21 mL, 1.17 mmol) at 0° C. and stirred for 10 minutes. To the above solution, acryloyl chloride (0.06 mL, 0.79 mmol) in DCM (3 ml) was slowly added at 0° C. The reaction mixture was stirred at 0° C. for 40 minutes. Reaction completion was confirmed by TLC using MeOH:DCM (5%). The reaction mixture was quenched with a saturated solution of NaHCO3 (10 mL), the whole solution was stirred for 10 minutes and then the organic layer was isolated. The aqueous layer was extracted again with DCM (10 mL x 2) and the combined organic layers were washed with brine solution (10 mL), dried over Na2SO4 and concentrated under reduced pressure to give a crude residue which was purified by column chromatography using 2-3% MeOH solution in DCM as the mobile phase. The pure fractions were collected and concentrated to give the desired product (0.065 gm, 29.94%). 1H-NMR (δppm, CDCl3,400MHz): δ7.25(m,5H),6.59(dd,1H),6.34(dd,1H),5.75(dd,1H),4.39(s,2H),3.82(s,3H) .3.74(m,7H),3.24(m,4H),3.08(t,2H),2.54(t,4H),2.35(d,3H),1.25(s,1H),1.19(s,1H).MS(m / z):557.2[M+H] + .HPLC purity: 95.88%.

[0280] Example 2: 1-(4-acryloylpiperazin-1-yl)-6-(8-chloronaphthalen-1-yl)-3-morpholino-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile: Prepared using the process as described above for Example 1 using Intermediate 19A to give 0.06 gm of 1-(4-acryloylpiperazin-1-yl)-6-(8-chloronaphthalen-1-yl)-3-morpholino-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile. 1H-NMR(δppm, CDCl3,400MHz):δ7.36-7.33(m,4H),7.31-7.28(m,1H),6.62-6.55(m,1H),6.3 5-6.31(m,1H),5.76-5.73(m,1H),4.33-4.23(m,2H),3.79-3.77(bs,4H),3.70-3.66(bs,4H) ,3.36(bs,4H),3.12-3.08(m,1H),2.72-2.68(m,1H),2.61-2.59(bs,4H),2.51(bs,3H),2.34 -2.30(m,1H),2.06-2.-01(m,1H),1.83-1.67(m,3H).MS(m / z):543.2[M+H]+.HPLC purity:96.69%.

[0281] Example 3: 1-(4-acryloylpiperazin-1-yl)-3-(2-morpholinoethoxy)-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile: Prepared using the process as described above for Example 1 using Intermediate 19D to give 0.17 gm of 1-(4-acryloylpiperazin-1-yl)-3-(2-morpholinoethoxy)-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile. 1H-NMR(δppm, CDCl3,400MHz):δ7.36-7.33(m,4H),7.31-7.28(m,1H),6.62-6.55(m,1H),6.3 5-6.31(m,1H),5.76-5.73(m,1H),4.33-4.23(m,2H),3.79-3.77(bs,4H),3.70-3.66(bs,4H) ,3.36(bs,4H),3.12-3.08(m,1H),2.72-2.68(m,1H),2.61-2.59(bs,4H),2.51(bs,3H),2.34 -2.30(m,1H),2.06-2.-01(m,1H),1.83-1.67(m,3H).MS(m / z):553.3[M+H]+.HPLC purity:96.11%.

[0282] Example 4: 1-(4-acryloylpiperazin-1-yl)-6-(8-chloronaphthalen-1-yl)-3-(2-morpholinoethoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile: Prepared using the process as described above for Example 1 using intermediate 19E to give 0.1 gm of 1-(4-acryloylpiperazin-1-yl)-6-(8-chloronaphthalen-1-yl)-3-(2-morpholinoethoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile. 1H-NMR(δppm, CDCl3,400MHz):δ7.36-7.33(m,4H),7.31-7.28(m,1H),6.62-6.55(m,1H), 6.35-6.31(m,1H),5.76-5.73(m,1H),4.33-4.23(m,2H),3.79-3.77(bs,4H),3.70-3.66(b s,4H),3.36(bs,4H),3.12-3.08(m,1H),2.72-2.68(m,1H),2.61-2.59(bs,4H),2.51(bs,3 H),2.34-2.30(m,1H),2.06-2.-01(m,1H),1.83-1.67(m,3H).MS(m / z):587.3[M+H]+.HPLC Purity: 96.11%.

[0283] Example 5: 3-(4-acryloylpiperazin-1-yl)-1-(2,6-dimethylmorpholino)-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile: Prepared using the process described above for Example 1 using intermediate 19H to give 0.12 gm of 3-(4-acryloylpiperazin-1-yl)-1-(2,6-dimethylmorpholino)-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile. 1H-NMR(δppm, CDCl3,400MHz):δ7.36-7.33(m,4H),7.31-7.28(m,1H),6.62-6.55(m,1H),6.3 5-6.31(m,1H),5.76-5.73(m,1H),4.33-4.23(m,2H),3.79-3.77(bs,4H),3.70-3.66(bs,4H) ,3.36(bs,4H),3.12-3.08(m,1H),2.72-2.68(m,1H),2.61-2.59(bs,4H),2.51(bs,3H),2.34 -2.30(m,1H),2.06-2.-01(m,1H),1.83-1.67(m,3H).MS(m / z):537.3[M+H]+.HPLC purity:98.23%.

[0284] Example 6: 3-(4-acryloylpiperazin-1-yl)-6-(8-chloronaphthalen-1-yl)-1-(2,6-dimethylmorpholino)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile: Prepared using the process as described above for Example 1 to give 0.1 gm of 3-(4-acryloylpiperazin-1-yl)-6-(8-chloronaphthalen-1-yl)-1-(2,6-dimethylmorpholino)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile. 1H-NMR(δppm, CDCl3,400MHz):δ7.36-7.33(m,4H),7.31-7.28(m,1H),6.62-6.55(m,1H),6.3 5-6.31(m,1H),5.76-5.73(m,1H),4.33-4.23(m,2H),3.79-3.77(bs,4H),3.70-3.66(bs,4H) ,3.36(bs,4H),3.12-3.08(m,1H),2.72-2.68(m,1H),2.61-2.59(bs,4H),2.51(bs,3H),2.34 -2.30(m,1H),2.06-2.-01(m,1H),1.83-1.67(m,3H).MS(m / z):571.3[M+H]+.HPLC purity:98.08%.

[0285] Example 7: 3-(4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-1-(2,6-dimethylmorpholino)-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, prepared using the process as described above for Example 1 using intermediate 19F to give the desired product (0.04 gm, 17.03%). 1H-NMR (δppm, CDCl3,400MHz): δ7.25(m,5H),6.59(dd,1H),6.34(dd,1H),5.75(dd,1H),4.39(s,2H),3.82(s,3H) .3.74(m,7H),3.24(m,4H),3.08(t,2H),2.54(t,4H),2.35(d,3H),1.25(s,1H),1.19(s,1H).MS(m / z):576.2[M+H] + .HPLC purity: 95.4%.

[0286] Example 8: (S)-1-(4-acryloylpiperazin-1-yl)-6-(8-chloronaphthalen-1-yl)-3-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile: Prepared using the process as described above for Example 1 to give (S)-1-(4-acryloylpiperazin-1-yl)-6-(8-chloronaphthalen-1-yl)-3-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile (0.05 gm, 12%) as an off-white solid. 1H-NMR(400MHz)(CDCl3):7.77(d,J=6.8Hz,1H),7.67-7.65(m,1H),7.54-7.52(m,1H),7.36-7.35(m,1H),7.34-7.2 8(m,1H),6.64-6.58(m,1H),6.37-6.32(m,1H),5.85-5.71(m,1H),4.94-4.92(m,1H),4.59-4.51(m,2H),3.94-3.80 (m,2H),3.81-3.65(m,2H),3.64-3.61(m,2H),3.60-3.54(m,2H),3.34-3.28(m,2H),3.16-3.10(m,2H),2.92(s,3H) ,2.62-2.59(m,2H),2.28-2.24(m,2H),2.06-2.01(m,2H),1.41-1.37(m,2H).MS(m / z):571.2(M+1).HPLC purity:94.39%.

[0287] Example 9: (S)-1-(4-acryloylpiperazin-1-yl)-6-(3-hydroxynaphthalen-1-yl)-3-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile: Prepared using the process as described above for Example 1 to give the desired product, (S)-1-(4-acryloylpiperazin-1-yl)-6-(3-hydroxynaphthalen-1-yl)-3-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile (0.035 gm) as a white solid. 1H-NMR(400MHz)(CDCl3):7.98(d,J=6.4Hz,1H),7.65(d,J=6.8Hz,1H),7.42-7.40(m,1H),7.32-7.29(m,1H),6.90(s ,1H),6.74(s,1H),6.59-6.53(m,1H),6.35-6.32(d,J=14Hz,1H),5.75(d,J=8.4Hz,1H),4.48-4.44(m,1H),4.33.4.3 0(m,2H),4.21-4.18(m,1H),3.78-3.61(m,4H),3.36-3.33(m,5H),3.18-3.15(m,1H),2.83-2.79(m,2H),2.62(s,3H) ,2.10-2.06(m,2H),1.82-1.81(m,1H),1.78-1.74(m,2H),1.44-1.41(m,2H).MS(m / z):553.5(M+1).HPLC purity:94.12%.

