WO2021088458A1 - Kras mutant protein inhibitor - Google Patents

Kras mutant protein inhibitor Download PDF

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Publication number
WO2021088458A1
WO2021088458A1 PCT/CN2020/109681 CN2020109681W WO2021088458A1 WO 2021088458 A1 WO2021088458 A1 WO 2021088458A1 CN 2020109681 W CN2020109681 W CN 2020109681W WO 2021088458 A1 WO2021088458 A1 WO 2021088458A1
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Prior art keywords
pharmaceutically acceptable
acceptable salt
atropisomer
stereoisomer
alkyl
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PCT/CN2020/109681
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English (en)
French (fr)
Inventor
Amin LI
Sujing LI
Peng Wang
Chaojie DANG
Dan Liu
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Jacobio Pharmaceuticals Co., Ltd.
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Priority to CN202080008063.5A priority Critical patent/CN113286794B/zh
Publication of WO2021088458A1 publication Critical patent/WO2021088458A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the invention relates to a KRAS mutant protein inhibitor, as shown by formula (I) , a composition containing the inhibitor and the use thereof.
  • RAS represents a population of 189 amino acid monomeric globular proteins (21 kDa molecular weight) that are associated with the plasma membrane and bind to GDP or GTP, and RAS acts as a molecular switch.
  • RAS contains bound GDP, it is in a stationary or closed position and is "inactive” .
  • RAS is induced to exchange their bound GDP for GTP.
  • RAS is "opened” and is capable of interacting with other proteins (its "downstream targets” ) and activating the proteins.
  • the RAS protein itself has an inherently low ability to hydrolyze GTP back to GDP, thereby turning itself into a closed state.
  • GAP GTPase activating protein
  • the RAS protein contains a G domain 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 can be post-translationally modified and responsible for targeting the protein to the membrane.
  • the G domain is approximately 21-25 kDa in size and contains a phosphate binding ring (P-ring) .
  • the P-loop represents a pocket of a binding nucleotide in a protein, and this is a rigid portion of a domain with conserved amino acid residues necessary for nucleotide binding and hydrolysis (glycine 12, sul Amino acid 26 and lysine 16) .
  • the G domain also contains a so-called switch I region (residues 30-40) and a switch II region (residues 60-76) , both of which are dynamic parts of the protein, since the dynamic portion is converted between stationary and loaded states. The ability is often expressed as a "spring loaded” mechanism.
  • the primary interaction is the hydrogen bond formed by threonine-35 and glycine-60 with the gamma-phosphate of GTP, which maintains the active conformation of the switch 1 region and the switch 2 region, respectively. After hydrolysis of GTP and release of phosphate, the two relax into an inactive GDP conformation.
  • the most notable members of the RAS subfamily are HRAS, KRAS and NRAS, which are primarily involved in many types of cancer. Mutation of any of the three major isoforms of the RAS gene (HRAS, NRAS or KRAS) is one of the most common events in human tumor formation. Approximately 30%of all tumors in human tumors were found to carry some mutations in the RAS gene. It is worth noting that KRAS mutations were detected in 25%-30%of tumors. In contrast, the rate of carcinogenic mutations in NRAS and HRAS family members was much lower (8%and 3%, respectively) . The most common KRAS mutations were found at residues G12 and G13 in the P-loop as well as at residue Q61.
  • G12C is a frequently occurring KRAS gene mutation (glycine-12 is mutated to cysteine) . This mutation has been found in about 13%of cancers, about 43%in lung cancer, and almost 100%in MYH-associated polyposis (familial colon cancer syndrome) . However, targeting this gene with small molecules is a challenge.
  • a compound of formula (I) a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof or a pharmaceutically acceptable salt of the atropisomer thereof:
  • R 4 is selected from each of is independently optionally substituted by 1 R 42 , 2 R 42 , 3 R 42 , 4 R 42 , 5 R 42 or 6 R 42 ;
  • G 1 , G 2 , G 3 and G 4 at each occurrence is independently selected from N or CR 5 ;
  • n1, n2, n3, n4, n5 at each occurrence is independently selected from 0, 1, 2, 3, 4, 5 or 6, provided that n1 and n2 is not 0 at the same time, n3 and n4 is not 0 at the same time;
  • R 41 at each occurrence is independently selected from
  • Each of R 4d at each occurrence is independently selected from halogen;
  • R 8 and R 9 at each occurrence is independently selected from hydrogen, -C 1-6 alkyl; or
  • R 8 and R 9 together with the N atom which they both attach to form a 3-10 membered heterocyclic ring
  • the 3-10 membered heterocyclic ring is independently optionally substituted by 1, 2, 3, 4, 5 or 6 substituents selected from halogen, oxo, -C 1-6 alkyl, -C 1-6 alkylene- (halo) 1-3 , heteroC 2-6 alkyl, -CN, -OH, -OC 1-6 alkyl, -C 1-6 alkylene- (OH) 1-3 , -C 1-6 alkylene- (OC 1-6 alkyl) 1-3 , -NH 2 , -NHC 1-6 alkyl, -N (C 1-6 alkyl) 2 , -C 1-6 alkylene-NH 2 , -C 1-6 alky
  • n is selected from 1, 2, 3, 4, 5 or 6.
  • R 1 is selected from phenyl substituted with 4 R 11 , naphthyl substituted with 4 R 11 , 5 membered heteroaryl substituted with 4 R 11 , 6 membered heteroaryl substituted with 4 R 11 , 7 membered heteroaryl substituted with 4 R 11 , 8 membered heteroaryl substituted with 4 R 11 , 9 membered heteroaryl substituted with 4 R 11 or 10 membered heteroaryl substituted with 4 R 11 , each of heteroaryl at each occurrence independently contains 1, 2, 3 or 4 heteroatoms selected from N, O or S.
  • R 1 is selected from phenyl substituted with 4R 11 , naphthyl substituted with 4 R 11 , 6 membered heteroaryl substituted with 4 R 11 or 9 membered heteroaryl substituted with 4 R 11 , each of heteroaryl at each occurrence independently contains 1 or 2 heteroatoms selected from N.
  • R 1 is selected from phenyl substituted with 4 R 11 , naphthyl substituted with 4 R 11 , pyridyl substituted with 4 R 11 , benzo [d] oxazolyl substituted with 4 R 11 , benzo [d] thiazolyl substituted with 4 R 11 , pyrrolo [2, 3-c] pyridyl substituted with 4 R 11 , pyrazolo [3, 4-c] pyridyl substituted with 4 R 11 , pyrazolo [1, 5-a] pyridyl substituted with 4 R 11 , imidazo [1, 2-a] pyridyl substituted with 4 R 11 , 2-oxo-indolyl substituted with 4 R 11 , pyrimidyl substituted with 4 R 11 , indolyl substituted with 4 R 11 , indazolyl substituted with 4 R 11 , benzo [d] imidazolyl substituted with 4 R 11 ,
  • R 1 is selected from phenyl substituted with 4 R 11 , naphthyl substituted with 4 R 11 , pyridyl substituted with 4 R 11 or indazolyl substituted with 4 R 11 .
  • R 1 is selected from:
  • R 1 is independently selected from:
  • R 1 is selected from:
  • R 8 and R 9 in R 11 at each occurrence is independently selected from hydrogen or -C 1-3 alkyl.
  • each of R 11 at each occurrence is independently selected from -F, -Cl, oxo, methyl, ethyl, propyl, isopropyl, ethenyl, propenyl, ethynyl, propynyl, -methylene- (halo) 1-3 , -ethylene- (halo) 1-3 , -propylene- (halo) 1-3 , heteroethyl, heteropropyl, -CN, -OR 8 , -methylene- (OR 8 ) 1-3 , -ethylene- (OR 8 ) 1-3 , -propylene- (OR 8 ) 1-3 , -O-methylene- (halo) 1-3 , -O-ethylene- (halo) 1-3 , -O-propylene- (halo) 1-3 , -SR 8 , -S-methylene- (halo) 1-3 , -S-ethylene- (halo) 1-3 ,
  • Each of (R 8 or R 9 ) in R 11 at each occurrence is independently selected from hydrogen, methyl, ethyl, propyl or isopropyl.
  • each of R 11 at each occurrence is independently selected from -F, -Cl, oxo, methyl, ethyl, propyl, isopropyl, ethenyl, propenyl, ethynyl, propynyl, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CH 2 CH 2 F, -CH 2 CH 2 CHF 2 , -CH 2 CH 2 CF 3 , -CH 2 OCH 3 , -CH 2 CH 2 OCH 3 , -CN, -OH, -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , -OCH (CH 3 ) 2 , -CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH, -OCH 2 F,
  • each of R 11 at each occurrence is independently selected from -F, -Cl, oxo, -OH, -NH 2 , -CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, -CF 3 , -OCF 3 , -NH (CH 3 ) , -N (CH 3 ) 2 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 OH, -SO 2 NH 2 , -CONH 2 ,
  • each of R 11 at each occurrence is independently selected from -F, -Cl, -OH, -NH 2 , methyl, methoxy, -OCF 3 , -CHF 2 , -CF 3 or
  • each of R 11 at each occurrence is independently selected from halogen; -C 1-6 alkyl; -C 1-6 alkyl substituted with halogen, -NH 2 , -CN or -OH; -OH; -O-C 1-6 alkyl; -O-C 1-6 alkyl substituted with halogen, -NH 2 , -CN or -OH; -NH 2 ; -NH (C 1-6 alkly) ; -N (C 1-6 alkyl) 2 ; -NHCOC 1-6 alkyl; -N (C 1-6 alkyl) COC 1-6 alkyl; -NHSO 2 C 1-6 alkyl; -N (C 1-6 alkyl) SO 2 C 1-6 alkyl; -SO 2 (C 1-6 alkyl) ; -SO 2 NH 2 ; -SO 2 NHC 1-6 alkyl; -SO 2 N (C 1-6 alkyl) 2 or -C 3-6
  • each of R 11 at each occurrence is independently selected from -F; -Cl; -Br; -C 1-3 alkyl; -C 1-3 alkyl substituted with -F or -Cl; -OH; -O-C 1-3 alkyl; -O-C 1-3 alkyl substituted with -F or -Cl; -NH 2 ; -NH (C 1-3 alkly) ; -N (C 1-3 alkyl) 2 ; -NHCOC 1-3 alkyl; -N (C 1-3 alkyl) COC 1-3 alkyl; -NHSO 2 C 1-3 alkyl; -N (C 1-3 alkyl) SO 2 C 1-3 alkyl; -SO 2 (C 1-3 alkyl) ; -SO 2 NH 2 ; -SO 2 NHC 1-3 alkyl; -SO 2 N (C 1-3 alkyl) 2 or -C 3-6 carbocyclyl.
