CN115197132A - HPK1 inhibitor and application thereof in medicine - Google Patents
HPK1 inhibitor and application thereof in medicine Download PDFInfo
- Publication number
- CN115197132A CN115197132A CN202210378257.5A CN202210378257A CN115197132A CN 115197132 A CN115197132 A CN 115197132A CN 202210378257 A CN202210378257 A CN 202210378257A CN 115197132 A CN115197132 A CN 115197132A
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- Prior art keywords
- aryl
- alkynyl
- cycloalkyl
- heterocyclyl
- radical
- Prior art date
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- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000011734 sodium Chemical class 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000005415 substituted alkoxy group Chemical group 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 125000001174 sulfone group Chemical group 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 229960004559 theobromine Drugs 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- WCNFFKHKJLERFM-UHFFFAOYSA-N thiomorpholinyl sulfone group Chemical group N1(CCSCC1)S(=O)(=O)N1CCSCC1 WCNFFKHKJLERFM-UHFFFAOYSA-N 0.000 description 1
- ZCAGUOCUDGWENZ-UHFFFAOYSA-N thiomorpholinyl sulfoxide group Chemical group N1(CCSCC1)S(=O)N1CCSCC1 ZCAGUOCUDGWENZ-UHFFFAOYSA-N 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 239000011701 zinc Chemical class 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/42—One nitrogen atom
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D241/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with nitrogen atoms directly attached to ring carbon atoms
- C07D241/28—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with nitrogen atoms directly attached to ring carbon atoms in which said hetero-bound carbon atoms have double bonds to oxygen, sulfur or nitrogen atoms
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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Abstract
The present invention relates to a novel compound having a cancer therapeutic activity. The invention also relates to a preparation method of the compounds and a pharmaceutical composition containing the compounds.
Description
Technical Field
The present invention relates to an HPK1 inhibitor having cancer therapeutic activity. The invention also relates to a preparation method of the compounds and a pharmaceutical composition containing the compounds.
Background
The medicine targeting HPK1 becomes one of the current medicine research and development hot spots, and the existing varieties enter the clinical stage. The invention provides a micromolecular HPK1 inhibitor with a novel structure, which has good anti-tumor activity.
Disclosure of Invention
The invention provides a compound shown as a general formula (I), a stereoisomer, a tautomer, a deuteron or a medicinal salt thereof:
wherein,
R 1 is selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-12 Aryl or 5-12 membered heteroaryl, said C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-12 Aryl or 5-12 membered heteroaryl optionally further substituted with at least one R 1a Substitution;
R 2 selected from H, halogen, cyano, C 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-12 Aryl or 5-12 membered heteroaryl, said C 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-12 Aryl or 5-12 membered heteroaryl optionally further substituted with at least one R 2a Substitution;
or R 1 And R 2 Together with the atom to which they are attached form C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-12 Aryl or 5-12 membered heteroaryl, said C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-12 Aryl or 5-12 membered heteroaryl optionally further substituted with one or more R 1b Substituted by a substituent;
R 3 selected from H, halogen, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO 2 、-OR b 、-SR b 、-SO 2 R b 、-SO 2 NR b R c 、-COR b 、-CO 2 R b 、-CONR b R c 、-NR b R c 、-NR b COR c 、-NR b CO 2 R c 、-NR b SONR c R d 、-NR b SO 2 NR c R d or-NR b SO 2 R c Said C is 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with at least one R 3a Substitution;
R 5 or R 6 Each independently selected from H, halogen,Cyano radicals, C 1-8 Alkyl radical, C 2-8 Alkenyl or C 2-8 Alkynyl, said C 1-8 Alkyl radical, C 2-8 Alkenyl or C 2-8 Alkynyl is optionally further substituted with at least one R a Substitution;
l is selected from the group consisting of a bond, C 1-3 Alkylene, O, S or NR a Said alkylene is optionally further substituted by at least one R a Substitution;
X 1 selected from N or CR 7 ;
X 2 Selected from N or CR 8 ;
X 3 Selected from N or CR 9 ;
X 4 Selected from N or CR 10 ;
X 5 Selected from N or CR 11 ;
R 7 、R 9 、R 10 Or R 11 Each independently selected from H, halogen, C 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO 2 、-OR b 、-SR b 、-SO 2 R b 、-SO 2 NR b R c 、-COR b 、-CO 2 R b 、-CONR b R c 、-NR b R c 、-NR b COR c 、-NR b CO 2 R c 、-NR b SONR c R d 、-NR b SO 2 NR c R d or-NR b SO 2 R c Said C is 1-8 Alkyl radical, C 1-8 Hydroxyalkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl optionally further substituted with at least one R a Substitution;
R 1a 、R 1b 、R 2a 、R 3a or R a Each independently selected from H, halogen, C 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO 2 、-OR b 、-SR b 、-SO 2 R b 、-SO 2 NR b R c 、-COR b 、-CO 2 R b 、-CONR b R c 、-NR b R c 、-NR b COR c 、-NR b CO 2 R c or-NR b SO 2 R c Said C is 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl optionally further substituted by a substituent selected from halogen, C 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO 2 、-OR b 、-SR b 、-SO 2 R b 、-SO 2 NR b R c 、-COR b 、-CO 2 R b 、-CONR b R c 、-NR b R c 、-NR b COR c 、-NR b CO 2 R c 、-NR b SONR c R d 、-NR b SO 2 NR c R d or-NR b SO 2 R c Substituted by a substituent;
R b 、R c or R d Each independently selected from hydrogen and C 1-8 Alkyl radical, C 1-8 Hydroxyalkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;
and R is 4 And X 2 There is a correspondence relationship between the presence of,
(3) When R is 4 Selected from aryl or heteroaryl, optionally further substituted by at least one R 4a Substitution; r 4a Selected from H, halogen, C 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO 2 、-OR b 、-SR b 、-SO 2 R b 、-SO 2 NR b R c 、-COR b 、-CO 2 R b 、-CONR b R c 、-NR b CO 2 R c or-NR b SO 2 R c Said C is 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl optionally further substituted by one or more halogen, C 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO 2 、-OR b 、-SR b 、-SO 2 R b 、-SO 2 NR b R c 、-COR b 、-CO 2 R b 、-CONR b R c 、-NR b R c 、-NR b COR c 、-NR b CO 2 R c 、-NR b SONR c R d 、-NR b SO 2 NR c R d or-NR b SO 2 R c Substituted by a substituent;
X 2 selected from N or CR 8 ;
R 8 Selected from H, halogen, C 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, oxo, -CN, -NO 2 、-OR b 、-SR b 、-SO 2 R b 、-SO 2 NR b R c 、-COR b 、-CO 2 R b 、-CONR b R c 、-NR b R c 、-NR b COR c 、-NR b CO 2 R c 、-NR b SONR c R d 、-NR b SO 2 NR c R d or-NR b SO 2 R c Said C is 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl is optionally further substituted with at least one R a Substitution;
(4) When R is 4 Selected from H, halogen, C 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, oxo, -CN, -NO 2 、-OR b 、-SR b 、-SO 2 R b 、-SO 2 NR b R c 、-COR b 、-CO 2 R b 、-CONR b R c Amino, -N (C) 1-6 Alkyl radical) 2 、-NHC 1-6 Alkyl, -NR b COR c 、-NR b CO 2 R c 、-NR b SONR c R d 、-NR b SO 2 NR c R d or-NR b SO 2 R c Said C is 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl is optionally further substituted with at least one R a Substitution;
X 2 selected from the group consisting of CR 8 ;
R 8 Selected from 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl, said 3-12 membered heterocyclyl, C 6-12 Aryl, 5-12 membered heteroaryl optionally further substituted with at least one R a And (4) substitution.
In some embodiments, formula (I) is selected from compounds of formula (IA):
wherein,
R 1 is selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-12 Aryl or 5-12 membered heteroaryl, said C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-12 Aryl or 5-12 membered heteroaryl optionally further substituted with at least one R 1a Substitution;
R 2 selected from H, halogen, cyano, C 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-12 Aryl or 5-12 membered heteroaryl, said C 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-12 Aryl or 5-12 membered heteroaryl optionally further substituted with at least one R 2a Substitution;
or R 1 And R 2 Together with the atom to which they are attached form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, optionally further substituted by one or more R 1b Substituted by a substituent;
R 3 selected from H, halogen, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO 2 、-OR b 、-SR b 、-SO 2 R b 、-SO 2 NR b R c 、-COR b 、-CO 2 R b 、-CONR b R c 、-NR b R c 、-NR b COR c 、-NR b CO 2 R c 、-NR b SONR c R d 、-NR b SO 2 NR c R d or-NR b SO 2 R c Said C is 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with at least one R 3a Substitution;
R 4 selected from aryl or heteroaryl, optionally further substituted by at least one R 4a Substitution; r 4a Selected from H, halogen, C 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO 2 、-OR b 、-SR b 、-SO 2 R b 、-SO 2 NR b R c 、-COR b 、-CO 2 R b 、-CONR b R c 、-NR b CO 2 R c or-NR b SO 2 R c Said C is 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl optionally further substituted by one or more halogen, C 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO 2 、-OR b 、-SR b 、-SO 2 R b 、-SO 2 NR b R c 、-COR b 、-CO 2 R b 、-CONR b R c 、-NR b R c 、-NR b COR c 、-NR b CO 2 R c 、-NR b SONR c R d 、-NR b SO 2 NR c R d or-NR b SO 2 R c Substituted by a substituent;
R 5 or R 6 Each independently selected from H, halogen, cyano, C 1-8 Alkyl radical, C 2-8 Alkenyl or C 2-8 Alkynyl radical, said C 1-8 Alkyl radical, C 2-8 Alkenyl or C 2-8 Alkynyl is optionally further substituted with at least one R a Substitution;
l is selected from the group consisting of a bond, alkylene, O, S, or NR a Said alkylene is optionally further substituted by at least one R a Substitution;
X 1 selected from N or CR 7 ;
X 2 Selected from N or CR 8 ;
X 3 Selected from N or CR 9 ;
X 4 Selected from N or CR 10 ;
X 5 Selected from N or CR 11 ;
R 7 、R 9 、R 10 Or R 11 Each independently selected from H, halogen, C 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO 2 、-OR b 、-SR b 、-SO 2 R b 、-SO 2 NR b R c 、-COR b 、-CO 2 R b 、-CONR b R c 、-NR b R c 、-NR b COR c 、-NR b CO 2 R c 、-NR b SONR c R d 、-NR b SO 2 NR c R d or-NR b SO 2 R c Said C is 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl optionally further substituted with at least one R a Substitution;
R 8 selected from H, halogenElement, C 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, oxo, -CN, -NO 2 、-OR b 、-SR b 、-SO 2 R b 、-SO 2 NR b R c 、-COR b 、-CO 2 R b 、-CONR b R c 、-NR b R c 、-NR b COR c 、-NR b CO 2 R c 、-NR b SONR c R d 、-NR b SO 2 NR c R d or-NR b SO 2 R c Said C is 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl is optionally further substituted with at least one R a Substitution;
R 1a 、R 1b 、R 2a 、R 3a or R a Each independently selected from H, halogen, C 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO 2 、-OR b 、-SR b 、-SO 2 R b 、-SO 2 NR b R c 、-COR b 、-CO 2 R b 、-CONR b R c 、-NR b R c 、-NR b COR c 、-NR b CO 2 R c or-NR b SO 2 R c Said C is 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl optionally further substituted by one or more halogen, C 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO 2 、-OR b 、-SR b 、-SO 2 R b 、-SO 2 NR b R c 、-COR b 、-CO 2 R b 、-CONR b R c 、-NR b R c 、-NR b COR c 、-NR b CO 2 R c 、-NR b SONR c R d 、-NR b SO 2 NR c R d or-NR b SO 2 R c Substituted by a substituent;
R b 、R c or R d Each independently selected from hydrogen, C 1-8 Alkyl radical, C 1-8 Hydroxyalkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl.