[0288] Example 10: (S)-1-(4-(2-fluoroacryloyl)piperazin-1-yl)-3-((1-methylpyrrolidin-2-yl)methoxy)-6-(quinazolin-4-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile: A 100 mL two-necked RBF was charged with (S)-3-((1-methylpyrrolidin-2-yl)methoxy)-1-(piperazine) in ethyl acetate (1.8 mL) at 0° C. To a suspension of (quinazolin-1-yl)-6-(quinazolin-4-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride (0.3 gm, 0.00062 mol) was added triethylamine (0.7 mL, 0.00496 mol), 2-fluoroprop-2-enoic acid (0.11 gm, 0.00124 mol) and T3P (1.2 mL, 0.00186 mol, 50 wt % in ethyl acetate). The mixture was allowed to warm to 15° C. over 30 minutes and the reaction mixture was diluted with saturated aqueous sodium carbonate (10 mL). The aqueous phase was extracted with ethyl acetate (15 mL×2) and the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give a crude residue. The residue was purified by preparative HPLC using a Waters Xbridge C18 150×50 mm×10 μm column and mobile phase A [water (10 mM NH4HCO3)], B (ACN), % of B: 42%-72%, 11.5 min) to give (S)-1-(4-(2-fluoroacryloyl)piperazin-1-yl)-3-((1-methylpyrrolidin-2-yl)methoxy)-6-(quinazolin-4-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile (0.065 gm, 18.83%). MS (m / z): 557.2 (M+1).

[0289] Example 11: (S)-6-(8-chloronaphthalen-1-yl)-3-((1-methylpyrrolidin-2-yl)methoxy)-1-(4-(vinylsulfonyl)piperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile: In a 100 mL two-necked RBF, to a suspension of (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 (0.32 gm, 0.00062 mol) in DCM (4 mL) was added TEA (0.26 mL, 0.00186 mol) at 0° C. After 5 minutes, a solution of 2-chloroethanesulfonyl chloride (0.1 mL, 0.00124 mol) in DCM (8.8 mL) was added dropwise and stirred at room temperature for 12 hours. Reaction completion was confirmed by TLC using methanol:DCM (5%) and one drop of ammonia in methanol as mobile phase. The reaction mixture was concentrated under reduced pressure to give the crude material, which was purified by column chromatography (100-200 mesh silica gel) using 5-8% MeOH in DCM as mobile phase to give (S)-6-(8-chloronaphthalen-1-yl)-3-((1-methylpyrrolidin-2-yl)methoxy)-1-(4-(vinylsulfonyl)piperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile (0.04 gm, 10.6%) as a white solid.1H-NMR (400 MHz) (CDCl3): 7.79 - 7.76 (m, 1H), 7.67 - 7.64 (m, 1H), 7.57 - 7.44 (m, 2H), 7.38 - 7.33 (m, 1H), 7.28 - 7.26 (m, 1H), 6.49 - 6.47 (m, 1H), 6.33 - 6.29 (m, 1H), 6.15 - 6.11 (m, 1H), 5.21 (bs, 1H), 4.58 - 4.54 (m, 2H), 3.96 - 3.90 (m, 2H), 3.67 - 3.55 (m, 4H), 3.47 - 3.42 (m, 2H), 3.39 - 3.34 (m, 2H), 3.30 - 3.26 (m, 2H), 3.16 - 2.86 (m, 6H), 2.59 - 2.50 (m, 1H), 2.36 - 2.32 (m, 2H), 2.13 - 2.07 (m, 2H). MS (m / z): 607.4 (M+1). HPLC purity: 92.22%.

[0290] Example 12: 6-(8-chloronaphthalen-1-yl)-1-(4-(2-fluoroacryloyl)-3-methylpiperazin-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile: Prepared using the process as described above for Example 10 to obtain the crude product, which was purified by preparative HPLC using a Sunfire C18 150×50 mm×10 μm column and a mobile phase of Further purification as A [Water (10 mM NH4HCO3)], B (ACN), % of B: 42%-72% to give 6-(8-chloronaphthalen-1-yl)-1-((R)-4-(2-fluoroacryloyl)-3-methylpiperazin-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile (0.16 gm, 22.4%). 1H-NMR(400MHz)(CDCl3):7.79-7.76(m,1H),7.67-7.64(m,1H),7.55-7.52(m,1H),7 .50-7.42(m,1H),7.37-7.33(m,1H),7.28-7.21(m,1H),5.35-5.14(m,2H),4.80-4.6 9(m, 2H), 4.62-4.51(m, 3H), 3.99-3.89(m, 2H), 3.75-3.55(m, 4H), 3.51-3.40(m, 2H), 3.34-2.53(m, 8H), 2.29-1.99(m, 4H), 1.50-1.19(m, 3H). MS(m / z): 603.2(M+1). HPLC purity: 96.3% (believed to include diastereomeric fractions).

[0291] Example 13: 1-(4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-3-(2,6-dimethylmorpholino)-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile: Prepared using the process as described above for Example 1 using Intermediate 19C to give 0.85 gm of 1-(4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-3-(2,6-dimethylmorpholino)-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile. The racemic mixture (0.8 gm) was isolated by chiral separation using CHIRALCEL-ODH (4.6×250 mm) 5 μm and acetonitrile (100%) as mobile phase to give 0.33 gm and 0.36 gm of Isomer 1 and Isomer 2 as Example 14 and Example 15, respectively. 1H-NMR (δ ppm, CDCl3, 400 MHz): δ 7.36-7.33 (m, 4H), 7.31-7.28 (m, 1H), 6.62-6.55 (m, 1H), 6.35-6.31 (m, 1H), 5.76-5.73 (m, 1H), 4.33-4.23 (m, 2H), 3.79-3.77 (bs, 4H), 3.70-3.66 (bs, 4H), 3.80-3.85 (bs, 5 ... s,4H),3.36(bs,4H),3.12-3.08(m,1H),2.72-2.68(m,1H),2.61-2.59(bs,4H),2.51(bs,3 H),2.34-2.30(m,1H),2.06-2.-01(m,1H),1.83-1.67(m,3H).MS(m / z):576.2[M+H]+.HPLC Purity: 96.72%.

[0292] Example 14: 1-((S)-4-Acryloyl-3-(cyanomethyl)piperazin-1-yl)-3-(2,6-dimethylmorpholino)-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile: 1H-NMR (δ ppm, CDCl3, 400 MHz): δ 7.36-7.33 (m, 4H), 7.31-7.28 (m, 1H), 6.62-6.55 (m, 1H), 6.35-6.31 (m, 1H), 5.76 -5.73(m,1H),4.33-4.23(m,2H),3.79-3.77(bs,4H),3.70-3.66(bs,4H),3.36(bs,4H),3.12-3.08(m,1H),2.72-2.68(m,1H) ),2.61-2.59(bs,4H),2.51(bs,3H),2.34-2.30(m,1H),2.06-2.-01(m,1H),1.83-1.67(m,3H).MS(m / z):576.2[M+H]+.HPLC Purity: 97.62%.

[0293] Example 15: 1-((R)-4-Acryloyl-3-(cyanomethyl)piperazin-1-yl)-3-(2,6-dimethylmorpholino)-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile: 1H-NMR (δ ppm, CDCl3, 400 MHz): δ 7.36-7.33 (m, 4H), 7.31-7.28 (m, 1H), 6.62-6.55 (m, 1H), 6.35-6.31 (m, 1H), 5.76 -5.73(m,1H),4.33-4.23(m,2H),3.79-3.77(bs,4H),3.70-3.66(bs,4H),3.36(bs,4H),3.12-3.08(m,1H),2.72-2.68(m,1H) ),2.61-2.59(bs,4H),2.51(bs,3H),2.34-2.30(m,1H),2.06-2.-01(m,1H),1.83-1.67(m,3H).MS(m / z):576.2[M+H]+.HPLC Purity: 97.31%.

[0294] Example 16: 1-(4-Acryloyl-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: Prepared using the process as described above for example 1. Pure fractions were collected and concentrated to give the desired product (0.61 gm, 34.51%). 1H-NMR(400MHz)(CDCl3):8.20-8.17(m,1H),7.88-7.86(m,1H),7.64(d,J=8.4Hz,1H),7.53-7.51(m, 2H),7.50-7.44(m,1H),7.18(d,J=7.2Hz,1H),6.64-6.59(m,1H),6.42-6.35(m,1H),5.84-5.77(m,1H) ),4.94-4.91(m,2H),4.49-4.41(m,4H),4.03-3.95(m,2H),3.86-3.83(m,1H),3.58-3.31(m,7H),3.0 2-2.98(m,5H),2.25-2.23(m,2H),2.03-1.98(m,3H),1.41-1.29(m,1H).MS(m / z):576.25(M+1).HPLC Purity: 95.04%.

[0295] Example 17: 1-((S)-4-acryloyl-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: 1-((S)-4-acryloyl-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 (0.13 gm) was purified by chiral separation using a CHIRALCEL-ODH (4.6×250 mm) 5 μm and acetonitrile (100%) as the mobile phase to prepare the racemic mixture 1-(4-acryloyl-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. Isolated from 8-tetrahydro-2,6-naphthyridine-4-carbonitrile (0.57 gm).1H-NMR (δ ppm, CDCl3, 400 MHz): δ 8.19-8.17 (m, 1H), 7.88-7.86 (m, 1H), 7.64 (d, J = 6 Hz, 1H), 7.52-7.51 (m, 2H), 7.46-7.43 (m, 1H), 7.18 (d, J = 6 Hz, 1H), 6.61 (bs, 1H), 6.40 (d, J = 12.4 Hz, 1H), 5.83 (d, J=8.4Hz,1H),5.09(bs,1H),4.86(bs,2H),4.51-4.43(m,4H),4.01-3.84(m,4H),3.59-3.35(m,4H),3.23-3.11(m,2H),3.01 -2.96(m,2H),2.84(s,3H),2.27-2.16(m,2H),2.03-1.99(m,2H),1.41-1.36(m,1H).MS(m / z):576.5[M+H]+.HPLC purity:96.8%.

