Disclosure of Invention
In one aspect, the invention provides a compound of formula (I), a stereoisomer thereof, a atropisomer thereof, a pharmaceutically acceptable salt of a stereoisomer thereof, or a pharmaceutically acceptable salt of a atropisomer thereof:
wherein,
R1 selected from the group consisting of 4R11 substituted-C6-10 Aryl or by 4RH Substituted 5-10 membered heteroaryl, each heteroaryl independently at each occurrence comprises 1, 2, 3 or 4 groups selected from N, O, S, S =o or S (=o)2 Is a heteroatom of (2);
each R11 Independently at each occurrence selected from halogen, -C1-6 Alkyl, -C2-6 Alkenyl, -C2-6 Alkynyl, -C1-6 Alkylene- (halogen)1-3 Impurity C2-6 Alkyl, -CN, -OR8 、-C1-6 Alkylene- (OR)8 )1-3 、-O-C1-6 Alkylene- (halogen)1-3 、-SR8 、-S-C1-6 Alkylene- (halogen)1-3 、-NR8 R9 、-C1-6 alkylene-NR8 R9 、-C(＝O)R8 、-C(＝O)OR8 、-OC(＝O)R8 、-C(＝O)NR8 R9 、-NR8 C(＝O)R8 、-NR8 SO2 R9 、-SO2 R8 、-S(＝O)2 NR8 R9 、-C3-6 Carbocyclyl, 3-6 membered heterocyclyl, -C6-10 Aryl, or 5-10 membered heteroaryl, each heterocyclyl and heteroaryl independently at each occurrence comprises 1, 2, 3 or 4 groups selected from N, O, S, S =o or S (=o)2 Each R is a heteroatom of11 Independently optionally substituted with 1, 2, 3, 4, 5 or 6 groups selected from halogen, -C1-6 Alkyl, -C1-6 Alkoxy, oxo, -OR8 、-NR8 R9 、-CN、-C(＝O)R8 、-C(＝O)OR8 、-OC(＝O)R8 、-C(＝O)NR8 R9 、-NR8 C(＝O)R8 or-S (=o)2 NR8 R9 Substituted or unsubstituted;
R21 or R is22 Independently selected from hydrogen, halogen, -C1-6 Alkyl, -C1-6 Alkylene- (halogen)1-3 Impurity C2-6 Alkyl, -CN, -OR8 、-C1-6 Alkylene- (OR)8 )1-3 、-NR8 R9 、-C1-6 alkylene-NR8 R9 、-C(＝O)R8 、-C(＝O)OR8 、-OC(＝O)R8 、-C(＝O)NR8 R9 、-NR8 C(＝O)R8 、-S(＝O)2 NR8 R9 or-C3-6 Carbocyclyl, each R21 Or R is22 Independently optionally substituted with 1, 2, 3, 4, 5 or 6 groups selected from halogen, -C1-6 Alkyl, -C1-6 Alkoxy, oxo, -OR8 、-NR8 R9 、-CN、-C(＝O)R8 、-C(＝O)OR8 、-OC(＝O)R8 、-C(＝O)NR8 R9 、-NR8 C(＝O)R8 or-S (=o)2 NR8 R9 Substituted or unsubstituted;
R3 selected from-C1-14 Alkyl, -C2-14 Alkenyl, -C2-14 Alkynyl, -C6-10 Aryl, -C1-6 alkylene-C6-10 Aryl, 5-10 membered heteroaryl, -C1-6 Alkylene- (5-10 membered heteroaryl), 3-14 membered heterocyclyl, -C1-6 Alkylene- (3-14 membered heterocyclyl), -C3-14 Carbocyclyl, -C1-6 alkylene-C3-14 Carbocyclyl group,Each C ring is independently selected at each occurrence from C3-14 Carbocycle or 3-14 membered heterocycle, each D ring being independently selected at each occurrence from C6-10 An aromatic ring or a 5-10 membered heteroaromatic ring, each heterocyclyl and heteroaryl independently at each occurrence comprising 1, 2, 3 or 4 groups selected from N, O, S, S =o or S (=o)2 Each R is a heteroatom of3 Is independently and optionally substituted at each occurrence with 1, 2, 3, 4, 5 or 6R31 Substituted or unsubstituted;
each R31 At each timeIndependently at each occurrence selected from halogen, -C1-6 Alkyl, -C2-6 Alkenyl, -C2-6 Alkynyl, -C1-6 Alkylene- (halogen)1-3 Impurity C2-6 Alkyl, -CN, -C1-6 alkylene-CN, -OR8 、-C1-6 Alkylene- (OR)8 )1-3 、-O-C1-6 Alkylene- (halogen)1-3 、-NR8 R9 、-C1-6 alkylene-NR8 R9 、-O-C1-6 alkylene-NR8 R9 、-C(＝O)R8 、-C1-6 alkylene-C (=o) R8 、-C(＝O)OR8 、-C1-6 alkylene-C (=o) OR8 、-OC(＝O)R8 、-C1-6 alkylene-OC (=o) R8 、-C(＝O)NR8 R9 、-C1-6 alkylene-C (=O) NR8 R9 、-NR8 C(＝O)R8 、-C1-6 alkylene-NR8 C(＝O)R8 、-SO2 R8 、-C1-6 alkylene-SO2 R8 、-S(＝O)2 NR8 R9 、-C1-6 alkylene-S (=o)2 NR8 R9 、-PO(R8 )2 、-C1-6 alkylene-PO (R)8 )2 、-C3-6 Carbocyclyl or 3-6 membered heterocyclyl, each heterocyclyl independently at each occurrence comprising 1, 2, 3 or 4 groups selected from N, O, S, S =o or S (=o)2 Each R is a heteroatom of31 Is independently and optionally substituted at each occurrence with 1, 2, 3, 4, 5 or 6 groups selected from halogen, -C1-6 Alkyl, -C1-6 Alkoxy, oxo, -OR8 、-NR8 R9 、-CN、-C(＝O)R8 、-C(＝O)OR8 、-OC(＝O)R8 、-C(＝O)NR8 R9 、-NR8 C(＝O)R8 or-S (=o)2 NR8 R9 Substituted or unsubstituted;
L4 selected from the group consisting of absence, (CR)5 R6 )m 、C(＝O)、O、NR8 S, S (=o) or S (=o)2 ；
R4 Selected from the group consisting ofEach->Independently optionally substituted with 1R42 2R42 3R42 4R42 5R42 Or 6R42 Substituted or unsubstituted;
each G1 、G2 、G3 And G4 Independently at each occurrence selected from N or CR5 ；
Each n1, n2, n3, n4, n5 is independently selected at each occurrence from 0, 1, 2, 3, 4, 5, or 6, provided that n1 and n2 are not both 0, and n3 and n4 are not both 0;
each R41 Independently at each occurrence selected from
Each Q is independently selected at each occurrence from C (=O), NR8 C(＝O)、S(＝O)2 Or NR (NR)8 S(＝O)2 ；
Selected from->Or->
When (when)Selected from->When each R4a 、R4b And R is4c Independent at each occurrenceIs selected from the group consisting of absent, hydrogen, halogen, -C1-6 Alkyl, -C1-6 Alkylene- (halogen)1-3 Impurity C2-6 Alkyl, -CN, -OR8 、-C1-6 Alkylene- (OR)8 )1-3 、-NR8 R9 、-C1-6 alkylene-NR8 R9 、-NR8 -C1-6 alkylene-OR8 、-C(＝O)R8 、-C(＝O)OR8 、-OC(＝O)R8 、-C(＝O)NR8 R9 、-C1-6 alkylene-C (=O) NR8 R9 、-NR8 C(＝O)R8 、-C1-6 alkylene-NR8 C(＝O)R8 、-C1-6 alkylene-O-C1-6 Aryl, -S (=o)2 NR8 R9 、-C3-10 Carbocyclyl, 3-10 membered heterocyclyl, -C1-6 Alkylene- (3-10 membered heterocyclyl); each R4a 、R4b Or R is4c Independently optionally substituted with 1, 2, 3, 4, 5 or 6 groups selected from halogen, -C1-6 Alkyl, -C1-6 Alkoxy, oxo, -OR8 、-NR8 R9 、-CN、-C(＝O)R8 、-C(＝O)OR8 、-OC(＝O)R8 、-C(＝O)NR8 R9 、-NR8 C(＝O)R8 or-S (=o)2 NR8 R9 Substituted or unsubstituted; or R is4b And R is4c Together with the carbon atoms to which they are both attached form C3-10 Carbocycles or 3-to 10-membered heterocycles; or R is4a And R is4c Together with the carbon atoms to which they are respectively attached form C3-10 Carbocycle or 3-10 membered heterocycle, each heterocyclyl comprising 1, 2 or 3 at each occurrence selected from N, O, S, S =o or S (=o)2 And C is the heteroatom of3-10 Carbocycles or said 3-10 membered heterocyclic ring are optionally substituted with 1, 2, 3, 4, 5 or 6 groups selected from halogen, -C1-6 Alkyl, -C1-6 Alkoxy, oxo, -OR8 、-NR8 R9 、-CN、-C(＝O)R8 、-C(＝O)OR8 、-OC(＝O)R8 、-C(＝O)NR8 R9 、-NR8 C(＝O)R8 or-S (=o)2 NR8 R9 Substituted or unsubstituted; or (b)
When (when)Selected from->When each R4a Is selected from the group consisting of absent, and R4b And R is4c One of which is absent, R4b And R is4c Another one of them is selected from hydrogen, halogen, -C1-6 Alkyl, -C1-6 Alkylene- (halogen)1-3 Impurity C2-6 Alkyl, -CN, -OR8 、-C1-6 Alkylene- (OR)8 )1-3 、-NR8 R9 、-C1-6 alkylene-NR8 R9 、-C(＝O)R8 、-C(＝O)OR8 、-OC(＝O)R8 、-C(＝O)NR8 R9 、-C1-6 alkylene-C (=O) NR8 R9 、-NR8 C(＝O)R8 、-C1-6 alkylene-NR8 C(＝O)R8 、-S(＝O)2 NR8 R9 or-C3-10 Carbocyclyl; each R4a Independently optionally substituted with 1, 2, 3, 4, 5 or 6 groups selected from halogen, -C1-6 Alkyl, -C1-6 Alkoxy, oxo, -OR8 、-NR8 R9 、-CN、-C(＝O)R8 、-C(＝O)OR8 、-OC(＝O)R8 、-C(＝O)NR8 R9 、-NR8 C(＝O)R8 or-S (=o)2 NR8 R9 Substituted or unsubstituted;
each R4d Independently at each occurrence selected from halogen;
each R42 Independently at each occurrence selected from halogen, oxo, -C1-6 Alkyl, -C1-6 Alkylene- (halogen)1-3 Impurity C2-6 Alkyl, -C2-6 Alkenyl, -C2-6 Alkynyl, -OR8 、-C1-6 Alkylene- (OR)8 )1-3 、-NR8 R9 、-C1-6 alkylene-NR8 R9 、-CN、-C1-6 alkylene-CN, -C (=o) R8 、-C1-6 alkylene-C (=o) R8 、-C(＝O)OR8 、-C1-6 alkylene-C (=o) OR8 、-OC(＝O)R8 、-C1-6 alkylene-OC (=o) R8 、-C(＝O)NR8 R9 、-C1-6 alkylene-C (=O) NR8 R9 、-NR8 C(＝O)R8 、-C1-6 alkylene-NR8 C(＝O)R8 、-S(＝O)2 NR8 R9 、-C1-6 alkylene-S (=o)2 NR8 R9 、-SO2 R8 、-C1-6 Alkylene SO2 R8 、-NR8 SO2 R8 or-C1-6 alkylene-NR8 SO2 R8 The method comprises the steps of carrying out a first treatment on the surface of the Each R42 Independently optionally substituted with 1, 2, 3, 4, 5 or 6 groups selected from halogen, -C1-6 Alkyl, -C1-6 Alkoxy, oxo, -OR8 、-NR8 R9 、-CN、-C(＝O)R8 、-C(＝O)OR8 、-OC(＝O)R8 、-C(＝O)NR8 R9 、-NR8 C(＝O)R8 or-S (=o)2 NR8 R9 Substituted or unsubstituted; or (b)
Two R42 Together with the atoms to which they are commonly attached or the atoms to which they are individually attached form C3-6 Carbocycles or 3-6 membered heterocycles, each of said heterocycles independently comprising 1, 2 or 3 heteroatoms selected from N or O, each C3-6 Carbocycles or 3-to 6-membered heterocycles are independently optionally substituted with 1, 2, 3, 4, 5 or 6 groups selected from halogen, -C1-6 Alkyl, -C1-6 Alkoxy, oxo, -OR8 、-NR8 R9 、-CN、-C(＝O)R8 、-C(＝O)OR8 、-OC(＝O)R8 、-C(＝O)NR8 R9 、-NR8 C(＝O)R8 or-S (=o)2 NR8 R9 Substituted or unsubstituted;
each R5 And R is6 Independently at each occurrence selected from hydrogen, halogen, -C1-6 Alkyl, -C2-6 Alkenyl, -C2-6 Alkynyl, oxo, -OR8 、-NR8 R9 、-CN、-C(＝O)R8 、-C(＝O)OR8 、-OC(＝O)R8 、-C(＝O)NR8 R9 、-NR8 C(＝O)R8 、-S(＝O)2 NR8 R9 or-C3-10 Carbocyclyl; each R5 Or R is6 Is independently and optionally substituted at each occurrence with 1, 2, 3, 4, 5 or 6 groups selected from halogen, oxo, -C1-6 Alkyl, -OR8 、-NR8 R9 、-CN、-C(＝O)R8 、-C(＝O)OR8 、-OC(＝O)R8 、-C(＝O)NR8 R9 、-NR8 C(＝O)R8 or-S (=o)2 NR8 R9 Substituted or unsubstituted;
each R8 And R is9 Independently at each occurrence selected from hydrogen, -C1-6 An alkyl group; or (b)
R8 And R is9 Together with the N atom to which they are attached form a 3-10 membered heterocyclic ring, said 3-10 membered heterocyclic ring optionally comprising 1, 2, 3 or 4 atoms from N, O, S, S (=o) or S (=o)2 And said 3-10 membered heterocyclic ring is independently optionally substituted with 1, 2, 3, 4, 5 or 6 heteroatoms selected from halogen, oxo, -C1-6 Alkyl, -C1-6 Alkylene- (halogen)1-3 Impurity C2-6 Alkyl, -CN, -OH, -OC1-6 Alkyl, -C1-6 Alkylene- (OH)1-3 、-C1-6 Alkylene- (OC)1-6 Alkyl group1-3 、-NH2 、-NHC1-6 Alkyl, -N (C)1-6 Alkyl group2 、-C1-6 alkylene-NH2 、-C1-6 alkylene-NHC1-6 Alkyl, -C1-6 alkylene-N (C)1-6 Alkyl group2 、-C(＝O)C1-6 Alkyl, -C (=o) OC1-6 Alkyl, -OC (=o) C1-6 Alkyl, -C (=o) NH2 、-C(＝O)NHC1-6 Alkyl, -C (=o) N (C)1-6 Alkyl group2 、-NHC(＝O)C1-6 Alkyl, -N (C)1-6 Alkyl) C (=o) C1-6 Alkyl, -S (=o)2 NH2 、-S(＝O)2 NH(CH3 )、-S(＝O)2 NHC1-6 Alkyl, -S (=o)2 N(C1-6 Alkyl) or-C3-6 Substituents of carbocyclyl are substituted or unsubstituted;
m is selected from 1, 2,3, 4, 5 or 6.
In some embodiments, R1 Selected from the group consisting of 4R11 Substituted phenyl, substituted with 4R11 Substituted naphthyl, substituted with 4R11 Substituted 5 membered heteroaryl, substituted with 4R11 Substituted 6 membered heteroaryl, substituted with 4R11 Substituted 7 membered heteroaryl, substituted with 4R11 Substituted 8 membered heteroaryl, substituted with 4R11 Substituted 9 membered heteroaryl or substituted with 4R11 Substituted 10 membered heteroaryl, each heteroaryl independently at each occurrence comprises 1, 2,3 or 4 heteroatoms selected from N, O or S.
In some embodiments, R1 Selected from the group consisting of 4R11 Substituted phenyl, substituted with 4R11 Substituted naphthyl, substituted with 4R11 Substituted 6 membered heteroaryl or substituted with 4R11 Substituted 9-membered heteroaryl, each heteroaryl independently at each occurrence comprises 1 or 2 heteroatoms selected from N.
In some embodiments, R1 Selected from the group consisting of 4R11 Substituted phenyl, substituted with 4R11 Substituted naphthyl, substituted with 4R11 Substituted pyridines, substituted with 4R11 Substituted benzo [ d ]]Oxazolyl, covered by 4R11 Substituted benzo [ d ]]Thiazolyl, substituted with 4R11 Substituted pyrrole [2,3-c ]]Pyridine, by 4R11 Substituted pyrazolo [3,4-c]Pyridine, by 4R11 Substituted pyrazolo [1,5-a ] ]Pyridine, by 4R11 Substituted imidazo [1,2-a ]]Pyridine, by 4R11 Substituted 2-oxo-indolyl, substituted with 4R11 Substituted pyrimidinyl, substituted with 4R11 Substituted indolyl, substituted with 4R11 Substituted indazolyl, substituted with 4R11 Substituted benzo [ d ]]Imidazolyl, substituted with 4R11 Substituted pyrazolo [3,4-b]Pyridine, by 4R11 Substituted 2 (3H) -oxo-oxazoles [4,5-b]Pyridine or by 4R11 Substituted isoquinolinyl.
In some embodiments, R1 Selected from the group consisting of 4R11 Substituted phenyl, substituted with 4R11 Substituted naphthyl, substituted with 4R11 Substituted pyridines or substituted by 4R11 Substituted indazolyl.
In some embodiments, R1 Selected from:
each R1 Independently at each occurrence by 4R11 And (3) substitution.
In some embodiments, R1 Independently selected from:
each R1 Independently at each occurrence by 4R11 And (3) substitution.
In some embodiments, R1 Selected from:
each R1 Independently at each occurrence by 4R11 And (3) substitution.
In some embodiments, each R11 Independently at each occurrence selected from the group consisting of-F, -Cl, -Br, -oxo, -C1-3 Alkyl, -C2-3 Alkenyl, -C2-3 Alkynyl, -C1-3 Alkylene- (halogen)1-3 Impurity C2-3 Alkyl, -CN, -OR8 、-C1-3 Alkylene- (OR)8 )1-3 、-O-C1-3 Alkylene- (halogen)1-3 、-SR8 、-S-C1-3 Alkylene- (halogen)1-3 、-NR8 R9 、-C1-3 alkylene-NR8 R9 、-C(＝O)R8 、-C(＝O)OR8 、-OC(＝O)R8 、-C(＝O)NR8 R9 、-NR8 C(＝O)R8 、-S(＝O)2 NR8 R9 、-C3-6 Carbocyclyl, 3-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl; each R11 Independently optionally substituted with 1, 2, 3, 4, 5 or 6 groups selected from-F, -Cl, -Br, -C1-3 Alkyl, -C1-3 Alkoxy, oxo, -OR8 、-NR8 R9 、-CN、-C(＝O)R8 、-C(＝O)OR8 、-OC(＝O)R8 、-C(＝O)NR8 R9 、-NR8 C(＝O)R8 or-S (=o)2 NR8 R9 Substituted or unsubstituted;
each R11 (R)8 Or R is9 ) Independently at each occurrence selected from hydrogen or-C1-3 An alkyl group.
In some embodiments, each R11 Independently at each occurrence selected from the group consisting of-F, -Cl, oxo, methyl, ethyl, propyl, isopropyl, ethenyl, propenyl, ethynyl, propynyl, -methylene- (halogen)1-3 Ethylene- (halogen)1-3 Propylene- (halogen)1-3 Heteroethyl, heteropropyl, -CN, -OR8 (III) methylene- (OR)8 )1-3 Ethylene- (OR)8 )1-3 Propylene- (OR)8 )1-3 -O-methylene- (halogen)1-3 -O-ethylene- (halogen)1-3 -O-propylene- (halogen)1-3 、-SR8 -S-methylene- (halogen)1-3 S-ethylene- (halogen)1-3 -S-propylene- (halogen)1-3 、-NR8 R9 -methylene-NR8 R9 -ethylene-NR8 R9 (III) -propylene-NR8 R9 、-C(＝O)R8 、-C(＝O)OR8 、-OC(＝O)R8 、-C(＝O)NR8 R9 、-NR8 C(＝O)R8 、-S(＝O)2 NR8 R9 3-membered carbocyclyl, 4-memberedCarbocyclyl, 5-membered carbocyclyl, 6-membered carbocyclyl, 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, phenyl, 5-membered heteroaryl or 6-membered heteroaryl; each heterocyclyl and heteroaryl independently at each occurrence contains 1, 2, or 3 heteroatoms selected from N, O or S, each R11 Independently optionally substituted with 1, 2, 3, 4, 5 OR 6 groups selected from-F, -Cl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, oxo, -OR8 、-NR8 R9 、-CN、-C(＝O)R8 、-C(＝O)OR8 、-OC(＝O)R8 、-C(＝O)NR8 R9 、-NR8 C(＝O)R8 or-S (=o)2 NR8 R9 Substituted or unsubstituted;
each R11 (R)8 Or R is9 ) Independently at each occurrence selected from hydrogen, methyl, ethyl, propyl or isopropyl.
In some embodiments, each R11 Independently at each occurrence selected from the group consisting of-F, -Cl, oxo, methyl, ethyl, propyl, isopropyl, ethenyl, propenyl, ethynyl, propynyl, -CH2 F、-CHF2 、-CF3 、-CH2 CH2 F、-CH2 CHF2 、-CH2 CF3 、-CH2 CH2 CH2 F、-CH2 CH2 CHF2 、-CH2 CH2 CF3 、-CH2 OCH3 、-CH2 CH2 OCH3 、-CN、-OH、-OCH3 、-OCH2 CH3 、-OCH2 CH2 CH3 、-OCH(CH3 )2 、-CH2 OH、-CH2 CH2 OH、-CH2 CH2 CH2 OH、-OCH2 F、-OCHF2 、-OCF3 、-OCH2 CH2 F、-OCH2 CHF2 、-OCH2 CF3 、-OCH2 CH2 CH2 F、-OCH2 CH2 CHF2 、-OCH2 CH2 CF3 、-SH、-SCH3 、-SCH2 CH3 、-SCH(CH3 )2 、-SCH2 F、-SCHF2 、-SCF3 、-SCH2 CH2 F、-SCH2 CHF2 、-SCH2 CF3 、-SCH2 CH2 CH2 F、-SCH2 CH2 CHF2 、-SCH2 CH2 CF3 、-NH2 、-NHCH3 、-NHCH2 CH3 、-NHCH2 CH2 CH3 、-NHCH(CH3 )2 、-N(CH3 )2 、-N(CH3 )CH2 CH3 、-N(CH3 )CH2 CH2 CH3 、-N(CH3 )CH(CH3 )2 、-CH2 NH2 、-CH2 CH2 NH2 、-CH2 CH2 CH2 NH2 、-CH2 N(CH3 )2 、-CH2 CH2 N(CH3 )2 、-CH2 CH2 CH2 N(CH3 )2 、-C(＝O)CH3 、-C(＝O)OCH3 、-C(＝O)OCH2 CH3 、-C(＝O)OCH2 CH2 CH3 、-OC(＝O)CH3 、-C(＝O)NH2 、-C(＝O)NH(CH3 )、-C(＝O)N(CH3 )2 、-NHC(＝O)CH3 、-N(CH3 )C(＝O)CH3 、-S(＝O)2 NH2 、-S(＝O)2 NH(CH3 )、-S(＝O)2 N(CH3 )2 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, 6-membered carbocyclyl, 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, phenyl, 5-membered heteroaryl or 6-membered heteroaryl; each heterocyclyl and heteroaryl independently at each occurrence contains 1 or 2 heteroatoms selected from N or O, each R11 Independently optionally substituted with 1, 2, 3, 4, 5 or 6 groups selected from-F, -Cl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, oxo, -OH, -NH2 、-NHCH3 、-N(CH3 )2 、-CN、-C(＝O)CH3 、-C(＝O)OCH3 、-OC(＝O)CH3 、-C(＝O)NH2 、-C(＝O)NH(CH3 )、-C(＝O)N(CH3 )2 、-NHC(＝O)CH3 、-N(CH3 )C(＝O)CH3 、-S(＝O)2 NH2 、-S(＝O)2 NH(CH3 ) or-S (=o)2 N(CH3 )2 Substituted or unsubstituted.
In some embodiments, each R11 Independently at each occurrence selected from the group consisting of-F, -Cl, oxo, -OH, -NH2 -CN, methyl, ethyl, propyl, isopropyl,Methoxy, ethoxy, propoxy, isopropoxy, -CF3 、-OCF3 、-NH(CH3 )、-N(CH3 )2 、-CH2 F、-CHF2 、-CF3 、-CH2 OH、-SO2 NH2 、-CONH2 、
In some embodiments, each R11 Independently at each occurrence selected from the group consisting of-F, -Cl, -OH, -NH2 Methyl, methoxy, -OCF3 、-CHF2 、-CF3 Or (b)
In some embodiments, each R11 Independently at each occurrence selected from halogen; -C1-6 An alkyl group; by halogen, -NH2 -CN or-OH substituted-C1-6 An alkyl group; -OH; -O-C1-6 An alkyl group; by halogen, -NH2 -CN or-OH substituted-O-C1-6 An alkyl group; -NH2 ；-NH(C1-6 alkly)；-N(C1-6 Alkyl group2 ；-NHCOC1-6 An alkyl group; -N (C)1-6 Alkyl) COC1-6 An alkyl group; -NHSO2 C1-6 An alkyl group; -N (C)1-6 Alkyl) SO2 C1-6 An alkyl group; -SO2 (C1-6 An alkyl group); -SO2 NH2 ；-SO2 NHC1-6 An alkyl group; -SO2 N(C1-6 Alkyl group2 or-C3-6 Carbocyclyl.
In some embodiments, each R11 Independently at each occurrence selected from-F; -Cl; -Br; -C1-3 An alkyl group; c substituted by-F or-Cl1-3 An alkyl group; -OH; -O-C1-3 An alkyl group; -O-C substituted by-F or-Cl1-3 An alkyl group; -NH2 ；-NH(C1-3 alkly)；-N(C1-3 Alkyl group2 ；-NHCOC1-3 An alkyl group; -N (C)1-3 Alkyl) COC1-3 An alkyl group; -NHSO2 C1-3 An alkyl group; -N (C)1-3 Alkyl) SO2 C1-3 An alkyl group; -SO2 (C1-3 An alkyl group); -SO2 NH2 ；-SO2 NHC1-3 An alkyl group; -SO2 N(C1-3 Alkyl group2 or-C3-6 Carbocyclyl.
In some embodiments, each R11 Independently at each occurrence selected from-F; -Cl; -Br; -C1-3 An alkyl group; c substituted by-F or-Cl1-3 An alkyl group; -OH; -O-C1-3 An alkyl group; -O-C substituted by-F or-Cl1-3 An alkyl group; -NH2 ；-NH(C1-3 alkly)；-N(C1-3 Alkyl group2 ；-NHCOC1-3 An alkyl group; -N (C)1-3 Alkyl) COC1-3 An alkyl group; -NHSO2 C1-3 An alkyl group; -N (C)1-3 Alkyl) SO2 C1-3 An alkyl group; -SO2 (C1-3 An alkyl group); -SO2 NH2 ；-SO2 NHC1-3 An alkyl group; -SO2 N(C1-3 Alkyl group2 or-C3-6 Carbocyclyl.
