Small molecules for treatment of cancer

Abstract

The present application relates to novel compounds described herein, methods of making the same, pharmaceutical compositions thereof, and methods of using the same. Specifically, the present invention relates to compounds of formula (A) or pharmaceutically acceptable salts thereof, which are inhibitors of the KRAS protein and are useful in the treatment, prevention and / or amelioration of diseases or disorders associated with KRAS, in particular cancer. # imgabs0 #

Description

[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 which are incorporated herein by reference in their entirety. Technical Field

[0002] The present application relates to novel compounds described herein, methods for preparing the same, pharmaceutical compositions thereof and methods of use thereof. Specifically, the present invention relates to compounds of formula (A) or pharmaceutically acceptable salts thereof, which are inhibitors of KRAS protein and can be used to treat, prevent and / or improve diseases or conditions associated with KRAS, especially cancer. Background Art

[0003] Genes are found in the DNA of every cell in the body and control how the cell functions, including: how fast it grows, how often it divides, or how long it lives. Genes control how the cell works by making proteins. Proteins have specific functions and act as messengers for the cell, and each gene must have the correct instructions for making a protein. This allows the protein to carry out the correct function for the cell. All cancers start when one or more genes in a cell mutate. A mutation is a change. It can produce an abnormal protein. Or it can prevent a protein from being made. The abnormal protein gives a different message than the normal protein. This can cause the cell to multiply uncontrollably and become cancerous.

[0004] Broadly, there are two basic types of gene mutations that researchers refer to: (a) Acquired mutations and factors that cause these mutations include smoking, exposure to ultraviolet (UV) radiation, viruses, or age. Cancers that occur due to acquired mutations are called sporadic cancers. (b) Germline mutations: Germline mutations are less common and occur in sperm cells or egg cells. Because the mutation affects reproductive cells, it can be passed down from generation to generation. Cancers caused by germline mutations are called hereditary cancers and account for about 5% to 20% of all cancers.

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

[0006] DNA repair genes. These repair errors that occur when DNA is replicated. Many of these act as tumor suppressor genes. BRCA1, BRCA2, and p53 are all DNA repair genes. If a person has errors in their DNA repair genes, the errors remain uncorrected and these errors can lead to mutations. These mutations can ultimately lead to cancer, especially if the mutations occur in tumor suppressor genes or oncogenes.

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

[0008] Oncogenes. These transform healthy cells into cancer cells. It is not known whether mutations in these genes are inherited. The two most common oncogenes are HER2, a special protein that controls the growth and spread of cancer. It is present in some cancer cells. For example, breast and ovarian cancer cells and RAS, a gene of the RAS family, which makes proteins involved in cell communication pathways, cell growth and cell death.

[0009] One such mutation that has been reported is a mutation in a RAS family gene. RAS is known to determine a molecular switch and is a monomeric globular protein associated with the plasma membrane. RAS can bind to 5'-guanosine diphosphate (GDP) (referred to as the resting state or inactive state) or 5'-guanosine triphosphate and convert GDP into GTP (referred to as the "on" state or active state). It is growth-promoting stimuli that lead to the induction of RAS, in which the exchange of GDP with GTP occurs by allowing the active state of RAS to interact with and activate other proteins. This activation of RAS provides a signal for cells to continue to grow and divide.

[0010] It is worth mentioning that the intrinsic ability of RAS proteins to shut down by switching from GTP back to GDP is very low, and RAS shuts down its need for GTPase-activating protein (GAP), which interacts with RAS and greatly accelerates the conversion of GTP to GDP. Any mutation in RAS that affects its ability to interact with GAP or convert GTP back to GDP will lead to long-term activation of the protein and, therefore, long-term and overactive RAS signaling, ultimately leading to cancer.

[0011] The RAS family is further divided into several 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; however, 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] Among the three HRAS, KRAS, and NRAS members, approximately 25-30% of mutations in most tumors are detected in the KRAS gene, and approximately 30% of human tumors have been reported to have some mutation in a RAS gene.

[0013] KRAS gene mutations are more common in pancreatic cancer, lung adenocarcinoma, colorectal cancer, gallbladder cancer, thyroid cancer, and bile duct cancer. KRAS mutations also occur in about 25% of patients with NSCLC, and some studies have shown that KRAS mutations are a negative prognostic factor for patients with NSCLC. Recently, KRAS mutations have been found to be resistant to epidermal growth factor receptor (EGFR)-targeted therapies for colorectal cancer; it seems increasingly important to know the status of KRAS mutations before using tyrosine kinase inhibitors (TKIs).

[0014] The most common KRAS mutations are found in the P-loop, at residues G12 and G13 and at residue Q61, with G12C being a frequent mutation of the KRAS gene. The G12C mutation has been reported to be approximately 14-15% in several cancers, with the majority reported in lung and colon cancers.

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

[0016] Cancer often has few treatment options, especially when the cancer is the result of metastasis and is unresectable. On the one hand, there have been some advances in treatment options, such as chemotherapy alone or in combination with radiation and / or surgery, but on the other hand, the prognosis of cancers, especially lung cancer, pancreatic cancer, prostate cancer, gastric cancer, endometrial cancer, ovarian cancer, colorectal cancer, etc., also faces great challenges.

[0017] Therefore, there is a real unmet medical need for treating such cancers and the present invention aims to address this problem. Summary of the invention

[0018] The present invention relates to a compound of formula (A) or a pharmaceutically acceptable salt or composition thereof and a method for treating with the same. Specifically, the present invention relates to a compound of formula (A) and a pharmaceutically acceptable salt thereof that can be used to treat RAS-mediated cancer.

[0019] In one embodiment of the present invention, the substituted naphthyridine compound is represented by structural formula (A):

[0020]

[0021] or its tautomer, its isotope, its prodrug, its N-oxide, its pharmaceutically acceptable ester, its pharmaceutically acceptable salt or its stereoisomer, wherein

[0022] A1 is absent or independently selected from 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-.

[0023] A2 is absent or independently selected from 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, -(CRb R c ) p -、-O-、-S-、-S(=O) p -, -C(=O)-, -NR x -、-CO-NR x -and-NR x -CO-.

[0024] Cy 1 is selected from cyclic groups, the cyclic groups being 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.

[0025] Cy 2 is selected from cyclic groups, the cyclic groups being 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, which is optionally substituted with E.

[0026] E is a group capable of forming a covalent bond, or an "electrophile" or "electrophile moiety" capable of forming a covalent bond.

[0027] R is independently selected at each occurrence from 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 .

[0028] R 1is independently selected at each occurrence 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 NRc 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 .

[0029] R a is independently selected at each occurrence 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 Rc ,-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 connected to form a substituted or unsubstituted saturated or unsaturated 3-6 membered ring, the 3-6 membered ring may optionally contain heteroatoms which may be the same or different and selected from O, NRa or S; or any two R connected to the same carbon atom a Can be linked to form oxo (C=O), imino (=NR b )、C=S(O) p or a substituted or unsubstituted saturated or unsaturated 3-6 membered ring, the 3-6 membered ring may optionally contain the same or different and selected from O, NR x or a heteroatom of S;

[0030] R b and R cis independently selected at each occurrence 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 heterocycle, substituted heterocyclylalkyl ring, or substituted or unsubstituted amino, or R x and R y Any two of the following may be linked when bound to a common atom to form (i) a substituted or unsubstituted saturated or unsaturated 3-14 membered ring, the 3-14 membered ring may optionally contain one or more which may be the same or different and are selected from O, NR x or S heteroatom, or (ii) oxo (=O), thio (=S) or imino (=NR x ) group;

[0031] R x and R z is independently selected at each occurrence from hydrogen, hydroxy, cyano, halogen, -OR a 、-COOR a ,-S(=O)qR a 、-NR a R b ,-C(=Z)-R a , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and substituted or unsubstituted cycloalkyl;

[0032] Z is selected from O or S; and

[0033] p is independently 0, 1 or 2 at each occurrence.

[0034] In one embodiment of the present invention, the substituted naphthyridine compound is represented by the structural formula (AI):

[0035]

[0036] or its tautomer, its isotope, its prodrug, its N-oxide, its pharmaceutically acceptable ester, its pharmaceutically acceptable salt or its stereoisomer, wherein

[0037] A1 is absent or independently selected from substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 2-4 Alkenyl, substituted or unsubstituted C 2-4Alkynyl, substituted or unsubstituted C 3-10 Cycloalkyl, substituted or unsubstituted C 3-10 Heterocycloalkyl, -(CR b R c ) p -、-O-、-S-、-S(=O) p -, -C(=O)-, -NR x -、-CO-NR x -and-NR x -CO-.

[0038] Cy 1 is selected from cyclic groups, the cyclic groups being 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.

[0039] Cy 2 is selected from cyclic groups, the cyclic groups being 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, which is optionally substituted with E.

[0040] E is a group capable of forming a covalent bond, or an "electrophile" or "electrophile moiety" capable of forming a covalent bond.

[0041] R 1 is independently selected at each occurrence 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 .

[0042] R a is independently selected at each occurrence 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 cC(=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 connected to form a substituted or unsubstituted saturated or unsaturated 3-6 membered ring, the 3-6 membered ring may optionally contain the same or different and selected from O, NR a or S; or any two R attached to the same carbon atom a Can be linked to form oxo (C=O), imino (=NR b )、C=S(O) p or a substituted or unsubstituted saturated or unsaturated 3-6 membered ring, the 3-6 membered ring may optionally contain the same or different and selected from O, NR x or a heteroatom of S;

[0043] R b and R c is independently selected at each occurrence 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 heterocycle, substituted heterocyclylalkyl ring, or substituted or unsubstituted amino, or R x and R y Any two of the following may be linked when bound to a common atom to form (i) a substituted or unsubstituted saturated or unsaturated 3-14 membered ring, the 3-14 membered ring may optionally contain one or more which may be the same or different and are selected from O, NR xor S heteroatom, or (ii) oxo (=O), thio (=S) or imino (=NR x ) group; and

[0044] p is independently 0, 1 or 2 at each occurrence.

[0045] In one embodiment of the present invention, the substituted naphthyridine compound is represented by structural formula (A-II):

[0046]

[0047] or its tautomer, its isotope, its prodrug, its N-oxide, its pharmaceutically acceptable ester, its pharmaceutically acceptable salt or its stereoisomer, wherein

[0048] A1 is absent or independently selected from 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-.

[0049] Cy 1 is selected from cyclic groups, the cyclic groups being 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.

[0050] Cy 2 is a substituted or unsubstituted heterocyclic group, wherein the substituted or unsubstituted heterocyclic group is optionally substituted by E.

[0051] E is a group capable of forming a covalent bond, or an "electrophile" or "electrophile moiety" capable of forming a covalent bond.

[0052] R 1is independently selected at each occurrence 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 NRc 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 .

[0053] R a is independently selected at each occurrence 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 Rc ,-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 connected to form a substituted or unsubstituted saturated or unsaturated 3-6 membered ring, the 3-6 membered ring may optionally contain the same or different and selected from O, NR a or S; or any two R attached to the same carbon atom a Can be linked to form oxo (C=O), imino (=NR b )、C=S(O) p or a substituted or unsubstituted saturated or unsaturated 3-6 membered ring, the 3-6 membered ring may optionally contain the same or different and selected from O, NR x or a heteroatom of S;

[0054] R b and R cis independently selected at each occurrence 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 heterocycle, substituted heterocyclylalkyl ring, or substituted or unsubstituted amino, or R x and R y Any two of the following may be linked when bound to a common atom to form (i) a substituted or unsubstituted saturated or unsaturated 3-14 membered ring, the 3-14 membered ring may optionally contain one or more which may be the same or different and are selected from O, NR x or S heteroatom, or (ii) oxo (=O), thio (=S) or imino (=NR x ) group; and

[0055] p is independently 0, 1 or 2 at each occurrence.

[0056] Further preferred are compounds of formula (A), (AI) or (A-II) wherein A1 is absent or is -CR b R c -; where R b and R c Each of is independently selected from hydrogen or substituted or unsubstituted alkyl.

[0057] Further preferred are compounds of formula (A), (AI) or (A-II) wherein A1 is absent or is -CR b R c -; where R b are independently methyl or ethyl, and R c It's hydrogen.

[0058] Further preferred are compounds of formula (A), (AI) or (A-II) wherein A1 is absent or is -CR b R c -; where R b is hydrogen, and R c It's hydrogen.

[0059] Further preferred are compounds of formula (A), (AI) or (A-II) wherein A1 is absent or is -CH2 or -(C=O).

[0060] Further preferred are compounds of formula (A), (AI) or (A-II), wherein A2 is absent or is -CR b R c -; where R b and R c Each of is independently selected from hydrogen, substituted or unsubstituted alkyl.

[0061] Further preferred are compounds of formula (A), (AI) or (A-II), wherein A2 is absent or is -CR b R c -; where R b are independently methyl or ethyl, and R c It's hydrogen.

[0062] Further preferred are compounds of formula (A), (AI) or (A-II) wherein A2 is absent.

[0063] Further preferred are compounds of formula (A), (AI) or (A-II), wherein Cy 1 is selected from a cyclic group, the cyclic group being selected from a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, a substituted or unsubstituted arylalkyl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted heteroarylalkyl group.

[0064] Further preferred are compounds of formula (A), (AI) or (A-II), wherein Cy 1 is selected from a cyclic group selected from a substituted or unsubstituted aryl group and a substituted or unsubstituted heteroaryl group.

[0065] Further preferred are compounds of formula (A), (AI) or (A-II), wherein Cy 1 Selected from

[0066]

[0067]

[0068] Further preferred are compounds of formula (A), (AI) or (A-II), wherein Cy 2 is selected from a cyclic group selected from a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted cycloalkylalkyl, a substituted or unsubstituted heterocyclyl and a substituted or unsubstituted heterocyclylalkyl.

[0069] Further preferred are compounds of formula (A), (AI) or (A-II), wherein Cy 2is selected from cyclic groups selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocyclyl and substituted or unsubstituted heterocyclylalkyl, each of which is optionally further substituted by a group E.

[0070] Further preferred are compounds of formula (A), (AI) or (A-II), wherein Cy 2 Selected from

[0071]

[0072] It is substituted by a group E capable of forming a covalent bond.

[0073] Further preferred are compounds of formula (A), (AI) or (A-II), wherein E is selected from

[0074]

[0075]

[0076] Further preferred are compounds of formula (A), (AI) or (A-II), wherein E is selected from

[0077]

[0078] Further preferred are compounds of formula (A), (AI) or (A-II), wherein A2-Cy 2 -E is selected from

[0079]

[0080] Further preferred are compounds of formula (A), (AI) or (A-II), wherein A2-Cy 2 -E is selected from

[0081]

[0082] Further preferred are compounds of formula (A), (AI) or (A-II), wherein R is cyano (CN).

[0083] Further preferred are compounds of formula (A), (AI) or (A-II), wherein R 1 Selected from hydrogen, halogen, OR b , SR b 、-S(=O)pR b -、-C(=O)-R b 、-NR b R c 、-CO-NRb R c -and-NR b -CO-R c .

[0084] Further preferred are compounds of formula (A), (AI) or (A-II), wherein R 1 Yes-OR b .

[0085] Further preferred are compounds of formula (A), (AI) or (A-II), wherein R 1 Yes - NR b R c .

[0086] Further preferred are compounds of formula (A), (AI) or (A-II), wherein R 1 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.

[0087] Further preferred are compounds of formula (A), (AI) or (A-II), wherein R 1 are independently selected from substituted or unsubstituted alkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, and substituted or unsubstituted heteroaryl.

[0088] Further preferred are compounds of formula (A), (AI) or (A-II), wherein R 1 Independently selected from

[0089]

[0090]

[0091] Further preferred are compounds of formula (A), (AI) or (A-II), wherein R a is hydrogen or substituted or unsubstituted alkyl.

[0092] Further preferred are compounds of formula (A), (AI) or (A-II) wherein two R attached to the same carbon atom are a A C=O (oxo) group is formed.

[0093] Further preferred are compounds of formula (A), (AI) or (A-II), wherein A1

[0094] (i) does not exist or is -CRb R c -; where R b and R c Each of is independently selected from hydrogen or substituted or unsubstituted alkyl; and / or

[0095] (ii) does not exist or is -CR b R c -; where R b are independently methyl or ethyl, and R c is hydrogen; and / or

[0096] (iii) does not exist or is -CR b R c -; where R b is hydrogen, and R c is hydrogen; and / or

[0097] (iv) absent or -CH2; and / or any combination thereof.

[0098] A2

[0099] (i) does not exist or is -CR b R c -; where R b and R c Each of is independently selected from hydrogen, substituted or unsubstituted alkyl; and / or

[0100] (ii) does not exist or is -CR b R c -; where R b are independently methyl or ethyl, and R c is hydrogen; and / or

[0101] (iii) does not exist and / or any combination thereof;

[0102] Cy 1 Select from the following:

[0103] (i) a cyclic group selected from a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, a substituted or unsubstituted arylalkyl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted heteroarylalkyl group; and / or

[0104] (ii) a cyclic group selected from a substituted or unsubstituted aryl group and a substituted or unsubstituted heteroaryl group; and / or a combination thereof

[0105] Cy 2 Select from the following:

[0106] (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

[0107] (ii) a cyclic group selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocyclyl and substituted or unsubstituted heterocyclylalkyl and / or combinations thereof, each of which is optionally further substituted by a group E;

[0108] R is cyano (CN); and

[0109] R 1 Selected from

[0110] (i) Hydrogen, halogen, OR b , SR 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

[0111] (ii)-OR b ; and / or

[0112] (iii)-NR b R c ; and / or

[0113] (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

[0114] (v) substituted or unsubstituted alkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl and substituted or unsubstituted heteroaryl and / or combinations thereof.

[0115] Further preferred are compounds of formula (A), (AI) or (A-II), wherein

[0116] R is independently selected at each occurrence from CN (cyano), COOH, CONH2, SO3H, C(=O)OR b 、-C(=O)R b 、-C(=S)Rb 、-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 、-CRb R c C(=O)R b or -CR b R c C(=S)R z .

[0117] A1 is absent or is substituted or unsubstituted C 1-4 alkyl;

[0118] A2 is absent or is substituted or unsubstituted C 1-4 alkyl;

[0119] Cy 1 is selected from substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;

[0120] Cy 2 is selected from substituted or unsubstituted heterocyclyl, wherein the substituted or unsubstituted heterocyclyl is optionally substituted with E.

[0121] E is a group capable of forming a covalent bond, or an "electrophile" or "electrophile moiety" capable of forming a covalent bond.

[0122] R 1 is independently selected at each occurrence 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 、-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 .

[0123] R a is independently selected at each occurrence 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 、-SO2Rb , -CR b R c C(=O)R b or -CR b R c C(=S)R z , or any two R a may be connected to form a substituted or unsubstituted saturated or unsaturated 3-6 membered ring, wherein the 3-6 ring may optionally contain the same or different and selected from O, NR a or S; or any two R attached to the same carbon atom a Can be linked to form oxo (C=O), imino (=NR b )、C=S(O) p or a substituted or unsubstituted saturated or unsaturated 3-6 membered ring, the 3-6 membered ring may optionally contain the same or different and selected from O, NR x or a heteroatom of S.