  • each of R 11 at each occurrence is independently selected from -F; -Cl; -Br; -C 1-3 alkyl; -C 1-3 alkyl substituted with -F or -Cl; -OH; -O-C 1-3 alkyl; -O-C 1-3 alkyl substituted with -F or -Cl; -NH 2 ; -NH (C 1-3 alkly) ; -N (C 1-3 alkyl) 2 ; -NHCOC 1-3 alkyl; -N (C 1-3 alkyl) COC 1-3 alkyl; -NHSO 2 C 1-3 alkyl; -N (C 1-3 alkyl) SO 2 C 1-3 alkyl; -SO 2 (C 1-3 alkyl) ; -SO 2 NH 2 ; -SO 2 NHC 1-3 alkyl; -SO 2 N (C 1-3 alkyl) 2 or -C 3-6 carbocyclyl.
  • each of R 11 at each occurrence is independently selected from -F; -Cl; methyl; ethyl; propyl; isopropyl; methyl substituted with -F; ethyl substituted with -F; propyl substituted with -F; isopropyl substituted with -F; -OH; methoxyl; ethoxyl; propoxyl; isopropoxyl; methoxyl substituted with -F; ethoxyl substituted with -F; propoxyl substituted with -F; isopropoxyl substituted with -F; -NH 2 ; -NHCH 3 ; -NHCH 2 CH 3 ; -NH (CH 2 CH 2 CH 3 ) ; -NH (CH (CH 3 ) 2 ) ; -N (CH 3 ) 2 ; -N (CH 2 CH 3 ) 2 ; -N (CH 3 ) (CH 2 CH 3 ) ; -N (CH 3 ) (
  • each of R 11 at each occurrence is independently selected from -F, -Cl, methyl, ethyl, propyl, isopropyl, -CH 2 F, -CHF 2 , -CF 3 , -OH, methoxyl, ethoxyl, propoxyl, isopropoxyl, -OCF 3 , -NH 2 , -NHCH 3 , -NHCH 2 CH 3 , -NH (CH 2 CH 2 CH 3 ) , -NH (CH 2 CH 2 CH 3 ) , -NH (CH (CH 3 ) 2 ) , -N (CH 3 ) 2 , -N (CH 2 CH 3 ) 2 , -N (CH 3 ) (CH 2 CH 3 ) , -NHCOCH 3 , -N (CH 3 ) COCH 3 , -NHSO 2 CH 3 , -N (CH 3 ) SO 2 CH 3 , -SO 2 CH 3 , -SO 2 CH
  • each of R 11 at each occurrence is independently selected from -F, -Cl, -CH 3 , -CF 3 , -OH, -OCH 3 , -OCF 3 , -NH 2 , -NHCH 3 , -NHCOCH 3 , -NHSO 2 CH 3 , -SO 2 CH 3 or -SO 2 NHCH 3 .
  • each of R 11 at each occurrence is independently selected from -F, -Cl, -OH or -NH 2 .
  • R 1 is selected from:
  • R 1 is selected from:
  • Each of (R 8 or R 9 ) in (R 21 or R 22 ) at each occurrence is independently selected from hydrogen or -C 1-3 alkyl.
  • R 21 or R 22 is independently selected from hydrogen, -F, -Cl, methyl, ethyl, propyl, isopropyl, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CH 2 CH 2 F, -CH 2 CH 2 CHF 2 , -CH 2 CH 2 CF 3 , -CH 2 OCH 3 , -CH 2 CH 2 OCH 3 , -CN, -OH, -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , -OCH (CH 3 ) 2 , -CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OCH 3 , -NH 2 , -NHCH 3 , -NHCH 2 CH 3 , -NHCH 2 CH 3 ,
  • R 21 or R 22 is independently selected from hydrogen, -F, -Cl, methyl, ethyl, propyl, isopropyl, -CH 2 F, -CHF 2 , -CF 3 , -OH, -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , -OCH (CH 3 ) 2 , -CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH, -NH 2 , -NHCH 3 , -NHCH 2 CH 3 , -NHCH 2 CH 2 CH 3 , -NHCH (CH 3 ) 2 or
  • R 21 is selected from -F, -Cl or and R 22 is selected from hydrogen.
  • R 21 is independently selected from hydrogen; halogen; -C 1-6 alkyl; -C 1-6 alkyl substituted with halogen, -NH 2 , -CN or -OH; -C 2-6 alkenyl or -C 3-6 carbocyclyl;
  • R 22 is selected from hydrogen, halogen or -C 1-6 alkyl.
  • R 21 is selected from hydrogen; -F; -Cl; -Br; -C 1-3 alkyl; -C 1-3 alkyl substituted with -F or -Cl; -C 2-3 alkenyl or -C 3-6 carbocyclyl.
  • 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 carbocyclyl; 4 membered carbocyclyl; 5 membered carbocyclyl or 6 membered carbocyclyl.
  • R 21 is selected from -F, -Cl, -CF 3 ,
  • R 21 is -F or -Cl.
  • R 22 is selected from hydrogen, -F, -Cl, -Br or -C 1-3 alkyl.
  • R 22 is selected from hydrogen, -F, -Cl, methyl, ethyl, propyl or isopropyl.
  • R 22 is hydrogen, or -CH 3 .
  • R 22 is hydrogen
  • R 3 is selected from -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 6-10 aryl, -C 1-3 alkyleneC 6-10 aryl, 5-10 membered heteroaryl, -C 1-3 alkylene- (5-10 membered heteroaryl) , 3-6 membered heterocyclic, -C 1-3 alkylene- (3-6 membered heterocyclic) , -C 3-6 carbocyclic, -C 1-3 alkylene-C 3-6 carbocyclic, each of ring C at each occurrence is independently selected from a C 3-6 carbocyclic or 3-6 membered heterocyclic ring, each of ring D at each occurrence is independently selected from a C 6-10 aryl or 5-10 membered heteroaryl ring, each of heterocyclic and heteroaryl at each occurrence independently contains 1, 2 or 3 heteroatoms selected from N, O or S, each of which at each occurrence is independently
  • R 3 is selected from -C 1-3 alkyl, -C 2-3 alkenyl, -C 2-3 alkynyl, phenyl, naphthyl, -methylene-C 6-10 aryl, -ethylene-C 6-10 aryl, -propylene-C 6-10 aryl, -isopropylene-C 6-10 aryl, 5 membered heteroaryl, 6 membered heteroaryl, 7 membered heteroaryl, 8 membered heteroaryl, 9 membered heteroaryl, 10 membered heteroaryl, -methylene- (5-10 membered heteroaryl) , -ethylene- (5-10 membered heteroaryl) , -propylene- (5-10 membered heteroaryl) , -isopropylene- (5-10 membered heteroaryl) , 3 membered heterocyclic, 4 membered heterocyclic, 5 membered heterocyclic, 6 membered heterocyclic, -methylene- (3-6 member
  • R 3 is selected from methyl, ethyl, propyl, isopropyl, ethenyl, propenyl, ethynyl, propynyl, phenyl, naphthyl, -methylene-phenyl, -ethylene-phenyl, -propylene-phenyl, -isopropylene-phenyl, 5 membered heteroaryl, 6 membered heteroaryl, 7 membered heteroaryl, 8 membered heteroaryl, 9 membered heteroaryl, 10 membered heteroaryl, -methylene- (5-10 membered heteroaryl) , -ethylene- (5-10 membered heteroaryl) , -propylene- (5-10 membered heteroaryl) , -isopropylene- (5-10 membered heteroaryl) , 3 membered heterocyclic, 4 membered heterocyclic, 5 membered heterocyclic, 6 membered heterocyclic, -m
  • R 3 is selected from -C 6-10 aryl or 5-10 membered heteroaryl, each of 5-10 membered heteroaryl at each occurrence independently contains 1, 2, 3 or 4 heteroatoms selected from N, O or S, each of -C 6-10 aryl or 5-10 membered heteroaryl at each occurrence is independently optionally substituted by 1 R 31 , 2 R 31 , 3 R 31 , 4 R 31 , 5 R 31 or 6 R 31 .
  • R 3 is selected from phenyl, naphthyl, 5 membered heteroaryl, 6 membered heteroaryl, 7 membered heteroaryl, 8 membered heteroaryl, 9 membered heteroaryl or 10 membered heteroaryl, each of heteroaryl at each occurrence independently contains 1, 2 or 3 heteroatoms selected from N or O, each of phenyl, naphthyl, or heteroaryl at each occurrence is independently optionally substituted by 1 R 31 , 2 R 31 , 3 R 31 , 4 R 31 , 5 R 31 or 6 R 31 .