In some embodiments, each R11 Independently at each occurrence selected from-F; -Cl; a methyl group; an ethyl group; a propyl group; an isopropyl group; -F substituted methyl; -F substituted ethyl; -F substituted propyl; -F substituted isopropyl; -OH; methoxy; ethyl oxideA base; a propoxy group; an isopropoxy group; -F substituted methoxy; -F substituted ethoxy; -F substituted propoxy; -F substituted isopropoxy; -NH2 ；-NHCH3 ；-NHCH2 CH3 ；-NH(CH2 CH2 CH3 )；-NH(CH(CH3 )2 )；-N(CH3 )2 ；-N(CH2 CH3 )2 ；-N(CH3 )(CH2 CH3 )；-NHCOCH3 ；-NHCOCH2 CH3 ；-NHCOCH2 CH2 CH3 ；-N(CH3 )COCH3 ；-N(CH3 )COCH2 CH3 ；-N(CH3 )COCH2 CH2 CH3 ；-NHSO2 CH3 ；-NHSO2 CH2 CH3 ；-NHSO2 CH2 CH2 CH3 ；-N(CH3 )SO2 CH3 ；-N(CH3 )SO2 CH2 CH3 ；-N(CH3 )SO2 CH2 CH2 CH3 ；-SO2 CH3 ；-SO2 CH2 CH3 ；-SO2 CH2 CH2 CH3 ；-SO2 (CH(CH3 )2 )；-SO2 NH2 ；-SO2 NHCH3 ；-SO2 NHCH2 CH3 ；-SO2 NHCH2 CH2 CH3 ；-SO2 N(CH3 )2 ；-SO2 N(CH2 CH3 )2 ；-SO2 N(CH2 CH2 CH3 )2 The method comprises the steps of carrying out a first treatment on the surface of the 3-membered carbocyclyl; 4-membered carbocyclyl; 5-membered carbocyclyl or 6-membered carbocyclyl.
In some embodiments, each R11 Independently at each occurrence selected from the group consisting of-F, -Cl, methyl, ethyl, propyl, isopropyl, -CH2 F、-CHF2 、-CF3 -OH, methoxy, ethoxy, propoxy, isopropoxy, -OCF3 、-NH2 、-NHCH3 、-NHCH2 CH3 、-NH(CH2 CH2 CH3 )、-NH(CH(CH3 )2 )、-N(CH3 )2 、-N(CH2 CH3 )2 、-N(CH3 )(CH2 CH3 )、-NHCOCH3 、-N(CH3 )COCH3 、-NHSO2 CH3 、-N(CH3 )SO2 CH3 、-SO2 CH3 、-SO2 CH2 CH3 、-SO2 CH2 CH2 CH3 、-SO2 (CH(CH3 )2 )、-SO2 NHCH3 、-SO2 N(CH3 )2 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl or 6-membered carbocyclyl.
In some embodiments, each R11 Independently at each occurrence selected from the group consisting of-F, -Cl, -CH3 、-CF3 、-OH、-OCH3 、-OCF3 、-NH2 、-NHCH3 、-NHCOCH3 、-NHSO2 CH3 、-SO2 CH3 or-SO2 NHCH3 。
In some embodiments, each R11 Independently at each occurrence selected from-F, -Cl, -OH or-NH2 。
In some embodiments, R1 Selected from:
in some embodiments, R1 Selected from:
in some embodiments, R21 Or R is22 Independently selected from hydrogen, -F, -Cl, -Br, -C1-3 Alkyl, -C1-3 Alkylene- (halogen)1-3 Impurity C2-3 Alkyl, -CN, -OR8 、-C1-3 Alkylene- (OR)8 )1-3 、-NR8 R9 、-C1-3 alkylene-NR8 R9 、-C(＝O)R8 、-C(＝O)OR8 、-OC(＝O)R8 、-C(＝O)NR8 R9 、-NR8 C(＝O)R8 、-S(＝O)2 NR8 R9 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl or 6-membered carbocyclyl; each R21 Or R is22 Independently optionally substituted with 1, 2, 3, 4, 5 or 6 groups selected from-F, -Cl, -Br, -C1-3 Alkyl, -C1-3 Alkoxy, oxo, -OR8 、-NR8 R9 、-CN、-C(＝O)R8 、-C(＝O)OR8 、-OC(＝O)R8 、-C(＝O)NR8 R9 、-NR8 C(＝O)R8 or-S (=o)2 NR8 R9 Substituted or unsubstituted;
each (R)21 Or R is22 ) (R)8 Or R is9 ) Independently at each occurrence selected from hydrogen or-C1-3 An alkyl group.
In some embodiments, R21 Or R is22 Independently selected from hydrogen, -F, -Cl, methyl, ethyl, propyl, isopropyl, -CH2 F、-CHF2 、-CF3 、-CH2 CH2 F、-CH2 CHF2 、-CH2 CF3 、-CH2 CH2 CH2 F、-CH2 CH2 CHF2 、-CH2 CH2 CF3 、-CH2 OCH3 、-CH2 CH2 OCH3 、-CN、-OH、-OCH3 、-OCH2 CH3 、-OCH2 CH2 CH3 、-OCH(CH3 )2 、-CH2 OH、-CH2 CH2 OH、-CH2 CH2 CH2 OH、-CH2 CH2 CH2 OCH3 、-NH2 、-NHCH3 、-NHCH2 CH3 、-NHCH2 CH2 CH3 、-NHCH(CH3 )2 、-N(CH3 )2 、-N(CH3 )CH2 CH3 、-N(CH3 )CH2 CH2 CH3 、-N(CH3 )CH(CH3 )2 、-CH2 NH2 、-CH2 CH2 NH2 、-CH2 CH2 CH2 NH2 、-CH2 N(CH3 )2 、-CH2 CH2 N(CH3 )2 、-CH2 CH2 CH2 N(CH3 )2 、-C(＝O)CH3 、-C(＝O)OCH3 、-C(＝O)OCH2 CH3 、-C(＝O)OCH2 CH2 CH3 、-OC(＝O)CH3 、-C(＝O)NH2 、-C(＝O)NH(CH3 )、-C(＝O)N(CH3 )2 、-NHC(＝O)CH3 、-N(CH3 )C(＝O)CH3 、-S(＝O)2 NH2 、-S(＝O)2 NH(CH3 )、-S(＝O)2 N(CH3 )2 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl or 6-membered carbocyclyl; each (R)21 Or R is22 ) Independently optionally substituted with 1, 2, 3, 4, 5 or 6 groups selected from-F, -Cl, -Br, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, oxo, -OH, -NH2 、-N(CH3 )2 、-CN、-C(＝O)CH3 、-C(＝O)OCH3 、-OC(＝O)CH3 、-C(＝O)NH2 、-C(＝O)NH(CH3 )、-C(＝O)N(CH3 )2 、-NHC(＝O)CH3 、-N(CH3 )C(＝O)CH3 、-S(＝O)2 NH2 、-S(＝O)2 NH(CH3 ) or-S (=o)2 N(CH3 )2 Substituted or unsubstituted.
In some embodiments, R21 Or R is22 Independently selected from hydrogen, -F, -Cl, methyl, ethyl, propyl, isopropyl, -CH2 F、-CHF2 、-CF3 、-OH、-OCH3 、-OCH2 CH3 、-OCH2 CH2 CH3 、-OCH(CH3 )2 、-CH2 OH、-CH2 CH2 OH、-CH2 CH2 CH2 OH、-NH2 、-NHCH3 、-NHCH2 CH3 、-NHCH2 CH2 CH3 、-NHCH(CH3 )2 Or (b)
In some embodiments, R21 Selected from-F, -Cl orAnd R22 is selected from hydrogen.
In some embodiments, R21 Independently selected from hydrogen; halogen; -C1-6 An alkyl group; by halogen, -NH2 -CN or-OH substituted-C1-6 An alkyl group; -C2-6 Alkenyl or-C3-6 Carbocyclyl;
R22 selected from hydrogen, halogen or-C1-6 An alkyl group.
In some embodiments, R21 Selected from hydrogen; -F; -Cl; -Br; -C1-3 An alkyl group; c substituted by-F or-Cl1-3 An alkyl group; -C2-3 Alkenyl or-C3-6 Carbocyclyl.
In some embodiments, R21 Selected from hydrogen, -F; -Cl; a methyl group; an ethyl group; a propyl group; an isopropyl group; -F substituted methyl; ethyl substituted by-F; propyl substituted with-F; isopropyl substituted by-F; vinyl; a propylene group; 3-membered carbocyclyl; 4-membered carbocyclyl; 5-membered carbocyclyl or 6-membered carbocyclyl.
In some embodiments, R21 Selected from-F, -Cl, -CF3 、
In some embodiments, R21 is-F or-Cl.
In some embodiments, R22 Selected from hydrogen, -F, -Cl, -Br or-C1-3 An alkyl group.
In some embodiments, R22 Selected from hydrogen, -F, -Cl, methyl, ethyl, propyl or isopropyl.
In some embodiments, R22 Is hydrogen or-CH3 。
In some embodiments, R22 Is hydrogen.
In some embodiments, R3 Selected from-C1-6 Alkyl, -C2-6 Alkenyl, -C2-6 Alkynyl, -C6-10 Aryl, -C1-3 Alkylene C6-10 Aryl, 5-10 membered heteroaryl, -C1-3 Alkylene- (5-10 membered heteroaryl), 3-6 membered heterocyclyl, -C1-3 Alkylene- (3-6 membered heterocyclyl), -C3-6 Carbocyclyl, -C1-3 alkylene-C3-6 Carbocyclyl group,Each ring C is independently selected at each occurrence from C3-6 Carbocycle or 3-6 membered heterocycle, each ring D is independently selected at each occurrence from C6-10 An aromatic ring or a 5-10 membered heteroaryl, each heterocyclyl and heteroaryl independently at each occurrence containing 1, 2 or 3 heteroatoms selected from N, O or S, each R3 Is independently and optionally substituted at each occurrence with 1, 2, 3, 4, 5 or 6R31 And (3) substitution.
In some embodiments, R3 Selected from-C1-3 Alkyl, -C2-3 Alkenyl, -C2-3 Alkynyl, phenyl, naphthyl, -methylene-C6-10 Aryl, -ethylene-C6-10 Aryl, -propylene-C6-10 Aryl, -isopropylidene-C6-10 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 heterocyclyl, 4 membered heterocyclyl, 5 membered heterocyclyl, 6 membered heterocyclyl, -methylene- (3-6 membered heterocyclyl), -ethylene- (3-6 membered heterocyclyl), -propylene- (3-6 membered heterocyclyl), -isopropylene- (3-6 membered heterocyclyl), 3 membered carbocyclyl, 4 membered carbocyclyl, 5 membered carbocyclyl, 6 membered carbocyclyl, -methylene-C3-6 Carbocyclyl, -ethylene-C3-6 Carbocyclyl, -propylene-C3-6 Carbocyclyl, -isopropylene-C3-6 Carbocyclyl group,Each ring C is independently selected at each occurrence from a 3-membered carbocycle, a 4-membered carbocycle, a 5-membered carbocycle, a 6-membered carbocycle, a 3-membered heterocycle, a 4-membered heterocycle, a 5-membered heterocycle, or a 6-membered heterocycle, each ring D is independently selected at each occurrence from a benzene ring, a 5-membered heteroaryl ring, or a 6-membered heteroaryl ring, each heterocycle, heterocyclyl, heteroaryl, or heteroaryl independently contains at each occurrence 1, 2, or 3 heteroatoms selected from N, O or S, each R3 Is independently and optionally substituted at each occurrence with 1, 2, 3, 4, 5 or 6R31 Substituted or unsubstituted.
In some embodiments, R3 Selected from the group consisting of methyl, ethyl, propyl, isopropyl, vinyl, 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 heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, -methylene- (3-6-membered heterocyclyl), -ethylene- (3-6-membered heterocyclyl), -propylene- (3-6-membered heterocyclyl), 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, 6-membered carbocyclyl, -methylene-C3-6 Carbocyclyl, -ethylene-C3-6 Carbocyclyl, -propylene-C3-6 Carbocyclyl, -isopropylidene-C3-6 Carbocyclyl group,Each ring C is independently selected at each occurrence from a 3-membered carbocycle, a 4-membered carbocycle, a 5-membered carbocycle, a 6-membered carbocycle, a 3-membered heterocycle, a 4-membered heterocycle, a 5-membered heterocycle, or a 6-membered heterocycle, each ring D is independently selected at each occurrence from a benzene ring, a 5-membered heteroaryl ring, or a 6-membered heteroaryl ring, each heterocycle, heterocyclyl, heteroaryl, or heteroaryl independently contains at each occurrence 1, 2, or 3 heteroatoms selected from N, O or S, each R3 Is independently and optionally substituted at each occurrence with 1, 2, 3, 4, 5 or 6R31 Substituted or unsubstituted.
In some embodiments, R3 Selected from-C6-10 Aryl or 5-10 membered heteroaryl, each 5-10 membered heteroaryl independently at each occurrence comprising 1, 2, 3 or 4 heteroatoms selected from N, O or S, each-C6-10 Aryl or 5-10 membered heteroaryl is independently and optionally substituted at each occurrence with 1R31 2R31 3R31 4R31 5R31 Or 6R31 Substituted or unsubstituted.
In some embodiments, R3 Selected from phenyl, naphthyl, 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 9-membered heteroaryl or 10-membered heteroaryl, each heteroaryl independently at each occurrence comprising 1, 2 or 3 heteroatoms selected from N or O, each phenyl, naphthyl or heteroaryl independently at each occurrence optionally being substituted with 1R31 2R31 3R31 4R31 5R31 Or 6R31 Substituted or unsubstituted.
In some embodiments, R3 Selected from phenyl or 6 membered heteroaryl, said 6 membered heteroaryl comprising 1 or 2 heteroatoms selected from N, each phenyl or 6 membered heteroaryl being independently and optionally substituted at each occurrence with 1R31 2R31 3R31 4R31 5R31 Or 6R31 Substituted or unsubstituted.
In some embodiments, R3 Selected from:
each R3 Independently optionally substituted with 1R31 2R31 3R31 4R31 5R31 Or 6R31 Substituted or unsubstituted.
In some embodiments, R3 Selected from:
each R3 Independently optionally substituted with 1R31 2R31 3R31 4R31 5R31 Or 6R31 Substituted or unsubstituted.
In some embodiments, each R31 Independently at each occurrence selected from the group consisting of-F, -Cl, -Br, -C1-3 Alkyl, -C2-3 Alkenyl, -C2-3 Alkynyl, -C1-3 Alkylene- (halogen)1-3 Impurity C2-3 Alkyl, -CN, -C1-3 alkylene-CN, -OR8 、-C1-3 alkylene-OR8 、-O-C1-3 Alkylene- (halogen)1-3 、-NR8 R9 、-C1-3 alkylene-NR8 R9 、-O-C1-3 alkylene-NR8 R9 、-C(＝O)R8 、-C1-3 alkylene-C (=o) R8 、-C(＝O)OR8 、-C1-3 alkylene-C (=o) OR8 、-OC(＝O)R8 、-C1-3 alkylene-OC (=o) R8 、-C(＝O)NR8 R9 、-C1-3 alkylene-C (=O) NR8 R9 、-NR8 C(＝O)R8 、-C1-3 alkylene-NR8 C(＝O)R8 、-SO2 R8 、-C1-3 alkylene-SO2 R8 、-S(＝O)2 NR8 R9 、-C1-3 alkylene-S (=o)2 NR8 R9 、-PO(R8 )2 、-C1-3 alkylene-PO (R)8 )2 、-C3-6 Carbocyclyl or 3-6 membered heterocyclyl, each heterocyclyl independently at each occurrence containing 1, 2 or 3 heteroatoms selected from N, O or S, each R31 Independently optionally substituted with 1, 2, 3, 4, 5 or 6 groups selected from-F, -Cl, -Br, -C1-3 Alkyl, -C1-3 Alkoxy, oxo, -OR8 、-NR8 R9 、-CN、-C(＝O)R8 、-C(＝O)OR8 、-OC(＝O)R8 、-C(＝O)NR8 R9 、-NR8 C(＝O)R8 or-S (=o)2 NR8 R9 Substituted or unsubstituted;
R31 (R)8 Or R is9 ) Independently at each occurrence selected from hydrogen or-C1-3 An alkyl group.
In some embodiments, each R31 Independently at each occurrence selected from the group consisting of-F, -Cl, methyl, ethyl, propyl, isopropyl, ethenyl, propenyl, ethynyl, propynyl, -methylene- (halogen)1-3 Ethylene- (halogen)1-3 Propylene- (halogen)1-3 -isopropylidene- (halogen)1-3 Heteroethyl, heteroaryl, -CN, -methylene-CN, -ethylene-CN, -propylene-CN, -isopropylidene-CN, -OR8 -methylene-OR8 ethylene-OR8 (iii) propylene-OR8 (ii) -isopropylidene-OR8 -O-methylene- (halogen)1-3 -O-ethylene- (halogen)1-3 -O-propylene- (halogen)1-3 -O-isopropylidene- (halogen)1-3 、-NR8 R9 -methylene-NR8 R9 -ethylene-NR8 R9 (III) -propylene-NR8 R9 (i) -isopropylidene-NR8 R9 -O-methylene-NR8 R9 -O-ethylene-NR8 R9 -O-propylene-NR8 R9 -O-isopropylidene-NR8 R9 、-C(＝O)R8 -methylene-C (=o) R8 -ethylene-C (=o) R8 -propylene-C (=o) R8 -isopropylidene-C (=o) R8 、-C(＝O)OR8 -methylene-C (=o) OR8 ethylene-C (=o) OR8 propylene-C (=O) OR8 -isopropylidene-C (=o) OR8 、-OC(＝O)R8 -methylene-OC (=o) R8 -ethylene-OC (=o) R8 -propylene-OC (=o) R8 -isopropylidene-OC (=o) R8 、-C(＝O)NR8 R9 -methylene-C (=o) NR8 R9 -ethylene-C (=o) NR8 R9 -propylene-C (=o) NR8 R9 -isopropylidene-C (=o) NR8 R9 、-NR8 C(＝O)R8 -methylene-NR8 C(＝O)R8 -ethylene-NR8 C(＝O)R8 (III) -propylene-NR8 C(＝O)R8 (i) -isopropylidene-NR8 C(＝O)R8 、-SO2 R8 -methylene-SO2 R8 ethylene-SO2 R8 propylene-SO2 R8 (ii) -isopropylidene-SO2 R8 、-S(＝O)2 NR8 R9 -methylene-S (=o)2 NR8 R9 ethylene-S (=o)2 NR8 R9 propylene-S (=o)2 NR8 R9 -isopropylidene-S (=o)2 NR8 R9 、-PO(R8 )2 -methylene-PO (R)8 )2 ethylene-PO (R)8 )2 propylene-PO (R)8 )2 -isopropylidene-PO (R)8 )2 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, 6-membered carbocyclyl, 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl or 6-membered heterocyclyl; each heterocyclyl independently at each occurrence comprises 1 or 2 heteroatoms selected from N or O; each R31 Independently optionally substituted with 1, 2, 3, 4, 5 OR 6 groups selected from-F, -Cl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, oxo, -OR8 、-NR8 R9 、-CN、-C(＝O)R8 、-C(＝O)OR8 、-OC(＝O)R8 、-C(＝O)NR8 R9 、-NR8 C(＝O)R8 or-S (=o)2 NR8 R9 Substituted or unsubstituted;
R31 (R)8 Or R is9 ) Independently at each occurrence selected from hydrogen, methyl, ethyl, propyl or isopropyl.
In some embodiments, each R31 Independently at each occurrenceSelected from the group consisting of-F, -Cl, methyl, ethyl, propyl, isopropyl, ethenyl, propenyl, ethynyl, propynyl, -CH2 F、-CHF2 、-CF3 、-CH2 CH2 F、-CH2 CHF2 、-CH2 CF3 、-CH2 CH2 CH2 F、-CH2 CH2 CHF2 、-CH2 CH2 CF3 、-CH(CH3 )(CF3 )、-CH2 OCH3 、-CH2 CH2 OCH3 、-CN、-CH2 CN、-CH2 CH2 CN、-CH2 CH2 CH2 CN、-OH、-OCH3 、-OCH2 CH3 、-OCH2 CH2 CH3 、-OCH(CH3 )2 、-CH2 OH、-CH2 CH2 OH、-CH2 CH2 CH2 OH、-CH2 CH2 CH2 OCH3 、-OCF3 、-OCH2 CF3 、-OCH2 CH2 CF3 、-NH2 、-NHCH3 、-NHCH2 CH3 、-NHCH2 CH2 CH3 、-NHCH(CH3 )2 、-N(CH3 )2 、-N(CH3 )CH2 CH3 、-N(CH3 )CH2 CH2 CH3 、-N(CH3 )CH(CH3 )2 、-CH2 NH2 、-CH2 CH2 NH2 、-CH2 CH2 CH2 NH2 、-CH2 N(CH3 )2 、-CH2 CH2 N(CH3 )2 、-CH2 CH2 CH2 N(CH3 )2 、-OCH2 NH2 、-OCH2 CH2 NH2 、-OCH2 CH2 CH2 NH2 、-C(＝O)CH3 、-CH2 C(＝O)CH3 、-CH2 CH2 C(＝O)CH3 、-CH2 CH2 CH2 C(＝O)CH3 、-C(＝O)OCH3 、-CH2 C(＝O)OCH3 、-CH2 CH2 C(＝O)OCH3 、-CH2 CH2 CH2 C(＝O)OCH3 、-OC(＝O)CH3 、-CH2 OC(＝O)CH3 、-CH2 CH2 OC(＝O)CH3 、-CH2 CH2 CH2 OC(＝O)CH3 、-C(＝O)NH2 、-C(＝O)NH(CH3 )、-C(＝O)N(CH3 )2 、-CH2 C(＝O)N(CH3 )2 、-CH2 CH2 C(＝O)N(CH3 )2 、-CH2 CH2 CH2 C(＝O)N(CH3 )2 、-NHC(＝O)CH3 、-N(CH3 )C(＝O)CH3 、-CH2 NHC(＝O)CH3 、-CH2 CH2 NHC(＝O)CH3 、-CH2 CH2 CH2 NHC(＝O)CH3 、-SO2 CH3 、-CH2 SO2 CH3 、-CH2 CH2 SO2 CH3 、-CH2 CH2 CH2 SO2 CH3 、-S(＝O)2 NH2 、-S(＝O)2 NH(CH3 )、-S(＝O)2 N(CH3 )2 、-CH2 S(＝O)2 N(CH3 )2 、-CH2 CH2 S(＝O)2 N(CH3 )2 、-CH2 CH2 CH2 S(＝O)2 N(CH3 )2 、-PO(CH3 )2 、-CH2 PO(CH3 )2 、-CH2 CH2 PO(CH3 )2 、-CH2 CH2 CH2 PO(CH3 )2 、Each R31 Independently optionally substituted with 1, 2, 3, 4, 5 or 6 groups selected from-F, -Cl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, oxo, -OH, -NH2 、-N(CH3 )2 、-CN、-C(＝O)CH3 、-C(＝O)OCH3 、-OC(＝O)CH3 、-C(＝O)NH2 、-C(＝O)NH(CH3 )、-C(＝O)N(CH3 )2 、-NHC(＝O)CH3 、-N(CH3 )C(＝O)CH3 、-S(＝O)2 NH2 、-S(＝O)2 NH(CH3 ) or-S (=o)2 N(CH3 )2 Substituted or unsubstituted.
In some embodiments, each R31 Independently at each occurrence selected from-Cl, -CH3 、-CH2 CH3 、-CH(CH3 )2 、-CN、-OCH2 CH2 NH2 、-SO2 CH3 、-PO(CH3 )2 、Each R31 Independently optionally substituted with 1, 2, 3, 4, 5 or 6 groups selected from-F, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, oxo, -OH, -NH2 、-N(CH3 )2 or-CN substituent is substituted or unsubstituted.
In some embodiments, each R31 Independently at each occurrence selected from-Cl, -CH3 、-CH2 CH3 、-CH(CH3 )2 、-CN、-OCH2 CH2 NH2 、-SO2 CH3 、-PO(CH3 )2 、
In some embodiments, each R31 Independently at each occurrence selected from-CH3 、-CH(CH3 )2 Or (b)
In some embodiments, each R31 Independently at each occurrence selected from halogen, -C1-6 Alkyl, -CN, -OH, -O-C1-6 Alkyl, -NH2 、-NH(C1-6 Alkyl), -N (C)1-6 Alkyl group2 or-C3-6 Carbocyclyl.
In some embodiments, each R31 Independently at each occurrence selected from the group consisting of-F, -Cl, -Br, -C1-3 Alkyl, -CN, -OH, -O-C1-3 Alkyl, -NH2 、-NH(C1-3 Alkyl), -N (C)1-3 Alkyl group2 or-C3-6 Carbocyclyl.
In some embodiments, each R31 Independently at each occurrence selected from the group consisting of-F, -Cl, methyl, ethyl, propyl, isopropyl, -CN, -OH, methoxy, ethoxy, propoxy, isopropoxy, -NH2 、-NHCH3 、-NHCH2 CH3 、-NH(CH2 CH2 CH3 )、-NH(CH(CH3 )2 )、-N(CH3 )2 、-N(CH2 CH3 )2 、-N(CH3 )(CH2 CH3 ) 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl or 6-membered carbocyclyl.
In some embodiments, each R31 Independently at each occurrence selected from methyl or isopropyl.
In some embodiments, R3 Selected from:
in some embodiments, each R3 Independently at each occurrence selected from:
in some embodiments, R3 Selected from the group consisting of
In some embodiments, L4 Selected from the group consisting of absence, (CR)5 R6 )m Or NR5 ；
L4 Each (R)5 Or R is6 ) Independently at each occurrence selected from hydrogen, methyl, ethyl, propyl, or isopropyl;
L4 m is selected from 1, 2 or 3.
In some embodiments, L4 Selected from the absence or NH.
In some embodiments, L4 Independently selected from the group consisting of absence, O or NH or N (C1-6 Alkyl).
In some embodiments, L4 Independently selected from the group consisting of absent, O, NH, N (CH)3 )、N(CH2 CH3 ) Or N (CH)2 CH2 CH3 )。
In some embodiments, L4 Independently selected from the absence or NH.
In some embodiments, L4 Independently selected from the absence.
In some embodiments, R4 is selected fromEach->Is independently and optionally substituted at each occurrence with 1R42 2R42 3R42 4R42 5R42 Or 6R42 Substituted or unsubstituted.
In some embodiments, R4 is selected fromIndependently optionally substituted with 1R42 2R42 3R42 4R42 5R42 Or 6R42 Substituted or unsubstituted.
In some embodiments, each G1 And G2 Independently at each occurrence selected from N or CR5 ；
(G1 Or G2 ) Each R in (a)5 Independently at each occurrence selected from hydrogen, methyl, ethyl, propyl or isopropyl.
In some embodiments, each G1 Independently at each occurrence selected from N or CH, and each G2 Independently at each occurrence selected from N or CH.
In some embodiments, each n1, n2, n3, n4, n5 is independently selected from 0, 1, 2, or 3 at each occurrence, provided that n1 and n2 are not both 0 and n3 and n4 are not both 0.
In some embodiments, n1 is selected from 1, 2, or 3; n2 is selected from 1, 2 or 3.
In some embodiments, n1 is selected from 1 or 2; n2 is selected from 1 or 2.
In some embodiments, R4 Selected from the group consisting ofEach->Is independently and optionally substituted at each occurrence with 1R42 2R42 3R42 4R42 5R42 Or 6R42 Substituted or unsubstituted.
In some embodiments, R4 Selected from the group consisting ofSaid->Independently optionally substituted with 1R42 2R42 3R42 Or 4R42 Substituted or unsubstituted.
In some embodiments, R4 Selected from the group consisting ofSaid->Optionally by 1R42 2R42 3R42 4R42 5R42 Or 6R42 Substituted or unsubstituted.