[0124] R b and R c is independently selected at each occurrence 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 heterocycle, substituted heterocyclylalkyl ring, or substituted or unsubstituted amino, or R x and R y Any two of the following may be linked when bound to a common atom to form (i) a substituted or unsubstituted saturated or unsaturated 3-14 membered ring, the 3-14 membered ring may optionally contain one or more which may be the same or different and are selected from O, NR x or S heteroatom, or (ii) oxo (=O), thio (=S) or imino (=NR x ) group;

[0125] R x and R z is independently selected at each occurrence from hydrogen, hydroxy, cyano, halogen, -OR a 、-COOR a ,-S(=O)qR a 、-NR a R b 、-C(=Z)-R a, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and substituted or unsubstituted cycloalkyl;

[0126] Z is selected from O or S; and

[0127] p is independently 0, 1 or 2 at each occurrence.

[0128] Further preferred are compounds of formula (A), (AI) or (A-II), wherein

[0129] A1 is absent or is substituted or unsubstituted alkyl;

[0130] Cy 1 is selected from cyclic groups, the cyclic groups being 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.

[0131] Cy 2 is selected from cyclic groups, the cyclic groups being 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, which is optionally substituted with E.

[0132] E is a group capable of forming a covalent bond, or an "electrophile" or "electrophilic moiety" capable of forming a covalent bond;

[0133] R is independently selected at each occurrence from CN (cyano), COOH, CONH2, SO3H, C(=O)OR b 、-C(=O)R b 、-C(=S)R b 、-C(=O)NR b R c 、-C(=O)ONR b R c 、-NR b R c ,-NR b C(=O)NR b R c 、-NRb S(=O)R c 、-NR b S(=O)2R c 、-NR b -OR c 、=N-NR b R c 、-NR b C(=O)OR c 、-NR b C(=O)R c 、-NR b C(=S)R c ,–NR b C(=S)NR b R c 、-SONR b R c 、-SO2NR b R c 、-OR b 、-OR b C(=O)NR b R c 、-OR b C(=O)OR c 、-OC(=O)R b 、-OC(=O)NR b R c 、-R b NR c C(=O)R b 、-R b OR c 、-R b C(=O)OR c 、-R b C(=O)NR b R c 、-R b C(=O)R c 、-R b OC(=O)R c 、-SR b 、-SOR c 、-SO2R b 、-CR b R c C(=O)R b 或-CR b R c C(=S)R z 。

[0134] R 1is independently selected at each occurrence 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 NRc 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 ;

[0135] R a is independently selected at each occurrence 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 Rc ,-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 connected to form a substituted or unsubstituted saturated or unsaturated 3-6 membered ring, the 3-6 membered ring may optionally contain the same or different and selected from O, NR a or S; or any two R attached to the same carbon atom a Can be linked to form oxo (C=O), imino (=NR b )、C=S(O) p or a substituted or unsubstituted saturated or unsaturated 3-6 membered ring, the 3-6 membered ring may optionally contain the same or different and selected from O, NR x or a heteroatom of S;

[0136] R b and R cis independently selected at each occurrence 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 heterocycle, substituted heterocyclylalkyl ring, or substituted or unsubstituted amino, or R x and R y Any two of the following may be linked when bound to a common atom to form (i) a substituted or unsubstituted saturated or unsaturated 3-14 membered ring, the 3-14 membered ring may optionally contain one or more which may be the same or different and are selected from O, NR x or S heteroatom, or (ii) oxo (=O), thio (=S) or imino (=NR x ) group;

[0137] R x and R z is independently selected at each occurrence from hydrogen, hydroxy, cyano, halogen, -OR a 、-COOR a ,-S(=O)qR a 、-NR a R b ,-C(=Z)-R a , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and substituted or unsubstituted cycloalkyl;

[0138] Z is selected from O or S; and

[0139] p is independently 0, 1 or 2 at each occurrence.

[0140] Further preferred are compounds of formula (A), (AI) or (A-II), wherein

[0141] Cy 1 is selected from substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;

[0142] A1 is absent or independently selected from 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 3-10Heterocycloalkyl, -(CR b R c ) p -、-O-、-S-、-S(=O) p -, -C(=O)-, -NR x -、-CO-NR x -and-NR x -CO-.

[0143] Cy 2 is selected from cyclic groups, the cyclic groups being 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, which is optionally substituted with E.

[0144] E is a group capable of forming a covalent bond, or an "electrophile" or "electrophile moiety" capable of forming a covalent bond.

[0145] R 1 is independently selected at each occurrence 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 、-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 .

[0146] R a is independently selected at each occurrence 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 、-SO2Rb , -CR b R c C(=O)R b or -CR b R c C(=S)R z , or any two R a may be connected to form a substituted or unsubstituted saturated or unsaturated 3-6 membered ring, the 3-6 membered ring may optionally contain the same or different and selected from O, NR a or S; or any two R attached to the same carbon atom a Can be linked to form oxo (C=O), imino (=NR b )、C=S(O) p or a substituted or unsubstituted saturated or unsaturated 3-6 membered ring, the 3-6 membered ring may optionally contain the same or different and selected from O, NR x or a heteroatom of S.

[0147] R b and R c is independently selected at each occurrence 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 heterocycle, substituted heterocyclylalkyl ring, or substituted or unsubstituted amino, or R x and R y Any two of the following may be linked when bound to a common atom to form (i) a substituted or unsubstituted saturated or unsaturated 3-14 membered ring, the 3-14 membered ring may optionally contain one or more which may be the same or different and are selected from O, NR x or S heteroatom, or (ii) oxo (=O), thio (=S) or imino (=NR x ) group;

[0148] R x and R z is independently selected at each occurrence from hydrogen, hydroxy, cyano, halogen, -OR a 、-COOR a ,-S(=O)qR a 、-NR a R b 、-C(=Z)-R a, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and substituted or unsubstituted cycloalkyl;

[0149] Z is selected from O or S; and

[0150] p is independently 0, 1 or 2 at each occurrence.

[0151] Further preferred are compounds of formula (A), (AI) or (A-II), wherein

[0152] Cy 2 is a substituted or unsubstituted heterocyclyl group, wherein the substituted or unsubstituted heterocyclyl group is optionally substituted by E;

[0153] E is a group capable of forming a covalent bond, or an "electrophile" or "electrophile moiety" capable of forming a covalent bond.

[0154] A1 is absent or independently selected from 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-.

[0155] Cy 1 is selected from cyclic groups, the cyclic groups being 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.

[0156] R 1is independently selected at each occurrence 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 NRc 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 .

[0157] R a is independently selected at each occurrence 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 Rc ,-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 connected to form a substituted or unsubstituted saturated or unsaturated 3-6 membered ring, the 3-6 membered ring may optionally contain the same or different and selected from O, NR a or S; or any two R attached to the same carbon atom a Can be linked to form oxo (C=O), imino (=NR b )、C=S(O) p or a substituted or unsubstituted saturated or unsaturated 3-6 membered ring, the 3-6 membered ring may optionally contain the same or different and selected from O, NR x or a heteroatom of S.

[0158] R b and R cis independently selected at each occurrence 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 heterocycle, substituted heterocyclylalkyl ring, or substituted or unsubstituted amino, or R x and R y Any two of the following may be linked when bound to a common atom to form (i) a substituted or unsubstituted saturated or unsaturated 3-14 membered ring, the 3-14 membered ring may optionally contain one or more which may be the same or different and are selected from O, NR x or S heteroatom, or (ii) oxo (=O), thio (=S) or imino (=NR x ) group;

[0159] R x and R z is independently selected at each occurrence from hydrogen, hydroxy, cyano, halogen, -OR a 、-COOR a ,-S(=O)qR a 、-NR a R b 、-C(=Z)-R a , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and substituted or unsubstituted cycloalkyl;

[0160] Z is selected from O or S; and

[0161] p is independently 0, 1 or 2 at each occurrence.

[0162] Further preferred are compounds of formula (A), (AI) or (A-II), wherein

[0163] R 1 Selected from hydrogen, halogen, -NR b R c OR b ;

[0164] A1 is absent or independently selected from 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 3-10Cycloalkyl, 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-.

[0165] Cy 1 is selected from cyclic groups, the cyclic groups being 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.

[0166] Cy 2 is selected from cyclic groups, the cyclic groups being 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, which is optionally substituted with E.

[0167] E is a group capable of forming a covalent bond, or an "electrophile" or "electrophile moiety" capable of forming a covalent bond.

[0168] R a is independently selected at each occurrence 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 、-NRb S(=O)R c 、-NR b S(=O)2R c 、-NR b -OR c , =N-NR b R c 、-NR b C(=O)OR c 、-NR b C(=O)R c 、-NR b C(=S)R c ,–NR b C(=S)NR b R c ,-SONR b R c 、-SO2NR b R c 、-OR b 、-OR b C(=O)NR b R c 、-OR b C(=O)OR c 、-OC(=O)R b 、-OC(=O)NR b R c , -R b NR c C(=O)R b , -R b OR c , -R b C(=O)OR c , -R b C(=O)NR b R c , -R b C(=O)R c , -R b OC(=O)R c 、-SR b 、-SOR c 、-SO2R b , -CR b R c C(=O)R b or -CR b R c C(=S)R z , or any two R a may be connected to form a substituted or unsubstituted saturated or unsaturated 3-6 membered ring, the 3-6 membered ring may optionally contain the same or different and selected from O, NRa or S; or any two R attached to the same carbon atom a Can be linked to form oxo (C=O), imino (=NR b )、C=S(O) p or a substituted or unsubstituted saturated or unsaturated 3-6 membered ring, the 3-6 membered ring may optionally contain the same or different and selected from O, NR x or a heteroatom of S.

[0169] R b and R c is independently selected at each occurrence from hydrogen, substituted or unsubstituted alkyl, or R b and R c The variables of together with the nitrogen to which they are attached may form a substituted or unsubstituted heterocyclic ring;

[0170] R x and R z is independently selected at each occurrence from hydrogen, hydroxy, cyano, halogen, -OR a 、-COOR a ,-S(=O)qR a 、-NR a R b ,-C(=Z)-R a , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and substituted or unsubstituted cycloalkyl;

[0171] Z is selected from O or S; and

[0172] p is independently 0, 1 or 2 at each occurrence.

[0173] In another embodiment of the present invention, the substituted naphthyridine compound is represented by structural formula (A-III):

[0174]

[0175] or its tautomer, its isotope, its prodrug, its N-oxide, its pharmaceutically acceptable ester, its pharmaceutically acceptable salt or its stereoisomer, wherein

[0176] A1 is absent or is substituted or unsubstituted alkyl;

[0177] Cy 1 is selected from substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;

[0178] R 1 is selected from hydrogen, halogen, substituted or unsubstituted alkyl, -NR bR c OR b ;

[0179] R b and R c is independently selected at each occurrence from hydrogen, substituted or unsubstituted alkyl, or R b and R c The variables of together with the nitrogen to which they are attached may form a substituted or unsubstituted heterocyclic ring;

[0180] X 1 is C or N;

[0181] X 2 Selected from -NE or CH2-E, O or S;

[0182] E is a group capable of forming a covalent bond, or an "electrophile" or "electrophile moiety" capable of forming a covalent bond.

[0183] R y is selected from hydrogen, halogen, substituted or unsubstituted alkyl; and

[0184] n is 0, 1, 2, 3, 4, 5, 6, 7 or 8.

[0185] Further preferred are compounds of formula (A-III) wherein A1 is absent or is methyl.

[0186] Further preferred are compounds of formula (A-III) wherein A1 is absent.

[0187] Further preferred are compounds of formula (A-III) wherein Cy 1 is selected from substituted or unsubstituted aryl;

[0188] Further preferred are compounds of formula (A-III) wherein Cy 1 is selected from phenyl or naphthalene, said phenyl or naphthalene being optionally substituted with halogen, hydroxyl or substituted or unsubstituted alkyl.

[0189] Further preferred are compounds of formula (A-III) wherein Cy 1 is selected from quinoline or quinazoline, the quinoline or quinazoline being optionally substituted with halogen, hydroxyl or substituted or unsubstituted alkyl.

[0190] Further preferred are compounds of formula (A-III) wherein R 1 Selected from hydrogen, halogen,

[0191]

[0192] Further preferred are compounds of formula (A-III) wherein X 1 It is N.

[0193] Further preferred are compounds of formula (A-III) wherein X 2 Selected from -NE or CH2-E or O, wherein E is selected from

[0194]

[0195] Further preferred are compounds of formula (A-III) wherein X 2 Selected from -NE or CH2-E or O, wherein E is selected from

[0196]

[0197] Further preferred are compounds of formula (A-III), wherein

[0198] A1 is absent or is a methyl group;

[0199] Cy 1 is selected from substituted or unsubstituted aryl;

[0200] R 1 Selected from hydrogen, halogen,

[0201]

[0202] X 1 is N; and

[0203] X 2 Selected from -NE or CH2-E or O, wherein E is selected from

[0204]

[0205] Non-limiting representative compounds of the present invention are listed below, as well as pharmaceutically acceptable salts thereof. The present invention should not be construed as being limited to these compounds.

[0206] 1.1-(4-acryloylpiperazine-1-yl)-3-(1,1-dioxothiomorpholino)-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile;

[0207] 2. 1-(4-Acryloylpiperazin-1-yl)-6-(8-chloronaphthalen-1-yl)-3-morpholino-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile;

[0208] 3. 1-(4-Acryloylpiperazin-1-yl)-3-(2-morpholinoethoxy)-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile;

[0209] 4. 1-(4-Acryloylpiperazin-1-yl)-6-(8-chloronaphthalen-1-yl)-3-(2-morpholinoethoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile;

[0210] 5. 3-(4-acryloylpiperazin-1-yl)-1-(2,6-dimethylmorpholino)-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile;

[0211] 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;

[0212] 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;

[0213] 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;

[0214] 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;

[0215] 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;

[0216] 11. (S)-6-(8-chloronaphth-1-yl)-3-((1-methylpyrrolidin-2-yl)methoxy)-1-(4-(vinylsulfonyl)piperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile;

[0217] 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.

[0218] 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;

[0219] 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;

[0220] 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;

[0221] 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;

[0222] 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;

[0223] 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;

[0224] 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;

[0225] 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;

[0226] 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;

[0227] 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;

[0228] 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;

[0229] 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;

[0230] 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;

[0231] 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;

[0232] 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;

[0233] 28. 6-(8-Chloronaphth-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;

[0234] 29. 1-(4-Acryloylpiperazin-1-yl)-6-benzyl-3-chloro-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile;

[0235] 30. N-(1-(6-Benzyl-3-chloro-4-cyano-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)piperidin-4-yl)acrylamide;

[0236] 31. N-(1-(6-Benzyl-4-cyano-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)piperidin-4-yl)acrylamide;

[0237] 32. 1,3-Bis(4-acryloylpiperazin-1-yl)-6-benzyl-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile;

[0238] 33. 1-(4-acryloylpiperazin-1-yl)-6-benzyl-4-cyano-5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl acrylate;

[0239] 34. 1-(4-Acryloylpiperazin-1-yl)-6-benzyl-3-morpholino-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile;

[0240] 35. 1-(4-Acryloylpiperazin-1-yl)-6-benzyl-3-(4-methylpiperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile;

[0241] 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;

[0242] 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;

[0243] 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;

[0244] 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;

[0245] 40. 1-(4-Acryloylpiperazin-1-yl)-6-benzyl-3-hydroxy-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile;

[0246] 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;

[0247] 42. 1-(4-Acryloylpiperazin-1-yl)-6-benzyl-3-(piperidin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile;

[0248] 43. 1-(4-Acryloylpiperazin-1-yl)-6-benzyl-3-(2-fluoropyridin-4-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile;

[0249] 44. 1-(4-Acryloylpiperazin-1-yl)-6-(naphthalen-1-yl)-3-(piperidin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile;

[0250] 45. 1-(4-Acryloylpiperazin-1-yl)-6-benzyl-3-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile;

[0251] 46. ​​1,3-Bis(4-acryloylpiperazin-1-yl)-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile;

[0252] 47. 1,3-Bis(4-acryloylpiperazin-1-yl)-6-(benzo[b]thiophen-4-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile;

[0253] 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;

[0254] 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;

[0255] 50. 1-(4-Acryloylpiperazin-1-yl)-3-morpholino-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile;

[0256] 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;

[0257] 52. 1-(4-Acryloylpiperazin-1-yl)-3-(2,6-dimethylmorpholino)-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile;

[0258] 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;

[0259] 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;

[0260] 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;

[0261] 56. 1-(4-Acryloylpiperazin-1-yl)-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile;

[0262] 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 pharmaceutically acceptable salts thereof.

[0263] Further preferred is a compound selected from

[0264] 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;

[0265] 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;

[0266] 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 pharmaceutically acceptable salts thereof.

[0267] Further preferred is a compound:

[0268] 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 pharmaceutically acceptable salts thereof.

[0269] Further preferred is a compound:

[0270] 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 pharmaceutically acceptable salts thereof.

[0271] Further preferred is a compound:

[0272] 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 pharmaceutically acceptable salts thereof.

[0273] Further preferred is a compound selected from

[0274] 6-(8-chloronaphth-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;

[0275] 6-(8-chloronaphth-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;

[0276] 6-(8-chloronaphth-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.

[0277] Further preferred is a compound:

[0278] 6-(8-chloronaphth-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 pharmaceutically acceptable salts thereof.

[0279] Further preferred is a compound:

[0280] 6-(8-chloronaphth-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 pharmaceutically acceptable salts thereof.

[0281] Further preferred is a compound:

[0282] 6-(8-chloronaphth-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.

[0283]

[0284]

[0285]

[0286]

[0287] Non-limiting representative compounds of the present invention and their pharmaceutically acceptable salts are listed below:

[0288] Table 2

[0289]

[0290]

[0291]

[0292] Another embodiment of the present invention is a composition comprising a compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0293] Yet another embodiment of the present invention is a method for 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 pharmaceutically acceptable salt thereof, or a composition comprising a compound of the present invention or a pharmaceutically acceptable salt thereof.

[0294] Without being bound by a particular theory, provided herein are compounds that can modulate (e.g., inhibit) one or more members of the KRAS family, e.g., one or more of the KRAS mutants. More specifically, and without being bound by a particular theory, it is believed that the compounds described herein can bind to KRAS G12C and act as covalent inhibitors of KRAS G12C.

[0295] Thus, in another embodiment, the present invention is a method of treating a KRAS-mediated disorder, particularly a KRAS G12C-mediated disorder, in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt thereof.

[0296] Another embodiment of the present invention is the use of a compound of the present invention for treating cancer or a RAS-mediated disorder, particularly a KRAS G12C-mediated disorder, in a subject.

[0297] Another embodiment of the present invention is the use of a compound of the present invention for the preparation of a medicament for treating cancer or a RAS-mediated disorder, particularly a KRAS G12C-mediated disorder, in a subject.

[0298] The compounds of the present invention and pharmaceutically acceptable salts and / or compositions thereof can be used to treat various cancers, such as solid cancers, and more specifically solid cancers with KRASG12 mutations. BRIEF DESCRIPTION OF THE DRAWINGS

[0299] Figure 1A : Line graph depicting the effect of Cpd A in KRASG12C mutant cell lines in a 2D cell viability assay.

[0300] Figure 1B : Line graph depicting the effect of Cpd A in KRASG12C mutant cell lines in a 3D cell viability assay.

