CN114524810B - Pyrimidine heterocyclic compounds, preparation method and application - Google Patents

Pyrimidine heterocyclic compounds, preparation method and application Download PDF

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CN114524810B
CN114524810B CN202111387596.1A CN202111387596A CN114524810B CN 114524810 B CN114524810 B CN 114524810B CN 202111387596 A CN202111387596 A CN 202111387596A CN 114524810 B CN114524810 B CN 114524810B
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alkyl
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pharmaceutically acceptable
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acceptable salt
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CN114524810A (en
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万惠新
王亚周
马金贵
王亚辉
查传涛
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Shanghai Lingda Biomedical Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Abstract

The invention discloses a pyrimido heterocyclic compound, a preparation method and application thereof, in particular to a pyrimido condensed ring compound shown in a general formula I, or pharmaceutically acceptable salt thereof, or enantiomer, diastereoisomer, tautomer, torsional isomer, solvate, polymorph or prodrug thereof, a preparation method thereof and application thereof in pharmacy, wherein the definition of each group is described in the specification.

Description

Pyrimidine heterocyclic compounds, preparation method and application
Technical Field
The invention belongs to the field of pharmaceutical chemistry, in particular relates to a pyrimido heterocyclic compound which has better SOS1 inhibition activity and can be used for preparing therapeutic and preventive drugs for treating diseases related to Ras activity or expression or mutation.
Background
Ras proteins are key mediators in normal cell growth and malignant transformation processes, including cell proliferation, survival and invasion, tumor angiogenesis and metastasis, and the like. In most human tumors, ras proteins are abnormally activated by mutations in the Ras gene itself or in the upstream or downstream Ras pathway components, or other changes in Ras signaling. Such mutations reduce the ability of RAS family gtpases to hydrolyze GTP, allowing the molecular switch to remain in an active GTP-bound form at all times, which drives unexamined oncogenic downstream signaling. One strategy to reduce the level of active RAS is directed to guanine nucleotide exchange factors (GEFs) that allow the RAS to cycle from an inactive GDP-bound state to an active GTP-bound form. By preventing the formation of KRAS-SOS1 complex, SOS1 inhibitors block the reloading of KRAS with GTP, resulting in antiproliferative activity. Inhibition of SOS1 may represent a viable approach to targeting RAS-driven tumors.
Ras-driven cancer remains the most clinically refractory class of diseases at present, and new therapeutic and prophylactic strategies are urgently needed for this cancer. The discovery of Ras-selective targeting drugs by the global academia and industry has been continued for many years, but has not been approved for marketing to date. In the last two years, targeting drugs against Ras drive have entered the clinical trial phase successively and showed better primary efficacy with encouraging results.
Therefore, the urgent need for Ras-driven tumors is that more therapeutic drugs with unique mechanisms, high efficiency and low toxicity enter the clinic, and the discovery and search of Ras-targeted drugs with high efficiency, low toxicity and novel structure is still a great hotspot field in the industry.
Disclosure of Invention
One of the technical problems to be solved by the invention is to provide a novel SOS1 inhibitor for preparing tumor therapeutic drugs.
The scheme for solving the technical problems is as follows:
in a first aspect of the present invention there is provided a pyrimidoheterocyclic compound having the general formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsional isomer, solvate, polymorph or prodrug thereof,
Wherein:
R 1 independently selected from C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 12 Cycloalkyl, C 4 -C 12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 5-12 membered aryl or 5-12 membered heteroaryl, carbocyclic or heteroatom containing spiro/bridged/fused rings, wherein said C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 12 Cycloalkyl, C 4 -C 12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 5-12 membered aryl or 5-12 membered heteroaryl, carbocyclic or heteroatom-containing spiro/bridged/fused rings, optionallyOptionally by 1-3R n Substitution; or two R n A 3-to 12-membered saturated or partially unsaturated, or aromatic ring system may be formed by a carbon chain or a heteroatom; said R is n Selected from hydrogen, deuterium, halogen, cyano, nitro, amide, sulfonamide, hydroxy, amino, ureido, phosphoryl, alkylphosphoxy, alkylsilyl, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, haloalkyl, haloalkoxy, C 1 -C 6 Monoalkylamino, C 1 -C 6 Dialkylamino, alkenyl, alkynyl, 3-8 membered cycloalkyl or heterocycloalkyl, C 1 -C 6 alkyl-S-, C 1 -C 6 alkyl-SO-, C 1 -C 6 alkyl-SO 2- Etc.;
R 2a and R is 2b Are independently selected from hydrogen, deuterium, halogen, C 1 -C 6 Alkyl, 3-8 membered cycloalkyl or heterocycloalkyl; and R is 2a And R is 2b Or R is 2a With substituents R on Ar m A 3-6 membered saturated or partially unsaturated or unsaturated ring system may be formed by a carbon chain or heteroatom;
R 3 is H, deuterium, halogen, hydroxy, amino, cyano, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkoxy, C 1 -C 6 Alkylamino, 3-8 membered cycloalkyl or heterocycloalkyl, C 2 -C 4 Alkenyl, C 2 -C 4 Alkynyl, 5-10 membered aromatic ring or aromatic heterocyclic group;
m is independently selected from N or CR 4 ，R 4 Selected from hydrogen, deuterium, halogen, cyano, C 1 -C 6 Alkyl, 3-8 membered cycloalkyl or heterocycloalkyl;
Ar 1 and Ar is a group 2 A monocyclic or bicyclic aryl or heteroaryl group independently selected from 5-12 membered, which may be substituted with one or more (e.g. 1, 2, 3, 4, 5) groups R selected from the group consisting of m The substitution is as follows: hydrogen, deuterium, halogen, cyano, nitro, substituted or unsubstituted amide, substituted or unsubstitutedSulfonamide, hydroxy, amino, ureido, phosphoryl, alkylphosphoxy, alkylsilyl, C 1 -C 10 Alkyl, C 1 -C 10 Alkoxy, C 1 -C 10 Alkoxyalkyl, C 1 -C 10 Haloalkyl, C 1 -C 10 Haloalkoxy, C1-C 10 Haloalkoxyalkyl, C 1 -C 10 Monoalkylamino, C 1 -C 10 Dialkylamino, C 1 -C 10 Monoalkylaminoalkyl, C 1 -C 10 Dialkylaminoalkyl, C 1 -C 10 Alkenyl, C 1 -C 10 Alkynyl, 3-12 membered cycloalkyl or heterocycloalkyl, C 1 -C 10 alkyl-S-, C 1 -C 10 alkyl-SO-, C 1 -C 10 alkyl-SO 2 -, substituted or unsubstituted 5-to 12-membered aryl or heteroaryl, etc., or both R' s m A 3-to 12-membered saturated or partially unsaturated, or aromatic ring system may be formed by a carbon chain or a heteroatom; .
One or more (e.g., 1, 2, 3, 4, 5) hydrogen atoms on any of the above groups may be substituted with a substituent selected from the group consisting of: including but not limited to deuterium, halogen, hydroxy, amino, C 1 -C 3 Monoalkylamino, C 1 -C 3 Dialkylamino, C 1 -C 3 Alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl alkyl; wherein the heteroaryl group comprises 1 to 3 heteroatoms selected from the group consisting of: n, O, P or S, said heterocycloalkyl comprising 1 to 3 heteroatoms selected from the group consisting of: n, O, P or S, said ring system comprising a spiro, bridged, fused, or other saturated or partially unsaturated ring system.
In some preferred embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsional isomer, solvate, polymorph or prodrug thereof, is preferably a compound of formula (II),
Wherein R is 3 Preferably selected from H, me, cyclopropyl, chlorine; m is preferably selected from N or C-H or C-F or C-CN or C-Me; the scope of the other groups is as defined above.
In some preferred embodiments, when R 2a And R is R 2b When not identical, R is 2a And R is 2b The commonly attached carbon atoms are in the R configuration.
In some preferred embodiments, the R 2a And R is 2b The commonly attached carbon atoms are those of the R configuration.
In some preferred embodiments, R 2a And R is 2b Each independently is hydrogen, C 1 -C 6 Alkyl groups, preferably hydrogen and methyl.
In some preferred embodiments, R 3 Is C 1 -C 3 Alkyl groups, preferably methyl groups.
In some preferred embodiments, M is C-H.
In some preferred embodiments, R 1 Selected from C 1 -C 6 Alkyl, C 3 -C 12 Cycloalkyl, -C 4 -C 12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 5-12 membered aryl or 5-12 membered heteroaryl, which may be optionally substituted with 1-3 Rn, said Rn being as described in the first aspect of the invention.
In some preferred embodiments, R 1 Selected from C 1 -C 6 Alkyl, C 3 -C 8 Cycloalkyl, 3-8 membered heterocycloalkyl, which may be optionally substituted with 1-3 Rn, said Rn being as described in the first aspect of the invention.
