KRAS mutant protein inhibitors

Abstract

The present invention relates to a KRAS mutant protein inhibitor represented by formula (I), compositions containing the inhibitor and uses thereof. [Formula 1] JPEG2023506532000192.jpg39170

Description

[Technical field]

[0001] The present invention relates to KRAS mutant protein inhibitors, compositions containing the inhibitors and uses thereof. [Background technology]

[0002] RAS represents a group of 189 amino acid monomeric globular proteins (molecular weight of 21 kDa) that are associated with the cell membrane and bind to GDP or GTP; RAS acts as a molecular switch. When RAS contains bound GDP, it is in a resting or closed position and is "inactive". When cells are exposed to certain growth-promoting stimuli, RAS is induced to exchange their bound GDP for GTP. When bound to GTP, RAS is "open" and is able to interact with and activate other proteins (its "downstream targets"). The RAS protein itself has an inherently low ability to hydrolyze GTP back to GDP, thereby rendering itself in a closed state. Closure of RAS requires an exogenous protein called a 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 results in prolonged protein activation and thus conduction to the cell to signal its continued growth and division. Because these signals cause cell growth and division, overactivated RAS signaling can ultimately lead to cancer.

[0003] Structurally, RAS proteins contain a G domain, which is responsible for the enzymatic activity of RAS, guanine nucleotide binding and hydrolysis (GTPase reaction). It also contains a C-terminal extension called the CAAX cassette, which is post-translationally modified and may be involved in targeting the protein to the membrane. The G domain contains a phosphate-binding ring (P-ring). The P-loop represents the pocket for binding nucleotides in the protein, which is a rigid part of the domain with conserved amino acid residues (glycine 12 and lysine 16) required for nucleotide binding and hydrolysis. The G domain also contains the so-called switch I region (residues 30-40) and switch II region (residues 60-76), both of which are dynamic parts of the protein since they can be converted between a resting and a loaded state. This ability is often described as a "spring loaded" mechanism. The main interaction is the hydrogen bond formed by threonine-35 and glycine-60 with the γ-phosphate of GTP, which maintains the active conformation of the switch 1 and switch 2 regions, respectively. After hydrolysis of GTP and release of phosphate, the two domains relax into the inactive GDP conformation.

[0004] The most notable members of the RAS subfamily are HRAS, KRAS and NRAS, which are primarily involved in many types of cancer. Mutations in any of the three major isoforms of the RAS gene (HRAS, NRAS or KRAS) are one of the most common events in human tumorigenesis. Approximately 30% of all tumors in human tumors have been found to have some mutation in the RAS gene. It is noteworthy that KRAS mutations were detected in 25%-30% of tumors. In contrast, the rate of oncogenic mutations in NRAS and HRAS family members was much lower (8% and 3%, respectively). The most frequent KRAS mutations were found at residues G12 and G13 in the P-loop and residue Q61.

[0005] G12C is a frequent KRAS gene mutation (glycine-12 is mutated to cysteine). This mutation is found in about 13% of cancers, about 43% of lung cancers, and nearly 100% of MYH-associated polyposis (familial colon cancer syndrome). However, targeting this gene with small molecules is a challenge. Summary of the Invention [Problem to be solved by the invention]

[0006] Thus, despite advances in the field, there remains a need in the art for improved compounds and methods for treating cancer, such as by inhibiting KRAS, HRAS or NRAS. The present invention fulfills this need and provides other related advantages. [Means for solving the problem]

[0007] In one embodiment, a compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharma- ceutically acceptable salt thereof, a pharma- ceutically acceptable salt of a stereoisomer thereof, or a pharma- ceutically acceptable salt of an atropisomer thereof: [ka] (In the formula: R 11 , R 12 , R 13 , R 14 or R 15 are independently selected from halogen, -C1-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, hetero C2-6 alkyl, -CN, -OC1-6 alkyl, -SC1-6 alkyl, -NR5R6, -C(=O)R5, -C(=O)OR5, -OC(=O)R5, -C(=O)NR5R6, -NR5C(=O)R6, -NR5SO2R6, -SO2R5, -S(=O)2NR5R6, -POR5R6, -C3-6 carbocyclic, 3- to 6-membered heterocyclic, -C6- 10 aryl, or 5-10 membered heteroaryl; R 11 , R 12 , R13 , R 14 or R 15 each hydrogen atom in each of the groups is independently selected from halogen, -C1-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, hetero C2-6 alkyl, -CN, oxo, -OC1-6 alkyl, -SC1-6 alkyl, -NR5R6, -C(=O)R5, -C(=O)OR5, -OC(=O)R5, -C(=O)NR5R6, -NR5C(=O)R6, -NR5SO2R6, -SO2R5, -S(=O)2NR5R6, -POR5R6, -C3-6 carbocyclic, 3- to 6-membered heterocyclic, -C6- 10 optionally substituted with 1, 2, 3, 4, 5, or 6 substituents selected from aryl, or 5-10 membered heteroaryl; each heterocyclic or heteroaryl at each occurrence contains 1, 2, 3, or 4 heteroatoms independently selected from N, O, S, S=O, or S(=O)2; R 21 or R 22 are independently hydrogen, halogen, -C1-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, heteroC2-6 alkyl, -CN, -OC1-6 alkyl, -SC1-6 alkyl, -NR5R6, -C(=O)R5, -C(=O)OR5, -OC(=O)R5, -C(=O)NR5R6, -NR5C(=O)R6, -NR5SO2R6, -SO2R5, -S(=O)2NR5R6, -POR5R6, -C3-6 carbocyclic, 3- to 6-membered heterocyclic, -C6- 10 aryl, or 5-10 membered heteroaryl; R 21 or R 22 each hydrogen atom in each of the groups is independently selected from halogen, -C1-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, heteroC2-6 alkyl, -CN, oxo, -OC1-6 alkyl, -SC1-6 alkyl, -NR5R6, -C(=O)R5, -C(=O)OR5, -OC(=O)R5, -C(=O)NR5R6, -NR5C(=O)R6, -S(=O)2NR5R6, -POR5R6, -C3-6 carbocyclic, 3- to 6-membered heterocyclic, -C6- 10optionally substituted with 1, 2, 3, 4, 5, or 6 substituents selected from aryl, or 5-10 membered heteroaryl; each heterocyclic or heteroaryl at each occurrence contains 1, 2, 3, or 4 heteroatoms independently selected from N, O, S, S=O, or S(=O)2; R3 is -C1~ 14 Alkyl, -C2~ 14 Alkenyl, -C 14 Alkynyl, -C6~ 10 Aryl, 5-10 membered heteroaryl, 3-14 membered heterocyclic, -C 14 Carbocyclic, [ka] each occurrence of ring C is independently selected from C 14 carbocyclic or 3- to 14-membered heterocyclic ring, each occurrence of ring D is independently selected from C6 to 10 aryl or 5-10 membered heteroaryl ring, each hydrogen in R3 is independently selected from 1, 2, 3, 4, 5 or 6 R 31 each heterocyclic or heteroaryl at each occurrence contains 1, 2, 3 or 4 heteroatoms independently selected from N, O, S, S=O, or S(=O)2; Each R 31 each occurrence independently represents halogen, -C1-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, heteroC2-6 alkyl, -CN, -OC1-6 alkyl, -SC1-6 alkyl, -NR5R6, -C(=O)R5, -C(=O)OR5, -OC(=O)R5, -C(=O)NR5R6, -NR5C(=O)R6, -NR5SO2R6, -SO2R5, -S(=O)2NR5R6, -POR5R6, -C3-6 carbocyclic, 3- to 6-membered heterocyclic, -C6- 10 aryl, or 5-10 membered heteroaryl; R 31each hydrogen atom in each of the groups is independently selected from halogen, -C1-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, heteroC2-6 alkyl, -CN, oxo, -OC1-6 alkyl, -SC1-6 alkyl, -NR5R6, -C(=O)R5, -C(=O)OR5, -OC(=O)R5, -C(=O)NR5R6, -NR5C(=O)R6, -S(=O)2NR5R6, -POR5R6, -C3-6 carbocyclic, 3- to 6-membered heterocyclic, -C6- 10 optionally substituted with 1, 2, 3, 4, 5, or 6 substituents selected from aryl, or 5-10 membered heteroaryl; each heterocyclic or heteroaryl at each occurrence contains 1, 2, 3, or 4 heteroatoms independently selected from N, O, S, S=O, or S(=O)2; R4, [ka] Selected from; each G1, G2, G3 or G4 at each occurrence is independently selected from N or CH; each n1, n2, n3, n4, or n5, at each occurrence, is independently selected from 0, 1, 2, 3, 4, 5, or 6, with the proviso that n1 and n2 are not simultaneously 0, and n3 and n4 are not simultaneously 0; [ka] Each hydrogen in 42 , two R 42 , the three R's 42 , the four R's 42 , the five R's 42 Or the six R's 42 Optionally replaced by; Each R 41 But each occurrence is independent. [ka] Selected from; each occurrence of Q is independently selected from C(=O), NR5C(=O), S(=O)2, or NR5S(=O)2; [ka] In [ka] but, [ka] Selected from; [ka] but, [ka] If R 4a , R 4b or R 4c are independently hydrogen, halogen, -C1-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, heteroC2-6 alkyl, -CN, -OC1-6 alkyl, -SC1-6 alkyl, -NR5R6, -C(=O)R5, -C(=O)OR5, -OC(=O)R5, -C(=O)NR5R6, -NR5C(=O)R6, -NR5SO2R6, -SO2R5, -S(=O)2NR5R6, -POR5R6, -C3-6 carbocyclic, 3- to 6-membered heterocyclic, -C6- 10 aryl, or 5-10 membered heteroaryl; R 4a , R 4b or R 4c each hydrogen atom in each of the groups is independently selected from halogen, -C1-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, hetero C2-6 alkyl, -CN, oxo, -OC1-6 alkyl, -SC1-6 alkyl, -NR5R6, -C(=O)R5, -C(=O)OR5, -OC(=O)R5, -C(=O)NR5R6, -NR5C(=O)R6, -NR5SO2R6, -SO2R5, -S(=O)2NR5R6, -POR5R6, -C3-6 carbocyclic, 3- to 6-membered heterocyclic, -C6- 10optionally substituted with 1, 2, 3, 4, 5, or 6 substituents selected from aryl, or 5-10 membered heteroaryl; each heterocyclic or heteroaryl at each occurrence contains 1, 2, 3, or 4 heteroatoms independently selected from N, O, S, S=O, or S(=O)2; or [ka] but, [ka] If R 4a is hydrogen, halogen, -C1-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, hetero C2-6 alkyl, -CN, -OC1-6 alkyl, -SC1-6 alkyl, -NR5R6, -C(=O)R5, -C(=O)OR5, -OC(=O)R5, -C(=O)NR5R6, -NR5C(=O)R6, -NR5SO2R6, -SO2R5, -S(=O)2NR5R6, -POR5R6, -C3-6 carbocyclic, 3- to 6-membered heterocyclic, -C6- 10 aryl, or 5-10 membered heteroaryl; R 4a each hydrogen atom in each of the groups is independently selected from halogen, -C1-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, hetero C2-6 alkyl, -CN, oxo, -OC1-6 alkyl, -SC1-6 alkyl, -NR5R6, -C(=O)R5, -C(=O)OR5, -OC(=O)R5, -C(=O)NR5R6, -NR5C(=O)R6, -NR5SO2R6, -SO2R5, -S(=O)2NR5R6, -POR5R6, -C3-6 carbocyclic, 3- to 6-membered heterocyclic, -C6- 10 R is optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from aryl, or 5-10 membered heteroaryl; 4b and R 4c But together with the carbon to which they are both attached, C3~ 10 Forms a carbocyclic ring or a 3- to 10-membered heterocyclic ring, 10Each hydrogen in the carbocycle or 3-10 membered heterocycle is replaced by halogen, -C1-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, heteroC2-6 alkyl, -CN, oxo, -OC1-6 alkyl, -SC1-6 alkyl, -NR5R6, -C(=O)R5, -C(=O)OR5, -OC(=O)R5, -C(=O)NR5R6, -NR5C(=O)R6, -NR5SO2R6, -SO2R5, -S(=O)2NR5R6, -POR5R6, -C3-6 carbocycle, 3-6 membered heterocycle, -C6- 10 optionally substituted with 1, 2, 3, 4, 5, or 6 substituents selected from aryl, or 5-10 membered heteroaryl; each heterocyclic or heteroaryl at each occurrence contains 1, 2, 3, or 4 heteroatoms independently selected from N, O, S, S=O, or S(=O)2; or [ka] but, [ka] If R 4a and R 4c However, together with the carbons to which they are attached, C3~ 10 Forms a carbocyclic ring or a 3- to 10-membered heterocyclic ring, 10 Each hydrogen in the carbocycle or 3-10 membered heterocycle is replaced by halogen, -C1-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, heteroC2-6 alkyl, -CN, oxo, -OC1-6 alkyl, -SC1-6 alkyl, -NR5R6, -C(=O)R5, -C(=O)OR5, -OC(=O)R5, -C(=O)NR5R6, -NR5C(=O)R6, -NR5SO2R6, -SO2R5, -S(=O)2NR5R6, -POR5R6, -C3-6 carbocycle, 3-6 membered heterocycle, -C6- 10 R is optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from aryl, or 5-10 membered heteroaryl; 4bis hydrogen, halogen, -C1-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, hetero C2-6 alkyl, -CN, -OC1-6 alkyl, -SC1-6 alkyl, -NR5R6, -C(=O)R5, -C(=O)OR5, -OC(=O)R5, -C(=O)NR5R6, -NR5C(=O)R6, -NR5SO2R6, -SO2R5, -S(=O)2NR5R6, -POR5R6, -C3-6 carbocyclic, 3- to 6-membered heterocyclic, -C6- 10 aryl, or 5-10 membered heteroaryl; R 4b each hydrogen atom in each of the groups is independently selected from halogen, -C1-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, hetero C2-6 alkyl, -CN, oxo, -OC1-6 alkyl, -SC1-6 alkyl, -NR5R6, -C(=O)R5, -C(=O)OR5, -OC(=O)R5, -C(=O)NR5R6, -NR5C(=O)R6, -NR5SO2R6, -SO2R5, -S(=O)2NR5R6, -POR5R6, -C3-6 carbocyclic, 3- to 6-membered heterocyclic, -C6- 10 optionally substituted with 1, 2, 3, 4, 5, or 6 substituents selected from aryl, or 5-10 membered heteroaryl; each heterocyclic or heteroaryl at each occurrence contains 1, 2, 3, or 4 heteroatoms independently selected from N, O, S, S=O, or S(=O)2; [ka] but, [ka] If R 4a does not exist and R 4b does not exist and R 4cis hydrogen, halogen, -C1-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, hetero C2-6 alkyl, -CN, -OC1-6 alkyl, -SC1-6 alkyl, -NR5R6, -C(=O)R5, -C(=O)OR5, -OC(=O)R5, -C(=O)NR5R6, -NR5C(=O)R6, -NR5SO2R6, -SO2R5, -S(=O)2NR5R6, -POR5R6, -C3-6 carbocyclic, 3- to 6-membered heterocyclic, -C6- 10 aryl, or 5-10 membered heteroaryl; R 4c each hydrogen atom in each of the groups is independently selected from halogen, -C1-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, hetero C2-6 alkyl, -CN, oxo, -OC1-6 alkyl, -SC1-6 alkyl, -NR5R6, -C(=O)R5, -C(=O)OR5, -OC(=O)R5, -C(=O)NR5R6, -NR5C(=O)R6, -NR5SO2R6, -SO2R5, -S(=O)2NR5R6, -POR5R6, -C3-6 carbocyclic, 3- to 6-membered heterocyclic, -C6- 10 optionally substituted with 1, 2, 3, 4, 5, or 6 substituents selected from aryl, or 5-10 membered heteroaryl; each heterocyclic or heteroaryl at each occurrence contains 1, 2, 3, or 4 heteroatoms independently selected from N, O, S, S=O, or S(=O)2; R 4d is a halogen; Each R 42 each occurrence independently represents halogen, -C1-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, heteroC2-6 alkyl, -CN, oxo, -OC1-6 alkyl, -SC1-6 alkyl, -NR5R6, -C(=O)R5, -C(=O)OR5, -OC(=O)R5, -C(=O)NR5R6, -NR5C(=O)R6, -NR5SO2R6, -SO2R5, -S(=O)2NR5R6, -POR5R6, -C3-6 carbocyclic, 3- to 6-membered heterocyclic, -C6- 10 aryl, or 5-10 membered heteroaryl; R 42each hydrogen atom in each of the groups is independently selected from halogen, -C1-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, hetero C2-6 alkyl, -CN, oxo, -OC1-6 alkyl, -SC1-6 alkyl, -NR5R6, -C(=O)R5, -C(=O)OR5, -OC(=O)R5, -C(=O)NR5R6, -NR5C(=O)R6, -NR5SO2R6, -SO2R5, -S(=O)2NR5R6, -POR5R6, -C3-6 carbocyclic, 3- to 6-membered heterocyclic, -C6- 10 optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from aryl, or 5-10 membered heteroaryl; or The Two R's 42 and each of them, together with the atom to which they are bonded, forms a C3-6 carbocyclic ring or a 3-6 membered heterocyclic ring, and each hydrogen in the C3-6 carbocyclic ring or the 3-6 membered heterocyclic ring is independently selected from halogen, -C1-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, heteroC2-6 alkyl, -CN, oxo, -OC1-6 alkyl, -SC1-6 alkyl, -NR5R6, -C(=O)R5, -C(=O)OR5, -OC(=O)R5, -C(=O)NR5R6, -NR5C(=O)R5, -NR5SO2R6, -SO2R5, -S(=O)2NR5R6, -PO(R5)2, -C3-6 carbocyclic ring, a 3-6 membered heterocyclic ring, -C6- 10 optionally substituted with 1, 2, 3, 4, 5, or 6 substituents selected from aryl, or 5-10 membered heteroaryl; each heterocyclic and heteroaryl at each occurrence independently contains 1, 2, 3, or 4 heteroatoms selected from N, O, S, S=O, or S(=O)2; each R5 and R6 at each occurrence is independently selected from hydrogen or -C1-6 alkyl; or R5 and R6 together with the atom to which they are both or each attached form a 3-10 membered heterocycle, the 3-10 membered heterocycle optionally further containing 1, 2, 3 or 4 heteroatoms selected from N, O, S, S(=O) or S(=O)2, and each hydrogen in the 3-10 membered heterocycle is independently selected from one R 51 , two R 51 , the three R's 51 , the four R's 51 , the five R's51 Or the six R's 51 Optionally replaced by; Each R 51 is halogen, -C1-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, hetero C2-6 alkyl, -CN, -OC1-6 alkyl, -SC1-6 alkyl, -NR7R8, -C(=O)R7, -C(=O)OR7, -OC(=O)R7, -C(=O)NR7R8, -NR7C(=O)R8, -NR7SO2R8, -SO2R7, -S(=O)2NR7R8, -POR7R8, -C3-6 carbocyclic, 3- to 6-membered heterocyclic, -C6- 10 aryl, or 5-10 membered heteroaryl; R 51 each hydrogen atom in each of the groups is independently selected from halogen, -C1-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, hetero C2-6 alkyl, -CN, oxo, -OC1-6 alkyl, -SC1-6 alkyl, -NR7R8, -C(=O)R7, -C(=O)OR7, -OC(=O)R7, -C(=O)NR7R8, -NR7C(=O)R8, -NR7SO2R8, -SO2R7, -S(=O)2NR7R8, -POR7R8, -C3-6 carbocyclic, 3- to 6-membered heterocyclic, -C6- 10 optionally substituted with 1, 2, 3, 4, 5, or 6 substituents selected from aryl, or 5-10 membered heteroaryl; each heterocyclic or heteroaryl at each occurrence contains 1, 2, 3, or 4 heteroatoms independently selected from N, O, S, S=O, or S(=O)2; Each occurrence of R7 and R8 is independently selected from hydrogen or -C1-6 alkyl. is provided herein.