[0301] Figure 1C: Line graph depicting the effect of Cpd A on the eCT26 cell line in a 3D cell viability assay.

[0302] Figure 1D : Line graph depicting the effect of Cpd A on CO-04-0070 (a patient-derived cell line) in a 3D cell viability assay.

[0303] Figure 1E : Line graph depicting the selectivity of Cpd A for non-KRASG12C cell lines in a 2D cell viability assay.

[0304] Figure 2 : Line graph depicting the anti-tumor effect of Cpd A in NCI-H358 xenografts. DETAILED DESCRIPTION

[0305] The following is a description of an example embodiment of the present invention.

[0306] The compounds of the present invention include those compounds generally described above, and are further described by the types, subclasses and species disclosed herein. As used herein, unless otherwise specified, the following definitions shall apply. 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, 75th edition. In addition, the general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999 and "March's Advanced Organic Chemistry", 5th edition, editors: Smith, MB and March, J., John Wiley & Sons, New York: 2001, the entire contents of the document are hereby incorporated by reference.

[0307] Unless otherwise specified in the specification, the nomenclature used in the specification generally follows the examples and rules described in Nomenclature of Organic Chemistry, Chapters A, B, C, D, E, F and H, Pergamon Press, Oxford, 1979, whose exemplary chemical structure names and chemical structure nomenclature rules are incorporated herein by reference. Optionally, the names of the compounds can be generated using a chemical nomenclature program: ACD / ChemSketch, Version 5.09 / September 2001, Advanced Chemistry Development, Inc., Toronto, Canada.

[0308] The compounds of the present invention may have asymmetric centers, chiral axes and chiral planes (for example, as described in EL Eliel and SH Wilen, Stereochemistry of Carbon Compounds, John Wiley & Sons, New York, 1994, pp. 1119-1190), and exist in the form of racemates, racemic mixtures and individual diastereomers or enantiomers, wherein all possible isomers and mixtures thereof, including optical isomers, are included in the present invention.

[0309] As used herein, the following definitions shall apply unless otherwise indicated. Further, many of the groups defined herein may be optionally substituted. The listing of substituents in the definitions is exemplary and should not be construed as limiting substituents defined elsewhere in the specification.

[0310] Unless otherwise indicated, the term "alkyl" refers to a straight or branched chain hydrocarbon group consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to eight carbon atoms, and attached to the rest of the molecule by a single bond, such as methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, and 1,1-dimethylethyl (tert-butyl). The term "C 1-3 "Alkyl" refers to an alkyl group as defined above having up to 3 carbon atoms. The term "C 1-6 "Alkyl" refers to an alkyl group as defined above having up to 6 carbon atoms. Where appropriate, the term "alkyl" refers to a divalent hydrocarbon chain radical as mentioned above.

[0311] Unless otherwise specified, the term "alkenyl" refers to an aliphatic hydrocarbon group containing one or more carbon-carbon double bonds and which may be straight or branched chain having about 2 to about 10 carbon atoms, for example, ethenyl, 1-propenyl, 2-propenyl (allyl), isopropenyl, 2-methyl-1-propenyl, 1-butenyl and 2-butenyl. The term "C 2-6 The term "alkenyl" refers to an alkenyl group as defined above having up to 6 carbon atoms. Where appropriate, the term "alkenyl" refers to a divalent hydrocarbon group as mentioned above.

[0312] Unless otherwise indicated, the term "alkynyl" refers to a straight or branched chain hydrocarbon group having at least one carbon-carbon triple bond and having carbon atoms in the range of 2 to 12 (preferably groups having carbon atoms in the range of 2 to 10), such as ethynyl, alkynyl and butyl. 2-6 "Alkynyl" refers to an alkynyl group as defined above having up to 6 carbon atoms. Where appropriate, the term "alkynyl" refers to a divalent hydrocarbon group as mentioned above.

[0313] Unless otherwise indicated, the term "alkoxy" means an alkyl, cycloalkyl or cycloalkylalkyl group as defined above, connected to the rest of the molecule via an oxygen bond. The term "substituted alkoxy" refers to an alkoxy group in which the alkyl component is substituted (i.e., -O-(substituted alkyl). For example, "alkoxy" refers to the group -O-alkyl, comprising 1 to 8 carbon atoms in a linear, branched, cyclic configuration and combinations thereof connected to the parent structure via an oxygen atom. Examples include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy and cyclohexyloxy. Where appropriate, the term "alkoxy" refers to a divalent group as mentioned above.

[0314] Unless otherwise indicated, the term "cycloalkyl" means a non-aromatic monocyclic or polycyclic ring system having about 3 to 12 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of polycyclic cycloalkyls include perhydronaphthyl, adamantyl, and norbornyl, bridged cyclic groups, and spirobicyclic groups, for example, dicarbon (4,4) non-2-yl. The term "C 3-6 "Cycloalkyl" means a cycloalkyl group as defined above having up to 6 carbon atoms.

[0315] Unless otherwise indicated, the term "cycloalkylalkyl" refers to a group containing a cyclic ring in the range of about 3 to 8 carbon atoms, which is directly attached to the alkyl group and then attached to the main structure at any carbon of the alkyl group, such as cyclopropylmethyl, cyclobutylethyl and cyclopentylethyl.

[0316] Unless otherwise indicated, the term "cycloalkenyl" refers to a cyclic ring containing radical having at least one carbon-carbon double bond, containing in the range of about 3 to 8 carbon atoms, such as cyclopropenyl, cyclobutenyl, and cyclopentenyl. The term "cycloalkenylalkyl" refers to a cycloalkenyl radical directly attached to an alkyl radical, which is then attached to the main structure at any carbon of the alkyl radical.

[0317] Unless otherwise indicated, the term "aryl" refers to aromatic groups having in the range of 6 to 20 carbon atoms, such as phenyl, naphthyl, tetrahydronaphthyl, indenyl, and biphenyl.

[0318] Unless otherwise indicated, the term "arylalkyl" refers to an aryl group as defined above directly bonded to an alkyl group as defined above, for example -CH2C6H5 and -C2H5C6H5.

[0319] Unless otherwise indicated, the term "heterocycle" refers to a 3- to 15-membered non-aromatic ring group consisting of carbon atoms and at least one heteroatom selected from nitrogen, phosphorus, oxygen and sulfur. For the purposes of the present invention, the heterocyclic group can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can contain a fused, bridged or spirocyclic system, and the nitrogen, phosphorus, carbon, oxygen or sulfur atom in the heterocyclic group can be optionally oxidized to various oxidation states. In addition, the nitrogen atom can be optionally quaternized. The heterocyclic group can be connected to the main structure at any heteroatom or carbon atom.

[0320] Unless otherwise indicated, the term "heterocyclyl" refers to a heterocyclic group as defined above. The heterocyclic group may be attached to the main structure at any heteroatom or carbon atom.

[0321] Unless otherwise indicated, the term "heterocyclylalkyl" refers to a heterocyclyl directly bonded to an alkyl group as defined above. Heterocyclylalkyl can be connected to the main structure at any carbon atom in the alkyl group. Examples of such heterocyclylalkyls 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-piperidone, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuranyl, trithienyl, tetrahydropyranyl, thiomorpholinyl, thiomorpholinyl, 1-oxo-thiomorpholinyl and 1,1-dioxo-thiomorpholinyl.

[0322] Unless otherwise stated, the term "heteroaryl" refers to an optionally substituted 5- to 14-membered aromatic ring having as ring atoms one or more heteroatoms selected from N, O and S. The heteroaryl group may be a monocyclic, bicyclic or tricyclic ring system. Examples of such "heterocyclic" or "heteroaryl" groups 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, tetrazolyl, tetrahydroisoquinolinyl, piperidinyl, Piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-hydropyrrolidinyl, 2-oxoazepinyl, azepinyl, 4-piperidinyl, pyrrolidinyl, pyridazinyl, oxazolinyl, oxazolidinyl, triazolyl, indanyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, isoindolyl, indolyl, isoindolyl, octahydroindolyl, octahydroisoindolyl, decahydroisoquinolinyl, benzimidazolyl, thiadiazolyl, benzopyranyl, tetrahydrofuranyl, tetrahydropyranyl, thienyl, benzothienyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, dioxaphospholyl, oxadiazolyl, chromanyl and isochromanyl. The heteroaryl group may be attached to the main structure at any heteroatom or carbon atom.The term "substituted heteroaryl" also encompasses ring systems substituted with one or more oxide (-O-) substituents, such as pyridyl N-oxide.

[0323] Unless otherwise indicated, the term "heteroarylalkyl" refers to a heteroaryl group as defined above directly bonded to an alkyl group. The heteroarylalkyl group may be attached to the main structure at any carbon atom from the alkyl group.

[0324] The term "cyclic ring" refers to a cyclic ring containing from 3 to 10 carbon atoms.

[0325] Unless otherwise indicated, the term "substituted" refers to substitution with any one or any combination of the following substituents, which may be the same or different and are independently selected from 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 heterocycle, 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)R y -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 OC(O)R y 、-SR x 、-SOR x 、-SO2R x and -ONO2, wherein R in each of the above groups x , R y and R z R 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 or substituted heterocyclicalkyl ring, or R x , R y and R z Any two of may be linked to form a substituted or unsubstituted saturated or unsaturated 3-10 membered ring, the 3-10 membered ring may optionally contain the same or different and selected from O, NR x (For example, R x Can be hydrogen or C 1-6 The heteroatoms of alkyl) or S are preferably those that result in the formation of stable or chemically feasible compounds. As used herein, the term stable refers to a compound or structure that does not substantially change when subjected to conditions that allow it to be produced, detected, and preferably recovered, purified, and incorporated into a pharmaceutical composition. The substituents in the above-mentioned "substituted" groups cannot be further substituted. For example, when the substituent on a "substituted alkyl" is a "substituted aryl", the substituent on the "substituted aryl" cannot be a "substituted alkenyl".

[0326] The term "halo," "halide," or alternatively "halogen" means fluorine, chlorine, bromine, or iodine.

[0327] The terms "haloalkyl", "haloalkenyl", "haloalkynyl" and "haloalkoxy" include alkyl, alkenyl, alkynyl and alkoxy structures substituted with one or more halo groups or combinations thereof. For example, the terms "fluoroalkyl" and "fluoroalkoxy" include haloalkyl and haloalkoxy, respectively, wherein the halo is fluorine.

[0328] The term "protecting group" or "PG" refers to a substituent that is used to block or protect a particular functional group. Other functional groups on the compound can remain reactive. For example, an "amino protecting group" is a substituent that protects the amino group, which blocks or protects the amino functional group in the compound. Suitable amino protecting groups include, but are not limited to, acetyl, trifluoroacetyl, tert-butyloxycarbonyl (BOC), benzyloxycarbonyl (CBz), and 9-fluorenylmethoxycarbonyl protecting group (Fmoc). Similarly, a "hydroxy protecting group" refers to a substituent that blocks or protects the hydroxyl group of the hydroxyl functional group. Suitable hydroxy protecting groups include, but are not limited to, acetyl and silyl. A "carboxyl protecting group" refers to a substituent that blocks or protects the carboxyl group of the carboxyl functional group. Suitable carboxyl protecting groups include, but are not limited to -CH2CH2SO2Ph, cyanoethyl, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(tosyl)ethyl, 2-(p-nitrophenylsulfinyl)ethyl, 2-(diphenylphosphino)ethyl and nitroethyl. For a general description of protecting groups and their uses, see TWGreene, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991.

[0329] Certain compounds described herein contain one or more asymmetric centers, and thus can produce enantiomers, diastereomers, and other stereoisomeric forms, which can be defined in terms of absolute stereochemistry as (R)- or (S)-. The chemical entities, pharmaceutical compositions, and methods of the present invention are intended 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, for example, using chiral synthons or chiral reagents, or resolved using conventional techniques. When the compounds described herein contain olefin double bonds or other centers of geometric asymmetry, and unless otherwise indicated, it is intended that the compounds include both E and Z geometric isomers.

[0330] The term "tautomer" refers to a compound characterized in that the isomeric forms are relatively easy to interconvert under equilibrium conditions. These isomers are intended to be encompassed by the present invention. "Tautomers" are structurally different isomers that are interconverted by tautomerization. "Tautomerization" is a form of isomerization and includes prototropic or proton shift tautomerization, which is considered a subset of acid-base chemistry. "Prototropic tautomerization" or "proton shift tautomerization" involves the migration of protons, accompanied by changes in bond order, usually the exchange of single bonds with adjacent double bonds. In cases where tautomerization may occur (e.g., in solution), a chemical equilibrium of tautomers can be reached. An example of tautomerization is keto-enol tautomerization. A specific example of keto-enol tautomerization is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-ene-2-one tautomers. Another example of tautomerization is phenol-ketone tautomerization. A specific example of phenol-keto tautomerization is the interconversion of pyridin-4-ol and pyridin-4(1H)-one tautomers.

[0331] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the compounds of the present invention are within the scope of the present invention. Unless otherwise stated, all tautomeric forms of the compounds of the present invention are within the scope of the present invention.

[0332] Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, by the replacement of hydrogen or 3C- or 3D- by deuterium or tritium. 14 Compounds produced by replacing carbon with C-enriched carbon are within the scope of the present invention. According to the present invention, such compounds can be used as, for example, analytical tools, probes in biological assays, or therapeutic agents. For example, in the case of variable R, (C1-C4) alkyl or -O-(C1-C4) alkyl can be suitably deuterated (e.g., -CD3, -OCD3).

[0333] The compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that make up such compounds. For example, the compounds may be treated with, for example, tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0334] The term "stereoisomer" refers to all isomers of a single molecule that differ only in the orientation of the atoms in space. It 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 each other (diastereomers).

[0335] An "electropophile" or "electropophilic moiety" is any moiety that is capable of reacting with nucleophilicity (e.g., a moiety having a pair of lone electrons, a negative charge, a partial negative charge, and / or an excess of electrons, such as an -SH group). An electrophile is typically electron-deficient or includes electron-deficient atoms. In certain embodiments, an electrophile contains a positive charge or a partial positive charge, has a resonance structure containing a positive charge or a partial positive charge, or is a moiety in which the delocalization or polarization of electrons produces one or more atoms containing a positive charge and a partial positive charge. In some embodiments, an electrophile includes a conjugated double bond, such as an α,β-unsaturated carbonyl or an α,β-unsaturated thiocarbonyl compound.

[0336] "Leaving group or atom (Lg or Ig)" is any group or atom that will cleave from the starting material under the reaction conditions, thereby promoting the reaction at a specific site. Unless otherwise specified, suitable examples of such groups are halogen atoms and methanesulfonyloxy, p-nitrobenzenesulfonyloxy and toluenesulfonyloxy.

[0337] "Prodrug" means a compound that can be converted to a biologically active compound described herein under physiological conditions or by solvolysis (e.g., compounds having structures (A), (AI), (A-II), and (A-III)). Thus, the term "prodrug" refers to a pharmaceutically acceptable precursor of a biologically active compound. In some aspects, a prodrug is generally inactive when administered to a subject, but is converted to an active compound in vivo, for example, by hydrolysis. Prodrug compounds generally provide advantages of solubility, tissue compatibility or delayed release in mammalian organisms (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam). Higuchi, T. et al., "Pro-drugs as Novel Delivery Systems", ACS Symposium Series, Vol. 14, and "Bioreversible Carriers in Drug Design", ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Publishers, 1987, provide a discussion of prodrugs, generally in Hardman et al. (eds.), Goodman and Gilman's: The Pharmacological Basis of Therapeutics. Prodrug design is discussed in "Prodrugs for the Treatment of Infectious Diseases", 9th edition, pages 11-16 (1996), all of which are incorporated herein by reference in their entirety. The term "prodrug" is also intended to include any covalently bonded carriers that release active compounds in vivo when such prodrugs are administered to mammalian subjects. Prodrugs of active compounds as described herein are generally prepared by modifying the functional groups present in the active compound in such a manner that the modifier is cleaved into the parent active compound in conventional manipulations or in vivo. Prodrugs include compounds in which hydroxyl, amino or sulfhydryl groups are bonded to any group, and when the prodrug of the active compound is administered to a mammalian subject, the group is cleaved to form free hydroxyl, free amino or free sulfhydryl groups, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of hydroxyl functional groups, or acetamide, formamide and benzamide derivatives of amine functional groups in active compounds, and the like.

[0338] In some embodiments, the prodrugs include compounds of structures (A), (AI), (A-II), and (A-III) having phosphate, phosphoalkoxy, ester, or boronate 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, wherein the hydroxyl group has been replaced by a phosphate, phosphoalkoxy, ester, or boronate group, such as a phosphate or phosphoalkoxy group. For example, in some embodiments, R 1 The hydroxyl groups on the moiety are replaced with phosphate, phosphoalkoxy, ester or borate groups, such as phosphoric acid or alkoxyphosphoric acid groups.

[0339] The term "ester" refers to a compound formed by the reaction between an acid and an alcohol with the elimination of water. Esters can be represented by the general formula RCOOR'.

[0340] Such prodrugs and esters are intended to be encompassed within the scope of the present invention.

[0341] In addition, the invention also encompasses compounds which differ only in the presence of one or more isotopically enriched atoms, for example by the replacement of hydrogen by deuterium or tritium, or by the replacement of 13C -or 14C -Enriched carbon replaces carbon.

[0342] When ranges are used herein for physical properties, such as molecular weight, or chemical characteristics, such as chemical formula, all combinations and subcombinations of ranges, as well as specific embodiments therein, are intended to be included.

[0343] When referring to a number or a numerical range, the term "about" means that the number or numerical range referred to is an approximation within the experimental variability (or within statistical experimental error), and thus the number or numerical range may vary, for example, between 1% and 15% of the number or numerical range.

[0344] The term "comprising" (and related terms such as "comprise" or "comprises", or "having" or "including") includes those embodiments that "consist of" or "consist essentially of" the described features, for example, embodiments of any composition of matter, composition, method, or process, etc.

[0345] The following abbreviations and terms have the meanings indicated throughout; the abbreviations used herein have their conventional meanings in the fields of chemistry and biology.

[0346] The term "cell proliferation" refers to the phenomenon in which a cell changes in number due to division. The term also encompasses cell growth, by which the cell morphology changes (eg, increases in size) consistent with a proliferation signal.

[0347] As used herein, the terms "co-administration", "combination administration", and grammatical equivalents thereof encompass 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 simultaneous administration in the form of separate compositions, administration at different times in the form of separate compositions, or administration in a composition in which both agents are present at the same time.

[0348] The term "effective amount" or "therapeutically effective amount" refers to the amount of the compound described herein that is sufficient to affect the intended application, including but not limited to the treatment of diseases as defined below. The therapeutically effective amount can vary depending on the intended application (in vitro or in vivo) or the subject to be treated and the condition (e.g., the weight and age of the subject, the severity of the condition, the mode of administration, etc.) that can be easily determined by a person of ordinary skill in the art. The term is also applicable to doses that will induce a specific response in target cells, for example, a reduction in platelet adhesion and / or cell migration. The specific dose will vary depending on the specific compound selected, the dosing regimen followed, whether it is administered in combination with other compounds, the timing of administration, the administration tissue, and the physical delivery system in which it is carried. In one embodiment, the amount of the compound administered is in the range of 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.