In some preferred embodiments, R 1 Selected from C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, 5-8 membered heterocycloalkyl, - (C1-C6 alkylene) -C 3 -C 6 Cycloalkyl, - (C1-C6 alkylene) -5-8 membered heterocycloalkyl, which may be optionally substituted by 1-3 Rn, which is halogen, C1-C3 alkyl.
In some preferred embodiments, R 1 Selected from 5-6 membered heterocycloalkyl- (C1-C3 alkylene) -5-6 membered heterocycloalkyl.
In some preferred embodiments, the heterocycloalkyl is a C5-C6 heterocycloalkyl comprising 1-3 (e.g., 1, 2, 3) heteroatoms selected from O, S, N.
In some preferred embodiments, the heteroatom or carbon atom may be further oxidized, e.g., -S-may be oxidized to-SO-or-SO 2 -, -C-is oxidizable to-CO-.
In some preferred embodiments, a compound of formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsional isomer, solvate, polymorph or prodrug thereof, is characterized by: r is R 1 Preferably selected from the following groups: wherein one or more (e.g. 1, 2, 3) R' s c Are each independently selected from hydrogen, deuterium, halogen, -C 1 -C 6 Alkyl, -OC 1 -C 6 Alkyl, cyano, hydroxy, amino, -SC 1 -C 6 Alkyl, -SOC 1 -C 6 Alkyl, -SO 2 C 1 -C 6 Alkyl, -COC 1 -C 6 Alkyl, -COOC 1 -C 6 Alkyl, -CONHC 1 -C 6 Alkyl, -CON (C) 1 -C 6 Alkyl) (C) 1 -C 6 Alkyl), 3-6 membered cycloalkyl or heterocycloalkyl, 5-10 membered aryl or heteroaryl, -C 1 -C 6 Haloalkyl, -C 1 -C 6 Haloalkoxy, -C 1 -C 6 Deuterated alkyl, -C 1 -C 6 Deuteroalkoxy, -O-3-6 membered cycloalkyl or heterocycloalkyl,-C 1 -C 6 Alkyl OC 1 -C 6 Alkyl, -C 1 -C 6 Alkyl NHCs 1 -C 6 Alkyl, -C 1 -C 6 Alkyl OH, -C 1 -C 6 Alkyl N (C) 1 -C 6 Alkyl) (C) 1 -C 6 Alkyl), and any two Rc may form a 3-to 10-membered saturated or partially unsaturated carbocyclic or heterocyclic ring through a carbon chain or heteroatom; r is R d Independently selected from hydrogen, -C 1 -C 6 Alkyl, -C 1 -C 6 Alkyl OC 1 -C 6 Alkyl, -C 1 -C 6 Alkyl SC 1 -C 6 Alkyl, -C 1 -C 6 Alkyl SOCs 1 -C 6 Alkyl, -C 1 -C 6 Alkyl SO 2 C 1 -C 6 Alkyl, -COC 1 -C 6 Alkyl, -COOC 1 -C 6 Alkyl, -CONHC 1 -C 6 Alkyl, -CON (C) 1 -C 6 Alkyl) (C) 1 -C 6 Alkyl), 3-6 membered cycloalkyl or heterocycloalkyl, 5-10 membered aryl or heteroaryl, -C 1 -C 6 Haloalkyl, -C 1 -C 6 Haloalkoxy, -C 1 -C 6 Deuterated alkyl, -C 1 -C 6 Deuterated alkoxy-C 1 -C 6 Alkyl, -C 1 -C 6 Alkyl O-3-6 membered cycloalkyl or heterocycloalkyl, -C 1 -C 6 Alkyl NHCs 1 -C 6 Alkyl, -C 1 -C 6 Alkyl OH, -C 1 -C 6 Alkyl N (C) 1 -C 6 Alkyl) (C) 1 -C 6 Alkyl), and the like.
In some preferred embodiments, R 1 Selected from the following groups:
wherein R is c 、R d As described in the first aspect of the invention.
In some preferred embodiments, R 1 Selected from the following groups:wherein R is c 、R d As described in the first aspect of the invention.
In some preferred embodiments, R c Independently preferably selected from hydrogen, halogen, -C 1 -C 3 Alkyl, -C 1 -C 3 Haloalkyl, 3-6 membered cycloalkyl or heterocycloalkyl; r is R d Independently selected from hydrogen, -C 1 -C 3 An alkyl group.
In some preferred embodiments, rn is selected from hydrogen, halogen, C 1 -C 3 Alkyl, 3-8 membered cycloalkyl or heterocycloalkyl.
In other preferred embodiments, ar 1 And Ar is a group 2 Each independently is a 6-10 membered aryl, furyl, thienyl, pyridyl, pyrazolyl.
In other preferred embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsional isomer, solvate, polymorph or prodrug thereof, is preferably a compound of formula (III): the scope of the other groups is as defined above.
In other preferred embodiments, R m Selected from hydrogen, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Alkenyl, C 1 -C 6 Alkynyl, hydroxy, amino, C 1 -C 8 Monoalkylamino, C 1 -C 8 Dialkylamino, C1-C8 amido, C1-C8 sulfonamido, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, 3-8 membered cycloalkylalkyl, 3-8 membered heterocycloalkylAminoalkyl, C 1 -C 6 alkyl-S-, C 1 -C 6 alkyl-SO-, C 1 -C 6 alkyl-SO 2 -, or two R as described above m By carbon chains or heteroatoms constituting 3-to 8-membered saturated or partially unsaturated, or aromatic ring systems, wherein R is m Can be further selected from amino, C 1 -C 3 Monoalkylamino, C 1 -C 3 Dialkylamino, C 1 -C 3 Alkyl, hydroxy, 3-6 membered heterocycloalkyl alkyl.
In other preferred embodiments, R m Selected from hydrogen, halogen, C 1 -C 6 Alkyl, C 1 -C 4 Alkoxy, C 1 -C 4 Alkenyl, C 1 -C 4 Alkynyl, hydroxy, amino, C 1 -C 6 Monoalkylamino, C 1 -C 6 Dialkylamino, C 1 -C 6 Amide group, C 1 -C 6 Sulfonamide group, 3-6 membered heterocycloalkyl- (C1-C3 alkyl) -, 5-10 membered aryl, 5-10 membered heteroaryl, C 1 -C 3 alkyl-SO 2 -, or two R as described above m By carbon chains or heteroatoms constituting 5-to 6-membered saturated or partially unsaturated, or aromatic ring systems, where R is m Can be further selected from amino, C 1 -C 3 Monoalkylamino, C 1 -C 3 Dialkylamino, C 1 -C 3 Alkyl, hydroxy, 3-6 membered heterocycloalkyl alkyl.
In other preferred embodiments, R m Selected from hydrogen, halogen, C 1 -C 4 Monoalkylamino, C 1 -C 4 Dialkylamino, 3-6 membered heterocycloalkyl- (C1-C3 alkyl) -, or both R m The 5-6 membered saturated ring is constituted by a carbon chain or a heteroatom.
In some preferred embodiments, R 1 、R 2a 、R 2b 、R 3 、Ar 1 、Ar 2 M are each independently a compound prepared in the examples The corresponding groups in items 1-86.
In some preferred embodiments, the compound is any one of compounds 1-86 prepared in the examples, or a pharmaceutically acceptable salt thereof.