In some embodiments, each R41 Independently at each occurrence selected from
Each Q is independently at each occurrence selected from-C (=o) -, -NHC (=o) -or-N (CH)3 )C(＝O)-。
In some embodiments, each R41 Independently at each occurrence selected from
In some embodiments, whenIs->When R is4a 、R4b Or R is4c Independently at each occurrence selected from hydrogen, -F, -Cl, -Br, -C1-3 Alkyl, -C1-3 Alkylene- (halogen)1-3 Impurity C2-3 Alkyl, -CN, -OR8 、-C1-3 Alkylene- (OR)8 )1-3 、-NR8 R9 、-C1-3 alkylene-NR8 R9 、-NR8 -C1-6 alkylene-OR8 、-C(＝O)R8 、-C(＝O)OR8 、-OC(＝O)R8 、-C(＝O)NR8 R9 、-C1-3 alkylene-C (=O) NR8 R9 、-NR8 C(＝O)R8 、-C1-3 alkylene-NR8 C(＝O)R8 、-C1-3 alkylene-O-C1-6 Aryl, -S (=o)2 NR8 R9 、-C3-6 Carbocyclyl, 3-6 membered heterocyclyl, -C1-3 Alkylene- (3-6 membered heterocyclyl) each R4a 、R4b Or R is4c Independently optionally substituted with 1, 2, 3, 4, 5 or 6 groups selected from-F, -Cl, -Br, -C1-3 Alkyl, -C1-3 Alkoxy, oxo, -OR8 、-NR8 R9 、-CN、-C(＝O)R8 、-C(＝O)OR8 、-OC(＝O)R8 、-C(＝O)NR8 R9 、-NR8 C(＝O)R8 or-S (=o)2 NR8 R9 Substituted or unsubstituted; or R is4b And R is4c Together with the carbon atoms to which they are both attached form C3-6 Carbocycle or 3-6 membered heterocycle; or R is4a And R is4c Together with the carbon atoms to which they are respectively attached form C3-6 Carbocycle or 3-6 membered heterocycle; each heterocycle comprises in each occurrence 1, 2 or 3 selected from N, O, S or S (=o)2 Optionally substituted with 1, 2, 3, 4, 5 or 6 heteroatoms selected from-F, -Cl, -Br, -C1-3 Alkyl, -C1-3 Alkoxy, oxo, -OR8 、-NR8 R9 、-CN、-C(＝O)R8 、-C(＝O)OR8 、-OC(＝O)R8 、-C(＝O)NR8 R9 、-NR8 C(＝O)R8 or-S (=o)2 NR8 R9 Substituted or unsubstituted;
when (when)Is->When each R4a Is absent and R4b And R is4c One of which is absent, R4b And R is4c The other is selected from hydrogen, -F, -Cl, -Br, oxo, -C1-3 Alkyl, -C1-3 Alkylene- (halogen)1-3 Impurity C1-3 Alkyl, -CN, -OR8 、-C1-3 Alkylene- (OR)8 )1-3 、-NR8 R9 、-C1-3 alkylene-NR8 R9 、-C(＝O)R8 、-C(＝O)OR8 、-OC(＝O)R8 、-C(＝O)NR8 R9 、-C1-3 alkylene-C (=O) NR8 R9 、-NR8 C(＝O)R8 、-C1-3 alkylene-NR8 C(＝O)R8 、-S(＝O)2 NR8 R9 or-C3-6 Carbocyclyl; each R4b Or R is4c Independently optionally substituted with 1, 2, 3, 4, 5 or 6 groups selected from-F, -Cl, -Br, -C1-3 Alkyl, -C1-3 Alkoxy, oxo, -OR8 、-NR8 R9 、-CN、-C(＝O)R8 、-C(＝O)OR8 、-OC(＝O)R8 、-C(＝O)NR8 R9 、-NR8 C(＝O)R8 or-S (=o)2 NR8 R9 Substituted or unsubstituted;
(R4a 、R4b or R is4c ) Each (R)8 Or R is9 ) Independently at each occurrence selected from hydrogen or-C1-3 An alkyl group;
each R4d Independently at each occurrence selected from-F, -Cl or-Br.
In some embodiments, whenSelected from->When R is4a 、R4b Or R is4c Independently at each occurrence selected from hydrogen, -F, -Cl, methyl, ethyl, propyl, isopropyl, -methylene- (halogen)1-3 Ethylene- (halogen)1-3 Propylene- (halogen)1-3 Heteroethyl, heteropropyl, -CN, -OR8 (III) methylene- (OR)8 )1-3 Ethylene- (OR)8 )1-3 Propylene- (OR)8 )1-3 、-NR8 R9 -methylene-NR8 R9 -ethylene-NR8 R9 (III) -propylene-NR8 R9 、-NR8 -methylene-OR8 、-NR8 -ethylene-OR8 、-NR8 -propylene-OR8 、-C(＝O)R8 、-C(＝O)OR8 、-OC(＝O)R8 、-C(＝O)NR8 R9 -methylene-C (=o) NR8 R9 -ethylene-C (=o) NR8 R9 -propylene-C (=o) NR8 R9 、-NR8 C(＝O)R8 -methylene-NR8 C(＝O)R8 -ethylene-NR8 C(＝O)R8 (III) -propylene-NR8 C(＝O)R8 -methylene-O-phenyl, -ethylene-O-phenyl, -propylene-O-phenyl, -S (=o)2 NR8 R9 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, 6-membered carbocyclyl, 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, -methylene- (3-6 heterocyclyl), -ethylene- (3-6 heterocyclyl) or-propylene- (3-6 heterocyclyl); each R4a 、R4b Or R is4c Independently optionally substituted with 1, 2, 3, 4, 5 OR 6 groups selected from-F, -Cl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, oxo, -OR8 、-NR8 R9 、-CN、-C(＝O)R8 、-C(＝O)OR8 、-OC(＝O)R8 、-C(＝O)NR8 R9 、-NR8 C(＝O)R8 or-S (=o)2 NR8 R9 Substituted or unsubstituted; or R is4b And R is4c Together with the carbon atoms to which they are both attached, form a 3-membered carbocyclic ring, a 4-membered carbocyclic ring, a 5-membered carbocyclic ring, a 6-membered carbocyclic ring, a 3-membered heterocyclic ring, a 4-membered heterocyclic ring, a 5-membered heterocyclic ring, or a 6-membered heterocyclic ring; or R is4a And R is4c Together with the carbon atoms to which they are each attached form a 3-membered carbocyclic ring, a 4-membered carbocyclic ring, a 5-membered carbocyclic ring, a 6-membered carbocyclic ring, a 3-membered heterocyclic ring, a 4-membered heterocyclic ring, a 5-membered heterocyclic ring, or a 6-membered heterocyclic ring; each heterocycle or heterocyclyl contains 1 or 2 at each occurrence a member selected from N, O or S (=o)2 And each carbocyclic, carbocyclyl, heterocyclic OR heterocyclic group is optionally substituted with 1, 2, 3, 4, 5 OR 6 groups selected from-F, -Cl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropyl, oxo, -OR8 、-NR8 R9 、-CN、-C(＝O)R8 、-C(＝O)OR8 、-OC(＝O)R8 、-C(＝O)NR8 R9 、-NR8 C(＝O)R8 or-S (=o)2 NR8 R9 Substituted or unsubstituted with various substituents;
when (when)Selected from->When each R4a Is absent and R4b And R is4c One of which is absent, R4b And R is4c The other of (a) is selected from hydrogen, -F, -Cl, oxo, methyl, ethyl, propyl, isopropyl, -methylene- (halogen)1-3 Ethylene- (halogen)1-3 Propylene- (halogen)1-3 Heteroethyl, heteropropyl, -CN, -OR8 (III) methylene- (OR)8 )1-3 Ethylene- (OR)8 )1-3 Propylene- (OR)8 )1-3 、-NR8 R9 -methylene-NR8 R9 -ethylene-NR8 R9 (III) -propylene-NR8 R9 、-C(＝O)R8 、-C(＝O)OR8 、-OC(＝O)R8 、-C(＝O)NR8 R9 -methylene-C (=o) NR8 R9 -ethylene-C (=o) NR8 R9 -propylene-C (=o) NR8 R9 、-NR8 C(＝O)R8 -methylene-NR8 C(＝O)R8 -ethylene-NR8 C(＝O)R8 (III) -propylene-NR8 C(＝O)R8 、-S(＝O)2 NR8 R9 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl or 6-membered carbocyclyl; each R4b Or R is4c Independently optionally substituted with 1, 2, 3, 4, 5 OR 6 groups selected from-F, -Cl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, oxo, -OR8 、-NR8 R9 、-CN、-C(＝O)R8 、-C(＝O)OR8 、-OC(＝O)R8 、-C(＝O)NR8 R9 、-NR8 C(＝O)R8 or-S (=o)2 NR8 R9 Substituted or unsubstituted;
(R4a 、R4b or R is4c ) Each (R)8 Or R is9 ) Independently at each occurrence selected from hydrogen, methyl, ethyl, propyl, or isopropyl;
each R4d Independently at each occurrence selected from-Cl or-Br.
In some embodiments, whenIs->When R is4a 、R4b Or R is4c Independently at each occurrence selected from hydrogen, -F, -Cl, methyl, ethyl, propyl, isopropyl, -CH2 F、-CHF2 、-CF3 、-CH2 CH2 F、-CH2 CHF2 、-CH2 CF3 、-CH2 CH2 CH2 F、-CH2 CH2 CHF2 、-CH2 CH2 CF3 、-CH2 OCH3 、-CH2 CH2 OCH3 、-CH2 CH2 CH2 OCH3 、-CN、-OH、-OCH3 、-OCH2 CH3 、-OCH2 CH2 CH3 、-OCH(CH3 )2 、-CH2 OH、-CH2 CH2 OH、-CH2 CH2 CH2 OH、-NH2 、-NHCH3 、-NHCH2 CH3 、-NHCH2 CH2 CH3 、-NHCH(CH3 )2 、-N(CH3 )2 、-N(CH3 )CH2 CH3 、-N(CH3 )CH2 CH2 CH3 、-N(CH3 )CH(CH3 )2 、-CH2 NH2 、-CH2 CH2 NH2 、-CH2 CH2 CH2 NH2 、-CH2 N(CH3 )2 、-CH2 NHCH3 、-CH2 CH2 N(CH3 )2 、-CH2 CH2 CH2 N(CH3 )2 、-NHCH2 OH、-NHCH2 CH2 OH、-NHCH2 CH2 CH2 OH、-C(＝O)CH3 、-COOH、-C(＝O)OCH3 、-C(＝O)OCH2 CH3 、-C(＝O)OCH2 CH2 CH3 、-OC(＝O)CH3 、-C(＝O)NH2 、-C(＝O)NH(CH3 )、-C(＝O)N(CH3 )2 、-CH2 C(＝O)N(CH3 )2 、-CH2 CH2 C(＝O)N(CH3 )2 、-CH2 CH2 CH2 C(＝O)N(CH3 )2 、-NHC(＝O)CH3 、-N(CH3 )C(＝O)CH3 、-CH2 NHC(＝O)CH3 、-CH2 CH2 NHC(＝O)CH3 、-CH2 CH2 CH2 NHC(＝O)CH3 、-S(＝O)2 NH2 、-S(＝O)2 NH(CH3 )、-S(＝O)2 N(CH3 )2 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, 6-membered carbocyclyl,/-membered carbocyclyl>Each R4a 、R4b Or R is4c Independently optionally substituted with 1, 2, 3, 4, 5 or 6 groups selected from-F, -Cl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, oxo, -OH, -NH2 、-NHCH3 、-N(CH3 )2 、-CN、-C(＝O)CH3 、-C(＝O)OCH3 、-OC(＝O)CH3 、-C(＝O)NH2 、-C(＝O)NH(CH3 )、-C(＝O)N(CH3 )2 、-NHC(＝O)CH3 、-N(CH3 )C(＝O)CH3 、-S(＝O)2 NH2 、-S(＝O)2 NH(CH3 ) or-S (=o)2 N(CH3 )2 Substituted or unsubstituted; or R is4b And R is4c Together with the carbon atoms to which they are both attached, form a 3-membered carbocyclic ring, a 4-membered carbocyclic ring, a 5-membered carbocyclic ring, a 6-membered carbocyclic ring, a 3-membered heterocyclic ring, a 4-membered heterocyclic ring, a 5-membered heterocyclic ring, or a 6-membered heterocyclic ring; or R is4a And R is4c Together with the carbon atoms to which they are each attached form a 3-membered carbocyclic ring, a 4-membered carbocyclic ring, a 5-membered carbocyclic ring, a 6-membered carbocyclic ring, a 3-membered heterocyclic ring, a 4-membered heterocyclic ring, a 5-membered heterocyclic ring, or a 6-membered heterocyclic ring; each heterocycle or heterocyclyl contains 1 or 2 at each occurrence a member selected from N, O or S (=o)2 And each carbocyclic, carbocyclyl, heterocyclic or heterocyclic group is optionally substituted with 1, 2, 3, 4, 5 or 6 groups selected from-F, -Cl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, oxo, -OH, -NH2 、-NHCH3 、-N(CH3 )2 、-CN、-C(＝O)CH3 、-C(＝O)OCH3 、-OC(＝O)CH3 、-C(＝O)NH2 、-C(＝O)NH(CH3 )、-C(＝O)N(CH3 )2 、-NHC(＝O)CH3 、-N(CH3 )C(＝O)CH3 、-S(＝O)2 NH2 、-S(＝O)2 NH(CH3 ) or-S (=o)2 N(CH3 )2 Is substituted by a substituent of (a); or (b)
When (when)Is->When each R4a Is absent and R4b And R is4c One of which is absent, R4b And R is4c The other one of (a) is selected from hydrogen, -F, -Cl, oxo, methyl, ethyl, propyl, isopropyl, -CH2 F、-CHF2 、-CF3 、-CH2 CH2 F、-CH2 CHF2 、-CH2 CF3 、-CH2 CH2 CH2 F、-CH2 CH2 CHF2 、-CH2 CH2 CF3 、-CH2 OCH3 、-CH2 CH2 OCH3 、-CH2 CH2 CH2 OCH3 、-CN、-OH、-OCH3 、-OCH2 CH3 、-OCH2 CH2 CH3 、-OCH(CH3 )2 、-CH2 OH、-CH2 CH2 OH、-CH2 CH2 CH2 OH、-NH2 、-NHCH3 、-NHCH2 CH3 、-NHCH2 CH2 CH3 、-NHCH(CH3 )2 、-N(CH3 )2 、-N(CH3 )CH2 CH3 、-N(CH3 )CH2 CH2 CH3 、-N(CH3 )CH(CH3 )2 、-CH2 NH2 、-CH2 CH2 NH2 、-CH2 CH2 CH2 NH2 、-CH2 N(CH3 )2 、-CH2 CH2 N(CH3 )2 、-CH2 CH2 CH2 N(CH3 )2 、-C(＝O)CH3 、-C(＝O)OCH3 、-C(＝O)OCH2 CH3 、-C(＝O)OCH2 CH2 CH3 、-OC(＝O)CH3 、-C(＝O)NH2 、-C(＝O)NH(CH3 )、-C(＝O)N(CH3 )2 、-CH2 C(＝O)N(CH3 )2 、-CH2 CH2 C(＝O)N(CH3 )2 、-CH2 CH2 CH2 C(＝O)N(CH3 )2 、-NHC(＝O)CH3 、-N(CH3 )C(＝O)CH3 、-CH2 NHC(＝O)CH3 、-CH2 CH2 NHC(＝O)CH3 、-CH2 CH2 CH2 NHC(＝O)CH3 、-S(＝O)2 NH2 、-S(＝O)2 NH(CH3 )、-S(＝O)2 N(CH3 )2 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl or 6-membered carbocyclyl; each R4a 、R4b Or R is4c Independently optionally substituted with 1, 2, 3, 4, 5 or 6 groups selected from-F, -Cl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, oxo, -OH, -NH2 、-NHCH3 、-N(CH3 )2 、-CN、-C(＝O)CH3 、-C(＝O)OCH3 、-OC(＝O)CH3 、-C(＝O)NH2 、-C(＝O)NH(CH3 )、-C(＝O)N(CH3 )2 、-NHC(＝O)CH3 、-N(CH3 )C(＝O)CH3 、-S(＝O)2 NH2 、-S(＝O)2 NH(CH3 ) or-S (=o)2 N(CH3 )2 Substituted or unsubstituted;
each R4d Independently at each occurrence selected from-Br.
In some embodiments, R4a 、R4b Or R is4c Independently at each occurrenceFrom hydrogen, -F, -Cl, -CH3 、-CH2 CH3 、CF3 、-CH2 CHF2 、-CH2 CH2 OCH3 、-CN、-CH2 OH、-N(CH3 )2 、-CH2 N(CH3 )2 、-CH2 NHCH3 、-CH2 CH2 NH2 、-NHCH2 CH2 OH、-COOH、-NHCOCH3 、Or R is4a And R is4c Together with the carbon atoms to which they are respectively attached form +.>
Each R4d Independently at each occurrence selected from-Br.
In some embodiments, R41 Selected from the group consisting of
R4a 、R4b 、R4c Or R is4e Independently at each occurrence selected from hydrogen, halogen, -C1-6 Alkyl or-C1-6 alkylene-N (C)1-6 Alkyl group2 。
In some embodiments, R4a 、R4b 、R4c Or R is4e Independently selected from hydrogen, -F, -Cl, -Br, -C1-3 Alkyl or-C1-3 alkylene-N (C)1-3 Alkyl group2 。
In some embodiments, R4a 、R4b 、R4c Or R is4e Independently selected from hydrogen, -F, -Cl, methyl, ethyl, propyl, isopropyl, -CH2 -N(CH3 )2 、-CH2 -N(CH2 CH3 )2 or-CH2 -N(CH3 )(CH2 CH3 )。
In some embodiments, R4a 、R4b 、R4c Or R is4e Independently selected from hydrogen, -F, methyl or-CH2 -N(CH3 )2 。
In some embodiments, R4a Selected from hydrogen or-F; r is R4b Is hydrogen; r is R4c Selected from hydrogen or-CH2 -N(CH3 )2 ；R4e Is methyl.
In some embodiments, each R41 Independently at each occurrence selected from
In some embodiments, each R41 Independently at each occurrence selected from:
in some embodiments, each R41 Independently at each occurrence selected from
In some embodiments, R4 Independently selected fromEach of which isIs independently and optionally substituted at each occurrence with 1R42 2R42 3R42 4R42 5R42 Or 6R42 Substituted or unsubstituted.
In some embodiments, each R42 Selected from-F-Cl, -Br, oxo, -C1-3 Alkyl, -C1-3 Alkylene- (halogen)1-3 Impurity C2-3 Alkyl, -C2-5 Alkenyl, -C2-5 Alkynyl, -OR8 、-C1-3 Alkylene- (OR)8 )1-3 、-NR8 R9 、-C1-3 alkylene-NR8 R9 、-CN、-C1-3 alkylene-CN, -C (=o) R8 、-C1-3 alkylene-C (=o) R8 、-C(＝O)OR8 、-C1-3 alkylene-C (=o) OR8 、-OC(＝O)R8 、-C1-3 alkylene-OC (=o) R8 、-C(＝O)NR8 R9 、-C1-3 alkylene-C (=O) NR8 R9 、-NR8 C(＝O)R8 、-C1-3 alkylene-NR8 C(＝O)R8 、-S(＝O)2 NR8 R9 、-C1-3 alkylene-S (=o)2 NR8 R9 、-SO2 R8 、-C1-3 alkylene-SO2 R8 、-NR8 SO2 R8 or-C1-3 alkylene-NR8 SO2 R8 The method comprises the steps of carrying out a first treatment on the surface of the Each R42 Independently optionally substituted with 1, 2, 3, 4, 5 or 6 groups selected from-F, -Cl, -Br, -C1-3 Alkyl, -C1-3 Alkoxy, oxo, -OR8 、-NR8 R9 、-CN、-C(＝O)R8 、-C(＝O)OR8 、-OC(＝O)R8 、-C(＝O)NR8 R9 、-NR8 C(＝O)R8 or-S (=o)2 NR8 R9 Substituted or unsubstituted; or (b)
Two R42 Together with the atoms to which they are jointly or separately attached form C3-6 Carbocycles or 3-6 membered heterocycles, each of said heterocycles independently comprising 1 or 2 heteroatoms selected from N or O, each carbocycle or heterocycle optionally being substituted with 1, 2, 3, 4, 5 or 6 heteroatoms selected from halogen, -C1-3 Alkyl, -C1-3 Alkoxy, oxo, -OR8 、-NR8 R9 、-CN、-C(＝O)R8 、-C(＝O)OR8 、-OC(＝O)R8 、-C(＝O)NR8 R9 、-NR8 C(＝O)R8 or-S (=o)2 NR8 R9 Substituted or unsubstituted;
R42 each (R)8 Or R is9 ) Independently at each occurrence selected from hydrogen or-C1-3 An alkyl group.
In some embodiments, each R42 Selected from the group consisting of-F, -Cl, -Br, oxo, -C1-3 Alkyl, -C1-3 Alkylene- (halogen)1-3 Impurity C2-3 Alkyl, -C2-5 Alkenyl, -C2-5 Alkynyl, -OR8 、-C1-3 Alkylene- (OR)8 )1-3 、-NR8 R9 、-C1-3 alkylene-NR8 R9 、-CN、-C1-3 alkylene-CN, -C (=o) R8 、-C1-3 alkylene-C (=o) R8 、-C(＝O)OR8 、-C1-3 alkylene-C (=o) OR8 、-OC(＝O)R8 、-C1-3 alkylene-OC (=o) R8 、-C(＝O)NR8 R9 、-C1-3 alkylene-C (=O) NR8 R9 、-NR8 C(＝O)R8 、-C1-3 alkylene-NR8 C(＝O)R8 、-S(＝O)2 NR8 R9 、-C1-3 alkylene-S (=o)2 NR8 R9 、-SO2 R8 、-C1-3 alkylene-SO2 R8 、-NR8 SO2 R8 or-C1-3 alkylene-NR8 SO2 R8 The method comprises the steps of carrying out a first treatment on the surface of the Each R42 Independently optionally substituted with 1, 2, 3, 4, 5 or 6 groups selected from-F, -Cl, -Br, -C1-3 Alkyl, -C1-3 Alkoxy, oxo, -OR8 、-NR8 R9 、-CN、-C(＝O)R8 、-C(＝O)OR8 、-OC(＝O)R8 、-C(＝O)NR8 R9 、-NR8 C(＝O)R8 or-S (=o)2 NR8 R9 Substituted or unsubstituted; or (b)
Two R42 Are co-located with themTogether with the atoms to which they are attached or respectively attached, form a 3-membered carbocyclic ring, a 4-membered carbocyclic ring, a 5-membered carbocyclic ring, a 6-membered carbocyclic ring, a 3-membered heterocyclic ring, a 4-membered heterocyclic ring, a 5-membered heterocyclic ring or a 6-membered heterocyclic ring, each heterocyclic ring independently comprising 1 or 2 heteroatoms selected from N or O, each carbocyclic ring or heterocyclic ring optionally being substituted with 1, 2, 3, 4, 5 or 6 heteroatoms selected from-F, -Cl, -Br, -C1-3 Alkyl, -C1-3 Alkoxy, oxo, -OR8 、-NR8 R9 、-CN、-C(＝O)R8 、-C(＝O)OR8 、-OC(＝O)R8 、-C(＝O)NR8 R9 、-NR8 C(＝O)R8 or-S (=o)2 NR8 R9 Substituted or unsubstituted;
R42 each (R)8 Or R is9 ) Independently at each occurrence selected from hydrogen or-C1-3 An alkyl group.
In some embodiments, each R42 Selected from the group consisting of-F, -Cl, oxo, methyl, ethyl, propyl, isopropyl, -methylene- (halogen)1-3 Ethylene- (halogen)1-3 Propylene- (halogen)1-3 Heteroethyl, heteropropyl, ethenyl, propenyl, butenyl, pentenyl, ethynyl, propynyl, butynyl, pentynyl, -OR8 (III) methylene- (OR)8 )1-3 Ethylene- (OR)8 )1-3 Propylene- (OR)8 )1-3 、-NR8 R9 -methylene-NR8 R9 -ethylene-NR8 R9 (III) -propylene-NR8 R9 -CN, -methylene-CN, -ethylene-CN, -propylene-CN, -C (=o) R8 -methylene-C (=o) R8 -ethylene-C (=o) R8 -propylene-C (=o) R8 、-C(＝O)OR8 -methylene-C (=o) OR8 ethylene-C (=o) OR8 propylene-C (=O) OR8 、-OC(＝O)R8 -methylene-OC (=o) R8 -ethylene-OC (=o) R8 -propylene-OC (=o) R8 、-C(＝O)NR8 R9 -methylene-C (=o) NR8 R9 -ethylene-C (=o) NR8 R9 -propylene-C (=o) NR8 R9 、-NR8 C(＝O)R8 -methylene-NR8 C(＝O)R8 -ethylene-NR8 C(＝O)R8 (III) -propylene-NR8 C(＝O)R8 、-S(＝O)2 NR8 R9 -methylene-S (=o)2 NR8 R9 ethylene-S (=o)2 NR8 R9 propylene-S (=o)2 NR8 R9 、-SO2 CH3 -methylene-SO2 CH3 ethylene-SO2 CH3 propylene-SO2 CH3 、-NHSO2 CH3 、-N(CH3 )SO2 CH3 -methylene-NHSO2 CH3 -ethylene-NHSO2 CH3 or-propylene-NHSO2 CH3 The method comprises the steps of carrying out a first treatment on the surface of the Each R42 Independently optionally substituted with 1, 2, 3, 4, 5 OR 6 groups selected from-F, -Cl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, oxo, -OR8 、-NR8 R9 、-CN、-C(＝O)R8 、-C(＝O)OR8 、-OC(＝O)R8 、-C(＝O)NR8 R9 、-NR8 C(＝O)R8 or-S (=o)2 NR8 R9 Substituted or unsubstituted; or (b)
Two R42 Together with the atoms to which they are attached OR separately attached, form a 3-membered carbocyclic ring, a 4-membered carbocyclic ring, a 5-membered carbocyclic ring, a 6-membered carbocyclic ring, a 3-membered heterocyclic ring, a 4-membered heterocyclic ring, a 5-membered heterocyclic ring, OR a 6-membered heterocyclic ring, each heterocyclic ring independently containing 1 OR 2 heteroatoms selected from N OR O, each carbocyclic ring OR heterocyclic ring optionally being substituted with 1, 2, 3, 4, 5, OR 6 heteroatoms selected from-F, -Cl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, oxo, -OR8 、-NR8 R9 、-CN、-C(＝O)R8 、-C(＝O)OR8 、-OC(＝O)R8 、-C(＝O)NR8 R9 、-NR8 C(＝O)R8 or-S (=o)2 NR8 R9 Substituted or unsubstituted;
R42 each (R)8 Or R is9 ) Independently at each occurrence selected from hydrogen, methyl, ethyl, propyl or isopropyl.
In some embodiments, each R42 Selected from the group consisting of-F, -Cl, oxo, methyl, ethyl, propyl, isopropyl, -CH2 F、-CH2 Cl、-CHF2 、-CF3 、-CH2 CH2 F、-CH2 CHF2 、-CH2 CF3 、-CH2 CH2 CH2 F、-CH2 CH2 CHF2 、-CH2 CH2 CF3 、-CH2 OCH3 、-CH2 CH2 OCH3 、-CH2 CH2 CH2 OCH3 Vinyl, propenyl, butenyl, pentenyl, ethynyl, propynyl, butynyl, pentynyl, -OH, -OCH3 、-OCH2 CH3 、-OCH2 CH2 CH3 、-OCH(CH3 )2 、-CH2 OH、-CH2 CH2 OH、-CH2 CH2 CH2 OH、-C(OH)(CH3 )2 、-NH2 、-NHCH3 、-NHCH2 CH3 、-NHCH2 CH2 CH3 、-NHCH(CH3 )2 、-N(CH3 )2 、-N(CH3 )CH2 CH3 、-N(CH3 )CH2 CH2 CH3 、-N(CH3 )CH(CH3 )2 、-CH2 NH2 、-CH2 CH2 NH2 、-CH2 CH2 CH2 NH2 、-CH2 N(CH3 )2 、-CH2 CH2 N(CH3 )2 、-CH2 CH2 CH2 N(CH3 )2 、-CN、-CH2 CN、-CH2 CH2 CN、-CH2 CH2 CN、-C(＝O)CH3 、-CH2 C(＝O)CH3 、-CH2 CH2 C(＝O)CH3 、-CH2 CH2 CH2 C(＝O)CH3 、-COOH、-CH2 COOH、-CH2 CH2 COOH、-C(＝O)OCH3 、-CH2 C(＝O)OCH3 、-CH2 CH2 C(＝O)OCH3 、-CH2 CH2 CH2 C(＝O)OCH3 、-C(＝O)OCH2 CH3 、-C(＝O)OCH2 CH2 CH3 、-OC(＝O)CH3 、-CH2 OC(＝O)CH3 、-CH2 CH2 OC(＝O)CH3 、-CH2 CH2 CH2 OC(＝O)CH3 、-C(＝O)NH2 、-C(＝O)NH(CH3 )、-C(＝O)N(CH3 )2 、-CH2 C(＝O)N(CH3 )2 、-CH2 CH2 C(＝O)N(CH3 )2 、-CH2 CH2 CH2 C(＝O)N(CH3 )2 、-NHC(＝O)CH3 、-N(CH3 )C(＝O)CH3 、-CH2 NHC(＝O)CH3 、-CH2 CH2 NHC(＝O)CH3 、-CH2 CH2 CH2 NHC(＝O)CH3 、-S(＝O)2 NH2 、-S(＝O)2 NH(CH3 )、-S(＝O)2 N(CH3 )2 、-CH2 S(＝O)2 N(CH3 )2 、-CH2 CH2 S(＝O)2 N(CH3 )2 、-CH2 CH2 CH2 S(＝O)2 N(CH3 )2 、-SO2 CH3 、-CH2 SO2 CH3 、-CH2 CH2 SO2 CH3 、-CH2 CH2 CH2 SO2 CH3 、-NHSO2 CH3 、-CH2 NHSO2 CH3 、-CH2 CH2 NHSO2 CH3 or-CH2 CH2 CH2 NHSO2 CH3 The method comprises the steps of carrying out a first treatment on the surface of the Each R42 Is independently optionally substituted with 1, 2, 3, 4, 5 or 6 groups selected from-F, -Cl, methyl, ethyl, propyl, isopropyl, methoxyEthoxy, propoxy, isopropoxy, oxo, -OH, -NH2 、-NHCH3 、-N(CH3 )2 、-CN、-C(＝O)CH3 、-C(＝O)OCH3 、-OC(＝O)CH3 、-C(＝O)NH2 、-C(＝O)NH(CH3 )、-C(＝O)N(CH3 )2 、-NHC(＝O)CH3 、-N(CH3 )C(＝O)CH3 、-S(＝O)2 NH2 、-S(＝O)2 NH(CH3 ) or-S (=o)2 N(CH3 )2 Substituted or unsubstituted; or (b)
Two R42 Together with the atoms to which they are attached or separately attached, form a 3-membered carbocyclic ring, a 4-membered carbocyclic ring, a 5-membered carbocyclic ring, a 6-membered carbocyclic ring, a 3-membered heterocyclic ring, a 4-membered heterocyclic ring, a 5-membered heterocyclic ring, or a 6-membered heterocyclic ring, each heterocyclic ring independently containing 1 or 2 heteroatoms selected from N or O.