[0008] In one embodiment, a compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a pharma- ceutically acceptable salt thereof, a pharma- ceutically acceptable salt of a stereoisomer thereof, or a pharma- ceutically acceptable salt of an atropisomer thereof: [ka] (In the formula: R 11 , R 12 , R13 , R 14 or R 15 are independently: -OH; halogen; -NR a R b ;-C1~6 alkyl;-OC 1-6 Alkyl;-C1-6 alkylene-OH;-C1-6 alkylene-O-C1-6 alkyl;-C1-6 alkyl substituted with halogen, -NH2, -CN or -OH;-O-C1-6 alkyl substituted with halogen, -NH2, -CN or -OH;-O-C1-6 alkyl;-SO2R a ;-CN;-C(=O)NR a R b ;-C(=O)R a ;-OC(=O)R a ;-C(=O)OR a or -C3-6 carbocyclic; R a or R b is independently selected from hydrogen or -C1-6 alkyl; R 21 is selected from hydrogen; halogen; -C1-6 alkyl; -C1-6 alkyl substituted with halogen, -NH2, -CN, or -OH; -C2-6 alkenyl; or -C3-6 carbocyclic; R 22 is selected from hydrogen; halogen; -C1-6 alkyl; -C1-6 alkyl substituted with halogen, -NH2, -CN, or -OH; -C2-6 alkenyl; or -C3-6 carbocyclic; R3 is -C6~ 10 aryl or 5-10 membered heteroaryl, each occurrence of which independently contains 1, 2, 3 or 4 heteroatoms selected from N, O or S; 10 Each occurrence of hydrogen in the aryl or 5- to 10-membered heteroaryl is independently selected from one R 31 , two R 31 , the three R's 31 , the four R's 31 , the five R's 31 Or the six R's 31 Optionally replaced by; Each R 31is independently selected from halogen, -C1-6 alkyl, -CN, -OH, -O-C1-6 alkyl, -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, or -C3-6 carbocyclic; R4, [ka] and [ka] Each hydrogen in 42 , two R 42 , the three R's 42 , the four R's 42 , the five R's 42 Or the six R's 42 Optionally replaced by; n1 or n2 are independently selected from 1, 2, 3, 4, 5, or 6; R 41 but, [ka] and; R 4a , R 4b or R 4c is independently selected from hydrogen, halogen, -C1-6 alkyl, or -C1-6 alkylene-N(C1-6 alkyl)2; Each R 42 each occurrence is independently selected from: -C1-6 alkyl; -C1-6 alkylene-CN, or -C1-6 alkyl substituted with halogen. is provided.

[0009] In one embodiment, R 11 , R 12 , R 13 , R 14 or R 15 are independently: -OH; -F; -Cl; -Br; -NR a R b;-C1-3 alkyl;-OC1-3 alkyl;-C1-3 alkylene-OH;-C1-3 alkylene-O-C1-3 alkyl;-C1-3 alkyl substituted with -F or -Cl;-O-C1-3 alkyl substituted with -F or -Cl;-SO2R a ;-CN;-C(=O)NR a R b ;-C(=O)R a ;-OC(=O)R a ;-C(=O)OR a ; selected from 3-membered carbocyclic; 4-membered carbocyclic; 5-membered carbocyclic or 6-membered carbocyclic; R a or R b is independently selected from hydrogen or -C1-3 alkyl.

[0010] In one embodiment, R 11 , R 12 , R 13 , R 14 or R 15 are independently selected from -OH, -F, -Cl, -NH2, -NHCH3, -N(CH3)2, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -CH2OH, -CH2CH2OH, -CH2OCH3, -CHF2, -CH2F, -CF3, -OCH2F, -OCHF2, -OCF3, -SO2CH3, -CN, -C(=O)NH2, -C(=O)CH3, -OC(=O)CH3, -C(=O)OCH3, or a 3-membered carbocyclic ring.

[0011] In one embodiment, R 11 , R 12 , R 13 , R 14 or R 15 is independently selected from -OH, -F, -Cl, -NH2, -CH3, or -CF3.

[0012] In one embodiment, in formula (I), [ka] but, [ka] is selected from.

[0013] In one embodiment, R 21 is selected from hydrogen; -F; -Cl; -Br; -C1-3 alkyl; -C1-3 alkyl substituted with -F or -Cl; -C2-3 alkenyl; or -C3-6 carbocyclic.

[0014] In one embodiment, R 21 is selected from hydrogen; -F; -Cl; methyl; ethyl; propyl; isopropyl; methyl substituted with -F; ethyl substituted with -F; propyl substituted with -F; isopropyl substituted with -F; ethenyl; propenyl; 3-membered carbocyclic; 4-membered carbocyclic; 5-membered carbocyclic; or 6-membered carbocyclic.

[0015] In one embodiment, R 21 is -Cl.

[0016] In one embodiment, R 22 is selected from hydrogen; -F; -Cl; -Br; -C1-3 alkyl; -C1-3 alkyl substituted with -F or -Cl; -C2-3 alkenyl; or -C3-6 carbocyclic.

[0017] In one embodiment, R 22 is selected from hydrogen; -F; -Cl; methyl; ethyl; propyl; isopropyl; methyl substituted with -F; ethyl substituted with -F; propyl substituted with -F; isopropyl substituted with -F; ethenyl; propenyl; 3-membered carbocyclic; 4-membered carbocyclic; 5-membered carbocyclic; or 6-membered carbocyclic.

[0018] In one embodiment, R 22 is hydrogen.

[0019] In certain embodiments, R3 is selected from phenyl, naphthyl, 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 9-membered heteroaryl, or 10-membered heteroaryl, where each heteroaryl at each occurrence contains 1, 2, or 3 heteroatoms independently selected from N or O, and each hydrogen in R3 at each occurrence is independently selected from one R 31 , two R 31 , the three R's 31 , the four R's 31 Or the 5 R's 31 is optionally replaced by

[0020] In one embodiment, R is selected from phenyl or a 6-membered heteroaryl, where the heteroaryl contains 1 or 2 heteroatoms selected from N, and each hydrogen in the phenyl or 6-membered heteroaryl is independently selected from one R 31 , two R 31 , the three R's 31 Or the four R's 31 is optionally replaced by

[0021] In one embodiment, R3 is [ka] each hydrogen in R3 at each occurrence is independently selected from one R 31 , two R 31 , the three R's 31 Or the four R's 31 is optionally replaced by

[0022] In some embodiments, each R 31 is independently selected from -F, -Cl, -Br, -C1-3 alkyl, -CN, -OH, -O-C1-3 alkyl, -NH2, -NH(C1-3 alkyl), -N(C1-3 alkyl)2, or -C3-6 carbocyclic.

[0023] In some embodiments, each R 31is independently selected from -F, -Cl, methyl, ethyl, propyl, isopropyl, -CN, -OH, methoxy, ethoxy, propoxy, isopropoxy, -NH, -NHCH, -NHCHCH, -NH(CHCHCH), -NH(CH(CH)), -N(CH), -N(CHCH), -N(CHCH), -N(CHCH), 3-membered carbocyclic, 4-membered carbocyclic, 5-membered carbocyclic, or 6-membered carbocyclic.

[0024] In some embodiments, each R 31 is independently selected from methyl or isopropyl at each occurrence.

[0025] In one embodiment, R3 is [ka] is selected from.

[0026] In one embodiment, R3 is [ka] It is.

[0027] In one embodiment, R4 is [ka] and [ka] Each hydrogen in 42 , two R 42 , the three R's 42 Or the four R's 42 Optionally replaced by; n1 is selected from 1, 2 or 3; n2 is selected from 1, 2 or 3.

[0028] In one embodiment, R4 is [ka] is selected from [ka] Each hydrogen in 42 Or two R's 42 Optionally replaced by; n1 is selected from 1 or 2; n2 is selected from 1 or 2.

[0029] In one embodiment, R4 is [ka] and [ka] Each hydrogen in 42 Or two R's 42 is optionally replaced by

[0030] In one embodiment, R 41 but, [ka] and; R 4a , R 4b , or R 4c is independently selected from hydrogen, -F, -Cl, -Br, -C1-3 alkyl, or -C1-3 alkylene-N(C1-3 alkyl)2.

[0031] In one embodiment, R 4a , R 4b or R 4c is independently selected from hydrogen, -F, -Cl, methyl, ethyl, propyl, isopropyl, -CH2-N(CH3)2, -CH2-N(CH2CH3)2, or -CH2-N(CH3)(CH2CH3).

[0032] In one embodiment, R 4a , R 4b or R4c is independently selected from hydrogen, -F, methyl, or -CH2-N(CH3)2.

[0033] In one embodiment, R 4a is selected from hydrogen or -F; R 4b is hydrogen; R 4c is selected from hydrogen or -CH2-N(CH3)2.

[0034] In one embodiment, R 41 but, [ka] is selected from.

[0035] In one embodiment, R4 is [ka] is selected from [ka] Each occurrence of hydrogen in 42 Or two R's 42 is optionally replaced by

[0036] In some embodiments, each R 42 is independently selected from: -C1-3 alkyl; -C1-3 alkylene-CN; or -C1-3 alkyl substituted with -F or -Cl.

[0037] In some embodiments, each R 42 is independently selected from: methyl; ethyl; propyl; isopropyl; -methylene-CN; -ethylene-CN; -propylene-CN; methyl substituted with -F; ethyl substituted with -F; propyl substituted with -F; or isopropyl substituted with -F.

[0038] In some embodiments, each R 42is independently selected from: methyl; ethyl; -methylene-CN, or methyl substituted with -F.

[0039] In some embodiments, each R 42 each occurrence is independently selected from -CH3, -CH2CH3, -CH2CN, -CHF2, or -CF3.

[0040] In one embodiment, R4 is [ka] is selected from.

[0041] In one embodiment, R4 is [ka] is selected from.

[0042] In one embodiment, the compound is [ka] JPEG0007644517000039.jpg255155JPEG0007644517000040.jpg255162JPEG000764451700 0041.jpg255156JPEG0007644517000042.jpg255162JPEG0007644517000043.jpg248170JP EG0007644517000044.jpg255170JPEG0007644517000045.jpg222170JPEG00076445170000 46.jpg230170JPEG0007644517000047.jpg254170JPEG0007644517000048.jpg255167JPEG 0007644517000049.jpg250170JPEG0007644517000050.jpg225170JPEG0007644517000051 .jpg240170JPEG0007644517000052.jpg255169JPEG0007644517000053.jpg249170JPEG00 07644517000054.jpg 240170 JPEG 0007644517000055.jpg 255167 JPEG 0007644517000056.jpg 241170 JPEG 0007644517000057.jpg 255161 JPEG 0007644517000058.jpg 232170 are selected.

[0043] In another embodiment, there is provided a process for preparing a compound of formula (I), its stereoisomer, its atropisomer, a pharma- ceutically acceptable salt, a pharma- ceutically acceptable salt of its stereoisomer, or a pharma- ceutically acceptable salt of its atropisomer, the process comprising a coupling reaction between a compound of formula (II) and a compound of formula (III) according to the following reaction scheme 1, or a coupling reaction between a compound of formula (II') and a compound of formula (III') catalyzed by a transition metal palladium or nickel reagent according to the following reaction scheme 2: Scheme 1: [ka] Scheme 2: [ka] wherein L in the compound of formula (III) or formula (II') is a leaving group; preferably, the leaving group is selected from halogen, -OS(O)2CF3 or -OTs; more preferably, the halogen is selected from -F, -Cl, -Br or -I; more preferably, the leaving group is -Cl or -Br; X in the compound of formula (II) or formula (III') is selected from a boronic acid, a borate ester or an organotin; more preferably, X is [ka] Selected from; Preferably, the coupling reaction is a Suzuki coupling reaction or a Stille coupling reaction; Preferably, the coupling reaction is catalyzed by a transition metal palladium reagent; more preferably, the transition metal palladium reagent is Pd(PPh3)4.

[0044] In another aspect, provided herein is a pharmaceutical composition comprising a compound of formula (I) of the present invention, a stereoisomer thereof, an atropisomer thereof, a pharma- ceutically acceptable salt thereof, a pharma- ceutically acceptable salt of the stereoisomer thereof, or a pharma- ceutically acceptable salt of the atropisomer thereof, and at least one pharma- ceutical acceptable excipient. In one embodiment, the weight ratio of the compound to the excipient is in the range of about 0.0001 to about 10.

[0045] In another aspect, the present specification provides the use of the compound of formula (I) of the present invention, its stereoisomer, its atropisomer, its pharmaceutically acceptable salt, its stereoisomer's pharmaceutically acceptable salt or its atropisomer's pharmaceutically acceptable salt; or the pharmaceutical composition of the present invention for the manufacture of a medicament for the treatment of a disease or condition associated with a KRAS mutant protein. In one embodiment, the disease or condition associated with a KRAS mutant protein is a disease or condition associated with a KRAS G12C mutant protein. In one embodiment, the disease or condition associated with a KRAS G12C mutant protein is a cancer associated with a KRAS G12C mutant protein. In one embodiment, the cancer is selected from blood cancer, pancreatic cancer, colon cancer, rectal cancer, colorectal cancer or lung cancer. In one embodiment, the blood cancer is selected from acute myeloid leukemia or acute lymphocytic leukemia; the lung cancer is selected from non-small cell lung cancer or small cell lung cancer.

[0046] In another aspect, the present invention provides a method for treating a subject suffering from a disease or condition associated with KRAS mutant protein, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) of the present invention, its stereoisomer, its atropisomer, its pharmaceutically acceptable salt, its stereoisomer's pharmaceutically acceptable salt, or its atropisomer's pharmaceutically acceptable salt; or a pharmaceutical composition of the present invention. In one embodiment, the disease or condition associated with KRAS mutant protein is a disease or condition associated with KRAS G12C mutant protein. In one embodiment, the disease or condition associated with KRAS G12C mutant protein is a cancer associated with KRAS G12C mutant protein. In one embodiment, the cancer is selected from hematological cancer, pancreatic cancer, colon cancer, rectal cancer, colorectal cancer, or lung cancer. In one embodiment, the hematological cancer is selected from acute myeloid leukemia or acute lymphocytic leukemia; the lung cancer is selected from non-small cell lung cancer or small cell lung cancer.

[0047] definition The term "halogen" or "halo" as used herein means fluoro, chloro, bromo or iodo unless otherwise indicated. Preferred halogen groups include -F, -Cl and -Br. Preferred halogen groups include -F and -Cl.

[0048] The term "alkyl" as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon groups having straight or branched chains. For example, alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl, and 2-methylpentyl. Similarly, C1-6, as in C1-6 alkyl, is defined to identify the group as having 1, 2, 3, 4, 5, or 6 carbon atoms in a straight or branched chain arrangement.

[0049] The term "alkylene" means a difunctional group obtained by removal of a hydrogen atom from an alkyl group that is defined above, for example, methylene (i.e., -CH2-), ethylene (i.e., -CH2-CH2- or -CH(CH3)-), and propylene (i.e., -CH2-CH2-CH2-, -CH(-CH2-CH3)-, or -CH2-CH(CH3)-).

[0050] The term "alkenyl" refers to a straight or branched chain hydrocarbon group containing one or more double bonds and typically between 2 and 20 carbon atoms in length. For example, a "C2-6 alkenyl" contains between 2 and 6 carbon atoms. Alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, 2-methyl-2-buten-1-yl, heptenyl, octenyl, and the like.

[0051] The term "alkynyl" includes straight or branched chain hydrocarbon groups containing one or more triple bonds and typically from 2 to 20 carbon atoms in length. For example, "C2-6 alkynyl" contains from 2 to 6 carbon atoms. Representative alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 1-butynyl, heptynyl, octynyl, and the like.

[0052] The term "alkoxy" group is an oxygen ether formed from an alkyl group as defined above.

[0053] The term "aryl" or "aryl ring" as used herein, unless otherwise indicated, refers to an unsubstituted or substituted monocyclic or polycyclic aromatic ring system containing only carbon ring atoms. Preferred aryls are monocyclic or bicyclic 6-10 membered aromatic ring systems. Phenyl and naphthyl are preferred aryls.

[0054] The term "heterocyclic" or "heterocycle" as used herein refers to unsubstituted and substituted monocyclic or polycyclic non-aromatic ring systems containing one or more ring heteroatoms, including monocyclic heterocyclic, bicyclic, bridged, fused, or spiro heterocyclic, unless otherwise indicated. Preferred heteroatoms include N, O, and S, including N-oxides, sulfur oxides, and dioxides. Preferably, heterocyclic rings are 3-10 membered and are fully saturated or have one or more degrees of unsaturation. Multiple degrees of substitution, preferably 1, 2, or 3, are included within the present definition of heterocyclic. Examples of such heterocyclic groups include, but are not limited to, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, oxoazepinyl, azepinyl, tetrahydrofuranyl, dioxolanyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, and oxadiazolyl.

[0055] The term "heteroaryl" or "heteroaryl ring" as used herein, unless otherwise indicated, refers to an aromatic ring system containing carbon and at least one heteroatom. The heteroaryl or heteroaryl ring may be monocyclic or polycyclic, substituted or unsubstituted. A monocyclic heteroaryl group may have 1-4 heteroatoms in the ring, while a polycyclic heteroaryl may contain 1-10 heteroatoms. A polycyclic heteroaryl ring may contain fused, spiro or bridged ring junctions, e.g., a bicyclic heteroaryl is a polycyclic heteroaryl. A bicyclic heteroaryl ring may contain 8-12 member atoms. A monocyclic heteroaryl ring may contain 5-8 member atoms (carbon and heteroatoms). Examples of heteroaryl groups include, but are not limited to, thienyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridazinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzisoxazolyl, benzoxazolyl, benzopyrazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl adeninyl, quinolinyl, or isoquinolinyl.