In a second aspect of the invention, there is provided a pyrimido condensed ring compound as shown in the general formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsion isomer, solvate, polymorph or prodrug thereof,
wherein:
R 1 independently selected from C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 12 Cycloalkyl, C 4 -C 12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 5-12 membered aryl, or 5-12 membered heteroaryl, wherein said C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 12 Cycloalkyl, C 4 -C 12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 5-12 membered aryl, or 5-12 membered heteroaryl may be optionally substituted with 1-3 Rn; or the two Rn may form a 3-12 membered saturated or partially unsaturated, or aromatic ring system through a carbon chain or heteroatom; said Rn is selected from hydrogen, deuterium, halogen, cyano, nitro, amide, sulfonamide, hydroxy, amino, ureido, phosphoryl, alkylphosphoroxy, alkylsilyl, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, haloalkyl, haloalkoxy, C 1 -C 6 Monoalkylamino, C 1 -C 6 Dialkylamino, alkenyl, alkynyl, 3-8 membered cycloalkyl or heterocycloalkyl, C 1 -C 6 alkyl-S-, C 1 -C 6 alkyl-SO-, C 1 -C 6 alkyl-SO 2- Etc.;
R 2a and R is 2b Are independently selected from hydrogen, deuterium, halogen, C 1 -C 6 Alkyl, 3-8 membered cycloalkyl or heterocycloalkyl; and R is 2a And R is 2b A 3-6 membered saturated or partially unsaturated or unsaturated ring system may be formed by a carbon chain or heteroatom;
R 3 is H, deuterium, halogen, hydroxy, amino, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C6 alkylamino, 3-8 membered cycloalkyl or heterocycloalkyl, C 2 -C 4 Alkenyl, C 2 -C 4 Alkynyl;
m is independently selected from N or CR 4 ，R 4 Selected from hydrogen, deuterium, halogen, cyano, C 1 -C 6 Alkyl, 3-8 membered cycloalkyl or heterocycloalkyl;
Ar 1 and Ar is a group 2 Each independently selected from 5-12 membered monocyclic or bicyclic aryl or heteroaryl groups, which may be substituted with one or more groups selected from the group consisting of: hydrogen, deuterium, halogen, cyano, nitro, substituted or unsubstituted amide, substituted or unsubstituted sulfonamide, hydroxy, amino, ureido, phosphoryl, alkylphosphoxy, alkylsilyl, C 1 -C 10 Alkyl, C 1 -C 10 Alkoxy, C 1 -C 10 Alkoxyalkyl, C 1 -C 10 Haloalkyl, C 1 -C 10 Haloalkoxy, C1-C 10 Haloalkoxyalkyl, C 1 -C 10 Monoalkylamino, C 1 -C 10 Dialkylamino, C 1 -C 10 Monoalkylaminoalkyl, C 1 -C 10 Dialkylaminoalkyl, C 1 -C 10 Alkenyl, C 1 -C 10 Alkynyl, 3-12 membered cycloalkyl or heterocycloalkyl, C 1 -C 10 alkyl-S-, C 1 -C 10 alkyl-SO-, C 1 -C 10 alkyl-SO 2 -and the like; and Ar is as described above 1 And Ar is a group 2 Any two adjacent substituents on the ring may form 3-8 members through a carbon chain or heteroatomSaturated or partially unsaturated or unsaturated ring systems.
One or more hydrogen atoms on any of the above groups may be substituted with a substituent selected from the group consisting of: including but not limited to deuterium, halogen, C 1 -C 3 Alkyl, 3-6 membered cycloalkyl or heterocycloalkyl; wherein the heteroaryl group comprises 1 to 3 heteroatoms selected from the group consisting of: n, O, P or S, said heterocycloalkyl comprising 1 to 3 heteroatoms selected from the group consisting of: n, O, P or S, said ring system comprising a spiro, bridged, fused, or other saturated or partially unsaturated ring system.
In some preferred embodiments, the compound is a compound of formula (II), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsional isomer, solvate, polymorph or prodrug thereof:
Wherein R is 3 Preferably selected from H, me; m is preferably selected from N or C-H or C-F or C-CN or C-Me; the scope of the other groups is as defined above.
In some preferred embodiments, the compound is a compound of formula (III), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsional isomer, solvate, polymorph or prodrug thereof:
wherein R is 1 、M、Ar 2 The ranges of (a) are as defined above.
In a third aspect of the present invention there is provided a process for the preparation of a compound of formula I, said process comprising steps a-d:
a) The compound of the general formula (A) and the compound of the general formula (B) undergo substitution reaction under the catalysis of alkali to generate an intermediate compound (C); and
b) Hydrolyzing the intermediate compound of formula (C) to form an intermediate compound (D);
c) Combining the intermediate (D) compound with R 1 NH 2 Generating an intermediate (E) by condensation reaction under the participation of a condensing agent;
d) The intermediate (E) is subjected to ring closure reaction under the catalysis of acid to generate the general formula (I).
R is alkyl, such as methyl, ethyl, tert-butyl, benzyl, etc.; the other groups are as defined above;
preferably, the steps a), b), c), d) are each carried out in a solvent, and the solvent is selected from the group consisting of: water, methanol, ethanol, isopropanol, butanol, ethylene glycol methyl ether, N-methylpyrrolidone, dimethyl sulfoxide, tetrahydrofuran, toluene, methylene chloride, 1, 2-dichloroethane, acetonitrile, N-dimethylformamide, N-dimethylacetamide, dioxane, or a combination thereof.
Preferably, the inorganic base is selected from the group consisting of: sodium hydride, potassium hydroxide, sodium acetate, potassium t-butoxide, sodium t-butoxide, potassium fluoride, cesium fluoride, potassium phosphate, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, or a combination thereof; the organic base is selected from the group consisting of: pyridine, triethylamine, N, N-diisopropylethylamine, 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU), lithium hexamethyldisilazide, sodium hexamethyldisilazide, lutidine, or combinations thereof.
Preferably, the condensing agent is selected from the group consisting of: DCC (dicyclohexylcarbodiimide), DIC (diisopropylcarbodiimide), CDI (carbonyldiimidazole), EDCI (1-ethyl-3 (3-dimethylpropylamine) carbodiimide), HOAt (1-hydroxy-7-azabenzotriazole), HOBt (1-hydroxybenzotriazole), BOP (carbo condensing agent), pyBOP (1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate), HATU (2- (7-azabenzotriazol) -N, N' -tetramethylurea hexafluorophosphate), TBTU (benzotriazole tetramethyl tetrafluoroboric acid), and the like, or combinations thereof.
Preferably, the acid is selected from the group consisting of: hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, toluenesulfonic acid, trifluoroacetic acid, formic acid, acetic acid, trifluoromethanesulfonic acid or combinations thereof.
The invention provides a class of preferred compounds of formula (I) including, but not limited to, the following structures:
it is another object of the present invention to provide a medicament for treating or preventing tumors and a composition thereof. The technical scheme for achieving the purpose is as follows:
a pharmaceutical composition for treating tumors, which consists of pyrimidoheterocyclic compounds shown in the general formula (I), or pharmaceutically acceptable salts thereof, or enantiomers, diastereomers, tautomers, torsional isomers, solvates, polymorphs or prodrugs thereof and pharmaceutically acceptable carriers.
It is a further object of the present invention to provide the use of the above compounds. The technical scheme for achieving the purpose is as follows:
the pyrimidoheterocyclic compound shown in the general formula (I), or pharmaceutically acceptable salt thereof, or enantiomer, diastereoisomer, tautomer, torsional isomer, solvate, polymorph or prodrug thereof is used for preparing medicines for treating diseases related to Ras mutation, activity or expression quantity, in particular to medicines for treating tumors. The tumor is independently selected from non-small cell lung cancer, lung adenocarcinoma, lung squamous carcinoma, breast cancer, prostate cancer, liver cancer, skin cancer, gastric cancer, intestinal cancer, bile duct cancer, brain cancer, leukemia, lymphoma, fibroma, sarcoma, basal cell carcinoma, glioma, renal cancer, melanoma, bone cancer, thyroid cancer, nasopharyngeal cancer, pancreatic cancer, etc.
The invention relates to a compound with the structural characteristics of a general formula (I), which can inhibit various tumor cells, especially can efficiently kill tumors related to abnormal Ras protein signal paths, and is a therapeutic drug with a brand-new action mechanism.
It is understood that within the scope of the present invention, the above-described technical features of the present invention and technical features specifically described below (e.g., in the examples) may be combined with each other to constitute new or preferred technical solutions. The limited space is not described in any more detail herein.
Detailed Description
The inventor has prepared a class of pyrimidine heterocyclic compounds with novel structure shown in formula I through long-term and intensive research, and found that the pyrimidine heterocyclic compounds have better SOS1 protein inhibition activity, and the compounds have specific inhibition effect on SOS1 protein at extremely low concentration (which can be lower than 100 nM), and have quite excellent cell proliferation inhibition activity related to Ras pathway, so that the pyrimidine heterocyclic compounds can be used for treating related diseases caused by RAS mutation or activity or expression quantity abnormality, such as tumors. Based on the above findings, the inventors have completed the present invention.
Terminology
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs. All patents, patent applications, and publications cited herein are hereby incorporated by reference in their entirety unless otherwise indicated.
It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the inventive subject matter. In the present application, the singular is used to include the plural unless specifically stated otherwise. It must be noted that, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. It should also be noted that the use of "or" means "and/or" unless stated otherwise. Furthermore, the terms "include," as well as other forms, such as "comprising," "including," and "containing," are not limiting.
Conventional methods within the skill of the art, such as mass spectrometry, NMR, IR and UV/VIS spectroscopy, and pharmacological methods are employed unless otherwise indicated. Unless specifically defined otherwise, the terms used herein in the description of analytical chemistry, organic synthetic chemistry, and pharmaceutical chemistry are known in the art. Standard techniques may be used in chemical synthesis, chemical analysis, pharmaceutical preparation, formulation and delivery, and treatment of patients. For example, the reaction and purification can be carried out using the manufacturer's instructions for the kit, or in a manner well known in the art or in accordance with the teachings of the present application. The techniques and methods described above may generally be practiced according to conventional methods well known in the art, based on a number of general and more specific descriptions in the literature cited and discussed in this specification. In this specification, groups and substituents thereof can be selected by one skilled in the art to provide stable moieties and compounds.