[0349] As used herein, "treatment," "treating," or "ameliorating" refers to an approach to obtaining a beneficial or desired result, including but not limited to a therapeutic benefit and / or a prophylactic benefit. "Therapeutic benefit" refers to the eradication or amelioration of the underlying condition being treated. Additionally, a therapeutic benefit is also achieved by eradication or amelioration of one or more physiological symptoms associated with the underlying condition, such that an improvement is observed in the patient, even though the patient may still be suffering from the underlying condition. For a prophylactic benefit, the composition may be administered to a patient at risk for a particular disease, or to a patient reporting one or more physiological symptoms of a disease, even though a diagnosis of the disease may not have been made. These terms are used interchangeably.

[0350] As used herein, the term "therapeutic effect" encompasses therapeutic benefits and / or preventive benefits as described above. A preventive effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of a disease or condition, slowing, stopping or reversing the progression of a disease or condition, or any combination thereof.

[0351] As used herein, an amount of a compound effective for treating a disorder, or "therapeutically effective amount" refers to an amount of the compound effective in curing, alleviating, relieving or ameliorating one or more symptoms of a disorder after single or multiple administrations to a subject or cell.

[0352] As used herein, an amount of a compound effective for preventing a disorder, or a "prophylactically effective amount" of a compound refers to an amount effective in preventing or delaying the onset or recurrence of a disorder or one or more symptoms of a disorder after single or multiple administrations to a subject.

[0353] As used herein, the term "subject" or "patient" is intended to include humans and non-human animals. Exemplary human subjects include human patients suffering from disorders, such as those described herein, or normal subjects. The term "non-human animals" of the present invention includes all vertebrates, for example, non-mammals (such as chickens, amphibians, reptiles) and mammals, such as non-human primates, domesticated and / or agriculturally useful animals, for example, sheep, cattle, pigs, etc., and companion animals (dogs, cats, horses, etc.).

[0354] The methods described herein can be used for both human therapeutics and veterinary applications (e.g., dogs, cats, cattle, sheep, pigs, horses, goats, chickens, turkeys, ducks, and geese).

[0355] In some embodiments, the patient is a mammal, and in some embodiments, the patient is a human.

[0356] "Radiation therapy" means exposing a patient to radiation emitters, such as 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, including but not limited to x-rays, gamma rays, and neutrons, using conventional methods and compositions known to practitioners.

[0357] 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, controlled release matrices, colorants / flavoring agents, carriers, buffers, stabilizers, solubilizers or other materials mixed with the active ingredient and combinations thereof to allow the formation of a pharmaceutical composition, i.e., a dosage form that can be administered to a patient. An example of such a carrier is a pharmaceutically acceptable oil commonly used for parenteral administration. Pharmaceutically acceptable carriers are well known in the art.

[0358] It should be understood that the substituents and substitution patterns on the compounds of the present invention can be selected by those of ordinary skill in the art to provide chemically stable compounds that can be easily synthesized by techniques known in the art and those methods listed below. Generally, whether or not there is the term "optionally" in front, the term "substituted" means that one or more hydrogens of the specified part are replaced by suitable substituents. Unless otherwise specified, the "optionally substituted" group can have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure can be substituted by more than one substituent selected from a specified group, at each position, the substituent may be the same or different. Alternatively, the "optionally substituted group" may be unsubstituted.

[0359] The combination of substituents contemplated by the present invention is preferably a combination of those substituents that form stable or chemically feasible compounds. If the substituent itself is substituted with more than one group, it should be understood that these multiple groups can be on the same carbon atom or on different carbon atoms, as long as a stable structure is produced. As used herein, the term "stable" refers to a compound that does not substantially change when subjected to conditions that allow it to be produced, detected, and in certain embodiments recovered, purified, and used for one or more of the purposes disclosed herein.

[0360] As used herein, the term "pharmaceutically acceptable salt" refers to salts that are suitable for contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic response, etc. and commensurate with a reasonable benefit / risk ratio within the scope of reasonable medical judgment. 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, and the relevant teachings of the document are incorporated herein by reference in their entirety. Pharmaceutically acceptable salts of the compounds of the present invention include salts derived from suitable inorganic and organic acids and bases that are compatible with the treatment of the patient.

[0361] Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of an amino group formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid) or organic acids (e.g., acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid), or by using other methods used in the art (e.g., ion exchange). Other pharmaceutically acceptable acid addition salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, 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, valerate and the like.

[0362] In certain embodiments, the exemplary inorganic acid forming suitable salt includes but is not limited to hydrochloride, hydrobromide, sulfate and phosphate and acid metal salt, such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate. The illustrative organic acid forming suitable salt includes monocarboxylic acid, dicarboxylic acid and tricarboxylic acid. Illustrative such acid is such as 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 acid, such as methanesulfonic acid and 2-hydroxyethanesulfonic acid. Monoacid or diacid can be formed, or such salt can exist in hydration, solvation or substantially anhydrous form. Generally, the acid addition salts of these compounds are more soluble in water and various hydrophilic organic solvents, and compared with their free alkali form, usually show higher fusing point.

[0363] In some embodiments, acid addition salts of compounds of Formula A are most suitably formed from pharmaceutically acceptable acids and include, for example, acid addition salts formed from inorganic acids such as hydrochloric acid, sulfuric acid or phosphoric acid and organic acids such as succinic acid, malic acid, acetic acid or fumaric acid.

[0364] Other non-pharmaceutically acceptable salts, such as oxalates, can be used, for example, to isolate compounds of formula (A), (AI), (A-II) and (A-III) for laboratory use, or for subsequent conversion to pharmaceutically acceptable acid addition salts. 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 into a desired compound salt is accomplished by applying standard techniques well known to those skilled in the art.

[0365] "Anticancer", "anti-tumor agent" or "chemotherapeutic agent" refers to any agent useful for treating a neoplastic condition. One class of anti-cancer agents includes chemotherapeutic agents. "Chemotherapy" refers to the administration of one or more chemotherapeutic drugs and / or other agents to a cancer patient by various methods, including intravenous, oral, intramuscular, intraperitoneal, intravesical, subcutaneous, transdermal, buccal or inhaled or in the form of a suppository. The term "cell proliferation" refers to the phenomenon of a change in the number of cells due to division. The term also encompasses cell growth, by which the cell morphology changes (e.g., increases in size) consistent with a proliferation signal.

[0366] The term "selective inhibition" or "selectively inhibit" refers to the ability of a biologically active agent, ie, an agent, to preferentially reduce target signaling activity as compared to off-target signaling activity through direct or indirect interaction with the target.

[0367] "Optional" or "optionally" means that the subsequently described event or circumstances may or may not occur, and that the description includes instances where the event or circumstances occurs and instances where it does not occur. For example, "optionally substituted aryl" means that the aryl group may or may not be substituted, and that the description includes both substituted aryl groups and aryl groups that are not substituted.

[0368] "Pharmaceutical composition" refers to a formulation of a compound of the invention and a medium generally accepted in the art for delivering the biologically active compound to a mammal (e.g., a human). Such a medium therefore includes all its pharmaceutically acceptable carriers, diluents, or excipients.

[0369] When introducing elements disclosed herein, the articles "a," "an," "the," and "said" are intended to mean that there are one or more of the elements. The terms "comprising," "having," and "including" are intended to be open ended and mean that there may be additional elements other than the listed elements.

[0370] For example, provided herein are methods for treating various cancers of mammals (including humans and non-humans), the methods comprising administering a compound of the present invention or a pharmaceutically acceptable salt thereof to a patient in need thereof. Such cancers include hematological malignancies (leukemias, lymphomas, myeloproliferative disorders, and myeloproliferative syndromes) and solid tumors (cancers, such as oral cancer, gallbladder cancer, prostate cancer, breast cancer, lung cancer, colon cancer, pancreatic cancer, kidney cancer, ovarian cancer, and soft tissue and bone sarcomas and stromal tumors).

[0371] Pharmaceutical composition

[0372] The present invention provides a pharmaceutical composition comprising one or more compounds of the present invention. The pharmaceutical composition may contain one or more additional active ingredients as described herein. The pharmaceutical composition may be administered for any condition described herein.

[0373] The subject pharmaceutical composition is usually formulated to provide a therapeutically effective amount of the compound of the present invention as an active ingredient. Where necessary, the pharmaceutical composition contains the compound of the present invention as an active ingredient and one or more pharmaceutically 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.

[0374] Pharmaceutical compositions of the present disclosure can be used alone or in combination with one or more other medicaments, which are also usually used in the form of pharmaceutical compositions. When necessary, the subject compound and one or more other medicaments can be mixed into preparations, or two components can be formulated into independent preparations for use alone or in combination.

[0375] The methods comprise administering a compound of the invention, alone or in combination as described herein, and in each case optionally comprising one or more suitable diluents, fillers, salts, disintegrants, binders, lubricants, viscosity enhancers, wetting agents, controlled release matrices, colorants / flavoring agents, carriers, excipients, buffers, stabilizers, solubilizers, and combinations thereof.

[0376] The formulation of various pharmaceutical compositions is known in the art, for example, Anderson, Philip O.; Knoben, James E.; Troutman, William G, eds., Handbook of Clinical Drug Data, 10th ed., McGraw-Hill, 2002; Pratt and Taylor, eds., Principles of Drug Action, 3rd ed., Churchill Livingston, New York, 1990; Katzung, ed., Basic and Clinical Pharmacology, 9th ed., McGraw-Hill, 2003; Goodman and Gilman, eds., The Pharmacological Basis of Therapeutics, 10th ed., McGraw-Hill, 2001; Remingtons Pharmaceutical Sciences, 1996. Sciences, 20th ed., Lippincott Williams & Wilkins., 2000; Martindale, The Extra Pharmacopoeia, 32nd ed. (The Pharmaceutical Press, London, 1999), all of which are incorporated herein by reference in their entirety.

[0377] The compound or pharmaceutical composition of the present invention can be administered by any route capable of delivering the compound to the site of action, such as oral route, intraduodenal route, parenteral injection (including intravenous, intraarterial, subcutaneous, intramuscular, intravascular, intraperitoneal or infusion), topical administration (e.g., transdermal administration), rectal administration, local delivery by catheter or stent or by inhalation. The compound can also be administered intrafatally or intrathecally.

[0378] The composition can be administered in solid, semisolid, liquid or gaseous form, or can be a dry powder, such as lyophilized form. The pharmaceutical composition can be packaged in a form that is convenient for delivery, including, for example, solid dosage forms, such as capsules, pouches, medicine bags, gelatin, papers, tablets, capsules, suppositories, pills, pills, lozenges and lozenges. The type of packaging will generally depend on the desired route of administration. Implantable sustained-release formulations are also contemplated as transdermal formulations.

[0379] Treatment

[0380] In another aspect, the present invention provides a compound of the present invention, its pharmaceutically acceptable salt use, for preparing a medicament for treating cancer. In some embodiments, the present invention provides a compound of the present invention use, for preparing a medicament for treating any cancer and / or neoplastic condition.

[0381] The compounds or compositions described herein can be used to treat neoplastic conditions. "Neoplastic conditions" are diseases or conditions characterized by cells with autonomous growth or replication capabilities, such as abnormal states or conditions characterized by proliferative cell growth. Exemplary neoplastic conditions include, but are not limited to, cancer; sarcomas; metastatic conditions; solid tumors, such as oral, gallbladder, prostate, breast, lung, colon, pancreas, kidney, ovary, and soft tissue and osteosarcomas; and stromal tumors, such as tumors of prostate, brain, bone, colon, pancreas, lung, breast, ovary, and liver origin; hematopoietic neoplastic conditions, such as leukemia, lymphoma, myeloma, myelodysplasia, myeloproliferative syndrome, and other malignant plasma cell conditions; 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 a compound can improve at least one symptom of a neoplastic condition in an effective amount, such as reducing cell proliferation, reducing tumor mass, and the like.

[0382] The disclosed methods can be used to prevent and treat cancers, including, for example, solid tumors, soft tissue tumors and their metastases, and familial cancer syndromes, such as Li-Fraumeni Syndrome, familial breast-ovarian cancer (BRCA1 or BRAC2 mutation) syndrome, etc. The disclosed methods can also be used to treat non-solid cancers. Exemplary solid tumors include malignant tumors (e.g., sarcomas, adenocarcinomas, and carcinomas) of various organ systems, such as lung, breast, lymph, gastrointestinal tract (e.g., colon) and urogenital tract (e.g., kidney, urothelial or testicular tumors), pharynx, prostate, and ovarian malignancies. Exemplary adenocarcinomas include colorectal cancer, renal cell carcinoma, liver cancer, non-small cell lung cancer, and small intestinal cancer.

[0383] Exemplary cancers include, but are not limited to, tumors such as lung cancer, prostate cancer, breast cancer, brain cancer, skin cancer, cervical cancer, testicular cancer, etc. More specifically, cancers that can be treated by the compositions and methods of the present invention include, but are not limited to, the following tumor types, such as astrocytic carcinoma, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, esophageal cancer, gastric cancer, head and neck cancer, hepatocellular carcinoma, laryngeal cancer, lung cancer, oral cancer, ovarian cancer, prostate cancer and thyroid cancer, as well as sarcomas. More specifically, these compounds can be used to treat: cardiac cancer: sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyosarcoma, fibroma, lipoma and teratoma; lung cancer: bronchial cancer (squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; gastrointestinal cancer: esophageal cancer (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), gastric cancer (carcinoma, lymphoma, leiomyosarcoma), pancreatic cancer (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vasodilatory peptide tumor), small intestine cancer (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma (Kaposi's Cancers of the genitourinary tract: renal cancer (adenocarcinoma, Wilms' tumor, lymphoma, leukemia); bladder and urethra cancer (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma); prostate cancer (adenocarcinoma, sarcoma); testicular cancer (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma); liver cancer: hepatocellular carcinoma (hepatoma / hepatocellular carcinoma), bile duct cancer, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; biliary cancer: gallbladder cancer, ampullary cancer, bile duct cancer; bone cancer: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticular cell sarcoma), multiple myeloma, malignant giant cell tumor, chordoma, osteochondroma (osteocartilaginous exostosis), benign enchondroma, chondroblast tumors, chondromyxoid fibroma, osteoid osteoma and giant cell tumor; nervous system cancer: skull cancer (osteoma, hemangioma, granuloma, xanthomas, osteitis deformans), meningeal cancer (meningioma, meningiosarcoma, glioma), brain cancer (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pinealoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal neurofibroma, meningioma, glioma, sarcoma);Gynecological cancers: uterine cancer (endometrial cancer), cervical cancer (cervical cancer, preneoplastic cervical atypical hyperplasia), ovarian cancer (ovarian cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa cell tumor, Sertoli-Leydig cell tumor Tumor, dysgerminoma, malignant teratoma), vulvar cancer (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vaginal cancer (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tube cancer (carcinoma); blood cancer: blood cancer (myeloid leukemia (acute and chronic), acute lymphocytic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); skin cancer: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and adrenal cancer: neuroblastoma.

[0384] Further preferably, the present invention provides a method for inhibiting KRAS activity in cells, comprising contacting the cells in which KRAS activity is desired to be inhibited with an effective amount of a compound of formula (A), (AI), (A-II) and (A-III), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the compound or a pharmaceutically acceptable salt thereof.

[0385] Further preferably, the present invention provides a method for inhibiting KRAS G12C activity in cells, comprising contacting the cells in which KRAS G12C activity is desired to be inhibited with an effective amount of a compound of formula (A), (AI), (A-II) and (A-III), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the compound or a pharmaceutically acceptable salt thereof.

[0386] In one embodiment, a cell in which inhibition of KRAS G12C activity is desired is contacted with an effective amount of a compound of Formula (A), (AI), (A-II) and (A-III) to negatively regulate the activity of KRAS G12C.

[0387] It is further preferred that a therapeutically effective amount of a pharmaceutically acceptable salt or a pharmaceutical composition containing a compound of formula (A), (AI), (A-II) and (A-III) can be used.

[0388] By negatively regulating the activity of KRAS G12C, the methods described herein are designed to inhibit undesirable cell proliferation caused by enhanced KRAS G12C activity within cells. Depending on the particular treatment regimen, cells may be contacted with a single dose or multiple doses to achieve the desired negative regulation of KRAS G12C.

[0389] It is further preferred to provide a method for treating cancer in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of formula (A), (AI), (A-II) and (A-III), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof.

[0390] Provided herein are compositions and methods that can be used to treat KRAS-related cancers in patients in need thereof, the methods comprising administering to the patient a therapeutically effective amount of a compound of formula (A), (AI), (A-II) and (A-III), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof. In one embodiment, the KRAS G12C-related cancer is lung cancer.

[0391] Provided herein are compositions and methods that can be used to treat KRAS G12C-related cancers in patients in need thereof, the methods comprising administering to the patient a therapeutically effective amount of a compound of formula (A), (AI), (A-II) and (A-III), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof. In one embodiment, the KRAS G12C-related cancer is lung cancer.

[0392] The compositions and methods provided herein can be used to treat a variety of cancers, including but not limited to tumors, such as lung cancer, prostate cancer, breast cancer, brain cancer, skin cancer, cervical cancer, testicular cancer, etc. More specifically, cancers that can be treated by the compositions and methods of the present invention include but are not limited to the following tumor types, such as astrocytic carcinoma, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, esophageal cancer, gastric cancer, head and neck cancer, hepatocellular carcinoma, laryngeal cancer, lung cancer, oral cancer, ovarian cancer, prostate cancer and thyroid cancer, as well as sarcomas. More specifically, these compounds can be used to treat: cardiac cancer: sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyosarcoma, fibroma, lipoma and teratoma; lung cancer: bronchial cancer (squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; gastrointestinal cancer: esophageal cancer (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), gastric cancer (carcinoma, lymphoma, leiomyosarcoma), pancreatic cancer (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vasodilatory peptide tumor), small intestine cancer (adenocarcinoma, Lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), colorectal cancer (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); genitourinary tract cancer: kidney cancer (adenocarcinoma, Wilms' tumor (Nephroblastoma), lymphoma, leukemia), bladder and urethra cancer (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate cancer (adenocarcinoma, sarcoma), testicular cancer (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatoid tumor, lipoma); liver cancer: hepatocellular carcinoma (hepatoma / hepatocellular carcinoma), bile duct cancer, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; biliary cancer: gallbladder cancer, ampullary cancer, bile duct cancer; bone cancer: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticular cell sarcoma), multiple myeloma, malignant giant cell tumor, chordoma, osteochondroma (osteocartilaginous exostosis), benign enchondroma, chondroblastoma, chondromyxoid fibroma Nervous system cancer: skull cancer (osteomas, hemangiomas, granulomas, xanthomas, osteitis deformans), meningeal cancer (meningioma, meningeal sarcoma, glioma), brain cancer (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pinealoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal neurofibroma, meningioma, glioma, sarcoma);Gynecological cancers: uterine cancer (endometrial cancer), cervical cancer (cervical cancer, preneoplastic cervical atypical hyperplasia), ovarian cancer (ovarian cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa cell tumor, Severe-Lyssen cell tumor, dysgerminoma, malignant teratoma), vulvar cancer (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vaginal cancer (clear cell carcinoma, squamous cell carcinoma, grape-like sarcoma (embryonal rhabdomyosarcoma), fallopian tube cancer (carcinoma); blood Blood cancers: Blood cancers (myeloid leukemia (acute and chronic), acute lymphocytic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); Skin cancers: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and Adrenal gland cancers: neuroblastoma. ;

[0393] It is further preferred that the cancer is non-small cell lung cancer, colorectal cancer or pancreatic cancer.