In some embodiments, R in formula (I) 1 Is selected fromR 1 Optionally further substituted with 1-4R 1a And (4) substitution.
In some embodiments, R in formula (I) 1a Is selected from H or C 1-3 An alkyl group.
In some embodiments, R in formula (I) 2 Selected from H, halogen, cyano, C 1-3 Alkyl, -CH 2 N(C 1-3 Alkyl radical) 2 Or C 1-3 A haloalkyl group.
In some embodiments, R in formula (I) 3 Selected from H, halogen, cyano, C 1-3 Alkyl, -CH 2 N(C 1-3 Alkyl radical) 2 Or C 1-3 A haloalkyl group.
In some embodiments, R in formula (I) 4 Is selected fromR 4 Optionally further substituted with 1-4R 4a And (4) substitution.
In some embodiments, R in formula (I) 4a Selected from H, -CON (C) 1-3 Alkyl radical) 2 、C 1-3 Alkoxy, haloalkyl, cyano or halogen.
In some embodiments, R in formula (I) 5 Or R 6 Each independently selected from H.
In some embodiments, X in formula (I) 1 The substituent(s) is selected from N or CH.
In some embodiments, X in formula (I) 2 The substituents being selected from N, CH or-CCH 2 CH 3 。
In some embodiments, X in formula (I) 3 The substituent(s) is selected from N or CH.
In some embodiments, X in formula (I) 4 The substituent(s) is selected from N or CH.
In some embodiments, X in formula (I) 5 The substituent(s) of (b) is selected from N or CH.
In some embodiments, the substituent for L in formula (I) is NH.
In some embodiments, formula (I) is selected from compounds of formula (IA-1),
R 1 -R 11 as defined in any of formulae (IA).
In some embodiments, the compound of formula (I) is selected from:
in some embodiments, formula (I) is selected from compounds represented by general formula (IB):
wherein,
R 1 is selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-12 Aryl or 5-12 membered heteroaryl, said C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-12 Aryl or 5-12 membered heteroaryl optionally further substituted with at least one R 1a Substitution;
R 2 selected from H, halogen, cyano, C 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-12 Aryl or 5-12 membered heteroaryl, said C 1-8 Alkyl radical, C 2-8 Alkenyl radical、C 2-8 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-12 Aryl or 5-12 membered heteroaryl optionally further substituted with at least one R 2a Substitution;
or R 1 And R 2 Together with the atom to which they are attached form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, optionally further substituted by one or more R 1b Substituted by a substituent;
R 3 selected from H, halogen, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO 2 、-OR b 、-SR b 、-SO 2 R b 、-SO 2 NR b R c 、-COR b 、-CO 2 R b 、-CONR b R c 、-NR b R c 、-NR b COR c 、-NR b CO 2 R c 、-NR b SONR c R d 、-NR b SO 2 NR c R d or-NR b SO 2 R c Said C is 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl optionally further substituted with at least one R 3a Substitution;
R 4 selected from H, halogen, C 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, oxo, -CN, -NO 2 、-OR b 、-SR b 、-SO 2 R b 、-SO 2 NR b R c 、-COR b 、-CO 2 R b 、-CONR b R c Amino, -N (C) 1-6 Alkyl radical) 2 、-NHC 1-6 Alkyl, -NR b COR c 、-NR b CO 2 R c 、-NR b SONR c R d 、-NR b SO 2 NR c R d or-NR b SO 2 R c Said C is 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, cycloalkaneThe radical, heterocyclyl, aryl or heteroaryl is optionally further substituted by at least one R a Substitution;
R 5 or R 6 Each independently selected from H, halogen, cyano, C 1-8 Alkyl radical, C 2-8 Alkenyl or C 2-8 Alkynyl radical, said C 1-8 Alkyl radical, C 2-8 Alkenyl or C 2-8 Alkynyl is optionally further substituted with at least one R a Substitution;
R 8 selected from 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl, said 3-12 membered heterocyclyl, C 6-12 Aryl, 5-12 membered heteroaryl optionally further substituted with at least one R a Substitution;
l is selected from the group consisting of a bond, alkylene, O, S or NR a Said alkylene is optionally further substituted by at least one R a Substitution;
X 1 selected from N or CR 7 ;
X 3 Selected from N or CR 9 ;
X 4 Selected from N or CR 10 ;
X 5 Selected from N or CR 11 ;
R 7 、R 9 、R 10 Or R 11 Each independently selected from H, halogen, C 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO 2 、-OR b 、-SR b 、-SO 2 R b 、-SO 2 NR b R c 、-COR b 、-CO 2 R b 、-CONR b R c 、-NR b R c 、-NR b COR c 、-NR b CO 2 R c 、-NR b SONR c R d 、-NR b SO 2 NR c R d or-NR b SO 2 R c Said C is 1-8 Alkyl radical C 2-8 Alkenyl radical, C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl optionally further substituted with at least one R a Substitution;
R 1a 、R 1b 、R 2a 、R 3a or R a Each independently selected from H, halogen, C 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO 2 、-OR b 、-SR b 、-SO 2 R b 、-SO 2 NR b R c 、-COR b 、-CO 2 R b 、-CONR b R c 、-NR b R c 、-NR b COR c 、-NR b CO 2 R c or-NR b SO 2 R c Said C is 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl optionally further substituted by one or more halogen, C 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO 2 、-OR b 、-SR b 、-SO 2 R b 、-SO 2 NR b R c 、-COR b 、-CO 2 R b 、-CONR b R c 、-NR b R c 、-NR b COR c 、-NR b CO 2 R c 、-NR b SONR c R d 、-NR b SO 2 NR c R d or-NR b SO 2 R c Substituted by a substituent;
R b 、R c or R d Each independently selected from hydrogen, C 1-8 Alkyl radical, C 1-8 Hydroxyalkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl.
In some embodiments, R in formula (I) 1 Is selected fromR 1 Optionally further substituted with 1-4R 1a And (4) substitution.
In some embodiments, R in formula (I) 1a Is selected from H orC 1-3 An alkyl group.
In some embodiments, R in formula (I) 2 Selected from H, halogen, cyano, C 1-3 Alkyl or C 1-3 A haloalkyl group.
In some embodiments, R in formula (I) 3 Selected from H, halogen, cyano, C 1-3 Alkyl or C 1-3 A haloalkyl group.
In some embodiments, R in formula (I) 4 Is H.
In some embodiments, R in formula (I) 5 Or R 6 Each independently selected from H.
In some embodiments, R in formula (I) 8 Is selected fromR 8 Optionally further substituted with 1-4R a And (4) substitution.
In some embodiments, R in formula (I) a Selected from H, halogen, -CN, -CONR b R c Or C 1-6 Alkoxy radical, R b Or R c Each independently selected from hydrogen or C 1-6 An alkyl group.
In some embodiments, X in formula (I) 1 The substituent(s) is selected from N or CH.
In some embodiments, X in formula (I) 3 The substituent(s) is selected from N or CH.
In some embodiments, X in formula (I) 4 The substituent(s) of (b) is selected from N or CH.
In some embodiments, X in formula (I) 5 The substituent(s) is selected from N or CH.
In some embodiments, the substituent for L in formula (I) is NH.
In some embodiments, formula (I) is selected from compounds of formula (IB-1),
R 1 -R 11 as defined in any one of formulas (IB).
In some embodiments, the compound of formula (I) is selected from:
the invention also provides a pharmaceutical composition, which is characterized by comprising at least one compound shown as the formula (I) in a therapeutically effective amount and at least one pharmaceutically acceptable auxiliary material.
The invention further provides a pharmaceutical composition, which is characterized in that the mass percentage of the therapeutically effective amount of at least one compound shown in the formula (I) and pharmaceutically acceptable auxiliary materials is 0.0001.
The invention provides application of a compound or a pharmaceutical composition shown in a structural formula (I) in preparation of a medicament.
The invention further provides a preferable technical scheme of the application:
preferably, the application is the application in preparing a medicament for treating and/or preventing cancer.
Preferably, the use is for the manufacture of a medicament for the treatment of a disease mediated by HPK 1. Preferably, the disease is cancer.
Preferably, the cancer is selected from breast cancer, multiple myeloma, bladder cancer, endometrial cancer, gastric cancer, cervical cancer, rhabdomyosarcoma, non-small cell lung cancer, pleomorphic lung cancer, ovarian cancer, esophageal cancer, melanoma, colorectal cancer, hepatoma, head and neck tumors, hepatobiliary cell carcinoma, myelodysplastic syndrome, glioblastoma, prostate cancer, thyroid cancer, schwann cell tumor, lung squamous cell carcinoma, lichenification, synovial sarcoma, skin cancer, pancreatic cancer, testicular cancer, or liposarcoma.
The invention also provides a method for treating and/or preventing diseases, which comprises the step of administering at least one compound shown in the structural formula (I) or a pharmaceutical composition containing the compound to a treated object in a therapeutically effective amount.
The invention also provides a method for treating and/or preventing diseases mediated by HPK1, which comprises the step of administering at least one compound shown in the structural formula (I) or a pharmaceutical composition containing the compound to a treated object in an effective amount.