[0056] The term "carbocyclic" or "carbocycle" refers to a substituted or unsubstituted monocyclic, bicyclic, bridged, fused, or spirocyclic non-aromatic ring system containing only carbon atoms. Carbocycles (rings) include cycloalkyls with no degree of substitution and carbocycles with a degree of substitution of one or more. Exemplary "cycloalkyl" groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0057] The term "oxo" together with the carbon atom to which it is attached represents the group [ka] This refers to the oxygen atoms that form

[0058] The term "-C1-6 alkylene-N(C1-6 alkyl)2" refers to a -C1-6 alkyl as defined above substituted with -N(C1-6 alkyl)2.

[0059] The term "-C1-6 alkylene-CN" refers to a -C1-6 alkyl as defined above substituted with -CN.

[0060] The term "heteroalkyl" refers to the presence of a heteroatom between any two carbon atoms in an alkyl group as defined above, such as an N or O atom. For example, a "heteroC2-6 alkyl" means that there is an N or O atom between any two carbon atoms in a C2-6 alkyl group, including, but not limited to, -CH2OCH3, -CH2CH2OCH3, -CH2NHCH3, or -CH2N(CH3)2.

[0061] The term "composition" as used herein is intended to encompass a product containing the specified ingredients in the specified amounts, as well as any product that is obtained directly or indirectly from the combination of the specified ingredients in the specified amounts. Thus, pharmaceutical compositions containing the compounds of the present invention as active ingredients, as well as methods for preparing the compounds of the present invention, are also part of the present invention.

[0062] The compounds of the present invention can also exist in the form of pharmaceutically acceptable salts.For use in medicine, the salts of the compounds of the present invention refer to non-toxic "pharmaceutically acceptable salts".Pharmaceutically acceptable salt forms include pharmaceutically acceptable acidic / anionic or basic / cationic salts.Pharmaceutically acceptable acidic / anionic salts generally take the form in which basic nitrogen is protonated with an inorganic or organic acid.

[0063] The present invention includes within its scope prodrugs of the compounds of the present invention. In general, such prodrugs will be functional derivatives of the compounds that are easily converted in vivo into the required compound. Thus, in the method of treatment of the present invention, the term "administering" is intended to encompass the treatment of the various disorders described with a specifically disclosed compound or a compound that may not be specifically disclosed but that is converted in vivo into the specified compound after administration to a subject. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.

[0064] It is intended that the definition of any substituent or variable at a particular location in a molecule be independent of its definitions elsewhere in that molecule. It is understood that substituents and substitution patterns in the compounds of the invention can be selected by those of ordinary skill in the art to provide compounds that are chemically stable and may be readily synthesized by techniques known in the art as well as the methods described herein.

[0065] The present invention includes the compounds described which may contain one or more asymmetric centers and thus may give rise to diastereomers and optical isomers. The present invention includes all such possible diastereomers as well as their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and pharma- ceutically acceptable salts thereof.

[0066] The present invention includes all stereoisomers of the compounds and their generally acceptable salts. In addition, mixtures of stereoisomers as well as isolated specific stereoisomers are included. During the synthetic procedures used to prepare such compounds, or when using racemization or epimerization procedures known to those skilled in the art, the products of such procedures may be mixtures of stereoisomers.

[0067] The term "stereoisomer" as used herein refers to isomers (including conformers and conformational isomers) in which the atoms or groups of atoms in a molecule are in the same order but are bonded to each other in different spatial arrangements. Conformers include geometric isomers and optical isomers, and optical isomers primarily include enantiomers and diastereomers. The present invention includes all possible stereoisomers of a compound.

[0068] Some of the compounds provided herein may exist as atropisomers, which are conformational stereoisomers that arise as a result of steric interactions with other parts of the molecule when rotation around a single bond in the molecule is prevented or significantly slowed down. The compounds provided herein include all atropisomers, either as pure individual atropisomer preparations, enriched preparations of each, or non-specific mixtures of each. If the rotation barrier around a single bond is high enough, the interconversion between conformations is slow enough that separation and isolation of the isomeric species can be permitted.

[0069] The present invention is intended to include all isotopes of atoms occurring in the compounds of the present invention. Isotopes include atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include deuterium and tritium. Isotopes of hydrogen include: 1 H (hydrogen), 2 H (deuterium) and 3 H (tritium). They are also commonly designated as D for deuterium and T for tritium. In this application, CD3 represents a methyl group in which all of the hydrogen atoms are deuterium. The isotopes of carbon are 13 C and 14 C. Isotopically labeled compounds of the present invention can generally be prepared by conventional techniques known to those of skill in the art or by methods analogous to those described herein, using an appropriate isotopically labeled reagent in place of a non-labeled reagent.

[0070] In cases where tautomers of the compounds exist, the present invention includes all possible tautomers and pharma- ceutically acceptable salts thereof, and mixtures thereof, unless otherwise specified.

[0071] The pharmaceutical compositions of the present invention comprise the compound (or a stereoisomer, an atropisomer thereof, a pharma- ceutically acceptable salt thereof, a pharma- ceutically acceptable salt of a stereoisomer, or a pharma- ceutically acceptable salt of an atropisomer) as an active ingredient, and a pharma- ceutical acceptable carrier and, optionally, other adjuvants. Compositions include those suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host to which the active ingredient is to be administered, as well as the nature and severity of the condition. The pharmaceutical compositions may be conveniently presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy.

[0072] In practice, the compounds of the present invention or their prodrugs or metabolites or pharma- ceutically acceptable salts can be combined as active ingredients in intimate admixture with pharmaceutical carriers according to conventional pharmaceutical compounding techniques. The carriers can take a variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous). Thus, the pharmaceutical compositions of the present invention can be presented as discrete units suitable for oral administration, such as capsules, cachets or tablets, each containing a predetermined amount of the active ingredient. Furthermore, the compositions can be presented as a powder, as granules, as a solution, as a suspension in an aqueous liquid, as a non-aqueous liquid, as an oil-in-water emulsion or as a water-in-oil liquid emulsion. In addition to the common dosage forms described above, the compounds or their pharma- ceutically acceptable salts can also be administered by controlled release means and / or delivery devices. The compositions can be prepared by any of the methods of pharmacy. In general, such methods include the step of combining the active ingredient with the carrier, which constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both. The product can then be conveniently shaped into the desired presentation.

[0073] The pharmaceutical carriers used can be, for example, solid, liquid or gas. Examples of solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate and stearic acid. Examples of liquid carriers are liquid sugar, peanut oil, olive oil and water. Examples of gaseous carriers include carbon dioxide and nitrogen. When preparing compositions for oral dosage forms, any convenient pharmaceutical medium can be used. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like can be used to form oral liquid preparations such as suspensions, elixirs and solutions; whereas carriers such as starch, sugar, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like can be used to form oral solid preparations such as powders, capsules and tablets. For ease of administration, tablets and capsules are the preferred oral dosage units, whereby solid pharmaceutical carriers are used. Optionally, tablets can be coated by standard aqueous or non-aqueous techniques.

[0074] Tablets containing the compositions of the present invention may be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants. Compressed tablets may be prepared by compressing the active ingredient in a free-flowing form, such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active agent or dispersant, in a suitable machine. Molded tablets may be made by molding a mixture of the powdered compound moistened with an inert liquid diluent in a suitable machine. Each tablet preferably contains from about 0.05 mg to about 5 g of the active ingredient, and each cachet or capsule preferably contains from about 0.05 mg to about 5 g of the active ingredient. For example, a formulation intended for oral administration to humans may contain from about 0.5 mg to about 5 g of the active agent, compounded with an appropriate and convenient amount of carrier material, which may vary from about 0.05 to about 95 percent of the total composition. A unit dosage form will generally contain from about 0.01 mg to about 2 g of active ingredient, typically 0.01 mg, 0.02 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, 1000 mg, 1500 mg or 2000 mg.

[0075] The pharmaceutical composition of the present invention suitable for parenteral administration can be prepared as a solution or suspension of the active compound in water.Can include suitable surfactant such as hydroxypropylcellulose.Dispersion can also be prepared in glycerol, liquid polyethylene glycol, and mixtures thereof in oil.Furthermore, preservatives can be included to prevent harmful growth of microorganisms.

[0076] The pharmaceutical compositions of the present invention suitable for injectable use include sterile aqueous solutions or dispersions. Moreover, the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile and effectively fluid for easy puncture. The pharmaceutical compositions must be stable under the conditions of manufacture and storage; thus, they should preferably be preserved against the contaminating action of microorganisms, such as bacteria and fungi. The carrier can be, for example, a solvent or dispersion medium containing water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.

[0077] The pharmaceutical composition of the present invention may be in a form suitable for topical use, such as, for example, an aerosol, cream, ointment, lotion, powder, etc. Furthermore, the composition may be in a form suitable for use in a transdermal device. These formulations may be prepared using the compound of the present invention or a pharma- ceutically acceptable salt thereof by conventional processing methods. For example, a cream or ointment is prepared by mixing a hydrophilic material and water together with about 0.05% by weight to about 10% by weight of the compound to produce a cream or ointment having a desired consistency.

[0078] The pharmaceutical composition of the present invention can be in a form suitable for rectal administration, where the carrier is solid.Preferably, the mixture forms a unit dose suppository.Suitable carriers include cocoa butter and other materials commonly used in the art.The suppository can be conveniently formed by first mixing the composition with the softened or melted carrier, followed by cooling and shaping in a mold.

[0079] In addition to the above-mentioned carrier components, the above-mentioned pharmaceutical preparations may contain one or more additional carrier components, such as diluents, buffers, flavoring agents, binders, surfactants, thickeners, lubricants, preservatives (including antioxidants), as necessary. Furthermore, other auxiliary agents may be included to make the preparation isotonic with the blood of the intended recipient. The composition containing the compound or its pharma-ceutically acceptable salt may also be prepared in powder or liquid concentrate form.

[0080] In general, dosage levels of about 0.001 mg / kg to about 150 mg / kg of body weight per day are useful in treating the conditions indicated above, or about 0.05 mg to about 7 g per patient per day. For example, inflammation, cancer, psoriasis, allergy / asthma, diseases and conditions of the immune system, and diseases and conditions of the central nervous system (CNS) can be effectively treated by administration of about 0.001 to 50 mg of compound per kilogram of body weight per day, or about 0.05 mg to about 3.5 g per patient per day.

[0081] However, it will be understood that the specific dosage level for any particular patient will depend on a variety of factors, including age, body weight, general health, sex, dietary habits, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease being treated. 1. [Brief description of the drawings]

[0082] [Figure 1] This is a ball and stick model of the absolute configuration of compound 1-2. [Diagram 2] 1 is an ellipsoidal model of the absolute configuration of compound 1-2. [Diagram 3] 1 is a graph of the unit cell structure of single crystal diffraction for compound 1-2. [Figure 4] 1 is a graph of hydrogen bonds from single crystal diffraction for compound 1-2. [Diagram 5] 1 is a graph of the 3D structure-a direction of single crystal diffraction for compound 1-2. [Figure 6] 1 is a graph of the 3D structure-b direction of single crystal diffraction for compound 1-2. [Figure 7] 1 is a graph of the 3D structure-c direction of single crystal diffraction for compound 1-2. [Figure 8] 1 shows the efficacy of Compound 1-2 and Compound 12-2 in the NCI-H1373 xenograft model. [Figure 9] 1 shows the safety of compound 1-2 in the MIA-PaCa-2 model. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0083] Method of preparation The compounds of the present invention can be synthesized from commercially available reagents using the synthetic methods described herein. The following examples outlining specific synthetic routes are intended to provide guidance to those skilled in the art of synthetic chemistry who will readily understand that solvents, concentrations, reagents, protecting groups, order of synthetic steps, times, temperatures, and the like, can be varied as necessary and well within the skill and judgment of the artisan.

[0084] The following examples are provided to better illustrate the present invention. All parts and percentages are by weight and all temperatures are in degrees Celsius unless otherwise specified. The following abbreviations in Table 1 are used in the examples:

[0085] [Table 1] EXAMPLES

[0086] 2. Example 1 4-(4-acryloylpiperazin-1-yl)-7-(2-amino-3,4,5,6-tetrafluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile ("Compound 1"); (P)-4-(4-acryloylpiperazin-1-yl)-7-(2-amino-3,4,5,6-tetrafluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile ("Compound 1-1"); and (M)-4-(4-acryloylpiperazin-1-yl)-7-(2-amino-3,4,5,6-tetrafluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile ("Compound 1-2") [ka] Step 1. 4-Methyl-2-(prop-1-en-2-yl)pyridin-3-amine In a 350 mL sealed tube purged and maintained with an inert atmosphere of nitrogen were placed 2-bromo-4-methylpyridin-3-amine (BD, APL099) (15.01 g, 80.25 mmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (BD, AQA827) (13.62 g, 81.05 mmol), Pd(dppf)Cl2 (5.95 g, 8.03 mmol), K2CO3 (33.52 g, 240 mmol), dioxane (150 mL) and water (20 mL). The reaction mixture was stirred at 100° C. for 8 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was applied to a silica gel column eluted with EA / Hexane (v:v=2:3). This gave 11.2 g (94%) of 4-methyl-2-(prop-1-en-2-yl)pyridin-3-amine as a yellow oil. LCMS: m / z=149 [M+1] + .

[0087] Step 2. 2-Isopropyl-4-methylpyridin-3-amine (Intermediate A). In a 250 mL round bottom flask purged and maintained with an inert atmosphere of nitrogen was placed 4-methyl-2-(prop-1-en-2-yl)pyridin-3-amine (11.2 g, 75.67 mmol) and MeOH (100 mL). Palladium on carbon (2.81 g) was added in three portions. The mixture was degassed under reduced pressure and then purged with H2 (gas) for three cycles. The mixture was stirred at 25° C. for 3 h. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure. This gave 11 g (crude) of 2-isopropyl-4-methylpyridin-3-amine, which was used directly in the next step. LCMS: m / z=151 [M+1] + .

[0088] Step 3. 2-Cyano-N-(2-isopropyl-4-methylpyridin-3-yl)acetamide. In a 100 mL round bottom flask purged and maintained with an inert atmosphere of nitrogen was placed 2-cyanoacetic acid (3 g, 35.27 mmol) and DCM (40 mL). Oxalyl chloride (6.2 g, 48.85 mmol) was added dropwise. After the addition, DMF (0.1 mL) was added. The mixture was stirred at 25° C. for 3 hours. The resulting solution was concentrated under reduced pressure. This gave 3.10 g (crude) of 2-cyanoacetyl chloride, which was used directly in the next step. In a 100 mL round bottom flask purged and maintained with an inert atmosphere of nitrogen was placed 2-isopropyl-4-methylpyridin-3-amine (2.00 g, 13.31 mmol), TEA (5.40 g, 53.36 mmol) and DCM (40 mL) and stirred. The mixture was cooled to 0° C., then 2-cyanoacetyl chloride (3.10 g, crude) was added dropwise. The resulting solution was stirred at room temperature for an additional 2 h. The reaction was then quenched by the addition of water (100 mL). The resulting solution was extracted with dichloromethane (3×50 mL), the organic layers were combined, washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure and applied to a silica gel column eluted with EA / hexanes (v:v=3:2). This afforded 1.00 g (34%) of 2-cyano-N-(2-isopropyl-4-methylpyridin-3-yl)acetamide as a yellow solid. LCMS: m / z=218[M+1] + .

[0089] Step 4. 2-Cyano-N-(2-isopropyl-4-methylpyridin-3-yl)-3-oxo-3-(2,5,6-trichloropyridin-3-yl)propanamide In a 100 mL round bottom flask, purged and maintained with an inert atmosphere of nitrogen, were placed 2,5,6-trichloronicotinic acid (5.01 g, 22.12 mmol) and SOCl2 (30 mL). The mixture was heated to 80° C. and stirred for 2 h. The solution was concentrated under reduced pressure. This gave 5.10 g (crude) of 2,5,6-trichloronicotinoyl chloride, which was used directly in the next step. In a 250 mL round bottom flask, were placed 2-cyano-N-(2-isopropyl-4-methylpyridin-3-yl)acetamide (3.01 g, 13.85 mmol) and THF (40 mL). The mixture was stirred at 0° C. NaH (1.16 g, 28.99 mmol) was added in three batches. The mixture was stirred at 0° C. for an additional 40 min. Then, 2,5,6-trichloronicotinoyl chloride (3.19 g, 13.03 mmol) in THF (10 mL) was added dropwise. The reaction mixture was stirred at 25° C. for 2 h. The reaction mixture was concentrated under reduced pressure. The resulting crude product was purified by elution with ACN / HO (v / v=1 / 3) 18 Further purification was performed by column chromatography. This gave 5.89 g (crude) of 2-cyano-N-(2-isopropyl-4-methylpyridin-3-yl)-3-oxo-3-(2,5,6-trichloropyridin-3-yl)propanamide as a yellow solid. LCMS: m / z=425[M+1] + .

[0090] Step 5. 6,7-Dichloro-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (Intermediate B) In a 250 mL round bottom flask purged and maintained with an inert atmosphere of nitrogen, 2-cyano-N-(2-isopropyl-4-methylpyridin-3-yl)-3-oxo-3-(2,5,6-trichloropyridin-3-yl)propanamide (5.89 g, 13.83 mmol) and THF (70 mL) were placed and stirred at room temperature. NaH (2.73 g, 68.25 mmol) was added batchwise. The mixture was stirred at 50° C. for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in 100 mL of water and the pH was adjusted to 7 with AcOH. The resulting solid was filtered and dried under reduced pressure to give 5.85 g (108% over two steps) of 6,7-dichloro-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile as a yellow solid. LCMS: m / z=389[M+1] + . 1 H NMR (400MHz, DMSO-d6)δ 8.77(d,J=5.7Hz, 1H), 8.38(s,1H), 7.89(d,J=5.4Hz, 1H), 3.01-2.88(m,1H), 2.19(s,3H), 1.21(d,J=6.9Hz, 3H), 1.14(d,J=6.9Hz, 3H).

[0091] A mixture of 6,7-dichloro-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile atropisomers (10.59 g, "Intermediate B") was purified by chiral preparative HPLC using the following conditions: column, CHIRALPAK IC, 3.0 x 100 mm, 3 μm; mobile phase, IPA / ACN = (v / v = 1 / 1); detection wavelength, UV 210 nm. This gave 4.99 g (47%) of 6,7-dichloro-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (first eluting isomer, "Intermediate B-1", M or P atropisomer) as a brown solid; 1H NMR(400MHz, CD3OD)δ 8.48(s,1H), 8.44(d,J=5.0Hz, 1H), 7.33-7.22(m,1H), 2.76-2.61(m,1H), 2.03(s,3H), 1.19(d,J=6.8Hz, 3H), 1.06(d,J=6.8Hz, 3H).

[0092] and 4.60 g (43%) of 6,7-dichloro-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (second eluting isomer, "Intermediate B-2", P or M atropisomer) as a brown solid; 1 H NMR(400MHz, CD3OD)δ 8.49(s,1H), 8.44(d,J=5.0Hz, 1H), 7.28(d,J=5.0Hz, 1H), 2.76-2.63(m,1H), 2.03(s,3H), 1.19(d,J=6.8Hz, 3H), 1.08-1.00(m,3H).