[0394] It is further preferred that the cancer is lung cancer or colorectal cancer.

[0395] The concentration and route of administration to the patient will vary depending on the cancer to be treated. The compounds, their pharmaceutically acceptable salts, and pharmaceutical compositions comprising such compounds and salts may also be co-administered with other anti-tumor compounds, such as chemotherapy, or used in combination with other treatments, such as other targeted agents or radiation or surgical interventions, as a pre- or post-operative adjuvant.

[0396] The present invention further provides herein a compound of formula (A), (AI), (A-II) and (A-III) as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof, for use in therapy.

[0397] The present invention further provides a compound of formula (A), (AI), (A-II) and (A-III) as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof, for use in treating cancer.

[0398] The present invention further provides a compound of formula (A), (AI), (A-II) and (A-III), or a pharmaceutically acceptable salt or solvate thereof, for use in inhibiting KRAS G12C.

[0399] The present invention further provides a compound of formula (A), (AI), (A-II) and (A-III) as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof, for use in treating a KRAS G12C-related disease or condition.

[0400] The present invention further provides herein the use of a compound of formula (A), (AI), (A-II) and (A-III) as defined herein, or a pharmaceutically acceptable salt or solvate thereof, for the preparation of a medicament for the treatment of cancer.

[0401] The present invention further provides herein a use of a compound of formula (A), (AI), (A-II) and (A-III) as defined herein, or a pharmaceutically acceptable salt or solvate thereof, for preparing a medicament for inhibiting the activity of KRAS G12C.

[0402] The present invention further provides herein a use of a compound of formula (A), (AI), (A-II) and (A-III) as defined herein, or a pharmaceutically acceptable salt or solvate thereof, for the preparation of a medicament for treating a KRAS G12C-related disease or condition.

[0403] The present invention further provides herein 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., as determined using an assay or kit approved by a regulatory agency, such as an FDA-approved assay); and (b) administering to the patient a therapeutically effective amount of a compound of Formula (A), (AI), (A-II) and (A-III), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0404] Metastasis of the above cancers can also be treated or prevented according to the methods described herein.

[0405] Combination therapy

[0406] In some embodiments, the compounds described herein are administered together with an additional "second" therapeutic agent or treatment. The selection of the second therapeutic agent can be made by any agent that is typically used in a monotherapy to treat the indicated disease or condition. As used herein, the term "administered together" and related terms refer to the simultaneous or sequential administration of therapeutic agents according to the present invention. For example, the compounds of the present invention can be administered simultaneously or sequentially with another therapeutic agent in a separate unit dosage form or administered together in a single unit dosage form. Therefore, the present invention provides a single unit dosage form, the dosage form comprising a compound of any formula described herein, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant or vehicle.

[0407] In one embodiment of the invention, when a second therapeutic agent is administered to a subject, the effective amount of the compound of the invention is less than the effective amount of the compound when the second therapeutic agent is not administered. In another embodiment, the effective amount of the second therapeutic agent is less than the effective amount of the second therapeutic agent when the compound of the invention is not administered. In this way, the undesirable side effects associated with a high dose of any medicament 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. As part of a multiple dose regimen, additional medicaments can be administered separately from the compound of the invention. Alternatively, those medicaments can be part of a single dosage form, which is mixed in a single composition together with the compound of the invention.

[0408] The compounds, their pharmaceutically acceptable salts, and pharmaceutical compositions comprising such compounds and salts may also be co-administered with other anti-tumor compounds, such as chemotherapy, or used in combination with other treatments, such as with other targeted agents or radiation or surgical intervention, as an adjunct before or after surgery.

[0409] The compounds, pharmaceutically acceptable salts thereof, and pharmaceutical compositions comprising such compounds include the step of simultaneously or sequentially administering to a subject in need thereof at least one other anticancer agent, anti-inflammatory agent, immunosuppressant, steroid, nonsteroidal anti-inflammatory agent, antihistamine, analgesic, or mixtures thereof.

[0410] Process for preparing the compounds of the present invention

[0411] The compounds of the invention of the present invention can be prepared by the following general methods. The methods provided herein can be similarly applied to the synthesis of all possible variants of the compounds of the present invention, and specifically the compounds of formula (A), (AI), (A-II) and (A-III) as provided above with all intended modifications or without any modifications. Unless otherwise indicated, the variables used herein in various intermediates or compounds of formula, such as R, R a , R 1 、A1、A2、Cy 1 , Cy 2 and E shall be constructed as the variables defined above with respect to the compounds of the present invention, and specifically with respect to compounds of formula (A), (AI), (A-II) and (A-III).

[0412] Synthetic Scheme A: This schematic representation of the scheme is intended to provide a possible route for preparing compounds of formula (A), (AI), (A-II) and (A-III).

[0413]

[0414] An intermediate of formula (A1), wherein Pg is a suitable protecting group when reacting with an intermediate of formula R-CH2-CONH2, using a suitable base or reagent to obtain an intermediate of formula (A2). The intermediate of formula (A2) can then be chlorinated using POCl3 to obtain an intermediate of formula (A3), which reacts with an intermediate of formula Lg-A2-Cy 2 The intermediate f of formula (A4) can be reacted with a suitable base, wherein Lg is a good leaving group, to obtain an intermediate of formula (A4). The intermediate of formula (A4) can then be reacted with a compound of formula Lg-R 1 The intermediate of formula (A5) is coupled with an intermediate of formula (A5), wherein Lg is a good leaving group, using a suitable base to obtain an intermediate of formula (A5). The intermediate (A5) can then be deprotected and subsequently reacted with the group Lg-A1-Cy under suitable conditions. 1 Coupling, such as bukward coupling or other suitable N-alkylation or N-arylation, provides the desired compound of formula (A).

[0415] A. The protocol of Example 1 provides the following illustrative use of protocol A:

[0416]

[0417] B. The following scheme provides yet another illustrative use of Scheme A to prepare compounds of the present invention.

[0418]

[0419] C. The following scheme provides yet another illustrative use of Scheme A to prepare compounds of the present invention.

[0420]

[0421] Experimental details

[0422] The examples and formulations provided below further illustrate and exemplify the compounds of the present invention and methods for preparing such compounds. It should be understood that the scope of the present invention is not limited in any way by the scope of the following examples and formulations. In the following examples, unless otherwise stated, molecules with a single chiral center exist as a racemic mixture. Unless otherwise stated, those molecules with two or more chiral centers exist as a racemic mixture of diastereomers. Single enantiomers / diastereomers can be obtained by methods known to those skilled in the art.

[0423] Part-A: Preparation of intermediates

[0424] Intermediate 1: (1-benzyl-3-oxopiperidine-4-carboxylic acid ethyl ester) In a reaction flask, (26g, 80.00mmol) of 4-(benzyl(2-methoxy-2-oxoethyl)amino)butyric acid ethyl ester and (11g, 160mmol) of sodium ethoxide were added to 260mL of toluene, and the reaction was heated to reflux for 5 hours. TLC monitored the complete reaction of the raw materials, and the reaction solution was cooled to room temperature, 150mL of water was added, and the reaction was extracted twice with 250mL of ethyl acetate to obtain an organic phase. The organic phase was washed with a certain amount of saturated saline solution, and the organic phase was distilled to obtain 14g of an oily compound. MS (m / z): 262.24 [M+H] + .

[0425] Intermediate 2: 6-Benzyl-1,3-dioxo-1,2,3,4,5,6,7,8-octahydro-2,6-naphthyridine-4-carbonitrile: In a 2-necked flask equipped with a mechanical stirrer and a condenser, intermediate 1 (14 g, 50.00 mmol) was placed 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 of KOH in 50 mL of MeOH). The resulting mixture was stirred and heated to reflux. After a few minutes, the product began to form 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). With the help of warm water (250 ml 55° C.), the white solid was transferred to a 1 L single-necked flask equipped with a mechanical stirrer. 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 in a hood overnight to give 10 g of the title compound. MS (m / z): 282.20 [M+H] + .

[0426] Intermediate 3: 6-Benzyl-1,3-dichloro-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile:

[0427] Method I: Intermediate 2 (5g, 10.00mmol) and phosphorus oxychloride (20mL). The container was sealed and heated at 180°C for 4 hours, and the reaction mixture was concentrated under reduced pressure. The residue was dissolved in dichloromethane (500ml) and added to a 1L 3-necked flask containing ice (about 45g) equipped with a mechanical stirrer. The resulting mixture was alkalized to pH=9-10 by adding approximately 50mL of 20% aqueous sodium hydroxide solution. During this addition, more ice was added to keep the internal temperature below 30°C. The mixture was stirred for 15 minutes and then filtered to remove the gel-type particles. The organic layer was separated, washed with brine (50mL), filtered through filter paper, and concentrated under reduced pressure. (1.5g), which is an oily substance that solidifies when standing. MS (m / z): 318.20 [M+H] + .

[0428] Method II: Intermediate 2 (20 gm g, 0.071 mol, salt-free), tetramethylammonium chloride (9.3 g, 0.085 mol) and phosphorus oxychloride (67 mL, 0.71 mol) were placed in a 500 mL sealed container and heated at 120° C. for 8 hours. The reaction was cooled to room temperature and the container was slowly opened. The reaction mixture was slowly poured into ice and the reaction mixture was stirred for 30 minutes. A saturated solution of NaOH was then slowly added to the cold and diluted RM to make it alkaline (pH=8-10) and the temperature was maintained below 40° C. A brown solid was formed and filtered on a filter bottle and dried within 2 hours to obtain 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] + .

[0429] Intermediate 4A: Benzyl-4-cyano-5,6,7,8-tetrahydro-2,6-naphthyridine-1,3-diyl bis(trifluoromethanesulfonate): Intermediate 2 (5 g, 0.01 mol) and 2,6-lutidine (5.9 g, 0.055 mol) were dissolved in DCM (200 ml) and cooled to 0°C under nitrogen atmosphere, then trifluoromethanesulfonic anhydride (10 g, 0.035) in DCM (25 ml) was added dropwise over a period of 20 minutes. The reaction was allowed to gradually warm to 25°C over a period of 2 hours. The reaction mixture was concentrated under vacuum and the resulting oil was dissolved in ethyl acetate and the organic layer was washed three times with 10% KHSO4 followed by brine and the organic layer was concentrated under vacuum. 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,CDCl3,400MHz):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] +

[0430] 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 carbamate piperidin-4-yl ester (0.5 g, 16 mmol) was dissolved in DMF (5 ml), followed by addition of potassium carbonate (0.54 g, 30 mmol) to the reaction mixture and stirring at room temperature for 10 minutes. Intermediate 3 (0.5 g, 10 mmol) was added to the reaction mixture and heated at 80 ° C for 20 minutes. The reaction was checked by TLC to be complete, and the reactants were 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 (0.3 g) compound that was used in the next step without analytical data.

[0431] 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 then dried over sodium sulphate. The organic layer was concentrated under reduced pressure to get the crude residue, which was purified by column chromatography using ethyl acetate: hexane (25%) to get 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] + .

[0432] 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. Intermediate 4A (2.7 gm, 0.0049 mol) in DCM (10 ml) was added dropwise to the reaction mixture. 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 another 12 hours. The reaction mixture was quenched with water, and the organic layer was separated and washed with brine and concentrated under vacuum to give an oily residue which was purified by column chromatography (100-200 mesh silica gel) using 30% ethyl acetate: hexanes to give Intermediate 9B (1.7 gm) as a white solid. 1H-NMR (δ ppm, CDCl3, 400 MHz): 7.38-7.33 (m, 5H), 4.6 2-4.60(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] + .

[0433] 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 to 1,4-dioxane (1000 ml) in a 4-neck 3 L RBF followed by the addition of DIPEA (144 mL, 0.75 mol) to 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 the formation of a new polar spot reaction mixture, it was cooled to room temperature and Boc-anhydride (98 mL, 0.45 mol) was added thereto and stirred at 55°C for 2 h. After the completion of the reaction, the RM 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 product was purified by column chromatography using petroleum ether containing 20-50% EtOAc 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 (δ ppm, CDCl3, 400 MHz): 7.35-7.34 (m, 4H), 7.31-7.29 (m, 1H), 4.59 (bs, 1H), 3.90 (bs, 1H), 3.83-3.68 (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] + .

[0434] 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 procedure 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] + .

[0435] Intermediate 5E: 6-Benzyl-4-cyano-1-(2,6-dimethylmorpholino)-5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl trifluoromethanesulfonate: Prepared using the procedure as described above for Intermediate 5A using 2,6-dimethylmorpholine (1.25 gm, 0.00688 mmmol) and Intermediate 4 (2.5 gm, 0.0045 mol) to give Intermediate 5E. MS (m / z): 510.95 [M+H] + .

[0436] 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 procedure 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] + ..

[0437] 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 procedure 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] + .

[0438] 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 procedure 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] + .

[0439] Intermediate 6: 1-(4-aminopiperidin-1-yl)-6-benzyl-3-chloro-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile: A solution of intermediate 5 (0.5 g) was dissolved in dioxane:HCl (10 ml) and the reaction mixture was stirred for 1 hour at 0° C. After completion of the reaction, 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.

[0440] Intermediate 6A1: tert-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, then 10% NaOH (5 ml) was added, and the mixture was stirred 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] + .

[0441] 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, then 10% NaOH (5 ml) was added and the mixture was stirred 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 6A2 (0.8 gm) as a brown solid. 1H-NMR (400 MHz) (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).

[0442] 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 (δ ppm, CDCl3, 400 MHz): 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]+.

[0443] Intermediate 6C: tert-Butyl 4-(6-benzyl-4-cyano-3-(1,1-dioxothiomorpholino)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)piperazine-1-carboxylate: Prepared using the procedure as described above for Intermediate 6B using thiomorpholine 1,1 dioxide (0.52 gm, 0.0051 mmol) and Intermediate 5B (1.5 gm, 0.0025 mol) to give Intermediate 6C (1.25 gm) as a white solid. H-NMR (δppm, CDCl3, 400MHz): 7.38-7.32(m,4H),7.31-7.30(m,1H),4.12-4.10(m,4H),3.76(m,4H),3.5 2-3.50(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] + .

[0444] 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 (δ ppm, CDCl3, 400 MHz): 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]+.

[0445] 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: Add H2O, K2CO3 (0.71 g, 0.0051 mol) and purge with N2 gas for 15 min. Add Tetrakis (0.13 g, 0.00012 mol) and purge with N2 gas again for 5 min. The reaction mixture was heated at 110°C for 2 h. The reaction mixture was cooled to room temperature and quenched with ice cold water and washed with (3X The crude residue was purified by column chromatography, eluting the compound in hexane containing 30% EA to afford intermediate 6E (0.2 gm) as a white solid. 1H-NMR (δ ppm, CDCl 3 , 400 MHz): 8.35-8.34 (m, 1H), 7.75-7.7 4(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]-.

[0446] 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 procedure 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 (δ ppm, CDCl3, 400 MHz): 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]+.

[0447] 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 the procedure as described above for Intermediate 6C using 2,6-dimorpholine (0.112 ml, 0.0012 mol) and Intermediate 5A (0.5 gm, 0.00086 mol) to give Intermediate 6G (0.4 gm). 1H-NMR (δ ppm, CDCl3, 400 MHz): 7.36-7.35 (m, 5H), 4.11-4.08 (m, 2H), 3.76-3.70 (m, 6H), 3.51-3.48 (m, 4H), 3.26-3.24 (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]+.

[0448] 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) was added DIPEA (1.29 ml, 0.0075 mmol) 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 a period of 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 afford intermediate 6H (1.2 gm). 1H-NMR (δ ppm, 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 )+ .

[0449] 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-carboxylic acid butyl ester: To a solution of piperazine (0.33 gm, 0.0028 mmol) in THF (15 ml) was added DIPEA (1.29 ml, 0.0075 mmol) and stirred at room temperature. To the above reaction mixture was added 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 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 a period of 10 minutes and stirred for 1 hour. The reaction mixture was quenched with water and extracted with ethyl acetate, the organic layer was washed with brine and dried over sodium sulfate, then evaporated to give a crude product, which was purified by column chromatography using ethyl acetate: hexane (25%) to give the desired compound (1.2 gm). 1H-NMR (δ ppm, 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 )+ .

[0450] 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) was added DIPEA (1.29 ml, 0.0075 mmol) and stirred at room temperature. To the reaction mixture was added 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 dropwise at the same temperature and heated at 80°C for 2 hours. The reaction was checked for completion 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 organic layer was separated and washed with brine. The organic layer was dried over sodium sulfate and evaporated to a crude product. The crude product was purified by column chromatography using ethyl acetate: hexane (25%) to give intermediate 6J (1.0 gm). 1H-NMR (δ ppm, CDCl3, 400 MHz): 7.38-7.32 (m, 4H), 7.30-7.28 (m, 1H), 3.76-3.70 (m, 6H), 3.60 (s, 4H), 3.56-3.54 (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 )+ .

[0451] Intermediate 7: 1-(4-aminopiperidin-1-yl)-6-benzyl-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile: 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) was dissolved in methanol (10 ml), triethylamine (20 ul) and Pd / C (0.35 g) and the reaction mixture was stirred at room temperature for 12 hours. After completion of the reaction, it was filtered through celite and the mixture was evaporated to get an oily compound (0.25 gm) which was used directly in the next step without analytical data.

[0452] 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 procedure 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 (δ ppm, CDCl3, 400 MHz): 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]+.

[0453] 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 the procedure described above for Intermediate 6C using tert-butyl piperazine-1-carboxylate (0.74 gm, 4.02 mmol) and Intermediate 5C (1.37 gm, 2.68 mmol) to give 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(m1H),2.60-2.58(t,2H),2.40-2.31(m,2H).,1.26(q,3H).MS(m / z):547.3(M+1).

[0454] 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 procedure 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).

[0455] Intermediate 7D: Di-tert-butyl 4,4'-(6-benzyl-4-cyano-5,6,7,8-tetrahydro-2,6-naphthyridine-1,3-diyl)bis(piperazine-1-carboxylate: 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 stirred at 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 under vacuum to give a crude residue which was purified by column chromatography using ethyl acetate: hexane (25%) to afford Intermediate 7D (1.25 gm). MS (m / z): 618.22 [M+H] + .

[0456] 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 procedure 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 )+ .

[0457] 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 procedure 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 (0.5 gm) as a white solid. MS (m / z): 546.23 (M+H )+ .

[0458] 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 procedure 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 )+ .

[0459] 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) was added NaH (60% in mineral oil) (213 mg, 0.0089 mmol) and stirred at 0°C for 20 minutes. 4(2-chloroethylmorpholine.HCl) (1.3 gm, 0.0071 mmol) was added slowly and the reaction mixture was stirred at 80°C for 3 hours. The reaction mixture was quenched with cold water (50 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with brine solution (30 mL), dried over Na2SO4 and evaporated under reduced pressure to get the crude product, which was purified by column chromatography using ethyl acetate and petroleum ether (50%) to afford 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 )+ .