In some embodiments, each R42 Selected from-F, =o, -CH3 、-CH2 CH3 、-CH(CH3 )2 、-CHF2 、-CH2 Cl、-CF3 、-CH2 CF3 、-CH2 OH、-C(OH)(CH3 )2 、-CN、-CH2 CN、-CH2 N(CH3 )2 、-COOH、-CH2 COOH、-CONH2 、Or (b)
Two R42 Together with atoms to which they are jointly or separately attached form
In some embodiments, each R42 Independently at each occurrence selected from-C1-6 An alkyl group; -C1-6 alkylene-CN or halogen, -NH2 -CN or-OH substituted-C1-6 An alkyl group.
In some embodiments, each R42 Independently at each occurrence selected from-C1-3 An alkyl group; -C1-3 alkylene-CN or-C substituted by-F or-Cl1-3 An alkyl group.
In some embodiments, each R42 Independently at each occurrence selected from methyl; an ethyl group; a propyl group; an isopropyl group; -methylene-CN; -ethylene-CN; -propylene-CN; methyl substituted by-F or-Cl; ethyl substituted by-F or-C1; propyl substituted by-F or-C1; or isopropyl substituted by-F or-C1.
In some embodiments, each R42 Independently at each occurrence selected from methyl; an ethyl group; -methylene-CN or methyl substituted by-F.
In some embodiments, each R42 Independently at each occurrence selected from-CH3 、-CH2 CH3 、-CH2 CN、-CHF2 or-CF3 。
In some embodiments, R4 Selected from:
in some embodiments, R4 Selected from:
in some embodiments, R4 Selected from:
in some embodiments, R4 -L4 -selected from:
in some embodiments, the compound is selected from:
in another aspect, the invention provides an intermediate of formula (II), a stereoisomer thereof, a atropisomer thereof, a pharmaceutically acceptable salt of a stereoisomer thereof, or a pharmaceutically acceptable salt of a atropisomer thereof:
wherein,
R4 ' selected fromSaid->Independently optionally substituted with 1R42 2R42 3R42 4R42 5R42 Or 6R42 Substituted or unsubstituted;
PG is a protecting group of N atom; preferably, PG is
(R1 、R21 、R22 、R3 、L4 、R4 、n1、n2、n3、n4、G1 、G2 、G3 Or R is42 ) Is as defined in any one of claims 1 to 102.
In some embodiments, the intermediate is selected from the group consisting of:
in another aspect, the invention provides an intermediate, a stereoisomer thereof, a atropisomer thereof, a pharmaceutically acceptable salt of a stereoisomer thereof or a pharmaceutically acceptable salt of a atropisomer thereof, wherein the intermediate is selected from the group consisting of:
In another aspect, the present invention provides a method for preparing a compound of formula (I), a stereoisomer thereof, a atropisomer thereof, a pharmaceutically acceptable salt of a stereoisomer thereof or a pharmaceutically acceptable salt of a atropisomer thereof, according to the present invention, comprising the steps of a or B:
step A:
and (B) step (B):
in step A, R is as follows1 ' is selected from 1R11 2R11 Or 3R11 substituted-C6-10 Aryl or by 1R11 2R11 Or 3R11 Substituted 5-10 membered heteroaryl; preferably, said R1 ' is 2R11 Substituted benzenesA base; in step A, (R21 、R22 、R3 、L4 、R4 、R1 Or R is11 ) Is as defined in any one of claims 1 to 101; in step A, R is obtained by reacting R in intermediate A01 ' halogenation to obtain a compound of formula (I), preferably the halogenating agent is NCS or NBS;
in step B, R is as follows1 ' is selected from 1R11 2R11 Or 3R11 substituted-C6-10 Aryl or by 1R11 2R11 Or 3R11 Substituted 5-10 membered heteroaryl; preferably, said R1 ' is 2R11 A substituted phenyl group; said R is4 ' is R with N atom protecting group4 Such as N-Boc piperazinyl; in step B1, R in intermediate B0 is obtained by1 ' halogenation to obtain intermediate B1, preferably the halogenating reagent is NCS or NBS; in step B2, R in intermediate B1 is obtained by4 The compounds of formula (I) are obtained by' deprotection followed by acylation of the N atom.
In some embodiments, R in step A or step B is as described1 ' is selected from:
-L in step B4 -R4 ' is selected from:
in another aspect, the present invention provides a pharmaceutical composition comprising at least one compound of formula (I) according to the present invention, a stereoisomer thereof, a atropisomer thereof, a pharmaceutically acceptable salt of a stereoisomer thereof or a pharmaceutically acceptable salt of a atropisomer thereof, and at least one pharmaceutically acceptable excipient. In some embodiments, the weight ratio of the compound to the excipient ranges from about 0.0001 to about 10. In some embodiments, the weight ratio of the compound to the excipient ranges from about 0.01 to about 0.8. In some embodiments, the weight ratio of the compound to the excipient ranges from about 0.02 to about 0.2. In some embodiments, the weight ratio of the compound to the excipient ranges from about 0.05 to about 0.15.
In yet another aspect, the present invention provides a compound of formula (I), a stereoisomer thereof, a atropisomer thereof, a pharmaceutically acceptable salt of a stereoisomer thereof or a pharmaceutically acceptable salt of a atropisomer thereof as described herein; or the use of the pharmaceutical composition of the invention in the manufacture of a medicament for the treatment of a disease or condition associated with KRAS muteins. In some embodiments, the KRAS mutein-related disease or disorder is a KRAS G12C mutein-related disease or disorder. In some embodiments, the KRAS mutein-associated disease or disorder is a cancer associated with KRAS G12C mutein. In some embodiments, the cancer is selected from hematological cancer, pancreatic cancer, colon cancer, rectal cancer, colorectal cancer, or lung cancer. In some embodiments, the hematological cancer is selected from acute myelogenous leukemia or acute lymphoblastic leukemia; the lung cancer is selected from non-small cell lung cancer or small cell lung cancer.
In yet another aspect, the invention provides a method of treating a patient suffering from a disease or disorder associated with KRAS muteins, the method comprising administering to the patient a therapeutically effective amount of at least one compound of formula (I) as described herein, a stereoisomer thereof, a atropisomer thereof, a pharmaceutically acceptable salt of a stereoisomer thereof, or a pharmaceutically acceptable salt of a atropisomer thereof; or the pharmaceutical composition of the invention. In some embodiments, the disease or disorder associated with the KRAS mutein is a disease or disorder associated with the KRAS G12C mutein. In some embodiments, the KRAS mutein-associated disease or disorder is KRAS G12C-associated cancer. In some embodiments, the cancer is selected from hematological cancer, pancreatic cancer, colon cancer, rectal cancer, colorectal cancer, or lung cancer. In some embodiments, the hematological cancer is selected from acute myelogenous leukemia or acute lymphoblastic leukemia; the lung cancer is selected from non-small cell lung cancer or small cell lung cancer.
In a further aspect, the present invention provides a compound of formula (I), a stereoisomer thereof, a atropisomer thereof, a pharmaceutically acceptable salt of a stereoisomer thereof or a pharmaceutically acceptable salt of a atropisomer thereof as described herein for use as a medicament; or a pharmaceutical composition according to the invention.
Definition of the definition
The term "halogen" as used herein, unless otherwise indicated, refers to fluorine, chlorine, bromine or iodine. Preferred halogen groups include-F, -Cl and-Br. More preferably the halogen is-F or-Cl.
The term "alkyl" as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight or branched chains. For example, alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3- (2-methyl) butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-methylpentyl and cyclohexyl. Similarly, C1-6 C in alkyl1-6 Defined as having 1, 2, 3, 4, 5 or 6 carbon atoms in a linear or branched arrangement.
The term "alkylene" refers to a difunctional group obtained by removing a hydrogen atom from an alkyl group as defined above. For example, methylene (i.e. -CH2 (-), ethylene (i.e. -CH)2 -CH2 -or-CH (CH)3 ) (-) and propylene (i.e. -CH)2 -CH2 -CH2 -、-CH(-CH2 -CH3 ) -or-CH2 -CH(CH3 )-)。
The term "alkenyl" refers to a straight or branched hydrocarbon radical containing one or more double bonds, typically 2 to 20 carbon atoms in length. For example, "C2-6 Alkenyl "contains 2 to 6 carbon atoms. For example, alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, butenyl, 2-methyl-2-buten-1-yl, heptenyl, octenyl, and the like 。
The term "alkynyl" contains a straight or branched hydrocarbon radical of one or more triple bonds, typically 2 to 20 carbon atoms in length. For example, "C2-6 Alkynyl "contains 2 to 6 carbon atoms. Representative alkynyl groups include, but are not limited to, for example, ethynyl, 1-propynyl, 1-butynyl, heptynyl, octynyl, and the like.
The term "alkoxy" group is an oxyether formed from the foregoing alkyl groups.
The term "aryl" as used herein, unless otherwise indicated, refers to an unsubstituted or substituted monocyclic or polycyclic aromatic ring system containing carbon ring atoms. Preferred aryl groups are monocyclic or bicyclic 6-10 membered aromatic ring systems. Phenyl and naphthyl are preferred aryl groups. The most preferred aryl group is phenyl.
The term "heterocyclyl" or "heterocycle" as used herein, unless otherwise specified, refers to an unsubstituted and substituted monocyclic or polycyclic non-aromatic ring system containing one or more (e.g., 2, 3, 4, 5, or 6) heteroatoms, which includes monocyclic heterocycles (groups), bicyclic heterocycles (groups), bridged heterocycles (groups), fused-ring heterocycles (groups), and spiro-ring heterocycles (groups). Preferred heteroatoms include N, O and S, including N-oxides, sulfur oxides, and dioxides. Preferably, the ring is a three to ten membered ring, either fully saturated or having one or more degrees of unsaturation. The present definition includes heterocyclyl or heterocyclo with multiple degrees of substitution (preferably one, two or three degrees of substitution). Examples of such heterocyclyl groups include, but are not limited to, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, oxoazepanyl, azepanyl, tetrahydrofuranyl, dioxolanyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, or oxadiazolyl.
The term "heteroaryl" or "heteroaromatic ring" as used herein, unless otherwise indicated, refers to an aromatic ring system containing carbon and at least one heteroatom. Heteroaryl or heteroaromatic rings may be monocyclic or polycyclic, substituted or unsubstituted. Monocyclic heteroaryl groups may have 1 to 4 heteroatoms in the ring, while polycyclic heteroaryl groups may contain 1 to 10 heteroatoms. Polycyclic heteroaryl rings may contain a fused, spiro, or bridged ring combination, e.g., bicyclic heteroaryl groups are polycyclic heteroaryl groups. The bicyclic heteroaryl ring may contain 8 to 12 member atoms. The monocyclic heteroaryl ring may contain 5 to 8 member atoms (carbon atoms and heteroatoms). Examples of heteroaryl groups include, but are not limited to, thienyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridazinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuryl, benzothienyl, benzisoxazolyl, benzoxazolyl, benzopyrazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazole, adenine, quinolinyl, or isoquinolinyl.
The term "carbocycle" refers to a substituted or unsubstituted monocyclic, bicyclic, or polycyclic non-aromatic saturated ring, optionally including an alkylene linker through which a cycloalkyl group may be attached. Exemplary "carbocyclyl" groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
The term "oxo" refers to the formation of oxygen together with the carbon atom to which it is attachedA group.
Term "-C1-6 alkylene-C6-10 Aryl "means C as defined above6-10 aryl-substituted-C1-6 An alkyl group.
Term "-C1-6 Alkylene- (5-10 membered heteroaryl) "means-C substituted with a 5-10 membered heteroaryl as defined above1-6 An alkyl group.
Term "-C1-6 Alkylene- (3-10 membered heterocyclyl) "means-C substituted with a 3-10 membered heterocyclyl as defined above1-6 An alkyl group.
Term "-C1-6 alkylene-C3-10 Carbocyclyl "means C as defined above3-10 carbocyclyl-substituted-C1-6 An alkyl group.
Term "-C1-6 Alkylene- (halogen)1-3 "means 1, 2 or 3 quilthalogen-substituted-C as defined above1-6 An alkyl group.
The term "hetero C2-6 Alkyl "means-C as defined above2-6 The group after substitution of one or more carbon atoms in the chain of alkyl groups by a heteroatom selected from O, S or N, preferably the heteroatom is O.
Term "-C1-6 Alkylene- (OR)8 )1-3 "means by 1, 2 OR 3 OR' s8 substituted-C1-6 Alkyl, wherein R is8 Definition of (A) is as above, preferably R8 Selected from hydrogen, methyl, ethyl or propyl.
Term "-C1-6 Alkylene- (SR)8 )1-3 "means by 1, 2 or 3 SR8 substituted-C1-6 Alkyl, wherein R is8 Definition of (A) is as above, preferably R8 Selected from hydrogen, methyl, ethyl or propyl.
The term "-O-C1-6 Alkylene- (halogen)1-3 "means-C as defined above1-6 Alkylene- (halogen)1-3 Is a mixed oxygen ether.
Term "-S-C1-6 Alkylene- (halogen)1-3 "means-C as defined above1-6 Alkylene- (halogen)1-3 S ether of (c).
Term "-C1-6 alkylene-NR8 R9 "means by-NR8 R9 substituted-C1-6 Alkyl, wherein R is8 And R is9 Is defined as above, preferably R8 、R9 Selected from hydrogen, methyl, ethyl or propyl.
Term "-C1-6 alkylene-C (=o) R8 "means being-C (=O) R8 substituted-C1-6 Alkyl, wherein R is8 Is defined as above, preferably R8 Selected from hydrogen, methyl, ethyl or propyl.
Term "-C1-6 alkylene-C (=o) OR8 "means being-C (=O) OR8 substituted-C1-6 Alkyl, wherein R is8 Is defined as above, preferably R8 Selected from hydrogen, methyl, ethyl or propylA base.
Term "-C1-6 alkylene-OC (=o) R8 "means being-OC (=O) R8 substituted-C1-6 Alkyl, wherein R is8 Is defined as above, preferably R8 Selected from hydrogen, methyl, ethyl or propyl.
Term "-C1-6 alkylene-C (=O) NR8 R9 "means by-C (=O) NR8 R9 substituted-C1-6 Alkyl, wherein R is8 And R is9 Is defined as above, preferably R8 、R9 Selected from hydrogen, methyl, ethyl or propyl.
Term "-C1-6 alkylene-NR8 C(＝O)R8 "means by-NR8 C(＝O)R8 substituted-C1-6 Alkyl, wherein R is8 Is defined as above, preferably R8 Selected from hydrogen, methyl, ethyl or propyl.
Term "-C1-6 alkylene-S (=o)2 NR8 R9 "means quilt-S (=O)2 NR8 R9 substituted-C1-6 Alkyl, wherein R is8 、R9 Is defined as above, preferably R8 、R9 Selected from hydrogen, methyl, ethyl or propyl.
Term "-C1-6 alkylene-CN "refers to-C substituted by-CN1-6 An alkyl group.
As used herein, the term "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 combination of the specified ingredients in the specified amounts. Thus, pharmaceutical compositions containing the compounds of the present invention as active ingredients and methods of preparing the compounds of the present invention are also part of the present invention.
The term "pharmaceutically acceptable salt" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids. When the compounds of the present invention are acidic, their corresponding salts can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic and organic bases. When the compounds of the present invention are basic, their corresponding salts 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, in particular at least 98% pure (% by weight).
The present invention includes within its scope prodrugs of the compounds of the present invention. Typically, such prodrugs are functional derivatives of the compounds that are readily convertible in vivo into the desired compound. Thus, in the methods of treatment of the present invention, the term "administering" shall include treating the various disorders described with a particular disclosed compound, or with a compound that may not be specifically disclosed, but that is converted to the particular compound in vivo after administration to a subject. Conventional methods for selecting and preparing suitable prodrug derivatives are described, for example, in "prodrug design" ("Design of Prodrugs", ed.h. bundegaad, elsevier, 1985).
The definition of any substituent or variable at a particular position in a molecule is intended to be independent of the definition of substituents or variables at other positions in the molecule. It will be appreciated that substituents and substitution patterns on the compounds of the invention may be selected by one of ordinary skill in the art to provide chemically stable compounds and may be readily synthesized by techniques known in the art and as set forth herein.
The invention includes that the compounds may contain one or more asymmetric centers and thus may produce diastereomers and optical isomers. The present invention includes all such possible diastereomers and racemic mixtures thereof, their substantially pure resolved enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof.
The present invention includes all stereoisomers of the compounds and pharmaceutically acceptable salts thereof. In addition, mixtures of stereoisomers and isolated specific stereoisomers are also included. During the synthetic methods used to prepare these compounds, or during the use of racemization or epimerization methods known to those skilled in the art, the products of these methods may be mixtures of stereoisomers.
"stereoisomers" as used herein refers to isomers of molecules in which atoms or groups of atoms are connected in the same order but in different spatial arrangements, and include configurational isomers and conformational isomers, wherein configurational isomers in turn include geometric isomers and optical isomers, and optical isomers include mainly enantiomers and diastereomers.
Certain compounds provided herein may exist as atropisomers, which are conformational stereoisomers that occur when rotation about a single bond in a molecule is prevented or greatly slowed due to steric interactions with other parts of the molecule. The compounds provided herein include all atropisomers, including pure individual atropisomers, respective enriched atropisomers or respective nonspecific mixtures. If the rotation barrier around the single bond is high enough and the interconversion between conformations is slow enough, the separation of atropisomers may be allowed.
The present invention is intended to include all atomic isotopes present in the compounds of the invention. Isotopes are atoms having the same atomic number but different mass numbers. By way of general example and not limitation, isotopes of hydrogen include deuterium and tritium. Isotopes of hydrogen can be represented as1 H (hydrogen),2 h (deuterium)3 H (tritium). They are also commonly denoted as D (deuterium) and T (tritium). In the present application, CD3 Represents methyl, wherein all hydrogen atoms are deuterium. Isotopes of carbon include13 C and C14 C. Isotopically-labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of a non-labeled reagent.
Unless otherwise indicated, when a tautomer of a compound of formula (I) is present, the present invention includes any of the possible tautomers and pharmaceutically acceptable salts thereof, and mixtures thereof.
When the compounds of formula (I) and pharmaceutically acceptable salts thereof are present in solvate or polymorphic forms, the present invention includes any possible solvate and polymorphic form. The type of solvent forming the solvate is not particularly limited as long as the solvent is pharmacologically acceptable.
The pharmaceutical composition of the present invention comprises a compound represented by the formula (I) (a stereoisomer thereof, a atropisomer thereof, a pharmaceutically acceptable salt of a stereoisomer thereof or a pharmaceutically acceptable salt of a atropisomer thereof) as an active ingredient, a pharmaceutically acceptable carrier and optionally other adjuvants. Although the most suitable route in any given case will depend on the particular host, and the nature and severity of the condition for which the active ingredient is being administered, for treatment of the condition, the compositions include compositions suitable for oral, rectal, topical and parenteral (including subcutaneous, intramuscular and intravenous) administration. The pharmaceutical composition may conveniently be presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.
In practice, the compounds represented by formula I of the present invention or prodrugs or metabolites thereof or pharmaceutically acceptable salts thereof may be combined as an active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a variety of forms depending on the form of formulation desired for the route of administration, such as oral or parenteral (including intravenous) routes of administration. Thus, the pharmaceutical compositions of the present invention may be presented as discrete units suitable for oral administration, e.g. capsules, cachets (tablets) or tablets each containing a predetermined amount of the active ingredient. Furthermore, the composition may be present in powder form, in particulate form, in solution form, in suspension in an aqueous liquid, in a non-aqueous liquid, in an oil-in-water emulsion or in a water-in-oil emulsion. In addition to the common dosage forms described above, the compounds represented by formula I or pharmaceutically acceptable salts thereof may also be administered by controlled release means and/or delivery means. The composition may be prepared by any pharmaceutical method. Typically, these methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more essential ingredients. Generally, the compositions are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both. The product can then be conveniently shaped into the desired pattern.
Accordingly, the pharmaceutical compositions of the present invention may comprise a pharmaceutically acceptable carrier and a compound of formula I or a pharmaceutically acceptable salt.
The pharmaceutical carrier used may be, for example, a solid, a liquid or a 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 syrup, peanut oil, olive oil, and water. Examples of gaseous carriers include carbon dioxide and nitrogen. In preparing the composition for oral dosage form, any convenient pharmaceutical medium may 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; and 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. Tablets and capsules are preferred oral dosage units for ease of administration, wherein solid pharmaceutical carriers are used. Optionally, the tablets may be coated by standard aqueous or non-aqueous techniques.
Tablets containing the compositions of the invention may be prepared by compression or moulding, 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 active ingredient, and each cachet or capsule preferably contains from about 0.05mg to about 5g of active ingredient. For example, a formulation for oral administration to humans may contain from about 0.5mg to about 5g of active agent admixed with a suitable and convenient amount of carrier material, which may constitute from about 0.05% to about 95% of the total composition. The unit dosage form will typically contain from about 0.01mg to about 2g of the active ingredient, typically 0.01mg, 0.02mg, 1mg, 2mg, 3mg, 4mg, 5mg, 6mg, 7mg, 8mg, 9mg, 10mg, 25mg, 50mg, 100mg, 200mg, 300mg, 400mg, 500mg, 600mg, 800mg, 1000mg, 1500mg or 2000mg.
Pharmaceutical compositions of the invention suitable for parenteral administration may be prepared as solutions or suspensions of the active compounds in water. Suitable surfactants may be included, such as hydroxypropyl cellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. In addition, preservatives may be included to prevent detrimental growth of microorganisms.
Pharmaceutical compositions of the present invention suitable for injectable use include sterile aqueous solutions or dispersions. Furthermore, the composition may be in the form of a sterile powder for extemporaneous preparation of such sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile and must be fluid to facilitate injection. The pharmaceutical composition must be stable under the conditions of manufacture and storage; therefore, it is preferable that the preservation should be prevented from contamination by microorganisms such as bacteria and fungi. The carrier may be, for example, a solvent or dispersion medium containing water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycols), vegetable oils, and suitable mixtures thereof.
The pharmaceutical composition of the present invention may be in a form suitable for topical use, such as an aerosol, cream, ointment, lotion, dusting powder, or the like. Furthermore, the composition may be in a form suitable for use in a transdermal device. With the compounds of formula I of the present invention or pharmaceutically acceptable salts thereof, these formulations can be prepared by conventional processing methods. For example, a cream or ointment is prepared by mixing a hydrophilic material and water with about 0.05wt% to about 10wt% of a compound to produce a cream or ointment having a desired consistency.
The pharmaceutical composition of the invention may be in a form suitable for rectal administration wherein the carrier is a solid. Preferably, the mixture forms a unit dose suppository. Suitable carriers include cocoa butter and other materials commonly used in the art. Suppositories may be conveniently formed by first mixing the composition with the softened or melted carrier and then cooling and shaping in a mold.
In addition to the carrier ingredients described above, the above pharmaceutical formulations may suitably include one or more additional carrier ingredients, such as diluents, buffers, flavoring agents, binders, surfactants, thickeners, lubricants, preservatives (including antioxidants), and the like. In addition, other adjuvants may be included to make the formulation isotonic with the blood of the intended recipient. Compositions containing the compounds of formula I or pharmaceutically acceptable salts thereof may also be prepared in the form of powders or liquid concentrates.
Generally, dosage levels of about 0.001mg/kg to about 150mg/kg body weight per day may be used to treat the above conditions, or about 0.05mg to about 7g per patient per day.
However, it will be appreciated that the specific dosage level for any particular patient will depend on a variety of factors including the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
These and other aspects will become apparent from the following written description of the invention.
Detailed Description
The compounds of the present invention can be synthesized from commercially available reagents using the synthetic methods and reaction schemes described herein. Examples of specific synthetic routes are summarized and the following general schemes are intended to provide guidance to synthetic chemists of skill in the art who will readily understand that solvents, concentrations, reagents, protecting groups, the sequence of synthetic steps, time, temperature, etc. can be modified as desired within the skill and judgment of those skilled in the art. For example, the compounds of the present invention may be prepared according to the following general synthetic scheme.
The following examples are provided to better illustrate the invention. All parts and percentages are by weight and all temperatures are degrees celsius unless explicitly stated otherwise. Abbreviations in table 1 below are used in the examples:
TABLE 1
General synthetic scheme
Scheme I:
in scheme I, X1 Represents a leaving group such as halogen, e.g., cl, br, I; x is X2 Represents a leaving group such as halogen, for example Cl; br; i, a step of I; LG represents a leaving group such as Cl, OTf; y is Y1 Represents H or a leaving group; r is R4 ' represents R4 with a protecting group, such as N-Boc piperazinyl; the other substituents or groups in scheme I are as defined above.
INT-A route
The compounds of formula (I) disclosed herein can be synthesized as described in scheme I. In step 1, the purchased or synthetically obtained starting material 1 is condensed with INT-A (INT-A route) in a condensing agent, such as HATU or EDCI/HOBT, or an acid chloride (prepared from compound 1) to give compound 2. The coupling reaction may be carried out in the presence of a base such as triethylamine or Hunig's base in a solvent such as dichloromethane or DMF. In step 2, 2 may be treated with a suitable base (e.g., liHMDS or NaH) to obtain intramolecular ring-closing product compound 3. In step 3, the monooxo group of the pyridinedione (compound 3) is converted to a leaving group by an activating reagent, including, but not limited to, acid chloride, triflic anhydride, phosphorus oxychloride, and phosphorus pentachloride, to form compound 4.In step 4, the leaving group is cleaved in a solvent (e.g., acetonitrile) and a base (e.g., DIPEA)1 -L4 -R4 L in4 -R4 ' substitution gives compound 5. In step 5, compound 5 is deprotected under the action of TFA/DCM or hydrogen chloride in methanol and reacted with an acylating agent to give compound 6, with the specific conditions including: acylating agents such as acryloyl chloride, solvents such as DCM or THF, bases such as TEA, DIEA or K3 PO4 An aqueous solution. Compound 6 and corresponding compound Z in step 61 -R1 Coupling introduction of R1 The compound of formula (I) is obtained by using a catalyst combination such as Pd2 (dba)3 X-Phos, solvents such as dioxane, bases such as cesium carbonate or sodium carbonate. In some cases R1 And R is3 There may be protecting groups that may be removed in a subsequent step of increasing the synthesis.
Purification of the compounds in all the above steps can be performed by common purification means such as column chromatography, crystallization purification, reversed-phase column HPLC or climbing plate Pre-TLC. The enantiomer compound (I) may be resolved and purified by well-known purification means such as chiral SFC or HPLC to give enantiomers or atropisomers, if necessary.
Scheme II:
in scheme II, X1 Represents a leaving group such as halogen, e.g., cl, br, I; x is X2 Represents a leaving group such as halogen, e.g., cl, br, I; LG represents a leaving group such as Cl, OTf; y is Y1 Represents H or a leaving group; r is R4 ' represents R with protecting group4 Such as N-Boc piperazinyl; the other substituents or groups in scheme II are as defined above.