  • R 3 is selected from phenyl or 6 membered heteroaryl, the 6 membered heteroaryl contains 1 or 2 heteroatoms selected from N, each of phenyl or 6 membered heteroaryl at each occurrence is independently optionally substituted by 1 R 31 , 2 R 31 , 3 R 31 , 4 R 31 , 5 R 31 or 6 R 31 .
  • R 3 is selected from:
  • R 3 is selected from:
  • R 8 or R 9 in R 31 at each occurrence is independently selected from hydrogen or -C 1-3 alkyl.
  • each of R 31 at each occurrence is independently selected from -F, -Cl, methyl, ethyl, propyl, isopropyl, ethenyl, propenyl, ethynyl, propynyl, -methylene- (halo) 1-3 , -ethylene- (halo) 1-3 , -propylene- (halo) 1-3 , -isopropylene- (halo) 1-3 , heteroethyl, heteropropyl, -CN, -methylene-CN, -ethylene-CN, -propylene-CN, -isopropylene-CN, -OR 8 , -methylene-OR 8 , -ethylene-OR 8 , -propylene-OR 8 , -isopropylene-OR 8 , -O-methylene- (halo) 1-3 , -O-ethylene- (halo) 1-3 , -O-propylene- (
  • R 8 or R 9 in R 31 at each occurrence is independently selected from hydrogen, methyl, ethyl, propyl or isopropyl.
  • each of R 31 at each occurrence is independently selected from -F, -Cl, methyl, ethyl, propyl, isopropyl, ethenyl, propenyl, ethynyl, propynyl, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CH 2 CH 2 F, -CH 2 CH 2 CHF 2 , -CH 2 CH 2 CF 3 , -CH (CH 3 ) (CF 3 ) , -CH 2 OCH 3 , -CH 2 CH 2 OCH 3 , -CN, -CH 2 CN, -CH 2 CH 2 CN, -CH 2 CH 2 CH 2 CN, -OH, -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , -OCH (CH 3 ) 2
  • each of R 31 at each occurrence is independently selected from -Cl, -CH 3 , -CH 2 CH 3 , -CH (CH 3 ) 2 , -CN, -OCH 2 CH 2 NH 2 , -SO 2 CH 3 , -PO (CH 3 ) 2 , each of which is independently optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from -F, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, oxo, -OH, -NH 2 , -N (CH 3 ) 2 or -CN.
  • each of R 31 at each occurrence is independently selected from -Cl, -CH 3 , -CH 2 CH 3 , -CH (CH 3 ) 2 , -CN, -OCH 2 CH 2 NH 2 , -SO 2 CH 3 , -PO (CH 3 ) 2 ,
  • each of R 31 at each occurrence is independently selected from -CH 3 , -CH (CH 3 ) 2 or
  • each of R 31 at each occurrence is independently selected from halogen, -C 1-6 alkyl, -CN, -OH, -O-C 1-6 alkyl, -NH 2 , -NH (C 1-6 alkyl) , -N (C 1-6 alkyl) 2 or -C 3-6 carbocyclyl.
  • each of R 31 at each occurrence is independently selected from -F, -Cl, -Br, -C 1-3 alkyl, -CN, -OH, -O-C 1-3 alkyl, -NH 2 , -NH (C 1-3 alkyl) , -N (C 1-3 alkyl) 2 or -C 3-6 carbocyclyl.
  • each of R 31 at each occurrence is independently selected from -F, -Cl, methyl, ethyl, propyl, isopropyl, -CN, -OH, methoxyl, ethoxyl, propoxyl, isopropoxyl, -NH 2 , -NHCH 3 , -NHCH 2 CH 3 , -NH (CH 2 CH 2 CH 3 ) , -NH (CH (CH 3 ) 2 ) , -N (CH 3 ) 2 , -N (CH 2 CH 3 ) 2 , -N (CH 3 ) (CH 2 CH 3 ) , -N (CH 3 ) (CH 2 CH 3 ) , 3 membered carbocyclyl, 4 membered carbocyclyl, 5 membered carbocyclyl or 6 membered carbocyclyl.
  • each of R 31 at each occurrence is independently selected from methyl or isopropyl.
  • R 3 is selected from:
  • each of R 3 at each occurrence is independently selected from:
  • R 3 is selected from
  • L 4 is selected from absent, (CR 5 R 6 ) m , or NR 5 ;
  • Each of (R 5 or R 6 ) in L 4 at each occurrence is independently selected from hydrogen, methyl, ethyl, propyl or isopropyl; m in L 4 is selected from 1, 2 or 3.
  • L 4 is selected from absent or NH.
  • L 4 is independently selected from absent, O or NH or N (C 1-6 alkyl) .
  • L 4 is independently selected from absent, O, NH, N (CH 3 ) , N (CH 2 CH 3 ) or N (CH 2 CH 2 CH 3 ) .
  • L 4 is independently selected from absent or NH.
  • L 4 is independently selected from absent.
  • R 4 is selected from each of at each occurrence is independently optionally substituted with 1 R 42 , 2 R 42 , 3 R 42 , 4 R 42 , 5 R 42 or 6 R 42 .
  • R 4 is selected from independently optionally substituted with 1 R 42 , 2 R 42 , 3 R 42 , 4 R 42 , 5 R 42 or 6 R 42 .
  • each of G 1 and G 2 at each occurrence is independently selected from N or CR 5 ;
  • Each of R 5 in (G 1 or G 2 ) at each occurrence is independently selected from hydrogen, methyl, ethyl, propyl or isopropyl.
  • each of G 1 at each occurrence is independently selected from N or CH and each of G 2 at each occurrence is independently selected from N or CH.
  • each of n1, n2, n3, n4, n5 at each occurrence is independently selected from 0, 1, 2 or 3, provided that n1 and n2 is not 0 at the same time, n3 and n4 is not 0 at the same time.
  • n1 is selected from 1, 2 or 3; n2 is selected from 1, 2 or 3.
  • n1 is selected from 1 or 2; n2 is selected from 1 or 2.
  • R 4 is selected from each of at each occurrence is independently optionally substituted with 1 R 42 , 2 R 42 , 3 R 42 , 4 R 42 , 5 R 42 or 6 R 42 .
  • R 4 is selected from the is independently optionally substituted by 1 R 42 , 2 R 42 , 3 R 42 or 4 R 42 .
  • R 4 is selected from the is optionally substituted with 1R 42 , 2 R 42 , 3 R 42 , 4 R 42 , 5 R 42 or 6 R 42 .
  • each of R 41 at each occurrence is independently selected from
  • each of R 41 at each occurrence is independently selected from
  • Each of (R 8 or R 9 ) in (R 4a , R 4b or R 4c ) at each occurrence is independently selected from hydrogen or -C 1-3 alkyl;
  • Each of R 4d at each occurrence is independently selected from -F, -Cl or -Br.
  • Each of (R 8 or R 9 ) in (R 4a , R 4b or R 4c ) at each occurrence is independently selected from hydrogen, methyl, ethyl, propyl or isopropyl;
  • Each of R 4d at each occurrence is independently selected from -Cl or -Br.
  • R 4a , R 4b or R 4c at each occurrence is independently selected from hydrogen, -F, -Cl, methyl, ethyl, propyl, isopropyl, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CH 2 CH 2 F, -CH 2 CH 2 CHF 2 , -CH 2 CH 2 CF 3 , -CH 2 OCH 3 , -CH 2 CH 2 OCH 3 , -CH 2 CH 2 CH 2 OCH 3 , -CN, -OH, -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , -OCH (CH 3 ) 2 , -CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH, -NH 2 , -NHCH 3 , -NHCH 3 ,
  • R 4a is absent and one of R 4b and R 4c is absent, another of R 4b and R 4c is selected from hydrogen, -F, -Cl, oxo, methyl, ethyl, propyl, isopropyl, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CH 2 CH 2 F, -CH 2 CH 2 CHF 2 , -CH 2 CH 2 CF 3 , -CH 2 OCH 3 , -CH 2 CH 2 OCH 3 , -CH 2 CH 2 CH 2 OCH 3 , -CN, -OH, -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , -OCH (CH 3 ) 2 , -CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH, -NH 2
  • Each of R 4d at each occurrence is independently selected from -Br.
  • R 4a , R 4b or R 4c at each occurrence is independently selected from hydrogen, -F, -Cl, -CH 3 , -CH 2 CH 3 , -CF 3 , -CH 2 CHF 2 , -CH 2 CH 2 OCH 3 , -CN, -CH 2 OH, -N (CH 3 ) 2 , -CH 2 N (CH 3 ) 2 , -CH 2 NHCH 3 , -CH 2 CH 2 NH 2 , -NHCH 2 CH 2 OH, -COOH, -NHCOCH 3 , or R 4a and R 4c with the carbon they respectively attach to form
  • Each of R 4d at each occurrence is independently selected from -Br.
  • R 41 is selected from
  • R 4a , R 4b , R 4c or R 4e is independently selected from hydrogen, halogen, -C 1-6 alkyl or -C 1-6 alkylene-N (C 1-6 alkyl) 2 .
  • R 4a , R 4b , R 4c or R 4e is independently selected from hydrogen, -F, -Cl, -Br, -C 1-3 alkyl or -C 1-3 alkylene-N (C 1-3 alkyl) 2 .