[0460] 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 a solution of methanesulfonyl chloride (0.5 mL, 0.0064 mol) in DCM (12 mL) was added slowly to the above solution and the reaction mixture was stirred at room temperature for 2 hours. The reaction was checked for completion by TLC using 40% ethyl acetate and hexanes as mobile phase. The reaction mixture was quenched into cold water and the organic layer was separated. The aqueous layer was extracted with more DCM (20 mL X 2) and the combined organic layers were washed with brine solution (20 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure and temperature (30-35°C) to get a crude residue which was purified by column chromatography (100-200 mesh silica gel) using 20-40% ethyl acetate in hexane as mobile phase. The pure fractions were collected and concentrated to get Intermediate 9A (1.72 gm, 70.72%) as an off-white solid which was used for the next reaction.

[0461] 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 procedure 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).

[0462] 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. Pd(OAc)2 (0.096 gm, 0.43 mmol) was added to the above reaction mixture 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 a crude product which was purified by column chromatography using ethyl acetate and petroleum ether (30-100%) to afford 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),2.3 1-2.29 (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%.

[0463] 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:

[0464] Method A: Prepared using the method 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).

[0465] Method B: In a 500 mL sealed tube, (S)-(1-methylpyrrolidin-2-yl)methanol (6.2 gm, 0.054 mol) was added and the reaction mixture was subsequently stirred at 0°C by adding anhydrous THF (150 ml). NaH (60%) (1.74 gm, 0.072 mol) was added to the reaction mixture 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 anhydrous THF (120 mL), added dropwise to the reaction mixture and stirred at 85°C for 12 hours. After the reaction was complete, the RM 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 obtain a crude residue. The crude product was purified by column chromatography using 3% DCM: methanol as mobile phase. The pure fractions were collected and concentrated under reduced pressure to give intermediate 6 (14 g) as a light 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] + .

[0466] 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, ethanol (18 mL) containing Intermediate 6B (0.9 gm, 1.59 mmol) was purged with N2 gas for 20 minutes followed by the 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. The completion of the reaction was checked by TLC using MeOH:DCM (5%). After completion of the reaction, the mixture was filtered through a celite bed under inert atmosphere and the filtrate was evaporated under reduced pressure to get a crude residue which was purified by column chromatography using 5% MeOH in DCM as mobile phase. The 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).

[0467] Intermediate 12: tert-Butyl 4-(4-cyano-3-(1,1-dioxothiomorpholino)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)piperazine-1-carboxylate: Prepared using the procedure as described above for Intermediate 11 using Intermediate 6C (0.9 gm, 0.0015 mmol) to give Intermediate 12 (0.6 gm) as a white solid. 1H-NMR (δ ppm, CDCl3, 400 MHz): 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] + .

[0468] 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 the procedure as described above for Intermediate 11 using Intermediate 8 (1.0 gm, 0.0017 mmol) to give Intermediate 13 (0.3 gm). 1H-NMR (δ ppm, CDCl3, 400 MHz): 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] + .

[0469] 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 the procedure as described above for Intermediate 11 using Intermediate 7A (2.6 gm, 0.0044 mmol) to give Intermediate 14 (2.2 gm) as a white solid. 1H-NMR (δ ppm, CDCl3, 400 MHz): 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] + .

[0470] 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 procedure described above for Intermediate 11 using Intermediate 7A (1.2 gm, 2.19 mmol) to give Intermediate 15 (0.4 gm, 40%). 1H-NMR (400 MHz z): 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).

[0471] 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 the procedure as described above for Intermediate 11 using Intermediate 7B (2.3 gm, 3.91 mmol) to give Intermediate 16 (0.9 gm, 46.46%). MS: m / z; 496.3 (M+1).

[0472] 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 the procedure described above for Intermediate 11 using Intermediate 10A (1.2 gm, 2.19 mmol) to give Intermediate 17 (0.32 gm, 32.37%). MS (m / z): 457.2 (M+1).

[0473] 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 two-necked 500 mL RBF, Intermediate 10B (10 g, 0.017 mol) in ethanol (200 mL) was degassed with N2 for 20 min. To the above solution was then added methanolic ammonia solution (12 mL) followed by 6 gm Pd(OH)2 / C (20%). The entire RM was stirred at 70°C under an atmosphere of H2 gas for 24 h. The reaction was checked for completion by TLC using 5% MeOH in DCM and 1 drop of methanolic ammonia. After completion of the reaction, the mixture was filtered through a celite bed under inert atmosphere, and the filtrate was evaporated under reduced pressure to afford the desired product (7.3 gm) of intermediate 17 as a light yellow solid. 1H-NMR (400 MHz) (CDCl3): 4.81-4.78 (m, 1H), 4.61 (bs, 1H), 4.49-4.44 (m, 1H), 4.14-4.04 (m, 3 H),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).

[0474] Intermediate 18A: Di-tert-butyl 4,4'-(4-cyano-5,6,7,8-tetrahydro-2,6-naphthyridine-1,3-diyl)bis(piperazine-1-carboxylate: To a solution of Intermediate 7D (1.0 gm, 0.001 mol) in ethanol was purged with nitrogen for 20 minutes and then 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 through a pad of celite and the filtrate was evaporated under reduced pressure to get the crude product. The crude product was purified by column chromatography using methanol: DCM (10%) to give intermediate 26 (0.4 gm) as a white solid. 1H-NMR (δ ppm, CDCl3, 400 MHz): 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] + .

[0475] 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 the procedure as described above for Intermediate 18A using Intermediate 6D (1.0 gm, 0.001 mol) to give Intermediate 18B (0.4 gm) as a white solid. 1H-NMR (δ ppm, CDCl3, 40 0MHz):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]+.

[0476] 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 the procedure as described above for Intermediate 18A using Intermediate 6F (0.6 gm, 0.0011 mol) to give Intermediate 18C as a white solid (0.4 gm). MS (m / z): 428.45 [M+H]+.

[0477] 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 procedure as described above for Intermediate 18A using Intermediate 6G (0.8 gm, 0.0018 mmol) to give Intermediate 18D (0.6 gm). 1H-NMR (δ ppm, CDCl3, 400 MHz): 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] + .

[0478] 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 the procedure as described above for Intermediate 18A using Intermediate 6H (1.0 gm, 0.0017 mmol) to give Intermediate 18E (0.6 gm) as a white solid. MS (m / z): 484.12 [M+H] + .

[0479] 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 the procedure as described above for Intermediate 18A using Intermediate 6I (1.0 gm, 0.0017 mol) to give Intermediate 18F (0.6 gm) as a white solid. 1H-NMR (δ ppm, CDCl3, 400 MHz): 4.113 (s, 2H), 3.68-3.66 (m, 4H), 3.54-3.51 (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] + .

[0480] 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 the procedure as described above for Intermediate 26 using Intermediate 6J (0.8 gm, 0.0017 mmol) to give Intermediate 18G (0.6 gm) as a white solid. 1H-NMR (δ ppm, CDCl3, 400 MHz): 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] + .

[0481] Intermediate 18H: tert-Butyl 4-(4-cyano-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)piperazine-1-carboxylate: Prepared using the procedure described above for Intermediate 11 using Intermediate 5H (0.7 gm, 0.0015 mol) to give Intermediate 18H (0.4 gm). 344.20 [M+H] + .

[0482] 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 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 a period of 10 minutes and stirred under nitrogen atmosphere. Then Pd2(dba)3 (0.068 gm, 0.000075 mmol) was added to the reaction mixture 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 afford 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).

[0483] Intermediate 19B: tert-Butyl 4-(4-cyano-3-(1,1-dioxothiomorpholino)-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)piperazine-1-carboxylate: Prepared using the procedure described above for Intermediate 19A using Intermediate 12 to give Intermediate 19B as a white solid (0.22 gm, 43.45%). 1H-NMR (400 MHz): δ 8.20-8.18 (m, 1H)), 7.89-7.87 (m, 1 H),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,1H),4.40(bs,2H),4.18-4.1 5(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).

[0484] 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: Prepared using the procedure as described above for Intermediate 19A using Intermediate 14 (1 g, 0.0020 mmol), 1-bromonaphthalene (0.59 ml, 0.004 mmol), cesium carbonate (1.97 gm, 0.0066 mmol), Ruphos (0.18 gm, 0.0004 mmol) and Pd2(dba)3 (0.184 gm, 0.000022 mmol) with toluene as solvent at 110°C for 3 hours to afford Intermediate 19C (0.9 gm) as a white solid. H-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),2.89- 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]+.

[0485] 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: Prepared using the procedure as described above for Intermediate 19A using Intermediate 13 (0.3 gm, 0.00063 mmol), 1-bromonaphthalene (0.18 mL, 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) with toluene as solvent and at 110°C for 4 hours to give Intermediate 19D (0.25 gm, 18.17%) was obtained as a white solid. 1H-NMR (400 MHz): δ 8.20-8.17 (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)

[0486] 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 the procedure as described above for Intermediate 19A 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) with toluene as solvent and at 110°C for 4 hours to afford Intermediate 19E (0.2 5gm, 18.17%).1H-NMR (400MHz): δ7.78-7.75(m,1H),7.65-7.63(m,1H),7.54-7.52( m,1H),7.47-7.23(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)

[0487] Intermediate 19F: (tert-butyl 4-(4-cyano-1-(2,6-dimethylmorpholino)-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)piperazine-1-carboxylate): Prepared using the procedure as described above for Intermediate 19A using Intermediate 16 (0.4 gm, 0.88 mmol), 1-bromonaphthalene (0.25 mL, 1.75 mmol), xantphos (0.1 gm, 0.17 mmol), Cs2CO3 (0.86 gm, 2.63 mmol) and Pd2(dba)3 with toluene as solvent at 110°C for 4 hours to give Intermediate 19E (0.32 gm, 63.7%). 1H-NMR (400 M Hz): δ8.22-8.20(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),7.20-7.18(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),2.7 2-2.62(m,2H),1.42(s,9H),1.28(s,3H),1.26(s,3H).MS(m / z):583.3(M+1).

[0488] 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): Using the procedure described above for Intermediate 19A, using Intermediate 16 (0.88 gm, 1.78 mmol), 1-bromonaphthalene (0.53 mL, 3.56 mmol) ), xantphos (0.2 gm, 0.36 mmol), Cs2CO3 (1.72 gm, 5.34 mmol) and Pd2(dba)3 (0.16 gm, 0.18 mmol) with toluene as solvent and at 110°C for 4 hours to give intermediate 19F (0.2 gm, 18.17%) as a white solid. MS (m / z): 622.3 (M+1)

[0489] 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 the procedure as described above for Intermediate 19A using Intermediate 17 (0.32 gm, 0.71 mmol), 1-bromonaphthalene (0.21 mL, 1.42 mmol), RuPhos (0.066 gm, 0.14 mmol), Cs2CO3 (0.7 gm, 2.13 mmol) and Pd2(dba)3 (0.064 gm, 0.071 mmol) with toluene as solvent and at 110°C for 3 hours to give 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),7.53-7.48(m,2 H),7.46-7.41(m,1H),7.19-7.17(m,1H),4.40-3.70(m,4H),3.67(bs,4H),3.30-3.1 2(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).

[0490] 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 Cs2CO3 (13.8 gm, 0.042 mol) were degassed with N2 in toluene (140 mL) for 20 min. Then Pd2(dba)3 (1.3 gm, 0.0014 mol) was added to the above solution and the whole RM was stirred at 120°C for 12 h. Use DCM containing 5%MeOH and 1 drop of methanolic ammonia to check reaction completion by TLC.After reaction is completed, reaction mixture is poured in cold water (20mL) and extracted with ethyl acetate (30mL × 2).Organic layer is washed with saline solution (10mL), through Na SO Dry and evaporate under reduced pressure, to obtain thick residue, described residue is used DCM containing 3%MeOH as mobile phase to carry out purification by column chromatography (100-200 mesh silica gel). The pure fractions were collected and concentrated to afford intermediate 19I (7.26 gm) as the desired product. 1H-NMR (400 MHz) (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),2.33-2.31(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%.

[0491] 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: Using the procedure described above for Intermediate 19A, Intermediate 18 (1.4 gm, 0.0028 mol), 3-(benzyloxy)-1-bromonaphthalene (1.77 gm, 0.003 mol) was added. m, 0.0056mol), Xantphos (0.32gm, 0.00056mol), Cs2CO3 (2.7gm, 0.0084mol), toluene (20mL) and Pd2(dba)3 (0.26gm, 0.00028mol) were prepared to obtain the desired product of Intermediate 19J (1gm, 49.06%). MS (m / z): 728.5 (M+1). HPLC: 80.75%.

[0492] Intermediate 19K: Di-tert-butyl 4,4'-(4-cyano-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-1,3-diyl)bis(piperazine-1-carboxylate: To a solution of Intermediate 18A (0.4 g, 0.00075 mmol) in 1,4-dioxane (10 ml) purged under nitrogen for 20 minutes, 1-bromonaphthalene (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 a period of 10 minutes and stirred under nitrogen atmosphere. Pd2(dba)3 (0.068 gm, 0.000075 mmol) was then added to the reaction mixture 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 afford Intermediate 19K (0.34 gm). 1H-NMR (δ ppm, CDCl3, 400 MHz): 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] + .

[0493] Intermediate 19L B: Di-tert-butyl 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: Prepared using the procedure 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) to give Intermediate 19L (0.3 gm). 1H-NMR (δ ppm, 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] + .

[0494] 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 using the procedure as described above for Intermediate 19K using Intermediate 18B (0.4 g, 0.009 mmol), 1-bromonaphthalene (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) to give Intermediate 19M (0.34 gm). 1H-NMR ( δppm, CDCl3, 400MHz):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]+.

[0495] 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 procedure as described above for Intermediate 19K using Intermediate 18C (0.27 g, 0.0006 mmol), 1-bromonaphthalene (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 (0.34gm).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]+.

[0496] 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 procedure as described above for Intermediate 19K using Intermediate 18D (0.5 g, 0.0010 mmol), 1-bromonaphthalene (0.25 ml, 0.0020 mmol), sodium tert-butoxide (0.38 gm, 0.004 mol), r-BINAP (0.12 gm, 0.0002 mol) and Pd2(dba)3 (0.09 gm, 0.00001 mol) to give Intermediate 19O (0.4 gm). 1H-NMR (δ ppm, C DCl3,400MHz):8.21-8.19(m,1H),7.87-7.85(m,1H),7.62-7.60(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(b s,2H),2.74-2.68(m,1H)1.54(s,9H),1.25(s,6H).MS(m / z):584.12[M+H]+.

[0497] 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 procedure as described above for Intermediate 19K using Intermediate 18E (0.5 g, 0.0010 mmol), 1-bromonaphthalene (0.25 ml, 0.0020 mmol), sodium tert-butoxide (0.38 gm, 0.004 mmol), r-BINAP (0.12 gm, 0.0002 mol) and Pd2(dba)3 (0.09 gm, 0.00001 mol) to give Intermediate 19P (0.4 gm). 1H-NMR (δpp m, 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]+.

[0498] 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: Prepared using the procedure as described above for Intermediate 19K using Intermediate 18F (0.6 g, 0.0011 mmol), 1-bromonaphthalene (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 19Q (0.4gm).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 .19-7.17(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).

[0499] 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 procedure as described above for Intermediate 19K using Intermediate 18G (0.6 g, 0.0011 mmol), 1-bromonaphthalene (0.5 ml, 0.0022 mmol), sodium tert-butoxide (0.42 gm, 0.0044 mol), r-BINAP (0.13 gm, 0.00022 mol) and Pd2(dba)3 (0.11 gm, 0.000011 mmol) to give Intermediate 19 as a white solid. R(0.4gm).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(b s,5H),2.68(bs,2H),2.14(s,3H),1.48(s,9H).MS(m / z):596.20[M+H]+.

[0500] 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 procedure as described above for Intermediate 19K using Intermediate 15 (0.6 g, 0.00131 mol), 1-bromo-8-chloronaphthalene (0.47 ml, 0.0019 mol), sodium tert-butoxide (0.44 gm, 0.0039 mmol), r-BINAP (0.13 gm, 0.00013 mmol) and Pd2(dba)3 (0.11 gm, 0.000013 mmol) to give Intermediate 19S (0.4 gm) as a white solid. 618.29 [M+H]+.

[0501] 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 procedure as described above for Intermediate 19K using Intermediate 15 (0.6 g, 0.00131 mol), 1-bromo-8-chloronaphthalene (0.47 ml, 0.0019 mol), sodium tert-butoxide (0.44 gm, 0.0039 mol), r-BINAP (0.13 g, 0.00013 mol) and Pd2(dba)3 (0.11 gm, 0.000013 mol) to give Intermediate 19S (0.35 g). 618.29 [M+H]+.

[0502] 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 procedure 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]+.

[0503] 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 procedure 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 (0.28 gm) as an off-white solid. 585.33 [M+H]+.

[0504] 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 procedure 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 mmol) to give Intermediate 19W (0.39 g) as an off-white solid. 584.50 [M+H]+.

[0505] 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 procedure 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]+.

[0506] 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 procedure 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]+.

[0507] 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 procedure 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 give Intermediate 19Z (0.36 gm). 622.35 [M+H]+.

[0508] 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 procedure 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 (~0.4 gm). 555.28 [M+H]+.

[0509] 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 procedure 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) to give Intermediate 20A (0.38 gm). 470.25 [M+H]+.

[0510] General procedure for deprotection (Method 20)

[0511] In a single-necked RBF, the desired solutions of intermediates 19A to 19Z, 20 and 20A (amounts as described above) in DCM were added with trifluoroacetic acid (TFA) or dioxane in HCl at 0°C for 1-2 hours. The reaction completion was checked by TLC using methanol:DCM (5%) and 1 drop of methanolic ammonia. The solvent was evaporated under reduced pressure to give a crude solid of the deprotected compound which was used in the next step without any purification or characterization.

[0512] Table 3

[0513]

[0514]

[0515]

[0516]

[0517]

[0518] Preparation of Part-B Compounds

[0519] Example 1: 1-(4-Acryloylpiperazin-1-yl)-3-(1,1-dioxothiomorpholino)-6-(naphthalen-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile: In a single-neck 100 mL RBF, DCM (5 mL) containing the deprotected intermediate from method 20 (0.2 gm, 0.39 mmol) was added with DIEPA (0.21 mL, 1.17 mmol) at 0°C and stirred for 10 minutes. Acryloyl chloride (0.06 mL, 0.79 mmol) in DCM (3 ml) was slowly added to the above solution at 0°C. The reaction mixture was stirred at 0°C for 40 minutes. The reaction was checked for completion by TLC using MeOH:DCM (5%). The reaction mixture was quenched with saturated NaHCO3 solution (10 mL) and the whole solution was stirred for 10 minutes before separating the organic layer. The aqueous layer was extracted again with DCM (10 mL×2) and the combined organic layers were washed with brine solution (10 mL), dried over Na 2 SO 4 and concentrated under reduced pressure to get the crude residue, which was purified by column chromatography using 2-3% MeOH in DCM as mobile phase. The pure fractions were collected and concentrated to give the desired product (0.065 gm, 29.94%). 1H-NMR (δ ppm, CDCl3, 400 MHz): δ 7.25 (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%.

[0520] 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 method 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%.

[0521] 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 method 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%.

[0522] 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 method 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),6.3 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):587.3[M+H]+.HPLC purity: 96.11%.

[0523] 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 method 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%.

[0524] 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 method 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%.

[0525] 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 method described above for Example 1 using Intermediate 19F to give the desired product (0.04 gm, 17.03%). 1H-NMR (δ ppm, CDCl3, 400 MHz): δ 7.2 5(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),3.2 4(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%.