When substituents are described by conventional formulas written from left to right, the substituents also include chemically equivalent substituents obtained when writing formulas from right to left. For example, -CH 2 O-is equivalent to-OCH 2 -。
The section headings used herein are for purposes of organizing articles only and should not be construed as limiting the subject matter. All documents or portions of documents cited in this disclosure, including but not limited to patents, patent applications, articles, books, operating manuals, and treatises, are hereby incorporated by reference in their entirety.
Certain chemical groups defined herein are preceded by a simplified symbol to indicate the total number of carbon atoms present in the group. For example, C1-6 alkyl refers to an alkyl group as defined below having a total of 1 to 6 carbon atoms. The total number of carbon atoms in the reduced notation does not include carbon that may be present in a substituent of the group.
In addition to the foregoing, when used in the specification and claims of the present application, the following terms have the meanings indicated below, unless otherwise specified.
In the present application, the term "halogen" refers to fluorine, chlorine, bromine or iodine; "hydroxy" refers to an-OH group; "hydroxyalkyl" refers to an alkyl group as defined below substituted with a hydroxy (-OH); "carbonyl" refers to-C (=) O) -group; "nitro" means-NO 2 The method comprises the steps of carrying out a first treatment on the surface of the "cyano" refers to-CN; "amino" means-NH 2 The method comprises the steps of carrying out a first treatment on the surface of the "substituted amino" refers to an amino group substituted with one or two alkyl, alkylcarbonyl, aralkyl, heteroaralkyl groups as defined below, e.g., mono-, di-, alkylamido, aralkylamino, heteroaralkylamino; "carboxy" refers to-COOH.
In the present application, as part of a group or other groups (e.g., as used in halogen-substituted alkyl groups and the like), the term "alkyl" means a straight or branched hydrocarbon chain group consisting of only carbon atoms and hydrogen atoms, free of unsaturated bonds, having, for example, 1 to 12 (preferably 1 to 8, more preferably 1 to 6) carbon atoms, and linked to the rest of the molecule by a single bond. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2-dimethylpropyl, n-hexyl, heptyl, 2-methylhexyl, 3-methylhexyl, octyl, nonyl, decyl and the like.
In the present application, the term "alkenyl" as part of a group or other group means a straight or branched hydrocarbon chain group consisting of only carbon and hydrogen atoms, containing at least one double bond, having, for example, 2 to 14 (preferably 2 to 10, more preferably 2 to 6) carbon atoms, and being linked to the rest of the molecule by a single bond, such as, but not limited to, ethenyl, propenyl, allyl, but-1-enyl, but-2-enyl, pent-1, 4-dienyl, and the like.
In the present application, the term "alkynyl" as part of a group or other group means a straight or branched hydrocarbon chain group consisting of only carbon atoms and hydrogen atoms, containing at least one triple bond and optionally one or more double bonds, having, for example, 2 to 14 (preferably 2 to 10, more preferably 2 to 6) carbon atoms and being linked to the rest of the molecule by single bonds, such as, but not limited to, ethynyl, prop-1-ynyl, but-1-ynyl, pent-1-en-4-ynyl, and the like.
In the present application, as part of a group or other group, the term "cycloalkyl" means a stable, non-aromatic, mono-or polycyclic hydrocarbon group consisting of only carbon and hydrogen atoms, which may include fused ring systems, bridged ring systems, or spiro ring systems, having from 3 to 15 carbon atoms, preferably from 3 to 10 carbon atoms, more preferably from 3 to 8 carbon atoms, and which is saturated or unsaturated and may be attached to the remainder of the molecule by a single bond via any suitable carbon atom. Unless otherwise specifically indicated in the specification, carbon atoms in cycloalkyl groups may optionally be oxidized. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexanyl, cyclooctyl, 1H-indenyl, 2, 3-indanyl, 1,2,3, 4-tetrahydro-naphthyl, 5,6,7, 8-tetrahydro-naphthyl, 8, 9-dihydro-7H-benzocyclohepten-6-yl, 6,7,8, 9-tetrahydro-5H-benzocycloheptenyl, 5,6,7,8,9, 10-hexahydro-benzocyclooctenyl, fluorenyl, bicyclo [2.2.1] heptyl, 7-dimethyl-bicyclo [2.2.1] heptyl, bicyclo [2.2.1] heptenyl, bicyclo [ 2.2.2.2 ] octyl, bicyclo [3.1.1] heptyl, bicyclo [3.2.1] octyl, bicyclo [2.2.2] octenyl, bicyclo [ 2.1.1 ] octadienyl, adamantylene, and the like.
In the present application, the terms "heterocyclyl", "heterocycloalkyl" and "heterocycloalkyl" are used interchangeably as part of a group or other group, and refer to a stable 3-to 20-membered non-aromatic cyclic group consisting of 2 to 14 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, phosphorus, oxygen and sulfur. Unless specifically indicated otherwise in the present specification, a heterocyclyl group may be a monocyclic, bicyclic, tricyclic or more cyclic ring system, which may include fused, bridged or spiro ring systems; the nitrogen, carbon or sulfur atoms in the heterocyclic groups thereof may optionally be oxidized (e.g. S-may be oxidized to-SO-or-SO 2 -C-oxidizable to-CO-); the nitrogen atom may optionally be quaternized; and the heterocyclyl may be partially or fully saturated. The heterocyclic group may be attached to the remainder of the molecule via a carbon atom or a heteroatom and by a single bond. In heterocyclyl groups containing fused rings, one or more of the rings may be aryl or heteroaryl as defined below, provided that the point of attachment to the remainder of the molecule is a non-aromatic ring atom. The application is thatFor purposes, the heterocyclyl is preferably a stable 4-to 11-membered non-aromatic monocyclic, bicyclic, bridged or spiro ring group comprising 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably a stable 4-to 8-membered (e.g. 4, 5, 6, 7, 8-membered) non-aromatic monocyclic, bicyclic, bridged or spiro ring group comprising 1 to 3 (e.g. 1, 2, 3) heteroatoms selected from nitrogen, oxygen and sulfur, wherein the nitrogen, carbon or sulfur atoms in the heterocyclyl may optionally be oxidized. Examples of heterocyclyl groups include, but are not limited to: pyrrolidinyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, thiomorpholinyl, 2, 7-diaza-spiro [3.5 ] ]Nonan-7-yl, 2-oxa-6-aza-spiro [3.3]Heptan-6-yl, 2, 5-diaza-bicyclo [2.2.1]Heptane-2-yl, azetidinyl, pyranyl, tetrahydropyranyl, thiopyranyl, tetrahydrofuranyl, oxazinyl, dioxacyclopentyl, tetrahydroisoquinolinyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, quinolizinyl, thiazolidinyl, isothiazolidinyl, isoxazolidinyl, indolinyl, octahydroindolyl, octahydroisoindolyl, pyrrolidinyl, pyrazolidinyl, phthalimidyl, and the like.
In the present application, the terms "heterocyclylalkyl", "heterocyclylalkylalkyl" are used interchangeably to refer to an alkyl group as defined above substituted with a heterocyclyl group as defined above, or a heterocyclyl group as defined above substituted with an alkyl group as defined above.
In the present application, the term "aryl" as part of a group or other group means a conjugated hydrocarbon ring system group having 6 to 18 carbon atoms, preferably having 6 to 10 carbon atoms. For the purposes of the present application, aryl groups may be monocyclic, bicyclic, tricyclic or more ring systems, and may also be fused to cycloalkyl or heterocyclyl groups as defined above, provided that the aryl groups are linked to the remainder of the molecule by single bonds via atoms on the aromatic ring. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthryl, phenanthryl, fluorenyl, 2, 3-dihydro-1H-isoindolyl, 2-benzoxazolinone, 2H-1, 4-benzoxazin-3 (4H) -one-7-yl, and the like.
In the present application, the term "arylalkyl" refers to an alkyl group as defined above substituted with an aryl group as defined above.