[0296] Example 18: 1-((R)-4-acryloyl-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: 1-((R)-4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro 1-(4-acryloyl-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 (0.125 gm) was separated into 1-(4-acryloyl-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 by chiral separation using CHIRALCEL-ODH (4.6 x 250 mm), 5 μm, and acetonitrile (100%) as the mobile phase. Isolated from tolyl (0.57 gm). 1H-NMR (δ ppm, CDCl3, 400 MHz): δ 8.19-8.17 (m, 1H), 7.88-7.86 (m, 1H), 7.64 (d, J = 6 Hz, 1H), 7.52-7.50 (m, 2H), 7.44-7.43 (m, 1H), 7.18 (d, J = 6 Hz, 1H), 6.60 (bs, 1H), 6.40 (d, J = 13.2 Hz, 1H), 5.83 (d, J = 8.4 Hz, 1H), 5.11-5.05 (m, 1H), 4.84-4.80 (m ,1H),4.53-4.39(m,4H),3.98-3.95(m,1H),3.84-3.82(m,1H),3.63(bs,2H),3.36-3.33(m,4H),3.11-3.10(m,2H),3.02-2.95(m,2H) ),2.86(s,3H),2.78-2.75(m,1H),2.26-2.14(m,2H),2.02-1.98(m,2H),1.37-1.32(m,1H).MS(m / z):576.5[M+H]+.HPLC purity: 93.99%.

[0297] Example 19: 1-(4-acryloyl-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: Prepared using intermediate 19J using the process as described above for example 1 to give 1-(4-acryloyl-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, which was purified by preparative HPLC using a Sunfire C18 150×50 mm×10 μm column and a mobile phase of Further purification as A [water (10 mM NH4HCO3)], B (ACN), % of B: 42%-72% gave 1-(4-acryloyl-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 (0.05 gm) as a white solid. 1H-NMR(400MHz)(CDCl3):8.00-7.96(m,1H),7.64(m,J=6Hz,1H),7.42-7.39(m,1H),7.32-7.29(m,1H),6.90 (s,1H),6.70(s,1H),6.55(bs,1H),6.37(d,J=13.2Hz,1H),5.81(d,J=8.4Hz,1H),5.01-4.92(m,1H),4.59-4. 58(m,1H),4.34-4.26(m,3H),3.85-3.82(m,1H),3.76-3.64(m,2H),3.44-3.24(m,4H),2.95-2.79(m,5H),2. 71(s,3H),2.49(bs,2H),2.10-1.99(m,3H),1.88-1.82(m,2H),1.62-1.60(m,1H).MS(m / z):592.5(M+1).HPLC Purity: 98.62%.

[0298] Example 20: 1-(3-(cyanomethyl)-4-(2-fluoroacryloyl)piperazin-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile. Prepared using the process as described above for Example 1 to give a crude residue. The residue was purified by preparative HPLC using a Sunfire C18 150×50 mm×10 μm column and mobile phases A [water (10 mM NH4HCO3)], B (ACN), % of B: 42%-72% to give 1-(3-(cyanomethyl)-4-(2-fluoroacryloyl)piperazin-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile (0.09%). gm,26.6%).1H-NMR(400MHz)(CDCl3):8.19-8.17(m,1H),7.88-7.85(m,1H),7.64(d,J=8.0Hz,1H) ,7.54-7.49(m,2H),7.46-7.42(m,1H),7.18(d,J=7.6Hz,1H),5.48-5.36(m,1H),5.28-5.23(m,1H ),4.92(bs,2H),4.50-4.43(m,3H),4.09-3.95(m,2H),3.84-3.81(m,1H),3.56-3.31(m,6H),3.09 -2.71(m,8H),2.31-2.15(m,2H),2.06-1.97(m,2H),1.43-1.41(m,1H).MS(m / z):594.4(M+1).HPLC Purity: 95.35%.

[0299] Example 21: (S)-1-(4-acryloylpiperazin-1-yl)-6-(isoquinolin-4-yl)-3-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile. Prepared using the process as described above for Example 1 to give a crude residue. The residue was purified by preparative HPLC using a Sunfire C18 150×50 mm×10 μm column and mobile phases A [water (10 mM NH4HCO3)], B (ACN), % of B: 42%-72% to give (S)-1-(4-acryloylpiperazin-1-yl)-6-(isoquinolin-4-yl)-3-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile (0.04 gm,12%).1H-NMR(400MHz)(CDCl3):9.05(s,1H),8.28(m,1H),8.13(d,J=6.4Hz,1H),8.01(d,J=6.4 Hz,1H),7.76-7.73(m,1H),7.66-7.63(m,1H),6.64-6.58(m,1H),6.35(d,J=14.0Hz,1H),5.77(d,J= 8.8Hz,1H),4.47-4.33(m,4H),3.84-3.73(m,4H),3.49-3.44(m,6H),3.19(bs,1H),2.87-2.80(m,3H) ),2.58(s,3H),2.39-2.31(m,1H),2.09-2.04(m,2H),2.03-1.92(m,2H).MS(m / z):538.5(M+1).HPLC Purity: 97.64%.

[0300] Example 22: (S)-1-(4-acryloylpiperazin-1-yl)-3-((1-methylpyrrolidin-2-yl)methoxy)-6-(quinolin-8-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile: Prepared using the process as described above for Example 1 to give a crude residue. The residue was purified by preparative HPLC using a Sunfire C18 150×50 mm×10 μm column and mobile phases A [water (10 mM NH4HCO3)], B (ACN), % of B: 42%-72% to give (S)-1-(4-acryloylpiperazin-1-yl)-6-(isoquinolin-4-yl)-3-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile (0.04 gm,12%).1H-NMR(400MHz)(CDCl3):9.05(s,1H),8.28(m,1H),8.13(d,J=6.4Hz,1H),8.01(d,J=6.4Hz, 1H),7.76-7.73(m,1H),7.66-7.63(m,1H),6.64-6.58(m,1H),6.35(d,J=14.0Hz,1H),5.77(d,J=8.8Hz ,1H),4.47-4.33(m,4H),3.84-3.73(m,4H),3.49-3.44(m,6H),3.19(bs,1H),2.87-2.80(m,3H),2.58( s,3H),2.39-2.31(m,1H),2.09-2.04(m,2H),2.03-1.92(m,2H).MS(m / z):538.5(M+1).HPLC purity:97.64%.

[0301] Example 23: 1-(4-Acryloyl-3-(cyanomethyl)piperazin-1-yl)-6-(8-chloronaphthalen-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile: To intermediate 9 (8 gm, 0.014 mol) in DCM (80 ml) was added DIPEA (5.1 ml, 0.028 mol) at 0° C. After 5 minutes, a solution of acryloyl chloride (1.7 mL, 0.021 mol) in DCM (15 mL) was added dropwise and stirred at 0° C. for 30 minutes. Reaction completion was confirmed by TLC using methanol:DCM (5%) as mobile phase. The reaction mixture was added with a saturated solution of NaHCO3 (20 mL), stirred for another 15 min, and then extracted with DCM (20 ml x 3). The organic layer was washed with NaHCO3 (10 mL), dried over Na2SO4, and evaporated under reduced pressure to give the desired product, which was analyzed by preparative HPLC using a TriArt column. Purification was performed with C18*250*20*mm*5um and mobile phase 0.1% NH3 in H2O, B:ACN (25:75) to obtain 1-(4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-6-(8-chloronaphthalen-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile (1.2g).1H-NMR(400MHz)(CDCl3):7.77-7.75(m,1H),7.66-7.62(m,1H),7.53-7.51(m,1H),7.46-7.41(m ,1H),7.36-7.32(m,1H),7.28-7.19(m,1H),6.59(bs,1H),6.37(m,1H),5.82(m ,1H),4.65-4.54(m,1H),4.32-4.12(m,2H),3.90-3.82(m,4H),3.62-3.52(m,2 H),3.45-3.47(m,1H),2.70-2.62(m,4H),2.52-2.42(m,5H),2.34(s,3H),1.87 -1.85(m,1H),1.82-1.78(m,1H),1.76-1.72(m,6H).MS(m / z):610.4(M+1).HPLC Purity: 97.16%.

[0302] The racemic mixture 1-(4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-6-(8-chloronaphthalen-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile (1.2 gm) was subjected to chiral separation using CHIRALCEL-ODH (4.6×250 mm) 5 μm with acetonitrile (100%):0.1% DEA as the mobile phase to obtain 1-((R)-4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-6-(8-chloronaphthalen-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile (1.2 gm). 1-((S)-4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-6-(8-chloronaphthalen-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile (isomer 1) (0.51 gm) and 1-((S)-4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-6-(8-chloronaphthalen-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile (isomer 2) (0.49 gm).

[0303] Example 24: 1-((R)-4-Acryloyl-3-(cyanomethyl)piperazin-1-yl)-6-(8-chloronaphthalen-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile (isomer 1): 1H-NMR (δ ppm, CDCl3, 400 MHz): δ 7.78-7.75 (m, 1H), 7.67-7.63 (m, 1H), 7.53 (d, J=7.6 Hz, 1H), 7.52-7.51 (m, 2H), 7.49-7.41 (m, 1H), 7.37-7.33 (m, 1H), 7.29-7.26 (m, 1H), 6.63-6. 56(m,1H),6.39(d,J=16.8Hz,1H),5.83(d,J=11.2Hz,1H),5.12-5.10(m,1H),4.64-4 .56(m,1H),4.38-4.29(m,2H),4.01-3.83(m,3H),3.68-3.59(m,2H),3.41-3.38(m,1 H),3.22-3.05(m,4H),2.94-2.84(m,1H),2.75-2.62(m,3H),2.54(s,3H),2.35-2.33 (m,1H),2.09-2.02(m,1H),1.88-1.73(m,1H).MS(m / z):610.4[M+H]+.HPLC purity:97.6%. Chiral purity: 99.01%.