[0526] 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 method 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 as an off-white solid (0.05 gm, 12%). 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%.

[0527] 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 method described above for Example 1 to give the desired product of (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%.

[0528] 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: In a 100 mL two-necked RBF, (S)-3-((1-methylpyrrolidin-2-yl)methoxy)-1-(piperazin-1-yl)-6-(quinazolin-4-yl) To a suspension of )-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride (0.3 gm, 0.00062 mol) in ethyl acetate (1.8 mL) were 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 warmed to 15° C. for 30 minutes, and the reaction mixture was diluted with saturated aqueous sodium carbonate solution (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 provide a crude residue. The residue was purified by preparative HPLC; column: Waters Xbridge C18 150x50mmx10μm, mobile phase: A [water (10mM NH4HCO3)], B (ACN), B%: 42%-72%, 11.5 minutes) 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 (0.065gm, 18.83%). MS (m / z): 557.2 (M+1).

[0529] 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 two-neck 100 mL RBF, 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. Completion of the reaction was checked by TLC using methanol:DCM (5%) and 1 drop of methanolic ammonia as mobile phase. The RM was concentrated under reduced pressure to give a crude mass 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(400MHz)(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),3.16-2.8 6(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%.

[0530] 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 method described above for Example 10 to give a crude product that was further purified by preparative HPLC; column Sunfire C18 150x50mmx10μm, mobile phase: A [water (10mM NH4HCO3)], B (ACN), B%: 42%-72%); to obtain 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),4.80-4.69(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% (considering the diastereoisomer part).

[0531] 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 method 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 separated by chiral separation using 5 μm CHIRALCEL-ODH (4.6×250 mm) and mobile phase: acetonitrile (100%) to provide 0.33 gm and 0.36 gm of isomer 1 and isomer 2 as Examples 14 and 15, respectively. 1H-NMR (δ ppm, CDCl 3 , 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, 1 H),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: 96.72%.

[0532] 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 (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), 4.33-4.2 3(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%.

[0533] 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 (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), 4.33-4.2 3(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%.

[0534] 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 procedure as described above for Example 1 to obtain collected pure fractions and concentrated to give the desired product (0.61 gm, 34.51%). 1H-NMR (400 MHz) (CDCl3): 8.20-8.17 (m, 1H), 7.88-7.86 (m, 1H), 7.64 (d, J=8.4 Hz, 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),5.84-5.7 7(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),3.02-2.98(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%.

[0535] 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 separated by chiral separation using 5 μm CHIRALCEL-ODH (4.6X250mm) and mobile phase: acetonitrile (100%) separated from a racemic mixture of 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 (0.57gm). 1H-NMR (δppm, CDCl3, 400MHz): δ8.19-8.17 (m, 1H), 7.88-7.86 (m, 1H), 7.64 (d, J=6Hz, 1H), 7.52-7.51 (m, 2H), 7.46-7.43 (m, 1H), 7.18 (d, J=6Hz,1H),6.61(bs,1H),6.40(d,J=12.4Hz,1H),5.83(d,J=8.4Hz,1H),5.0 9(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%.

[0536] 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-2,6-naphthyridine-4-carbonitrile (0.125 gm) was separated by chiral separation using 5 μm CHIRALCEL-ODH (4.6X250mm) and mobile phase: acetonitrile (100%) separated from a racemic mixture of 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 (0.57 gm) .1H-NMR (δppm, CDCl3, 400MHz): δ8.19-8.17(m,1H),7.88-7.86(m,1H),7.64(d,J=6H z,1H),7.52-7.50(m,2H),7.44-7.43(m,1H),7.18(d,J=6Hz,1H),6.60(bs,1H),6.40 (d,J=13.2Hz,1H),5.83(d,J=8.4Hz,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%.

[0537] 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 the method as described above for Example 1 using Intermediate 19J 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 subjected to preparative HPLC; column: Sunfire C18 150x50mmx10μm, mobile phase: A [water (10mMNH4HCO3)], B (ACN), B%: 42%-72%) was further purified 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 (0.05gm) 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%.

[0538] 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 method described above for Example 1 to provide a crude residue. The residue was purified by preparative HPLC; column: Sunfire C18 150x50mmx10μm, mobile phase: A [water (10mM NH4HCO3)], B (ACN), B%: 42%-72%) was purified 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 (400 MHz) (CDCl3): 8.19-8.17 (m, 1H), 7.88-7.85 (m, 1H), 7.64 (d, J=8.0 Hz, 1H), 7.54-7.49 (m, 2H), 7.46-7.70 (m, 3H), 7.80-7.81 (m, 3H), 7.81-7.80 (m, 3H), 7.80-7.81 ... .42(m,1H),7.18(d,J=7.6Hz,1H),5.48-5.36(m,1H),5.28-5.23(m,1 H),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%.

[0539] 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 method described above for Example 1 to give a crude residue. The residue was purified by preparative HPLC; column: Sunfire C18 150x50mmx10μm, mobile phase: A [water (10mM NH4HCO3)], B (ACN), 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 (400 MHz) (CDCl3): 9.05 (s, 1H), 8.28 (m, 1H), 8.13 (d, J = 6.4 Hz, 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%.

[0540] 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 method described above for Example 1 to give a crude residue. The residue was purified by preparative HPLC; column: Sunfire C18 150x50mmx10μm, mobile phase: A [water (10mM NH4HCO3)], B (ACN), 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 (400 MHz) (CDCl3): 9.05 (s, 1H), 8.28 (m, 1H), 8.13 (d, J = 6.4 Hz, 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%.

[0541] 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. The completion of the reaction was checked by TLC using methanol:DCM (5%) as the mobile phase. A saturated solution of NaHCO3 (20 mL) was added to the reaction mixture and stirred for more than 15 minutes 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, which was subjected to preparative HPLC; column TriArt C18*250*20*mm*5um, mobile phase: H2O containing 0.1% NH3, B: ACN (25:75), to obtain 1-(4-acryloyl-3-(cyanomethyl)piperazine-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,2H),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%.

[0542] A chiral separation of a racemic mixture of 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 performed using 5 μm CHIRALCEL-ODH (4.6×250 mm) and mobile phase: acetonitrile (100%):0.1% DEA to afford 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 (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).

[0543] 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=7.6Hz,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),4.3 8-4.29(m,2H),4.01-3.83(m,3H),3.68-3.59(m,2H),3.41-3.38(m,1H),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%.

[0544] Example 25: 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 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,2H),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%.

[0545] 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: At 0°C, 6-(8-Chloronaphthalen-1-yl)-1-(3-(cyanomethyl)piperazin-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile was added to 1,2-dihydro-1,4-dihydro-2,6-naphthyridine-4-carbonitrile. To a suspension of 2-(4-(2-(2-(4-(2-(methoxy)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile)hydrochloride (1.8 gm, 0.00324 mol) in ethyl acetate (10.8 mL) were 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 warmed to 15° C. for 30 minutes, and the reaction mixture was diluted with saturated aqueous sodium carbonate solution (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 provide a crude residue. The residue was purified by preparative HPLC; column: Sunfire C18 150×50 mm×10 μm, mobile phase: A: water (10 mM NH4HCO3), B: ACN, 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%).

[0546] 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)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile (0.075 gm, chiral purity: 99%) was prepared by chiral separation using 5 μm CHIRALCEL-ODH (4.6×250 mm) and mobile phase: acetonitrile (100%) were used to separate a racemic mixture of 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. (0.42gm).1H-NMR (δppm, CDCl3, 400MHz): δ7.79-7.76(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),4.38-4.27(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%.

[0547] 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)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile (0.095 gm, chiral purity: 99%) was prepared by chiral separation using 5 μm CHIRALCEL-ODH (4.6×250 mm) and mobile phase: acetonitrile (100%) were used to separate a racemic mixture of 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. ((0.42gm).1H-NMR (δppm, CDCl3, 400MHz): δ7.79-7.76(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),4.38-4.27(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%.

[0548] 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 anhydrous DCM (10 ml) was added DIPEA (0.3 g, 1.5 mmol) and the reaction mixture was stirred at 0° C. for 20 minutes. Acryloyl chloride (0.053 g, 0.6 mmol) was added dropwise to 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 (δ ppm, CDCl3, 400 MHz): 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%.

[0549] 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 anhydrous DCM (10 ml) was added DIPEA (0.23 g, 157 mmol) and the reaction mixture was stirred at 0°C for 20 minutes. Acryloyl chloride (0.2 g, 62 mmol) was added dropwise to 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 (25 mg). 1H-NMR (δ ppm, CDCl3, 400 MHz): 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), 2.70-2.62 (m, 4H), 2.08-2.03 (m, 2H), MS (m / z): 402.21 [M+H]+. HPLC purity: 97.00%.

[0550] 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 anhydrous DCM (10 ml) was added DIPEA (0.17 g, 91 mmol) and the reaction mixture was stirred at 0°C for 20 minutes. Acryloyl chloride (0.033 g, 35 mmol) was added dropwise to 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 (25 mg). 1H-NMR (δ ppm, CDCl3, 400 MHz): 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%.

[0551] Example 32: 1,3-bis(4-acryloylpiperazin-1-yl)-6-benzyl-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile: Prepared using the method described above for Example 1 using Intermediate 7D to give 20 mg of 1,3-bis(4-acryloylpiperazin-1-yl)-6-benzyl-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile 1H-NMR (δ ppm, CDCl3, 400 MHz) :7.38-7.26(m,5H),6.57-6.53(m,2H),6.34-6.31(m,2H),5.75-5.73(m,2H),3.81-3.61(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%.

[0552] 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 method described above for Example 1 using Intermediate 6A1 to give 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%.

[0553] Example 34: 1-(4-Acryloylpiperazin-1-yl)-6-benzyl-3-morpholino-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile: Prepared using the method described above for Example 1 using Intermediate 6B to give 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%.

[0554] 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 method 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%.

[0555] 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 method described above for Example 1 to give 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%.

[0556] 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 method described above for Example 1 to give 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,2H),3.85-3.8 3(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%.

[0557] 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 method 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,3 H),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%.

[0558] 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 method 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%.

[0559] Example 40: 1-(4-Acryloylpiperazin-1-yl)-6-benzyl-3-hydroxy-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile: Prepared using the method described above for Example 1 using Intermediate 6A1 to give 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%.

[0560] Example 41: 1-(4-Acryloylpiperazin-1-yl)-3-(4-methylpiperazin-1-yl)-6-(naphthalene-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile: Prepared using the method described above for Example 1 using Intermediate 19M to give 113 mg of 1-(4-acryloylpiperazin-1-yl)-3-(4-methylpiperazin-1-yl)-6-(naphthalene-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%.

[0561] 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 method 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%.

[0562] 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 method 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%.

[0563] Example 44: 1-(4-Acryloylpiperazin-1-yl)-6-(naphthalene-1-yl)-3-(piperidin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile: Prepared using the method described above for Example 1 using Intermediate 19N to give 150 mg of 1-(4-acryloylpiperazin-1-yl)-6-(naphthalene-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%.

[0564] 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 method 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%.

[0565] Example 46: 1,3-bis(4-acryloylpiperazin-1-yl)-6-(naphthalene-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile: Prepared using the method described above for Example 1 using Intermediate 19K to give 85 mg of 1,3-bis(4-acryloylpiperazin-1-yl)-6-(naphthalene-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,2H),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%.

[0566] Example 47: 1,3-bis(4-acryloylpiperazin-1-yl)-6-(benzo[b]thiophene-4-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile: Prepared using the method described above for Example 1 using Intermediate 19L to give 60 mg of 1,3-bis(4-acryloylpiperazin-1-yl)-6-(benzo[b]thiophene-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,2H),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%.

[0567] Example 48: 1-(4-Acryloylpiperazin-1-yl)-6-(naphthalene-1-yl)-3-(4-propionylpiperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile: Prepared using the method described above for Example 1 using Intermediate 19P to give 55 mg of 1-(4-acryloylpiperazin-1-yl)-6-(naphthalene-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,2H),3.83-3.72(m,6H),3.65-3.63(m, 6H),3.41(bs,4H),3.40-3.35(m,2H),2.87(s,2H),1.20-1.16(m,3H).564.11[M+H] + .HPLC purity: 97.59%.

[0568] 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:

[0569] 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 procedure similar to that described above for Example 41 with necessary changes in starting materials and reactants to afford 150 mg of the title compound. 609.34 [M+H] + .

[0570] Step 2: Prepared using the method described above for Example 1 (using the intermediate of 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 (δ ppm, CDCl3, 400 MHz): 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,2H),3.84-3.72(m,6H),3.67-3.62(m,6H),3.4 0-3.36(m,6H),2.88-2.87(m,2H),2.43-2.38(m,2H),1.22-1.17(m,3H).564.52[M+H] + .HPLC purity: 97.49%.

[0571] 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 method described above for Example 1 to give 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),7.6 3-7.61(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,2H),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%.

[0572] Example 51: 3-(4-Acetylpiperazin-1-yl)-1-(4-acryloylpiperazin-1-yl)-6-(naphthalene-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile: Prepared using the method described above for Example 1 using Intermediate 19R to give 75 mg of 3-(4-acetylpiperazin-1-yl)-1-(4-acryloylpiperazin-1-yl)-6-(naphthalene-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%.

[0573] 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 method described above for Example 1 using Intermediate 19O to give 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%.

[0574] 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 method 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 (δ ppm, CDCl3, 400 MHz): 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,6H),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%.

[0575] 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:

[0576] 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 Prepared using the procedure 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] + .

[0577] Step 2: Prepared using the method as described above for Example 1 (using the intermediate of 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),7.63-7.6 2(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,2H),3.84-3.72(m,9H),3.4 9-3.43(m,7H),2.88(s,4H),2.80-2.78(m,2H),1.33-1.23(m,3H).536.13[M+H] + .HPLC purity: 98.10%.

[0578] 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 method described above for Example 1 to give 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%.

[0579] Example 56: 1-(4-Acryloylpiperazin-1-yl)-6-(naphthalene-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile: Prepared using the method described above for Example 1 to give 60 mg of 1-(4-acryloylpiperazin-1-yl)-6-(naphthalene-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,1 H),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%.

[0580] 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: To a solution of 6-(naphthalen-1-yl)-1-(piperazin-1-yl)-3-(4-propionylpiperazin-1-yl)-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile hydrochloride (0.30 g, 0.54 mmol) in ethyl acetate (19 mL) at 0°C were 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 warmed to 15 ° C for 30 minutes and the reaction mixture was diluted with saturated sodium carbonate solution (20 mL). The aqueous phase was extracted with ethyl acetate (2x20 mL) and the combined organic layer was dried over Na2SO4, filtered and concentrated to provide a crude residue. The residue was purified by column chromatography using DCM containing 4% MeOH. The pure fractions were concentrated under reduced pressure to obtain 0.06 gm of 1- (4- (2-fluoroacryloyl) piperazine-1-yl) -6- (naphthalene-1-yl) -3- (4-propionyl piperazine-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),7.66-7.6 4(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%.

[0581] Other intermediates and other illustrated compounds required to prepare any of the above examples can be synthesized using the general and specific methods as described above, with all possible variations necessary to synthesize the intermediates and compounds as contemplated herein.

[0582] Section C: Biological Activity

[0583] The biological and / or pharmacological properties of the compounds of the invention can be demonstrated by various assays. Biological and / or pharmacological assays that can be performed with the compounds according to the invention and / or their pharmaceutically acceptable salts are exemplified below.

[0584] Test 1: In vitro cell proliferation assay of NCI-H358 and MIAPACA-2 cell lines

[0585] Growth inhibition assays should be performed using culture medium supplemented with 10% FBS. Cells are seeded in 96-well plates at a desired concentration of 1500-6,000 cells / well. Test compounds in a concentration range of 1-30uM will be added after 24 hours. Growth will be assessed using a CCK-8 kit to measure the reduction of 0 hours (before adding the test compound) and 72 hours after adding the test compound. Read absorbance on a BIO-RAD iMark microplate or any equivalent microplate reader at a wavelength of 450nm. Data are analyzed and the percentage inhibition due to the test compound compared to the control is calculated accordingly.

[0586] Table 4

[0587]

[0588]

[0589] Test 2: In vitro cell proliferation assay of KRASG12 cell line

[0590] Growth inhibition assays were performed using culture medium supplemented with 10% FBS. Cells were seeded in well plates with a desired number of wells at a desired concentration of 1000-6,000 cells / well. Test compounds were added within the desired concentration range after 24 hours. Growth was assessed using Cell Titer-Glo (CTG, Cell Signaling Company) to measure reduction at 0 hours (before adding the test compound) and 3 days (2D) or 7 days (3D) after adding the test compound. Read absorbance at a predetermined wavelength, such as 450nm, on a BIO-RAD iMark microplate or any equivalent microplate reader. Data were analyzed and the inhibition percentage and / or IC50 of each test compound were calculated accordingly.

[0591] Results: Data provide representative Cpd A across various cell lines, including selective

[0592] Table 5

[0593]

[0594]

[0595] Table 6

[0596]

[0597] Test 3: Nucleotide exchange assay

[0598] HTRF-based nucleotide exchange assay to detect GTP binding to K-Ras

[0599] Human KRAS G12C protein (corresponding to amino acids 2-169) was mixed with a-GST Tb antibody (1.5x solution), and 10uL of the solution was added to the reaction well. Then an acoustic dispenser (Echo, Labcyte) was used to deliver the compound (10 concentrations each or any other selected concentration, 3-fold or selected multiples for a serial dilution with a starting concentration of about 300uM or 100μM or 50uM) to the reaction well and incubated with Kras / aGST Tb antibody at room temperature for 1 hour. After 1 hour 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) was added to the reaction wells to initiate the exchange reaction. The HTRF-based SOS1-mediated exchange of GDP with GTP was measured at an excitation wavelength of 337 nm and emission wavelengths of 665 and 620 nm on a microplate reader PEHRAstar (BMG Labtech). No-SOS1 reaction or the highest control compound concentration was used as a blank, and the sigmoidal dose response (variable slope) equation was used to calculate the inhibition % and / or determine the IC50. Representative compound Cpd A showed an IC50 of <10 nM.

[0600] Test 4: Protein-Protein Interaction Assay (PPI Assay): HTRF-based PPI assay to detect binding of KRAS to cRAF proteins (KRAS:cRAF)

[0601] 5 μL of 3x human KRAS G12C protein (b-KRAS G12C (GppNHp); corresponding to amino acids 2-169) was delivered to the assay wells. Compounds (tested in 10-concentration IC50 mode with 3-fold serial dilutions at a starting concentration of 10 μM in duplicate) were added to the assay wells using acoustic technology (ECHO, Labcyte) and then incubated at room temperature for 30 minutes. After incubation, 5uL of 3x cRAF protein (GST-cRAF corresponding to amino acids 2-303)) was added to the assay wells. After incubation for 30 minutes, 5uL of 3x detection mixture containing MAb anti-GST Tb (Cisbio 61GSTTLB) and streptavidin-XL665 (Cisbo610SAXLB) cryptate was added to the assay wells. After 60-120 minutes of incubation, the HTRF-based signal was measured on a microplate reader PEHRAstar (BMGLabtech) at an excitation wavelength of 337 nm and emission wavelengths of 665 and 620 nm. When the activity of the highest concentration of the compound was less than 65%, the IC50 was determined using a sigmoidal dose response (variable slope) equation.