In the present application, the term "heteroaryl" as part of a group or other group means a 5-to 16-membered conjugated ring system group having 1 to 15 carbon atoms (preferably 1 to 10 carbon atoms) and 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur in the ring. Unless otherwise specifically indicated in the present specification, heteroaryl groups may be monocyclic, bicyclic, tricyclic or more ring systems, and may also be fused to cycloalkyl or heterocyclyl groups as defined above, provided that heteroaryl groups are attached to the remainder of the molecule via an atom on an aromatic ring by a single bond. The nitrogen, carbon, or sulfur atoms in the heteroaryl group may optionally be oxidized; the nitrogen atom may optionally be quaternized. For the purposes of the present application, heteroaryl groups are preferably stable 5-to 12-membered aromatic groups comprising 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably stable 5-to 10-membered aromatic groups comprising 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur or 5-to 6-membered aromatic groups comprising 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. Examples of heteroaryl groups include, but are not limited to, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzimidazolyl, benzopyrazolyl, indolyl, furanyl, pyrrolyl, triazolyl, tetrazolyl, triazinyl, indolizinyl, isoindolyl, indazolyl, isoindazolyl, purinyl, quinolinyl, isoquinolinyl, naphthyridinyl, quinoxalinyl, pteridinyl, carbazolyl, carbolinyl, phenanthridinyl, phenanthrolinyl, acridinyl, phenazinyl, isothiazolyl, benzothiazolyl, benzothienyl, oxatriazolyl, cinnolinyl, quinazolinyl, thiophenyl, indolizinyl, phenanthroline, isoxazolyl, phenoxazinyl, phenothiazinyl, 4,5,6, 7-tetrahydrobenzo [ b ] thienyl, naphthyridinyl, [1,2,4] triazolo [4, 3-triazolo [1, 4] pyridazine, 3-1, 4-imidazo [1, 4] triazolo [1, 4, 3-triazolo [1, 4] pyridazine, 3-1, 4-imidazo [ 2,4] a ] 1, 4-imidazo [ 2, 4-a ] and the like.
In the present application, the term "heteroarylalkyl" refers to an alkyl group as defined above substituted with a heteroaryl group as defined above.
In the present application, the term "amido" includes-alkyl-CONH as defined above 2 or-CONH-alkyl as defined above or-CON (alkyl as defined above) 2 Wherein the alkyl group is preferably a C1-C6 alkyl group, more preferably a C1-C3 alkyl group. In the present application, "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "optionally substituted aryl" means that the aryl group is substituted or unsubstituted, and the description includes both substituted aryl groups and unsubstituted aryl groups.
The terms "moiety", "structural moiety", "chemical moiety", "group", "chemical group" as used herein refer to a particular fragment or functional group in a molecule. Chemical moieties are generally considered to be chemical entities that are embedded or attached to a molecule.
"stereoisomers" refer to compounds that consist of the same atoms, are bonded by the same bonds, but have different three-dimensional structures. The present application is intended to cover various stereoisomers and mixtures thereof.
When an olefinic double bond is contained in the compounds of the present invention, the compounds of the present invention are intended to include both E-and Z-geometric isomers unless otherwise specified.
"tautomer" refers to an isomer formed by the transfer of a proton from one atom of a molecule to another atom of the same molecule. All tautomeric forms of the compounds of the invention are also intended to be included within the scope of the invention.
The compounds of the invention or pharmaceutically acceptable salts thereof may contain one or more chiral carbon atoms and thus may be produced in enantiomers, diastereomers and other stereoisomeric forms. Each chiral carbon atom may be defined as (R) -or (S) -, based on stereochemistry. The present invention is intended to include all possible isomers, as well as racemates and optically pure forms thereof. The compounds of the invention may be prepared by selecting racemates, diastereomers or enantiomers as starting materials or intermediates. Optically active isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as crystallization and chiral chromatography.
Conventional techniques for preparing/separating individual isomers include chiral synthesis from suitable optically pure precursors, or resolution of racemates (or racemates of salts or derivatives) using, for example, chiral high performance liquid chromatography.
In the present application, the term "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
By "pharmaceutically acceptable acid addition salt" is meant a salt with an inorganic or organic acid that retains the biological effectiveness of the free base without other side effects. Inorganic acid salts include, but are not limited to, hydrochloride, hydrobromide, sulfate, nitrate, phosphate, and the like; organic acid salts include, but are not limited to, formate, acetate, 2-dichloroacetate, trifluoroacetate, propionate, hexanoate, octanoate, decanoate, undecylenate, glycolate, gluconate, lactate, sebacate, adipate, glutarate, malonate, oxalate, maleate, succinate, fumarate, tartrate, citrate, palmitate, stearate, oleate, cinnamate, laurate, malate, glutamate, pyroglutamate, aspartate, benzoate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, alginate, ascorbate, salicylate, 4-aminosalicylate, naphthalenedisulfonate, and the like. These salts can be prepared by methods known in the art.
By "pharmaceutically acceptable base addition salt" is meant a salt formed with an inorganic or organic base that is capable of maintaining the bioavailability of the free acid without other side effects. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Preferred inorganic salts are ammonium, sodium, potassium, calcium and magnesium salts. Salts derived from organic bases include, but are not limited to, the following: primary, secondary and tertiary amines, substituted amines including natural substituted amines, cyclic amines and basic ion exchange resins such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. These salts can be prepared by methods known in the art.
"polymorphs" refer to the different solid crystalline phases of certain compounds of the present invention in the solid state due to the presence of two or more different molecular arrangements. Certain compounds of the present invention may exist in more than one crystal form, and the present invention is intended to include various crystal forms and mixtures thereof.
In general, crystallization will produce solvates of the compounds of the present invention. The term "solvate" as used herein refers to an aggregate comprising one or more molecules of a compound of the invention and one or more solvent molecules. The solvent may be water, in which case the solvate is a hydrate. Alternatively, the solvent may be an organic solvent. Thus, the compounds of the present invention may exist as hydrates, including monohydrate, dihydrate, hemihydrate, sesquihydrate, trihydrate, tetrahydrate, and the like, as well as the corresponding solvated forms. The compounds of the invention may form true solvates, but in some cases may also retain only adventitious water or a mixture of water plus a portion of the adventitious solvent. The compounds of the invention may be reacted in a solvent or precipitated or crystallized from a solvent. Solvates of the compounds of the present invention are also included within the scope of the present invention.
The application also includes prodrugs of the above compounds. In the present application, the term "prodrug" means a compound that can be converted into the biologically active compound of the present application under physiological conditions or by solvolysis. Thus, the term "prodrug" refers to a pharmaceutically acceptable metabolic precursor of a compound of the application. Prodrugs may not be active when administered to an individual in need thereof, but are converted in vivo to the active compounds of the present application. Prodrugs are typically rapidly converted in vivo to the parent compounds of the present application, for example, by hydrolysis in blood. Prodrug compounds generally provide solubility, histocompatibility, or sustained release advantages in mammalian organisms. Prodrugs include known amino protecting groups and carboxyl protecting groups.
In the present application, "pharmaceutical composition" refers to a formulation of a compound of the present application with a medium commonly accepted in the art for delivery of biologically active compounds to a mammal (e.g., a human). The medium includes a pharmaceutically acceptable carrier. The purpose of the pharmaceutical composition is to promote the administration of organisms, facilitate the absorption of active ingredients and further exert biological activity.
The term "pharmaceutically acceptable" as used herein refers to a material (e.g., carrier or diluent) that does not affect the biological activity or properties of the compounds of the present application, and is relatively non-toxic, i.e., the material can be administered to an individual without causing an adverse biological reaction or interacting in an adverse manner with any of the components contained in the composition.
In the present application, "pharmaceutically acceptable carrier" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye/colorant, flavoring agent, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonizing agent, solvent, or emulsifying agent that is approved by the relevant government regulatory agency as acceptable for human or livestock use.
The "tumor", "cell proliferation abnormality related disease", and the like of the present application include, but are not limited to, leukemia, gastrointestinal stromal tumor, histiocytic lymphoma, non-small cell lung cancer, pancreatic cancer, lung squamous carcinoma, lung adenocarcinoma, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell cancer, cervical cancer, ovarian cancer, intestinal cancer, nasopharyngeal cancer, brain cancer, bone cancer, esophageal cancer, melanoma, renal cancer, oral cancer, and the like.
The terms "prevent", "preventing" and "preventing" as used herein include reducing the likelihood of a patient from developing or worsening a disease or condition.
The term "treatment" and other similar synonyms as used herein include the following meanings:
(i) Preventing the occurrence of a disease or disorder in a mammal, particularly when such mammal is susceptible to the disease or disorder, but has not been diagnosed as having the disease or disorder;
(ii) Inhibiting the disease or disorder, i.e., inhibiting its progression;
(iii) Alleviating a disease or condition, i.e., causing the state of the disease or condition to subside; or alternatively
(iv) Alleviating symptoms caused by the disease or condition.
The term "effective amount," "therapeutically effective amount," or "pharmaceutically effective amount" as used herein refers to an amount of at least one agent or compound that is sufficient to alleviate one or more symptoms of the disease or disorder being treated to some extent after administration. The result may be a reduction and/or alleviation of signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an "effective amount" for treatment is the amount of a composition comprising a compound disclosed herein that is required to provide clinically significant relief from a disorder. Effective amounts suitable in any individual case can be determined using techniques such as a dose escalation test.