[0304] Example 25: 1-((S)-4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-6-(8-chloronaphthalen-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile (isomer 2) (Cpd A):1H-NMR(δppm,CDCl3,400MHz):δ7.78-7.76(m,1H),7.67-7.63(m,1H),7.53(d,J=7.6Hz,1H),7.49-7.42(m,1H),7.37- 7.33(m,1H),7.29-7.26(m,1H),6.59-6.56(m,1H),6.39(d,J=16.8Hz,1H),5.83(d,J=10.4Hz,1H),5.12(bs,1H),4.64-4. 56(m,1H),4.42-4.29(m,2H),4.01-3.83(m,3H),3.69-3.59(m,1H),3.42-3.38(m,1H),3.23-3.04(m,4H),2.91-2.77(m,2 H),2.71-2.67(m,1H),2.55(s,3H),2.40-2.33(m,1H),2.10-2.03(m,2H),2.01-1.73(m,5H).MS(m / z):610.4[M+H]+.HPLC Purity: 98.9%. Chiral purity: 99.6%

[0305] Example 26: 6-(8-chloronaphthalen-1-yl)-1-(3-(cyanomethyl)-4-(2-fluoroacryloyl)piperazin-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile: 6-(8-chloronaphthalen-1-yl)-1-(3-(cyanomethyl)piperazin-1-yl) in ethyl acetate (10.8 mL) at 0° C. To a suspension of )-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride (1.8 gm, 0.00324 mol) was added triethylamine (3.6 mL, 0.02592 mol), 2-fluoroprop-2-enoic acid (0.58 gm, 0.00647 mol) and T3P (6.2 mL, 0.00972 mol, 50 wt % in ethyl acetate). The mixture was allowed to warm to 15° C. over 30 minutes and the reaction mixture was diluted with saturated aqueous sodium carbonate (40 mL). The aqueous phase was extracted with ethyl acetate (100 mL×2) and the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give a crude residue. The residue was purified by preparative HPLC using column Sunfire C18 150×50 mm×10 μm and mobile phase A: water (10 mM NH4HCO3), B: ACN, % of B: 25%-55% to give 6-(8-chloronaphthalen-1-yl)-1-(3-(cyanomethyl)-4-(2-fluoroacryloyl)piperazin-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile (0.42 gm, 20.64%).

[0306] Example 27: 6-(8-chloronaphthalen-1-yl)-1-((S)-3-(cyanomethyl)-4-(2-fluoroacryloyl)piperazin-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile: 6-(8-chloronaphthalen-1-yl)-1-((S)-3-(cyanomethyl)-4-(2-fluoroacryloyl)piperazin-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy) The racemic mixture 6-(8-chloronaphthalen-1-yl)-1-(3-(cyanomethyl)-4-(2-fluoroacryloyl)piperazin-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile (0.075 gm, chiral purity: 99%) was separated by chiral separation using CHIRALCEL-ODH (4.6 × 250 mm) 5 μm and mobile phase acetonitrile (100%). ,6,7,8-Tetrahydro-2,6-naphthyridine-4-carbonitrile (0.42 gm).1H-NMR (δppm, CDCl3, 400MHz): δ 7.79-7.76 (m, 1H), 7.67-7.63 (m, 1H), 7.53 (d, J=7.2Hz, 1H), 7.49-7.42 (m, 1H), 7.37-7.33 (m, 1H), 7.29-7.26 (m, 1H), 5.48-5.36 (m, 1H), 5.28-5.23 (m, 1H), 4.64-4.56 (m, 1H), 4.38-4.4 .27(m,2H),4.09-3.81(m,3H),3.67-3.59(m,2H),3.51-3.45(m,1H),3.41-3.36(m,1H),3.29-3.10(m,4H),2.99-2.89(m,2H),2.74-2.70 (m,2H),2.53(s,3H),2.36-2.29(m,1H),2.10-1.98(m,1H),1.89-1.61(m,3H),1.29-1.23(m,1H).MS(m / z):628.3[M+H]+.HPLC purity: 97.6%.

[0307] Example 28: 6-(8-chloronaphthalen-1-yl)-1-((R)-3-(cyanomethyl)-4-(2-fluoroacryloyl)piperazin-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile: 6-(8-chloronaphthalen-1-yl)-1-((R)-3-(cyanomethyl)-4-(2-fluoroacryloyl)piperazin-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy) The racemic mixture 6-(8-chloronaphthalen-1-yl)-1-(3-(cyanomethyl)-4-(2-fluoroacryloyl)piperazin-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile (0.095 gm, chiral purity: 99%) was separated by chiral separation using CHIRALCEL-ODH (4.6 x 250 mm) 5 μm and mobile phase acetonitrile (100%). ,6,7,8-Tetrahydro-2,6-naphthyridine-4-carbonitrile (0.42 gm).1H-NMR (δppm, CDCl3, 400MHz): δ 7.79-7.76 (m, 1H), 7.67-7.63 (m, 1H), 7.53 (d, J=7.2Hz, 1H), 7.49-7.42 (m, 1H), 7.37-7.33 (m, 1H), 7.29-7.26 (m, 1H), 5.48-5.36 (m, 1H), 5.28-5.23 (m, 1H), 4.64-4.56 (m, 1H), 4.38-4.4 .27(m,2H),4.09-3.81(m,3H),3.67-3.59(m,2H),3.51-3.45(m,1H),3.41-3.36(m,1H),3.29-3.10(m,4H),2.99-2.89(m,2H),2.74-2.70 (m,2H),2.53(s,3H),2.36-2.29(m,1H),2.10-1.98(m,1H),1.89-1.61(m,3H),1.29-1.23(m,1H).MS(m / z):628.3[M+H]+.HPLC purity: 97.6%.

[0308] Example 29: 1-(4-Acryloylpiperazin-1-yl)-6-benzyl-3-chloro-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile: To a solution of intermediate 4 (0.2 g, 0.5 mmol) dissolved in dry DCM (10 ml), DIPEA (0.3 g, 1.5 mmol) was added and the reaction mixture was stirred at 0° C. for 20 minutes. Acryloyl chloride (0.053 g, 0.6 mmol) was added dropwise into the reaction mixture and stirred at the same temperature for 30 minutes. The reaction mixture was diluted with DCM and washed with water. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give the title solid compound. Yield (20 mg).1H-NMR(δppm,CDCl3,400MHz):7.36-7.29(m,5H),6.60-6.54(m,1H),6.34-6.30(m,1H,),5.75-5.73(m ,1H),3.80(s,4H),3.68-3.65(m,4H),3.43-3.41(m,4H),2.67-2.59(m,4H).,MS(m / z):422.19[M+H]+.HPLC Purity: 97.38%.

[0309] Example 30: N-(1-(6-benzyl-3-chloro-4-cyano-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)piperidin-4-yl)acrylamide: To a solution of intermediate 7 (0.2 g, 52 mmol) dissolved in dry DCM (10 ml), DIPEA (0.23 g, 157 mmol) was added and the reaction mixture was stirred at 0° C. for 20 minutes. Acryloyl chloride (0.2 g, 62 mmol) was added dropwise into the reaction mixture and stirred at the same temperature for 30 minutes. The reaction mixture was diluted with DCM and washed with water. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain the title solid compound. Yield (25mg).1H-NMR (δppm, CDCl3,400MHz):8.32(s,1H),7.36-7.34(m,5H),6 .31-6.27(m,1H),6.09-6.03(m,1H,),5.67-5.65(m,1H),5.43-5.41(d,1H) ,4.41-4.08(m,1H),3.80(s,2H),3.75-3.71(m,4H),3.06-3.01(m,2H),2.7 0-2.62(m,4H),2.08-2.03(m,2H),MS(m / z):402.21[M+H]+.HPLC purity:97.00%.

[0310] Example 31: N-(1-(6-benzyl-4-cyano-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)piperidin-4-yl)acrylamide: To a solution of intermediate 6 (0.12 g, 31 mmol) dissolved in dry DCM (10 ml), DIPEA (0.17 g, 91 mmol) was then added and the reaction mixture was stirred at 0° C. for 20 minutes. Acryloyl chloride (0.033 g, 35 mmol) was added dropwise into the reaction mixture and stirred at the same temperature for 30 minutes. The reaction mixture was diluted with DCM and washed with water. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give the title solid compound. Yield (25mg).1H-NMR (δppm, CDCl3,400MHz):7.36-7.27(m,5H),6.30-6.27(m,1H),6.08-6.03(m,1H,),5.67-5.65(m,1H),5.43-5.41(d,1H),4.14- 4.10(m,1H),3.80(s,4H),3.78-3.68(m,2H),3.09-3.04(m,2H),2.64-2 .61(m,5H),2.21-2.02(m,3H),MS(m / z):436.12[M+H]+.HPLC purity:96.25%.

[0311] Example 32: 1,3-bis(4-acryloylpiperazin-1-yl)-6-benzyl-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile: Prepared using the process as described above for Example 1 using Intermediate 7D to yield 20 mg of 1,3-bis(4-acryloylpiperazin-1-yl)-6-benzyl-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile. 1H-NMR (δppm, CDCl3,400MHz):7.38-7.26(m,5H),6.57-6.53(m,2H),6.34-6.31(m,2H),5.75-5.73(m,2H),3.8 1-3.61(m,9H),3.33(s,4H),2.63(s,4H),1.53-1.50(m,2H),1.42-1.41(m,2H),1.29-1.23(m,4H)526.27[M+H] + .HPLC purity:97.67%

[0312] Example 33 1-(4-acryloylpiperazin-1-yl)-6-benzyl-4-cyano-5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl acrylate: Prepared using the process as described above for Example 1 using Intermediate 6A1 to yield 50 mg of 1-(4-acryloylpiperazin-1-yl)-6-benzyl-4-cyano-5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl acrylate. 1H-NMR(δppm, CDCl3,500MHz):δ7.37-7.33(m,4H),7.32-7.29(m,1H),6.7 0-6.66(m,1H),6.60-6.53(m,1H),6.37-6.29(m,2H),6.12-6.10(m,1H),5 .75-5.72(m,1H),3.83(s,2H),3.77(bs,2H),3.73(s,2H),3.66(bs,2H),3 .40(bs,4H),2.70-2.66(m,4H).MS(m / z):458.25[M+H]+.HPLC purity:96.00%.