[0602] Test 5: Evaluation of biomarkers in NCI-H358 and MIA PaCa-2 cells using Western blotting

[0603] Protein lysates were prepared using RIPA lysis buffer representing both control and test samples. In the present invention, a 9-point concentration-response was used to measure the regulation of pERK, and protein lysates were prepared using NCI-H358 and MIA PaCa-2 cells, which were treated with representative examples of the present invention over a period of time. Total protein was estimated by the Bradford method, and absorbance was measured at 595 nm using a Bio-Rad imark reader. The separated total protein was separated on a 10% SDS PAGE electrophoresis and transferred to a nitrocellulose membrane. After transfer, the membrane was blocked at room temperature for 1 hour using 5% BSA prepared in PBST (0.1% tween-20) and washed with 1x PBS and PBST. The membrane was then probed with rabbit monoclonal primary antibodies such as pERK (MA5-15173), ERK (MA5-15134), which were obtained from Invitrogen of Thermo Fisher Scientific, USA. TM Primary antibodies were prepared in 5% BSA, 0.1% tween-20 solution (diluted 1:2000) at 4°C overnight. After incubation with primary antibodies, membranes were washed three times with 1x PBS and PBST, followed by incubation with goat anti-rabbit secondary IgG HRP conjugate (from Invitrogen TM) (prepared at 1:10,000 dilution in 3% skim milk, 0.1% tween-20) and incubated at room temperature for 1 hour. After incubation, the cells were analyzed using a Bio-Rad Chemidoc TM G-biosciences femtoLUCENT in imaging systems TM The blots were washed and developed using PLUS-HRP chemiluminescent reagent, and the resulting bands on the blots were quantified using Image J software.

[0604] Results: Representative compounds tested demonstrated dose- and time-dependent modulation of pERK, a downstream biomarker indicative of KRAS signaling.

[0605] Table 7

[0606]

[0607] ΩΩΩΩ=<5nm; ΩΩΩ=>5nm to 25nM; ΩΩ=>25 to 50nM; Ω=>50 to 100nM T1=3 hours; T2=6 hours; T3=24 hours

[0608] Test 6: Antitumor effects of the compounds of the present invention in female Balb / c nude mice bearing NCI-H358 human non-small cell lung cancer xenografts

[0609] NCI-H358 xenografts are used to test representative compounds of the invention, wherein in NCI-H358, cells are inoculated in a mouse model representing lung cancer, the mouse model having two different cohorts / groups, including a control group (vehicle-treated, G1) and two treatment cohorts / groups, i.e., paclitaxel (10 mg / kg Q3D, IV, G3) as a standard and a test compound (100 mg / kg QD, Cpd A, G3) for each cohort / group. Treatment was initiated when maximum tumor growth reached >200 mm3, and treatment was continued until the vehicle reached a maximum tumor volume of 2000 mm3.

[0610] result:

[0611] The test compound showed >65% tumor growth inhibition (TGI), with statistically significant (P<0.01) reductions in tumor volume noted starting on day 3 (n=5). The test compound showed statistically significant reductions in tumor volume compared to paclitaxel at 10 mg / kg Q3DX3 weeks, IV. No significant effects on overall body weight were found over the 21-day study period.

[0612] The present invention has been described above with the aid of functional building blocks, which illustrate embodiments of specified functions and their relationships. For ease of description, the boundaries of these functional building blocks have been arbitrarily defined herein. Alternative boundaries may be defined as long as the specified functions and their relationships are properly performed.

[0613] The foregoing description of the specific embodiments will so completely reveal the general nature of the invention that others can easily modify and / or adapt the various applications of such specific embodiments by applying knowledge within the art without excessive experimentation and without departing from the general concept of the invention. Therefore, based on the teachings and guidance presented herein, such adaptations and modifications are intended to be within the meaning and scope of equivalents of the disclosed embodiments. It should be understood that the wording or terminology herein is for descriptive and non-restrictive purposes, so that the terms or wording of this specification will be interpreted by the technician in view of the teachings and guidance.

Claims

1. A compound of formula (A): or its tautomer, its isotope, its prodrug, its N-oxide, its pharmaceutically acceptable ester, its pharmaceutically acceptable salt or its stereoisomer, wherein A1 is absent or independently selected from 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 selected from 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 cyclic groups, the cyclic groups being 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, the cyclic groups being 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, which is optionally substituted with E. E is a group capable of forming a covalent bond, or an "electrophile" or "electrophile moiety" capable of forming a covalent bond. R is independently selected at each occurrence from 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 或-CR b R c C(=S)R z 。 R 1 is independently selected at each occurrence 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 。 R a is independently selected at each occurrence 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 connected to form a substituted or unsubstituted saturated or unsaturated 3-6 membered ring, the 3-6 membered ring may optionally contain heteroatoms which may be the same or different and selected from O, NRa or S; or any two R connected to the same carbon atom a Can be linked to form oxo (C=O), imino (=NR b )、C=S(O) p or a substituted or unsubstituted saturated or unsaturated 3-6 membered ring, the 3-6 membered ring may optionally contain the same or different and selected from O, NR x or a heteroatom of S; R b and R c is independently selected at each occurrence 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 heterocycle, substituted heterocyclylalkyl ring, or substituted or unsubstituted amino, or R x and R y Any two of the following may be linked when bound to a common atom to form (i) a substituted or unsubstituted saturated or unsaturated 3-14 membered ring, the 3-14 membered ring may optionally contain one or more which may be the same or different and are selected from O, NR x or S heteroatom, or (ii) oxo (=O), thio (=S) or 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)qR a 、-NR a R b ,-C(=Z)-R a , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and substituted or unsubstituted cycloalkyl; Z is selected from O or S; and p is independently 0, 1 or 2 at each occurrence.

2. A compound of formula (AI): or its tautomer, its isotope, its prodrug, its N-oxide, its pharmaceutically acceptable ester, its pharmaceutically acceptable salt or its stereoisomer, wherein A1 is absent or independently selected from 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 cyclic groups, the cyclic groups being 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, the cyclic groups being 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, which is optionally substituted with E. E is a group capable of forming a covalent bond, or an "electrophile" or "electrophile moiety" capable of forming a covalent bond. R 1 is independently selected at each occurrence 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 。 R a is independently selected at each occurrence 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 connected to form a substituted or unsubstituted saturated or unsaturated 3-6 membered ring, the 3-6 membered ring may optionally contain the same or different and selected from O, NR a or S; or any two R attached to the same carbon atom a Can be linked to form oxo (C=O), imino (=NR b )、C=S(O) p or a substituted or unsubstituted saturated or unsaturated 3-6 membered ring, the 3-6 membered ring may optionally contain the same or different and selected from O, NR x or a heteroatom of S. R b and R c is independently selected at each occurrence 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 heterocycle, substituted heterocyclylalkyl ring, or substituted or unsubstituted amino, or R x and R y Any two of the following may be linked when bound to a common atom to form (i) a substituted or unsubstituted saturated or unsaturated 3-14 membered ring, the 3-14 membered ring may optionally contain one or more which may be the same or different and are selected from O, NR x or S heteroatom, or (ii) oxo (=O), thio (=S) or imino (=NR x ) group; and p is independently 0, 1 or 2 at each occurrence.

3. A compound of formula (A-II): or its tautomer, its isotope, its prodrug, its N-oxide, its pharmaceutically acceptable ester, its pharmaceutically acceptable salt or its stereoisomer, wherein A1 is absent or independently selected from 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 cyclic groups, the cyclic groups being 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 heterocyclic group, wherein the substituted or unsubstituted heterocyclic group is optionally substituted by E. E is a group capable of forming a covalent bond, or an "electrophile" or "electrophile moiety" capable of forming a covalent bond. R 1 is independently selected at each occurrence 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 。 R a is independently selected at each occurrence 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 connected to form a substituted or unsubstituted saturated or unsaturated 3-6 membered ring, the 3-6 membered ring may optionally contain the same or different and selected from O, NR a or S; or any two R attached to the same carbon atom a Can be linked to form oxo (C=O), imino (=NR b )、C=S(O) p or a substituted or unsubstituted saturated or unsaturated 3-6 membered ring, the 3-6 membered ring may optionally contain the same or different and selected from O, NR x or a heteroatom of S. R b and R c is independently selected at each occurrence 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 heterocycle, substituted heterocyclylalkyl ring, or substituted or unsubstituted amino, or R x and R y Any two of the following may be linked when bound to a common atom to form (i) a substituted or unsubstituted saturated or unsaturated 3-14 membered ring, the 3-14 membered ring may optionally contain one or more which may be the same or different and are selected from O, NR x or S heteroatom, or (ii) oxo (=O), thio (=S) or imino (=NR x ) group; and p is independently 0, 1 or 2 at each occurrence.

4. The compound according to any one of claims 1 to 3, wherein A1 is absent or is -CR b R c -; where R b and R c Each of is independently selected from hydrogen or substituted or unsubstituted alkyl.

5. The compound according to any one of claims 1 to 4, wherein A1 is absent or is -CR b R c -; where R b are independently methyl or ethyl, and R c It's hydrogen.

6. The compound according to any one of claims 1 to 5, wherein A1 is absent or is -CR b R c -; where R b is hydrogen, and R c It's hydrogen.

7. The compound according to any one of claims 1 to 6, wherein A1 is absent or is -CH2 or -(C=O).

8. A compound according to any one of claims 1 to 7, wherein A2 is absent or is -CR b R c -; where R b and R c Each of is independently selected from hydrogen, substituted or unsubstituted alkyl.

9. The compound according to any one of claims 1 to 8, wherein A2 is absent or is -CR b R c -; where R b are independently methyl or ethyl, and R c It's hydrogen.

10. The compound according to any one of claims 1 to 9, wherein A2 is absent.

11. A compound according to any one of claims 1 to 10, wherein Cy 1 is selected from a cyclic group, the cyclic group being selected from a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, a substituted or unsubstituted arylalkyl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted heteroarylalkyl group.

12. A compound according to any one of claims 1 to 11, wherein Cy 1 is selected from a cyclic group selected from a substituted or unsubstituted aryl group and a substituted or unsubstituted heteroaryl group.

13. A compound according to any one of claims 1 to 12, wherein Cy 1 Selected from 14. A compound according to any one of claims 1 to 13, wherein Cy 2 is selected from a cyclic group selected from a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted cycloalkylalkyl, a substituted or unsubstituted heterocyclyl and a substituted or unsubstituted heterocyclylalkyl.

15. A compound according to any one of claims 1 to 14, wherein Cy 2 is selected from cyclic groups selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocyclyl and substituted or unsubstituted heterocyclylalkyl, each of which is optionally further substituted by a group E.

16. A compound according to any one of claims 1 to 15, wherein Cy 2 Selected from It is substituted by a group E capable of forming a covalent bond.

17. A compound according to any one of claims 1 to 16, wherein E is selected from 18. A compound according to any one of claims 1 to 17, wherein E is selected from 19. A compound according to any one of claims 1 to 18, wherein A2-Cy 2 -E is selected from 20. A compound according to any one of claims 1 to 19, wherein A2-Cy 2 -E is selected from 21. The compound according to any one of claims 1 to 20, wherein R is cyano (CN).

22. A compound according to any one of claims 1 to 21, wherein R 1 Selected from hydrogen, halogen, OR b , SR b 、-S(=O)pR b -、-C(=O)-R b ,-NR b R c 、-CO-NR b R c -and-NR b -CO-R c .

23. A compound according to any one of claims 1 to 22, wherein R 1 Yes-OR b .

24. A compound according to any one of claims 1 to 23, wherein R 1 Yes - NR b R c .

25. A compound according to any one of claims 1 to 24, wherein R 1 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.

26. A compound according to any one of claims 1 to 25, wherein R 1 are independently selected from substituted or unsubstituted alkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, and substituted or unsubstituted heteroaryl.

27. A compound according to any one of claims 1 to 26, wherein R 1 Independently selected from 28. A compound according to any one of claims 1 to 27, wherein R a is hydrogen or substituted or unsubstituted alkyl.

29. according to the compound described in any one of claims 1 to 28, wherein two R that are connected to the same carbon atom a A C=O (oxo) group is formed.

30. A compound of formula (A-III): or its tautomer, its isotope, its prodrug, its N-oxide, its pharmaceutically acceptable ester, its pharmaceutically acceptable salt or its stereoisomer, 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 selected from hydrogen, halogen, substituted or unsubstituted alkyl, -NR b R c OR b ; R b and R c is independently selected at each occurrence from hydrogen, substituted or unsubstituted alkyl, or R b and R c The variables of together with the nitrogen to which they are attached may form a substituted or unsubstituted heterocyclic ring; X 1 is C or N; X 2 Selected from -NE or CH2-E, O or S; E is a group capable of forming a covalent bond, or an "electrophile" or "electrophile 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.

31. A compound according to any one of claims 1 to 30, wherein A1 is absent or is methyl.

32. A compound according to any one of claims 1 to 31, wherein A1 is absent.

33. A compound according to any one of claims 1 to 32, wherein Cy 1 is selected from substituted or unsubstituted aryl.

34. according to the compound described in any one of claims 1 to 33, wherein Cy 1 is selected from phenyl or naphthalene, said phenyl or naphthalene being optionally substituted with halogen, hydroxyl or substituted or unsubstituted alkyl.

35. according to the compound described in any one of claims 1 to 34, wherein Cy 1 is selected from quinoline or quinazoline, the quinoline or quinazoline being optionally substituted with halogen, hydroxyl or substituted or unsubstituted alkyl.

36. A compound according to any one of claims 1 to 35, wherein R 1 Selected from hydrogen, halogen, 37. A compound according to any one of claims 30 to 36, wherein X 1 It is N.

38. A compound according to any one of claims 30 to 37, wherein X 2 Selected from -NE or CH2-E or O, wherein E is selected from 39. A compound according to any one of claims 30 to 38, wherein X 2 Selected from -NE or CH2-E or O, wherein E is selected from 40. A compound according to any one of claims 30 to 39, wherein A1 is absent or is a methyl group; Cy 1 is selected from substituted or unsubstituted aryl; R 1 Selected from hydrogen, halogen, X 1 is N; and X 2 Selected from -NE or CH2-E or O, wherein E is selected from 41. A compound selected from: 1-(4-Acryloylpiperazin-1-yl)-3-(1,1-dioxothiomorpholino)-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-morpholinoethoxy)-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-chloronaphth-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-chloronaphth-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-chloronaphth-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-chloronaphth-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.

42. A compound selected from: 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; and pharmaceutically acceptable salts thereof.

43. A compound selected from: 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 pharmaceutically acceptable salts thereof.

44. A compound selected from: 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 pharmaceutically acceptable salts thereof.

45. A compound 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 pharmaceutically acceptable salts thereof.

46. ​​A compound selected from: 6-(8-chloronaphth-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-chloronaphth-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-chloronaphth-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.

47. A compound selected from: 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 pharmaceutically acceptable salts thereof.

48. A compound selected from: 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 pharmaceutically acceptable salts thereof.

49. A compound selected from: 6-(8-chloronaphth-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.

50. A compound selected from: or a pharmaceutically acceptable salt thereof.

51. A compound selected from: or a pharmaceutically acceptable salt thereof.

52. A compound selected from: or a pharmaceutically acceptable salt thereof.

53. A compound selected from: or a pharmaceutically acceptable salt thereof.

54. A pharmaceutical composition comprising a compound according to claims 1 to 59 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

55. A method for treating cancer in a subject in need thereof, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to claims 1 to 54 or a pharmaceutically acceptable salt thereof, or a composition comprising a compound according to claims 1 to 54 or a pharmaceutically acceptable salt thereof.

56. The method of claim 55, further comprising the step of simultaneously or sequentially administering to a subject in need thereof at least one other anti-cancer agent, anti-inflammatory agent, immunosuppressant, steroid, nonsteroidal anti-inflammatory agent, antihistamine, analgesic, or mixtures thereof.

57. A method of treating a KRAS-mediated disorder, particularly a KRAS G12C-mediated disorder, in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound according to claims 1 to 54 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound according to claims 1 to 54 or a pharmaceutically acceptable salt thereof.

58. Use of a compound according to claims 1 to 54 for treating cancer or a RAS-mediated disorder, particularly a KRAS G12C-mediated cancer or disorder, in a subject.

59. Use of a compound according to claims 1 to 54 for the preparation of a medicament for treating cancer or a RAS-mediated disorder, particularly a KRAS G12C-mediated cancer or disorder, in a subject.

60. A method for treating a variety of cancers, such as solid cancers and more specifically solid cancers with KRASG12 mutations, wherein the method comprises administering to a subject a compound according to claims 1 to 54 or a pharmaceutically acceptable salt thereof and / or a composition.

61. The method of claims 55 to 60, wherein the cancer is selected from the group consisting of cardiac cancer: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma; Lung cancer: bronchial cancer (squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma), alveolar (bronchiolar) cancer, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal cancer: esophageal cancer (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), gastric cancer (carcinoma, lymphoma, leiomyosarcoma), pancreatic cancer (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vasodilatory peptide tumor), small intestine cancer (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), colorectal cancer (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); Urogenital tract cancer: renal cancer (adenocarcinoma, Wilms' tumor tumor) (Wilms tumor), lymphoma, leukemia), bladder and urethral cancer (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate cancer (adenocarcinoma, sarcoma), testicular cancer (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatoid tumor, lipoma); Liver cancer: hepatocellular carcinoma (hepatoma / hepatocellularcarcinoma), bile duct cancer, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Biliary tract cancer: gallbladder cancer, ampullary cancer, bile duct cancer; Bone cancer: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticular cell sarcoma), multiple myeloma, malignant giant cell tumor, chordoma, osteochondroma (osteocartilaginous exostosis), benign enchondroma, chondroblastoma, chondromyxoid fibroma, osteoid osteoma and giant cell tumor; Nervous system cancer: skull cancer (osteomas, hemangiomas, granulomas, xanthomas, osteitis deformans), meningeal cancer (meningiomas, meningeal sarcomas, gliomatosis), brain cancer (astrocytomas, medulloblastomas, gliomas, ependymomas, germ cell tumors (pinealomas), glioblastoma multiforme, oligodendrogliomas, neurothecomas, retinoblastomas, congenital tumors), spinal neurofibromas, meningiomas, gliomas, sarcomas); gynecological cancer: uterine cancer (endometrial cancer), cervical cancer (cervical cancer, preneoplastic cervical atypical hyperplasia), ovarian cancer (ovarian cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified cancer), granulosa cell tumors, Sertoli-Leydig cell tumors tumor), dysgerminoma, malignant teratoma), vulvar cancer (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vaginal cancer (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tube cancer (carcinoma); blood Cancer: Blood cancers (myeloid leukemias (acute and chronic), acute lymphocytic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); Skin cancers: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and Adrenal gland cancer: neuroblastoma.

62. The method of claims 55 to 61, wherein the cancer is lung cancer, pancreatic cancer, or colorectal cancer.

63. The method of claim 62, wherein the cancer is lung cancer.

64. The method of claim 62, wherein the cancer is non-small cell lung cancer.

65. The method of claim 62, wherein the cancer is pancreatic cancer.

66. The method of claim 62, wherein the cancer is colorectal cancer.

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