The invention also provides a method for treating cancer, which comprises administering a therapeutically effective amount of at least one compound shown in the structural formula (I) or a pharmaceutical composition containing the compound to a treated object.
Preferably, in the above method, the HPK1 mediated disease is cancer.
Preferably, in the above method, the cancer is selected from breast cancer, multiple myeloma, bladder cancer, endometrial cancer, gastric cancer, cervical cancer, rhabdomyosarcoma, non-small cell lung cancer, pleomorphic lung cancer, ovarian cancer, esophageal cancer, melanoma, colorectal cancer, hepatoma, head and neck tumor, hepatobiliary cell carcinoma, myelodysplastic syndrome, glioblastoma, prostate cancer, thyroid cancer, schwann cell tumor, lung squamous cell carcinoma, lichenification keratosis, synovial sarcoma, skin cancer, pancreatic cancer, testicular cancer, or liposarcoma.
Unless otherwise indicated, general chemical terms used in the structural formulae have the usual meanings.
For example, the term "halogen" as used herein, unless otherwise specified, refers to fluorine, chlorine, bromine or iodine.
In the present invention, unless otherwise specified, "alkyl" includes straight or branched chain monovalent saturated hydrocarbon groups. 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 the like. Similarly, "C 1-8 Alkyl group "of" 1-8 "refers to a group comprising 1,2,3,4, 5, 6, 7, or 8 carbon atoms arranged in a straight or branched chain.
"alkoxy" refers to the oxygen ether of a straight or branched chain alkyl group as previously described.
The term "alkylene" refers to a divalent alkyl linkageA group. By alkylene is meant formally an alkane in which the two C-H bonds are replaced by the point of attachment of the alkylene to the remainder of the compound. Similarly, C 1-3 "C" in alkylene 1-3 "refers to an alkylene group containing 1,2, or 3 carbon atoms, including but not limited to methylene, 1, 2-ethylene, 1, 3-propylene, or 1, 2-isopropylene.
In the present invention, "a", "an", "the", "at least one" and "one or more" are used interchangeably. Thus, for example, a composition that includes "a" pharmaceutically acceptable excipient may be interpreted to mean that the composition includes "one or more" pharmaceutically acceptable excipients.
The term "haloalkyl" refers to an alkyl group in which one or more H have been replaced with a halogen atom. The term "haloalkoxy" refers to the group of-O-haloalkyl.
The term "oxo" or "oxo" refers to an oxygen atom in the form of a divalent substituent which when attached to C forms a carbonyl group, which when attached to a heteroatom forms a sulfoxide or sulfone group or an N-oxide group.
In the present invention, the term "aromatic ring", "aromatic ring" or "aromatic heterocycle" is a carbocyclic or heterocyclic ring of polyunsaturated rings having aromatic character (having (4 n + 2) delocalized pi electrons, where n is an integer), unless otherwise indicated.
The term "aryl", as used herein, unless otherwise specified, refers to an unsubstituted or substituted monocyclic or fused ring aromatic group comprising carbocyclic atoms. Preferably C 6-12 Aryl, more preferably aryl is C 6-10 A monocyclic or bicyclic aromatic ring group of (a). Preferably phenyl or naphthyl. Most preferred is phenyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl group, wherein the ring attached to the parent structure is an aryl ring, non-limiting examples include, but are not limited to, benzocyclopentyl.
The term "heterocyclyl" refers to a ring system having at least one cyclized alkyl or cycloalkenyl group containing a heteroatom selected from the group consisting of N, O, and/or S. The heterocyclic group can include monocyclic or polycyclic (e.g., having 2,3, or 4 fused rings, spiro rings, bridged rings, etc.). The heterocyclic group may be attached to the rest of the compound via a ring-forming carbon atom or a ring-forming heteroatom. Preferably 3-12 membered heterocyclic group, "3-12 membered" in 3-12 membered heterocyclic group means heterocyclic group consisting of ring-constituting atoms containing 3-12 carbon atoms, N, O or S; more preferably 3-8 membered heterocyclic group, still more preferably 3-6 membered heterocyclic group. Wherein the nitrogen or sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatoms may optionally be quaternized. Examples of such heterocyclyl groups include, but are not limited to, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, tetrahydrofuranyl, dioxolanyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, and tetrahydrooxadiazolyl. The heterocyclyl group may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring to which the parent structure is attached is heterocyclyl.
The term "heteroaryl", as used herein, unless otherwise indicated, refers to a monocyclic or polycyclic (e.g., fused bicyclic) aromatic heterocycle having at least one heteroatom selected from N, O and/or S, and wherein the nitrogen or sulfur heteroatom may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. Preferably 5-18 membered heteroaryl, wherein "5-18 membered" in 5-18 membered heteroaryl means heteroaryl consisting of 5-18 ring-forming atoms of C, N, O or S. More preferred are 5-10 membered heteroaryl; more preferred are 5-6 membered heteroaryl groups. 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, benzofuranyl, benzothienyl, benzisoxazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl adenine, quinolinyl, or isoquinolinyl. The heteroaryl group can be fused to an aryl, heterocyclyl, or cycloalkyl ring, wherein the ring that is attached to the parent structure is a heteroaryl ring.
The term "cycloalkyl" refers to a compound having at least one ringAlkylated ring systems. Preferably C 3-12 Cycloalkyl radicals of which "C 3-12 By "it is meant that the cycloalkyl group may have 3,4, 5, 6, 7, 8, 9, 10, 11, or 12 ring-forming atoms. Cycloalkyl groups can include monocyclic and polycyclic (e.g., having 2,3, or 4 fused rings, spiro rings, bridged rings, etc.). Cycloalkyl groups in some embodiments include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and the like; the cycloalkyl groups may also be fused to aryl, heterocyclyl, or heteroaryl rings, wherein the ring to which the parent structure is attached is cycloalkyl.
The term "substituted" means that one or more hydrogen atoms in a group are replaced by the same or different substituents, respectively. Typical substituents include, but are not limited to, halogen (F, cl, br or I), C 1-8 Alkyl radical, C 3-12 Cycloalkyl, -OR 1 、-SR 1 、=O、=S、-C(O)R 1 、-C(S)R 1 、=NR 1 、-C(O)OR 1 、-C(S)OR 1 、-NR 1 R 2 、-C(O)NR 1 R 2 Cyano, nitro, -S (O) 2 R 1 、-O-S(O 2 )OR 1 、-O-S(O) 2 R 1 、-OP(O)(OR 1 )(OR 2 ) (ii) a Wherein R is 1 And R 2 Independently selected from-H, C 1-6 Alkyl radical, C 1-6 Haloalkyl or C 3-6 A cycloalkyl group. In some embodiments of the present invention, the, the substituents are independently selected from the group consisting of-F, -Cl, -Br, -I, -OH, trifluoromethoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, -SCH 3 、-SC 2 H 5 Formaldehyde group, -C (OCH) 3 ) Cyano, nitro, -CF 3 、-OCF 3 Amino, dimethylamino, methylthio, sulfonyl and acetyl groups.
Examples of substituted alkyl groups include, but are not limited to, 2, 3-dihydroxypropyl, 2-aminoethyl, 2-hydroxyethyl, pentachloroethyl, trifluoromethyl, methoxymethyl, pentafluoroethyl, phenylmethyl, dioxolanylmethyl, and piperazinylmethyl.
Examples of substituted alkoxy groups include, but are not limited to, 2-hydroxyethoxy, 2-fluoroethoxy, 2-difluoroethoxy, 2-methoxyethoxy, 2-aminoethoxy, 2, 3-dihydroxypropoxy, cyclopropylmethoxy, aminomethoxy, trifluoromethoxy, 2-diu le "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids.
When the compound provided by the present invention is an acid, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Salts derived from inorganic bases include salts of aluminum, ammonium, calcium, copper (high and low), ferric, ferrous, lithium, magnesium, manganese (high and low), potassium, sodium, zinc and the like. Particularly preferred are ammonium, calcium, magnesium, potassium and sodium salts. Non-toxic organic bases which can be derivatized to form pharmaceutically acceptable salts include primary, secondary and tertiary amines, as well as cyclic amines and substituted amines, such as naturally occurring and synthetic substituted amines. Other pharmaceutically acceptable non-toxic organic bases capable of forming salts include ion exchange resins and arginine, betaine, caffeine, choline, N' -dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, reduced glucamine, glucosamine, histidine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, chloroprocaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.
When the compounds provided by the present invention are bases, their corresponding salts can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include, for example, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, formic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, oxalic, propionic, glycolic, hydroiodic, perchloric, cyclohexanesulfonic, salicylic, 2-naphthalenesulfonic, saccharinic, trifluoroacetic, tartaric, and p-toluenesulfonic acids and the like. Preferably, citric, hydrobromic, formic, hydrochloric, maleic, phosphoric, sulfuric and tartaric acids. More preferably formic acid and hydrochloric acid.
Since the compounds of formula (I) are intended for pharmaceutical use, it is preferred to use them in a certain purity, for example, at least 60% pure, more suitably at least 75% pure, and especially at least 98% pure (% by weight).
Prodrugs of the compounds of the present invention are included within the scope of the invention. In general, the prodrug refers to a functional derivative that is readily converted in vivo to the desired compound. For example, any pharmaceutically acceptable salt, ester, salt of an ester, or other derivative of a compound of the present application, which upon administration to a subject is capable of providing, directly or indirectly, a compound of the present application or a pharmaceutically active metabolite or residue thereof.
The compounds of the present invention may contain one or more asymmetric centers and may thus give rise to diastereomers and optical isomers. The present invention includes all possible diastereomers and racemic mixtures thereof, substantially pure resolved enantiomers thereof, all possible geometric isomers thereof, and pharmaceutically acceptable salts thereof.
When the compounds of formula (I) exist as tautomers, the present invention includes any possible tautomers and pharmaceutically acceptable salts thereof, and mixtures thereof, unless otherwise specified.
Certain therapeutic advantages may be provided when compounds of formula (I) are replaced with heavier isotopes such as deuterium, for example, which may be attributed to greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements.
When solvates or polymorphs exist of the compounds of formula (I) and pharmaceutically acceptable salts thereof, the present invention includes any possible solvates and polymorphs. The type of solvent forming the solvate is not particularly limited as long as the solvent is pharmaceutically acceptable. For example, water, ethanol, propanol, acetone, and the like can be used.