[0313] Example 34: 1-(4-acryloylpiperazin-1-yl)-6-benzyl-3-morpholino-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile: Prepared using the process as described above for Example 1 using Intermediate 6B to yield 70 mg of 1-(4-acryloylpiperazin-1-yl)-6-benzyl-3-morpholino-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile. 1H-NMR (δppm, CDCl3,400MHz): δ7.36(m,4H),7.30(m,1H),6.58(m,1H),6.33(m,1H),5.74(m,1H),3.81(m,4H),3. 77(s,4H),3.71(m,2H),3.66(s,2H),3.60(m,4H),3.34(s,4H),2.60(s,4H).MS(m / z):473[M+H]+.HPLC purity:99.75%.

[0314] Example 35: 1-(4-acryloylpiperazin-1-yl)-6-benzyl-3-(4-methylpiperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile: Prepared using the process as described above for Example 1 using Intermediate 6D to give 30 mg of 1-(4-acryloylpiperazin-1-yl)-6-benzyl-3-(4-methylpiperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile. 1H-NMR (δppm, CDCl3,400MHz):7.39-7.33(m,4H),7.30-7.27(m,1H),6.61-6.55(m,1H),6.34-6.30(m,1H),5.74-5.71 (m,1H),3.76(s,4H),3.70(s,2H),3.66-3.64(m,6H),3.33(bs,4H),2.59(bs,4H),2.55-2.53(m,4H),2.34(s,3H).HPLC Purity: 99.06%

[0315] Example 36: 1-(4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-6-benzyl-3-(4-methylpiperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile: Prepared using the process as described above for Example 1 to yield 70 mg of 1-(4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-6-benzyl-3-(4-methylpiperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile. 1H-NMR (δppm, CDCl3,400MHz): δ7.33(m,5H),6.57(m,1H),6.35(m,1H),5.79(m,1H),3.86(m,1H),3.77(m,2H),3.66(m,7H),3.53(s,1 H),3.22(s,1H),2.91(q,2H),2.73(m,2H),2.67(m,2H),2.60(m,4H),2.52(s,2H),2.37(s,3H).MS(m / z):525[M+H]+.HPLC purity: 97.00%.

[0316] Example 37: 6-(1-naphthoyl)-1-(4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-3-(4-methylpiperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile: Prepared using the process as described above for Example 1 to yield 40 mg of 6-(1-naphthoyl)-1-(4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-3-(4-methylpiperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile. 1H-NMR (δppm, CDCl3,400MHz):7.93-7.80(m,3H),7.54-7.32(m,4H),6.59-6.51(m,1H),6.42-6.34(m,1H),5.84-5.78(m,1H),4.44-4.42(m,2) H),3.85-3.83(m,1H),3.77-3.67(m,4H),3.64-3.61(m,4H),3.29-3.21(m,2H),2.95-2 .77(m,4H),2.61-2.57(m,1H),2.54-2.49(s,4H),2.47-2.46(m,1H),2.30(s,3H).HPLC Purity: 88.73%

[0317] Example 38: (S)-1-(4-acryloyl-2-methylpiperazin-1-yl)-6-benzyl-3-(4-methylpiperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile: Prepared using the process as described above for Example 1 using Intermediate 7F to give 95 mg of (S)-1-(4-acryloyl-2-methylpiperazin-1-yl)-6-benzyl-3-(4-methylpiperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile. 1H-NMR (δppm, CDCl3, 400MHz): δ7.39-7.27(m,5H),6.65-6.51(m,1H),6.36-6. 30(m,1H),5.76-5.71(m,1H),4.00-4.04(m,1H),3.86-3.80(m,1H),3.77-3.74( m,3H),3.66-3.61(m,4H),3.53-3.43(m,2H),3.37-3.25(m,1H),2.64-2.55(m, 8H),2.35(s,3H),2.12-1.88(m,3H),1.24(s,3H).MS(m / z):500.02[M+H]+.HPLC Purity: 95%.

[0318] Example 39: (R)-1-(4-acryloyl-2-methylpiperazin-1-yl)-6-benzyl-3-(4-methylpiperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile: Prepared using the process as described above for Example 1 using intermediate 7E to give 114 mg of (R)-1-(4-acryloyl-2-methylpiperazin-1-yl)-6-benzyl-3-(4-methylpiperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile. 1H-NMR(δppm, CDCl3,500MHz):δ7.39-7.35(m,4H),7.33-7.28(m,1H),6.64-6.50(m,1H) ),6.35-6.30(m,1H),5.77-5.71(m,1H),4.39-4.36(m,1H),4.16-4.13(m,1H),3.99-3.9 7(m,2H),3.83-3.64(m,4H),3.62-3.35(m,4H),3.31-3.17(m,3H),2.67-2.65(m,4H),2 .62-2.53(m,4H),2.40(s,3H),1.15-1.14(m,3H).MS(m / z):500[M+H]+.HPLC purity:96.42%.

[0319] Example 40: 1-(4-acryloylpiperazin-1-yl)-6-benzyl-3-hydroxy-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile: Prepared using the process as described above for Example 1 using Intermediate 6A1 to yield 30 mg of 1-(4-acryloylpiperazin-1-yl)-6-benzyl-3-hydroxy-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile. 1H-NMR (δppm, CDCl3,500MHz): δ12.13(bs,1H),7.38-7.34(m,4H),7.32-7.27(m,1H),6.64-6.58(m,1H),6.34-6.31(m,1H),5.77 -5.74(m,1H),3.78(bs,4H),3.75(s,2H),3.65(s,2H),3.53(bs,2H),3.42(bs,2H),2.59-2.54(m,4H).MS(m / z):404[M+H]+.HPLC Purity: 99.79%.

[0320] Example 41: 1-(4-acryloylpiperazin-1-yl)-3-(4-methylpiperazin-1-yl)-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile: Prepared using the process as described above for Example 1 using Intermediate 19M to give 113 mg of 1-(4-acryloylpiperazin-1-yl)-3-(4-methylpiperazin-1-yl)-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile. 1H-NMR(δppm, CDCl3,500MHz):δ8.21-8.19(m,1H),7.88-7.86(m,1H),7.62(d,J=8.0Hz,1H) ,7.52-7.49(m,2H),7.45-7.42(m,1H),7.19-7.18(d,J=7.0Hz,1H),6.64-6.58(m,1H),6.42- 6.33(m,2H),6.17-6.12(m,1H),5.86-5.74(m,2H),4.39(bs,2H),3.84(bs,2H),3.75-3.71(m ,6H),3.42(bs,6H),2.87(bs,2H),2.65-2.63(m,4H),2.39(s,3H).MS(m / z):523[M+H]+.HPLC Purity: 95.75%.

[0321] Example 42: 1-(4-acryloylpiperazin-1-yl)-6-benzyl-3-(piperidin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile: Prepared using the process as described above for Example 1 using Intermediate 6F to give 65 mg, 0.065 gm of 1-(4-acryloylpiperazin-1-yl)-6-benzyl-3-(piperidin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile. 1H-NMR (δppm, CDCl3,500MHz): δ7.39-7.33(m,4H),7.30-7.28(m,1H),6.61-6.55(m,1H),6.34-6.29(m,1H),5.73-5.71(m,1H) ,3.76(bs,4H),3.70(s,2H),3.65(bs,2H),3.58(bs,4H),3.32(bs,4H),2.59(bs,4H),1.65(bs,6H).MS(m / z):471[M+H]+.HPLC Purity: 99.53%.

[0322] Example 43: 1-(4-acryloylpiperazin-1-yl)-6-benzyl-3-(2-fluoropyridin-4-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile: Prepared using the process as described above for Example 1 using intermediate 6E to give 110 mg of 1-(4-acryloylpiperazin-1-yl)-6-benzyl-3-(2-fluoropyridin-4-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile. 1H-NMR (δppm, CDCl3,400MHz): δ8.35(d,J=5.6Hz,1H),7.76-7.73(m,1H),7.44(bs,1H),7.40-7.35(m,4H),7.33-7.23(m,1H),6.63-6.56(m,1H) ),6.36-6.31(m,1H),5.77-5.74(m,1H),3.91-3.72(m,8H),3.49-3.44( m,4H),2.80-2.78(m,2H),2.71-2.69(m,2H).MS(m / z):483[M+H]+.HPLC Purity: 99.8%.

[0323] Example 44: 1-(4-acryloylpiperazin-1-yl)-6-(naphthalen-1-yl)-3-(piperidin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile: Prepared using the process as described above for Example 1 using intermediate 19N to give 150 mg of 1-(4-acryloylpiperazin-1-yl)-6-(naphthalen-1-yl)-3-(piperidin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile. 1H-NMR (δppm, CDCl3,400MHz): δ8.21(m,1H),7.86(m,1H),7.62(m,1H),7.51(m,2H),7.43(m,1H),7.19(m,1H),6.61(m,1H),6.34(s,1H),5. 75(m,1H),4.38(s,2H),3.84(s,2H),3.72(s,2H),3.63(m,4H),3.37(m,6H),2.83(d,2H),1.68(m,6H),MS(m / z):507[M+H]+.HPLC purity: 98.89%.

[0324] Example 45: 1-(4-acryloylpiperazin-1-yl)-6-benzyl-3-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile: Prepared using the process as described above for Example 1 using Intermediate 10A to give 52 mg of 1-(4-acryloylpiperazin-1-yl)-6-benzyl-3-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile. 1H-NMR (δppm, CDCl3, 400MHz): δ7.36-7.33(m,4H),7.31-7.28(m,1H),6.62-6.55(m,1H),6. 35-6.31(m,1H),5.76-5.73(m,1H),4.33-4.23(m,2H),3.79-3.77(bs,4H),3.70-3.66(bs,4H) ),3.36(bs,4H),3.12-3.08(m,1H),2.72-2.68(m,1H),2.61-2.59(bs,4H),2.51(bs,3H),2.3 4-2.30(m,1H),2.06-2.-01(m,1H),1.83-1.67(m,3H).MS(m / z):502[M+H]+.HPLC purity:96.86%.