[0093] Step 6. 4,6,7-Trichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile In a 50 mL round bottom flask purged and maintained with an inert atmosphere of nitrogen was placed 6,7-dichloro-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (Intermediate B, 980 mg, 2.51 mmol), POCl3 (1150 mg, 7.50 mmol), DIEA (1.32 g, 10.21 mmol) and acetonitrile (12 mL). The mixture was stirred at 80° C. for 2 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. This gave crude 4,6,7-trichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile, which was used directly in the next step.

[0094] Step 7. tert-Butyl 4-(6,7-dichloro-3-cyano-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)piperazine-1-carboxylate In a 100 mL round bottom flask purged and maintained with an inert atmosphere of nitrogen, 4,6,7-trichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (1.20 g, crude) and acetonitrile (20 mL) were placed. DIEA (660 mg, 5.10 mmol) and tert-butyl piperazine-1-carboxylate (0.57 g, 3.06 mmol) were added. The reaction mixture was stirred at room temperature for 2 h. Then, the reaction was quenched by the addition of water (50 mL). The resulting solution was extracted with ethyl acetate (3×50 mL) and the organic layers were combined, washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by a silica gel column eluted with EA / Hexane (v / v=30%-70%). This gave 0.92 g (65% over two steps) of tert-butyl 4-(6,7-dichloro-3-cyano-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)piperazine-1-carboxylate as a yellow solid. LCMS: m / z=557[M+1] + .

[0095] Step 8. 4-(4-Acryloylpiperazin-1-yl)-6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (Intermediate C). In a 20 mL sealed tube purged and maintained with an inert atmosphere of nitrogen was placed tert-butyl 4-(6,7-dichloro-3-cyano-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)piperazine-1-carboxylate (920 mg, 1.65 mmol), TFA (4 ml) and DCM (15 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved with DCM (15 mL) in a 50 mL round bottom flask. DIEA (1.02 g, 10.08 mmol) was added. The reaction mixture was cooled to 0° C. and acryloyl chloride (190 mg, 2.09 mmol) was added. The mixture was stirred at room temperature for 2 hours. The reaction was then quenched by the addition of water (30 mL). The resulting solution was extracted with ethyl acetate (3×50 mL) and the organic layers were combined, washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by a silica gel column eluted with EA / Hexane (v / v=40%-80%). This gave 0.86 g (crude) of 4-(4-acryloylpiperazin-1-yl)-6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile as a yellow solid. LCMS: m / z=511[M+1] + .

[0096] Step 9. 2-Bromo-3,4,5,6-tetrafluoroaniline In a 50 mL round bottom flask were placed 2,3,4,5-tetrafluoroaniline (1.99 g, 12.05 mmol), sodium acetate (1.32 g, 16.09 mmol), iron (0.10 g, 1.79 mmol) and AcOH (7 mL). The reaction mixture was heated to 45° C. After this, bromine (3.02 g, 18.90 mmol) in AcOH (7 mL) was added. The reaction mixture was heated to 60° C. and stirred for 1.5 h. The reaction mixture was quenched by the addition of saturated aqueous Na2S2O3 (30 mL). The resulting solution was extracted with ethyl acetate (2×50 mL) and the organic layers were combined, washed with saturated aqueous Na2CO3 (50 mL) and brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. This gave 2.28 g (77%) of 2-bromo-3,4,5,6-tetrafluoroaniline as a yellow solid. LCMS: m / z=244,246[M+1] + .

[0097] Step 10. 2,3,4,5-Tetrafluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline In a 150 mL sealed tube purged and maintained with an inert atmosphere of nitrogen, 2-bromo-3,4,5,6-tetrafluoroaniline (2.28 g, 9.35 mmol), bis(pinacolato)diboron (3.96 g, 15.59 mmol), Pd(dppf)Cl2 (1.21 g, 1.65 mmol), AcOK (1.84 g, 18.75 mmol) and dioxane (20 mL) were placed. The reaction mixture was stirred at 100 °C for 2 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was applied to a silica gel column eluted with EA / Hexane (v / v=0%-20%). This afforded 2.28 g (81% yield) of 2,3,4,5-tetrafluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline as a white solid. LCMS: m / z=210[M+1] + .

[0098] Step 11. 4-(4-acryloylpiperazin-1-yl)-7-(2-amino-3,4,5,6-tetrafluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile ("Compound 1") In a 20 mL sealed tube purged and maintained with an inert atmosphere of nitrogen was placed 4-(4-acryloylpiperazin-1-yl)-6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (221 mg, 0.43 mmol), 2,3,4,5-tetrafluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (513 mg, 1.76 mmol), Pd(PPh3)4 (151 mg, 0.13 mmol), Na2CO3 (161 mg, 1.52 mmol), dioxane (5 mL) and water (0.5 mL). The reaction mixture was stirred at 80° C. for 1 h. The reaction mixture was filtered and concentrated under reduced pressure. The obtained crude product was purified by elution with CH3CN / HO (v / v = 40% to 80%). 18 Further purification was performed by column chromatography. This gave 7 mg (2% yield) of 4-(4-acryloylpiperazin-1-yl)-7-(2-amino-3,4,5,6-tetrafluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile ("Compound 1") as a yellow solid. LCMS: m / z=640 [M+1] + . 1 H NMR(400MHz, CD3OD)δ 8.55(s,1H), 8.43(d,J=5.0Hz, 1H), 7.33-7.20(m,1H), 6.87(dd,J=16.7, 10.6Hz, 1H), 6.31(d,J=16.9Hz, 1H), 5.84(d,J=10.6H) z, 1H), 3.98(d,J=23.5Hz, 8H), 2.73(d,J=28.0Hz, 1H), 2.00(d,J=31.9Hz, 3H), 1.32-1.10(m,3H), 1.00(dd,J=40.7, 6.8Hz, 3H).

[0099] A mixture of 4-(4-acryloylpiperazin-1-yl)-7-(2-amino-3,4,5,6-tetrafluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile atropisomers (356 mg, several batches) was purified by chiral preparative HPLC using the following conditions: column, CHIRALPAK IG, 3 cm x 25 cm, 5 um; mobile phase, CO2:EtOH=55:45; detection wavelength, UV 220 nm. This gave 175 mg (49.16%) of 4-(4-acryloylpiperazin-1-yl)-7-(2-amino-3,4,5,6-tetrafluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (first eluting isomer, "compound 1-1") as a yellow solid. LCMS: m / z=640 [M+1] + . 1 H NMR(400MHz, CD3OD)δ 8.45(d,J=1.9Hz, 1H), 8.34(d,J=5.0Hz, 1H), 7.17(d,J=5.0Hz, 1H), 6.78(dd,J=16.8, 10.6Hz, 1H), 6.21(dd,J=16.8, 2.0Hz, 1H), 5. 74(dd,J=10.6, 2.0Hz, 1H), 4.02-3.72(m,8H), 2.70-2.58(m,1H), 1.97-1.88(m,3H), 1.07(dd,J=8.2, 6.7Hz, 3H), 0.97-0.88(m,3H).

[0100] and 184 mg (51.69%) of 4-(4-acryloylpiperazin-1-yl)-7-(2-amino-3,4,5,6-tetrafluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (second eluting isomer, "compound 1-2") as a yellow solid. LCMS: m / z=640[M+1] + . 1 H NMR(400MHz, CD3OD)δ 8.57(s,1H), 8.45(d,J=5.0Hz, 1H), 7.31(d,J=4.7Hz, 1H), 6.88(dd,J=16.7, 10.7Hz, 1H), 6.32(d,J=16.8Hz, 1H), 5.88 (d,J=10.5Hz, 1H), 4.08-3.92(m,8H), 2.81-2.66(m,1H), 2.06-1.98(m,3H), 1.18(t,J=7.4Hz, 3H), 1.06-0.96(m,3H).

[0101] Approximately 10 mg of compound 1-2 was taken in a glass vial and dissolved in 0.8 mL of ethanol and 0.4 mL of n-heptane. The clear solution was evaporated to dryness at room temperature through a small hole to obtain bulk crystals as samples for single crystal diffraction studies using the following equipment and parameters in Table 2.

[0102] [Table 2]

[0103] The results are shown in Tables 3, 4, 5, 6 and 7.

[0104] Crystallographic data

[0105] [Table 3]

[0106] Molecular structure of compound 1-2

[0107] [Table 4]

[0108] Crystal structure solution data

[0109] [Table 5] JPEG0007644517000069.jpg21170

[0110] [Table 6]

[0111] [Table 7] JPEG0007644517000072.jpg31170

[0112] The following conclusions were reached by crystal structure analysis: The crystal system of compound 1-2 is monoclinic, has two symmetries and one central vector, and the space group is C2.

[0113] The single crystal of compound 1-2 has four molecules in the unit cell.

[0114] Compound 1-2 has one planar chirality (axial chirality). The absolute configuration is M.

[0115] The unit cell has two types of hydrogen bonds, O2---H6A-N6 and N3---H6B-N6. Three-dimensional structures such as chains, stacks and networks are formed by hydrogen bonds and van der Waals forces in the crystal.

[0116] 3. Example 2 4-(4-acryloylpiperazin-1-yl)-7-(3-amino-2,6-dichloro-4,5-difluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile ("Compound 2") [ka] Step 1. 2-(3,4-difluoro-5-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane In a 40 mL sealed tube purged and maintained with an inert atmosphere of nitrogen were placed 5-bromo-1,2-difluoro-3-nitrobenzene (207 mg, 0.38 mmol), bis(pinacolato)diboron (2.16 g, 8.51 mmol), Pd(dppf)Cl2 (0.322 g, 0.44 mmol), KOAc (1.199 g, 12.22 mmol) and dioxane (10 mL). The reaction mixture was stirred at 100 °C for 2 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was applied to a silica gel column eluted with EA / Hexane (v / v=0%-5%). This gave 1.528 g (crude) of 2-(3,4-difluoro-5-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane as an off-white solid.

[0117] Step 2. 2,3-Difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline In a 40 mL round bottom flask was placed 2-(3,4-difluoro-5-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.489 g, 5.22 mmol), iron (1.546 g, 27.68 mmol), NH4Cl (2.654 g, 49.62 mmol), EtOH (15 mL) and HO (5 mL). The reaction mixture was stirred at 80° C. for 1 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was washed with DCM (20 mL), filtered and concentrated under reduced pressure. This gave 0.957 g of 2,3-difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline as an off-white solid. LCMS: m / z=256[M+1] + .

[0118] Step 3. 4-(4-acryloylpiperazin-1-yl)-7-(3-amino-4,5-difluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile In a 20 mL sealed tube purged and maintained with an inert atmosphere of nitrogen was placed 4-(4-acryloylpiperazin-1-yl)-6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (0.21 g, 0.41 mmol), 2,3-difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.279 g, 1.09 mmol), Pd(PPh3)4 (57 mg, 0.05 mmol), Na2CO3 (206 mg, 1.94 mmol), dioxane (5 mL) and water (1 mL). The reaction mixture was stirred at 80° C. for 1 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was applied to a silica gel column eluted with EA / Hexane (v / v=50%-100%). This gave 125 mg of 4-(4-acryloylpiperazin-1-yl)-7-(3-amino-4,5-difluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile as a yellow solid. LCMS: m / z=604[M+1] + .

[0119] Step 4. 4-(4-acryloylpiperazin-1-yl)-7-(3-amino-2,6-dichloro-4,5-difluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile ("Compound 2") In a 50 mL round bottom flask purged and maintained with an inert atmosphere of nitrogen, 4-(4-acryloylpiperazin-1-yl)-7-(3-amino-4,5-difluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (103 mg, 170.52 μmol), NCS (51 mg, 381.93 μmol) and DMA (1.5 mL) were placed. The reaction mixture was stirred at room temperature for 15 h. The reaction was then quenched by the addition of H2O (20 mL). The resulting solution was extracted with ethyl acetate (3 x 20 mL) and the organic layers were combined and concentrated under reduced pressure. The residue was purified by preparative HPLC eluted with CH3CN / H2O (v / v=7 / 1). This gave 30 mg (26%) of 4-(4-acryloylpiperazin-1-yl)-7-(3-amino-2,6-dichloro-4,5-difluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile ("Compound 2"). LCMS: m / z=672 [M+1] + . 1 H NMR(400MHz, CD3OD)δ 8.56(s,1H), 8.40(d,J=5.0Hz, 1H), 7.29-7.15(m,1H), 6.87(dd,J=16.8, 10.6Hz, 1H), 6.30(d,J=16.8Hz, 1H), 5.83 (d,J=10.7Hz, 1H), 4.30-3.77(m,8H), 2.85-2.66(m,1H), 1.99(s,3H), 1.18(d,J=6.7Hz, 3H), 1.01(d,J=6.8Hz, 3H).

[0120] 4. Example 3 4-(4-acryloylpiperazin-1-yl)-7-(2-amino-3-chloro-4,5,6-trifluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile ("Compound 3") [ka] Step 1. 2-Bromo-3,4,5-trifluoroaniline In a 100 mL round bottom flask were placed 2-bromo-3,4,5-trifluoro-1-nitrobenzene (2.64 g, 10.31 mmol), iron (5.71 g, 102.25 mmol), ammonium chloride (5.67 g, 106.00 mmol), ethanol (25 mL) and water (25 mL). The reaction mixture was heated to 55° C. and stirred for 1.5 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethanol (30 mL) and purified by elution with CH3CN / H2O (v:v=9:1). 18 This gave 1.33 g (57%) of 2-bromo-3,4,5-trifluoroaniline. LCMS: m / z=226, 228 [M+1] + .

[0121] Step 2. 3,4,5-Trifluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline In a 40 mL sealed tube purged and maintained with an inert atmosphere of nitrogen, 2-bromo-3,4,5-trifluoroaniline (2.99 g, 13.23 mmol), bis(pinacolato)diboron (10.20 g, 40.17 mmol), Pd(dppf)Cl2 (0.98 g, 1.34 mmol), KOAc (4.18 g, 42.59 mmol) and dioxane (40 mL) were placed. The reaction mixture was stirred at 100° C. for 5 h. The reaction mixture was concentrated under reduced pressure. The residue was applied to a silica gel column eluted with EA / Hexane (v / v=0%-10%). This gave 5.34 g (crude) of 3,4,5-trifluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline.

[0122] Step 3. 4-(4-acryloylpiperazin-1-yl)-7-(6-amino-2,3,4-trifluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile In a 20 mL sealed tube purged and maintained with an inert atmosphere of nitrogen was placed 4-(4-acryloylpiperazin-1-yl)-6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (0.547 g, 1.08 mmol), 3,4,5-trifluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.279 g, 1.09 mmol), Pd(PPh3)4 (1.376 g, 5.04 mmol), Na2CO3 (0.347 g, 3.27 mmol), dioxane (5 mL) and water (1 mL). The reaction mixture was stirred at 80° C. for 4 hours. The reaction mixture was filtered and concentrated under reduced pressure. The residue was applied to a silica gel column eluted with EA / Hexane (v / v=50%-100%). This gave 115 mg of 4-(4-acryloylpiperazin-1-yl)-7-(6-amino-2,3,4-trifluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile as a yellow solid. LCMS: m / z=622[M+1] + .

[0123] Step 4. 4-(4-acryloylpiperazin-1-yl)-7-(2-amino-3-chloro-4,5,6-trifluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile ("Compound 3") Into a 50 mL round bottom flask purged and maintained with an inert atmosphere of nitrogen was placed 4-(4-acryloylpiperazin-1-yl)-7-(6-amino-2,3,4-trifluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (100 mg, 160.76 μmol), NCS (0.035 g, 262.11 μmol) and AcOH (1 mL). The reaction mixture was stirred at 35° C. for 7 h and at room temperature for 15 h. The reaction was then quenched by the addition of saturated aqueous NaHCO3 (30 mL). The resulting solution was extracted with ethyl acetate (2×10 mL) and the organic layers were combined and concentrated under reduced pressure. The residue was purified by preparative HPLC eluted with CH3CN / H2O (v / v=6 / 1). This gave 6 mg (5%) of 4-(4-acryloylpiperazin-1-yl)-7-(2-amino-3-chloro-4,5,6-trifluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile ("Compound 3") as a yellow solid. LCMS: m / z=656 [M+1] + . 1 H NMR(400MHz, CD3OD)δ 8.66-8.51(m,1H), 8.43(d,J=5.1Hz, 1H), 7.26(d,J=5.1Hz, 1H), 6.88(dd,J=16.8, 10.7Hz, 1H), 6.31(d,J=16.7Hz, 1H), 5.84 (d,J=10.7Hz, 1H), 4.06-3.92(m,8H), 2.84-2.62(m,1H), 2.06-1.92(m,3H), 1.17(dd,J=9.6, 7.0Hz, 3H), 1.06-0.94(m,3H).

[0124] 5. Example 4 4-(4-acryloylpiperazin-1-yl)-7-(2-amino-3,5-dichloro-4,6-difluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile ("Compound 4") [ka] Step 1. 3,5-Difluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline In a 100 mL sealed tube purged and maintained with an inert atmosphere of nitrogen, 2-bromo-3,5-difluoroaniline (3.01 g, 14.47 mmol), bis(pinacolato)diboron (6.46 g, 25.43 mmol), Pd(dppf)Cl2 (1.03 g, 1.41 mmol), KOAc (4.20 g, 42.83 mmol), and dioxane (20 mL) were placed. The reaction mixture was stirred at 80° C. for 12 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by a silica gel column eluted with EA / Hexane (v / v=1 / 19). This gave 6.01 g (crude) of 3,5-difluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline as a yellow oil. LCMS: m / z=256[M+1] + .

[0125] Step 2. tert-Butyl 4-(7-(2-amino-4,6-difluorophenyl)-6-chloro-3-cyano-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)piperazine-1-carboxylate In a 100 mL sealed tube purged and maintained with an inert atmosphere of nitrogen was placed 3,5-difluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (5.86 g, 23.00 mmol), tert-butyl 4-(6,7-dichloro-3-cyano-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)piperazine-1-carboxylate (1.29 g, 2.31 mmol), Pd(PPh3)4 (0.73 g, 0.63 mmol), Na2CO3 (0.84 g, 7.89 mmol), dioxane (15 mL) and water (2 mL). The reaction mixture was stirred at 80° C. for 2 hours. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column eluted with EA / hexane (v / v=1 / 1). This gave 1.42 g (crude) of tert-butyl 4-(7-(2-amino-4,6-difluorophenyl)-6-chloro-3-cyano-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)piperazine-1-carboxylate as a yellow solid. LCMS: m / z=650[M+1] + .