The terms "administering," "administering," and the like as used herein refer to a method capable of delivering a compound or composition to a desired site for biological action. These methods include, but are not limited to, oral routes, duodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration, and rectal administration. In preferred embodiments, the compounds and compositions discussed herein are administered orally.
The terms "pharmaceutical combination", "co-administration", "administration of other treatments", "administration of other therapeutic agents" and the like as used herein refer to a pharmaceutical treatment obtained by mixing or combining more than one active ingredient, which includes both fixed and non-fixed combinations of active ingredients. The term "fixed combination" refers to the simultaneous administration of at least one compound described herein and at least one synergistic agent to a patient in the form of a single entity or single dosage form. The term "ambulatory combination" refers to the simultaneous administration, co-administration, or sequential administration of at least one compound described herein and at least one synergistic formulation as separate entities to a patient at variable intervals. These also apply to cocktail therapies, for example, administration of three or more active ingredients.
It will also be appreciated by those skilled in the art that in the methods described below, the intermediate compound functional groups may need to be protected by appropriate protecting groups. Such functional groups include hydroxyl, amino, mercapto and carboxylic acid. Suitable hydroxy protecting groups include trialkylsilyl or diarylalkylsilyl groups (e.g., t-butyldimethylsilyl, t-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl, and the like. Suitable protecting groups for amino, amidino and guanidino groups include t-butoxycarbonyl, benzyloxycarbonyl and the like. Suitable mercapto-protecting groups include-C (O) -R "(wherein R" is alkyl, aryl or aralkyl), p-methoxybenzyl, trityl, and the like. Suitable carboxyl protecting groups include alkyl, aryl or aralkyl esters.
Protecting groups may be introduced and removed according to standard techniques known to those skilled in the art and as described herein. The protecting group may also be a polymeric resin.
The invention will be further illustrated with reference to specific examples. It should be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. The experimental methods in the following examples, in which specific conditions are not noted, are generally in accordance with conventional conditions, or in accordance with the conditions recommended by the manufacturer. Percentages and parts are weight percentages and parts unless otherwise indicated.
Examples general preparation method
The first step: the 6-chloropyrimidine intermediate (1 eq.) was dissolved in an appropriate solvent, and the organic base (3 eq.) and the amine intermediate (1 eq.) were added sequentially, capped, heated to 100 degrees and stirred overnight. LC-MS monitoring reaction is complete, cooling to room temperature, adding water into the reaction solution, extracting the water phase with dichloromethane three times, drying the extract liquid with anhydrous sodium sulfate, concentrating under reduced pressure, separating and purifying the residue to obtain a target product, and confirming a structure by adopting nuclear magnetism and mass spectrum.
And a second step of: the product of the first step (1 eq.) was dissolved in a suitable solvent, inorganic base was added and stirred at room temperature for several hours. TLC monitoring reaction is complete, filtering and decompressing concentration are carried out, and crude target products are obtained through vacuum drying, and nuclear magnetism and mass spectrum are adopted to confirm the structure.
And a third step of: the above second step product (1 eq.) is dissolved in a suitable solvent and condensing agent (1.1 eq.), base (1.2 eq.) and R are added in sequence 1 NH 2 (1 eq.) was reacted overnight at room temperature under nitrogen. TLC monitoring reaction is complete, decompression concentration is carried out, the residue is separated and purified by silica gel column chromatography to obtain a target product, and nuclear magnetism and mass spectrum are adopted to confirm the structure.
Fourth step: the product of the third step (1 eq.) was dissolved in isopropanol, 5N aqueous HCl (10 eq.) was added and stirred at 80 ℃ for 6 hours. TLC monitoring reaction is complete, decompression concentration is carried out, the residue is separated and purified by silica gel column chromatography to obtain the target compound, and nuclear magnetism and mass spectrum are adopted to confirm the structure.
Intermediate preparation
Intermediate 1: (R) -1- (2 '- ((dimethylamino) methyl) - [1,1' -biphenyl ] -3-yl) ethyl-1-amine hydrochloride
Step one: tetraethyltitanate (11.3 g,49.56 mmol) was added to 3-bromo-acetophenone (5.40 g,27.26 mmol), (R) - (+) t-butylsulfinamide (3.0 g,24.78 mmol) in tetrahydrofuran (42 mL) under nitrogen. The reaction mixture was heated to 70℃and reacted at this temperature for 16 hours. The reaction mixture was heated to 70℃and reacted at this temperature for 16 hours. The reaction solution was cooled to room temperature, 70mL of brine was added,stirring was continued for 10 minutes, the reaction mixture was filtered through celite and washed twice with ethyl acetate (100 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered and the filtrate concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether=1:4) to give the intermediate compound (6.05 g) as a colourless oil. LCMS (ESI) m/z 301.9[ M+H ] ] + 。 1 H NMR(400MHz,DMSO-d6)δ8.03(s,1H),7.90(d,J＝7.8Hz,1H),7.80-7.73(m,1H),7.47(m,1H),2.72(s,3H),1.22(s,9H)。
Step two: diisobutylaluminum hydride (39.9 mL,39.86 mmol) was added to tetrahydrofuran (200 mL) of the above intermediate (6.0 g,19.93 mmol) at-78 ℃. The reaction was slowly warmed to room temperature and allowed to react at this temperature for 16 hours. The reaction was quenched by addition of dilute sodium hydroxide solution under ice-bath cooling. The reaction mixture was filtered through celite and washed twice with ethyl acetate (100 mL). The combined organic phases were concentrated under reduced pressure and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=4:1) to give the compound as a colourless oil (5.25 g). LCMS (ESI) m/z 303.1[ M+H ]] + 。 1 H NMR(400MHz,DMSO-d6)δ7.63(s,1H),7.45-7.36(m,2H),7.29(m,1H),5.77(d,J＝7.7Hz,1H),4.37(m,1H),1.38(d,J＝6.8Hz,3H),1.12(s,9H)。
Step three: tetratriphenylphosphine palladium (1.52 g,1.32 mmol) was added to 1, 4-dioxane (50 mL) containing the above intermediate compound (4.0 g,13.20 mmol), 2- (N, N-dimethylaminomethyl) phenylboronic acid (3.07 g,17.16 mmol), potassium carbonate (3.64 g,26.40 mmol) and water (10 mL) under nitrogen. The reaction mixture was heated to 100℃and reacted at this temperature for 16 hours. After the reaction mixture was diluted with ethyl acetate (200 mL), it was washed with water (100 mL). The separated organic phase was concentrated under reduced pressure, and the crude product was purified by reverse phase column to give the compound (3.46 g) as a brown oil. LCMS (ESI) m/z 359.2[ M+H ]] + 。 1 H NMR(400MHz,DMSO-d6)δ7.54-7.47(m,1H),7.43(s,1H),7.38(d,J＝4.8Hz,2H),7.33(m,2H),7.29-7.22(m,2H),5.69(m,1H),4.43(m,1H),3.32(s,2H),2.08(s,6H),1.43(d,J＝6.8Hz,3H),1.12(s,9H)。
Step four: a solution of hydrochloric acid in methanol (4M, 15mL,45 mmol) was added to methanol (15 mL) of the above intermediate compound (3.46 g,9.66 mmol). The reaction mixture was reacted at 20℃for 2 hours . The LC-MS detection reaction was substantially complete, the solvent was removed by concentration under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol=9:1) to give the compound (2.5 g) as a pale yellow solid. LCMS (ESI) m/z 255.2[ M+H ]] + 。 1 H NMR(400MHz,CD 3 OD)δ7.82-7.69(m,1H),7.66-7.53(m,4H),7.50(s,1H),7.41(d,J＝6.1Hz,2H),4.59(m,1H),4.42(s,2H),2.67(s,6H),1.70(d,J＝6.2Hz,3H)。
The preparation conditions are as follows: separation column (SunFire Prep C18 OBD) TM 10um,19 x 250 mm); gradient (5% -95% acetonitrile/0.1% formic acid/water, 16min, flow 20 mL/min).
Analysis conditions: analytical column (Waters SunFire C18,4.6×50mm,5 um); gradient (5% -95% acetonitrile/0.1% formic acid/water, 3.0min, flow rate 2.0mL/min,2.6 min); column temperature: 40 ℃; detection wavelength: 254nM.