[0325] Example 46: 1,3-bis(4-acryloylpiperazin-1-yl)-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile: Prepared using the process as described above for Example 1 using intermediate 19K to give 85 mg of 1,3-bis(4-acryloylpiperazin-1-yl)-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile. 1H-NMR (δppm, CDCl3,400MHz):8.21-8.18(m,1H),7.88-7.85(m,1H),7.64-7.62(m,1H),7.53-7.48(m,2H) ,7.45-7.41(m,1H),7.19-7.17(m,1H),6.63-6.56(m,2H),6.37-6.31(m,2H),5.77-5.73(m,2H),4.40(s,2 H),3.84(bs,4H),3.72(bs,4H),3.68-3.66(m,4H),3.50-3.35(m,6H),2.88(bs,2H).562[M+H] + .HPLC purity:98.56%

[0326] Example 47: 1,3-bis(4-acryloylpiperazin-1-yl)-6-(benzo[b]thiophen-4-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile: Prepared using the process as described above for Example 1 using Intermediate 19L to yield 60 mg of 1,3-bis(4-acryloylpiperazin-1-yl)-6-(benzo[b]thiophen-4-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile. 1H-NMR(δppm, CDCl3,400MHz):7.63-7.61(m,1H),7.45-7.44(m,2H),7.33-7.29(m,1H) ,6.99-6.97(m,1H),6.63-6.56(m,2H),6.37-6.31(m,2H),5.77-5.72(m,2H),4.43(s,2 H),3.88(bs,4H),3.72-3.66(m,8H),3.43-3.40(m,6H),2.84-2.82(m,2H).568.41[M+H] +.HPLC purity: 99.38%

[0327] Example 48: 1-(4-acryloylpiperazin-1-yl)-6-(naphthalen-1-yl)-3-(4-propionylpiperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile: Prepared using the process as described above for Example 1 using Intermediate 19P to give 55 mg of 1-(4-acryloylpiperazin-1-yl)-6-(naphthalen-1-yl)-3-(4-propionylpiperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile. 1H-NMR (δppm, CDCl3,400MHz):8.21-8.18(m,1H),7.88-7.65(m,1H),7.64-7.62(m,1H),7.53-7.49(m,2H) ,7.45-7.41(m,1H),7.21-7.18(m,1H),6.64-6.57(m,1H),6.37-6.32(m,1H),5.77-5.74(m,1H),4.40(s,2) 564.11[M+H] + .HPLC purity: 97.59%

[0328] Example 49: 3-(4-acryloylpiperazin-1-yl)-6-(naphthalen-1-yl)-1-(4-propionylpiperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile: Step 1: tert-Butyl 4-(4-cyano-6-(naphthalen-1-yl)-1-(4-propionylpiperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)piperazine-1-carboxylate was prepared using a process similar to that described above for Example 41, with necessary changes in starting materials and reactants, to give 150 mg of gradient compound. 609.34 [M+H] + . Step 2: Prepared using the process as described above for Example 1 (using the intermediate from Step 1) to give 85 mg of 3-(4-acryloylpiperazin-1-yl)-6-(naphthalen-1-yl)-1-(4-propionylpiperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile. 1H-NMR (δppm, CDCl3,400MHz):8.21-8.18(m,1H),7.88-7.86(m,1H),7.64-7.62(m,1H),7.53-7.49(m,2H) ,7.46-7.42(m,1H),7.19-7.18(m,1H),6.63-6.56(m,1H),6.36-6.31(m,1H),5.76-5.73(m,1H),4.40(s,2) 564.52[M+H] + .HPLC purity:97.49%

[0329] Example 50: 1-(4-acryloylpiperazin-1-yl)-3-morpholino-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile: Prepared using the process as described above for Example 1 to yield 80 mg of 1-(4-acryloylpiperazin-1-yl)-3-morpholino-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile. 1H-NMR (δppm, CDCl3,400MHz):8.21-8.18(m,1H),7.88-7.84(m,1H),7.63-7.61(m,1H),7.53-7.49(m,2H) ,7.45-7.41(m,1H),7.19-7.17(m,1H),6.64-6.57(m,1H),6.37-6.32(m,1H),5.77-5.74(m,1H),4.39(s,2 H),3.84-3.82(m,6H),3.72-3.64(m,6H),3.41(bs,4H),2.88(s,2H).509.44[M+H] + .HPLC purity:95.74%

[0330] Example 51: 3-(4-acetylpiperazin-1-yl)-1-(4-acryloylpiperazin-1-yl)-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile: Prepared using the process as described above for Example 1 using intermediate 19R to give 75 mg of 3-(4-acetylpiperazin-1-yl)-1-(4-acryloylpiperazin-1-yl)-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile. 1H-NMR(δppm, CDCl3,400MHz):8.21-8.18(m,1H),7.88-7.86(m,1H),7.64-7.62( m,1H),7.52-7.50(m,2H),7.45-7.42(m,1H),7.19-7.17(m,1H),6.64-6.57(m,1H) ,6.37-6.32(m,1H),5.77-5.74(m,1H),4.40(s,2H),3.78-3.75(m,2H),3.67-3.6 5(m,4H),3.62-3.60(m,6H),3.40(bs,6H),2.88(s,2H),2.14(m,3H).550.51[M+H] + .HPLC purity:98.69%

[0331] Example 52: 1-(4-acryloylpiperazin-1-yl)-3-(2,6-dimethylmorpholino)-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile: Prepared using the process described above for Example 1 using intermediate 19O to yield 60 mg of 1-(4-acryloylpiperazin-1-yl)-3-(2,6-dimethylmorpholino)-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile. 1H-NMR(δppm, CDCl3,400MHz):8.22-8.19(m,1H),7.88-7.84(m,1H),7.63-7.61(m,1H) ,7.53-7.49(m,2H),7.48-7.41(m,1H),7.19-7.17(m,1H),6.66-6.58(m,1H),6.37-6.32 (m,1H),5.77-5.74(m,1H),4.39(s,2H),4.17-4.14(m,2H),3.84-3.81(m,2H),3.79-3.7 2(m,5H),3.39(bs,5H),2.88(s,2H),2.74-2.68(m,2H),1.25-1.20(m,6H).535.35[M+H] + .HPLC purity:99.19%

[0332] Example 53: 1-(4-acryloylpiperazin-1-yl)-3-(4-(methylsulfonyl)piperazin-1-yl)-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile: Prepared using the process as described above for Example 1 using intermediate 19Q to give 61 mg of 1-(4-acryloylpiperazin-1-yl)-3-(4-(methylsulfonyl)piperazin-1-yl)-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile. 1H-NMR(δppm, CDCl3,400MHz):8.20-8.18(m,1H),7.88-7.86(m,1H),7.64-7.62(m, 1H),7.52-7.50(m,2H),7.46-7.42(m,1H),7.19-7.17(m,1H),6.65-6.58(m,1H),6. 38-6.33(m,1H),5.78-5.75(m,1H),4.40(s,2H),3.84-3.73(m,2H),3.71-3.68(m,6 H),3.49(bs,4H),3.43-3.378(m,6H),2.88(s,2H),2.86-2.83(s,2H).586.07[M+H] + .HPLC purity:98.43%

[0333] Example 54: 1-(4-acryloylpiperazin-1-yl)-3-(4-ethylpiperazin-1-yl)-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile: Step 1: tert-Butyl 4-(4-cyano-3-(4-ethylpiperazin-1-yl)-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)piperazine-1-carboxylate was prepared using the process as described above for Example 41 using intermediate 5A and 1-ethylpiperazine instead of 1-methylpiperazine to give 120 mg of the desired intermediate. 581.35 [M+H] + . Step 2: Prepared using the process as described above for Example 1 (using the intermediate from Step 1) to give 45 mg of 1-(4-acryloylpiperazin-1-yl)-3-(4-ethylpiperazin-1-yl)-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile. 1H-NMR (δppm, CDCl3,400MHz):8.20-8.18(m,1H),7.87-7.86(m,1H),7.63-7.62(m,1H),7.52-7.48(m,2H) ,7.45-7.42(m,1H),7.19-7.17(m,1H),6.64-6.58(m,1H),6.41-6.33(m,1H),5.77-5.75(m,1H),4.39(s,2) 536.13[M+H] + .HPLC purity:98.10%

[0334] Example 55: (S)-1-(4-acryloylpiperazin-1-yl)-3-((1-methylpyrrolidin-2-yl)methoxy)-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile: Prepared using the process as described above for Example 1 to yield 50 mg of (S)-1-(4-acryloylpiperazin-1-yl)-3-((1-methylpyrrolidin-2-yl)methoxy)-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile. 1H-NMR (δppm, CDCl3,400MHz):δ8.20-8.18(m,1H),7.88-7.85(m,1H),7.64-7.61(m,1H),7.53-7.48(m,2H),7 .45-7.41(m,1H),7.18-7.17(m,1H),6.64-6.57(m,1H),6.37-6.33(m,1H),5.78-5.75(m,1H),4.41(bs,2H),4 .34-4.27(m,2H),3.84-3.73(m,4H),3.44-3.34(m,6H),3.12-3.08(m,1H),2.88(bs,2H),2.73-2.70(m,1H),2 .52(s,3H),2.35-2.28(m,1H),2.08-2.03(m,1H),1.84-1.69(m,3H).MS(m / z):537.24[M+H]+.HPLC purity:97.91%