  • R 4a , R 4b , R 4c or R 4e is independently selected from hydrogen, -F, -Cl, methyl, ethyl, propyl, isopropyl, -CH 2 -N (CH 3 ) 2 , -CH 2 -N (CH 2 CH 3 ) 2 or -CH 2 -N (CH 3 ) (CH 2 CH 3 ) .
  • R 4a , R 4b , R 4c or R 4e is independently selected from hydrogen, -F, methyl or -CH 2 -N (CH 3 ) 2 .
  • R 4a is selected from hydrogen or -F; R 4b is hydrogen; R 4c is selected from hydrogen or -CH 2 -N (CH 3 ) 2 ; R 4e is methyl.
  • each of R 41 at each occurrence is independently selected from
  • each of R 41 at each occurrence is independently selected from:
  • each of R 41 at each occurrence is independently selected from
  • R 4 is independently selected from each of at each occurrence is independently optionally substituted with 1R 42 , 2R 42 , 3R 42 , 4R 42 , 5R 42 or 6 R 42 .
  • Each of (R 8 or R 9 ) in R 42 at each occurrence is independently selected from hydrogen or -C 1-3 alkyl.
  • Each of (R 8 or R 9 ) in R 42 at each occurrence is independently selected from hydrogen or -C 1-3 alkyl.
  • each of R 42 is selected from -F, -Cl, oxo, methyl, ethyl, propyl, isopropyl, -methylene- (halo) 1-3 , -ethylene- (halo) 1-3 , -propylene- (halo) 1-3 , heteroethyl, heteropropyl, ethenyl, propenyl, butenyl, pentenyl, ethynyl, propynyl, butynyl, pentynyl, -OR 8 , -methylene- (OR 8 ) 1-3 , -ethylene- (OR 8 ) 1-3 , -propylene- (OR 8 ) 1-3 , -NR 8 R 9 , -methylene-NR 8 R 9 , -ethylene-NR 8 R 9 , -propylene-NR 8 R 9 , -CN, -methylene-CN, -ethylene-CN, -propylene
  • Each of (R 8 or R 9 ) in R 42 at each occurrence is independently selected from hydrogen, methyl, ethyl, propyl or isopropyl.
  • each of R 42 is selected from -F, -Cl, oxo, methyl, ethyl, propyl, isopropyl, -CH 2 F, -CH 2 Cl, -CHF 2 , -CF 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CH 2 CH 2 F, -CH 2 CH 2 CHF 2 , -CH 2 CH 2 CF 3 , -CH 2 OCH 3 , -CH 2 CH 2 OCH 3 , -CH 2 CH 2 CH 2 OCH 3 , -CH 2 CH 2 CH 2 OCH 3 , ethenyl, propenyl, butenyl, pentenyl, ethynyl, propynyl, butynyl, pentynyl, -OH, -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , -OCH (
  • each of R 42 at each occurrence is independently selected from -C 1-6 alkyl; -C 1-6 alkylene-CN or -C 1-6 alkyl substituted with halogen, -NH 2 , -CN or -OH.
  • each of R 42 at each occurrence is independently selected from -C 1-3 alkyl; -C 1-3 alkylene-CN or -C 1-3 alkyl substituted with -F or -Cl.
  • each of R 42 at each occurrence is independently selected from methyl; ethyl; propyl; isopropyl; -methylene-CN; -ethylene-CN; -propylene-CN; methyl substituted with -F or -Cl; ethyl substituted with -F or -Cl; propyl substituted with -F or -Cl; or isopropyl substituted with -F or -Cl.
  • each of R 42 at each occurrence is independently selected from methyl; ethyl; -methylene-CN or methyl substituted with -F.
  • each of R 42 at each occurrence is independently selected from -CH 3 , -CH 2 CH 3 , -CH 2 CN, -CHF 2 or -CF 3 .
  • R 4 is selected from:
  • R 4 is selected from:
  • R 4 is selected from:
  • R 4 -L 4 - is selected from:
  • the compound is selected from:
  • an intermediate of formula (II) a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof or a pharmaceutically acceptable salt of the atropisomer thereof:
  • R 4 ’ is selected from the is independently optionally substituted by 1 R 42 , 2 R 42 , 3 R 42 , 4 R 42 , 5 R 42 or 6 R 42 ;
  • PG is the protecting group of the N atom; preferably, PG is
  • the intermediate is selected from:
  • an intermediate a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof or a pharmaceutically acceptable salt of the atropisomer thereof of the present invention, wherein the intermediate is selected from:
  • a method for preparing the compound of formula (I) , a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof or a pharmaceutically acceptable salt of the atropisomer thereof of the present invention comprising the following step A or step B:
  • step B
  • the R 1 ’ is selected from -C 6-10 aryl substituted with (1R 11 , 2R 11 or 3R 11 ) ; or 5-10 membered heteroaryl substituted with (1 R 11 , 2 R 11 or 3 R 11 ) ; preferably, the R 1 ’ is phenyl substituted with 2R 11 ;
  • the definition of (R 21 , R 22 , R 3 , L 4 , R 4 , R 1 or R 11 ) is as defined in the present invention ;
  • the compound of formula (I) is provided by halogenation of the R 1 ’ in the Intermediate A0, preferably, the halogenating reagent is NCS or NBS;
  • the R 1 ’ is selected from -C 6-10 aryl substituted with 1R 11 , 2R 11 or 3R 11 ; or 5-10 membered heteroaryl substituted with 1R 11 , 2R 11 or 3R 11 ; preferably, the the R 1 ’ is phenyl substituted with 2R 11 ;
  • the R 4 ’ is R 4 with N protecting group, such as N-Boc piperazinyl;
  • the Intermediate B1 is obtained by halogenation of the R 1 ’ in the Intermediate B0, preferably, the halogenating reagent is NCS or NBS;
  • the compound of Formula (I) is provided by deprotecting of the R 4 ’ in the Intermediate B1 and subsequent acylating reaction on the N atom.
  • the R 1 ’ in the step A or step B is selected from:
  • the -L 4 -R 4 ’ in the step B is selected from
  • a pharmaceutical composition comprising at least one compound of formula (I) , stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof or a pharmaceutically acceptable salt of the atropisomer thereof of the present invention, and at least one pharmaceutically acceptable excipient.
  • the said compound in a weight ratio to the said excipient within the range from about 0.0001 to about 10.
  • the said compound in a weight ratio to the said excipient within the range from about 0.01 to about 0.8.
  • the diseases or conditions related to KRAS mutant protein is the diseases or conditions related to KRAS G12C mutant protein. In some embodiments, the diseases or conditions related to KRAS mutant protein is cancer related to KRAS G12C mutant protein.
  • the cancer is selected from blood cancer, pancreatic cancer, colon cancer, rectal cancer, colorectal cancer or lung cancer.
  • 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.
  • the diseases or conditions related to KRAS mutant protein is the deseases or conditions related to KRAS G12C mutant protein.
  • the diseases or conditions related to KRAS mutant protein is cancer related to KRAS G12C mutant protein.
  • the cancer is selected from blood cancer, pancreatic cancer, colon cancer, rectal cancer, colorectal cancer or lung cancer.
  • 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.
  • the compound of formula (I) a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof or a pharmaceutically acceptable salt of the atropisomer thereof of the present invention or the pharmaceutical composition of the present invention for use as a medicament.
  • halogen or “halo” , as used herein, unless otherwise indicated, means fluoro, chloro, bromo or iodo.
  • the preferred halogen groups include -F, -Cl and -Br. More preferably, the halo or halogen is -F or -Cl.
  • alkyl as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight or branched.
  • alkyl radicals 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.
  • C 1-6 as in C 1-6 alkyl is defined to identify the group as having 1, 2, 3, 4, 5 or 6 carbon atoms in a linear or branched arrangement.
  • alkylene means a difunctional group obtained by removal of a hydrogen atom from an alkyl group that is defined above.
  • methylene i.e., -CH 2 -
  • ethylene i.e., -CH 2 -CH 2 -or -CH (CH 3 ) -
  • propylene i.e., -CH 2 -CH 2 -CH 2 -, -CH (-CH 2 -CH 3 ) -or -CH 2 -CH (CH 3 ) -
  • alkenyl means a straight or branch-chained hydrocarbon radical containing one or more double bonds, typically the number of carbon atoms is from 2 to 20.
  • C 2-6 alkenyl contains carbon atoms from 2 to 6.
  • Alkenyl group include, but are not limited to, for example, ethenyl, propenyl, butenyl, 2-methyl-2-buten-1-yl, hepetenyl, octenyl and the like.
  • alkynyl contains a straight or branch-chained hydrocarbon radical containing one or more triple bonds, typically the number of carbon atoms is from 2 to 20 carbon atoms.
  • C 2-6 alkynyl contains caron atoms from 2 to 6.
  • Representative alkynyl groups include, but are not limited to, for example, ethynyl, 1-propynyl, 1-butynyl, heptynyl, octynyl and the like.
  • alkoxy radicals are oxygen ethers formed from the previously described alkyl groups.
  • aryl or “aryl ring, as used herein, unless otherwise indicated, refers to an unsubstituted or substituted mono or polycyclic aromatic ring system containing carbon ring atoms.
  • the preferred aryls are mono cyclic or bicyclic 6-10 membered aromatic ring systems. Phenyl and naphthyl are preferred aryls.
  • heterocyclic or “heterocyclic ring” , as used herein, unless otherwise indicated, refers to unsubstituted and substituted mono or polycyclic non-aromatic ring system containing one or more (such as 2, 3, 4, 5 or 6) heteroatoms, which comprising moncyclic heterocyclic ring, bicyclic heterocyclic ring, bridged heterocyclic ring, fused heterocyclic ring or sipro heterocyclic ring.