INT-A route:
compounds of formula (I) as disclosed hereinCan be synthesized as described in scheme II. In step 1, the starting material 1 obtained by purchase or synthesis is reacted with a condensing agent such as: under the action of HATU or EDCI/HOBT, or compound 1 forms acid chloride first and then condenses with INT-A (INT-A route) to obtain compound 2. The solvent used for condensation can be dichloromethane or DMF, and the base used can be TEA or DIEA. Compound 2 in step 2 may be prepared in a base such as: the intramolecular ring closure under the action of LiHMDS or NaH forms compound 3. In step 3, the hydroxyl groups are formed into compound 4 by the action of activating reagents including, but not limited to, acid chloride, triflic anhydride, phosphorus oxychloride, and phosphorus pentachloride. The leaving group obtained by activation in step 4 is reacted with Y in a solvent such as acetonitrile, a base such as DIPEA1 -L4 -R4 L in4 -R4 ' substitution gives compound 5. Compound 5 and the corresponding compound Z in step 51 -R1 Coupling introduction of R1 Compound 6 is obtained using a reagent which may be a combination of catalysts such as Pd2 (dba)3 X-Phos, solvents such as dioxane, bases such as cesium carbonate or sodium carbonate. The compound 6 in the step 6 is deprotected under the action of TFA/DCM or hydrogen chloride in methanol and reacted with an acylating agent to give the compound of formula (I). The specific conditions include: acylating agents such as acryloyl chloride, solvents such as DCM or THF, bases such as TEA, DIEA or K3 PO4 An aqueous solution. In some cases R1 And R is3 There may be protecting groups that may be removed in a subsequent step of increasing the synthesis.
Purification of the compounds in all the above steps can be performed by common purification means such as column chromatography, crystallization purification, reversed-phase column HPLC or climbing plate Pre-TLC. The enantiomer compound (I) may be resolved and purified by well-known purification means such as chiral SFC or HPLC to give enantiomers or atropisomers, if necessary.
Scheme III:
in scheme III, X1 Represents a leaving group such as halogen, e.g., cl, br, I; x is X2 Representing halogen or the likeLeaving groups such as Cl, br, I; LG represents a leaving group such as Cl, OTf; y is Y1 Represents H or a leaving group; r is R4 ' represents R with protecting group4 Such as N-Boc piperazinyl; r is R1 ' is represented by 1R11 2R11 Or 3R11 substituted-C6-10 Aryl or by 1R11 2R11 Or 3R11 Substituted 5-10 membered heteroaryl. The other substituents or groups in scheme III are as defined above.
INT-A route:
the compounds of formula (I) disclosed herein can be synthesized as described in scheme III. In step 1, the starting material 1 obtained by purchase or synthesis is reacted with a condensing agent such as: under the action of HATU or EDCI/HOBT, or compound 1 forms acid chloride first and then condenses with INT-A (INT-A route) to obtain compound 2. The solvent used for condensation can be dichloromethane or DMF, and the base used can be TEA or DIEA. Compound 2 in step 2 may be prepared in a base such as: and Guan Huange in molecule is formed into a compound 3 under the action of LiHMDS or NaH. In step 3, the hydroxyl groups are formed into compound 4 by the action of activating reagents including, but not limited to, acid chloride, triflic anhydride, phosphorus oxychloride, and phosphorus pentachloride. The leaving group obtained by activation in step 4 is reacted with Y in a solvent such as acetonitrile, a base such as DIPEA1 -L4 -R4 L in4 -R4 ' substitution gives compound 5. Deprotection of compound 5 in step 5 with TFA/DCM or hydrogen chloride in methanol and reaction with an acylating reagent gives compound 6 under conditions comprising: acylating agents such as acryloyl chloride, solvents such as DCM or THF, bases such as TEA, DIEA or K3 PO4 An aqueous solution. Compound 6 and corresponding compound Z in step 61 -R1 ' coupling introduces R1 ' Compound 7 is obtained, the reagent used may be a combination of catalysts such as Pd2 (dba)3 X-Phos, solvents such as dioxane, bases such as cesium carbonate or sodium carbonate. In step 7, compound 7 may be halogenated to give formula (I)The compound, the reagent such as NCS/AcOH is used. In some cases R1 ′、R1 And R is3 There may be protecting groups which are removed in a subsequent step of increasing the synthesis.
Purification of the compounds in all the above steps can be performed by common purification means such as column chromatography, crystallization purification, reversed-phase column HPLC or climbing plate Pre-TLC. The enantiomer compound (I) may be resolved and purified by well-known purification means such as chiral SFC or HPLC to give enantiomers or atropisomers, if necessary.
Scheme IV:
in scheme IV, X1 Represents a leaving group such as halogen, e.g., cl, br, I; x is X2 Represents a leaving group such as halogen, e.g., cl, br, I; LG represents a leaving group such as Cl, OTf; y is Y1 Represents H or a leaving group; r is R4 ' represents R with protecting group4 Such as N-Boc piperazinyl; r is R1 ' is represented by 1R11 2R11 Or 3R11 substituted-C6-10 Aryl or by 1R11 2R11 Or 3R11 Substituted 5-10 membered heteroaryl. The definition of the other substituents or groups in scheme Iv are as defined above.
INT-A route:
the compounds of formula (I) disclosed herein can be synthesized as described in scheme III. In step 1, the starting material 1 obtained by purchase or synthesis is reacted with a condensing agent such as: under the action of HATU or EDCI/HOBT, or compound 1 forms acid chloride first and then condenses with INT-A (INT-A route) to obtain compound 2. The solvent used for condensation can be dichloromethane or DMF, and the base used can be TEA or DIEA. Step 2, may be carried out in the presence of a base such as: the intramolecular ring closure under the action of LiHMDS or NaH forms compound 3. In step 3, the hydroxyl group acts on the activating reagentCompound 4 is formed below, and the activating reagent includes, but is not limited to, acid chloride, trifluoromethanesulfonic anhydride, phosphorus oxychloride, and phosphorus pentachloride. The leaving group obtained by activation in step 4 is reacted with Y in a solvent such as acetonitrile, a base such as DIPEA1 -L4 -R4 L in4 -R4 ' substitution gives compound 5. Compound 5 and the corresponding compound Z in step 51 -R1 ' coupling introduces R1 ' Compound 6 is obtained, the reagent used may be a combination of catalysts such as Pd2 (dba)3 In step 6, compound 6 may be halogenated with a halogenating agent such as NCS/AcOH to give compound 7. The compound 7 in step 7 is deprotected under the action of TFA/DCM or hydrogen chloride in methanol and reacted with an acylating agent to give the compound of formula (I). The specific conditions include: acylating agents such as acryloyl chloride, solvents such as DCM or THF, bases such as TEA, DIEA or K3 PO4 An aqueous solution. In some cases R1 ′，R1 And R is3 There may be protecting groups that may be removed in a subsequent step of increasing the synthesis.
Purification of the compounds in all the above steps can be performed by common purification means such as column chromatography, crystallization purification, reversed-phase column HPLC or climbing plate Pre-TLC. The enantiomer compound (I) may be resolved and purified by well-known purification means such as chiral SFC or HPLC to give enantiomers or atropisomers, if necessary.
Example 1
4- (4-Acrylpiperazin-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-methyl-2- (prop-1-en-2-yl) pyridin-3-amine.
2-bromo-4-methylpyridin-3-amine (BD, APL 099) (15.01 g,80.25 mmol), 4, 5-tetramethyl-2- (prop-1-en-2-yl) -1,3, 2-dioxaborolan (13.62 g,81.05 m) mol)、Pd(dppf)Cl2 (5.95g，8.03mmol)、K2 CO3 (33.52 g,240 mmol), dioxane (150 mL) and water (20 mL) were added to a 350-mL sealed tube purged and maintained with a nitrogen inert atmosphere. The reaction mixture was stirred at 100℃for 8h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was applied to a silica gel column eluted with EA/n-hexane (v: v=2:3). 11.2g (94%) of 4-methyl-2 (prop-1-en-2-yl) pyridin-3-amine were thus obtained as a yellow oil. LCMS: m/z=149 [ m+1 ]]+ 。
Step 2.2-isopropyl-4-methyl-3-pyridinamine (intermediate A)
4-methyl 2- (prop-1-en-2-yl) pyridin-3-amine (11.2 g,75.67 mmol) and MeOH (100 mL) were added to a 250-mL round bottom flask purged with nitrogen and maintained and Pd/C (2.81 g) was added in three portions. The mixture was depressurized and vented with H2 Ball purge three times-. The reaction mixture was stirred at 25℃for 3h. The resulting solution was filtered and a filtrate was obtained, which was then concentrated under reduced pressure. 11g (crude) of directly used 2-isopropyl-4-methylpyridin-3-amine are thus obtained. LCMS: m/z=151 [ m+1 ]]+ 。
Step 3.2-cyano-nitrogen- (2-isopropyl-4-methylpyridin-3-yl) acetamide.
2-cyanoacetic acid (3 g,35.27 mmol) and DCM (40 mL) were placed in a 100-mL round-bottom flask purged with nitrogen and maintained, and oxalyl chloride (6.2 g,48.85 mmol) was added dropwise. After completion of the dropwise addition, DMF (0.1 mL) was added. The resulting mixture was stirred at 25℃for 3h. The resulting solution was concentrated under reduced pressure, whereby 3.10g (crude product) of 2-cyanoacetyl chloride was obtained for direct use.
2-isopropyl-4-methylpyridin-3-amine (2.00 g,13.31 mmol), TEA (5.40 g,53.36 mmol), DCM (40 mL) were added to a 100-mL round bottom flask purged with nitrogen and maintained with stirring. The resulting mixture was cooled to 0deg.C and then 2-cyanoacetyl chloride (3.10 g, trude) was added dropwise. The resulting solution was stirred at room temperature for 2h. The reaction was quenched by addition of 100 mL. The resulting solution was extracted with dichloromethane (3X 50 mL), and the combined organic phases were washed with saturated brine (50 mL) and with anhydrous Na2 SO4 Drying and concentrating under reduced pressure to obtain residue for use in EA/n-hexaneAn alkane (v: v=3:2) eluting silica gel column. Thus, 1.00g (34%) of 2-cyano-N- (2-isopropyl-4-methylpyridine-3-cyanoacetamide was obtained as a yellow solid LCMS: m/z=218 [ M+1 ]]+ 。
Step 4.2-cyano-3- (2, 6-dichloro-5-fluoropyridin-3-yl) -N- (2-isopropyl-4-methylpyridin-3-yl) -3-oxopropanamide.
2, 6-dichloro-5-fluoronicotinic acid (3 g,14.28 mmol), thionyl chloride (30 mL) was added to a 100-mL round bottom flask that was purged with a nitrogen atmosphere and maintained. The resulting mixture was heated to 80 ℃ and stirred for 1h. The resulting solution was concentrated under reduced pressure. 3.10g (crude) of 2, 6-dichloro-5-fluoronicotinoyl chloride was thus obtained which was directly used in the next step.
2-cyano-N- (2-isopropyl-4-methylpyridin-3-yl) acetamide (650 mg,2.99 mmol) and THF (10 mL) were added to a 50-mL round bottom flask and the resulting mixture stirred at 0deg.C. NaH (250 mg,6.25 mmol) was added in three portions. The resulting mixture was stirred at 0℃for a further 40min. 2, 6-dichloro-5-fluoronicotinoyl chloride (820 mg,3.59 mmol) dissolved in THF (5 mL) was then added dropwise. The resulting reaction mixture was stirred at 25℃for 2h. The resulting reaction mixture was concentrated under reduced pressure. The crude product thus obtained is further purified by using ACN/H2 C eluted with O (v: v=3:7)18 And (5) purifying by a column. Thus, 1.00g (82%) of 2-cyano-3- (2, 6-dichloro-5-fluoropyridin-3-yl) -N- (2-isopropyl-4-methylpyridin-3-yl) -3-oxopropanamide was obtained as a yellow solid. LCMS: m/z=409 [ m+1 ]]+ 。
Step 5.7-chloro-6-fluoro-4-hydroxy-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile (intermediate B).
2-cyano-3- (2, 6-dichloro-5-fluoropyridin-3-yl) -N- (2-isopropyl-4-methylpyridin-3-yl) -3-oxopropanamide (1.10 g,2.68 mmol) THF (20 mL) was placed in a 50-mL round bottom pancake purged and maintained with a nitrogen atmosphere and stirred at room temperature. NaH (530 mg,13.25 mmol) was added. The resulting mixture was stirred at 50℃for 12h. The reaction was concentrated under reduced pressure. The resulting residue was dissolved in 40mL of water and the pH was adjusted to 7 with acetic acid. The resulting solid was filtered and dried under reduced pressure to give 0.80g (88%) of 7-chloro-6-fluoro-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=373 [ m+1 ]]+ 。
Step 6.4- (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-carboxylic acid tert-butyl ester
7-chloro-6-fluoro-4-hydroxy-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile (389 mg,1.04 mmol), phosphorus oxychloride (552 mg,3.60 mmol), DIEA (651 mg,5.04 mmol) and acetonitrile (15 mL) were placed in a 50-mL round bottom flask. The resulting mixture was stirred at 80℃for 1h. The reaction was cooled to room temperature and concentrated under reduced pressure. The crude 4, 7-dichloro-6-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile obtained was dissolved in acetonitrile (15 mL) and DIEA (480 mg,3.71 mmol) and tert-butylpiperazine-1-carboxylate (233 mg,1.25 mmol) were then added. The reaction mixture was stirred at room temperature for 0.5h. After the completion of the reaction, water (50 mL) was added to quench the reaction. The resulting solution was extracted with ethyl acetate (3X 50 mL), the organic phases were combined and washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue obtained was purified by column chromatography on silica eluting with EA/n-hexane (V/v=2/1). Thus, 0.45g (79%) of 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 was obtained as a yellow solid. LCMS: m/z=541 [ m+1 ] ]+ 。
Step 7.4- (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-carboxylic acid tert-butyl ester
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-carboxylic acid tert-butyl ester (155 mg,0.29 mmol), 3-fluoro-2- (4,4,5.5-tetramethyl-1, 3, 2-dioxaborane-2-yl) aniline (206 mg,0.87 mmol), pd (PPh3 )4 (50 mg,0.04 mmol), sodium carbonate (107 mg,1.01 mmol) dioxane (2 mL) and water (0.2 mL) were placed in a 20-mL sealed tube purged and maintained with an inert atmosphere of nitrogen. The resulting reaction mixture was stirred at 80℃for 1h. Filtering the reaction mixture andconcentrating under reduced pressure. The residue obtained was purified by column chromatography on silica eluting with EA/n-hexane (2/1 (v: v)). Thus 187mg (crude) of 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 are obtained as a yellow solid. LCMS: m/z=616 [ m+1 ]]+ 。
Step 8.4- (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-carboxylic acid tert-butyl ester
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-carboxylic acid tert-butyl ester (150 mg,0.24 mmol), acOH (4 mL), NCS (72 mg,0.54 mmol) were placed in a 50-mL round bottom flask purged and maintained with an inert atmosphere of nitrogen. The resulting mixture was stirred at room temperature for 2 days. The reaction was quenched with water (50 mL), the resulting solution was extracted with ethyl acetate (3X 50 mL), and the combined organic phases were washed with saturated brine (1X 50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. 150mg (90%) of 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 are thus obtained as a yellow solid. LCMS: m/z=684 [ m+1 ]]+ 。
Step 9.4- (4-Acrylpiperazin-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")
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-carboxylic acid tert-butyl ester (100 mg,0.15 mmol), DCM (10 mL), TFA (2 mL) were placed in a 20-mL round bottom flask which was purged and maintained with an inert atmosphere of nitrogen. The resulting mixture was stirred at room temperature for 2h. The reaction mixture was concentrated under reduced pressure. In a 25-mL round bottom flask, the resulting residue was dissolved with DCM (3 mL) and DIEA (82 mg,0.64 mmol) was added. The resulting reaction mixture was cooled to 0deg.C and acryloyl chloride (15 mg,0.15 mmol) was added dropwise . The resulting mixture was stirred at room temperature for 2h. The reaction was quenched with water (20 mL) and extracted with ethyl acetate (3X 50 mL). The organic phases were combined and washed with saturated brine (1X 50 mL) and dried over anhydrous Na2 SO4 Dried, filtered and concentrated under reduced pressure. The residue obtained was purified by Prep-HPLC (CH3 CN/H2 O=6/4 (v: v)) purification. 22mg (23% two-step yield) of 4- (4-propenylpiperazin-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) were thus obtained as a yellow solid. LCMS: m/z=638 [ m+1 ]]+ 。
1 HNMR(400MHz，CD3 OD)δ8.67(d，J＝5.7Hz，1H)，8.42(d，J＝9.1Hz，1H)，7.82(d，J＝5.7Hz，1H)，7.47(d，J＝7.4Hz，1H)，6.90(dd，J＝16.7，10.6Hz，1H)，6.34(d，J＝16.8Hz，1H)，5.87(d，J＝10.6Hz，1H)，4.30-3.85(m，8H)，3.13-2.96(m，1H)，2.28(s，3H)，1.32(d，J＝6.9Hz，3H)，1.15(d，J＝6.8Hz，3H)。
Example 2
4- (4-propenoyl-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 ("Compound 2")
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
7-chloro-6-fluoro-4-hydroxy-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile (389 mg,1.04 mmol), POCl3 (552 mg,3.60 mmol), DIEA (651 mg,5.04 mmol) and acetonitrile (15 mL) were placed in a 50-mL round-bottom flask purged with nitrogen and maintained in an inert atmosphere. The reaction mixture was stirred for 1h at 80 ℃. The reaction was cooled to room temperature and concentrated under reduced pressure. Crude 4, 7-dichloro-6-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo 1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile was dissolved in acetonitrile (15 mL), followed by DIEA (480 mg,3.71 mmol) and 2- (piperazin-2-yl) acetonitrile (169 mg,1.35 mmol). The resulting reaction mixture was stirred at room temperature for 0.5h. The resulting reaction mixture was cooled to 0deg.C and acryloyl chloride (120 mg,1.33 mmol) was added. The reaction was stirred for 1h. After the completion of the reaction, the reaction was quenched by addition of water (50 mL). The resulting solution was extracted with ethyl acetate (3X 50 mL), and the organic phases were combined and washed with saturated brine (50 mL), with anhydrous Na2 SO4 Dried, filtered and concentrated under reduced pressure. The residue obtained was purified by column chromatography on silica eluting with EA/n-hexane (2/1 (v: v)). This gave 0.55g (98% yield in two steps) of 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 as a pale yellow solid. LCMS: m/z=534 [ m+1 ]]+ 。
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
To a 8-mL flask was added 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 (232 mg,0.43 mmol), 2-fluoro-6-hydroxyphenylboronic acid (299 mg,1.92mmol,4.41 eq), pd (PPh) with a nitrogen atmosphere3 )4 (218mg，0.19mmol，0.43eq)、Na2 CO3 (308 mg,2.91mmol,6.69 eq), dioxane (5 mL), and water (2 mL). The resulting mixture was stirred at 90℃for 2.5h. The resulting reaction mixture was filtered and concentrated under reduced pressure. The residue obtained was purified by column chromatography on silica eluting with EA/n-hexane (7/3 (v: v)). 62mg (crude) of 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 were thus obtained as a yellow solid. LCMS: m/z=610 [ m+1 ]]+ 。
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 ("Compound 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 (62 mg,0.10 mmol), NCS (27 mg,0.20mmol,2.00 eq) and AcOH (4 mL) were placed in a 20-mL reaction bottle. The resulting reaction mixture was stirred at room temperature for 36h. The reaction was quenched by the addition of water (4 mL). The resulting solution was extracted with ethyl acetate (3X 10 ml), the organic layers were combined and concentrated in vacuo. The residue obtained was purified by Prep-HPLC (CH3 CN/H2 O=3/2 (v: v)) purification. 13mg of 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 were thus obtained as a yellow solid ("compound 2"). LCMS: m/z=678 [ m+1 ]]+ .
1 HNMR(400MHz，CD3 OD)δ8.83(s，1H)，8.43(d，J＝5.0Hz，1H)，7.54(d，J＝7.8Hz，1H)，7.29(t，J＝4.7Hz，1H)，6.91(s，1H)，6.36(d，J＝16.5Hz，1H)，5.90(d，J＝10.9Hz，1H)，4.28-3.94(m，4H)，3.80-3.40(m，3H)，3.08-2.96(m，1H)，2.91-2.77(m，1H)，2.71-2.54(m，1H)，2.15-2.90(m，3H)，1.19(dd，J＝16.1，6.7Hz，3H)，1.01(dd，J＝19.9，6.8Hz，3H)。
Example 3
4- ((s) -4-propenoyl-3- (cyanomethyl) piperazin-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 3")
Step 1.2-cyano-N- (2-isopropyl-4-methylpyridin-3-yl) acetamide.
2-cyanoacetic acid (3 g,35.27 mmol), DCM (40 mL) was placed in a 100-mL round bottom flask that was purged with nitrogen and maintained. Oxalyl chloride (6.2 g,48.85 mmol) was added dropwise. After completion of the dropwise addition, DMF (0.1 mL) was added. The resulting mixture was stirred at 25℃for 3h. The resulting reaction solution was concentrated under reduced pressure. This gives 3.10g (crude) of 2-cyanoacetyl chloride, which can be used directly.
2-isopropyl-4-methylpyridin-3-amine (2.00 g,13.31 mmol), TEA (5.40 g,53.36 mmol), DCM (40 mL) were added to a 100-mL round bottom flask purged with nitrogen and maintained with stirring. The resulting mixture was cooled to 0deg.C and then 2-cyanoacetyl chloride (3.10 g, trude) was added dropwise. The resulting solution was stirred at room temperature for 2h. The reaction was quenched by the addition of water (100 mL). The resulting mixed solution was extracted with dichloromethane (3X 50 mL), the organic phases were combined and washed with saturated brine (50 mL), and dried over anhydrous Na2 SO4 And (5) drying. The residue obtained by concentration under reduced pressure was applied to a silica gel column eluted with EA/n-hexane (v: v=3:2). Thus, 1.00g (34%) of 2-cyano-N- (2-isopropyl-4-methylpyridin-3-yl) acetamide was obtained as a yellow solid. LCMS: m/z=218 [ m+1 ]]+ 。
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), thionyl chloride (30 mL) was placed in a 100-mL round bottom flask purged with nitrogen and maintained under an inert atmosphere. The resulting mixture was heated to 80 ℃ and stirred for 2h. The resulting solution was concentrated under reduced pressure. This gives 5.10g (crude) of 2,5, 6-trichloronicotinoyl chloride, which is used directly in the next step.
2-cyano N- (2-isopropyl-4-methylpyridin-3-yl) acetamide (3.01 g,13.85 mmol) and tetrahydrofuran (40 mL) were placed in a 250-mL round bottom flask and the resulting mixture was stirred at 0 ℃. NaH (1.16 g,28.99 mmol) was added in three portions. The resulting mixture was stirred for a further 40min at 0 ℃. 2,5, 6-trichloronicotinoyl chloride (3.19 g,13.03 mmol) dissolved in tetrahydrofuran (10 mL) was then added dropwise. The resulting reaction mixture was stirred at 25℃for 2h. The resulting reaction mixture was concentrated under reduced pressure. The crude product obtained is further purified by the use of ACN/H2 Reversed phase C eluted by O (0% -30%)18 And (5) purifying by a column. Thus, 5.89g (crude) of 2-cyano-N- (2-isopropyl-4-methylpyridin-3-yl) -3-oxo-3- (2, 5, 6-trichloropyridin-3-yl) propionamide was obtained as a yellow solid. LCMS: m/z=425 [ m+1 ]]+ 。
Step 3.6,7-dichloro-4-hydroxy-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile (intermediate C).
2-cyano-N- (2-isopropyl-4-methylpyridin-3-yl) -3-oxo-3- (2, 5, 6-trichloropyridin-3-yl) propionamide (5.89 g,13.83 mmol) and tetrahydrofuran (70 mL) were placed in a 250-mL round bottom flask purged and maintained with an inert atmosphere of nitrogen and stirred at room temperature. NaH (2.73 g,68.25 mmol) was added. The resulting mixture was stirred at 50℃for 2h. The reaction was concentrated under reduced pressure. The residue was dissolved in 100mL of water and the pH was adjusted to 7 with AcOH. The resulting solid was filtered and dried under reduced pressure, whereby 5.85g (two-step yield 108%) of 6, 7-dichloro-4-hydroxy-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile was obtained as a yellow solid. LCMS: m/z=389 [ m+1 ]]+ 。
1 HNMR(400MHz，DMSO-d6 )68.77(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).
(s) -3- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester.
A solution of 1-benzyl-4- (tert-butyl) (S) -2- (cyanomethyl) piperazine-1, 4-carbonate (2.99 g,8.32 mmol) in tetrahydrofuran (40 mL) was treated with 10% Pd/C (1.03 g) with hydrogen at atmospheric pressure at room temperature for 2h. The catalyst was filtered and the filtrate was concentrated under reduced pressure. Thus, 2.3g of tert-butyl (S) -3- (cyanomethyl) piperazine-1-carboxylate was obtained as a colorless oil. LCMS: m/z=226 [ m+1 ] ]+ 。
(S) -2- (piperazin-2-yl) acetonitrile.
Tert-butyl (S) -3- (cyanomethyl) piperazine-1-carboxylate (2.3 g,10.21 mmol), HCl/dioxane (10 mL), dioxane (10 mL) was placed in a 100-mL round bottom flask that was purged and maintained with an inert atmosphere of nitrogen. The resulting reaction mixture was stirred at room temperature for 2h. The reaction mixture was concentrated under reduced pressure. Thus, 1.8g (crude) of (S) -2- (piperazin-2-yl) acetonitrile was obtained as a white solid. LCMS: m/z=126 [ m+1 ]]+ 。
1 HNMR(400MHz，DMSO-d6 )610.10(s，2H)，4.07-3.82(m，1H)，3.80-3.41(m，4H)，3.41-2.93(m，4H)。
(S) -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
6, 7-dichloro-4-hydroxy-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile (2.51 g,6.45 mmol), POCl3 (3.12 g,20.34 mmol), DIEA (3.21 g,24.84 mmol) and acetonitrile (30 mL) were placed in a 100-mL round-bottomed flask purged with nitrogen and maintained in an inert gas atmosphere. The resulting mixture was stirred at 80℃for 1h. The reaction was cooled to room temperature and concentrated under reduced pressure. 4,6, 7-trichloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile (2.63 g,6.45 mmol), acetonitrile (30 mL), DIEA (3.24 g,20.05 mmol) and (S) -2- (piperazin-2-yl) acetonitrile (1.272 g,7.87 mmol) were placed in a 100-mL round bottom flask purged and maintained with an inert atmosphere of nitrogen. The reaction mixture was stirred at room temperature for 0.5h. The reaction mixture was cooled to 0deg.C and acryloyl chloride (602 mg,6.65 mmol) was added. The reaction mixture was stirred for a further 0.5h at room temperature and concentrated under reduced pressure. The residue was purified by column chromatography on silica eluting with EA/n-hexane=3/2 (v: v). This gave 1.45g (three-step yield 41%) of (S) -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 as a pale yellow solid. LCMS: m/z=550 [ m+1 ] ]+ 。
1 HNMR(400MHz，CD3 OD)δ8.50(d，J＝3.9Hz，2H)，7.37-7.24(m，1H)，6.87(s，1H)，6.33(d，J＝16.6Hz，1H)，5.87(d，J＝10.8Hz，1H)，4.43-3.89(m，5H)，3.77-3.36(m，2H)，3.13(s，1H)，3.02-2.89(m，1H)，2.85-2.47(m，1H)，2.08-1.92(m，3H)，1.20-0.98(m，6H)。
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
(S) -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 (204 mg,0.37 mmol), 3-fluoro-2- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenol (83 mg,0.53 mmol), pd (dppf) Cl2 (58 mg,0.08 mmol), sodium carbonate (140 mg,1.32 mmol), dioxane (5 mL) and water (1 mL) 25-mL were added to the round bottom flask. The resulting mixture was stirred at 80℃for 1h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by using CH3 CN/H2 O(0.05％NH4 HCO3 ) Prep-HPLC purification with 3/2 (v: v) elution. Thus, 32mg (41%) of 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 was obtained as a yellow solid. LCMS: m/z=626 [ m+1 ]]。
1 HNMR(400MHz，DMSO-d6 )δ10.15(d，J＝10.1Hz，1H)，8.52(s，1H)，8.41(d，J＝4.7Hz，1H)，7.29-7.15(m，2H)，6.94(s，1H)，6.80-6.54(m，2H)，6.24(d，J＝16.5Hz，1H)，5.82(d，J＝10.6Hz，1H)，5.31-4.44(m，2H)，4.32-3.83(m，4H)，3.68-3.37(m，2H)，3.08-2.88(m，1H)，2.84-2.63(m，1H)，1.98-1.78(m，3H)，1.23-0.99(m，3H)，0.97-0.75(m，3H).