[0335] Example 56: 1-(4-acryloylpiperazin-1-yl)-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile: Prepared using the process as described above for Example 1 to yield 60 mg of 1-(4-acryloylpiperazin-1-yl)-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile. 1H-NMR (δppm, CDCl3, 400MHz): δ8.42(s,1H),8.20-8.18(m,1H),7.89-7.86( m,1H),7.66-7.64(m,1H),7.53-7.52(m,2H),7.51-7.45(m,1H),7.21-7.19(m ,1H),6.64-6.59(m,1H),6.37-6.33(m,1H),5.77-5.75(m,1H),4.45(bs,2H), 3.86-3.75(m,4H),3.45(bs,6H),2.99(bs,2H).MS(m / z):424.13[M+H]+.HPLC Purity:99.08%

[0336] Example 57: 1-(4-(2-fluoroacryloyl)piperazin-1-yl)-6-(naphthalen-1-yl)-3-(4-propionylpiperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile: 6-(naphthalen-1-yl)-1-(piperazin-1-yl)-3-(4-propionyl) in ethyl acetate (19 mL) at 0° C. To a solution of piperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride (0.30 g, 0.54 mmol) was added triethylamine (0.62 mL, 4.4 mmol), 2-fluoroprop-2-enoic acid (0.086 mL, 1.1 mmol) and T3P (0.98 mL, 1.65 mmol, 50 wt % in ethyl acetate). The mixture was allowed to warm to 15° C. over 30 min and the reaction mixture was diluted with saturated sodium carbonate solution (20 mL). The aqueous phase was extracted with ethyl acetate (2×20 mL) and the combined organic layers were dried over Na2SO4, filtered and concentrated to give a crude residue. The crude was purified by column chromatography using 4% MeOH in DCM. The pure fractions were concentrated under reduced pressure to give 0.06 gm of 1-(4-(2-fluoroacryloyl)piperazin-1-yl)-6-(naphthalen-1-yl)-3-(4-propionylpiperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile. 1H-NMR (δppm, CDCl3, 400MHz): δ8.20-8.18(m,1H),7.88-7.86(m,1H),7.66-7 .64(m,1H),7.52-7.49(m,2H),7.46-7.42(m,1H),7.20-7.18(m,1H),5.39-5. 16(m,2H),4.40(bs,2H),3.77(bs,6H),3.66-3.63(m,6H),3.43(bs,6H),2.88 (bs,2H),2.42-2.36(m,2H),1.18-1.68(m,3H).MS(m / z):582.26[M+H]+.HPLC Purity: 98.33%

[0337] Other intermediates required to prepare any of the above examples and other exemplified compounds may be synthesized using the general and specific processes as described herein above, with all possible modifications required to synthesize such intermediates and compounds as envisioned herein.

[0338] Part C: Biological activity The biological and / or pharmacological properties of the compounds of the present invention can be confirmed by various assays. The biological and / or pharmacological assays which can be carried out with the compounds according to the present invention and / or their pharma- ceutically acceptable salts are exemplified below.

[0339] Test 1: In vitro cell proliferation assay in NCI-H358 and MIAPACA-2 cell lines Growth inhibition assays will be performed using 10% FBS supplemented media. Cells will be seeded at the desired concentration of 1500-6,000 cells / well in 96-well plates. Test compounds will be added 24 hours later at concentrations ranging from 1-30 uM. Proliferation will be assessed using a CCK-8 kit to measure reduction at 0 hours (before addition of test compound) and 72 hours after addition of test compound. Absorbance was read at a wavelength of 450 nm 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 calculated accordingly. [Table 4]

[0340] 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 1000-6,000 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. Results: Data are provided for representative Cpd A on various cell lines, including selectivity. [Table 5] [Table 6]

[0341] Test 3: Nucleotide exchange assay An HTRF-based nucleotide exchange assay to detect GTP binding to K-Ras Human KRAS G12C 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. Compounds (10 concentrations at 3x or optimal multiplication factor for serial dilutions with starting concentrations of approximately 300um or 100μM or 50uM, respectively, or other optimal concentrations) were then dispensed into the reaction well using an acoustic 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 start 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. Representative compound Cpd A showed an IC50 of <10 nM.

[0342] Test 4: Protein-Protein Interaction Assay (PPI Assay): HTRF-Based PPI Assay Detecting Binding of KRAS to cRAF Protein (KRAS:cRAF) 5 μL of 3× human KRAS G12C protein (b-Kras G12C (GppNHp), corresponding to amino acids 2-169) was placed in the assay wells. Compounds (tested in IC50 mode at 10 concentrations in duplicate 3-fold serial dilutions at a starting concentration of 10 μM) were added to the assay wells using acoustic technology (ECHO, Labcyte), followed by incubation for 30 min at room temperature. After incubation, 5 uL of 3× cRAF protein (GST-cRAF, corresponding to amino acids 2-303) was added to the assay wells. After 30 min incubation, 5 uL of 3× detection mix containing MAb anti-GST-Tb (Cisbio 61GSTTLB) and streptavidin-XL665 (Cisbio 610SAXLB) cryptate was added to the assay wells. After 60–120 min of incubation, the HTRF-derived signal was measured in a microplate reader PEHRAstar (BMG Labtech) at an excitation wavelength of 337 nm and emission wavelengths of 665 and 620 nm. IC50 was determined using a sigmoidal dose-response (variable slope) equation when the activity at the highest concentration of the compound was less than 65%.

[0343] Study 5: Biomarker evaluation in NCI-H358 and MIA PaCa-2 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 NCI-H358 cells and MIA PaCa-2 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 the primary antibody membrane, it was washed three times with 1x PBS and PBST, followed by incubation with goat anti-rabbit secondary IgG HRP conjugate (from Invitrogen™) (1:10000 dilution, prepared in 3% skim milk, 0.1% tween-20) for 1 hour at room temperature. After incubation, the blot was washed and developed using G-biosciences femto LUCENT™ PLUS-HRP Chemiluminescent reagent in a Bio-Rad Chemidoc™ Imager system. The resulting bands on the blot were quantified using Image J software. Results: Representative compounds tested showed dose- and time-dependent modulation of pERK, a downstream biomarker indicative of KRAS signaling. [Table 7]

[0344] Study 6: Antitumor Efficacy of Compounds of the Invention in Female Balb / c Nude Mice Bearing NCI-H358 Human Non-Small Cell Lung Cancer Xenografts Representative compounds of the present invention were tested using NCI-H358 xenografts, where NCI-H358 cells were inoculated into a mouse model of lung cancer with two different cohorts / groups, namely a control (treated with vehicle, G1) and two treatment cohorts / groups, each of which included paclitaxel as standard (10 mg / kg Q3D, IV, G3) and a test compound (100 mg / kg QD, Cpd A, G3). Treatment was initiated when maximum tumor growth reached >200 mm3 and continued until vehicle reached a maximum tumor volume of 2000 mm3.

[0345] result: Test compounds demonstrated >65% tumor growth inhibition (TGI) with a statistically significant (P<0.01^) reduction in tumor volume from day 3 onwards (n=5). Test compounds demonstrated a statistically significant reduction in tumor volume compared to paclitaxel, IV at 10 mg / kg Q3D x 3 weeks. No significant effect on total body weight was observed over the 21 day study period.

[0346] 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 herein. Alternative boundaries may be defined as long as the specific functions and their relationships are appropriately implemented.

[0347] 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. A compound of formula (A), 【Chemical 1】 or a tautomer thereof, an isotope thereof, a prodrug thereof, an N-oxide thereof, a pharmaceutically acceptable ester thereof, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: A １ 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-, A ２ 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 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 optionally substituted by E; E is a group capable of forming a covalent bond, or an "electrophile" or "electrophilic moiety" capable of forming a covalent bond; 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[[ID=6,3]] ｃ , -SONR ｂ R ｃ , -SO ２ NR ｂ R ｃ , -OR ｂ [[ID=,6]] -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 , -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 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 OC(=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, 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) 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 OC(=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 may contain a heteroatom selected from O, NRa or S, or any two R ａ together to 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 O, NR ｘ or S, R ｂ and R ｃ is, at each occurrence, 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 when attached to a common atom, R ｘ and R ｙ any two of 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 selected from O, NR ｘ or S, or (ii) an oxo (=O) group, a thio (=S) group, or an imino (=NR ｘ ) group, R ｘ and R ｚ is independently selected at each occurrence from 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 p is, at each occurrence, independently 0, 1, or 2.

2. A compound of formula (AI), 【Chemistry 2】 or a tautomer thereof, an isotope thereof, a prodrug thereof, an N-oxide thereof, a pharmaceutically acceptable ester thereof, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: A １ 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 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 optionally substituted by E; E is a group capable of forming a covalent bond, or an "electrophile" or "electrophilic moiety" capable of forming a covalent bond; 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 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 OC(=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, 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) 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 OC(=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 to 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 O, NR ｘ or S, R ｂ and R ｃ is, at each occurrence, 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 when attached to a common atom, R ｘ and R ｙ any two of 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 selected from O, NR ｘ or S, or (ii) an oxo (=O) group, a thio (=S) group, or an imino (=NR ｘ ) group, and 2. The compound of claim 1, wherein p is independently 0, 1, or 2 at each occurrence.

3. A compound of formula (A-II), 【Chemistry 3】 or a tautomer thereof, an isotope thereof, a prodrug thereof, an N-oxide thereof, a pharmaceutically acceptable ester thereof, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: A １ 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 E; E is a group capable of forming a covalent bond, or an "electrophile" or "electrophilic moiety" capable of forming a covalent bond; 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 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 OC(=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, 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) 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 OC(=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 to 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 O, NR ｘ or S, R ｂ and R ｃ is, at each occurrence, 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 when attached to a common atom, R ｘ and R ｙ any two of 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 selected from O, NR ｘ or S, or (ii) an oxo (=O) group, a thio (=S) group, or an imino (=NR ｘ ) group, and 2. The compound of claim 1, wherein p is independently 0, 1, or 2 at each occurrence.