  • Preferred heteroatoms include N, O, and S, including N-oxides, sulfur oxides, and dioxides.
  • the ring is three to ten membered and is either fully saturated or has one or more degrees of unsaturation.
  • Heterocyclic or heterocyclic ring with multiple degrees of substitution, preferably one, two or three, are included within the present definition.
  • 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 or oxadiazolyl.
  • heteroaryl represents an aromatic ring system containing carbon (s) and at least one heteroatom.
  • Heteroaryl may be monocyclic or polycyclic, substituted or unsubstituted.
  • a monocyclic heteroaryl group may have 1 to 4 heteroatoms in the ring, while a polycyclic heteroaryl may contain 1 to 10 hetero atoms.
  • a polycyclic heteroaryl ring may contain fused, spiro or bridged ring junction, for example, bycyclic heteroaryl is a polycyclic heteroaryl.
  • Bicyclic heteroaryl rings may contain from 8 to 12 member atoms.
  • Monocyclic heteroaryl rings may contain from 5 to 8 member atoms (cabons and heteroatoms) .
  • 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.
  • carbocyclic refers to a substituted or unsubstituted monocyclic ring, bicyclic ring bridged ring, fused ring, sipiro ring non-aromatic ring system onle containing carbon atoms.
  • Examplary “carbocyclic” groups includes but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and so on.
  • -C 1-6 alkyleneC 6-10 aryl refers to the -C 1-6 alkyl as defined above substituted by C 6-10 aryl as defined above.
  • -C 1-6 alkylene- (5-10 membered heteroaryl) refers to the -C 1-6 alkyl as defined above substituted by 5-10 membered heteroaryl as defined above.
  • -C 1-6 alkylene- (3-10 membered heterocyclic) refers to the -C 1-6 alkyl as defined above substituted by 3-10 membered heterocyclic as defined above.
  • -C 1-6 alkylene-C 3-10 carbocyclic refers to the -C 1-6 alkyl as defined above substituted by C 3-10 carbocyclic as defined above.
  • -C 1-6 alkylene- (halo) 1-3 refers to the -C 1-6 alkyl as defined above substituted by 1, 2 or 3 halogen as defined above.
  • heteroC 2-6 alkyl refers to the C 2-6 alkyl as defined above wherein one or more carbon atoms in the chain are replaced by a heteroatom selected from O, S or N, preferred heteratom is O.
  • -C 1-6 alkylene- (OR 8 ) 1-3 refers to the -C 1-6 alkyl as defined above substituted by 1, 2 or 3 OR 8 , wherein R 8 is defined as above, preferred R 8 is selected from hydrogen, methyl, ethyl or propyl.
  • -C 1-6 alkylene- (SR 8 ) 1-3 refers to the -C 1-6 alkyl as defined above substituted by 1, 2 or 3 SR 8 , wherein R 8 is defined as above, preferred R 8 is selected from hydrogen, methyl, ethyl or propyl.
  • -O-C 1-6 alkylene- (halo) 1-3 refers to the oxygen ethers of -C 1-6 alkylene- (halo) 1-3 as defined above.
  • -S-C 1-6 alkylene- (halo) 1-3 refers to the S ethers of -C 1-6 alkylene- (halo) 1-3 as defined above.
  • -C 1-6 alkylene-NR 8 R 9 refers to the -C 1-6 alkyl as defined above substituted by -NR 8 R 9 , wherein the R 8 and R 9 is defined as above.
  • preferred R 8 , R 9 is selected from hydrogen, methyl, ethyl or propyl.
  • -C 1-6 alkylene-CN refers to the -C 1-6 alkyl as defined above substituted by -CN.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts. Accordingly, pharmaceutical compositions containing the compounds of the present invention as the active ingredient as well as methods of preparing the instan
  • pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids.
  • the compound of the present invention is acidic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases.
  • the compound of the present invention is basic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Since the compounds of Formula (I) are intended for pharmaceutical use they are preferably provided in substantially pure form, for example at least 60%pure, more suitably at least 75%pure, especially at least 98%pure (%are on a weight for weight basis) .
  • the present invention includes within its scope the prodrugs of the compounds of this invention.
  • such prodrugs will be functional derivatives of the compounds that are readily converted in vivo into the required compound.
  • the term “administering” shall encompass the treatment of the various disorders described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the 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.
  • the present invention includes compounds described can contain one or more asymmetric centers and may thus 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 pharmaceutically acceptable salts thereof.
  • the present invention includes all stereoisomers of the compound and pharmaceutically acceptable salts thereof. Further, mixtures of stereoisomers as well as isolated specific stereoisomers are also included. During the course of the synthetic procedures used to prepare such compounds or in using racemization or epimerization procedures known to those skilled in the art, the products of such procedures can be a mixture of stereoisomers.
  • stereoisomer refers to an isomer in which atoms or groups of atoms in the molecule are connected to each other in the same order but differ in spatial arrangement, including conformational isomers and conformational isomers.
  • the configuration isomers include geometric isomers and optical isomers, and optical isomers mainly include enantiomers and diastereomers.
  • the invention includes all possible stereoisomers of the compound.
  • Certain of the compounds provided herein may exist as atropisomers, which are conformational stereoisomers that occur when rotation about a single bond in the molecule is prevented, or greatly slowed, as a result of steric interactions with other parts of the molecule.
  • the compounds provided herein include all atropisomers, both as pure individual atropisomer preparations, enriched preparations of each, or a non-specific mixture of each. Where the rotational barrier about the single bond is high enough, and interconversion between conformations is slow enough, separation and isolation of the isomeric species may be permitted.
  • the present invention is intended to include all isotopes of atoms occurring in the present compounds.
  • Isotopes include those atoms having the same atomic number but different mass numbers.
  • isotopes of hydrogen include deuterium and tritium.
  • the isotopes of hydrogen can be denoted as 1 H (hydrogen) , 2 H (deuterium) and 3 H (tritium) . They are also commonly denoted as D for deuterium and T for tritium.
  • CD 3 denotes a methyl group wherein all of the hydrogen atom are deuterium.
  • Isotopes of carbon include 13 C and 14 C.
  • Isotopically-labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by prcesses analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent.
  • the present invention includes any possible tautomers and pharmaceutically acceptable salts thereof, and mixtures thereof, except where specifically stated otherwise.
  • the present invention includes any possible solvates and polymorphic forms.
  • a type of a solvent that forms the solvate is not particularly limited so long as the solvent is pharmacologically acceptable.
  • compositions of the present invention comprise a compound represented by Formula (I) (or a pharmaceutically acceptable salt thereof) as an active ingredient, a pharmaceutically acceptable carrier and optionally other therapeutic ingredients or adjuvants.
  • the compositions include compositions 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, and nature and severity of the conditions for which the active ingredient is being administered.
  • the pharmaceutical compositions may be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.
  • the compounds represented by Formula (I) or a prodrug or a metabolite or pharmaceutically acceptable salts thereof, of this invention can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
  • the carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g. oral or parenteral (including intravenous) .
  • 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.
  • 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.
  • the compound represented by Formula I or a pharmaceutically acceptable salt thereof may also be administered by controlled release means and/or delivery devices.
  • the compositions may be prepared by any of the methods of pharmacy. In general, such methods include a step of bringing into association the active ingredient with the carrier that constitutes one or more necessary ingredients.
  • 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.
  • compositions of this invention may include a pharmaceutically acceptable carrier and a compound or a pharmaceutically acceptable salt, of Formula I.
  • the compounds of Formula I or pharmaceutically acceptable salts thereof, can also be included in pharmaceutical compositions in combination with one or more other therapeutically active compounds.
  • the pharmaceutical carrier employed can be, for example, a solid, liquid or gas.
  • solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid.
  • liquid carriers are sugar syrup, peanut oil, olive oil, and water.
  • gaseous carriers include carbon dioxide and nitrogen.
  • oral liquid preparations such as suspensions, elixirs and solutions
  • carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like may be used to form oral solid preparations such as powders, capsules and tablets.
  • oral solid preparations such as powders, capsules and tablets.
  • tablets and capsules are the preferred oral dosage units whereby solid pharmaceutical carriers are employed.
  • tablets may be coated by standard aqueous or nonaqueous techniques.
  • a tablet containing the composition of this invention may be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants.
  • Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent.
  • Each tablet preferably contains from about 0.05mg to about 5g of the active ingredient and each cachet or capsule preferably containing from about 0.05mg to about 5g of the active ingredient.
  • a formulation intended for the oral administration to humans may contain from about 0.5mg to about 5g of 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.
  • Unit dosage forms will generally contain between from about 0.0lmg to about 2g of the active ingredient, typically 0.01mg, 0.02mg, 1mg, 2mg, 3mg, 4mg, 5mg, 6mg, 7mg, 8mg, 9mg, 10mg, 25mg, 50mg, l00mg, 200mg, 300mg, 400mg, 500mg, 600mg, 800mg, l000mg, 1500mg or 2000mg.
  • compositions of the present invention suitable for parenteral administration may be prepared as solutions or suspensions of the active compounds in water.
  • a suitable surfactant can be included such as, for example, hydroxypropylcellulose.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Further, a preservative can be included to prevent the detrimental growth of microorganisms.
  • compositions of the present invention suitable for injectable use include sterile aqueous solutions or dispersions.
  • the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions.
  • the final injectable form must be sterile and must be effectively fluid for easy syringability.