The term "composition", as used herein, 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. Accordingly, pharmaceutical compositions containing the compounds of the invention as active ingredients as well as methods for preparing the compounds of the invention are also part of the present invention. In addition, some crystalline forms of the compounds may exist as polymorphs and as such are intended to be included in the present invention. In addition, some compounds may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates also fall within the scope of the present invention.
The pharmaceutical composition provided by the invention comprises a compound (or a medicinal salt thereof) shown as a formula (I) as an active component, a pharmaceutically acceptable excipient and other optional therapeutic components or auxiliary materials. Although the most suitable mode of administration of the active ingredient in any given case will depend on the particular host, host nature and severity of the condition being treated, the pharmaceutical compositions of the present invention include those suitable for oral, rectal, topical and parenteral (including subcutaneous, intramuscular, intravenous) administration. The pharmaceutical compositions of the present invention may be conveniently prepared in unit dosage forms well known in the art and by any of the methods of preparation well known in the pharmaceutical arts.
Detailed Description
In order to make the above-mentioned contents clearer and clearer, the present invention will be further illustrated by the following examples. The following examples are intended only to illustrate specific embodiments of the present invention so as to enable those skilled in the art to understand the present invention, but not to limit the scope of the present invention. In the embodiments of the present invention, technical means or methods not specifically described are conventional in the art.
All parts and percentages herein are by weight and all temperatures are in degrees Celsius, unless otherwise specified. The following abbreviations are used in the examples:
PdCl 2 (dppf): 1, 1-bis (diphenylphosphino) dicyclopentadieny iron palladium dichloride;
[PdCl 2 (dppf)]CH 2 Cl 2 : [1,1' -bis (diphenylphosphino) ferrocene]A palladium dichloride dichloromethane complex;
BrettPhos Pd G3: methanesulfonic acid (2-dicyclohexylphosphine) -3, 6-dimethoxy-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) (2 '-amino-1, 1' -biphenyl-2-yl) palladium (II);
DCM: dichloromethane;
DCE:1, 2-dichloroethane;
a Dioxane: dioxane;
DMSO, DMSO: dimethyl sulfoxide;
DIEA: n, N-diisopropylethylamine;
EA: ethyl acetate;
ESI-MS: electrospray ionization mass spectrometry;
MeOH: methanol;
PE: petroleum ether;
parkin's catalyst: (dimethylphosphonic acid) platinum (II) hydride complex;
Pre-HPLC: preparing high performance liquid chromatography;
RuPhos Pd G2: (2 ' -amino- [1,1' -biphenyl ] -2-yl) (dicyclohexyl (2 ',6' -diisopropoxy- [1,1' -biphenyl ] -2-yl) phosphoryl) palladium chloride;
THF: tetrahydrofuran.
Synthesis of intermediate compound M1
Step 1: synthesis of Compound M1-2
M1-1 (100.00 g) was dissolved in DCM (750 mL) and acetic anhydride (75 mL) was slowly added dropwise while cooling on ice and stirred at room temperature for 1 hour. Filtration and washing of the filter cake with a small amount of dichloromethane gave compound M1-2 (107.67g, 89% yield).
ESI-MS m/z:242.10[M+H] + 。
Step 2: synthesis of Compound M1-3
M1-2 (50.00 g), tris (dibenzylidene-BASE acetone) dipalladium (9.45 g), 2- (tert-butylphosphine) biphenyl (6.16 g) were added to a 1000mL three-necked flask at room temperature and dissolved with THF (100 mL) with stirring, nitrogen was replaced, N-methylpiperazine (103 mL) was added, 1mol/L lithium bistrimethylsilylamide (516 mL) was added while cooling on ice, and the mixture was heated to 70 ℃ and stirred for 2 days. The reaction was cooled and quenched with dropwise water (20 mL) under ice bath, diluted with DCM, filtered through celite, extracted with water and DCM, the organic layers were combined, concentrated under reduced pressure, and purified by column chromatography (PE: EA =9, 1-1, 4) to give compound M1-3 (24.75g, 46% yield.
ESI-MS m/z:262.25[M+H] + 。
And step 3: synthesis of Compound M1
M1-3 (24.75 g) was dissolved in MeOH (250 mL), concentrated hydrochloric acid (100 mL) was slowly added dropwise while cooling on ice, and the mixture was stirred for 2 hours while warming to 90 ℃. Cooling, pH to 8 was adjusted by slow addition of sodium carbonate under ice bath, filtered, washed with methanol (100 mL), concentrated under reduced pressure, and purified by column chromatography (DCM: meOH =50, 1-9) to give compound M1 (14.13g, 85% yield.
ESI-MS m/z:220.24[M+H] + 。
Synthesis of intermediate compound M2
Step 1: synthesis of Compound M2-2
Dimethylamine (2M/THF) (130.43 mL) was slowly added to a solution of M2-1 (40.00 g) in THF (200 mL) under ice-bath conditions, stirred at room temperature for half an hour, and sodium triacetoxyborohydride (55.28 g) was slowly added in portions while cooling on ice, and reacted at room temperature overnight. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (PE: EA = 20).
ESI-MS m/z:258.98[M+H] + 。
And 2, step: synthesis of Compound M2-3
At room temperature, adding PdCl 2 (dppf) (8.58 g) was added to a mixed solution of M2-2 (30.38 g), 3, 6-dihydro-2H-pyran-4-boronic acid pinacol ester (27.09 g) and potassium carbonate (48.61 g) in Dioxane (300 mL) and water (60 mL), and the temperature was raised to 100 ℃ with displacement of nitrogen, followed by stirring for 5 hours. The reaction solution was cooled, diluted with water, extracted with EA, and the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (PE: EA = 10)Compound M2-3 (30.00g, 98% yield).
ESI-MS m/z:263.23[M+H] + 。
And step 3: synthesis of Compound M2
M2-3 (30.00 g) was dissolved in ethanol (300 mL) at room temperature, palladium on carbon (1.22 g) was added to replace hydrogen, and the mixture was stirred at room temperature for 2 hours. The reaction solution was filtered, and the filtrate was concentrated. The residue was dissolved in ethanol (300 mL), palladium on carbon (3.57 g) and palladium hydroxide (1.57 g) were added to replace hydrogen, the temperature was raised to 40 ℃ and the mixture was stirred for 1 hour. The reaction was filtered, the filtrate was concentrated, and purified by column chromatography (DCM: meOH = 20) to give compound M2 (13.00g, 50% yield).
ESI-MS m/z:235.26[M+H] + 。
Synthesis of intermediate compound M3
Step 1: synthesis of Compound M3-2
N-iodosuccinimide (13.89 g) was dissolved in concentrated sulfuric acid (50 mL) under ice-bath conditions, M3-1 (10.00 g) was added in portions, and after stirring for 30 minutes, the ice-bath was removed and the reaction was allowed to proceed for 15 hours. The reaction solution was added dropwise to ice water, the pH was adjusted to alkalinity with a saturated sodium carbonate solution, and a solid was precipitated, filtered, and the filter cake was dried to give compound M3-2 (16.60g, 97% yield).
ESI-MS m/z:305.07[M+H] + 。
Step 2: synthesis of Compound M3-3
Formaldehyde (37%/water) (1.40 mL) and acetic acid (0.1 mL) were added to a mixed solution of M3-2 (3.80 g) of DCE (40 mL) and methanol (8 mL) at room temperature, stirred for 30 minutes, added in portions to sodium triacetoxyborohydride (3.97 g), and reacted at room temperature for 15 hours. The reaction solution was concentrated, the residue was added dropwise to ice water, the pH was adjusted to alkalinity with a saturated sodium carbonate solution, a solid was precipitated, filtration was performed, and the filter cake was dried to obtain compound M3-3 (3.89g, 98% yield).
ESI-MS m/z:319.07[M+H] + 。
And step 3: synthesis of Compound M3-4
At room temperature, [ PdCl ] will react 2 (dppf)]CH 2 Cl 2 (1.00 g) was added to a mixed solution of Dioxane (40 mL) of M3-3 (3.89 g), methylboronic acid (1.10 g) and potassium carbonate (3.38 g) in water (10 mL), and the mixture was heated to 130 ℃ while displacing nitrogen and stirred for 2.5 hours. The reaction was cooled, filtered with celite, and the filtrate was concentrated and purified by column chromatography (DCM: meOH =33: 1) to give compound M3-4 (1.89g, 75% yield).
ESI-MS m/z:207.17[M+H] + 。
And 4, step 4: synthesis of Compound M3
M3-4 (1.89 g) and ammonium chloride (2.45 g) were dissolved in a mixed solution of ethanol (30 mL) and water (10 mL) at room temperature, and iron powder (2.55 g) was added thereto, and the mixture was stirred at 70 ℃ for 4 hours. The reaction solution was cooled, filtered with celite, and the filtrate was concentrated and purified by column chromatography (DCM: meOH = 9).
ESI-MS m/z:177.24[M+H] + 。
Example 1: synthesis of Compound 1 (5- (3- (dimethylcarbamoyl) phenyl) -3- ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyridinamide)
Step 1: synthesis of Compound 1-2
1-1 (0.50 g) and 4- (4-methylpiperazine) aniline (0.53 g) were dissolved in DMSO (2 mL) at room temperature, triethylamine (1 mL) was added, and the mixture was heated to 120 ℃ and stirred for 2 hours. Diluted with water, extracted three times with EA, the organic layers were combined, washed with saturated brine, concentrated under reduced pressure, and purified by column chromatography (DCM: meOH = 20.
ESI-MS m/z:372.17[M+H] + 。
Step 2: synthesis of Compounds 1-3
At room temperature, [ PdCl 2 (dppf)]CH 2 Cl 2 (8.74 mg) to 1-2 (80.00 mg), pinacol ester of 3- (N, N-dimethylaminocarbonyl) phenylboronic acid (45.63 mg) and potassium carbonate (59.40 mg)) In a mixed solution of Dioxane (2 mL) and water (1 mL), nitrogen was replaced, the temperature was raised to 100 ℃ and the mixture was stirred overnight. The reaction was cooled, diluted with EA, filtered through celite, and the filtrate was concentrated under reduced pressure and purified by column chromatography (DCM: meOH = 12).
ESI-MS m/z:441.34[M+H] + 。
And 3, step 3: synthesis of Compound 1
1-3 (72.00 mg) was dissolved in a mixed solution of ethanol (2 mL) and water (1 mL) at room temperature, parkin's reagent (7.00 mg) was added, and the mixture was heated to 80 ℃ and stirred for 3h. The reaction was cooled, filtered through a filter, the filtrate was concentrated under reduced pressure, and purified by Pre-HPLC to give the objective compound 1 (30.00mg, 40% yield).