4. A １ is absent or -CR ｂ R ｃ - and R ｂ and R ｃ are each independently selected from hydrogen or substituted or unsubstituted alkyl; A 2 is absent or is —CR b R c —, where each of R b and R c is independently selected from hydrogen, substituted alkyl, or unsubstituted alkyl; 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; Cy 2 is selected from a cyclic group 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 an E group; E is selected from the following: 【Chemistry 4】 R is cyano (CN), R 1 is selected from: (i) selected from hydrogen, halogen, OR b , S—R b , —S(═O)pR b —, —C(═O)—R b , —NR b R c , —CO—NR b R c —, and —NR b —CO—R c ; (ii) -O-R b ; (iii) -NR b R c , or (iv) 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; R a is selected from: (i) is hydrogen or substituted alkyl or unsubstituted alkyl, or (ii) The compound according to claim 1, wherein two R a s attached to the same carbon atom form a C═O (oxo) group.

5. A １ is either absent or selected from: (i)-CR ｂ R ｃ -, wherein R ｂ is hydrogen, and R ｃ is hydrogen, or (ii) is —CH 2 or —(C═O); A 2 is absent, Cy 1 is selected from: 【Chemistry 5】 Cy 2 is selected from: 【Chemistry 6】 These are substituted with a group E capable of forming a covalent bond, E is selected from the following: 【Chemistry 7】 2. The compound of claim 1, wherein R<1> is independently selected from the following: 【Chemistry 8】

6. A ２ -Cy ２ The compound of claim 1, wherein E is selected from the following: 【Chemistry 9】

7. A compound of formula (A-III): 【Chemistry 10】 or a tautomer thereof, an isotope thereof, a prodrug thereof, an N-oxide thereof, a pharmaceutically acceptable ester thereof, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: A １ 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 -OR ｂ is selected from R ｂ and R ｃ is, at each occurrence, independently selected 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 -NE or CH ２ - selected from E, O or S, E is a group capable of forming a covalent bond, or an "electrophile" or "electrophilic moiety" capable of forming a covalent bond; R ｙ is selected from hydrogen, halogen, substituted or unsubstituted alkyl, and n is 0, 1, 2, 3, 4, 5, 6, 7, or 8).

8. A １ is absent or is methyl, Cy 1 is selected from substituted or unsubstituted aryl; R 1 is selected from hydrogen, halogen, 【Chemistry 11】 X 1 is N; 2. The compound of claim 1, wherein X 2 is selected from -NE or CH 2 -E or O, and E is selected from: 【Chemistry 12】

9. A １ does not exist, Cy 1 is selected from the following: (i) phenyl or naphthalene optionally substituted with halogen, hydroxy, or substituted or unsubstituted alkyl, or (ii) quinoline or quinazoline optionally substituted with halogen, hydroxy, or substituted or unsubstituted alkyl; 2. The compound of claim 1, wherein X 2 is selected from -NE or CH 2 -E or O, and E is selected from: 【Chemistry 13】

10. A １ is absent or is methyl, Cy １ is selected from substituted or unsubstituted aryl; R １ is selected from hydrogen, halogen, 【Chemistry 14】 X １ is N, and X ２ is -NE or CH ２ 8. The compound of claim 7, wherein E is selected from: -E or O, wherein E is selected from: 【Chemistry 15】 11. 1-(4-acryloylpiperazin-1-yl)-3-(1,1-dioxidethiomorpholino)-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile. 1-(4-acryloylpiperazin-1-yl)-6-(8-chloronaphthalen-1-yl)-3-morpholino-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, 1-(4-acryloylpiperazin-1-yl)-3-(2-morpholinoethoxy)-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, 1-(4-acryloylpiperazin-1-yl)-6-(8-chloronaphthalen-1-yl)-3-(2-orphorinoethoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, 3-(4-acryloylpiperazin-1-yl)-1-(2,6-dimethylmorpholino)-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, 3-(4-acryloylpiperazin-1-yl)-6-(8-chloronaphthalen-1-yl)-1-(2,6-dimethylmorpholino)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, 3-(4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-1-(2,6-dimethylmorpholino)-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, (S)-1-(4-acryloylpiperazin-1-yl)-6-(8-chloronaphthalen-1-yl)-3-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, (S)-1-(4-acryloylpiperazin-1-yl)-6-(3-hydroxynaphthalen-1-yl)-3-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, (S)-1-(4-(2-fluoroacryloyl)piperazin-1-yl)-3-((1-methylpyrrolidin-2-yl)methoxy)-6-(quinazolin-4-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, (S)-6-(8-chloronaphthalen-1-yl)-3-((1-methylpyrrolidin-2-yl)methoxy)-1-(4-(vinylsulfonyl)piperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, 6-(8-chloronaphthalen-1-yl)-1-(4-(2-fluoroacryloyl)-3-methylpiperazin-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, 1-(4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-3-(2,6-dimethylmorpholino)-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, 1-((S)-4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-3-(2,6-dimethylmorpholino)-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, 1-((R)-4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-3-(2,6-dimethylmorpholino)-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, 1-(4-acryloyl-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, 1-((S)-4-acryloyl-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, 1-((R)-4-acryloyl-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, 1-(4-acryloyl-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, 1-(3-(cyanomethyl)-4-(2-fluoroacryloyl)piperazin-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, (S)-1-(4-acryloylpiperazin-1-yl)-6-(isoquinolin-4-yl)-3-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, (S)-1-(4-acryloylpiperazin-1-yl)-3-((1-methylpyrrolidin-2-yl)methoxy)-6-(quinolin-8-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, 1-(4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-6-(8-chloronaphthalen-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, 1-((R)-4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-6-(8-chloronaphthalen-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, 1-((S)-4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-6-(8-chloronaphthalen-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, 6-(8-chloronaphthalen-1-yl)-1-(3-(cyanomethyl)-4-(2-fluoroacryloyl)piperazin-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, 6-(8-chloronaphthalen-1-yl)-1-((S)-3-(cyanomethyl)-4-(2-fluoroacryloyl)piperazin-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, 6-(8-chloronaphthalen-1-yl)-1-((R)-3-(cyanomethyl)-4-(2-fluoroacryloyl)piperazin-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, 1-(4-acryloylpiperazin-1-yl)-6-benzyl-3-chloro-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, N-(1-(6-benzyl-3-chloro-4-cyano-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)piperidin-4-yl)acrylamide, N-(1-(6-benzyl-4-cyano-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)piperidin-4-yl)acrylamide, 1,3-bis(4-acryloylpiperazin-1-yl)-6-benzyl-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, 1-(4-acryloylpiperazin-1-yl)-6-benzyl-4-cyano-5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl acrylate, 1-(4-acryloylpiperazin-1-yl)-6-benzyl-3-morpholino-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, 1-(4-acryloylpiperazin-1-yl)-6-benzyl-3-(4-methylpiperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, 1-(4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-6-benzyl-3-(4-methylpiperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, 6-(1-naphthoyl)-1-(4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-3-(4-methylpiperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, (S)-1-(4-acryloyl-2-methylpiperazin-1-yl)-6-benzyl-3-(4-methylpiperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, (R)-1-(4-acryloyl-2-methylpiperazin-1-yl)-6-benzyl-3-(4-methylpiperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, 1-(4-acryloylpiperazin-1-yl)-6-benzyl-3-hydroxy-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, 1-(4-acryloylpiperazin-1-yl)-3-(4-methylpiperazin-1-yl)-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, 1-(4-acryloylpiperazin-1-yl)-6-benzyl-3-(piperidin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, 1-(4-acryloylpiperazin-1-yl)-6-benzyl-3-(2-fluoropyridin-4-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, 1-(4-acryloylpiperazin-1-yl)-6-(naphthalen-1-yl)-3-(piperidin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, 1-(4-acryloylpiperazin-1-yl)-6-benzyl-3-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, 1,3-bis(4-acryloylpiperazin-1-yl)-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, 1,3-bis(4-acryloylpiperazin-1-yl)-6-(benzo[b]thiophen-4-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, 1-(4-acryloylpiperazin-1-yl)-6-(naphthalen-1-yl)-3-(4-propionylpiperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, 3-(4-acryloylpiperazin-1-yl)-6-(naphthalen-1-yl)-1-(4-propionylpiperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, 1-(4-acryloylpiperazin-1-yl)-3-morpholino-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, 3-(4-acetylpiperazin-1-yl)-1-(4-acryloylpiperazin-1-yl)-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, 1-(4-acryloylpiperazin-1-yl)-3-(2,6-dimethylmorpholino)-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, 1-(4-acryloylpiperazin-1-yl)-3-(4-(methylsulfonyl)piperazin-1-yl)-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, 1-(4-acryloylpiperazin-1-yl)-3-(4-ethylpiperazin-1-yl)-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, (S)-1-(4-acryloylpiperazin-1-yl)-3-((1-methylpyrrolidin-2-yl)methoxy)-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, 1-(4-acryloylpiperazin-1-yl)-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, 1-(4-(2-fluoroacryloyl)piperazin-1-yl)-6-(naphthalen-1-yl)-3-(4-propionylpiperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, and pharmaceutically acceptable salts thereof.

12. 1-(4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-6-(8-chloronaphthalen-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile. 1-((R)-4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-6-(8-chloronaphthalen-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, 1-((S)-4-acryloyl-3-(cyanomethyl)piperazin-1-yl)-6-(8-chloronaphthalen-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, 6-(8-chloronaphthalen-1-yl)-1-(3-(cyanomethyl)-4-(2-fluoroacryloyl)piperazin-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, 6-(8-chloronaphthalen-1-yl)-1-((S)-3-(cyanomethyl)-4-(2-fluoroacryloyl)piperazin-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, 6-(8-chloronaphthalen-1-yl)-1-((R)-3-(cyanomethyl)-4-(2-fluoroacryloyl)piperazin-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, and pharmaceutically acceptable salts thereof.

13. The following: 【Chemistry 16】 【Chemistry 17】 or a pharmaceutically acceptable salt thereof.

14. 10. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

15. 10. Use of a compound according to claim 1 for treating cancer or a RAS-mediated disorder, particularly a KRAS G12C-mediated cancer or disorder, in a subject.

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