  • the pharmaceutical compositions must be stable under the conditions of manufacture and storage; thus, preferably should be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol) , vegetable oils, and suitable mixtures thereof.
  • compositions of the present invention can be in a form suitable for topical use such as, for example, an aerosol, cream, ointment, lotion, dusting powder or the like. Further, the compositions can be in a form suitable for use in transdermal devices. These formulations may be prepared, utilizing a compound represented by Formula I of this invention or a pharmaceutically acceptable salt thereof, via conventional processing methods. As an example, a cream or ointment is prepared by admixing hydrophilic material and water, together with about 0.05wt%to about 10wt%of the compound, to produce a cream or ointment having a desired consistency.
  • compositions of this invention can be in a form suitable for rectal administration wherein the carrier is a solid. It is preferable that the mixture forms unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. The suppositories may be conveniently formed by first admixing the composition with the softened or melted carrier (s) followed by chilling and shaping in molds.
  • the pharmaceutical formulations described above may include, as appropriate, one or more additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including antioxidants) and the like.
  • additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including antioxidants) and the like.
  • additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including antioxidants) and the like.
  • additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including antioxidants) and the like.
  • other adjuvants can be included to render the formulation isotonic with the blood of the intended recipient.
  • dosage levels on the order of from about 0.001mg/kg to about 150mg/kg of body weight per day are useful in the treatment of the above-indicated conditions or alternatively about 0.05mg to about 7g per patient per day.
  • inflammation, cancer, psoriasis, allergy/asthma, disease and conditions of the immune system, disease and conditions of the central nervous system (CNS) may be effectively treated by the administration of from about 0.001 to 50mg of the compound per kilogram of body weight per day or alternatively about 0.05mg to about 3.5g per patient per day.
  • Figure 1 is a graph showing the tumor volume of mice varies with the number of days after cell inoculation in the experiment of using compound 11 to inhibit tumor growth.
  • Figure 2 shows the body weight of mice varies with the number of days after cell inoculation in the safety exploration experiment of using compound 11B.
  • X 1 represents halogen, such as Cl, Br or I
  • X 2 represents halogen, such as Cl, Br or I
  • LG represents leaving group, such as Cl, OTf
  • Y 1 represents H or leaving group
  • R 4 ’ represents R 4 with protecting group, such as N-Boc piperazinyl; the definition of other groups or substituents in the Scheme I are describled as above.
  • a compound of Formula (I) as disclosed herein can be synthesized as outlined in Scheme I.
  • starting material such as 1, which is purchased or synthesized, can be coupled with INT-A (INT-A route) to form compound 2 by treatment with a condensation reagent such as HATU or EDCI/HOBT, or an acyl chloride (which is prepared using the compound 1) .
  • This coupling may proceed in a solvent such as dichloromethane or DMF in the presence of a base such as triethylamine or Hunig’s base.
  • 2 could be treated with suitable base such as LiHMDS or NaH to get intramolecular cyclization product compound 3.
  • step 3 the mono oxo group of the pyridinone (compound 3) is converted to leaving group using an activating agent to form compound 4.
  • the activating agents include, but not limited to, thionyl chloride, triflic anhydride, phosphorus oxychloride, and phosphorus pentachloride.
  • step 4 the leaving group is then replaced with a -L 4 -R 4 ’ group in the Y 1 -L 4 -R 4 ’ to form compound 5 in a solvent such as acetonitrile and a base such as DIPEA.
  • step 5 compounds such as 5 can be de-protected by treatment with acid, typically TFA in DCM or HCl in MeOH, to provide the amino compounds, the amino compounds was then acetylated to provide compounds such as 6, typically by treatment with acryloyl chloride in DCM with TEA or DIPEA as base.
  • the R 1 group could be introduced by cross-coupling reaction with the appropriate Z 1 -R 1 reagent, for example in the presence of a palladium catalyst such as Pd 2 (dba) 3 /X-Phos in a solvent such as dioxane with a base such as cesium carbonate or sodium carbonate to provide Formula (I) .
  • the species R 1 and R 3 may contain protecting groups, which can be removed by an additional step in the synthetic sequence.
  • X 1 represents halogen, such as Cl, Br or I
  • X 2 represents halogen, such as Cl, Br or I
  • LG represents leaving group, such as Cl, OTf
  • Y 1 represents H or leaving group
  • R 4 ’ represents R 4 with protecting group, such as N-Boc piperazine; the definition of other groups or substituents in the Scheme II are describled as above.
  • a compound of Formula (I) as disclosed herein can be synthesized as outlined in Scheme II.
  • starting material such as 1, which is purchased or synthesized, can be coupled with INT-A (INT-A route) to form a cyano-oxobutanamide such as 2 by treatment with a condensation reagent such as HATU or EDCI/HOBT, or an acyl chloride.
  • a condensation reagent such as HATU or EDCI/HOBT
  • acyl chloride an acyl chloride.
  • This coupling proceeds in a solvent such as dichloromethane or DMF in the presence of a base such as triethylamine or Hunig’s base.
  • 2 could be treated with suitable base such as LiHMDS or NaH to get intramolecular cyclization product such as 3.
  • step 3 the mono oxo group of the pyridinone is then converted to leaving group using an activating agent to form 4.
  • Contemplated activating agents include, but not limited to, thionyl chloride, triflic anhydride, phosphorus oxychloride, and phosphorus pentachloride.
  • step 4 the leaving group is then replaced with a Y 1 -L 4 -R 4 ’ group to form a substituted compound such as 5 in a solvent such as acetonitrile and a base such as DIPEA.
  • the R 1 group could be introduced by cross-coupling reaction with the appropriate Z 1 -R 1 reagent, for example in the presence of a palladium catalyst such as Pd 2 (dba) 3 /X-Phos in a solvent such as dioxane with a base such as cesium carbonate or sodium carbonate to provide 6.
  • a palladium catalyst such as Pd 2 (dba) 3 /X-Phos
  • a solvent such as dioxane
  • a base such as cesium carbonate or sodium carbonate
  • compounds such as 6 can be de-protected by treatment with acid, typically TFA in DCM or HCl in MeOH, to provide the amino compounds, the amino compounds was then acetylated to provide Formula (I) , typically by treatment with acryloyl chloride in DCM with TEA or DIPEA as base to provide Formula (I) .
  • the species R 1 and R 3 may contain protecting groups, which can be removed by an additional step in the synthetic sequence.
  • X 1 represents halogen, such as Cl, Br or I
  • X 2 represents halogen, such as Cl, Br or I
  • LG represents leaving group, such as Cl, OTf
  • Y 1 represents H or leaving group
  • R 4 ’ represents R 4 with protecting group, such as N-Boc piperazinyl
  • R 1 ' represents -C 6-10 aryl substituted with 1R 11 , 2R 11 or 3R 11 ; or 5-10 membered heteroaryl substituted with 1R 11 , 2R 11 or 3R 11 ; the definition of other groups or substituents in the Scheme III and the definition of R 11 are describled as above.
  • a compound of Formula (I) as disclosed herein can be synthesized as outlined in Scheme III.
  • starting material such as 1, which is purchased or synthesized can be coupled with INT-A (INT-A route) to form a cyano-oxobutanamide such as 2 by treatment with a condensation reagent such as HATU or EDCI/HOBT, or an acyl chloride.
  • a condensation reagent such as HATU or EDCI/HOBT
  • acyl chloride an acyl chloride.
  • This coupling proceeds in a solvent such as dichloromethane or DMF in the presence of a base such as triethylamine or Hunig’s base.
  • 2 could be treated with suitable base such as LiHMDS or NaH to get intramolecular cyclization product such as 3.
  • step 3 the mono oxo group of the pyridinone is then converted to leaving group using an activating agent to form 4.
  • Contemplated activating agents include, but not limited to, thionyl chloride, triflic anhydride, phosphorus oxychloride, and phosphorus pentachloride.
  • step 4 the leaving group is then replaced with a Y 1 -L 4 -R 4 ’ group to form a substituted compound such as 5 in a solvent such as acetonitrile and a base such as DIPEA.
  • step 5 compounds such as 5 can be de-protected by treatment with acid, typically TFA in DCM or HCl in MeOH, to provide the amino compounds, the amino compounds was then acetylated to provide compounds such as 6, typically by treatment with acryloyl chloride in DCM with TEA or DIPEA as base.
  • the R 1 group could be introduced by cross-coupling reaction with the appropriate Z 1 -R 1 ' reagent, for example in the presence of a palladium catalyst such as Pd 2 (dba) 3 /X-Phos in a solvent such as dioxane with a base such as cesium carbonate or sodium carbonate to provide compounds such as 7.
  • compounds such as 7 could be halogenated with reagent such as NCS to provide Formula (I) .
  • the species R 1 ', R 1 and R 3 may contain protecting groups, which can be removed by an additional step in the synthetic sequence.
  • X 1 represents halogen, such as Cl, Br or I
  • X 2 represents halogen, such as Cl, Br or I
  • LG represents leaving group, such as Cl, OTf
  • Y 1 represents H or leaving group
  • R 4 ’ represents R 4 with protecting group, such as N-Boc piperazinyl
  • R 1 ' represents -C 6-10 aryl substituted with 1R 11 , 2R 11 , or 3R 11 , or 5-10 membered heteroaryl substituted with 1R 11 , 2R 11 or 3R 11
  • the definition of other groups or substituents in the Scheme IV and the definition of R 11 are describled as above.
  • a compound of Formula (I) as disclosed herein can be synthesized as outlined in Scheme IV.