Step 8.4- ((s) -4-propenoyl-3- (cyanomethyl) piperazin-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 3")
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 (124 mg,0.20 mmol), NCS (48 mg,0.36 mmol), glacial acetic acid (5 mL) was placed in a 25-mL round bottom flask. The reaction mixture was stirred at room temperature for 2 days. The reaction mixture was filtered and concentrated under reduced pressure. Residue passing Prep-HPLCCH3 CN/H2 O(0.05％NH4 HCO3 ) =2/1 purification. Thus, 8mg (6%) of 4- ((S) -4-propenoyl-3- (cyanomethyl) piperazin-1-yl) -6-chloro-7- (3, 5-dichloro) were obtained-2-fluoro-6-hydroxyphenyl) -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=694 [ m+1 ]]+ 。
1 HNMR(400MHz，CD3 OD)δ8.55(s，1H)，8.43(d，J＝4.8Hz，1H)，7.51(s，1H)，7.27(s，1H)，6.94(s，1H)，6.36(d，J＝16.4Hz，1H)，5.90(d，J＝10.5Hz，1H)，5.39-5.11(m，1H)，4.36-3.86(m，4H)，3.82-3.37(m，2H)，3.10-2.75(m，2H)，2.74-2.45(m，1H)，2.14-1.90(m，3H)，1.26-1.12(m，3H)，1.09-0.84(m，3H).
Example 4
4- ((S) -4-propenoyl-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 ("Compound 4")
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.
(S) -4- (4-propenoyl-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 (101 mg,0.36 mmol), 3-fluoro-2- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline (149 mg,1.01 mmol), tetrakis triphenylphosphine palladium (69 mg,0.12 mmol), sodium carbonate (92 mg,1.36 mmol), dioxane (8 mL) and water (2 mL) were placed in a 50-mL sealed tube purged and maintained with nitrogen inert atmosphere. The reaction mixture was stirred at 80℃for 4h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by using ACN/H2 O (0.5%) hcl=7/3 eluted C18 column purification. 29mg (13%) of 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 are thus obtained as yellowColor solids. LCMS: m/z=625 [ m+1 ]]+ 。
1 HNMR(400MHz，CD3 OD)δ8.60(dd，J＝10.0，5.6Hz，2H)，7.75-7.65(m，1H)，7.18-6.84(m，2H)，6.52(d，J＝8.3Hz，1H)，6.43-6.32(m，2H)，5.91(d，J＝10.7Hz，1H)，5.44-5.16(m，1H)，4.40-3.95(m，5H)，3.64(s，2H)，3.15-2.90(m，2H)，2.40-2.10(m，3H)，1.45-1.00(m，6H).
Step 2.4- ((S) -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 ("compound 4").
4- ((S) -4-propenoyl-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 (157 mg,0.25 mmol), NCS (65 mg,0.49 mmol) and glacial acetic acid (6 mL) were placed in a 50-mL round bottom flask which was purged and maintained with an inert atmosphere of nitrogen. The resulting mixture was stirred at room temperature for 48h. The reaction was quenched with water (100 mL), the resulting solution was extracted with ethyl acetate (2X 100 mL), the organic phases were combined and washed with saturated brine (10 mL), and dried over anhydrous Na2 SO4 Dried, filtered and concentrated under reduced pressure. The residue was purified by Prep-HPLC (ACN/H2 O(0.5％)NH4 HCO3 =7/3 (v: v)) purification. Thus, 22mg (13% two-step yield) of 4- ((S) -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 ("compound 4") was obtained as a yellow solid. LCMS: m/z=693 [ m+1 ] ]+ 。1 HNMR(400MHz，CD3 OD)68.64-8.56(m，1H)，8.45(t，J＝4.9Hz，1H)，7.46-7.25(m，2H)，6.91(s，1H)，6.37(d，J＝16.8Hz，1H)，5.86(d，J＝10.7Hz，1H)，5.48-5.08(m，2H)，4.35-3.95(m，4H)，3.61(s，1H)，3.10-2.50(m，3H)，2.16-1.88(m，3H)，1.23-1.13(m，3H)，1.12-0.93(m，3H).
Example 5
4- ((S) -4-acryloyl-2-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 5")
Step 1. Tert-butyl (S) -4- (6, 7-dichloro-3-cyano-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridin-4-yl) -3-methylpiperazine-1-carboxylate
6, 7-dichloro-4-hydroxy-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile (3.68 g,9.46 mmol), phosphorus oxychloride (4.52 g,29.50 mmol), DIEA (5.21 g,40.29 mmol) and acetonitrile (40 mL) were placed in a 100-mL round bottom flask purged and maintained with an inert atmosphere of nitrogen. The mixture was stirred at 80℃for 0.5h. The reaction was cooled to room temperature and concentrated under reduced pressure. 4,6, 7-trichloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile (3.84 g,9.46 mmol), acetonitrile (30 mL), DIEA (5.29 g,40.93 mmol) and tert-butyl (S) -3-methylpiperazine-1-carboxylate (2.034 g,10.17 mmol) were placed in a 100-mL round bottom flask purged and maintained with an inert atmosphere of nitrogen. The reaction mixture was stirred at room temperature for 0.5h. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica eluting with EA/n-hexane=3/2 (v: v). Thus, 2.24g (two-step yield 41%) of (S) -4- (6, 7-dichloro-3-cyano-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridin-4-yl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester was obtained as a pale yellow solid. LCMS: m/z=571 [ m+1 ] ]+ 。
(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
(S) -4- (6, 7-dichloro-3-cyano-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridin-4-yl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (2.24 g,3.92 mmol), trifluoroacetic acid (3 mL) and dichloromethane (15 mL) were placed in a 100-mL round bottom flask that was purged and maintained with an inert atmosphere of nitrogen. The reaction mixture was stirred at room temperature for 1h. The reaction was concentrated under reduced pressure.
(S) -6, 7-dichloro-1- (2-isopropyl-4-methylpyridin-3-yl) -4- (2-methylpiperazin-1-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile (1.84 g,3.92 mmol), dichloromethane (20 mL), DIEA (1.872 g,14.48 mmol) and acryloyl chloride (0.442 g,4.88 mmol) were placed in a 100-mL round bottom flask purged and maintained with nitrogen inert atmosphere. The reaction mixture was stirred at room temperature for 0.5h. By H2 O (100 mL) was quenched, extracted three times with dichloromethane (100 mL), washed with saturated brine (100 mL), and dried over Na2 SO4 Dried and concentrated under reduced pressure. The residue was purified by column chromatography on silica eluting with EA/n-hexane=3/2 (v: v). This gave 1.87g (two-step yield 91%) of (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 as a pale yellow solid. LCMS: m/z=525 [ m+1 ] ]+ 。
1 HNMR(400MHz，CD3 OD)δ8.50(d，J＝5.0Hz，1H)，8.44(s，1H)，7.34-7.28(m，1H)，6.94-6.76(m，1H)，6.32(d，J＝17.2Hz，1H)，5.87-5.79(m，1H)，4.51-4.37(m，2H)，4.01-3.75(m，1H)，3.60(d，J＝12.4Hz，2H)，2.86-2.72(m，1H)，2.72-2.62(m，1H)，2.62-2.47(m，1H)，2.02(d，J＝9.4Hz，3H)，1.21-1.15(m，3H)，1.15-1.07(m，3H)，1.04-1.02(m，3H)。
Step 3.4- ((s) -4-acryloyl-2-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
25-mL (S) -4- (4-propenoyl-2-methylpiperazin-1-yl) -6, 7-dichloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile (0.305 g,0.78 mmol), 3-fluoro-2- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline (0.524 g,2.21 mmol), tetrakis triphenylphosphine palladium (0.105 g,0.09 mmol), sodium carbonate (0.325 g,3.07 mmol), dioxane (8 mL) and water (1 mL) were placed in a 20-mL round bottom flask purged and maintained with a nitrogen inert atmosphere. The reaction mixture was stirred at 80℃for 1h. By H2 O (50 mL) quenched the reaction mixture and extracted with dichloromethane (50 mL)) Three times, washed with saturated saline (50 mL), anhydrous Na2 SO4 Dried and concentrated under reduced pressure. The residue was purified by column chromatography on silica eluting with EA/n-hexane=3/2 (v: v). This gives 269mg (57%) of 4- ((S) -4-acryloyl-2-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 as a yellow solid. LCMS: m/z=600 [ m+1 ] ]+ 。
Step 4.4- ((S) -4-propenoyl-2-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 5")
4- ((S) -4-acryloyl-2-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 (182 mg,0.30 mmol), NCS (89 mg,0.67 mmol), HOAc (5 mL) was placed in a 25-mL round bottom flask. The reaction mixture was stirred at room temperature for 2 days. The reaction was quenched with water (50 mL), extracted three times with dichloromethane (50 mL), washed with 50mL of saturated sodium bicarbonate (50 mL) and saturated brine (50 mL), and concentrated by anhydrous Na2 SO4 Dried and concentrated under reduced pressure. The residue was purified by Prep-HPLC (CH3 CN/H2 O(0.05％NH4 HCO3 ) =2/1 purification. Thus, 8mg (6%) of 4- ((S) -4-acryloyl-2-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 were obtained as a yellow solid ("compound 5"). LCMS: m/z=668 [ m+1 ]]+ 。
1 HNMR(400MHz，CD3 OD)δ8.75-8.25(m，2H)，7.58-7.14(m，2H)，7.05-6.70(m，1H)，6.36(d，J＝15.7Hz，1H)，5.90(d，J＝10.5Hz，1H)，4.73-3.95(m，5H)，3.85-3.50(m，2H)，2.95-2.50(m，1H)，2.25-1.80(m，3H)，1.50-0.70(m，9H)。
Example 6
4- ((3S, 5R) -4-propenoyl-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 ("Compound 6")
(P) -4- ((3S, 5R) -4-propenoyl-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
(M) -4- ((3S, 5R) -4-propenoyl-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
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) was placed in a 1000-mL round bottom flask, purged with nitrogen and maintained in an inert atmosphere. The mixture was heated to 80 ℃ and stirred for 3h. The solution was concentrated under reduced pressure. Thus, 100.97 (93.68% yield) of 2,5, 6-trichloronicotinoyl chloride was obtained, which was directly used in the next step.
2-cyano-N- (2-isopropyl-4-methylpyridin-3-yl) acetamide (15.08 g,69.40 mmol) and tetrahydrofuran (150 mL) were placed in a 500-mL round bottom flask and the mixture was stirred at 0 ℃. NaH (6.05 g,151.25 mmol) was added in three portions. The mixture was stirred for a further 1h at 0 ℃.2, 5, 6-trichloronicotinoyl chloride (15.43 g,63.01 mmol) dissolved in THF (50 mL) was then added dropwise. The reaction mixture was stirred at 0℃for 2h. The reaction mixture was concentrated under reduced pressure. The resulting crude product was poured into 5% aqueous acetic acid (200 mL) and stirred for 30min. The resulting solid was filtered and dried in vacuo, thereby affording 21.98g (74%) of 2-cyano-N- (2-isopropyl-4-methylpyridin-3-yl) -3-oxo-3- (2, 5, 6-trichloropyridin-3-yl) propionamide as a yellow solid. LCMS: m/z=425 [ m+1 ] ]+ 。
Step 2.6,7-dichloro-4-hydroxy-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile
2-cyano-N- (2-isopropyl-4-methylpyridin-3-yl) -3-oxo-3- (2, 5, 6-trichloropyridin-3-yl) propionamide (20.08 g,47.17 mmol) acetonitrile (200 mL) was placed in a 500-mL round bottom flask purged and maintained with an inert atmosphere of nitrogen and stirred at room temperature. Cesium carbonate (72.32 g,221.96 mmol) was added. The mixture was stirred at 50℃for 1h. The reaction was filtered and the mother liquor was concentrated in vacuo. The residue was dissolved in 100mL of water and the pH was adjusted to 6 with AcOH. The resulting solid was filtered and dried in vacuo, thereby affording 15g (82% yield) 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 ]]+ 。
Step 3.4- ((3R, 5S) -4-propenoyl-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
500-mL eggplant-shaped bottle, maintaining nitrogen atmosphere 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), phosphorus oxychloride (6.88 g,48.87 mmol), DIEA (6.80 g,52.61 mmol) and acetonitrile (100 mL) were placed in a 500-mL round bottom flask purged and maintained with nitrogen atmosphere. The mixture was stirred at 80℃for 2h. The reaction was cooled to room temperature and concentrated in vacuo. This gives 4,6, 7-trichloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile, which is used directly in the next step.
Another 500-mL eggplant-shaped bottle was taken and kept under nitrogen atmosphere to add 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), acetonitrile (100 mL), (2S, 6R) -2, 6-dimethylpiperazine (2.17 g,19.00 mmol) to a 500-mL round bottom flask purged and kept under nitrogen atmosphere. The mixture was stirred at room temperature for 1h. LCMS monitored the end of the reaction. Acryloyl chloride (2.61 g,28.83 mmol) was added to the reaction solution. The mixture was stirred at room temperature for 1h. The resulting solution was concentrated in vacuo and applied to a silica gel column eluting with EA/n-hexane. 4.30g (50% yield) of 4- ((3R, 5S) -4-propenoyl-3, 5-dimethylpiperazin-1-yl) -6 are thus obtained,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 ]]+ 。
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
4- ((3S, 5R) -4-propenoyl-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 (289 mg,0.54 mmol), 3-fluoro-2- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline (281mg, 1.19mmol,2.2 leq), pd (dppf) Cl2 (73 mg, 99.77. Mu. Mol,0.19 eq), sodium carbonate (193 mg,1.82mmol,3.40 eq), dioxane (4 mL) and water (1 mL) were placed in an 8-mL sealed tube purged and maintained with a nitrogen inert atmosphere. The reaction mixture was stirred at 80℃for 1.5h. The reaction mixture was filtered and concentrated under vacuum. The residue was purified by column chromatography on silica eluting with EA/n-hexane (7/3 (v: v)). 282mg (crude) of 4- ((3S, 5R) -4-propenoyl-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 are thus obtained as a yellow solid. LCMS: m/z=614 [ m+1 ]]+ 。
Step 5.4- ((3S, 5R) -4-propenoyl-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 ("Compound 6")
4- ((3S, 5R) -4-propenoyl-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 (282 mg,0.46 mmol), NCS (125 mg,0.94 mmol) and AcOH (20 mL) were placed in a 500-mL reaction bottle. The reaction mixture was stirred at room temperature for 48h. The reaction mixture was warmed to 50 ℃ and stirred for 3h. The reaction mixture was quenched with water (40 mL). The resulting solution was extracted with ethyl acetate (3X 30 mL), the organic phases were combined and concentrated in vacuo. The residue was purified by Prep-HPLC (CH3 CN/H2 O=3/2 (v: v)) purification. This gave 31mg (9.88%) of 4- ((3 s,5 r) -4-propenoyl-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 ("compound 6") as a yellow solid. LCMS: m/z=682 [ m+1 ]]+ 。
1 HNMR(400MHz，CD3 OD)δ8.83(s，1H)，8.43(d，J＝5.0Hz，1H)，7.39(dd，J＝7.5，2.3Hz，1H)，7.27(d，J＝4.9Hz，1H)，6.88(dd，J＝16.7，10.7Hz，1H)，6.32(dd，J＝16.7，2.0Hz，1H)，5.83(dd，J＝10.6，1.9Hz，1H)，4.78(s，2H)，4.06-3.92(m，2H)，3.90-3.74(m，2H)，2.70-2.63(m，1H)，2.10-1.92(m，3H)，1.66(t，J＝6.1Hz，6H)，1.22-1.11(m，3H)，1.06(d，J＝6.8Hz，1H)，0.96(d，J＝6.8Hz，2H).
A mixture of 4- ((3 r,5 s) -4-propenoyl-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 (150 mg, "compound 6") was purified by Chiral-Prep-HPLC according to the following conditions: columns, chiralpakIBN,0.46cmI.D.×15cmL; mobile phase: meOH (with 100% MeOH for 6 min); detection wavelength: UV 254nm. 61mg (41%) of 4- ((3R, 5S) -4-propenoyl-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 (first eluate, "compound 6A", M or P atropisomer) are isolated as a yellow solid;
1 HNMR(400MHz，CD3 OD)δ8.73(s，1H)，8.33(d，J＝5.0Hz，1H)，7.29(dd，J＝7.4，2.8Hz，1H)，7.19-7.14(m，1H)，6.88-6.72(m，1H)，6.23(d，J＝16.6Hz，1H)，5.74(d，J＝10.7Hz，1H)，4.67(s，2H)，3.96-3.84(m，2H)，3.81-3.67(m，2H)，2.73-2.52(m，1H)，2.01-1.83(m，3H)，1.56(t，J＝5.9Hz，6H)，1.07(dd，J＝10.1，6.9Hz，3H)，0.89-0.76(m，3H)；
and 47mg (31%) of 4- ((3 r,5 s) -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 (second eluate, "compound 6B", P or M atropisomer) as a yellow solid;
1 HNMR(400MHz，CD3 OD)δ8.73(s，1H)，8.34(d，J＝5.0Hz，1H)，7.29(dd，J＝7.5，2.6Hz，1H)，7.17(d，J＝5.0Hz，1H)，6.89-6.72(m，1H)，6.23(d，J＝16.6Hz，1H)，5.74(d，J＝10.6Hz，1H)，4.67(s，2H)，3.98-3.85(m，2H)，3.78-3.65(m，2H)，2.71-2.53(m，1H)，2.02-1.82(m，3H)，1.56(t，J＝5.8Hz，6H)，1.12-1.01(m，3H)，1.00-0.83(m，3H).
Example 7
4- ((3S, 5R) -4-propenoyl-3, 5-dimethylpiperazin-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 7")
Step 4- ((3S, 5R) -4-propenoyl-3, 5-dimethylpiperazin-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
4- ((3S, 5R) -4-propenoyl-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 (150 mg,0.28 mmol), 3-fluoro-2- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenol (83 mg,0.53 mmol), pd (dppf) Cl2 (22 mg,0.03 mmol), sodium carbonate (152 mg,1.55 mmol), dioxane (5 mL), and water (1 mL) were placed in a 25-mL round bottom flask. The reaction mixture was stirred at 80℃for 1h. The reaction mixture was quenched with water (50 mL), extracted three times with DCM (50 mL), washed with saturated brine (50 mL), and dried over Na2 SO4 Dried and concentrated under vacuum. Purification of the residue CH by Prep-HPLC3 CN/H2 O(0.05％NH4 HCO3 )＝3/2(v∶v). Thus, 47mg (26%) of 4- ((3 s,5 r) -4-propenoyl-3, 5-dimethylpiperazin-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 were obtained as a yellow solid. LCMS: m/z=615 [ m+1 ] ]+ 。
1 HNMR(400MHz，CD3 OD)δ8.82(s，1H)，8.66(d，J＝5.4Hz，1H)，7.87(s，1H)，7.25(d，J＝7.2Hz，1H)，6.97-6.83(m，1H)，6.75-6.53(m，2H)，6.35(d，J＝16.6Hz，1H)，5.86(d，J＝10.7Hz，1H)，4.79(s，2H)，4.05(d，J＝13.0Hz，2H)，3.89(s，2H)，3.20-3.05(m，1H)，2.30(s，3H)，1.67(d，J＝6.0Hz，6H)，1.34(d，J＝6.6Hz，3H)，1.19(d，J＝6.4Hz，3H)。
Step 2.4- ((3S, 5R) -4-propenoyl-3, 5-dimethylpiperazin-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 7")
4- ((3S, 5R) -4-propenoyl-3, 5-dimethylpiperazin-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 (356 mg,0.35 mmol), NCS (104 mg,0.78 mmol), HOAc (5 mL) was placed in a 25-mL round bottom flask. The reaction mixture was stirred at room temperature for 2 days. By H2 The reaction mixture was quenched with O (50 mL), extracted three times with DCM (50 mL), saturated NaHCO3 Aqueous solution (50 mL) and saturated brine (50 mL), anhydrous Na2 SO4 And (5) drying. The reaction mixture was filtered and concentrated under vacuum. The residue was purified by Prep-HPLC CH3 CN/H2 O(0.05％NH4 HCO3 ) =1/1 (v: v) purification. Thus, 70mg (28%) of 4- ((3 s,5 r) -4-propenoyl-3, 5-dimethylpiperazin-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 7") were obtained as a yellow solid. LCMS: m/z=683 [ m+1 ]]+ 。
1 HNMR(400MHz，CD3 OD)δ8.81(s，1H)，8.43(d，J＝5.1Hz，1H)，7.54(d，J＝7.7Hz，1H)，7.30(s，1H)，6.89(dd，J＝16.7，10.6Hz，1H)，6.32(dd，J＝16.7，1.9Hz，1H)，5.83(dd，J＝10.6，1.8Hz，1H)，4.77(s，2H)，4.07-3.93(m，2H)，3.91-3.75(m，2H)，2.83-2.67(m，1H)，2.04(s，3H)，1.71-1.59(m，6H)，1.18(d，J＝6.8Hz，3H)，1.01(d，J＝6.8Hz，3H)。
Example 8
4- ((R) -4-propenoyl-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")
(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-carboxylic acid tert-butyl ester
6, 7-dichloro-4-hydroxy-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile (1.05 g,2.71 mmol), phosphorus oxychloride (2.04 g,13.27 mmol), DIEA (3.09 g,23.93 mmol) and acetonitrile (20 mL) were placed in a 50-mL round bottom flask purged and maintained with an inert atmosphere of nitrogen. The mixture was stirred at 80℃for 2h. The reaction was cooled to room temperature and concentrated in vacuo. This gives 4,6, 7-trichloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile, which is used directly in the next step.
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) were placed in a 100-mL round bottom flask purged and maintained with an inert atmosphere of nitrogen. DIEA (3.09 g,23.93 mmol) and (R) -2-methylpiperazine-1-carboxylic acid tert-butyl ester (507 mg,2.53 mmol) were added. The reaction mixture was stirred at room temperature for 2h. The reaction was then quenched by the addition of water (50 mL). Extracted with ethyl acetate (3X 50 mL), the organic phases were combined and washed with saturated brine (50 mL), dried over anhydrous Na2 SO4 Dried, filtered and concentrated under vacuum. The residue was purified by eluting with EA/n-hexane (V/v=5/4)Purification on a silica gel column gave 0.95g (two-step yield 65%) of (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-carboxylic acid tert-butyl ester as a red solid. LCMS: m/z=571 [ m+1 ]]+ 。
1 HNMR(400MHz，CD3 OD)δ8.55-8.45(m，2H)，7.38-7.28(m，1H)，4.48(s，1H)，4.20-4.08(m，2H)，3.99-3.81(m，2H)，3.74-3.51(m，2H)，2.78-2.50(m，1H)，2.10-1.98(m，3H)，1.59-1.44(m，9H)，1.34(dd，J＝14.7，7.2Hz，3H)，1.22-1.01(m，6H)。
(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
(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-carboxylic acid tert-butyl ester (2.58 g,4.51 mmol), DCM (60 mL), trifluoroacetic acid (23.10 g,202.59 mmol) were placed in a 250mL round bottom flask. The reaction was allowed to react for 1h at room temperature. The reaction mixture was concentrated under vacuum. The residue was dissolved in DCM (40 mL) and triethylamine (2.91 g,28.78 mmol) and acryloyl chloride (0.640 g,7.12 mmol) were added at room temperature and the reaction was allowed to react at room temperature for 30min. The reaction mixture was concentrated under vacuum and applied to a silica gel column eluting with EA/Hex (V/v=0% -45%). The eluate was collected and concentrated under vacuum. Thus, 6, 7-dichloro-1- (2-isopropyl-4-methyl-3-pyridinyl) -4- [ (3R) -3-methyl-4-prop-2-enoyl-piperazin-1-yl was obtained (1.69 g,3.22mmol, 71.29%) ]-2-oxo-1, 8-naphthyridine-3-carbonitrile as a yellow solid. LCMS: m/z=525 [ m+1 ]]+ 。
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
(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 (401 mg,0.76 mmol), (2-fluoro-6-hydroxyphenyl)Boric acid (618 mg,3.64 mmol), palladium tetraphenylphosphine (123 mg,0.11 mmol), sodium carbonate (320 mg,3.02 mmol), dioxane (5 mL) and water (2 mL) were placed in an 8-mL sealed tube purged and maintained with an inert atmosphere of nitrogen. The reaction mixture was stirred at 80℃for 1.5h. The reaction mixture was filtered and concentrated under vacuum. The residue was purified by column chromatography on silica eluting with EA/n-hexane (7/3 (v: v)). Thus, 213mg (crude) of 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 were obtained as a yellow solid. LCMS: m/z=601 [ m+1 ]]+ 。
Step 4.4- ((R) -4-propenoyl-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")
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 (147 mg,0.24 mmol), NCS (77 mg,0.58 mmol) and AcOH (4 mL) were placed in a 25-mL round bottom flask. The reaction mixture was stirred at room temperature for 1h. The temperature was raised to 50 ℃ and the mixture was stirred for an additional 3h. The reaction mixture was quenched by the addition of water (20 mL). The resulting solution was extracted with ethyl acetate (3×20 mL), the organic phases were combined and concentrated in vacuo. The residue was purified by Prep-HPLC (CH3 CN/H2 O=3/2 (v: v)) purification. This gave 12mg of 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") as a yellow solid. LCMS: m/z=669 [ m+1 ]]+ 。
Example 9
4- ((R) -4-propenoyl-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")
(P) -4- ((R) -4-propenoyl-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
(M) -4- ((R) -4-propenoyl-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
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.
(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 (403 mg,0.77 mmol), (2-amino-6-fluorophenyl) boronic acid (569 mg,2.40 mmol), palladium tetraphenylphosphine (260 mg,0.23 mmol), sodium carbonate (438 mg,4.13 mmol), dioxane (8 mL) and water (2 mL) were placed in a 25-mL sealed tube purged and maintained with a nitrogen inert atmosphere. The reaction mixture was stirred at 80℃for 4h. The reaction mixture was filtered and concentrated under vacuum. The residue was purified by Prep-HPLC (CH3 CN/H2 O=4/6 (v: v)) purification. Thus, 50mg (11%) of 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 were obtained as a yellow solid. LCMS: m/z=600 [ m+1 ] ]+ 。
1 HNMR(400MHz，CD3 OD)δ8.62-8.52(m，1H)，8.45(dd，J＝12.2，5.0Hz，1H)，7.36-7.22(m，1H)，7.17-7.06(m，1H)，6.87(dd，J＝16.8，10.7Hz，1H)，6.57-6.47(m，1H)，6.43-6.26(m，2H)，5.85(d，J＝10.7Hz，1H)，4.76-3.82(m，6H)，3.66(s，1H)，2.90-2.55(m，1H)，2.20-1.85(m，3H)，1.53-1.41(m，3H)，1.23-1.12(m，3H)，1.10-0.88(m，3H)。
Step 2.4- ((R) -4-propenoyl-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")
4- ((R) -4-propenoyl-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 (255 mg,0.42 mmol), NCS (125 mg,0.84 mmol), and AcOH (4 mL) were placed in a 50-mL round bottom flask purged and maintained with an inert atmosphere of nitrogen. The mixture was stirred at room temperature for 2 days. The reaction was then quenched with water (50 mL) and extracted with ethyl acetate (3X 50 mL). The organic phases were combined and washed with saturated brine (50 mL) and dried over anhydrous Na2 SO4 Dried, filtered and concentrated under vacuum. The residue was purified by Prep-HPLC (CH3 CN/H2 O=6/4 (v: v)). Thus, 60mg (21%) of 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 were obtained as a yellow solid ("compound 9"). LCMS: m/z=668 [ m+i ]]+ 。
1 HNMR(400MHz，CD3 OD)δ8.63-8.53(m，1H)，8.49-8.41(m，1H)，7.43-7.37(m，1H)，7.32-7.24(m，1H)，6.86(dd，J＝16.7，10.6Hz，1H)，6.30(dd，J＝16.7，1.7Hz，1H)，5.84(dd，J＝10.6，1.7Hz，1H)，4.50-4.16(m，2H)，4.14-3.84(m，3H)，3.79-3.50(m，2H)，2.90-2.50(m，1H)，2.19-1.89(m，3H)，1.55-1.35(m，3H)，1.25-1.13(m，3H)，1.12-0.92(m，3H)。
The atropisomer mixture of 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 (600 mg, "compound 9") was purified by Chiral-Prep-HPLC using the following conditions: columns, chiralpakIBN,0.46cmI.D.×15cmL; mobile phase, n-hexane/etoh=50/50 (V/V); detection wavelength, UV254nm. Thus 262mg (43.7%) of 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 (first eluate, compound 9A ", M or P atropisomer) were obtained as a yellow solid;
1 HNMR(400MHz，CD3 OD)δ8.46(d，J＝5.7Hz，1H)，8.39-8.26(m，1H)，7.33-7.22(m，1H)，7.24-7.15(m，1H)，6.88-6.66(m，1H)，6.20(d，J＝16.7Hz，1H)，5.73(dd，J＝10.7，1.8Hz，1H)，4.16(d，J＝12.6Hz，2H)，4.05-3.70(m，3H)，3.69-3.30(m，2H)，2.75-2.63(m，1H)，1.96-1.83(m，3H)，1.38-1.25(m，3H)，1.12-0.85(m，6H)；
And 272mg (45.3%) of 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 (second eluent, "compound 9B", P or M atropisomers) as a yellow solid.