ESI-MS m/z:459.33[M+H] + 。
1 H NMR(500MHz,DMSO-d 6 )δ10.29(s,1H),8.23(s,1H),8.19(s,1H),7.68(d,J=4.7Hz,2H),7.61(s,1H),7.56–7.51(m,2H),7.45(d,J=7.5Hz,1H),7.19(d,J=8.7Hz,2H),6.98(d,J=8.7Hz,2H),3.15–3.09(m,4H),2.99(s,3H),2.91(s,3H),2.52–2.44(m,4H),2.24(s,3H).
Synthesis of example 2 the synthesis method of steps 2 to 3 in reference example 1, 1-2 and 4-methoxyphenylboronic acid pinacol ester were coupled to give the corresponding product, which was then hydrolyzed by Parkin's reagent to give the objective compound 2. The corresponding boronic ester intermediates are as follows:
example 3: synthesis of Compound 3 (5- (3-cyanophenyl) -3- ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrazine-2-carboxamide)
Step 1: synthesis of Compound 3-2
3-1 (1.00 g) and 4- (4-methylpiperazine) aniline (1.00 g) were dissolved in Dioxane (20.00 mL) at room temperature, DIEA (2 mL) was added, and the mixture was heated to 110 ℃ and stirred for 3 hours. Water dilution, extraction with EA three times, combining the organic layers, washing with saturated brine, concentration under reduced pressure, and column chromatography purification (DCM: meOH = 15).
ESI-MS m/z:347.25[M+H] + 。
And 2, step: synthesis of Compound 3
At room temperature, [ PdCl 2 (dppf)]CH 2 Cl 2 (8.74 mg) was added to a mixed solution of 3-2 (100.00 mg), 3-cyanophenylboronic acid pinacol ester (72.64 mg) and potassium carbonate (79.69 mg) in Dioxane (2 mL) and water (1 mL), the temperature was raised to 100 ℃ with replacement of nitrogen, and the mixture was stirred overnight. The reaction solution was cooled, diluted with EA, filtered through celite, and the filtrate was concentrated under reduced pressure and purified by column chromatography (DCM: meOH = 25).
ESI-MS m/z:414.31[M+H] + 。
1 H NMR(500MHz,DMSO-d 6 )δ11.16(s,1H),8.65(s,1H),8.59(s,1H),8.46(d,J=6.3Hz,2H),8.04–7.95(m,2H),7.78(t,J=7.8Hz,1H),7.58(d,J=8.9Hz,2H),6.98(d,J=9.0Hz,2H),3.36(s,2H),3.14–3.07(m,4H),2.48–2.44(m,4H),2.22(s,3H).
Synthesis of examples 4,5 the synthesis of step 2 in reference example 3, from 3-2 coupled with different boronic acids or boronic esters gives the corresponding target compounds. The corresponding boronic acid or boronic ester intermediates are as follows:
example 6: synthesis of compound 6 (3- ((3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -5- (2-fluoro-6-methoxyphenyl) pyrazine-2-carboxamide)
Step 1: synthesis of Compound 6-2
6-1 (1.00 g) and M1 (1.00 g) were dissolved in Dioxane (10.00 mL) at room temperature, DIEA (2 mL) was added, and the mixture was heated to 110 ℃ and stirred for 1 hour. Diluted with water, extracted three times with EA, the organic layers were combined, washed with saturated brine, concentrated under reduced pressure, and purified by column chromatography (DCM: meOH =25: 1) to give compound 6-2 (1.26g, 74% yield).
ESI-MS m/z:375.26[M+H] + 。
Step 2: synthesis of Compound 6
At room temperature, [ PdCl 2 (dppf)]CH 2 Cl 2 (32.67 mg) was added to a mixed solution of 6-2 (300.00 mg), 2-fluoro-6-methoxyphenylboronic acid (149.60 mg) and potassium carbonate (221.22 mg) in Dioxane (5 mL) and water (2 mL), the nitrogen gas was replaced, the temperature was raised to 100 ℃ and the mixture was stirred overnight. The reaction solution was cooled, diluted with EA, filtered through celite, and the filtrate was concentrated under reduced pressure and purified by column chromatography (DCM: meOH =25 1) to obtain the objective compound 6 (195.58mg, 53% yield).
ESI-MS m/z:465.36[M+H] + 。
1 H NMR(500MHz,DMSO-d 6 )δ11.10(s,1H),8.43(s,1H),8.08(s,1H),7.97(s,1H),7.52(dd,J=15.3,8.3Hz,1H),7.30(s,2H),7.07(d,J=8.4Hz,1H),7.01(t,J=9.0Hz,1H),3.84(s,3H),2.97(s,4H),2.39(s,4H),2.22(d,J=2.6Hz,9H).
Synthesis of examples 7 to 17 the synthesis of step 2 in reference example 6, from 6-2 and different boronic acids or boronic esters are coupled to give the corresponding target compounds. The corresponding boronic acid or boronic ester intermediates are as follows:
example 18: synthesis of compound 18- ((3- ((dimethylamino) methyl) -4- (tetrahydro-2H-pyran-4-yl) phenyl) amino) -5- (2-fluoro-6-methoxyphenyl) pyrazine-2-carboxamide
EXAMPLE 18 Synthesis of reference example 6 by nucleophilic substitution of 6-1 with Compound M2 to give 18-1, which was coupled with (2-fluoro-6-methoxyphenyl) boronic acid to give the target Compound 18.
ESI-MS m/z:480.37[M+H] + 。
1 H NMR(500MHz,DMSO-d 6 )δ11.20(s,1H),8.43(s,1H),8.08(s,1H),7.97(s,1H),7.59(d,J=8.8Hz,1H),7.52(dd,J=15.2,8.4Hz,1H),7.48(s,1H),7.21(d,J=8.4Hz,1H),7.06(d,J=8.5Hz,1H),6.98(t,J=9.1Hz,1H),3.92(d,J=7.1Hz,2H),3.82(s,3H),3.40(t,J=11.1Hz,4H),3.13–3.05(m,1H),2.11(s,6H),1.68–1.62(m,2H),1.59–1.54(m,2H).
Synthesis of examples 19 to 20 the synthesis of step 2 in reference example 18, from 18-1 and different boronic acids or boronic esters via coupling gives the corresponding target compounds. The corresponding boronic acid intermediates are shown in the following table:
example 21: synthesis of the compound 21- ((3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -6-ethyl-5- (2-fluoro-6-methoxyphenyl) pyrazine-2-carboxamide trifluoroacetate
Example 21 Synthesis the synthesis procedure of reference example 6 was followed, using nucleophilic substitution of 21-1 with compound M1 to give 21-2, followed by coupling with (2-fluoro-6-methoxyphenyl) boronic acid and then Pre-HPLC (mobile phase: acetonitrile/water/0.1% trifluoroacetic acid) to prepare the title compound 21.
ESI-MS m/z:493.39[M+H] + 。
1 H NMR(500MHz,DMSO-d 6 )δ10.88(s,1H),9.74(s,1H),8.30(s,1H),7.98(s,1H),7.52(dd,J=15.5,8.0Hz,1H),7.23(d,J=29.4Hz,2H),7.09–6.95(m,2H),3.79(s,3H),3.43(d,4H),3.11(q,J=9.5Hz,2H),2.97(d,J=12.6Hz,2H),2.86(s,3H),2.46(q,2H),2.20(s,6H),1.11(t,J=7.4Hz,3H).
Synthesis of examples 22 to 25 the synthesis of step 2 in reference example 21, from 21-2 and various boronic acids or boronic esters via coupling gives the corresponding target compounds. The corresponding boronic acid intermediates are as follows:
example 26: synthesis of compound 26- ((3- ((dimethylamino) methyl) -4- (tetrahydro-2H-pyran-4-yl) phenyl) amino) -6-ethyl-5- (2-fluoro-6-methoxyphenyl) pyrazine-2-carboxamide formate
Example 26 Synthesis of the synthetic method of reference example 6, 26-1 was obtained by nucleophilic substitution of 21-1 and Compound M2, and after coupling with (2-fluoro-6-methoxyphenyl) boronic acid, the objective Compound 26 was prepared by Pre-HPLC (mobile phase: acetonitrile/water/0.1% formic acid).
ESI-MS m/z:508.37[M+H] + 。
1 H NMR(500MHz,DMSO-d 6 )δ11.14(s,1H),9.42(s,1H),8.38(s,1H),8.05(s,1H),7.98(dd,J=8.7,2.0Hz,1H),7.53(dd,J=15.4,8.4Hz,1H),7.37(d,J=2.2Hz,1H),7.32(d,J=8.7Hz,1H),7.06(d,J=8.5Hz,1H),7.00(t,J=8.7Hz,1H),4.33(d,J=5.2Hz,2H),3.90(d,J=7.9Hz,2H),3.79(s,3H),3.49(t,J=11.1Hz,2H),3.06–2.95(m,1H),2.75(d,J=4.4Hz,6H),2.46(dd,J=14.5,7.3Hz,2H),1.72–1.62(m,2H),1.55–1.49(m,2H),1.11(t,J=7.5Hz,3H).
Synthesis of examples 27 to 29 the synthesis of step 2 in reference example 26 from 26-1 was coupled with different boronic acids or esters to give the corresponding target compounds. The corresponding boronic acid intermediates are as follows:
example 30: synthesis of compound 30- ((2, 5-dimethyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) -6-ethyl-5- (2-fluoro-6-methoxyphenyl) pyrazine-2-carboxamide formate
Example 30 Synthesis of reference example 6 Synthesis method, nucleophilic substitution of 21-1 with Compound M3 gave 30-1, which was coupled with (2-fluoro-6-methoxyphenyl) boronic acid and then subjected to Pre-HPLC (mobile phase: acetonitrile/water/0.1% formic acid) to prepare the title compound 30.
ESI-MS m/z:450.38[M+H] + 。
1 H NMR(500MHz,DMSO-d 6 )δ10.85(s,1H),8.29(s,1H),8.19(s,1H),7.97(s,1H),7.52(dd,J=15.4,8.4Hz,1H),7.19(s,1H),7.12(s,1H),7.05(d,J=8.5Hz,1H),7.00(t,J=8.7Hz,1H),3.80(s,3H),3.38(s,2H),2.58(s,4H),2.46(q,J=7.3Hz,2H),2.30(s,3H),2.09(s,3H),1.11(t,J=7.5Hz,3H).