[0126] Step 3. tert-Butyl 4-(7-(2-amino-3,5-dichloro-4,6-difluorophenyl)-6-chloro-3-cyano-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)piperazine-1-carboxylate Into a 50 mL round bottom flask purged and maintained with an inert atmosphere of nitrogen was placed tert-butyl 4-(7-(2-amino-4,6-difluorophenyl)-6-chloro-3-cyano-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)piperazine-1-carboxylate (1.21 g, 1.87 mmol), NCS (0.49 g, 3.73 mmol) and AcOH (30 mL). The reaction mixture was stirred at room temperature for 48 h. The reaction was then quenched by the addition of water (100 mL). The resulting solution was extracted with ethyl acetate (2×100 mL) and the organic layers were combined, washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column eluted with EA / hexane (v / v=1 / 1). This gave 0.53 g (crude) of tert-butyl 4-(7-(2-amino-3,5-dichloro-4,6-difluorophenyl)-6-chloro-3-cyano-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)piperazine-1-carboxylate as a yellow solid. LCMS: m / z=718[M+1] + .

[0127] Step 4. 4-(4-acryloylpiperazin-1-yl)-7-(2-amino-3,5-dichloro-4,6-difluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile ("Compound 4") In a 20 mL round bottom flask purged and maintained with an inert atmosphere of nitrogen was placed tert-butyl 4-(7-(2-amino-3,5-dichloro-4,6-difluorophenyl)-6-chloro-3-cyano-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)piperazine-1-carboxylate (0.53 g, 0.73 mmol), TFA (5 ml) and DCM (20 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in a 25 mL round bottom flask with DCM (10 mL). DIEA (1.22 g, 9.48 mmol) was added. The reaction mixture was cooled to 0° C. and acryloyl chloride (0.08 g, 0.88 mmol) was added. The mixture was stirred at room temperature for 0.5 hours. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (CH3CN / H2O (v / v=7 / 3)). This gave 239 mg (50% over two steps) of 4-(4-acryloylpiperazin-1-yl)-7-(2-amino-3,5-dichloro-4,6-difluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile ("Compound 4") as a yellow solid. LCMS: m / z=672 [M+1] + . 1 H NMR(400MHz, CD3OD)δ 8.55(s,1H), 8.43(s,1H), 7.26(s,1H), 6.87(dd,J=16.1, 11.1Hz, 1H), 6.31(d,J=16.3Hz, 1H), 5. 84(d,J=10.1Hz, 1H), 4.25-3.75(m,8H), 2.85-2.60(m,1H), 2.14-1.88(m,3H), 1.25-0.87(m,6H).

[0128] 6. Example 5 4-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-7-(2-amino-3,5-dichloro-4,6-difluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile ("Compound 5") [ka] Step 1. 4-((3R,5S)-4-Acryloyl-3,5-dimethylpiperazin-1-yl)-6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (Intermediate D) In a 500 mL round bottom flask purged and maintained with an inert atmosphere of nitrogen was placed 6,7-dichloro-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (6.21 g, 15.95 mmol), POCl3 (6.88 g, 48.87 mmol), DIEA (6.80 g, 52.61 mmol) and acetonitrile (100 mL). The mixture was stirred at 80° C. for 2 hours. The reaction was cooled to room temperature and concentrated under reduced pressure. This provided 4,6,7-trichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile, which was used directly in the next step.

[0129] In a 500 mL round bottom flask purged and maintained with an inert atmosphere of nitrogen, 4,6,7-trichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (crude), DIEA (6.80 g, 52.61 mmol) and acetonitrile (100 mL) were added, and (2S,6R)-2,6-dimethylpiperazine (2.17 g, 19.00 mmol) was added. The mixture was stirred at room temperature for 1 h. The resulting solution was concentrated under reduced pressure and applied to a silica gel column eluted with EA / Hexane (v / v=2 / 1). This gave 4.30 g (50% yield) of 4-((3R,5S)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile as a yellow solid. LCMS: m / z=539[M+1] + .

[0130] Step 2. 3,5-Difluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline In a 40 mL sealed tube purged and maintained with an inert atmosphere of nitrogen, 2-bromo-3,5-difluoroaniline (2.06 g, 9.91 mmol), bis(pinacolato)diboron (4.95 g, 19.49 mmol), Pd(dppf)Cl2 (809 mg, 1.11 mmol), KOAc (2.23 g, 22.69 mmol), and dioxane (20 mL) were placed. The reaction mixture was stirred at 100 °C for 19 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by elution with CH3CN / H2O (v / v = 5% to 100%). 18 Column was applied. This gave 1.19 g of 3,5-difluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline as an off-white solid. LCMS: m / z=256[M+1] + .

[0131] Step 3. 4-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-7-(2-amino-4,6-difluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydroquinoline-3-carbonitrile In a 20 mL sealed tube purged and maintained with an inert atmosphere of nitrogen was placed 4-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydroquinoline-3-carbonitrile (0.196 g, 0.36 mmol), 3,5-difluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.27 g, 1.06 mmol), Pd(PPh3)4 (78 mg, 0.07 mmol), Na2CO3 (207 mg, 1.95 mmol), dioxane (5 mL) and water (1 mL). The reaction mixture was stirred at 80° C. for 1 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was applied to a silica gel column eluted with EA / Hexane (v / v=50%-100%). This gave 223 mg of 4-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-7-(2-amino-4,6-difluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydroquinoline-3-carbonitrile as a yellow solid. LCMS: m / z=632[M+1] + .

[0132] Step 4. 4-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-7-(2-amino-3,5-dichloro-4,6-difluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydroquinoline-3-carbonitrile ("Compound 5") In a 20 mL round bottom flask was placed 4-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-7-(2-amino-4,6-difluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydroquinoline-3-carbonitrile (223 mg, 0.35 mmol), NCS (98 mg, 0.73 mmol) and HOAc (3 mL). The reaction mixture was stirred at room temperature for 1 day. The reaction was heated to 45° C. and stirred at this temperature for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC CH3CN / H2O (0.05% NH4HCO3) (v / v=2 / 1). This gave 55 mg (22%) of 4-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-7-(2-amino-3,5-dichloro-4,6-difluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydroquinoline-3-carbonitrile ("Compound 5") as a yellow solid. LCMS: m / z=700 [M+1] + . 1 H NMR(400MHz, CD3OD)δ 8.83(s,1H), 8.43(d,J=5.0Hz, 1H), 7.27(d,J=5.0Hz, 1H), 6.95-6.82(m,1H), 6.33(d,J=16.5Hz, 1H), 5.84(d,J=10.8Hz, 1H), 4.77(s,2H) , 4.13-3.92(m,2H), 3.84(d,J=9.4Hz, 2H), 2.80-2.60(m,1H), 2.08-1.93(m,3H), 1.72-1.59(m,6H), 1.25-1.10(m,3H), 1.10-0.89(m,3H).

[0133] 7. Example 6 4-(4-acryloylpiperazin-1-yl)-7-(3-amino-2,4,5,6-tetrafluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile ("Compound 6") [ka] Step 1. 4-(4-acryloylpiperazin-1-yl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-7-(tributylstannyl)-1,2-dihydro-1,8-naphthyridine-3-carbonitrile In a 30 mL sealed tube purged and maintained with an inert atmosphere of nitrogen, 4-(4-acryloylpiperazin-1-yl)-6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (1.039 g, 2.04 mmol), 1,1,1,2,2,2-hexabutyl-distannane (4.124 g, 7.11 mmol), Pd(PPh3)4 (0.566 g, 0.49 mmol) and dioxane (10 mL) were placed. The reaction mixture was stirred at 100° C. for 1 day. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column eluted with EA / Hexane (v / v=2 / 1). This gave 273 mg (17%) of 4-(4-acryloylpiperazin-1-yl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-7-(tributylstannyl)-1,2-dihydro-1,8-naphthyridine-3-carbonitrile as a yellow solid. LCMS: m / z=767[M+1] + .

[0134] Step 2. 4-(4-acryloylpiperazin-1-yl)-7-(3-amino-2,4,5,6-tetrafluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile ("Compound 6") In a 25 mL round bottom flask purged and maintained with an inert atmosphere of nitrogen was placed 4-(4-acryloylpiperazin-1-yl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-7-(tributylstannyl)-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (0.272 g, 0.36 mmol), 2,3,4,6-tetrafluoro-5-iodoaniline (0.630 g, 2.17 mmol), Pd(PPh3)4 (0.187 g, 0.16 mmol), cuprous iodide (0.294 g, 1.54 mmol), and dioxane (10 mL). The reaction mixture was stirred at 100° C. for 1 day. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC eluted with ACN / H2O (v / v=1 / 2). This gave 6 mg (3%) of 4-(4-acryloylpiperazin-1-yl)-7-(3-amino-2,4,5,6-tetrafluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile ("Compound 6") as a yellow solid. LCMS: m / z=640 [M+1] + . 1 H NMR(400MHz, CD3OD)δ 8.56(s,1H), 8.42(d,J=4.9Hz, 1H), 7.31-7.20(m,1H), 6.87(dd,J=16.7, 10.6Hz, 1H), 6.30(dd,J=16.8, 1.7Hz, 1H), 5.83 (dd,J=10.6, 1.8Hz, 1H), 4.08-3.87(m,8H), 2.79-2.62(m,1H), 2.00(s,3H), 1.17(d,J=6.8Hz, 3H), 0.98(d,J=6.7Hz, 3H).

[0135] 8. Example 7 4-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-7-(3-amino-2-chloro-4,5,6-trifluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile ("Compound 7") [ka] Step 1. 4-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-7-(5-amino-2,3,4-trifluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile In a 30 mL sealed tube purged and maintained with an inert atmosphere of nitrogen was placed 4-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (0.822 g, 1.52 mmol), (5-amino-2,3,4-trifluorophenyl)boronic acid (0.608 g, 2.23 mmol), Pd(PPh3)4 (0.650 g, 0.56 mmol), Na2CO3 (0.575 g, 5.43 mmol), dioxane (10 mL) and water (2 mL). The reaction mixture was stirred at 80° C. for 1 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column eluted with EA / hexane (v / v=2 / 1). This gave 1.079 g (91%) of 4-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-7-(5-amino-2,3,4-trifluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile as a yellow solid. LCMS: m / z=650[M+1] + .

[0136] Step 2. 4-((3S,5R)-4-Acryloyl-3,5-dimethylpiperazin-1-yl)-7-(3-amino-2-chloro-4,5,6-trifluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile ("Compound 7"). Into a 50 mL round bottom flask purged and maintained with an inert atmosphere of nitrogen was placed 4-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-7-(5-amino-2,3,4-trifluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (0.622 g, 0.96 mmol), NCS (0.703 g, 5.27 mmol), and AcOH (5 mL). The mixture was stirred at room temperature for 2 days. The reaction was then quenched by the addition of water (10 mL). The resulting solution was extracted with ethyl acetate (3×10 mL) and the organic layers were combined, washed with brine (1×50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (CHCN / HO (v / v=6 / 4)). This gave 35 mg (5%) of 4-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-7-(3-amino-2-chloro-4,5,6-trifluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile ("Compound 7") as a yellow solid. LCMS: m / z=684 [M+1] + . 1 H NMR(400MHz, CD3OD)δ 8.83(s,1H), 8.42(d,J=5.0Hz, 1H), 7.22-7.10(m,1H), 6.88(dd,J=16.7, 10.7Hz, 1H), 6.32(d,J=16.5Hz, 1H), 5.74(dd,J=10.6, 2.0Hz, 1H), 4.76(s,2H), 4.06-3.73(m,4H), 2.82-2.69(m,1H), 2.10-1.94(m,3H), 1.63-1.35(m,6H), 1.17(d,J=6.5Hz, 3H), 1.06-0.89(m,3H).

[0137] 9. Example 8 4-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-7-(3-amino-2,4,5,6-tetrafluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile ("Compound 8") [ka] Step 1. 4-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile In a 20 mL round bottom flask purged and maintained with an inert atmosphere of nitrogen were placed 6,7-dichloro-4-((3S,5R)-3,5-dimethylpiperazin-1-yl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (6.503 g, 13.39 mmol), DIEA (5.21 g, 40.31 mmol), DCM (6 mL) and acryloyl chloride (1.18 g, 13.04 mmol). The reaction mixture was stirred at room temperature for 0.5 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column eluted with EA / Hexane (v / v=1 / 1). This gave 1.80 g (crude) of 4-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile as a yellow solid. LCMS: m / z=539[M+1] + .

[0138] Step 2. 4-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-7-(tributylstannyl)-1,2-dihydro-1,8-naphthyridine-3-carbonitrile In a 20 mL sealed tube purged and maintained with an inert atmosphere of nitrogen, 4-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (1.77 g, 3.28 mmol), hexabutyldistannane (23.85 g, 6.64 mmol), Pd(PPh3)4 (0.26 g, 0.23 mmol) and dioxane (20 mL) were placed. The reaction mixture was stirred at 110° C. for 18 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column eluted with EA / Hexane (v / v=2 / 1). This gave 0.52 g (crude) of 4-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-7-(tributylstannyl)-1,2-dihydro-1,8-naphthyridine-3-carbonitrile as a yellow solid. LCMS: m / z=795[M+1] + .

[0139] Step 3. 4-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-7-(3-amino-2,4,5,6-tetrafluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile ("Compound 8") Into a 20 mL round bottom flask purged and maintained with an inert atmosphere of nitrogen was placed 4-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-7-(tributylstannyl)-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (0.40 g, 0.51 mmol), 2,3,4,6-tetrafluoro-5-iodoaniline (0.27 g, 0.93 mmol), Pd(PPh3)4 (0.27 g, 0.23 mmol), CuI (0.40 g, 2.11 mmol), and DMA (15 mL). The reaction mixture was stirred at 90° C. for 18 hours. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (CH3CN / H2O (v / v=7 / 3)). This gave 8 mg (2.3% over two steps) of 4-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-7-(3-amino-2,4,5,6-tetrafluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile ("Compound 8") as a yellow solid. LCMS: m / z=668 [M+1] + . 1 H NMR (400MHz, CD3OD) δ 8.73(s,1H), 8.34(d,J=5.0Hz, 1H), 7.23-7.15(m,1H), 6.79(dd,J=16.7, 10.7Hz, 1H), 6.23(dd,J=16.7, 2.0Hz, 1H), 5.74(dd,J=10.6, 2.0Hz, 1H) , 4.73-4.58(m,2H), 3.95-3.70(m,4H), 2.66-2.57(m,1H), 1.93(d,J=8.4 Hz, 3H), 1.55-1.57(m,6H), 1.07(d,J=6.8Hz, 3H), 0.89(d,J=5.7Hz, 3H).

[0140] 10. Example 9 (P)-4-((R)-4-acryloyl-3-methylpiperazin-1-yl)-7-(2-amino-3,4,5,6-tetrafluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile; or (M)-4-((R)-4-acryloyl-3-methylpiperazin-1-yl)-7-(2-amino-3,4,5,6-tetrafluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile; (“Compound 9”) [ka] Step 1. 6,7-Dichloro-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile In a 250 mL round bottom flask purged and maintained with an inert atmosphere of nitrogen, 2-cyano-N-(2-isopropyl-4-methylpyridin-3-yl)-3-oxo-3-(2,5,6-trichloropyridin-3-yl)propanamide (5.89 g, 13.83 mmol) and THF (70 mL) were placed and the mixture was stirred at room temperature. After this, NaH (2.73 g, 68.25 mmol) was added batchwise. The mixture was stirred at 50° C. for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in 100 mL of water and the pH was adjusted to 7 with AcOH. The resulting solid was filtered and dried under reduced pressure to give 5.85 g (108% over two steps) of 6,7-dichloro-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile as a yellow solid. LCMS: m / z=389[M+1] + . 1H NMR (400MHz, DMSO-d6)δ 8.77(d,J=5.7Hz, 1H), 8.38(s,1H), 7.89(d,J=5.4Hz, 1H), 3.01-2.88(m,1H), 2.19(s,3H), 1.21(d,J=6.9Hz, 3H), 1.14(d,J=6.9Hz, 3H).

[0141] A mixture of 6,7-dichloro-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile atropisomers (10.59 g, "Intermediate B", several batches) was purified by chiral preparative HPLC using the following conditions: column, CHIRALPAK IC, 3.0 x 100 mm, 3 μm; mobile phase, IPA / ACN=1 / 1 (V / V); detection wavelength, UV 210 nm. This gave 4.99 g (47%) of 6,7-dichloro-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (first eluting isomer, "Intermediate B-1", M or P atropisomer) as a brown solid; 1 H NMR(400MHz, CD3OD)δ 8.48(s,1H), 8.44(d,J=5.0Hz, 1H), 7.33-7.22(m,1H), 2.76-2.61(m,1H), 2.03(s,3H), 1.19(d,J=6.8Hz, 3H), 1.06(d,J=6.8Hz, 3H).

[0142] and 4.60 g (43%) of 6,7-dichloro-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (second eluting isomer, "Intermediate B-2", P or M atropisomer) as a brown solid; 1H NMR(400MHz, CD3OD)δ 8.49(s,1H), 8.44(d,J=5.0Hz, 1H), 7.28(d,J=5.0Hz, 1H), 2.76-2.63(m,1H), 2.03(s,3H), 1.19(d,J=6.8Hz, 3H), 1.079-1.00(m,3H).

[0143] Step 2. tert-Butyl (R)-4-(6,7-dichloro-3-cyano-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)-2-methylpiperazine-1-carboxylate (single isomer). In a 50 mL round bottom flask purged and maintained with an inert atmosphere of nitrogen was placed 6,7-dichloro-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (first eluting isomer in step 1) (1.05 g, 2.71 mmol), POCl3 (2.04 g, 13.27 mmol), DIEA (3.09 g, 23.93 mmol) and acetonitrile (20 mL). The mixture was stirred at 80° C. for 2 hours. The reaction was cooled to room temperature and concentrated under reduced pressure. This gave 4,6,7-trichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile, which was used directly in the next step.

[0144] In a 100 mL round bottom flask purged and maintained with an inert atmosphere of nitrogen, 4,6,7-trichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (crude) and acetonitrile (10 mL), DIEA (3.09 g, 23.93 mmol) were placed, and tert-butyl (R)-2-methylpiperazine-1-carboxylate (507 mg, 2.53 mmol) was added. The reaction mixture was stirred at room temperature for 2 h. Then, the reaction was quenched by the addition of water (50 mL). The resulting solution was extracted with ethyl acetate (3×50 mL), and the organic layers were combined, washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by a silica gel column eluted with EA / Hexane (v / v=5 / 4). This gave 0.95 g (65% over two steps) of tert-butyl (R)-4-(6,7-dichloro-3-cyano-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)-2-methylpiperazine-1-carboxylate (single isomer, P or M) as a red solid. LCMS: m / z=571 [M+1] + .