  • starting material such as 1, which is purchased or synthesized can be coupled with INT-A (INT-A route) to form a cyano-oxobutanamide such as 2 by treatment with a condensation reagent such as HATU or EDCI/HOBT, or an acyl chloride.
  • a condensation reagent such as HATU or EDCI/HOBT
  • acyl chloride an acyl chloride.
  • This coupling proceeds in a solvent such as dichloromethane or DMF in the presence of a base such as triethylamine or Hunig’s base.
  • 2 could be treated with suitable base such as LiHMDS or NaH to get intramolecular cyclization product such as 3.
  • step 3 the mono oxo group of the pyridinone is then converted to leaving group using an activating agent to form 4.
  • Contemplated activating agents include, but not limited to, thionyl chloride, triflic anhydride, phosphorus oxychloride, and phosphorus pentachloride.
  • step 4 the leaving group is then replaced with Y 1 -L 4 -R 4 ’ group to form a substituted compound such as 5 in a solvent such as acetonitrile and a base such as DIPEA.
  • the R 1 group could be introduced by cross-coupling reaction with the appropriate Z 1 -R 1 ' reagent, for example in the presence of a palladium catalyst such as Pd 2 (dba) 3 /X-Phos in a solvent such as dioxane with a base such as cesium carbonate or sodium carbonate to provide 6.
  • a palladium catalyst such as Pd 2 (dba) 3 /X-Phos
  • a solvent such as dioxane
  • a base such as cesium carbonate or sodium carbonate
  • compounds such as 6 could be halogenated with reagent such as NCS to provide compounds such as 7.
  • step 7 compounds such as 7 can be de-protected by treatment with acid, typically TFA in DCM or HCl in MeOH, to provide the amino compounds, the amino compounds was then acetylated to provide Formula (I) , typically by treatment with acryloyl chloride in DCM with TEA or DIPEA as base to provide Formula (I) .
  • the species R 1 ', R 1 and R 3 may contain protecting groups, which can be removed by an additional step in the synthetic sequence.
  • Step 1 4-methyl-2- (prop-1-en-2-yl) pyridin-3-amine.
  • Step 2 2-isopropyl-4-methylpyridin-3-amine (Intermediate A) .
  • Step 4 2-cyano-3- (2, 6-dichloro-5-fluoropyridin-3-yl) -N- (2-isopropyl-4-methylpyridin-3-yl) -3-oxoprop anamide.
  • Step 5 7-chloro-6-fluoro-4-hydroxy-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthy ridine-3-carbonitrile (Intermediate B) .
  • Step 6 tert-butyl 4- (7-chloro-3-cyano-6-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridin-4-yl) piperazine-1-carboxylate.
  • Step 7 tert-butyl 4- (7- (2-amino-6-fluorophenyl) -3-cyano-6-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridin-4-yl) piperazine-1-carboxylate.
  • Step 8 tert-butyl 4- (7- (2-amino-3, 5-dichloro-6-fluorophenyl) -3-cyano-6-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridin-4-yl) piperazine-1-carboxylate.
  • Step 9 4- (4-acryloylpiperazin-1-yl) -7- (2-amino-3, 5-dichloro-6-fluorophenyl) -6-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile ( “Compound 1” ) .
  • Step 1 4- (4-acryloyl-3- (cyanomethyl) piperazin-1-yl) -7-chloro-6-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile.
  • Step 2 4- (4-acryloyl-3- (cyanomethyl) piperazin-1-yl) -6-fluoro-7- (2-fluoro-6-hydroxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile.
  • Step 3 4- (4-acryloyl-3- (cyanomethyl) piperazin-1-yl) -7- (3, 5-dichloro-2-fluoro-6-hydroxyphenyl) -6-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile ( “Comp ound 2” ) .
  • Step 2 2-cyano-N- (2-isopropyl-4-methylpyridin-3-yl) -3-oxo-3- (2, 5, 6-trichloropyridin-3-yl) propanamide.
  • 2, 5, 6-trichloronicotinic acid (5.01 g, 22.12 mmol)
  • SOCl 2 (30 mL)
  • the mixture was heated to 80 °C and stirred for 2 h.
  • the solution was concentrated under vacuum. This resulted in 5.10 g (crude) of 2, 5, 6-trichloronicotinoyl chloride which was used directly for next step.
  • Step 3 6, 7-dichloro-4-hydroxy-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthy ridine-3-carbonitrile (Intermediate C) .
  • Step 7 4- ( (S) -4-acryloyl-3- (cyanomethyl) piperazin-1-yl) -6-chloro-7- (2-fluoro-6-hydroxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile
  • Step 8 4- ( (S) -4-acryloyl-3- (cyanomethyl) piperazin-1-yl) -6-chloro-7- (3, 5-dichloro-2-fluoro-6-hydroxy phenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile ( “Compound 3” )
  • Step 1 4- ( (S) -4-acryloyl-3- (cyanomethyl) piperazin-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.
  • reaction mixture was quenched with H 2 O (100 mL) , extracted with DCM (100 mL) for 3 times, washed with brine (100 mL) , dried over anhydrous Na 2 SO 4 and concentrated under vacuum.
  • reaction mixture was stirred at 80 °C for 1 h.
  • the reaction mixture was quenched with H 2 O (50 mL) , extracted with DCM (50 mL) for 3 times, washed with brine (50 mL) , dried over anhydrous Na 2 SO 4 and concentrated under vacuum.
  • reaction mixture was quenched with H 2 O (50 mL) , extracted with DCM (50 mL) for 3 times, washed with saturated NaHCO 3 (aq) (50 mL) and brine (50 mL) , dried over anhydrous Na 2 SO 4 and concentrated under vacuum.
  • Step 1 2-cyano-N- (2-isopropyl-4-methylpyridin-3-yl) -3-oxo-3- (2, 5, 6-trichloropyridin-3-yl) propanamide.
  • 2, 5, 6-trichloronicotinic acid 99.63 g, 439.98 mmol
  • SOCl 2 500 mL
  • the mixture was heated to 80 °C and stirred for 3 h.
  • the solution was concentrated under vacuum. This resulted in 100.97 g (93.68%yield) of 2, 5, 6-trichloronicotinoyl chloride which was used directly for next step.
  • Step 2. 6, 7-dichloro-4-hydroxy-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile.
  • Step 3 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.
  • Step 4 4- ( (3S, 5R) -4-acryloyl-3, 5-dimethylpiperazin-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.
  • Step 5 4- ( (3S, 5R) -4-acryloyl-3, 5-dimethylpiperazin-1-yl) -7- (2-amino-3, 5-dichloro-6-fluorophenyl) -6-chloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile ( “Comp ound 6” ) .
  • reaction mixture was stirred at 80 °C for 1 h.
  • the reaction mixture was quenched with H 2 O (50 mL) , extracted with DCM (50 mL) for 3 times, washed with saturated brine (50 mL) , dried over anhydrous Na 2 SO 4 and concentrated under vacuum.
  • Step 2 4- ( (3S, 5R) -4-acryloyl-3, 5-dimethylpiperazin-1-yl) -6-chloro-7- (3, 5-dichloro-2-fluoro-6-hydroxy phenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile ( “Com pound 7” )
  • reaction mixture was quenched with H 2 O (50 mL) , extracted with DCM(50 mL) for 3 times, washed with saturated NaHCO 3 (aq) (50 mL) and brine (50 mL) , dried over anhydrous Na 2 SO 4 .
  • Step 3 4- ( (R) -4-acryloyl-3-methylpiperazin-1-yl) -6-chloro-7- (2-fluoro-6-hydroxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile.
  • Step 4 4- ( (R) -4-acryloyl-3-methylpiperazin-1-yl) -6-chloro-7- (3, 5-dichloro-2-fluoro-6-hydroxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile ( “Compound 8” ) .
  • Step 1 4- ( (R) -4-acryloyl-3-methylpiperazin-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.
  • Step 2 4- ( (R) -4-acryloyl-3-methylpiperazin-1-yl) -7- (2-amino-3, 5-dichloro-6-fluorophenyl) -6-chloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile ( “Compound 9” ) .
  • the reaction was allowed to react for 12 h at 89°C.
  • the reaction was filtered and concentrated under vacuum.
  • the fraction was collected and concentrated under vacuum.
  • reaction was quenched with saturated Na 2 CO 3 (aq) (150mL) , extracted with EA (80mL ⁇ 3) , the organic was combined , washed with water (100mL) and brine (100mL) , dried over Na 2 SO 4 . The reaction was concentrated under vacuum.
  • Step 1. 6, 7-trichloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile.
  • 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
  • Step 4 4- (4-acryloylpiperazin-1-yl) -7- (2-amino-6-fluorophenyl) -6-chloro-1- (2-isopropyl-4-methyl pyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile ( “Compound 11-4” )
  • Step 5 4- (4-acryloylpiperazin-1-yl) -7- (2-amino-3, 5-dichloro-6-fluorophenyl) -6-chloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile
  • Step 1 4- (4-acryloyl-3- (cyanomethyl) piperazin-1-yl) -7-chloro-6-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile.
  • the reaction mixture was cooled to 0 °C and acryloyl chloride (120 mg, 1.33 mmol) was added. The reaction was then quenched by the addition of water (50 mL) . The resulting solution was extracted with ethyl acetate (3 ⁇ 50 mL) , the organic layers combined and washed with brine (50 mL) , dried over anhydrous Na 2 SO 4 , filtered and concentrated under vacuum. The residue was purified by silica gel column eluted with EA/hexane (2/1 (v: v) ) .