1 HNMR(400MHz，CD3 OD)δ8.47(s，1H)，8.35-8.28(m，1H)，7.33-7.22(m，1H)，7.19-7.10(m，1H)，6.88-6.66(m，1H)，6.20(d，J＝16.7，1.8Hz，1H)，5.73(dd，J＝10.6，1.8Hz，1H)，4.14(d，J＝13.2Hz，2H)，4.00-3.76(m，3H)，3.69-3.30(m，2H)，2.64-2.40(m，1H)，2.02-1.88(m，3H)，1.40-1.31(m，3H)，1.05(dd，J＝10.8，6.8Hz，3H)，0.96-0.83(m，3H)。
Example 10
7- (2-amino-3, 5-dichloro-6-fluorophenyl) -4- (4- (2-butynyl) piperazin-1-yl) -6-chloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile ("Compound 10")
Step 1.4- (7- (2-amino-6-fluorophenyl) -6-chloro-3-cyano-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridin-4-yl) piperazine-1-carboxylic acid tert-butyl ester
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-carboxylic acid tert-butyl ester (183.00 g,328.27 mmol), 3-fluoro-2- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) aniline (235.77 g,994.48 mmol), pdCl2 (dppf)2 (25.14 g,34.36 mmol), sodium carbonate (105.32 g,993.69 mmol), water (900 mL), 1, 4-dioxane (3600 mL) were placed in a 10L three-necked round bottom flask purged and maintained with an inert atmosphere of nitrogen. The reaction was stirred at 89℃for 12 hours. The reaction was filtered and concentrated in vacuo. The residue was applied to a silica gel column eluting with n-hexane/ethyl acetate (V/v=20% -60%). The eluate was collected and concentrated under vacuum. The crude product was slurried with n-hexane/ethyl acetate (V/v=10/1) and the mixture was filtered. Thus, 4- [7- (2-amino-6-fluoro-benzene y 1) -6-chloro-3-cyano-1- (2-isopropyl-4-methyl-3-pyridinyl) -2-oxo-1, 8-naphthyridin-4-yl (154.39 g,244.24mmol, yield 74.40%) was obtained ]Piperazine-1-carboxylic acid tert-butyl ester as yellow solid.
Step 2.4- (7- (2-amino-3, 5-dichloro-6-fluorophenyl) -6-chloro-3-cyano-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridin-4-yl) piperazine-1-carboxylic acid tert-butyl ester
4- [7- (2-amino-6-fluoro-phenyl) -6-chloro-3-cyano-1- (2-isopropyl-4-methyl-3-pyridine) -2-oxo-1, 8-naphthyridin-4-yl ] piperazine-1-carboxylic acid tert-butyl ester (0.933 g,1.48 mmol), NCS (0.457 g,3.38 mmol), acetic acid (20 mL) were added to a 100mL three-necked flask, the reaction was allowed to react at 25℃for 12 hours, and then the reaction was heated to 50℃for 2.5 hours. The reaction was quenched with saturated sodium carbonate (aqueous solution) (150 mL), extracted with ethyl acetate (80 mL. Times.3), and the organic phase was collected, washed with water (100 mL) and saturated brine (100 mL), and dried over anhydrous sodium sulfate. The reaction was concentrated in vacuo. Thus, 4- [7- (2-amino-3, 5-dichloro-6-fluoro-benzene y 1) -6-chloro-3-cyano-1- (2-isopropyl-4-methyl-3-pyridine) -2-oxo-1, 8-naphthyridin-4-yl ] piperazine-1-carboxylic acid tert-butyl ester (0.98 g,1.40mmol, yield 94.62%) was obtained as a yellow solid.
Step 3.7- (2-amino-3, 5-dichloro-6-fluorophenyl) -4- (4- (2-butynyl) piperazin-1-yl) -6-chloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile ("compound 10").
4- (7- (2-amino-3, 5-dichloro-6-fluorophenyl) -6-chloro-3-cyano-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2Di-hydro-1, 8-naphthyridin-4-yl) piperazine-1-carboxylic acid tert-butyl ester (271mg, 0.39 mmol), trifluoroacetic acid (0.5 mL), dichloromethane (2 mL) were placed in a 50-mL round bottom flask purged and maintained under an inert atmosphere of nitrogen. The reaction mixture was stirred at room temperature for 0.5 hours. The reaction mixture was concentrated under vacuum. The residue was dissolved with MeCN (3 mL) followed by DIEA (3.0 mL,21.58 mmol), HATU (178 mg,0.47 mmol), 2-butynoic acid (33 mg,0.39 mmol). The reaction was stirred at room temperature for 0.5 hours. The reaction was quenched by the addition of water (30 mL). Extracted with ethyl acetate (3X 20 mL), the combined organic phases were washed with saturated brine (30 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by Prep-HPLC (acetonitrile/water=0% -60%). 64mg (yield 25%) of 7- (2-amino-3, 5-dichloro-6-fluorophenyl) -4- (4- (2-butynyl) piperazin-1-yl) -6-chloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile were thus obtained as a yellow solid. LCMS: m/z=666 [ m+1 ]]+ 。
1 HNMR(400MHz，Methanol-d4 )68.53(d，J＝2.2Hz，1H)，8.43(d，J＝5.0Hz，1H)，7.38(dd，J＝7.5，2.5Hz，1H)，7.29-7.23(m，1H)，4.19-4.09(m，2H)，4.04-3.81(m，6H)，2.84-2.70(m，1H)，2.12-1.93(m，6H)，1.22-1.12(m，3H)，1.00(dd，J＝42.8，6.7Hz，3H)。
Example 11
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 ("Compound 11")
(P) -4- (4-propenoylpiperazin-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
(M) -4- (4-propenoylpiperazin-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 1.4,6,7-trichloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile
6, 7-dichloro-4-hydroxy-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile (480 mg,2.51 mmol), phosphorus oxychloride (1150 mg,7.50 mmol), DIEA (1.32 g,10.21 mmol) and acetonitrile (12 mL) were placed in a 50-mL round bottom flask purged and maintained with an inert atmosphere of nitrogen. The mixture was stirred at 80℃for 2 hours. The reaction was cooled to room temperature and concentrated in vacuo. This gives 4,6, 7-trichloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile, which is used directly in the next step.
Step 2.4- (6, 7-dichloro-3-cyano-1- (2-isopropyl-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridin-4-yl) piperazine-1-carboxylic acid tert-butyl ester
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), DIEA (660 mg,5.10 mmol) and tert-butylpiperazine-1-carboxylate (0.57 g,3.06 mmol) were placed in a 100-mL round bottom flask purged and maintained with an inert atmosphere of nitrogen. The reaction mixture was stirred at room temperature for 2 hours. The reaction was quenched by the addition of water (50 mL). The resulting solution was extracted with ethyl acetate (3X 50 mL), the organic phases were combined and washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica eluting with ethyl acetate/n-hexane (V/v=30% -70%). Thus, 0.92g (65% yield in 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 was obtained as a yellow solid. LCMS: m/z=557 [ m+1 ]]+ 。
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
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 The ester (920 mg,1.65 mmol), trifluoroacetic acid (4 mL), dichloromethane (15 mL) were placed in a 50-mL round bottom flask purged and maintained with an inert atmosphere of nitrogen. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under vacuum. The residue was dissolved in DCM (15 mL) in a 50mL round bottom flask, followed by the addition of DIEA (1.02 g,10.08 mmol). The reaction mixture was cooled to 0deg.C and acryloyl chloride (190 mg,2.09 mmol) was added. The mixture was stirred at room temperature for 2h. The reaction was quenched by the addition of water (30 mL). The resulting solution was extracted with ethyl acetate (3×50 mL), the organic phases were combined and washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica eluting with ethyl acetate/n-hexane (V/v=40% -80%). Thus, 0.86g (crude) of 4- (4-propenoylpiperazin-1-yl) -6, 7-dichloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile was obtained as a yellow solid. LCMS: m/z=511 [ m+1 ]]+ 。
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 11-4")
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, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline (78 mg,0.33 mmol), palladium tetraphenylphosphine (44 mg,0.03 mmol), sodium carbonate (65 mg,0.61 mmol), dioxane (4 mL) and water (1 mL) were placed in a 20-mL sealed tube purged and maintained under an inert atmosphere of nitrogen. The reaction mixture was stirred at 90℃for 2 hours. The reaction mixture was filtered and concentrated under vacuum. The residue was purified by Prep-HPLC (acetonitrile/water=1/1 (v: v)). Thus, 12mg (10%) of 4- (4-propenoylpiperazin-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 were obtained as a yellow solid. LCMS: m/z=586 [ m+1 ]]+ 。
1 HNMR(400MHz，CD3 OD)δ8.52(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)。
Step 5.4- (4-propenylpiperazin-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
4- (4-propenoylpiperazin-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 11-4") (104 mg,0.18 mmol), NCS (56 mg,0.42 mmol) and acetic acid (3 mL) were placed in an 8-mL sealed tube purged and maintained under an inert atmosphere of nitrogen. The reaction mixture was stirred overnight at 25 ℃. The reaction mixture was concentrated directly under vacuum and purified by Prep-HPLC (acetonitrile/water=4/1) to give 11mg (9.46%) of 4- (4-propenoylpiperazin-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 as a yellow solid ("compound 11"). LCMS: m/z=654 [ m+1 ] ]+ 。
1 HNMR(400MHz，CD3 OD)δ8.57(s，1H)，8.45(d，J＝4.8Hz，1H)，7.41(d，J＝7.1Hz，1H)，7.29(s，1H)，6.90(dd，J＝16.7，10.7Hz，1H)，6.33(dd，J＝16.4Hz，1H)，5.86(d，J＝10.7Hz，1H)，4.14-3.88(m，8H)，2.82-2.63(m，1H)，2.15-1.95(m，3H)，1.23-0.95(m，6H)。
A atropisomer mixture of 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 atropisomer (150 mg) was purified by Chiral-Prep-HPLC according to the following conditions: columns, chiralpakIBN,0.46cmI.D.×15cmL; mobile phase, n-hexane/ethanol=50/50 (V/V); detection wavelength, UV254 nm). Thus, 61mg (41%) of 4- (4-propenoylpiperazin-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 (first eluate, "compound 11A", M or P atropisomer) was obtained as a yellow solid;
1 HNMR(400MHz，CD3OD)δ8.54(d，J＝1.2Hz，1H)，8.41(d，J＝5.0Hz，1H)，7.39-7.33(m，1H)，7.31-7.17(m，1H)，6.87(dd，J＝16.8，10.6Hz，1H)，6.30(dd，J＝16.8，1.9Hz，1H)，5.83(dd，J＝10.6，1.9Hz，1H)，4.04-3.85(m，8H)，2.92-2.60(m，1H)，2.10-1.88(m，3H)，1.18-1.14(m，3H)，1.09-0.93(m，3H)。
and 47mg (31%) of 4- (4-propenoylpiperazin-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 (second eluate, "compound 11B", P or M atropisomer) as a yellow solid;1 HNMR(400MHz，CD3 OD)δ8.54(d，J＝1.3Hz，1H)，8.41(d，J＝5.0Hz，1H)，7.39-7.33(m，1H)，7.28-7.19(m，1H)，6.87(dd，J＝16.8，10.6Hz，1H)，6.31(dd，J＝16.8，1.8Hz，1H)，5.84(dd，J＝10.6，1.8Hz，1H)，4.10-3.84(m，8H)，2.84-2.62(m，1H)，2.08-1.94(m，3H)，1.18-1.13(m，3H)，1.09-0.93(m，3H)。
example 12
4- (4-propenoyl-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 ("Compound 12")
Step 1.4- (4-propenoyl-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
7-chloro-6-fluoro-4-hydroxy-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile (389 mg,1.04 mmol), phosphorus oxychloride (552 mg,3.60 mmol), DIEA (651 mg,5.04 mmol) and acetonitrile (15 mL) were placed in a 50-mL round bottom flask purged and maintained with an inert atmosphere of nitrogen. The mixture was stirred at 80℃for 1 hour. The reaction was cooled to room temperature and concentrated under vacuum.
4, 7-chloro-6-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile (480 mg,3.71 mmol), acetonitrile (20 mL), DIEA (480 mg,3.71 mmol) and 2- (piperazin-2-yl) acetonitrile (169 mg,1.35 mmol) were placed in a 100-mL round bottom flask purged and maintained with an inert atmosphere of nitrogen. The reaction mixture was stirred at room temperature for 0.5 hours. The reaction mixture was cooled to 0deg.C and acryloyl chloride (120 mg,1.33 mmol) was added. The reaction was quenched by the addition of water (50 mL). The resulting solution was extracted with ethyl acetate (3×50 mL), the organic phases were combined and washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica eluting with ethyl acetate/n-hexane (2/1 (v: v)). Thus, 0.55g (86% of two-step yield) of 4- (4-propenoyl-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 was obtained as a pale yellow solid. LCMS: m/z=534 [ m+1 ] ]+ 。
Step 2.4- (4-propenoyl-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
4- (4-propenoyl-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 (61 mg,0.11 mmol), 3-fluoro-2- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline (63 mg,0.27 mmol), tetrakis triphenylphosphine palladium (21 mg,0.02 mmol), sodium carbonate (81 mg,0.76 mmol), dioxane (1 mL) and water (0.1 mL) were placed in a 20-mL sealed tube purged and maintained under an inert atmosphere of nitrogen. The reaction mixture was stirred at 80℃for 1 hour. The reaction mixture was filtered and concentrated under vacuum. The residue was purified by Prep-HPLC (CH3 CN/H2 O=5/4 (v: v)) purification. 16mg (23%) of 4- (4-propenoyl-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 are thus obtained,it is a yellow solid. LCMS: m/z=609 [ m+1 ]]+ 。
1 HNMR(400MHz，CD3 OD)δ8.69(d，J＝5.5Hz，1H)，8.38(d，J＝9.2Hz，1H)，7.91-7.72(m，1H)，7.30-7.04(m，1H)，6.91(s，1H)，6.53(d，J＝8.2Hz，1H)，6.47-6.28(m，2H)，5.90(d，J＝10.5Hz，1H)，5.29(s，1H)，4.45-3.84(m，4H)，3.49(d，J＝74.7Hz，2H)，3.30-2.88(m，3H)，2.43-2.05(m，3H)，1.45-1.21(m，3H)，1.21-1.00(m，3H)。
Step 3.4- (4-propenoyl-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
4- (4-propenoyl-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 (86 mg,0.14 mmol), NCS (39 mg,0.29 mmol), acetic acid (2 mL) were placed in a 20-mL round bottom flask. The reaction mixture was stirred at room temperature for 2 days. The reaction mixture was concentrated under vacuum. The residue was purified by Prep-HPLC CH3 CN/H2 O(0.05％NH4 HCO3 ) (V/v=2/1)) purification. 14mg (17%) of 4- (4-propenoyl-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 were thus obtained as a yellow solid ("compound 12"). LCMS: m/z=677 [ m+1 ]]+ 。
1 HNMR(400MHz，DMSO)δ8.62-8.42(m，2H)，7.62(d，J＝7.8Hz，1H)，7.24(t，J＝5.1Hz，1H)，6.25(d，J＝16.4Hz，1H)，5.83(d，J＝12.1Hz，1H)，5.64(d，J＝11.1Hz，1H)，5.35-4.90(m，2H)，4.53(s，1H)，3.80-4.25(m，5H)，3.04-2.88(m，1H)，2.83-2.69(m，1H)，2.04-1.84(m，3H)，1.05(dd，J＝13.0，6.6Hz，3H)，0.91(dd，J＝24.1，6.6Hz，3H)。
Example 13
4- (4-propenoyl-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 ("Compound 13")
Step 1.4- (4-propenoyl-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.
6, 7-dichloro-4-hydroxy-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile (1.02 g,2.63 mmol), phosphorus oxychloride (2.81 g,18.29 mmol), DIEA (3.90 g,30.18 mmol) and acetonitrile (20 mL) were placed in a 50-mL round bottom flask purged and maintained with nitrogen inert atmosphere. The mixture was stirred at 80℃for 1 hour. The reaction was cooled to room temperature and concentrated in vacuo. The crude product was used directly in the next step.
4, 7-dichloro-6-chloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile (crude), acetonitrile (20 mL), DIEA (1 mL) and 2- (piperazin-2-yl) acetonitrile (586 mg,2.96 mmol) were placed in a 100-mL round bottom flask purged and maintained with a nitrogen inert atmosphere. The reaction mixture was stirred at room temperature for 0.5 hours. The reaction mixture was cooled to 0deg.C and acryloyl chloride (294 mg,3.28 mmol) was added. The reaction was quenched with water (50 mL), the resulting solution was extracted with ethyl acetate (3X 50 mL), the organic phases were combined and washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica eluting with ethyl acetate/n-hexane (7/3 (v: v)). Thus, 4- (4-propenoyl-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 was obtained (0.686 g,1.25mmol, yield 47.37%) as a pale yellow solid. LCMS: m/z=550 [ m+1 ]]+ 。
Step 2.4- (4-propenoyl-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
4- (4-propenoyl-3- (cyanomethyl) piperaquineOxazin-1-yl) -6, 7-dichloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile (457 mg,822.98 mol), 3-fluoro-2- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline (748 mg,3.16 mol), palladium tetraphenylphosphine (279 mg,241.44 mol), sodium carbonate (390 mg,3.68 mmol), dioxane (10 mL) and water (2 mL) were placed in a 25-mL sealed tube purged and maintained under an inert atmosphere of nitrogen. The reaction mixture was stirred at 80℃for 1 hour. The reaction mixture was filtered and concentrated under vacuum. The residue was purified by silica gel column (EA/n-hexane (3/1 (v: v)) to give 4- (4-propenoyl-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 as a yellow solid (0.413 g,660.70umol, yield 80.28%). LCMS: m/z=625 [ M+1:]+ 。
step 3.4- (4-propenoyl-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
4- (4-propenoyl-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 (307 mg,0.49 mmol), NCS (148 mg,1.11 mmol), acetic acid (6 mL) were placed in a 20-mL round bottom flask. The reaction mixture was stirred at room temperature for 16 hours. The reaction was then warmed to 50 ℃ and reacted for 1 hour. With 50mL saturated NaHCO3 The reaction mixture was quenched (with aqueous solution) and extracted with ethyl acetate (30 ml×3) and concentrated under vacuum. The residue was purified by Prep-HPLC CH3 CN/H2 O(0.05％NH4 HCO3 ) (V/v=2/1) purification. Thus was obtained 7- (2-amino-3, 5-dichloro-6-fluoro-phenyl) -6-chloro-4- [3- (cyanomethyl) -4-prop-2-enoyl-piperazin-1-yl) (compound 13, 80mg,115.276 mol, yield 23.47%)]-1- (2-isopropyl-4-methyl-3-pyridine) -2-oxo-1, 8-naphthyridine-3-carbonitrile as a yellow solid. LCMS: m/z=693 [ m+1 ]]+ 。
1 HNMR(400MHz，CD3 OD)δ8.55(d，J＝4.3Hz，1H)，8.46(dd，J＝14.0，5.0Hz，1H)，7.27(dd，J＝14.7，4.9Hz，1H)，7.11(dt，J＝14.7，6.1Hz，1H)，6.52(d，J＝8.1Hz，1H)，6.44-6.30(m，1H)，5.90(dd，J＝10.6，1.8Hz，1H)，5.30(s，1H)，4.31-3.91(m，4H)，3.59-3.51(m，2H)，3.07-2.94(m，1H)，2.92-2.78(m，1H)，2.75-2.51(m，1H)，2.16-1.90(m，3H)，1.26-1.12(m，3H)，1.10-0.87(m，3H)。
Example 14
4- (4-Acryloylpiperazin-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 ("Compound 14")
Step 1.4- (6, 7-dichloro-3-cyano-1- (4, 6-diisopropylpyrimidin-5-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridin-4-yl) piperazine-1-carboxylic acid tert-butyl ester
6, 7-dichloro-1- (4, 6-diisopropylpyrimidin-5-yl) -4-hydroxy-2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile (2.931 g, 7.0071 mmol), phosphorus oxychloride (3.239 g,21.124 mmol), DIEA (3.982 g, 30.81mmol) and acetonitrile (35 mL) were placed in a 50-mL round bottom flask purged and maintained with an inert atmosphere of nitrogen. The mixture was stirred at 80℃for 2 hours. The reaction was cooled to room temperature and concentrated in vacuo. This gives 4,6, 7-trichloro-1- (4, 6-diisopropylpyrimidin-5-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile, which is used directly in the next step.
4,6, 7-trichloro-1- (4, 6-diisopropylpyrimidin-5-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile (crude) and acetonitrile (35 mL) were placed in a 100-mL round bottom flask purged and maintained with an inert atmosphere of nitrogen. DIEA (3.982 g,30.810 mmol) and tert-butyl piperazine-1-carboxylate (1.157 g,6.212 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. The reaction was quenched by the addition of water (50 mL). The resulting solution was extracted with ethyl acetate (3×50 mL), the organic phases were combined and washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by extraction with ethyl acetate/n-hexane (V/v=2/8) purification by column chromatography on silica gel. 1.422g (23% yield in two steps) of 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 are thus obtained. LCMS: m/z=586 [ m+1 ]]+ 。
Step 2. Tert-butyl 4- (7- (2-amino-6-fluorophenyl) -6-chloro-3-cyano-1- (4, 6-diisopropylpyrimidin-5-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridin-4-yl) piperazine-1-carboxylate
4- (6, 7-dichloro-3-cyano-1- (4, 6-diisopropylpyrimidin-5-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridin-4-yl) piperazine-1-carboxylic acid tert-butyl ester (0.502 g,0.86 mmol), (2-amino-6-fluorophenyl) boronic acid (0.4572 g,1.907 mmol), palladium tetraphenylphosphine (0.099 g,0.086 mmol), sodium carbonate (0.170 g,1.604 mmol), dioxane (10 mL) and water (3 mL) were placed in a 25-mL sealed tube purged and maintained under an inert atmosphere of nitrogen. The reaction mixture was reacted at 90℃for 4 hours. The reaction mixture was filtered and concentrated under vacuum. The residue was purified by column chromatography on silica eluting with ethyl acetate/n-hexane (V/v=2/1). 600mg (95%) of tert-butyl 4- (7- (2-amino-6-fluorophenyl) -6-chloro-3-cyano-1- (4, 6-diisopropylpyrimidin-5-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridin-4-yl) piperazine-1-carboxylate are thus obtained as a yellow solid. LCMS: m/z=661 [ m+1 ] ]+ 。
Step 3.4- (7- (2-amino-3, 5-dichloro-6-fluorophenyl) -6-chloro-3-cyano-1- (4, 6-diisopropylpyrimidin-5-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridin-4-yl) piperazine-1-carboxylic acid tert-butyl ester
4- (7- (2-amino-6-fluorophenyl) -6-chloro-3-cyano-1- (4, 6-diisopropylpyrimidin-5-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridin-4-yl) piperazine-1-carboxylic acid tert-butyl ester (0.598 g,0.91 mmol), NCS (0.261 g,1.955 mmol) and acetic acid (8 mL) were placed in a 20-mL round bottom flask purged and maintained with nitrogen inert atmosphere. The mixture was stirred at room temperature for 2 days. The reaction was quenched by the addition of water (10 mL). The resulting solution was extracted with ethyl acetate (3×10 mL), the organic phases were combined and washed with saturated brine (1×50 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with (EA/n-hexane (V/v=7/3)). Thus 470mg was obtained(71%) 4- (7- (2-amino-3, 5-dichloro-6-fluorophenyl) -6-chloro-3-cyano-1- (4, 6-diisopropylpyrimidin-5-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridin-4-yl) piperazine-1-carboxylic acid tert-butyl ester as a yellow solid. LCMS: m/z=729 [ m+1 ]]+ 。
Step 4.4- (4-propenylpiperazin-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
4- (7- (2-amino-3, 5-dichloro-6-fluorophenyl) -6-chloro-3-cyano-1- (4, 6-diisopropylpyrimidin-5-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridin-4-yl) piperazine-1-carboxylic acid tert-butyl ester (0.4638 g,0.64 mmol), trifluoroacetic acid (4 mL) and dichloromethane (20 mL) were placed in a 20-mL round bottom flask purged and maintained with nitrogen inert atmosphere. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under vacuum. The residue was dissolved with DCM (3 mL) in a 25-mL round bottom flask. DIEA (1.107 g,8.57 mmol) was added. The reaction mixture was cooled to 0deg.C and acryloyl chloride (0.063 g,0.70 mmol) was added. The mixture was stirred at room temperature for 2 hours. The reaction was quenched by the addition of water (10 mL). The resulting solution was extracted with ethyl acetate (3×50 mL), the organic phases combined and washed with saturated brine (1×50 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by Prep-HPLC (CH3 CN/H2 O (V/v=6/4)). 156mg (36% two-step yield) of 4- (4-propenoylpiperazin-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 were thus obtained as a yellow solid ("compound 14"). LCMS: m/z=683 [ m+1 ] ]+ 。
1 HNMR(400MHz，CD3 OD)δ9.08(s，1H)，8.58(s，1H)，7.41(d，J＝7.5Hz，1H)，6.89(dd，J＝16.8，10.6Hz，1H)，6.33(dd，J＝16.7，1.5Hz，1H)，5.86(dd，J＝10.6，1.5Hz，1H)，4.14-3.85(m，8H)，2.89-2.74(m，1H)，2.73-2.57(m，1H)，1.24-1.14(m，6H)，1.10(d，J＝6.7Hz，3H)，0.99(d，J＝6.7Hz，3H)。
Example 15
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 ("Compound 15")
(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-carboxylic acid tert-butyl ester
6, 7-dichloro-1- (4, 6-diisopropylpyrimidin-5-yl) -4-hydroxy-2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile (3.586 g,8.57 mmol), phosphorus oxychloride (3.961 g,25.83 mmol), DIEA (4.768 g,36.89 mmol) and acetonitrile (45 mL) were placed in a 50-mL round bottom flask purged and maintained with a nitrogen inert atmosphere. The mixture was stirred at 80℃for 2h. The reaction was cooled to room temperature and concentrated in vacuo. This gives 4,6, 7-trichloro-1- (4, 6-diisopropylpyrimidin-5-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile, which is used directly in the next step.
4,6, 7-trichloro-1- (4, 6-diisopropylpyrimidin-5-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile (crude) and acetonitrile (45 mL) were placed in a 100-mL round bottom flask purged and maintained with an inert atmosphere of nitrogen. DIEA (4.768 g,36.89 mmol) and tert-butyl (R) -2-methylpiperazine-1-carboxylate (1.911 g,9.57 mmol) were added. The reaction mixture was stirred at room temperature for 2h. The reaction was quenched by the addition of water (50 mL). The resulting solution was extracted with ethyl acetate (3×50 mL), the organic phases were combined and washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica eluting with EA/n-hexane (V/v=2/8). Thus was obtained 2.152g (two-step yield 42%) of (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-carboxylic acid tert-butyl ester as a yellow solid. LCMS: m/z=600 [ m+1 ] ]+ 。
(2R) -4- (7- (2-amino-6-fluorophenyl) -6-chloro-3-cyano-1- (4, 6-diisopropylpyrimidin-5-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridin-4-yl) -2-methylpiperazine-1-carboxylic acid tert-butyl ester.