[0145] Step 3. (R)-4-(4-acryloyl-3-methylpiperazin-1-yl)-6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile Into a 50 mL round bottom flask purged and maintained with an inert atmosphere of nitrogen was placed tert-butyl (R)-4-(6,7-dichloro-3-cyano-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)-2-methylpiperazine-1-carboxylate (P or M isomer, 1.01 g, 1.767 mmol), DCM (8 mL) and TFA (4.605 g, 40.386 mmol). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in a 50 mL round bottom flask with DCM (10 mL) and triethylamine (1.30 g, 12.85 mmol) was added. The reaction mixture was cooled to 0° C. and acryloyl chloride (0.23 g, 2.541 mmol) was added. The mixture was stirred at room temperature for 0.5 h. The reaction was then quenched by the addition of water (20 mL). The resulting solution was extracted with ethyl acetate (3×20 mL) and the organic layers were combined, washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC CH3CN / H2O (v / v=3 / 2). This afforded 1.46 g (crude) of (R)-4-(4-acryloyl-3-methylpiperazin-1-yl)-6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (P or M isomer) as a yellow solid. LCMS: m / z=525[M+1] + .

[0146] Step 4. 4-((R)-4-acryloyl-3-methylpiperazin-1-yl)-7-(2-amino-3,4,5,6-tetrafluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (P or M isomer, "Compound 9") Into a 100 mL round bottom flask purged and maintained with an inert atmosphere of nitrogen was placed (R)-4-(4-acryloyl-3-methylpiperazin-1-yl)-6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (P or M isomer, 1.64 g, 3.11 mmol), (2-amino-3,4,5,6-tetrafluorophenyl)boronic acid (1.37 g, 6.57 mmol), Pd(PPh3)4 (0.37 g, 315.86 μmol), Na2CO3 (1.11 g, 10.49 mmol), 1,4-dioxane (15 mL) and water (2 mL). The resulting mixture was stirred at 80° C. for 30 minutes. Three batches of (2-amino-3,4,5,6-tetrafluorophenyl)boronic acid (2.84 g, 13.59 mmol) were added over 3 h. After the reaction was completed, the reaction was evaporated under reduced pressure and applied to a silica gel column eluted with EA / Hexane (v / v=7 / 3), and the crude product was purified by HPLC eluted with CH3CN / H2O (v / v=3 / 2), which gave (784 mg, 38.50%) 7-(2-amino-3,4,5,6-tetrafluoro-phenyl)-6-chloro-1-(2-isopropyl-4-methyl-3-pyridyl)-4-[(3R)-3-methyl-4-prop-2-enoyl-piperazin-1-yl]-2-oxo-1,8-naphthyridine-3-carbonitrile (P or M isomer, "Compound 9") as a pale yellow solid. LCMS: m / z=654[M+1] + . 1 H NMR(400MHz, CD3OD)δ 8.48(s,1H), 8.42-8.31(m,1H), 7.23(d,J=5.0Hz, 1H), 6.76(dd,J=16.7, 10.7 Hz, 1H), 6.20(dd,J=16.7, 1.8Hz, 1H), 5.73(dd,J=10.6, 1.9Hz, 1H), 4.40(s,1 H), 4.18-4.10(m,2H), 3.94-3.83(m,2H), 3.65-3.54(m,2H), 2.64-2.51(m,1H ), 2.06-1.92(m,3H), 1.44-1.30(m,3H), 1.10-1.03(m,3H), 0.96-0.81(m,3H).

[0147] 11. Example 10 4-((R)-4-acryloyl-3-methylpiperazin-1-yl)-7-(2-amino-6-chloro-3,4,5-trifluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile ("Compound 10"); (P)-4-((R)-4-acryloyl-3-methylpiperazin-1-yl)-7-(2-amino-6-chloro-3,4,5-trifluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile; and (M)-4-((R)-4-acryloyl-3-methylpiperazin-1-yl)-7-(2-amino-6-chloro-3,4,5-trifluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile [ka] Step 1. (R)-4-(4-acryloyl-3-methylpiperazin-1-yl)-7-(2-amino-3,4,5-trifluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile In a 20 mL round bottom flask was placed (R)-4-(4-acryloyl-3-methylpiperazin-1-yl)-6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (1.114 g, 2.12 mmol), (2-amino-3,4,5-trifluorophenyl)boronic acid (0.787 g, 4.12 mmol), Pd(PPh3)4 (0.527 g, 0.45 mmol), Na2CO3 (0.652 g, 6.15 mmol), dioxane (15 mL) and water (3 mL). The reaction mixture was stirred at 80° C. for 1 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC CH3CN / H2O (0.05% NH4HCO3) (v / v=2 / 1). This gave 1.941 g (69%) of (R)-4-(4-acryloyl-3-methylpiperazin-1-yl)-7-(2-amino-3,4,5-trifluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile as a yellow solid. LCMS: m / z=636[M+1] + .

[0148] Step 2. 4-((R)-4-acryloyl-3-methylpiperazin-1-yl)-7-(2-amino-6-chloro-3,4,5-trifluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile ("Compound 10") In a 50 mL round bottom flask purged and maintained with an inert atmosphere of nitrogen, (R)-4-(4-acryloyl-3-methylpiperazin-1-yl)-7-(2-amino-3,4,5-trifluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (1.904 g, 3.00 mmol), NCS (0.946 g, 6.17 mmol) and AcOH (5 mL) were placed. The mixture was stirred at room temperature for 1 day. The residue was purified by preparative HPLC (CH3CN / H2O) (v / v=6 / 4). This gave 0.497 g (25%) of 4-((R)-4-acryloyl-3-methylpiperazin-1-yl)-7-(2-amino-6-chloro-3,4,5-trifluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile ("Compound 10") as a yellow solid. LCMS: m / z=670 [M+1] + .

[0149] Step 3. 4-((R)-4-acryloyl-3-methylpiperazin-1-yl)-7-(2-amino-6-chloro-3,4,5-trifluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (first eluting isomer, "Compound 10-1") and 4-((R)-4-acryloyl-3-methylpiperazin-1-yl)-7-(2-amino-6-chloro-3,4,5-trifluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (second eluting isomer, "Compound 10-2") A mixture of 4-((R)-4-acryloyl-3-methylpiperazin-1-yl)-7-(2-amino-6-chloro-3,4,5-trifluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile atropisomers (495 mg) was purified by chiral preparative HPLC using the following conditions: column, CHIRAL ART Cellulose-SB, 3 cm x 25 cm, 5 um; mobile phase, (Hex:DCM=3:1):EtOH (v / v=90:10); detection wavelength, UV 220 nm. This gave 204 mg (41.21%) of 4-((R)-4-acryloyl-3-methylpiperazin-1-yl)-7-(2-amino-6-chloro-3,4,5-trifluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (first eluting isomer, "compound 10-1") as a yellow solid. LCMS: m / z=670[M+1] + . 1 H NMR(400MHz, CD3OD)δ 8.58(s,1H), 8.41(dd,J=5.0, 1.4Hz, 1H), 7.23(dd,J=8.4, 3.2Hz, 1H), 6.85(dd,J=16.7, 10.7Hz, 1H), 6.29(dd,J=16.8, 1.8Hz, 1H), 5.82(dd,J=10.6, 1.9Hz, 1H), 4.88(s,2H), 4.6 0(s,1H), 4.29-4.22(m,1H), 4.09-3.90(m,2H), 3.62(s,1H), 2.89-2.70(m,1H), 1.95(d,J =12.6Hz, 3H), 1.45(d,J=6.5Hz, 3H), 1.18(t,J=8.0Hz, 3H), 1.00(dd,J=12.5, 6.8Hz, 3H).

[0150] and 170 mg (28.34%) of 4-((R)-4-acryloyl-3-methylpiperazin-1-yl)-7-(2-amino-6-chloro-3,4,5-trifluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (second eluting isomer, "compound 10-2") was obtained as a yellow solid. LCMS: m / z=670[M+1] + . 1 H NMR(400MHz, CD3OD)δ 8.59(s,1H), 8.41(d,J=5.0Hz, 1H), 7.34-7.17(m,1H), 6.85(dd,J=16.7, 10.7Hz, 1H ), 6.29(dd,J=16.8, 1.8Hz, 1H), 5.82(dd,J=10.6, 1.9Hz, 1H), 4.88(s,2H), 4.60(s,1 H), 4.27-4.18(m,1H), 4.00(s,2H), 3.73-3.56(m,1H), 2.77-2.49(m,1H), 2.05(d,J =10.4Hz, 3H), 1.46(d,J=6.5Hz, 3H), 1.16(dd,J=6.8, 1.3Hz, 3H), 1.06-0.84(m,3H).

[0151] 12. Example 11 4-((S)-4-acryloyl-2-methylpiperazin-1-yl)-7-(2-amino-3,4,5,6-tetrafluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile ("Compound 11"); (P)-4-((S)-4-acryloyl-2-methylpiperazin-1-yl)-7-(2-amino-3,4,5,6-tetrafluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile; and (M)-4-((S)-4-acryloyl-2-methylpiperazin-1-yl)-7-(2-amino-3,4,5,6-tetrafluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile. [ka] Step 1. 4-((S)-4-acryloyl-2-methylpiperazin-1-yl)-7-(2-amino-3,4,5,6-tetrafluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile ("Compound 11") In a 20 mL round bottom flask was placed (S)-4-(4-acryloyl-2-methylpiperazin-1-yl)-6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (0.311 g, 0.59 mmol), (2-amino-3,4,5,6-tetrafluorophenyl)boronic acid (0.512 g, 1.49 mmol), Pd(PPh3)4 (0.085 g, 0.073 mmol), Na2CO3 (0.126 g, 1.19 mmol), dioxane (8 mL) and water (2 mL). The reaction mixture was stirred at 80° C. for 1 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC CH3CN / H2O (0.05% NH4HCO3) (v / v=2 / 1). This gave 135 mg (35%) of 4-((S)-4-acryloyl-2-methylpiperazin-1-yl)-7-(2-amino-3,4,5,6-tetrafluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile as a yellow solid ("Compound 11"). LCMS: m / z=654 [M+1] + .

[0152] Step 2. 4-((S)-4-acryloyl-2-methylpiperazin-1-yl)-7-(2-amino-3,4,5,6-tetrafluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (first eluting isomer, "Compound 11-1") and 4-((S)-4-acryloyl-2-methylpiperazin-1-yl)-7-(2-amino-3,4,5,6-tetrafluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (second eluting isomer, "Compound 11-2") A mixture of 4-((S)-4-acryloyl-2-methylpiperazin-1-yl)-7-(2-amino-3,4,5,6-tetrafluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile atropisomers (135 mg) was purified using the following conditions: column, CHIRALPAK IF, 2 cm x 25 cm, 5 um Purification was performed by chiral preparative HPLC using a mobile phase of (Hex:DCM=3:1):IPA=80:20; detection wavelength, UV 220 nm. This gave 67 mg (49%) of 4-((S)-4-acryloyl-2-methylpiperazin-1-yl)-7-(2-amino-3,4,5,6-tetrafluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (first eluting isomer, "compound 11-1") as a yellow solid. LCMS: m / z=654 [M+1] + . 1H NMR(400MHz, CD3OD)δ 8.52(s,1H), 8.43-8.44(m,1H), 7.26(t,J=5.5Hz, 1H), 7.02-6.77(m,1H), 6.33(d,J=16.2Hz, 1H), 5.85(d,J=10.5Hz, 1H), 4.67-4.39(m,2 H), 4.17-4.18(m,3H), 3.78-3.56(m,2H), 2.81-2.83(m,1H), 1.93-1.94(m,3H), 1.38-1.40(m,3H), 1.18-1.19(m,3H), 1.01-1.04(m,3H).

[0153] and 61 mg (45%) of 4-((S)-4-acryloyl-2-methylpiperazin-1-yl)-7-(2-amino-3,4,5,6-tetrafluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (second eluting isomer, "compound 11-2") was obtained as a yellow solid. LCMS: m / z=654[M+1] + . 1 H NMR(400MHz, CD3OD)δ 8.53(s,1H), 8.43-8.44(m,1H), 7.29-7.25(m,1H), 6.85-6.86(m,1H), 6.33(d,J=15.3Hz, 1H), 5.85(d,J=10.7Hz, 1H), 4.53-4.54(m,2H) ), 4.16-4.17(m,3H), 3.65-3.67(m,2H), 2.58-2.59(m,1H), 2.16-2.02(m,3H), 1.38-1.40(m,3H), 1.19-1.11(m,3H), 0.98-0.99(m,3H).

[0154] 13. Example 12 4-(4-acryloylpiperazin-1-yl)-7-(3-amino-2-chloro-4,5,6-trifluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile ("Compound 12"); (P)-4-(4-acryloylpiperazin-1-yl)-7-(3-amino-2-chloro-4,5,6-trifluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile; and (M)-4-(4-acryloylpiperazin-1-yl)-7-(3-amino-2-chloro-4,5,6-trifluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile [ka] Step 1. 2,3,4-Trifluoro-1-iodo-5-nitrobenzene In a 250 mL three-necked bottom flask purged and maintained with an inert atmosphere of nitrogen, 1,2,3-trifluoro-4-nitrobenzene (4.98 g, 28.12 mmol), N-iodosuccinimide (15.99 g, 71.07 mmol), trifluoromethanesulfonic acid (25 mL) were placed and stirred. The resulting solution was stirred at room temperature overnight. The reaction was then quenched by slow addition of water (200 mL). The resulting solution was extracted with EA (2×100 mL), the organic layers were combined and washed with water (100 mL) and brine (100 mL), dried over anhydrous Na2SO4, and the residue was concentrated under reduced pressure. The resulting crude product was purified by elution with ACN / H2O (v / v=0%-100%) to give C 1H 2 O. 18 It was further purified by column chromatography, which gave 4.66 g (54.69% yield) of 2,3,4-trifluoro-1-iodo-5-nitrobenzene.

[0155] Step 2. 2,3,4-Trifluoro-5-iodoaniline In a 250 mL round bottom flask purged and maintained with an inert atmosphere of nitrogen, 2,3,4-trifluoro-1-iodo-5-nitrobenzene (4.66 g, 15.38 mmol), Fe(5.02 g, 89.93 mmol), ammonium chloride (8.57 g, 160.25 mmol), EtOH (30 mL) and water (30 mL) were placed. The reaction mixture was stirred at 55° C. for 1 h. The reaction was filtered and the filter cake was washed with EA (2×20 mL). The organic layers were combined, washed with brine (100 mL) and dried over anhydrous Na2SO4. The resulting solution was concentrated under reduced pressure and applied to a silica gel column eluted with EA / hexane (v / v=1 / 1). This afforded 3.69 g (87% yield) of 2,3,4-trifluoro-5-iodoaniline as a yellow oil. LCMS: m / z=274[M+1] + .

[0156] Step 3. (5-Amino-2,3,4-trifluorophenyl)boronic acid In a 250 mL sealed tube purged and maintained with an inert atmosphere of nitrogen were placed 2,3,4-trifluoro-5-iodoaniline (2.09 g, 7.67 mmol), bis(pinacolato)diboron (9.46 g, 37.25 mmol), Pd(dppf)Cl2 (1.06 g, 1.45 mmol), KOAc (5.10 g, 52.00 mmol) and NMP (80 mL). The reaction mixture was stirred at 95 °C for 2 h. The reaction was then quenched by the addition of saturated aqueous sodium carbonate solution (100 mL). The reaction mixture was stirred at room temperature for 2 h. The resulting solution was extracted with EA (3 x 100 mL), the organic layers were combined, then washed with brine (100 mL), dried over anhydrous Na2SO4 and the residue was concentrated under reduced pressure. The resulting crude product was purified by C elution with ACN / HO (v / v = 30% to 50%). 18 Further purification was performed by column chromatography. This gave 1.48 g (106% yield) of (5-amino-2,3,4-trifluorophenyl)boronic acid as a yellow oil. LCMS: m / z=192[M+1] + .

[0157] Step 4. 4-(4-acryloylpiperazin-1-yl)-7-(5-amino-2,3,4-trifluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile In a 40 mL sealed tube purged and maintained with an inert atmosphere of nitrogen was placed 4-(4-acryloylpiperazin-1-yl)-6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (0.68 g, 1.34 mmol), (5-amino-2,3,4-trifluorophenyl)boronic acid (0.51 g, 2.67 mmol), Pd(PPh3)4 (0.31 g, 0.27 mmol), Na2CO3 (0.41 g, 3.86 mmol), dioxane (20 mL) and water (4 mL). The reaction mixture was stirred at 80° C. for 2 hours. The reaction was then quenched by the addition of water (50 mL) and ethyl acetate (20 mL). The resulting solution was extracted with ethyl acetate (1×50 mL), and the organic layers were combined, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The resulting crude product was purified by elution with ACN / HO (v / v=0%-60%). 18 Further purification by column. This gave 0.15 g (18% yield) of 4-(4-acryloylpiperazin-1-yl)-7-(5-amino-2,3,4-trifluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile as a yellow solid. LCMS: m / z=622[M+1] + .

[0158] Step 5. 4-(4-acryloylpiperazin-1-yl)-7-(3-amino-2-chloro-4,5,6-trifluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile ("Compound 12") Into an 8 mL sealed tube purged and maintained with an inert atmosphere of nitrogen was placed 4-(4-acryloylpiperazin-1-yl)-7-(5-amino-2,3,4-trifluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (0.15 g, 0.25 mmol), NCS (0.10 g, 0.77 mmol) and AcOH (4 mL). The mixture was stirred at room temperature overnight. The reaction was then quenched by the addition of water (50 mL). The resulting solution was extracted with ethyl acetate (2×50 mL) and the organic layers were combined, washed with saturated aqueous sodium bicarbonate (2×50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting crude product was purified by column chromatography (C) eluted with ACN / H2O (0.15% NH4HCO3) (v / v = 30%-80%). 18 Further purification was performed by column chromatography. This gave 21 mg (13% yield) of 4-(4-acryloylpiperazin-1-yl)-7-(3-amino-2-chloro-4,5,6-trifluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile ("Compound 12") as a yellow solid. LCMS: m / z=656 [M+1] + . 1 H NMR (400MHz, DMSO-d6)δ 8.57(s,1H), 8.44(d,J=4.7Hz, 1H), 7.23(t,J=4.6Hz, 1H), 6.92(dd,J=16.7, 10.5Hz, 1H), 6.20(dd,J=16.6, 2.3Hz, 1H), 5.86(s,2H), 5.7 7(dd,J=10.4, 2.2Hz, 1H), 4.29-3.50(m,8H), 3.72-3.66(m,1H), 1.89(d,J=10.7Hz, 3H), 1.08(dd,J=6.6, 2.4Hz, 3H), 0.97-0.77(m,3H).