Synthesis of example 31 the synthesis of step 2 in reference example 30, from 30-1 and (2, 6-difluorophenyl) boronic acid was coupled to give the corresponding title compound. The corresponding boronic acid intermediates are as follows:
example 32: synthesis of Compound 32 (4- ((3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -2- (2-fluoro-6-methoxyphenyl) pyrimidine-5-carboxamide) formate
Step 1: synthesis of Compound 32-2
32-1 (100.00 mg) and M1 (125.65 mg) were dissolved in THF (2.00 mL) at room temperature, DIEA (0.26 mL) was added in an ice bath, and the mixture was stirred at 0 ℃ for 1 hour. Dilution with water, extraction with EA three times, combining the organic layers, washing with saturated brine, concentration under reduced pressure, and column chromatography purification (DCM: meOH = 15) gave compound 32-2 (120.00mg, 61% yield.
ESI-MS m/z:375.26[M+H] + 。
And 2, step: synthesis of Compound 32
At room temperature, [ PdCl 2 (dppf)]CH 2 Cl 2 (7.84 mg) to 32-2 (120.00 mg), 2-fluoroA mixed solution of Dioxane (5 mL) and water (2 mL) of-6-methoxyphenylboronic acid (35.94 mg) and potassium carbonate (221.22 mg) was purged with nitrogen, warmed to 100 ℃ and stirred overnight. The reaction was cooled, diluted with EA, filtered through celite, and the filtrate was concentrated under reduced pressure and purified by Pre-HPLC (mobile phase: acetonitrile/water/0.1% formic acid) to give the title compound 32 (4.23mg, 5% yield).
ESI-MS m/z:465.36[M+H] + 。
1 H NMR(500MHz,DMSO-d 6 )δ11.06(s,1H),8.91(s,1H),8.42(s,1H),8.18(s,1H),7.87(s,1H),7.45(q,J=7.2Hz,1H),7.26(s,2H),7.00(d,J=8.5Hz,1H),6.92(t,J=8.8Hz,1H),3.79(d,J=0.8Hz,3H),3.00–2.92(m,4H),2.44–2.38(m,4H),2.24(s,3H),2.21(s,6H).
Example 33: synthesis of compound 33 (3- ((3, 5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -5- (2-fluoro-6-methoxyphenyl) pyridinoline)
Step 1: synthesis of Compound 33-2
At room temperature, [ PdCl ] will react 2 (dppf)]CH 2 Cl 2 (3.54 mg) was added to a mixed solution of 33-1 (200.00 mg), 2-fluoro-6-methoxyphenylboronic acid (162.39 mg) and potassium carbonate (239.48 mg) in Dioxane (4 mL) and water (2 mL), the nitrogen gas was replaced, the temperature was raised to 100 ℃, and the mixture was stirred overnight. The reaction was cooled, diluted with EA, filtered through celite, and the filtrate was concentrated under reduced pressure and purified by column chromatography (DCM: meOH =20 1) to give compound 33-2 (180.13mg, 74% yield).
ESI-MS m/z:277.19[M+H] + 。
And 2, step: synthesis of Compound 33-3
RuPhos Pd G2 (49.48 mg) was added to a solution of 33-2 (176.00 mg), 1- (4-bromo-2, 6-dimethylphenyl) -4-methylpiperazine (198.47 mg) and cesium carbonate (415.16 mg) in xylene (4 mL) at room temperature, while displacing nitrogen, raising the temperature to 150 ℃ and stirring for 9 hours. The reaction was cooled, diluted with EA, filtered through celite, and the filtrate was concentrated under reduced pressure and purified by column chromatography (DCM: meOH =14, 1) to give compound 33-3 (150.00mg, 49% yield).
ESI-MS m/z:479.36[M+H] + 。
And 3, step 3: synthesis of Compound 33
33-3 (150.00 mg) was dissolved in 7mol/L ammonia in methanol (5 mL) at room temperature, stirred at room temperature for 2 days, filtered, and dried to give the objective compound 33 (63.70mg, 44% yield).
ESI-MS m/z:464.36[M+H] + 。
1 H NMR(500MHz,DMSO-d 6 )δ10.31(s,1H),8.24(s,1H),7.94(s,1H),7.68(s,1H),7.56(s,1H),7.44(dd,J=15.3,8.3Hz,1H),7.01(d,J=8.5Hz,1H),6.95(t,J=9.0Hz,1H),6.85(s,2H),3.82(s,3H),3.02–2.95(m,4H),2.42–2.35(m,4H),2.25(s,6H),2.21(s,3H).
Example 34: synthesis of compound 34 (6- (4- (dimethylcarbamoyl) phenyl) -3- ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyridinamide)
Step 1: synthesis of Compound 34-2
At room temperature, [ PdCl 2 (dppf)]CH 2 Cl 2 (141.40 mg) was added to a mixed solution of 34-1 (400.00 mg), (4- (dimethylcarbamoyl) phenyl) boronic acid (401.00 mg) and potassium carbonate (478.50 mg) in Dioxane (8 mL) and water (2 mL), the nitrogen gas was replaced, the temperature was raised to 100 ℃ and the microwave reaction was carried out for 1 hour. The reaction was cooled, diluted with EA, filtered through celite, and the filtrate was concentrated under reduced pressure and purified by column chromatography (DCM: meOH = 30.
ESI-MS m/z:300.21[M+H] + 。
Step 2: synthesis of Compound 34-3
BrettPhos Pd G3 (60.55 mg) was added to a solution of 34-2 (200.00 mg), 1- (4-bromophenyl) -4-methylpiperazine (204.58) and cesium carbonate (653.14 mg) in Dioxane (2 mL) at room temperature, the nitrogen was replaced, the temperature was raised to 100 ℃ and the reaction was carried out by microwave reaction for 30 minutes. The reaction was cooled, diluted with EA, filtered through celite, and the filtrate was concentrated under reduced pressure and purified by column chromatography (DCM: meOH = 20).
ESI-MS m/z:474.44[M+H] + 。
And step 3: synthesis of Compound 34
34-3 (286.00 mg) was dissolved in a methanol solution (10 mL) of 7mol/L ammonia at room temperature, and the temperature was raised to 100 ℃ to conduct microwave reaction for 30 minutes. The reaction mixture was cooled, and a solid was precipitated, filtered, and dried to obtain the objective compound 34 (106.60mg, 40% yield).
ESI-MS m/z:459.42[M+H] + 。
1 H NMR(500MHz,DMSO-d 6 )δ10.31(s,1H),8.39(d,J=2.8Hz,1H),8.20(d,J=8.1Hz,2H),7.97(d,J=9.0Hz,1H),7.74(d,J=2.8Hz,1H),7.46(dd,J=8.5,6.1Hz,3H),7.14(d,J=8.8Hz,2H),6.98(d,J=8.6Hz,2H),3.13(t,J=5.0Hz,4H),2.98(d,J=19.6Hz,6H),2.46(t,J=4.7Hz,4H),2.23(s,3H).
Example 35: synthesis of compound 35 (6- (4-cyanophenyl) -3- ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrazine-2-carboxamide)
Step 1: synthesis of Compound 35-2
35-1 (1.00 g) and 4- (4-methylpiperazine) aniline (0.65 g) were dissolved in MeOH (30.00 mL) at room temperature, DIEA (2 mL) was added, and stirring was performed under reflux for 3 hours. Cooled to room temperature, diluted with water, extracted three times with EA, the organic layers were combined, washed with saturated brine, concentrated under reduced pressure, and purified by column chromatography (DCM: meOH = 10.
ESI-MS m/z:406.24[M+H] + 。
Step 2: synthesis of Compound 35-3
35-2 (1.30 g) was dissolved in 7mol/L ammonia in methanol (10 mL) at room temperature, stirred at room temperature for 4 hours, filtered, and dried to give compound 35-3 (1.25g, 99% yield).
ESI-MS m/z:391.22[M+H] + 。
And 3, step 3: synthesis of Compound 35
At room temperature, [ PdCl ] will react 2 (dppf)]CH 2 Cl 2 (6.29 mg) was added to a mixed solution of 35-3 (60.00 mg), 4-cyanophenylboronic acid pinacol ester (37.24 mg) and potassium carbonate (42.38 mg) in Dioxane (2 mL) and water (1 mL), the nitrogen gas was replaced, the temperature was raised to 100 ℃ and the mixture was stirred overnight. The reaction was cooled, diluted with EA, filtered through celite, and the filtrate was concentrated under reduced pressure and purified by column chromatography (DCM: meOH = 25.
ESI-MS m/z:414.37[M+H] + 。
1 H NMR(500MHz,DMSO-d 6 )δ11.28(s,1H),9.09(s,1H),8.71(s,1H),8.46(d,J=8.3Hz,2H),8.05(s,1H),7.92(d,J=8.3Hz,2H),7.54(d,J=8.8Hz,2H),6.95(d,J=8.8Hz,2H),3.14–3.07(m,4H),2.51–2.42(m,4H),2.22(s,3H).
Synthesis of examples 36-43 the synthesis of step 3 in reference example 35, using 35-3 and various boronic acids or boronic esters via coupling gives the corresponding target compounds. The corresponding boronic acid or boronic ester intermediates are as follows:
pharmacological experiments
Example 1: enzymatic activity assay
(1) 4 Xkinase buffer (Promega, cat. No. V9102)
(2) Compound gradient dilution: the compound to be tested is diluted by 3 times, 11 gradient concentrations are set, and each concentration is set with a multi-well detection. Solutions were diluted in 384-well formulation plates in steps to the corresponding 100-fold final concentration and then transferred with Echo to 0.1. Mu.L to 384-well reaction plates for assay. 100% DMSO of 0.1. Mu.L transferred in Min and Max wells.
(3) HPK1 enzyme working solution was prepared with 4x kinase buffer.
(4) mu.L of HPK1 enzyme working solution was added to each well, 5. Mu.L of 1 Xkinase buffer was added to Min wells, centrifuged at 1000rpm for 1min, and incubated at 25 ℃ for 15Min.
(5) During incubation, substrate working solution was prepared with 4x kinase buffer.
(6) mu.L of substrate working solution was added to each well of the reaction plate, centrifuged at 1000rpm for 1min, and incubated at 25 ℃ for 60min.
(7) At the end of incubation, 5 μ L ADP Glo reagent (Promega, cat. No. v9102) was added to each well. Centrifuge at 1000rpm for 1min and incubate at 25 ℃ for 60min.