(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-carboxylic acid tert-butyl ester (0.504 g,0.84 mmol), (2-amino-6-fluorophenyl) boronic acid (0.427 g,1.80 mmol), tetrakis triphenylphosphine palladium (0.114 g,0.098 mmol), sodium carbonate (0.163 g,1.54 mmol), dioxane (10 mL) and water (3 mL) were placed in a 20-mL sealed tube purged and maintained under an inert atmosphere of nitrogen. The reaction mixture was stirred at 90℃for 4h. The reaction mixture was filtered and concentrated under vacuum. The residue was purified by column chromatography on silica gel eluting with (EA/n-hexane (V/v=2/1)). Thus, 500mg (88%) of (2R) -4- (7- (2-amino-6-fluorophenyl) -6-chloro-3-cyano-1- (4, 6-diisopropylpyrimidin-5-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridin-4-yl) -2-methylpiperazine-1-carboxylic acid tert-butyl ester was obtained as a yellow solid. LCMS: m/z=675 [ m+1 ]]+ 。
(2R) -4- (7- (2-amino-3, 5-dichloro-6-fluorophenyl) -6-chloro-3-cyano-1- (4, 6-diisopropylpyrimidin-5-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridin-4-yl) -2-methylpiperazine-1-carboxylic acid tert-butyl ester
(2R) -4- (7- (2-amino-6-fluorophenyl) -6-chloro-3-cyano-1- (4, 6-diisopropylpyrimidin-5-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridin-4-yl) -2-methylpiperazine-1-carboxylic acid tert-butyl ester (0.510 g,0.76 mmol), NCS (0.225 g,1.685 mmol) and acetic acid (8 mL) were placed in a 25-mL round bottom flask purged and maintained with a nitrogen inert atmosphere. The mixture was stirred at room temperature for 2 days. The reaction was quenched by the addition of water (10 mL). The resulting solution was extracted with ethyl acetate (3×10 mL), the organic phases were combined and washed with saturated brine (1×50 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with (EA/n-hexane (V/v=7/3)). Thus, 410mg (73%) of (2R) -4- (7- (2-amino-3, 5-dichloro-6-fluorophenyl) -6-chloro-3-cyano-1- (4, 6-diisopropylpyrimidin-5-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridin-4-yl) -2-methylpiperazine-1-carboxylic acid tert-butyl ester was obtained as a yellow solid. LCMS: m/z=743 [ m+1 ]]+ 。
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.
(2R) -4- (7- (2-amino-3, 5-dichloro-6-fluorophenyl) -6-chloro-3-cyano-1- (4, 6-diisopropylpyrimidin-5-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridin-4-yl) -2-methylpiperazine-1-carboxylic acid tert-butyl ester (0.408 g,0.55 mmol), trifluoroacetic acid (4 mL), dichloromethane (20 mL) were placed in a 50-mL round bottom flask purged and maintained under an inert atmosphere of nitrogen. The reaction mixture was stirred at room temperature for 2h. The reaction mixture was concentrated under vacuum. The residue was dissolved in 25-mL round bottom flask with dichloromethane (3 mL). DIEA (0.963 g,7.45 mmol) was added. The reaction mixture was cooled to 0deg.C and acryloyl chloride (0.052 g,0.57 mmol) was added dropwise. The mixture was stirred at room temperature for 2h. The reaction was quenched by the addition of water (10 mL). The resulting solution was extracted with ethyl acetate (3×50 mL), the organic phases were combined and washed with saturated brine (1×50 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by Prep-HPLC (CH3 CN/H2 O=6/4). Thus, 89mg (23% two-step yield) of 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 were obtained as a yellow solid ("compound 15"). LCMS: m/z=697 [ m+1 ]]+ 。
1 HNMR(400MHz，CD3 OD)δ9.08(s，1H)，8.60(d，J＝4.2Hz，1H)，7.41(d，J＝7.5Hz，1H)，6.87(dd，J＝16.7，10.7Hz，1H)，6.32(d，J＝16.5Hz，1H)，5.85(d，J＝11.0Hz，1H)，4.34-4.22(m，1H)，4.12-3.91(m，3H)，3.82-3.48(m，2H)，2.95-2.50(m，3H)，1.53-1.41(m，3H)，1.25-1.20(m，3H)，1.19-1.15(m，3H)，1.14-1.06(m，3H)，1.05-0.92(m，3H).
Example 16
4- ((3S, 5R) -4-propenoyl-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 ("Compound 16")
Step 1.4,6-2 (prop-1-en-2-yl) pyrimidin-5-amine
4, 6-dichloropyrimidin-5-amine (50.61 g,308.61 mmol), 4, 5-tetramethyl-2-allyl-1, 3, 2-dioxaborolan (154.16 g,917.40 mmol), pd (dppf) Cl2 (21.00 g,28.31 mmol), potassium carbonate (132.11 g,955.90 mmol), dioxane (500 mL) and water (10 mL) were placed in a 1000-mL sealed tube purged and maintained under an inert atmosphere of nitrogen. The reaction mixture was stirred at 90 ℃ overnight. The reaction mixture was filtered and concentrated under vacuum. The residue was applied to a silica gel column eluted with (EA/n-hexane (0% -5%)). 56.19g (crude) of 4, 6-2- (prop-1-en-2-yl) pyrimidin-5-amine are thus obtained as yellow oil. LCMS: m/z=176 [ m+1 ] ]+ 。
1 HNMR(400MHz，Methanol-d4 )δ8.37(s，1H)，5.59-5.54(m，2H)，5.44-5.36(m，2H)，2.13(s，6H)。
Step 2.4,6-diisopropylpyrimidin-5-amine
4, 6-2- (prop-1-en-2-yl) pyrimidin-5-amine (56.19 g,320.66 mmol), methanol (500 mL), pd/C (11.04 g) were placed in a 1000-mL round bottom flask. The mixture was degassed under vacuum and then purged three times with a hydrogen balloon. The mixture was stirred at room temperature for 6.5h. The resulting solution was filtered and concentrated under vacuum. 41.68g (crude) of 4, 6-diisopropylpyrimidin-5-amine are thus obtained, which can be used directly in the next step. LCMS: m/z=180 [ m+1 ]]+ 。
1 HNMR(400MHz，Methanol-d4 )δ8.33(s，1H)，3.28-3.13(m，2H)，1.25(d，J＝6.8Hz，12H)。
Step 3.2-cyano-N- (4, 6-diisopropylpyrimidin-5-yl) acetamide
4, 6-diisopropylpyrimidin-5-amine (41.68 g,232.51 mmol), 2-cyanoacetic acid (36.33 g,427.10 mmol), HATU (133.82 g,351.95 mmol), DMF (500 mL), DIEA (96.99, 351.95 mmol) were placed in a 1000-mL round bottom flask purged and maintained under an inert atmosphere of nitrogen. The mixture was stirred at room temperature for 1.5h. The reaction was quenched by the addition of water (500 mL). The obtained solutionThe solution was extracted with ethyl acetate (3 x200 mL), the organic phases were combined and washed with saturated brine (500 mL), dried over anhydrous sodium sulfate, concentrated in vacuo to give a residue which was applied to a silica gel column eluting with EA/n-hexane (0% to 40%). This gave 37g (yield 65%) of 2-cyano-N- (4, 6-diisopropylpyrimidin-5-yl) acetamide as a white solid. LCMS: m/z=247 [ m+1 ] ]+ 。
1 HNMR(400MHz，Methanol-d4 )δ8.95(s，1H)，3.88(s，2H)，3.283.17(m，2H)，1.23(d，J＝6.8Hz，13H).
Step 4.6,7-dichloro-1- (4, 6-diisopropylpyrimidin-5-yl) -4-hydroxy-2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile
2-cyano N- (2-isopropyl-4-methylpyridin-3-yl) acetamide (2.016 g,8.18 mmol), cesium carbonate (5.416 g,16.62 mmol), acetonitrile (25 mL) were placed in a 500-mL round bottom flask and the mixture stirred at 20℃for 0.5h. 2,5, 6-trichloronicotinoyl chloride (2.00 g,8.18 mmol) dissolved in acetonitrile (10 mL) was then added dropwise. The reaction mixture was stirred at 20℃for 3h. The reaction mixture was stirred at 80℃for 1h. The reaction was then quenched by the addition of water (50 mL). The resulting solution was extracted with ethyl acetate (3X 50 mL), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. Thus, 3.15g (crude) of 6, 7-dichloro-1- (4, 6-diisopropylpyrimidin-5-yl) -4-hydroxy-2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile were obtained as a yellow solid. LCMS: m/z=418 [ m+1 ]]+ 。
1 HNMR(400MHz，CD3 OD)δ9.07(s，1H)，8.49(s，1H)，2.76-2.66(m，2H)，1.21(d，J＝7.2Hz，6H)，1.05(d，J＝6.8Hz，6H)。
Step 5.4- ((3R, 5S) -4-propenoyl-3, 5-dimethylpiperazin-1-yl) -6, 7-dichloro-1- (4, 6-diisopropylpyrimidin-5-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile
6, 7-dichloro-1- (4, 6-diisopropylpyrimidin-5-yl) -4-hydroxy-2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile (3.15 g,7.53 mmol), phosphorus oxychloride (3.50 g,22.83 mmol), DIEA (4.13 g,31.92 mmol) and acetonitrile (30 mL) were placed under an inert atmosphere of nitrogen and purged In a maintained 100-mL round bottom flask. The mixture was stirred at 80℃for 0.5h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was dissolved in acetonitrile (30 mL), followed by DIEA (2.4 mL,14.49 mmol), (2S, 6R) -2, 6-dimethylpiperazine (0.868 g,7.60 mmol). The resulting mixture was stirred at room temperature for 0.5h. The reaction mixture was cooled to 0℃and acryloyl chloride (0.71 g,7.89 mmol) was added. The resulting mixture was stirred at room temperature for an additional 0.5h. The resulting solution was concentrated in vacuo and applied to a silica gel column eluted with (EA/n-hexane (0% -40%)). This gives 1.33g (51% yield) of 4- ((3 r,5 s) -4-propenoyl-3, 5-dimethylpiperazin-1-yl) -6, 7-dichloro-1- (4, 6-diisopropylpyrimidin-5-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile as a red solid. LCMS: m/z=568 [ m+1 ]]+ 。
1 HNMR(400MHz，CD3 OD)δ9.14(s，1H)，8.73(s，1H)，6.87(dd，J＝16.7，10.6Hz，1H)，6.36-6.19(m，1H)，5.90-5.77(m，1H)，4.74(s，2H)，3.96(d，J＝13.0Hz，2H)，3.87-3.74(m，2H)，2.78-2.61(m，2H)，1.66-1.57(m，6H)，1.21-1.14(m，6H)，1.07(d，J＝6.7Hz，6H).
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
4- ((3S, 5R) -4-propenoyl-3, 5-dimethylpiperazin-1-yl) -6, 7-dichloro-1- (4, 6-diisopropylpyrimidin-5-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile (0.284 g,1.20 mmol), 3-fluoro-2- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline (0.224 g,0.39 mmol), tetrakis triphenylphosphine palladium (0.164 g,0.14 mmol), sodium carbonate (0.140 g,1.32 mmol), dioxane (10 mL) and water (2 mL) were placed in a 20-mL sealed tube purged and maintained under an inert atmosphere of nitrogen. The reaction mixture was stirred at 80℃for 4h. The reaction mixture was filtered and concentrated under vacuum. The residue was purified by flash column (CH3 CN/H2 O, V/v=1/1). Thus, 150mg of 4- ((3S, 5R) -4-propenoyl-3, 5-dimethylpiperazin-1-yl) -7- (2-amino-6-fluorophenyl) -6-chloro-1- (4, 6-diisopropylpyrimidin-5-yl) -2-oxo was obtained-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile as a yellow solid. LCMS: m/z=643 [ m+1 ]]+ 。
Step 7.4- ((3S, 5R) -4-propenoyl-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
4- ((3S, 5R) -4-propenoyl-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 (0.178 g,0.277 mmol), NCS (0.06 g,0.45 mmol) and acetic acid (10 mL) were placed in a 20-mL sealed tube purged and maintained with an inert atmosphere of nitrogen. The reaction mixture was stirred at 25℃for 4h. The reaction mixture was filtered and concentrated under vacuum. The residue was purified by Prep-HPLC (CH3 CN/H2 O, V/v=1/1). This gave 22mg of 4- ((3 s,5 r) -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 ("compound 16") as a yellow solid. LCMS: m/z=711 [ m+1 ] ]+ 。
1 HNMR(400MHz，MeOD)δ9.09(s，1H)，8.86(s，1H)，7.42(d，J＝7.5Hz，1H)，6.91(dd，J＝16.7，10.5Hz，1H)，6.35(d，J＝16.7Hz，1H)，5.86(d，J＝10.7Hz，1H)，4.80-4.83(m，2H)，4.01-4.05(m，2H)，3.84-3.87(m，2H)，2.80-2.82(m，1H)，2.65-2.67(m，1H)，1.66-1.68(m，6H)，1.19(dd，J＝10.6，6.8Hz，6H)，1.11(d，J＝6.6Hz，3H)，1.00(d，J＝6.6Hz，3H)。
The compounds listed in table 2 can be synthesized by methods similar to those listed in the examples above:
TABLE 2
Amgen 6
4- (4-Acrylpiperazin-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")
Step 1.4- (4-Acylpiperazin-1-yl) -6-chloro-7- (2-fluorophenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile
4- (4-Acylpiperazin-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 mmole), sodium carbonate (69 mg,0.65 mmole), dioxane (1 mL) and water (0.2 mL) were placed in an 8-mL sealed tube purged and maintained under an inert atmosphere of nitrogen. The reaction mixture was stirred at 90℃for 2h. The reaction mixture was filtered and concentrated under vacuum. The residue was purified by column chromatography on silica eluting with EA/n-hexane (7/3). The eluate was collected and concentrated under vacuum. The residue was purified by Prep-HPLC (CH3 CN/H2 O=3/2) purification. This gave 22mg of 4- (4-propenylpiperazin-1-yl) -6-chloro-7- (2-fluorophenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile ("amben 6") as a yellow solid. LCMS: m/z=571 [ m+1 ] ]+ 。
1 HNMR(400MHz，CD3 OD)δ8.52(s，lH)，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)。
The atropisomer mixture of 4- (4-propenoylpiperazin-1-yl) -6-chloro-7- (2-fluorophenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile (1.59 g) was purified by Chiral-Prep-HPLC as follows: column, CHIRALCellulose-SB,3 cm. Times.25 cm,5um; mobile phase, CO2 IPA: acn=1:1; detection wavelength, UV 254nm. Thus, 739mg (46%) of 4- (4-propenylpiperazin-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 eluate) was obtained as a yellow solid; LCMS: m/z=571 [ m+1 ]]+ 。
And 709mg (45%) of 4- (4-propenylpiperazin-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 eluate) as a yellow solid. LCMS: m/z=571 [ m+1 ]]+ 。
1 HNMR(400MHz，CD3 OD)δ8.50(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)。
Amgen6.3
4- (4-Acrylpiperazin-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")
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
4- (7- (2-amino-6-fluorophenyl) -6-chloro-3-cyano-l- (4, 6-diisopropylpyrimidin-5-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridin-4-yl) piperazine-1-carboxylic acid tert-butyl ester (5.39 g,8.15 mmol), trifluoroacetic acid (5 mL) and dichloromethane (50 mL) were placed in a 100-mL round bottom flask. The reaction mixture was stirred at room temperature for 1h. After the reaction was completed, the solution was spin-dried under vacuum to give 4.36g of 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 as a yellow oil.
Step 2.4- (4-Acrylpiperazin-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
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 (4.36 g,7.77 mmol), potassium phosphate (7.401 g,34.87 mmol), tetrahydrofuran (40 mL) and water (20 mL) were placed in a 100-mL round bottom flask. Acryloyl chloride (0.65 g,7.14 mmol) was added dropwise to the reaction mixture at 0deg.C and stirred at room temperature for 1h. When the reaction was complete, the solution was evaporated to dryness and purified by pre-HPLC to give 1.168g of 4- (4-propenylpiperazin-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 ("amben 6.3") as a yellow solid. LCMS: m/z=615 [ m+1 ] ]+ 。
1 HNMR(400MHz，DMSO-d6)δ9.09(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(dd，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)。
Amgen7.3
4- ((3S, 5R) -4-propenoyl-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")
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
4- ((3S, 5R) -4-propenoyl-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), tetrakis triphenylphosphine palladium (85 mg,0.073 mmol), sodium carbonate (69 mg,0.65 mmol), dioxane (6 mL) and water (2 mL) were placed in a 20-mL sealed tube purged and maintained under an inert atmosphere of nitrogen3 CN/H2 O (V/v=1/1)). This gave 31mg (26% two-step yield) of 4- ((3 s,5 r) -4-propenoyl-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 ("amben 7.3") as a yellow solid. LCMS: m/z=599 [ m+1 ] ]+ .
1 HNMR(400MHz，CD3 OD)δ8.80(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).
A atropisomer mixture of 4- ((3 s,5 r) -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 (1.48 g) was purified by Chiral-Prep-HPLC according to the following conditions: column, CHIRALCellulose-SB,3 cm. Times.25 cm,5um; mobile phase, hex/etoh=50/50 (V/V); detection wavelength, UV254nm. 625mg (42%) of 4- ((3S, 5R) -4-propenoyl-3, 5-di-are thus obtainedMethylpiperazin-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 eluate) as a yellow solid; LCMS: m/z=599 [ m+1 ]]+ ，
1 HNMR(400MHz，CD3 OD) delta 8.68 (s, 1H), 8.32 (d, j=5.0 Hz, 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, 1H), 1.93 (s, 3H), 1.55 (d, j=7.0 Hz and 669mg (45%) of 4- ((3 s,5 r) -4-acryloyl-3, 5-dimethylpiperazin-1-yl) -6-chloro-7- (2-fluorophenyl) -1- (2-isopropyl-1-dimethyl-1-yl) -1-naphthyridine, 1-2-naphthyridine, and yellow solid eluting. LCMS: m/z=599 [ m+1 ] ]+ 。
1 HNMR(400MHz，CD3 OD)δ8.80(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)。
Pharmacological experiments
SOS1 catalyzed guanylate exchange experiments
HIS-KRAS (G12C, aa 2-185,Sino biological) was first diluted to 5. Mu.M with EDTA buffer (20mM HEPES,pH 7.4, 50mM NaCl,10mM EDTA,0.01% (v/v) Tween-20) and incubated at 25℃for 30 min. After use of assay buffer (25mM HEPES,pH 7.4, 120mM NaCl,5mM MgCl)2 1mM DTT,0.01% (v/v) Tween 20,0.1% (w/v) BSA EDTA-pretreated HIS-KRAS (G12C) was diluted to 12nM and incubated with 120nM GDP and 6HIS-Tb cryptate Gold (Cisbio) at 25℃for 60 min to prepare GDP-KRAS (G12C). After pre-incubation of GDP-KRAS (G12C) with diluted compounds in 384 well plates for 1 hour, SOS1 ExD (Flag tag, aa 564-1049) and BODIPY were addedTM FL GTP (Invitrogen) initiating an exchange reaction (reaction System: 3nM HIS-KRAS (G12C), 2. Mu.M SOS1 ExD,80nM BODIPY)TM FL GTP,21ng/mL MAb Anti 6HIS-Tb conjugate Gold), was reacted at 25℃for 4 hours. The TR-FRET signal was measured using a Tecan Spark microplate reader, and the detection parameters were set as follows: f486 excitation wavelength 340 (35) nm, absorption wavelength 486 (10) nm, delay time 100 μs, integration time 200 μs; f515: excitation wavelength 340 (35) nm, absorption wavelength 515 (10) nm, delay time 100 μs, integration time 200 μs. The TR-FRET ratio for each well was calculated by the equation TR-FRET ratio= (F515 signal/F486 signal) 10000. IC was then calculated using four-parameter logistic model analysis data50 Values. SOS1 catalyzed nucleotide exchange experiments are shown in Table 3 below:
TABLE 3 Table 3
As can be seen from Table 3, the compounds of the examples of the present invention have strong inhibitory activity in SOS 1-catalyzed nucleotide exchange experiments.
2. Intracellular phosphorylated ERK1/2 (THR 202/TYR 204) protein level assay (HTRF)
NCI-H358 cells expressing KRAS G12C were incubated in RPMI1640 medium (Gibco) containing 10% fetal bovine serum (Gibco). Cells in the medium were seeded at 40000 cells/well in 96-well plates and allowed to adhere overnight. The next day, the medium was removed and compounds diluted with assay medium (RPMI 1640+0.1% fbs) were added. At 37℃5% CO2 After 2 hours incubation in a cell incubator of (2), the assay medium was removed, then 50 μl of 1 x supplemented lysis buffer was added and the well plate was incubated at 25 ℃ for 45 minutes with shaking. Cell lysis of 10. Mu.L was also transferred from 96-well plates to wells containing 2.5. Mu.L/wellIn 384-well plates (Greiner) of pre-mixed antibodies (Cisbio 64 AERPEH). Incubation at 25℃for 4 hours followed by reading HTRF in a Tecan Spark microplate readerValues. Analysis of data and calculation of IC using four parameter logistic model50 Values. The experimental results of the Phospho-ERK1/2 (THR 202/TYR 204) HTRF are shown in Table 4 below:
TABLE 4 Table 4
| Compounds of formula (I) | p-ERK IC50 (nM) | Compounds of formula (I) | p-ERK IC50 (nM) |
| Compound 1 | 56.15 | Compound 10 | 244.9 |
| Compound 2 | 235.3 | Compound 11-4 | 14.18 |
| Compound 3 | 407.6 | Compound 11 | 10.36 |
| Compound 4 | 12.25 | Compound 11A | 60.63 |
| Compound 5 | 42.07 | Compound 11B | 11.69 |
| Compound 6 | 38.11 | Compound 12 | 16.92 |
| Compound 6A | 34.26 | Compound 13 | 14.92 |
| Compound 6B | 57.91 | Compound 14 | 18.51 |
| Compound 7 | 17.66 | Compound 15 | 73.33 |
| Compound 8 | 220.1 | Compound 16 | 101.3 |
| Compound 9 | 28.8 | Amgen-6 | 29.9 |
| Compound 9A | 69.54 | Amgen-6.3 | 20.1 |
| Compound 9B | 23.9 | Amgen-7.3 | 44.5 |
As can be seen from Table 4, the compounds of the examples of the present invention have strong inhibitory activity in the Phospho-ERK1/2 (THR 202/TYR 204) HTRF assay.
3. Cell proliferation inhibition assay
NCI-H358 cells expressing KRAS G12C were cultured in RPMI1640 medium (Gibco) containing 10% fetal bovine serum (Gibco). Cells in the medium were seeded into 96-well plates at a concentration of 3000 cells/well (100 μl/well) and allowed to adhere overnight. The next day, the compounds were diluted in medium and added to the well plate. At 37 ℃/5% CO2 After 6 days incubation in the cell incubator, the medium was removed and then 100. Mu.L of 1 XCCK-8 (MCE) in the medium was added to each well. Orifice plate at 37 ℃/5% CO2 Is incubated in the cell incubator for 1.5-2 hours. OD450 signals were read with a Tecan Spark multimode microplate reader and analyzed and ICsa values were calculated using a 4-parameter logistic model. The results are shown in Table 5:
TABLE 5
As can be seen from Table 5, the compounds of the examples of the present invention have strong inhibitory activity against NCI-H358 cells expressing KRAS G12C muteins.
4. Mouse PK evaluation
The purpose of this experiment was to evaluate the PK profile of compounds after a single dose in Balb/c mice (male). Prior to dosing, mice fasted overnight and were free to drink. Mice corresponding to each compound were divided into 2 groups (n=3/group). Group A mice were given a single dose of 3mg/kg of compound (iv). Group B mice were given a single dose of 10mg/kg of compound (po). For group a mice, blood samples were collected at 0.0833, 0.25, 0.5, 1, 2, 4, 6, 8, 24h before and after dosing. For group B mice, blood samples were collected at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 24h before and after dosing. The blood sample was placed on ice until centrifugation to give plasma. Plasma samples were stored at-80 ℃ until analysis. The concentration of the compound in the plasma sample was determined by LC-MS/MS method. The results are shown in Table 6:
TABLE 6
From the pharmacokinetic test results of the mice shown in table 6, it can be seen that: preferred compounds 6 and 11 of the invention have superior pharmacokinetic parameters in mice than those of control compounds 11-4, amben 6 and amben 6.3. The exposure amount of the compound 6 may be 10 times or more the exposure amount of the control compound amben 6 and 6 times or more the exposure amount of the control compound amben 6.3. The exposure of the compound 11 can be more than 6 times of the control compound Amgen 6, more than 3 times of the control compound Amgen 6.3 and more than 30 times of the control compound 11-4; at the same time, the half-lives of compound 6 and compound 11 are also greatly prolonged. Thus, it is more compatible with the administration requirements.
5. Beagle PK evaluation
The aim of this experiment was to evaluate the PK profile of the compounds after a single administration in beagle dogs. Prior to dosing, dogs fasted overnight and were free to drink water. Dogs for each compound were divided into 2 groups (one male and one female/each group). Group A dogs were given a single dose of 1mg/kg of compound (iv). Group B dogs were given a single dose of 10mg/kg of compound (po). For group a dogs, blood samples were collected at 0.0833, 0.25, 0.5, 1, 2, 4, 6, 8, 24h before and after dosing. For group B dogs, blood samples were collected at 0.25, 0.5, 1, 2, 4, 6, 8, 24h before and after dosing. The blood sample was placed on ice until centrifugation to give plasma. The plasma samples were stored at-80 ℃ until analysis. The concentration of the compound in the plasma sample was determined by LC-MS/MS method. The results obtained are shown in Table 7:
TABLE 7
As can be seen from table 7, the preferred compounds 9, 11 and 11B of the present invention have superior pharmacokinetic parameters in male or female dogs and their exposure is significantly higher than that of the control compounds amben 6, amben 6 (second eluent) and amben 6.3, especially compound amben 6.3 (which is hardly absorbed by male dogs). For example, the exposure of compound 11B is 5.8-11.2 times that of compound amben 6, 3.4-4.2 times that of compound amben 6 (second eluent). Thus, it is more compatible with the administration requirements.
Effectiveness test in MIA PaCa-2 xenograft model
A mixture of MIAPaCa-2 cells (1.0E+07 cells) and corning (corning) was injected subcutaneously on the right side of female BALB/c mice (6-8 weeks). Mice were monitored daily and caliper measurements were started when tumors became visible. The tumor volume was calculated by measuring two perpendicular diameters using the following formula: (L.times.W2 ) And/2, wherein L and W refer to the length and width of the tumor diameter. When the average tumor volume reaches 200mm3 At that time, mice were grouped (n=6/group) and given the compound. Tumor volume and mouse weight were measured 2 times per week during dosing (-3 weeks). By the formula TGI% = (1- (Vt-Vt)0 )/(Vc-Vc0 ) Calculating tumor growth inhibition rate of 100%, wherein Vc and Vt are the average tumor volumes of the control group and the dosing group at the end of the experiment, vc0 And Vt (V.sub.t)0 Mean tumor volume for the control and dosing groups at the beginning. The results obtained are shown in Table 8, and the tumor volume of the mice is shown in FIG. 1 as a function of the days after cell inoculation.
TABLE 8
As can be seen from table 8 and fig. 1, compound 11 has a good activity of inhibiting tumor growth.
Safety exploration in nci-H1373 xenograft model
A mixture of NCI-H1373 cells (5.0E+06 cells) and Corning (Corning) was injected subcutaneously on the right side of female BALB/c mice (6-8 weeks). Mice were monitored daily and caliper measurements were started when tumors became visible. The tumor volume was calculated by measuring two perpendicular diameters using the following formula: (L.times.W2 ) And/2, wherein L and W refer to the length and width of the tumor diameter, respectively. After grouping the mice, we explore safety using the remaining mice (n=8). Mice were dosed with compound 11B (po, QD) at a dose of 4000mg/kg for 15 days, and the body weight of the mice was measured 2 times per week during the dosing period. The body weight of the mice as a function of the days following cell inoculation is shown in figure 2.
As can be seen from fig. 2, compound 11B has good safety.
It should be understood that if the present invention refers to any prior art publication, it is to be understood that: such reference does not constitute an admission that the publication forms part of the common general knowledge in the art in any country. Although the foregoing invention has been described in some detail by way of illustration for purposes of clarity of understanding, certain minor changes and modifications will become apparent to those skilled in the art. Accordingly, the specification and examples should not be construed as limiting the scope of the invention.