  • Step 2 4- (4-acryloyl-3- (cyanomethyl) piperazin-1-yl) -7- (2-amino-6-fluorophenyl) -6-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile
  • Step 3 4- (4-acryloyl-3- (cyanomethyl) piperazin-1-yl) -7- (2-amino-3, 5-dichloro-6-fluorophenyl) -6-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile
  • Step 1 4- (4-acryloyl-3- (cyanomethyl) piperazin-1-yl) -6, 7-dichloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile.
  • the reaction mixture was cooled to 0 °C and acryloyl chloride (297 mg, 3.28 mmol) was added. The reaction was then quenched by the addition of water (50 mL) . The resulting solution was extracted with ethyl acetate (3 ⁇ 50 mL) , the organic layers combined and washed with brine (50 mL) , dried over anhydrous Na 2 SO 4 , filtered and concentrated under vacuum. The residue was purified by silica gel column eluted with EA/hexane (7/3 (v: v) ) .
  • Step 2 4- (4-acryloyl-3- (cyanomethyl) piperazin-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
  • Step 3 4- (4-acryloyl-3- (cyanomethyl) piperazin-1-yl) -7- (2-amino-3, 5-dichloro-6-fluorophenyl) -6-chloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile
  • reaction mixture was quenched with 50 mL saturated NaHCO 3 (aq) and extracted with EA (30mL ⁇ 3) concentrated under vacuum.
  • Step 1 tert-butyl 4- (6, 7-dichloro-3-cyano-1- (4, 6-diisopropylpyrimidin-5-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridin-4-yl) piperazine-1-carboxylate.
  • Step 3 tert-butyl 4- (7- (2-amino-3, 5-dichloro-6-fluorophenyl) -6-chloro-3-cyano-1- (4, 6-diisopropyl pyrimidin-5-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridin-4-yl) piperazine-1-carboxylate.
  • Step 4 4- (4-acryloylpiperazin-1-yl) -7- (2-amino-3, 5-dichloro-6-fluorophenyl) -6-chloro-1- (4, 6-diisopropyl pyrimidin-5-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile.
  • Step 1 tert-butyl (R) -4- (6, 7-dichloro-3-cyano-1- (4, 6-diisopropylpyrimidin-5-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridin-4-yl) -2-methylpiperazine-1-carboxylate.
  • Step 4 4- ( (R) -4-acryloyl-3-methylpiperazin-1-yl) -7- (2-amino-3, 5-dichloro-6-fluorophenyl) -6-chloro-1- (4, 6-diisopropylpyrimidin-5-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile.
  • Step 1 6-di (prop-1-en-2-yl) pyrimidin-5-amine
  • Step 4. 6, 7-dichloro-1- (4, 6-diisopropylpyrimidin-5-yl) -4-hydroxy-2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile
  • Step 5 4- ( (3R, 5S) -4-acryloyl-3, 5-dimethylpiperazin-1-yl) -6, 7-dichloro-1- (4, 6-diisopropylpyrimidin-5-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile
  • Step 6 4- ( (3S, 5R) -4-acryloyl-3, 5-dimethylpiperazin-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.
  • Step 7 4- ( (3S, 5R) -4-acryloyl-3, 5-dimethylpiperazin-1-yl) -7- (2-amino-3, 5-dichloro-6-fluorophenyl) -6-chloro-1- (4, 6-diisopropylpyrimidin-5-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile.
  • 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.
  • the reaction mixture was stirred at 90 °C for 2 h.
  • the reaction mixture was filtered and concentrated under vacuum.
  • the residue was purified by silica gel column eluted with EA/hexane (7/3) .
  • the Collecting fluid concentrated under vacuum.
  • Step 1 7- (2-amino-6-fluorophenyl) -6-chloro-1- (4, 6-diisopropylpyrimidin-5-yl) -2-oxo-4- (piperazin-1-yl) -1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile
  • Step 2 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
  • 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.
  • the reaction mixture was stirred at 80 °C for 4 h.
  • the reaction was then quenched by the addition of water (100 mL) .
  • the resulting solution was extracted with ethyl acetate (3 x 100 mL) , the organic layers combined and washed with brine (10 mL) , dried over anhydrous Na 2 SO 4 , filterd and concentrated under vacuum.
  • HIS-KRAS (G12C, aa 2-185, Sino biological) was diluted to 5 ⁇ M in EDTA buffer (20 mM HEPES, pH 7.4, 50 mM NaCl, 10 mM EDTA, 0.01% (v/v) Tween-20) and incubated for 30 min at 25 °C.
  • the EDTA pretreated HIS-KRAS was diluted to 12 nM in assay buffer (25 mM HEPES, pH 7.4, 120 mM NaCl, 5 mM MgCl 2 , 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 for 1 hour at 25 °C to prepare GDP-loaded HIS-KRAS (G12C) .
  • assay buffer 25 mM HEPES, pH 7.4, 120 mM NaCl, 5 mM MgCl 2 , 1 mM DTT, 0.01% (v/v) Tween 20, 0.1% (w/v) BSA
  • MAb Anti 6HIS-Tb cryptate Gold Cisbio
  • the GDP-loaded HIS-KRAS was pre-incubation with diluted compounds in a 384-well plate (Greiner) for 1 hour, then purified SOS1 ExD (Flag tag, aa 564-1049) and BODIPY TM FL GTP (Invitrogen) were added to the assay wells (Final concentration: 3 nM HIS-KRAS (G12C) , 2 ⁇ M SOS1 ExD, 80 nM BODIPY TM FL GTP, 21 ng/mL MAb Anti 6HIS-Tb cryptate Gold) and incubated for 4 hours at 25 °C. TR-FRET signals were then read on Tecan Spark multimode microplate reader.
  • TR-FRET ratio (Signal F515/Signal F486) *10000. Then the data were analyzed using a 4-parameter logistic model to calculate IC 50 values.
  • the results of the SOS1 catalyzed nucleotide exchange assay are in the following Table 3:
  • NCI-H358 cells express KRAS G12C were cultured in RPMI 1640 medium (Gibco) containing 10%fetal bovine serum (Gibco) .
  • Cells in culture medium were plated in 96-well plates at a concentration of 40,000 cells/well and allowed to attach overnight. The next day, culture medium was removed and added compounds diluted in assay medium (RPMI 1640, 0.1%FBS) . After 2 hours incubation in a 37°C/5%CO 2 cell incubator, the assay medium was removed, then 50 ⁇ L of 1X supplemented lysis buffer (Cisbio) was added and the plates were incubated at 25°C for 45 min with shaking.
  • RPMI 1640, 0.1%FBS assay medium
  • NCI-H358 cells express KRAS G12C were cultured in RPMI 1640 medium (Gibco) containing 10%fetal bovine serum (Gibco) .
  • Cells in culture medium were plated in 96-well plates at a concentration of 3000 cells/well (100 ⁇ L/well) and allowed to attach overnight. The next day, compounds were diluted in culture medium and added to the plates. After 6 days incubation in a 37°C/5%CO 2 cell incubator, the medium was removed, then 100 ⁇ L of 1X CCK-8 (MCE) in culture medium was added in each well. The plates were incubated 1.5-2 hours in a 37°C/5%CO 2 cell incubator. OD450 signals were read on Tecan Spark multimode microplate reader and analyzed using a 4-parameter logistic model to calculate IC 50 values. The results are in the following Table 5:
  • group A blood samples were collected at pre-dose, and 0.083, 0.25, 0.5, 1, 2, 4, 6, 8 and 24 h post-dose.
  • group B blood samples were collected at pre-dose, and 0.25, 0.5, 1, 2, 3, 4, 6, 8 and 24 h post-dose. Blood samples were placed on ice until centrifuged to obtain plasma sample. The plasma samples ware stored at -80°C until analysis. The concentration of compound in plasma samples were determined using a LC-MS/MS method. The results are in the following Table 6:
  • mice of the preferred compound 6 and 11 of the present invention are superior to those of the control compound 11-4, Amgen 6 and Amgen 6.3.
  • the exposure amount of compound 6 can reach more than 10 times as much as that of the control compound Amgen 6, more than 6 times as much as that of the control compound Amgen 6.3.
  • the exposure amount of compound 11 can reach more than 6 times as much as that of the control compound Amgen 6, more than 3 times as much as that of the control compound Amgen 6.3, more than 30 times as much as that of the control compound 11-4; Meanwhile, the half-life of the compound 6 and 11 is also greatly extended. Therefore, it is more in line with the medical requirements of administration.
  • TGI% (1- (Vt-Vt 0 ) / (Vc-Vc 0 ) ) *100%, where Vc, Vt are the mean tumor volume of control and treated groups at the end of the study, and Vc 0 and Vt 0 are the mean tumor volume of control and treated groups at the start.
  • Table 8 the tumor volume of mice varies with the number of days after cell inoculation is shown in Figure 1.

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PCT/CN2020/109681 2019-11-04 2020-08-18 Kras mutant protein inhibitor WO2021088458A1 (en)

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WO2022060583A1 (en) 2020-09-03 2022-03-24 Revolution Medicines, Inc. Use of sos1 inhibitors to treat malignancies with shp2 mutations
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CN117295742A (zh) * 2021-05-12 2023-12-26 北京加科思新药研发有限公司 化合物ⅰ的新形式及它们的应用
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WO2022060583A1 (en) 2020-09-03 2022-03-24 Revolution Medicines, Inc. Use of sos1 inhibitors to treat malignancies with shp2 mutations
WO2024081674A1 (en) 2022-10-11 2024-04-18 Aadi Bioscience, Inc. Combination therapies for the treatment of cancer

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