(8) Add 10. Mu.L of assay per well, centrifuge at 1000rpm for 1min, and incubate at 25 ℃ for 60min.
(9) EnVision readings were used.
The inhibition rate calculation formula is as follows:
signal value _ max: reading of DMSO control wells
Signal value _ min-reading of non-enzyme wells
Signal value sample well reading
The log value of the concentration is taken as an X axis, the percent inhibition rate is taken as a Y axis, and an analysis software GraphPad Prism 5 'log (inhibitor) vs. response-Variable slope' module is adopted to fit a dose-effect curve, so that the IC of the compound for inhibiting the combination of the kinase is obtained 50 The value is obtained.
Examples enzymatic IC of Compounds on HPK1 50 See table 1 for data.
TABLE 1
Name of the Compound | IC 50 (nM) | Name of Compound | IC 50 (nM) |
1 | 1877 | 23 | 1 |
3 | 81 | 24 | 1.3 |
4 | 10 | 25 | 1 |
5 | 82 | 26 | 0.1 |
6 | 0.8 | 27 | 0.2 |
7 | 6 | 28 | 1.7 |
8 | 16 | 29 | 0.3 |
9 | 1 | 30 | 0.3 |
10 | 2 | 31 | 0.5 |
11 | 2 | 32 | 11 |
12 | 17 | 33 | 16 |
13 | 8 | 34 | 154 |
14 | 4 | 35 | 68 |
15 | 0.6 | 36 | 16 |
16 | 2.4 | 37 | 1 |
17 | 0.5 | 38 | 12 |
18 | 0.6 | 39 | 14 |
19 | 1.3 | 40 | 5 |
20 | 1.1 | 41 | 12 |
21 | 0.2 | 42 | 2 |
22 | 0.6 | 43 | 10 |
While the present invention has been fully described by way of embodiments thereof, it is to be noted that various changes and modifications will be apparent to those skilled in the art. Such changes and modifications are intended to be included within the scope of the appended claims.
Claims (36)
1. A compound of formula (I), a stereoisomer, a tautomer, a deuteride, or a pharmaceutically acceptable salt thereof:
wherein,
R 1 is selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-12 Aryl or 5-12 membered heteroaryl, said C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-12 Aryl or 5-12 membered heteroaryl optionally further substituted with at least one R 1a Substitution;
R 2 selected from H, halogen, cyano, C 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, C 3-12 Cycloalkyl, 3-to 12-memberedHeterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, said C 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-12 Aryl or 5-12 membered heteroaryl optionally further substituted with at least one R 2a Substitution;
or R 1 And R 2 Together with the atom to which they are attached form C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-12 Aryl or 5-12 membered heteroaryl, said C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-12 Aryl or 5-12 membered heteroaryl optionally further substituted with one or more R 1b Substituted by a substituent;
R 3 selected from H, halogen, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO 2 、-OR b 、-SR b 、-SO 2 R b 、-SO 2 NR b R c 、-COR b 、-CO 2 R b 、-CONR b R c 、-NR b R c 、-NR b COR c 、-NR b CO 2 R c 、-NR b SONR c R d 、-NR b SO 2 NR c R d or-NR b SO 2 R c Said C is 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with at least one R 3a Substitution;
R 5 or R 6 Each independently selected from H, halogen, cyano, C 1-8 Alkyl radical, C 2-8 Alkenyl or C 2-8 Alkynyl, said C 1-8 Alkyl radical, C 2-8 Alkenyl or C 2-8 Alkynyl is optionally further substituted with at least one R a Substitution;
l is selected from the group consisting of a bond, C 1-3 Alkylene, O, S or NR a Said alkylene group is optionally further substituted by at least one R a Substitution;
X 1 selected from N or CR 7 ;
X 2 Selected from N or CR 8 ;
X 3 Selected from N or CR 9 ;
X 4 Selected from N or CR 10 ;
X 5 Selected from N or CR 11 ;
R 7 、R 9 、R 10 Or R 11 Each independently selected from H, halogen, C 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO 2 、-OR b 、-SR b 、-SO 2 R b 、-SO 2 NR b R c 、-COR b 、-CO 2 R b 、-CONR b R c 、-NR b R c 、-NR b COR c 、-NR b CO 2 R c 、-NR b SONR c R d 、-NR b SO 2 NR c R d or-NR b SO 2 R c Said C is 1-8 Alkyl radical, C 1-8 Hydroxyalkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with at least one R a Substitution;
R 1a 、R 1b 、R 2a 、R 3a or R a Each independently selected from H, halogen, C 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO 2 、-OR b 、-SR b 、-SO 2 R b 、-SO 2 NR b R c 、-COR b 、-CO 2 R b 、-CONR b R c 、-NR b R c 、-NR b COR c 、-NR b CO 2 R c or-NR b SO 2 R c Said C is 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl optionally further substituted by one or more substituents selected from halogen, C 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO 2 、-OR b 、-SR b 、-SO 2 R b 、-SO 2 NR b R c 、-COR b 、-CO 2 R b 、-CONR b R c 、-NR b R c 、-NR b COR c 、-NR b CO 2 R c 、-NR b SONR c R d 、-NR b SO 2 NR c R d or-NR b SO 2 R c Substituted by a substituent;
R b 、R c or R d Each independently selected from hydrogen and C 1-8 Alkyl radical, C 1-8 Hydroxyalkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;
and R is 4 And X 2 There is a correspondence relationship that the following is present,
(1) When R is 4 Selected from aryl or heteroaryl, optionally further substituted by at least one R 4a Substitution; r is 4a Selected from H, halogen, C 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO 2 、-OR b 、-SR b 、-SO 2 R b 、-SO 2 NR b R c 、-COR b 、-CO 2 R b 、-CONR b R c 、-NR b CO 2 R c or-NR b SO 2 R c Said C is 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl optionally further substituted by one or more halogen, C 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO 2 、-OR b 、-SR b 、-SO 2 R b 、-SO 2 NR b R c 、-COR b 、-CO 2 R b 、-CONR b R c 、-NR b R c 、-NR b COR c 、-NR b CO 2 R c 、-NR b SONR c R d 、-NR b SO 2 NR c R d or-NR b SO 2 R c Substituted by a substituent;
X 2 selected from N or CR 8 ;
R 8 Selected from H, halogen, C 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, oxo, -CN, -NO 2 、-OR b 、-SR b 、-SO 2 R b 、-SO 2 NR b R c 、-COR b 、-CO 2 R b 、-CONR b R c 、-NR b R c 、-NR b COR c 、-NR b CO 2 R c 、-NR b SONR c R d 、-NR b SO 2 NR c R d or-NR b SO 2 R c Said C is 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl is optionally further substituted with at least one R a Substitution;
(2) When R is 4 Selected from H, halogen, C 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, oxo, -CN, -NO 2 、-OR b 、-SR b 、-SO 2 R b 、-SO 2 NR b R c 、-COR b 、-CO 2 R b 、-CONR b R c Amino, -N (C) 1-6 Alkyl radical) 2 、-NHC 1-6 Alkyl, -NR b COR c 、-NR b CO 2 R c 、-NR b SONR c R d 、-NR b SO 2 NR c R d or-NR b SO 2 R c Said C is 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl is optionally further substituted with at least one R a Substitution;
X 2 selected from the group consisting of CR 8 ;
R 8 Selected from 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl, said 3-12 membered heterocyclyl, C 6-12 Aryl, 5-12 membered heteroaryl optionally further substituted with at least one R a And (4) substitution.
2. The compound, its stereoisomers, tautomers, deuterons or pharmaceutically acceptable salts thereof according to claim 1, selected from the compounds represented by general formula (IA):
wherein,
R 1 is selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-12 Aryl or 5-12 membered heteroaryl, said C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-12 Aryl or 5-12 membered heteroaryl optionally further substituted with at least one R 1a Substitution;
R 2 selected from H, halogen, cyano, C 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-12 Aryl or 5-12 membered heteroaryl, said C 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-12 Aryl or 5-12 membered heteroaryl optionally further substituted with at least one R 2a Substitution;
or R 1 And R 2 Together with the atom to which they are attached form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, optionally further substituted by one or more R 1b Substituted by a substituent;
R 3 selected from H, halogen, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO 2 、-OR b 、-SR b 、-SO 2 R b 、-SO 2 NR b R c 、-COR b 、-CO 2 R b 、-CONR b R c 、-NR b R c 、-NR b COR c 、-NR b CO 2 R c 、-NR b SONR c R d 、-NR b SO 2 NR c R d or-NR b SO 2 R c Said C is 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl optionally further substituted with at least one R 3a Substitution;
R 4 selected from aryl or heteroaryl, optionally further substituted by at least one R 4a Substitution; r is 4a Selected from H, halogen, C 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO 2 、-OR b 、-SR b 、-SO 2 R b 、-SO 2 NR b R c 、-COR b 、-CO 2 R b 、-CONR b R c 、-NR b CO 2 R c or-NR b SO 2 R c Said C is 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl optionally further substituted by one or more halogen, C 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO 2 、-OR b 、-SR b 、-SO 2 R b 、-SO 2 NR b R c 、-COR b 、-CO 2 R b 、-CONR b R c 、-NR b R c 、-NR b COR c 、-NR b CO 2 R c 、-NR b SONR c R d 、-NR b SO 2 NR c R d or-NR b SO 2 R c Substituted by a substituent;
R 5 or R 6 Each independently selected from H, halogen, cyano, C 1-8 Alkyl radical, C 2-8 Alkenyl or C 2-8 Alkynyl, said C 1-8 Alkyl radical, C 2-8 Alkenyl or C 2-8 Alkynyl is optionally further substituted with at least one R a Substitution;
l is selected from the group consisting of a bond, alkylene, O, S, or NR a Said alkylene group is optionally further substituted by at least one R a Substitution;
X 1 selected from N or CR 7 ;
X 2 Selected from N or CR 8 ;
X 3 Selected from N or CR 9 ;
X 4 Selected from N or CR 10 ;
X 5 Selected from N or CR 11 ;
R 7 、R 9 、R 10 Or R 11 Each independently selected from H, halogen, C 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO 2 、-OR b 、-SR b 、-SO 2 R b 、-SO 2 NR b R c 、-COR b 、-CO 2 R b 、-CONR b R c 、-NR b R c 、-NR b COR c 、-NR b CO 2 R c 、-NR b SONR c R d 、-NR b SO 2 NR c R d or-NR b SO 2 R c Said C is 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with at least one R a Substitution;
R 8 selected from H, halogen, C 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, oxo, -CN, -NO 2 、-OR b 、-SR b 、-SO 2 R b 、-SO 2 NR b R c 、-COR b 、-CO 2 R b 、-CONR b R c 、-NR b R c 、-NR b COR c 、-NR b CO 2 R c 、-NR b SONR c R d 、-NR b SO 2 NR c R d or-NR b SO 2 R c Said C is 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl is optionally further substituted with at least one R a Substitution;
R 1a 、R 1b 、R 2a 、R 3a or R a Each independently selected from H, halogen, C 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO 2 、-OR b 、-SR b 、-SO 2 R b 、-SO 2 NR b R c 、-COR b 、-CO 2 R b 、-CONR b R c 、-NR b R c 、-NR b COR c 、-NR b CO 2 R c or-NR b SO 2 R c Said C is 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl optionally further substituted by one or more halogen, C 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO 2 、-OR b 、-SR b 、-SO 2 R b 、-SO 2 NR b R c 、-COR b 、-CO 2 R b 、-CONR b R c 、-NR b R c 、-NR b COR c 、-NR b CO 2 R c 、-NR b SONR c R d 、-NR b SO 2 NR c R d or-NR b SO 2 R c Substituted by a substituent;
R b 、R c or R d Each independently selected from hydrogen and C 1-8 Alkyl radical, C 1-8 Hydroxyalkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl.