[0159] Step 6. 4-(4-acryloylpiperazin-1-yl)-7-(3-amino-2-chloro-4,5,6-trifluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (first eluting isomer, "Compound 12-1") and 4-(4-acryloylpiperazin-1-yl)-7-(3-amino-2-chloro-4,5,6-trifluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (second eluting isomer, "Compound 12-2") A mixture of 4-(4-acryloylpiperazin-1-yl)-7-(3-amino-2-chloro-4,5,6-trifluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile atropisomers (110 mg, several batches) was purified by chiral preparative HPLC using the following conditions: column, CHIRAL ART Cellulose-SB, 3 cm x 25 cm, 5 um; mobile phase, (Hex:DCM=3:1):EtOH (v / v=95:5); detection wavelength, UV 220 nm. This gave 53 mg (48.18%) of 4-(4-acryloylpiperazin-1-yl)-7-(3-amino-2-chloro-4,5,6-trifluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (first eluting isomer, "compound 12-1") as a yellow solid. LCMS: m / z=656[M+1] + . 1H NMR (400MHz, DMSO-d6)δ 8.57(s,1H), 8.44(dd,J=4.9, 1.5Hz, 1H), 7.24(t,J=4.8Hz, 1H), 6.92(dd,J=16.7, 10.4Hz, 1H), 6.21(dd,J=16.6, 2.4Hz, 1H), 5.88(s,2H), 5 .77(dd,J=10.4, 2.4Hz, 1H), 4.25-2.64(d,J=27.7Hz, 8H), 2.78-2.60(m,1H), 1.89(d,J=10.4Hz, 3H), 1.12-1.01(m,3H), 0.97-0.83(m,3H).

[0160] and 51 mg (46.36%) of 4-(4-acryloylpiperazin-1-yl)-7-(3-amino-2-chloro-4,5,6-trifluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (second eluting isomer, "compound 12-2") was obtained as a yellow solid. LCMS: m / z=656[M+1] + . 1 H NMR (400MHz, DMSO-d6)δ 8.57(s,1H), 8.44(d,J=4.9Hz, 1H), 7.24(t,J=4.7Hz, 1H), 6.92(dd,J=16.6, 10.4Hz, 1H), 6.21(dd,J=16.6, 2.5Hz, 1H), 5.88(s,2H), 5.77(dd,J =10.3, 2.4Hz, 1H), 3.89(d,J=25.8Hz, 8H), 2.73-2.64(m,1H), 1.89(d,J=10.5Hz, 3H), 1.08(dd,J=6.8, 2.6Hz, 3H), 0.90(dd,J=19.2, 6.7Hz, 3H).

[0161] 14. Example 13 4-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-7-(2-amino-3,4,5,6-tetrafluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile ("Compound 13"); (P)-4-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-7-(2-amino-3,4,5,6-tetrafluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile; and (M)-4-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-7-(2-amino-3,4,5,6-tetrafluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile [ka] Step 1. 4-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-7-(2-amino-3,4,5,6-tetrafluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile ("Compound 13") In a 20 mL round bottom flask was placed 4-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (0.312 g, 0.58 mmol), 2,3,4,5-tetrafluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.601 g, 2.07 mmol), Pd(pph3)4 (0.125 g, 0.11 mmol), Na2CO3 (0.189 g, 1.78 mmol), dioxane (8 mL) and water (2 mL). The reaction mixture was stirred at 80° C. for 1 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC CH3CN / H2O (0.05% NH4HCO3) (v / v=2 / 1). This gave 0.132 g (34%) of 4-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-7-(2-amino-3,4,5,6-tetrafluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile ("Compound 13") as a yellow solid. LCMS: m / z=668 [M+1] + . 1 H NMR(400MHz, CD3OD)δ 8.85(s,1H), 8.67(d,J=5.8Hz, 1H), 7.85(d,J=5.9Hz, 1H), 6.94-6.81(m,1H), 6.33(d,J=16.6Hz, 1H), 5.84(d,J=10.8Hz, 1H), 4.78(s,2H) ), 4.09-3.95(m,2H), 3.95-3.81(m,2H), 3.13-2.99(m,1H), 2.33-2.18(m,3H), 1.68-1.59(m,6H), 1.36-1.24(m,3H), 1.23-1.09(m,3H).

[0162] Step 2. 4-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-7-(2-amino-3,4,5,6-tetrafluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (first eluting isomer, "Compound 13-1") and 4-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-7-(2-amino-3,4,5,6-tetrafluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (second eluting isomer, "Compound 13-2") A mixture of 4-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-7-(2-amino-3,4,5,6-tetrafluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile atropisomers (930 mg, several batches) was purified by chiral preparative HPLC using the following conditions: column, CHIRALPAK IA, 3 cm x 25 cm, 5 um; mobile phase, Hex:EtOH=80:20; detection wavelength, UV 220 nm. This gave 424 mg (45.59%) of 4-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-7-(2-amino-3,4,5,6-tetrafluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (first eluting isomer, "compound 13-1") as a yellow solid. LCMS: m / z=668[M+1] + . 1H NMR (400MHz, CD3OD) δ 8.83(s,1H), 8.52(d,J=5.3Hz, 1H), 7.47(d,J=5.2Hz, 1H), 6.88(dd,J=16. 7, 10.6Hz, 1H), 6.33(dd,J=16.7, 1.9Hz, 1H), 5.84(dd,J=10.6, 1.9Hz, 1H), 4.77(s,2H), 4.10-3.94(m,2H), 3.91-3.79(m,2H), 2.81-2.83(m,1H), 2.08 -2.10(m,3H), 1.65(t,J=6.0Hz, 6H), 1.26-1.19(m,3H), 1.01-1.02(m,3H).

[0163] and 372 mg (40.00%) of 4-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-7-(2-amino-3,4,5,6-tetrafluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (second eluting isomer, “compound 13-2”) was obtained as a yellow solid. LCMS: m / z=668[M+1] + . 1 H NMR (400MHz, CD3OD) δ 8.83(s,1H), 8.52(d,J=5.3Hz, 1H), 7.47(d,J=5.2Hz, 1H), 6.88(dd,J=16. 7, 10.6Hz, 1H), 6.33(dd,J=16.7, 1.9Hz, 1H), 5.84(dd,J=10.6, 1.9Hz, 1H), 4.77(s,2H), 4.10-3.94(m,2H), 3.91-3.79(m,2H), 2.82-2.83(m,1H), 2.09 -2.11(m,3H), 1.65(t,J=6.0Hz, 6H), 1.26-1.19(m,3H), 1.04-1.06(m,3H).

[0164] 15. Example 14 4-((R)-4-acryloyl-3-methylpiperazin-1-yl)-7-(2-amino-3,4,5,6-tetrafluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile ("Compound 14") [ka] Step 1. 4-((R)-4-acryloyl-3-methylpiperazin-1-yl)-7-(2-amino-3,4,5,6-tetrafluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile ("Compound 14") In a 20 mL sealed tube purged and maintained with an inert atmosphere of nitrogen was placed (R)-4-(4-acryloyl-3-methylpiperazin-1-yl)-6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (353 mg, 0.67 mmol), 2,3,4,5-tetrafluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (604 mg, 2.08 mmol), Pd(PPh3)4 (185 mg, 0.16 mmol), Na2CO3 (235 mg, 2.22 mmol), dioxane (7 mL) and water (0.7 mL). The reaction mixture was stirred at 80° C. for 1 h. The reaction mixture was filtered and concentrated under reduced pressure. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (CH3CN / H2O (v / v=7 / 3)). This gave 29 mg (7% yield) of 4-((R)-4-acryloyl-3-methylpiperazin-1-yl)-7-(2-amino-3,4,5,6-tetrafluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile ("Compound 14") as a yellow solid. LCMS: m / z=654 [M+1] + . 1H NMR(400MHz, CD3OD)δ 8.50(d,J=52.4Hz, 2H), 7.27(s,1H), 6.96-6.66(m,1H), 6.29(d,J=16.2Hz, 1H), 5.83(d,J=9.6Hz, 1H), 4.70-4.43( m,1H), 4.18-4.08(m,4H), 3.70-3.60(m,2H), 2.82-2.48(m,1H), 2.03(s,3H), 1.48-1.40(m,3H), 1.24-0.84(m,6H).

[0165] 16. Example 15 4-((S)-4-acryloyl-2-methylpiperazin-1-yl)-7-(3-amino-2-chloro-4,5,6-trifluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile ("Compound 15"); (P)-4-((S)-4-acryloyl-2-methylpiperazin-1-yl)-7-(3-amino-2-chloro-4,5,6-trifluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile; and (M)-4-((S)-4-Acryloyl-2-methylpiperazin-1-yl)-7-(3-amino-2-chloro-4,5,6-trifluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile [ka] Step 1. (S)-4-(4-acryloyl-2-methylpiperazin-1-yl)-7-(5-amino-2,3,4-trifluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile In a 20 mL round bottom flask purged and maintained with an inert atmosphere of nitrogen was placed (S)-4-(4-acryloyl-2-methylpiperazin-1-yl)-6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (0.310 g, 0.59 mmol), (5-amino-2,3,4-trifluorophenyl)boronic acid (0.285 g, 1.49 mmol), Pd(PPh3)4 (0.085 g, 0.073 mmol), Na2CO3 (0.126 g, 1.19 mmol), dioxane (8 mL) and water (2 mL). The reaction mixture was stirred at 80° C. for 1 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC CH3CN / H2O (0.05% NH4HCO3) (v / v=2 / 1). This gave 135 mg (35%) of (S)-4-(4-acryloyl-2-methylpiperazin-1-yl)-7-(5-amino-2,3,4-trifluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile as a yellow solid. LCMS: m / z=636 [M+1] + .

[0166] Step 2. 4-((S)-4-acryloyl-2-methylpiperazin-1-yl)-7-(3-amino-2-chloro-4,5,6-trifluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile ("Compound 15") In an 8 mL sealed tube purged and maintained with an inert atmosphere of nitrogen was placed (S)-4-(4-acryloyl-2-methylpiperazin-1-yl)-7-(5-amino-2,3,4-trifluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (0.123 g, 193.376 μmol), NCS (0.053 g, 396.906 μmol) and AcOH (2 mL). The mixture was stirred at room temperature overnight. The reaction was then quenched by the addition of saturated aqueous sodium bicarbonate (100 mL). The resulting solution was extracted with ethyl acetate (3×100 mL) and the organic layers were combined and concentrated under reduced pressure. The resulting crude product was purified by column chromatography (C) eluted with ACN / H2O (0.15% NH4HCO3) (v / v = 30%-80%). 18 Further purification was performed by column chromatography. This gave 55 mg (42% yield) of 4-((S)-4-acryloyl-2-methylpiperazin-1-yl)-7-(3-amino-2-chloro-4,5,6-trifluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile ("Compound 15") as a yellow solid. LCMS: m / z=670 [M+1] + . 1 H NMR(400MHz, CD3OD)δ 8.54(s,1H), 8.41(d,J=4.8Hz, 1H), 7.24(dd,J=11.5, 5.9Hz, 1H), 6.98-6.74(m,1H), 6.33(d,J=16.3Hz, 1H), 5.84(d,J=10.5Hz, 1H), 4.69-3.97(m,5H), 3.78-3.52(m,2H), 2.86-2.56(m,1H), 2.12-1.88(m,3H), 1.47-1.30(m,3H), 1.25-1.10(m,3H), 1.07-0.88(m,3H).

[0167] Step 2. 4-((S)-4-acryloyl-2-methylpiperazin-1-yl)-7-(3-amino-2-chloro-4,5,6-trifluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (first eluting isomer, "Compound 15-1") and 4-((S)-4-acryloyl-2-methylpiperazin-1-yl)-7-(3-amino-2-chloro-4,5,6-trifluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (second eluting isomer, "Compound 15-2") A mixture of 4-((S)-4-acryloyl-2-methylpiperazin-1-yl)-7-(3-amino-2-chloro-4,5,6-trifluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile atropisomers (53 mg) was purified by chiral preparative HPLC using the following conditions: column, CHIRALPAK IF, 2 cm x 25 cm, 5 um mobile phase, (Hex:DCM=3:1):EtOH (v / v=9:1); detection wavelength, UV 220 nm. This gave 20 mg (49%) of 4-((S)-4-acryloyl-2-methylpiperazin-1-yl)-7-(3-amino-2-chloro-4,5,6-trifluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (first eluting isomer, "compound 15-1") as a yellow solid. LCMS: m / z=670 [M+1] + . 1H NMR(400MHz, CD3OD)δ 8.56(s,1H), 8.43(d,J=5.0Hz, 1H), 7.28(t,J=4.9Hz, 1H), 6.99-6.79(m,1H), 6.35(d,J=18.0Hz, 1H), 5.87(d,J=10.7Hz, 1H), 4.68-4.0 6(m,5H), 3.78-3.56(m,2H), 2.69-2.56(m,1H), 2.09(d,J=9.8Hz, 3H), 1.42(s,3H), 1.17(d,J=6.8Hz, 3H), 0.98(dd,J=18.6, 6.8Hz, 3H).

[0168] and 17 mg (45%) of 4-((S)-4-acryloyl-2-methylpiperazin-1-yl)-7-(3-amino-2-chloro-4,5,6-trifluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (second eluting isomer, “compound 15-2”) as a yellow solid. LCMS: m / z=670[M+1] + . 1 H NMR(400MHz, CD3OD)δ 8.56(s,1H), 8.44(d,J=5.0Hz, 1H), 7.26(t,J=5.4Hz, 1H), 6.87(d,J=27.5Hz, 1H), 6.97-6.80(m,1H), 5.87(d,J=11.5Hz, 1H), 4.65-4.05(m ,5H), 3.78-3.57(m,2H), 2.88-2.78(m,1H), 1.95(d,J=12.5Hz, 3H), 1.44-1.34(m,3H), 1.22(d,J=6.7Hz, 3H), 1.03(dd,J=11.9, 6.8Hz, 3H).

[0169] The following compounds may be synthesized following methods similar to those described in the examples above: [ka] JPEG0007644517000088.jpg254170JPEG0007644517000089.jpg250170JPEG0007644517000090.jpg246170JPEG0007644517000091.jpg25 1170JPEG0007644517000092.jpg253170JPEG0007644517000093.jpg240170JPEG0007644517000094.jpg255169JPEG0007644517000095.j pg231170JPEG0007644517000096.jpg247170JPEG0007644517000097.jpg230170JPEG0007644517000098.jpg238170JPEG00076445170000 99.jpg220170JPEG0007644517000100.jpg251170JPEG0007644517000101.jpg241170JPEG0007644517000102.jpg242170JPEG0007644517 000103.jpg255170JPEG0007644517000104.jpg232170JPEG0007644517000105.jpg238170JPEG0007644517000106.jpg239170JPEG000764 4517000107.jpg221170JPEG0007644517000108.jpg234170JPEG0007644517000109.jpg233170JPEG0007644517000110.jpg234170JPEG00 07644517000111.jpg230170JPEG0007644517000112.jpg230170JPEG0007644517000113.jpg238170JPEG0007644517000114.jpg236170JP EG0007644517000115.jpg245170JPEG0007644517000116.jpg238170JPEG0007644517000117.jpg215170JPEG0007644517000118.jpg41170

[0170] 17. Example A 4-(4-acryloylpiperazin-1-yl)-7-(2-amino-6-fluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile ("Compound A") [ka] Step 1. 4,6,7-Trichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile. In a 50 mL round bottom flask purged and maintained with an inert atmosphere of nitrogen was placed 6,7-dichloro-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (980 mg, 2.51 mmol), POCl3 (1150 mg, 7.50 mmol), DIEA (1.32 g, 10.21 mmol) and acetonitrile (12 mL). The mixture was stirred at 80° C. for 2 hours. The reaction was cooled to room temperature and concentrated under reduced pressure. This provided 4,6,7-trichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile, which was used directly in the next step.

[0171] Step 2. tert-Butyl 4-(6,7-dichloro-3-cyano-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)piperazine-1-carboxylate In a 100 mL round bottom flask purged and maintained with an inert atmosphere of nitrogen, 4,6,7-trichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (1.20 g, crude), acetonitrile (20 mL), DIEA (660 mg, 5.10 mmol) and tert-butyl piperazine-1-carboxylate (0.57 g, 3.06 mmol) were placed. The reaction mixture was stirred at room temperature for 2 h. Then, the reaction was quenched by the addition of water (50 mL). The resulting solution was extracted with ethyl acetate (3×50 mL) and the organic layers were combined, washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by a silica gel column eluted with EA / Hexane (v / v=30%-70%). This gave 0.92 g (65% over two steps) of tert-butyl 4-(6,7-dichloro-3-cyano-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)piperazine-1-carboxylate as a yellow solid. LCMS: m / z=557[M+1] + .

[0172] Step 3. 4-(4-acryloylpiperazin-1-yl)-6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile In a 50 mL sealed tube purged and maintained with an inert atmosphere of nitrogen was placed tert-butyl 4-(6,7-dichloro-3-cyano-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)piperazine-1-carboxylate (920 mg, 1.65 mmol), TFA (4 ml) and DCM (15 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in a 50 mL round bottom flask with DCM (15 mL) followed by the addition of DIEA (1.02 g, 10.08 mmol). The reaction mixture was cooled to 0° C. and acryloyl chloride (190 mg, 2.09 mmol) was added. The mixture was stirred at room temperature for 2 hours. The reaction was then quenched by the addition of water (30 mL). The resulting solution was extracted with ethyl acetate (3×50 mL) and the organic layers were combined, washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by a silica gel column eluted with EA / Hexane (V / V=40%-80%). This gave 0.86 g (crude) of 4-(4-acryloylpiperazin-1-yl)-6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile as a yellow solid. LCMS: m / z=511[M+1] + .

[0173] Step 4. 4-(4-acryloylpiperazin-1-yl)-7-(2-amino-6-fluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile ("Compound A") In a 20 mL sealed tube purged and maintained with an inert atmosphere of nitrogen was placed 4-(4-acryloylpiperazin-1-yl)-6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (99 mg, 0.19 mmol), 3-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (78 mg, 0.33 mmol), Pd(PPh3)4 (44 mg, 0.03 mmol), Na2CO3 (65 mg, 0.61 mmol), dioxane (4 mL) and water (1 mL). The reaction mixture was stirred at 90° C. for 2 hours. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC CH3CN / H2O (v:v=1 / 1). This gave 12 mg (10%) of 4-(4-acryloylpiperazin-1-yl)-7-(2-amino-6-fluorophenyl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile ("Compound A") as a yellow solid. LCMS: m / z=586 [M+1] + . 1 H NMR(400MHz, CD3OD)δ 8.52(s,1H), 8.46(d,J=5.0Hz, 1H), 7.29(d,J=4.7Hz, 1H), 7.11(d,J=6.6Hz, 1H), 6.89(dd,J=16.7, 10.6Hz, 1H), 6.56-6.49(m,1H), 6. 38-6.30(m,2H), 5.90-5.81(m,1H), 4.18-3.84(m,8H), 2.82-2.70(m,1H), 2.08-1.98(m,3H), 1.19(t,J=7.1Hz, 3H), 1.10-0.93(m,3H).