Intermediate 3: (R) -1- (5- (2- (pyrrol-1-ylmethyl) phenyl) thiophen-2-yl) ethyl-1-amine hydrochloride
Step one: tetraethyltitanate (30.1 g,132 mmol) was added to 1- (5-bromothiophen-2-yl) ethyl-1-one (14.89 g,72.61 mmol), (R) - (+) t-butylsulfinamide (8 g,66 mmol) in tetrahydrofuran (100 mL) under nitrogen and the reaction mixture was heated to 70 ℃ and reacted at this temperature for 16 hours. After the reaction solution was cooled to room temperature, 100ml of brine was added thereto, and stirring was continued for 10 minutes. The reaction mixture was filtered through celite, and the filtrate was extracted 2 times with ethyl acetate (100 mL). The combined organic phases were dried over anhydrous sodium sulfate and the crude product was purified by column chromatography on silica gel (eluent: ethyl acetate/petroleum ether=4:1) to give the intermediate compound (15 g, crude) as a brown solid. LCMS (ESI) m/z 307.9[ M+H ] ] + 。 1 H NMR(400MHz,DMSO-d6)δ7.64(d,J＝4.1Hz,1H),7.35(d,J＝4.1Hz,1H),2.64(s,3H),1.18(s,9H)。
Step two: DIBAL-H (61 mL,61 mmol) was slowly added dropwise to tetrahydrofuran (200 mL) of the above intermediate compound (9.3 g,30.17 mmol) under nitrogen protection at-78deg.C cooling, and the reaction mixture was followedThe solution was slowly warmed to room temperature and reacted at this temperature for 16 hours, LCMS detected no starting material, most converted to the desired product. Methanol (50 ml) was added to quench, the solvent was removed by concentration under reduced pressure, and the crude product was slurried with methanol (200 ml) and filtered through celite. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=4:1) to give a brown oily liquid compound (15 g, crude). LCMS (ESI) m/z 309.9[ M+H ]] + 。 1 H NMR(400MHz,DMSO-d6)δ7.06(d,J＝3.8Hz,1H),6.89(dd,J＝3.8,0.9Hz,1H),5.90(m,1H),4.57(m,1H),1.47(d,J＝6.8Hz,3H),1.12(s,9H)。
Step three: tetratriphenylphosphine palladium (1.12 g,0.965 mmol) was added to the above intermediate compound (3 g,9.65 mmol), 2-formylphenylboronic acid (1.88 g,12.55 mmol), potassium carbonate (2.67 g,19.3 mmol), and water (12 mL) in 1, 4-dioxane (60 mL) under nitrogen. The reaction mixture was heated to 100℃and reacted at this temperature for 16 hours. The reaction was diluted with ethyl acetate (200 mL) and then washed with water (100 mL). The separated organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product obtained was purified by HPLC preparation to give intermediate compound (2.6 g) as brown oil. LCMS (ESI) m/z 336.0[ M+H ] ] + 。 1 H NMR(400MHz,CDCl 3 )δ10.21(d,J＝0.6Hz,1H),8.00(dd,J＝7.8,1.1Hz,1H),7.61(m,1H),7.55-7.46(m,2H),7.08(d,J＝3.0Hz,1H),6.92(d,J＝3.6Hz,1H),4.90-4.82(m,1H),3.58(d,J＝3.6Hz,1H),1.66(d,J＝6.6Hz,3H),1.26(s,9H).
Step four: 1 drop of glacial acetic acid was added to the above intermediate compound (2.6 g,7.75 mmol) and tetrahydropyrrole (662 mg,9.3 mmol) in methanol (30 mL) at room temperature, and the reaction mixture was reacted at 20℃for 2 hours. Sodium cyanoborohydride (1.46 g,23.25 mmol) was then added to the reaction solution and the reaction was continued for 12 hours, with LCMS detecting the product as a dominant one. The crude product obtained by concentrating under reduced pressure to remove the solvent was purified by silica gel column chromatography (eluent: dichloromethane/methanol=9:1) to give the compound as a pale yellow solid intermediate compound (2.1 g). LCMS (ESI) m/z 391.1[ M+H ]] + 。
Step five: hydrogen chloride in methanol HCl (g)/MeOH (15 mL,45 mmol) was added to methanol (15 mL) of the above intermediate compound (2.1 g,5.38 mmol). Reaction mixtureThe reaction was carried out at 20℃for 2 hours. LCMS detected complete reaction. After the solvent was removed by concentrating the reaction solution under reduced pressure, the obtained crude product was purified by silica gel column chromatography (eluent: dichloromethane/methanol=9:1) to obtain the objective compound (1.2 g) as a pale yellow solid. LCMS (ESI) m/z 287.1[ M+H ]] + 。 1 H NMR(400MHz,CD 3 OD)δ7.79-7.75(m,1H),7.60-7.50(m,3H),7.32(d,J＝3.6Hz,1H),7.13(d,J＝3.6Hz,1H),4.83(m,1H),4.58(s,2H),3.54-3.44(m,2H),3.02(d,J＝8.1Hz,2H),2.06-1.94(m,4H),1.77(d,J＝6.9Hz,3H)。
Reference to the preparation and isolation methods for the preparation of (R) -1- (2 '- ((dimethylamino) methyl) - [1,1' -biphenyl ] -3-yl) ethyl-1-amine hydrochloride and (R) -1- (5- (2- (pyrrol-1-ylmethyl) phenyl) thiophen-2-yl) ethyl-1-amine hydrochloride, the following intermediates 2 and 4-12 were synthesized:
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Example 1:4- (((R) -1- (5- (2- ((dimethylamino) methyl) phenyl) thiophen-2-yl) -ethyl) amino) -2-methyl-6- ((S or R) -1, 1-trifluoropropyl-2-yl) pyridin [4,3-d ] pyrimidin-7 (6H) -one
Step one: methyl 2- (6-chloro-5- (1, 3-dioxolan-2-yl) -2-methylpyrimidin-4-yl) acetate (360 mg,1.32 mmol), (R) -1- (5- (2- ((dimethylamino) methyl) phenyl) thiophen-2-yl) ethan-1-amine (347 mg,1.32 mmol) and N, N-diisopropylethylamine (515 mg,3.96 mmol) were added to dimethyl sulfoxide (7 mL) and the reaction was capped at 100℃overnight. LC-MS monitored complete reaction and cooled to room temperature. The reaction mixture was added with water (30 mL), extracted three times with methylene chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to reverse-phase column chromatography to give 160mg of a solid product. LC-MS (ESI))m/z：497.1[M+H] + 。 1 H-NMR(400MHz，DMSO-d6)：δ7.39-7.30(m，4H)，7.16(d,J＝3.6Hz，1H)，7.03(m,2H)，5.89(s,1H)，5.75-5.58(m,1H)，4.15-4.00(m,2H),3.98-3.81(m,2H)，3.71-3.60(m,4H),3.37(s,3H),2.35(s,3H),2.11(s,6H),1.61(d,J＝6.8Hz,3H)。
Step two: to the above solid (228 mg,0.46 mmol) in tetrahydrofuran (4 mL) was added an aqueous solution (1 mL) of lithium hydroxide (88 mg,3.676 mmol), and the reaction was stirred at room temperature for 3 hours. TLC detects the disappearance of the reaction material, and after removing the solvent under reduced pressure, 220mg of a pale yellow solid crude product is obtained, which is directly fed to the next reaction. LC-MS (ESI) m/z 483.1[ M+H ]] + 。
Step three: 2- (7-Azabenzotriazol) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU) (514 mg,1.35 mmol) was added to a solution of the above solid (220 mg, 0.457mmol), 1-trifluoropropan-2-amine (102 mg,0.901 mmol) and N, N-diisopropylethylamine (233 mg,1.803 mmol) in tetrahydrofuran (20 mL). The reaction was stirred at room temperature overnight. After concentrating under reduced pressure to remove the solvent, the residue was purified by silica gel column chromatography (ethyl acetate/methanol volume ratio 20:1) to give 200mg of brown oil. LC-MS (ESI) m/z 578.1[ M+H ] ] + 。
Step four: to a solution of the above oil (200 mg,0.346 mmol) in isopropanol (8 mL) was added 5N aqueous hydrochloric acid (1.5 mL,7.5 mmol). The reaction mixture was reacted at 80℃for 2 hours. LC-MS detected complete reaction of the starting materials. The reaction mixture was diluted with dichloromethane (100 mL), and the reaction mixture was washed twice with brine (50 mL). The separated organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by HPLC to give compound 1-1 (rt=5.15 min,3.6mg, pale yellow solid) and compound 1-2 (rt=7.55 min,4.1mg, pale yellow solid).
The preparation conditions are as follows: separation column (SunFire Prep C18 OBD) TM 10um,19 x 250 mm); gradient (5% -95% acetonitrile/0.1% formic acid/water, 16min, flow 20 mL/min).
Analysis conditions: analytical column (Waters SunFire C18,4.6×50mm,5 um); gradient (5% -95% acetonitrile/0.1% formic acid/water, 3.0min, flow rate 2.0mL/min,2.6 min); column temperature: 40 ℃; detection wavelength: 254nM.