4. The compound, its stereoisomers, tautomers, deuterons or pharmaceutically acceptable salts thereof, according to any one of claims 2-3, wherein R is 1a Is selected from H or C 1-3 An alkyl group.
5. The compound, its stereoisomers, tautomers, deuterons or pharmaceutically acceptable salts thereof according to any one of claims 2-4, wherein R is 2 Selected from H, halogen, cyano, C 1-3 Alkyl, -CH 2 N(C 1-3 Alkyl radical) 2 Or C 1-3 A haloalkyl group.
6. The compound, its stereoisomers, tautomers, deuterons or pharmaceutically acceptable salts thereof, according to any one of claims 2-5, wherein said R is 3 Selected from H, halogen, cyano, C 1-3 Alkyl, -CH 2 N(C 1-3 Alkyl radical) 2 Or C 1-3 A haloalkyl group.
8. The compound of any one of claims 2-7A stereoisomer, tautomer, deuterated compound or pharmaceutically acceptable salt thereof, wherein R is as defined above 4a Selected from H, -CON (C) 1-3 Alkyl radical) 2 、C 1-3 Alkoxy, haloalkyl, cyano or halogen.
9. The compound, its stereoisomers, tautomers, deuterons or pharmaceutically acceptable salts thereof, according to any one of claims 2-8, wherein said R is 5 Or R 6 Each independently selected from H.
10. The compound, its stereoisomers, tautomers, deuterons or pharmaceutically acceptable salts thereof, according to any one of claims 2-9, wherein X is 1 The substituent(s) is selected from N or CH.
11. The compound, its stereoisomers, tautomers, deuterons or pharmaceutically acceptable salts thereof, according to any one of claims 2-10, wherein X is 2 The substituents being selected from N, CH or-CCH 2 CH 3 。
12. The compound, its stereoisomers, tautomers, deuterons or pharmaceutically acceptable salts thereof, according to any one of claims 2-11, wherein X is 3 The substituent(s) is selected from N or CH.
13. The compound, its stereoisomers, tautomers, deuterons or pharmaceutically acceptable salts thereof, according to any one of claims 2-12, wherein X is 4 The substituent(s) is selected from N or CH.
14. The compound, its stereoisomers, tautomers, deuterons or pharmaceutically acceptable salts thereof according to any one of claims 2-13, wherein X is 5 The substituent(s) of (b) is selected from N or CH.
15. The compound, a stereoisomer, a tautomer, a deuteron, or a pharmaceutically acceptable salt thereof according to any one of claims 2 to 14, wherein the substituent of L is NH.
18. the compound, its stereoisomers, tautomers, deuterons or pharmaceutically acceptable salts thereof according to claim 1, selected from the compounds represented by general formula (IB):
wherein,
R 1 is selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-12 Aryl or 5-12 membered heteroaryl, said C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-12 Aryl or 5-12 membered heteroaryl optionally further substituted with at least one R 1a Substitution;
R 2 selected from H, halogen, cyano, C 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-12 Aryl radicalsOr 5-12 membered heteroaryl, said C 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-12 Aryl or 5-12 membered heteroaryl optionally further substituted with at least one R 2a Substitution;
or R 1 And R 2 Together with the atom to which they are attached form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, optionally further substituted by one or more R 1b Substituted by a substituent;
R 3 selected from H, halogen, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO 2 、-OR b 、-SR b 、-SO 2 R b 、-SO 2 NR b R c 、-COR b 、-CO 2 R b 、-CONR b R c 、-NR b R c 、-NR b COR c 、-NR b CO 2 R c 、-NR b SONR c R d 、-NR b SO 2 NR c R d or-NR b SO 2 R c Said C is 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with at least one R 3a Substitution;
R 4 selected from H, halogen, C 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, oxo, -CN, -NO 2 、-OR b 、-SR b 、-SO 2 R b 、-SO 2 NR b R c 、-COR b 、-CO 2 R b 、-CONR b R c Amino, -N (C) 1-6 Alkyl radical) 2 、-NHC 1-6 Alkyl, -NR b COR c 、-NR b CO 2 R c 、-NR b SONR c R d 、-NR b SO 2 NR c R d or-NR b SO 2 R c Said C is 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl optionally further substituted with at least one R a Substitution;
R 5 or R 6 Each independently selected from H, halogen, cyano, C 1-8 Alkyl radical, C 2-8 Alkenyl or C 2-8 Alkynyl radical, said C 1-8 Alkyl radical, C 2-8 Alkenyl or C 2-8 Alkynyl is optionally further substituted with at least one R a Substitution;
R 8 selected from 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl, said 3-12 membered heterocyclyl, C 6-12 Aryl, 5-12 membered heteroaryl optionally further substituted with at least one R a Substitution;
l is selected from the group consisting of a bond, alkylene, O, S or NR a Said alkylene is optionally further substituted by at least one R a Substitution;
X 1 selected from N or CR 7 ;
X 3 Selected from N or CR 9 ;
X 4 Selected from N or CR 10 ;
X 5 Selected from N or CR 11 ;
R 7 、R 9 、R 10 Or R 11 Each independently selected from H, halogen, C 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO 2 、-OR b 、-SR b 、-SO 2 R b 、-SO 2 NR b R c 、-COR b 、-CO 2 R b 、-CONR b R c 、-NR b R c 、-NR b COR c 、-NR b CO 2 R c 、-NR b SONR c R d 、-NR b SO 2 NR c R d or-NR b SO 2 R c Said C is 1-8 Alkyl radical C 2-8 Alkenyl radical, C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with at least one R a Substitution;
R 1a 、R 1b 、R 2a 、R 3a or R a Each independently selected from H, halogen, C 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO 2 、-OR b 、-SR b 、-SO 2 R b 、-SO 2 NR b R c 、-COR b 、-CO 2 R b 、-CONR b R c 、-NR b R c 、-NR b COR c 、-NR b CO 2 R c or-NR b SO 2 R c Said C is 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl optionally further substituted by one or more halogen, C 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO 2 、-OR b 、-SR b 、-SO 2 R b 、-SO 2 NR b R c 、-COR b 、-CO 2 R b 、-CONR b R c 、-NR b R c 、-NR b COR c 、-NR b CO 2 R c 、-NR b SONR c R d 、-NR b SO 2 NR c R d or-NR b SO 2 R c Substituted by a substituent;
R b 、R c or R d Each independently selected from hydrogen and C 1-8 Alkyl radical, C 1-8 Hydroxyalkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl.
20. The compound, its stereoisomers, tautomers, deuterons or pharmaceutically acceptable salts thereof, according to claim 18 or 19, wherein R is 1a Is selected from H or C 1-3 An alkyl group.
21. The compound, its stereoisomers, tautomers, deuterons or pharmaceutically acceptable salts thereof according to any one of claims 18-20, wherein said R is 2 Selected from H, halogen, cyano, C 1-3 Alkyl or C 1-3 A haloalkyl group.
22. The compound, its stereoisomers, tautomers, deuterons or pharmaceutically acceptable salts thereof according to any one of claims 18-21, wherein said R is 3 Selected from H, halogen, cyano, C 1-3 Alkyl or C 1-3 A haloalkyl group.
23. The compound, its stereoisomers, tautomers, deuterons or pharmaceutically acceptable salts thereof, according to any one of claims 18-22, wherein said R is 4 Is H.
24. The compound, its stereoisomers, tautomers, deuterons or pharmaceutically acceptable salts thereof, according to any one of claims 18-23, wherein said R is 5 Or R 6 Each independently selected from H.
26. The compound, its stereoisomers, tautomers, deuterons or pharmaceutically acceptable salts thereof, according to any one of claims 18-25, wherein said R is a Selected from H, halogen, -CN, -CONR b R c Or C 1-6 Alkoxy radical, R b Or R c Each independently selected from hydrogen or C 1-6 An alkyl group.
27. The compound, its stereoisomers, tautomers, deuterons or pharmaceutically acceptable salts thereof according to any one of claims 18-26, wherein X is 1 The substituent(s) is selected from N or CH.
28. The compound, its stereoisomers, tautomers, deuterons or pharmaceutically acceptable salts thereof, according to any one of claims 18-27, wherein X is 3 The substituent(s) of (b) is selected from N or CH.
29. The compound, its stereoisomers, tautomers, deuterons or pharmaceutically acceptable salts thereof according to any one of claims 18-28, wherein X is 4 The substituent(s) of (b) is selected from N or CH.
30. The compound, its stereoisomers, tautomers, deuterons or pharmaceutically acceptable salts thereof, according to any one of claims 18-29, wherein X is 5 The substituent(s) is selected from N or CH.
31. The compound, a stereoisomer, a tautomer, a deuteron, or a pharmaceutically acceptable salt thereof according to any one of claims 18-30, wherein the substituent of L is NH.
34. a pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of claims 1-33 and at least one pharmaceutically acceptable excipient.
35. Use of a compound according to any one of claims 1 to 33 or a pharmaceutical composition according to claim 34 in the manufacture of a medicament.
36. A method of treating and/or preventing a disease comprising administering to a subject a therapeutically effective amount of a compound of any one of claims 1-33 or a pharmaceutical composition of claim 34.
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