[0174] Amgen 6 4-(4-acryloylpiperazin-1-yl)-6-chloro-7-(2-fluorophenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile ("Amgen 6") [ka] Step 1. 4-(4-acryloylpiperazin-1-yl)-6-chloro-7-(2-fluorophenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile In an 8 mL sealed tube purged and maintained with an inert atmosphere of nitrogen, 4-(4-acryloylpiperazin-1-yl)-6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (75 mg, 0.15 mmol), (2-fluorophenyl)boronic acid (56 mg, 0.40 mmol), Pd(dppf)Cl2 (25 mg, 34.17 umol), Na2CO3 (69 mg, 0.65 mmol), dioxane (1 mL) and water (0.2 mL) were placed. The reaction mixture was stirred at 90° C. for 2 hours. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by a silica gel column eluted with EA / Hexane (v / v=7 / 3). The collected fluid was concentrated under reduced pressure. The residue was purified by preparative HPLC CH3CN / H2O (v / v=3 / 2). This gave 22 mg of 4-(4-acryloylpiperazin-1-yl)-6-chloro-7-(2-fluorophenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile ("Amgen 6") as a yellow solid. LCMS: m / z=571 [M+1] + . 1 H NMR(400MHz, CD3OD)δ 8.52(s,1H), 8.43(d,J=5.0Hz, 1H), 7.54-7.46(m,1H), 7.32-7.13(m,4H), 6.89(dd,J=16.7, 10.6Hz, 1H), 6.33(d,J=16.7Hz, 1H), 5.86(d,J=10.6Hz, 1H), 4.15-3.90(m,8H), 2.79-2.65(m,1H), 2.04(s,3H), 1.19(d,J=6.8Hz, 3H), 1.00(d,J=6.7Hz, 3H).

[0175] A mixture of 4-(4-acryloylpiperazin-1-yl)-6-chloro-7-(2-fluorophenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile atropisomers (1.59 g) was purified by chiral preparative HPLC using the following conditions: column, CHIRAL Cellulose-SB, 3 cm x 25 cm, 5 um; mobile phase, CO2, IPA:ACN=1:1; detector, UV 254 nm. This gave 739 mg (46%) of 4-(4-acryloylpiperazin-1-yl)-6-chloro-7-(2-fluorophenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (first eluting isomer, "Amgen 6-1") as a yellow solid; LCMS: m / z=571 [M+1] + . and 709 mg (45%) of 4-(4-acryloylpiperazin-1-yl)-6-chloro-7-(2-fluorophenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (second eluting isomer, "Amgen 6-2") as a yellow solid; LCMS: m / z=571 [M+1] + . 1 H NMR(400MHz, CD3OD)δ 8.50(s,1H), 8.41(d,J=5.0Hz, 1H), 7.52-7.37(m,1H), 7.30-7.08(m,4H), 6.87(dd,J=16.8, 10.6Hz, 1H),6.38-6.24(m,1H), 5 .83(dd,J=10.6, 1.8Hz, 1H), 4.09-3.82(m,8H),2.78-2.63(m,1H), 2.02(s,3H), 1.16(d,J=6.8Hz, 3H), 0.98(d,J=6.8Hz, 3H).

[0176] Amgen 6.3 4-(4-acryloylpiperazin-1-yl)-7-(2-amino-6-fluorophenyl)-6-chloro-1-(4,6-diisopropylpyrimidin-5-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile ("Amgen 6.3") [ka] 4-(4-Acryloylpiperazin-1-yl)-7-(2-amino-6-fluorophenyl)-6-chloro-1-(4,6-diisopropylpyrimidin-5-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile ("Amgen 6.3") was prepared according to the previous method as a yellow solid. LCMS: m / z=615 [M+1] + . 1 H NMR (400MHz, DMSO-d6)δ 9.09(s,1H), 8.48(s,1H), 7.05(q, J=7.8Hz, 1H), 6.93(dd,J=16.6, 10.4Hz, 1H), 6 .44(d,J=8.3Hz, 1H), 6.31(t,J=8.9Hz, 1H), 6.21(dd,J=16.7, 2.4Hz, 1H), 5.77(d d,J=10.4, 2.4Hz, 1H), 5.08(s,2H), 3.90(m,8H), 2.90-2.74(m,1H), 2.70-2.55(m ,1H), 1.07(dd,J=12.2, 6.7Hz, 6H), 1.00(d,J=6.6Hz, 3H), 0.86(d,J=6.7Hz, 3H).

[0177] Amgen 7.3 4-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-6-chloro-7-(2-fluorophenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile ("Amgen 7.3") [ka] Step 1. 4-((3S,5R)-4-Acryloyl-3,5-dimethylpiperazin-1-yl)-6-chloro-7-(2-fluorophenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile. Into a 20 mL sealed tube purged and maintained with an inert atmosphere of nitrogen was placed 4-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (109 mg, 0.20 mmol), ((2-fluorophenyl)boronic acid (110 mg, 0.79 mmol), Pd(PPh3)4 (85 mg, 0.073 mmol), Na2CO3 (69 mg, 0.65 mmol), dioxane (6 mL) and water (2 mL). The reaction mixture was stirred at 80 °C for 4 h. The reaction was then cooled to rt. The reaction mixture was quenched by the addition of water (100 mL). The resulting solution was extracted with ethyl acetate (3×100 mL) and the organic layers were combined, washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (CH3CN / H2O (v / v=1 / 1). This afforded 31 mg (26% over two steps) of 4-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-6-chloro-7-(2-fluorophenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile ("Amgen 7.3") as a yellow solid. LCMS: m / z=599 [M+1] + . 1H NMR(400MHz, CD3OD)δ 8.80(s,1H), 8.44(d,J=5.0Hz, 1H), 7.48(dd,J=8.4, 4.6Hz, 1H), 7.40-7.22(m,4H), 6.98-6.85(m,1H), 6.35(d,J=16.5Hz, 1H), 5.86(d,J=10. 6Hz, 1H), 4.79(s,2H), 4.14-3.79(m,4H), 2.80-2.74(m,1H), 2.05(s,3H), 1.68(d,J=7.0Hz, 6H), 1.19(d,J=6.8Hz, 3H), 1.01(d,J=6.7Hz, 3H).

[0178] A mixture of 4-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-6-chloro-7-(2-fluorophenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile atropisomers (1.48 g) was purified by chiral preparative HPLC using the following conditions: column, CHIRAL Cellulose-SB, 3 cm x 25 cm, 5 um; mobile phase, Hex / EtOH=(v / v=50 / 50); detection wavelength, UV 254 nm. This gave 625 mg (42%) of 4-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-6-chloro-7-(2-fluorophenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (first eluting isomer, "Amgen 7.3-1") as a yellow solid; LCMS: m / z=599[M+1] + . 1H NMR(400MHz, CD3OD)δ 8.68(s,1H), 8.32(d,J=5.0Hz, 1H), 7.42-7.30(m,1H), 7.23-7.01(m,4H), 6. 78(dd,J=16.7, 10.6Hz, 1H), 6.22(dd,J=16.7, 1.9Hz, 1H), 5.73(dd,J=10.6, 1 .9Hz, 1H), 4.66(s,2H), 3.99-3.83(m,2H), 3.74-3.72(m,2H), 2.63-2.61(m,1 H), 1.93(s,3H), 1.55(d,J=7.0Hz, 6H), 1.10-1.08(m,3H), 0.90-0.89(m,3H).

[0179] and 669 mg (45%) of 4-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-6-chloro-7-(2-fluorophenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (second eluting isomer, "Amgen 7.3-2") as a yellow solid; LCMS: m / z=599[M+1] + . 1 H NMR(400MHz, CD3OD)δ 8.80(s,1H), 8.43(d,J=5.0Hz, 1H), 7.57-7.41(m,1H), 7.37-7.07(m,4H), 6. 90(dd,J=16.7, 10.6Hz, 1H), 6.34(dd,J=16.7, 1.9Hz, 1H), 5.85(dd,J=10.6, 1.9Hz, 1H), 4.78(s,2H), 4.07-3.98(m,2H), 3.86-3.84(m,2H), 2.76-2.74(m ,1H), 2.05(s,3H), 1.68-1.66(m,6H), 1.12-1.10(m,3H), 0.91-0.89(m,3H).

[0180] Pharmacological testing 18. 1.SOS1-catalyzed nucleotide exchange assay HIS-KRAS (G12C, aa 2-185, Sino biological) was diluted to 5 μM in EDTA buffer (20 mM HEPES, pH 7.4, 50 mM NaCl, 10 mM EDTA, 0.01% (v / v) Tween-20) and incubated at 25° C. for 30 min. EDTA-pretreated HIS-KRAS(G12C) was diluted to 12 nM in assay buffer (25 mM HEPES, pH 7.4, 120 mM NaCl, 5 mM MgCl2, 1 mM DTT, 0.01% (v / v) Tween 20, 0.1% (w / v) BSA) containing 120 nM GDP (Sigma) and MAb Anti 6HIS-Tb cryptate Gold (Cisbio) and incubated at 25 °C for 1 h to prepare GDP-loaded HIS-KRAS(G12C). GDP-loaded HIS-KRAS(G12C) was pre-incubated with diluted compounds in 384-well plates (Greiner) for 1 h, then purified SOS1 ExD (Flag tag, aa 564-1049) and BODIPY™ FL GTP (Invitrogen) were added to the assay wells (final concentrations: 3 nM HIS-KRAS(G12C), 2 μM SOS1 ExD, 80 nM BODIPY™ FL GTP, 21 ng / mL MAb Anti 6HIS-Tb cryptate Gold) and incubated for 4 h at 25° C. TR-FRET signals were then read on a Tecan Spark multimode microplate reader. The parameters were: F486: excitation 340 nm, emission 486 nm, lag time 100 μs, integration time 200 μs; F515: excitation 340 nm, emission 515 nm, lag time 100 μs, integration time 200 μs. The TR-FRET ratio of each individual well was calculated using the formula: TR-FRET ratio = (signal F515 / signal F486). * The data were then analyzed using a four-parameter logistic model to determine the IC 50 Values ​​were calculated. The results of the SOS1-catalyzed nucleotide exchange assay are shown in Table 8 below.

[0181] [Table 8]

[0182] From Table 8, it can be seen that the representative compounds in the present invention have better activity for inhibiting SOS1-catalyzed nucleotide exchange.

[0183] 19. 2. Phospho-ERK1 / 2 (THR202 / TYR204) HTRF Assay NCI-H358 cells expressing KRAS G12C were cultured in RPMI 1640 medium (Gibco) containing 10% fetal bovine serum (Gibco). NCI-H358 cells in culture medium were seeded into 96-well plates at a concentration of 40,000 cells / well, then placed in a 37°C / 5% CO2 cell incubator and incubated overnight. The next day, culture medium was removed, and compounds diluted in assay medium (RPMI 1640, 0.1% FBS) were added to each well. After 2 hours of incubation in a 37°C / 5% CO2 cell incubator, assay medium in the 96-well plates was removed, then 50 μL of 1× blocking reagent-supplemented lysis buffer (Cisbio) was added, and the plates were incubated at 25°C for 45 minutes with shaking. 10 μL of cell lysate from the 96-well plate was transferred to a 384-well plate (Greiner) containing 2.5 μL / well of HTRF® premixed antibody (Cisbio 64AERPEH). After 4 hours of incubation at 25° C., the HTRF signal was then read on a Tecan Spark multimode microplate reader. Data was analyzed using a four-parameter logistic model to determine IC 50 Values ​​were calculated. The results of the phospho-ERK1 / 2 (THR202 / TYR204) HTRF assay are shown in Table 9 below.

[0184] [Table 9]

[0185] From Table 9, it can be seen that the representative compounds in the present invention have better activity for inhibiting the phosphorylation of ERK1 / 2 the NCI-H358 cells.

[0186] 20. 3. Pharmacokinetic study in mice The purpose of this study was to evaluate the pharmacokinetic properties of compounds in Balb / c mice (female) after single dose administration. The day before dosing, the mice were fasted overnight and water was provided ad libitum. Six mice were required for each compound, and the six mice were divided into two groups (n=3 / group), group A and group B. The mice in group A were treated with a single 3 mg / kg dose of the compound (intravenous (iv)). The mice in group B were treated with a single 10 mg / kg dose of the compound (orally (po)). For each mouse in group A, blood samples were taken before dosing and at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after dosing. For each mouse in group B, blood samples were taken before dosing and at 0.25, 0.5, 1, 2, 3, 4, 6, 8, and 24 hours after dosing. The blood samples were placed on ice until centrifugation to obtain plasma samples. The plasma samples were stored at -80°C until analysis. The concentrations of the compounds in the plasma samples were determined using an LC-MS / MS method. The results are shown in Table 10 below.

[0187] [Table 10]

[0188] From Table 10, Compound 1, Compound 11, Compound 13 and Compound 14 have superior pharmacokinetic properties (higher C) in the mouse model compared to Compound A, Amgen 6 and Amgen 6.3. max and AUC, etc.), which makes them more suitable for treating cancers with KRAS G12C mutation as oral therapeutic active ingredients in clinical practice.

[0189] 21. 4. Pharmacokinetic study in dogs The purpose of this study was to evaluate the pharmacokinetic properties of compounds in beagle dogs after single dose administration. The day before administration, the dogs were fasted overnight and water was provided ad libitum. Four beagle dogs were required for each compound, and the four dogs were divided into two groups (one male (M) and one female (F) in each group). The dogs in group A were treated with a single 1 mg / kg dose of the compound (intravenous (iv)). The dogs in group B were treated with a single 10 mg / kg dose of the compound (orally (po)). For the dogs in group A, blood samples were taken before administration and at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours after administration. For the dogs in group B, blood samples were taken before administration and at 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours after administration. The blood samples were placed on ice until centrifugation to obtain plasma samples. The plasma samples were stored at -80°C until analysis. The concentrations of the compounds in the plasma samples were determined using an LC-MS / MS method. The results are shown in Table 11 below.

[0190] [Table 11]

[0191] From Table 11, Compounds 1-2 and Compound 9 have superior pharmacokinetic properties (higher C max and AUC, etc.), which makes them more suitable for treating cancers with KRAS G12C mutation as oral therapeutic active ingredients in clinical practice.

[0192] 22. 5. Pharmacokinetic study in cynomolgus monkeys The purpose of this study was to evaluate the pharmacokinetic properties of the compounds in cynomolgus monkeys after a single dose administration. The day before administration, the monkeys were fasted overnight and water was provided ad libitum. Four monkeys were required for each compound, and the four monkeys were divided into two groups (one male (M) and one female (F) in each group), Group A and Group B. The monkeys in Group A were treated with a single 1 mg / kg dose of the compound (intravenous (iv)). The monkeys in Group B were treated with a single 3 mg / kg dose of the compound (orally (po)). For the monkeys in Group A, blood samples were taken before administration and at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours after administration. For the monkeys in Group B, blood samples were taken before administration and at 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours after administration. The blood samples were placed on ice until centrifugation to obtain plasma samples. The plasma samples were stored at -80°C until analysis. The concentrations of the compounds in the plasma samples were determined using an LC-MS / MS method. The results are shown in Table 12 below.

[0193] [Table 12]

[0194] From Table 12, Compounds 1-2 and Compound 9 exhibited superior pharmacokinetic properties (higher C max and AUC, etc.), which makes them more suitable for treating cancers with KRAS G12C mutation as oral therapeutic active ingredients in clinical practice.

[0195] 23. 6. Efficacy in NCI-H1373 xenograft model NCI-H1373 cells (5.0E+06 cells) were subcutaneously injected into the right flank of female BALB / c nude mice (6-8 weeks old) in a mixture of PBS and Matrigel (Corning) (PBS / Matrigel = 1:1 (v / v)). Mice were monitored daily and caliper measurements were initiated when tumors became visible. Tumor volume was calculated using the formula: (L * W 2The mean tumor volume was calculated by measuring the two perpendicular diameters using the formula: 1 / 2 (where L and W refer to the length and width of the tumor diameter, respectively). 3 When the tumor volume reached 100 mg / kg, the mice were randomly divided into groups (n=6 / group) and treated with compounds. The tumor volume and mouse body weight were measured twice a week during the treatment (approximately 3 weeks). The tumor growth inhibition rate was calculated as TGI%=(1-(Vt-Vt0) / (Vc-Vc0)). * 100% (where Vc and Vt are the mean tumor volumes of the control and treated groups at the end of the study, respectively, and Vc0 and Vt0 are the mean tumor volumes of the control and treated groups at the start, respectively). The results are shown in Table 13 below and in Figure 8.

[0196] [Table 13]

[0197] From Table 13 and FIG. 8, it can be seen that Compound 1-2 and Compound 12-2 have excellent efficacy in vivo.

[0198] 24. 7.Safety study in MIA PaCa-2 xenograft model MIA PaCa-2 cells (1.0E+07 cells) were subcutaneously injected into the right flank of female BALB / c nude mice (6-8 weeks old) in a mixture of PBS and Matrigel (Corning) (PBS / Matrigel = 1:1 (v / v)). Mice were monitored daily and caliper measurements were initiated when tumors became visible. Tumor volume was calculated using the following formula: (L * W 2) / 2 (where L and W refer to the length and width of the tumor diameter, respectively). After the mice were grouped to test efficacy, the remaining mice (n=6) were used to investigate safety. The mice were treated with 400 mg / kg of compound 1-2 (orally (po), once daily (QD)) for 22 days, and the weight of the mice was measured twice a week during the treatment. The change in mouse weight with the number of days after cell inoculation is shown in Figure 9. From Figure 9, it can be seen that compound 1-2 has good safety.

[0199] If any prior art publication is referred to in this specification; it should be understood that such reference does not constitute an admission that this publication forms part of the common general knowledge in the art of any country. The above invention has been described in some detail by way of illustration and example for clarity of understanding, but it will be apparent to those skilled in the art that some minor changes and modifications may be implemented. Therefore, the specification and examples should not be construed as limiting the scope of the present invention.

Claims

1. The compound is 【Chemistry 12】 or a pharma- ceutically acceptable salt thereof.

2. The compound, 【Chemistry 13】 2. The compound of claim 1, wherein:

3. 3. A pharmaceutical composition comprising a compound according to claim 1 or 2, or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable excipient.

4. 4. The pharmaceutical composition of claim 3 for use in the treatment of cancer associated with KRAS G12C mutant protein.

5. A pharmaceutical composition for use according to claim 4, comprising The pharmaceutical composition, wherein the cancer is selected from pancreatic cancer, colon cancer, or lung cancer.

6. A pharmaceutical composition for use according to claim 5, comprising: The pharmaceutical composition, wherein the lung cancer is non-small cell lung cancer.

7. 10. Use of a compound according to claim 1 or 2, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for treating a cancer associated with a KRAS G12C mutant protein.

8. 8. The use according to claim 7, The use, wherein the cancer is selected from pancreatic cancer, colon cancer, or lung cancer.

9. The use according to claim 8, The use, wherein the lung cancer is non-small cell lung cancer.

10. Use of the pharmaceutical composition of claim 3 in the manufacture of a medicament for treating cancer associated with KRAS G12C mutant protein.

11. The use according to claim 10, The use, wherein the cancer is selected from pancreatic cancer, colon cancer, or lung cancer.

12. The use according to claim 11, The use, wherein the lung cancer is non-small cell lung cancer.

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