Compound 1-1: LC-MS (Rt=1.207 Min) (ESI) m/z 516.1[ M+H ]] + 。 1 H-NMR(400MHz,DMSO-d6)：δ9.09(m,1H),9.04(s,1H),8.21(s,1H),7.42(m,2H),7.34-7.29(m,2H),7.20(d,J＝3.6Hz,1H),7.11(d,J＝3.3Hz,1H),6.22(s,1H),6.08(m,1H),5.96(m,1H),3.36(s,2H),2.33(s,3H),2.10(s,6H),1.71(d,7.2Hz,3H)，1.69(d,J＝6.9Hz,3H)。
Compound 1-2: LC-MS (Rt=1.230 Min) (ESI) m/z 516.1[ M+H ]] + 。 1 H-NMR(400MHz,DMSO-d6)：δ9.10(s,1H),9.03(s,1H),8.22(s,1H),7.46–7.41(m,1H),7.39(dd,J＝6.6,2.2Hz,1H),7.34-7.28(m,2H),7.20(d,J＝3.6Hz,1H),7.12(d,J＝3.3Hz,1H),6.22(s,1H),6.13-6.00(m,1H),5.95(d,J＝5.1Hz,1H),3.37(s,2H),2.33(s,3H),2.12(s,6H),1.72(d,7.2Hz,3H)，1.69(d,J＝6.9,3H)。
Referring to the procedure of example 1, the synthesis of (R) or (S) -1- (5- (2- ((dimethylamino) methyl) phenyl) thiophen-2-yl) ethan-1-amine and various commercial amine reagents as starting materials was performed in place of 1, 1-trifluoropropan-2-amine to give examples 2-18:
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Example 19: (R) -N- (2- (dimethylamino) ethyl) -3'- (1- ((2-methyl-7-oxo-6- ((tetrahydro-2H-pyran-4-yl) methyl) -6, 7-dihydropyridin [4,3-d ] pyrimidin-4-yl) amino) ethyl) - [1,1' -diphenyl ] -4-carbonic acid amide
Step one: methyl 2- (6-chloro-5- (1, 3-dioxolan-2-yl) -2-methylpyrimidin-4-yl) acetate (3.0 g,11.03 mmol), (R) -1- (3-bromophenyl) ethyl-1-amino hydrochloride (2.85 g,12.13 mmol) and N, N-diisopropylethylamine (4.28 g,33.08 mmol) were added to dimethyl sulfoxide (15 mL) and the reaction was sealed at 100℃overnight. LC-MS monitored complete reaction and cooled to room temperature. The reaction mixture was taken up in water (50 mL), extracted three times with dichloromethane, the extract dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to reverse-phase column chromatography to give 2.04g of a pale yellow solid product. LCMS (ESI) m/z 437.9[ M+H ]] +.1 H NMR(400MHz,DMSO-d6)δ7.57(m,1H),7.46-7.35(m,2H),7.29(m,1H),6.97(d,J＝7.8Hz,1H),5.92(s,1H),5.34(m,1H),4.15-4.10(m,2H),3.98-3.93(m,2H),3.70(s,2H),3.59(s,3H),2.26(s,3H),1.47(d,J＝7.0Hz,3H)。
Step two: to a tetrahydrofuran solution (20 mL) of the above solid (2.0 g,4.60 mmol) was added an aqueous solution (5 mL) of lithium hydroxide (883 mg,36.77 mmol), and the reaction was stirred at room temperature for 5 hours. TLC checked for disappearance of starting material and removal of solvent under reduced pressure gave a crude product (1.96 g) as a pale yellow solid, which was directly fed to the next reaction step. LC-MS (ESI) m/z 423.9[ M+H ]] + 。
Step three: the above intermediate compound (1.96 g,4.60 mmol) was dissolved in tetrahydrofuran (200 mL), and (tetrahydro-2H-pyran-4-yl) -methylamine (1.59 g,13.8 mmol), 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (7.0 g,18.4 mmol), N, N-diisopropylethylamine (2.38 g,18.4 mmol) was added sequentially, and the reaction mixture was reacted at 70℃for 2 hours. LCMS detected the reaction product as the main, ethyl acetate (100 mL) diluted the reaction and separated the organic phase, dried over anhydrous sodium sulfate, and the filtrate concentrated under reduced pressure and the crude product purified by silica gel column chromatography (ethyl acetate: methanol=20:1) to give 2.1g of a pale yellow solid product. LC-MS (ESI) m/z 519.1[ M+H ] ] +.1 H NMR(400MHz,CDCl 3 )δ8.34(d,J＝7.5Hz,1H),7.44(m,2H),7.26-7.17(m,2H),7.07(m,1H),6.00(s,1H),5.39(m,1H),4.20-4.08(m,4H),3.94(m,2H),3.85(s,2H),3.36(m,2H),3.15(t,J＝6.4Hz,2H),2.57(s,3H),1.83-1.71(m,1H),1.67-1.54(m,5H),1.33-1.21(m,2H).
Step four: aqueous HCl (5N, 7.0 mL) was added to tetrahydrofuran (32 mL) of the above compound (1.35 g,2.605 mmol) at room temperature, and the reaction mixture was reacted at 80℃for 2 hours. LCMS detected completion of the reaction, and dichloromethane (200 mL) diluted the reaction with brine. The organic phase was separated, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether=4:1 to 2:1) to obtain 1.35g of a pale yellow solid. LCMS (ESI) m/z 457.1[ M+H ]] + . 1 H NMR(400MHz,CDCl 3 )δ9.02(s,1H),8.28(s,1H),7.50(s,1H),7.32(m,2H),7.13(m,1H),6.40(s,1H),5.69(m,1H),3.96(m,1H),3.89-3.74(m,3H),3.18(m,2H),2.42(s,3H),2.11(m,1H),1.58(d,J＝6.9Hz,3H),1.44(m,2H),1.22(m,2H).
Step five: tetratriphenylphosphine palladium (40 mg,0.035 mmol) was added to the above compound (0.16 g,0.351 mmol), 4- ((2- (dimethylamino) ethyl) carbonic acyl) phenyl) boronic acid (124 mg, 0.455 mmol), potassium carbonate (97 mg, 0.704 mmol), water (2 mL) in 1, 4-dioxane (12 mL) under nitrogen. The reaction mixture was heated to 100℃and reacted at this temperature for 16 hours. After diluting the reaction solution with ethyl acetate (200 mL), the reaction solution was washed with water and brine, respectively. The separated organic phase was dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The crude product obtained was purified by HPLC to give 10.60mg of a pale yellow solid. LCMS (Rt=0.879 min) (ESI) m/z 469.4[ M+H ]] + . 1 H NMR(400MHz,DMSO-d6)δ9.11(s,1H),8.53(d,J＝7.8Hz,1H),8.42(m,1H),7.93(d,J＝8.3Hz,2H),7.85-7.76(m,3H),7.61(d,J＝3.6Hz,1H),7.47(d,J＝4.9Hz,2H),6.09(s,1H),5.71-5.64(m,1H),4.01-4.81(m,4H),3.39-3.34(m,2H),3.27-3.21(m,2H),2.43-2.40(m,2H),2.25(s,3H),2.19(s,6H),2.12–2.07(m,1H),1.63(d,J＝7.0Hz,3H),1.53(m,2H),1.33–1.25(m,2H).
Referring to the methods of examples 1 and 19, the synthesis of examples 20-22 was carried out using commercially available different amines as starting materials instead of (tetrahydro-2H-pyran-4-yl) -methylamine and different boric acids as starting materials instead of 4- ((2- (dimethylamino) ethyl) carbonic acyl) phenyl) boronic acid:
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Example 32: (R) -4- ((1- (5- (4, 5-difluoro-2- (pyrrol-1-ylmethyl) phenyl) thiophen-2-yl) ethyl) amino) -2-methyl-6- ((tetrahydro-2H-pyran-4-yl) methyl) pyrido [4,3-d ] pyrimidin-7 (6H) -one
Step one: methyl 2- (6-chloro-5- (1, 3-dioxolan-2-yl) -2-methylpyrimidin-4-yl) acetate (500 mg,1.84 mmol), (R) -1- (5-bromothiophen-2-yl) ethyl-1-amino hydrochloride (480 mg,2.2 mmol) and N, N-diisopropylethylamine (951 mg,7.36 mmol) were added to DMSO (5 mL) and the reaction was sealed at 100℃overnight. The reaction mixture was diluted with water (100 mL), extracted three times with ethyl acetate (100 mL), and the combined organic phases were concentrated under reduced pressure and purified by HPLC to give a white intermediate compound (250 mg). LCMS (ESI) m/z 443.8[ M+H ]] + 。 1 H NMR(400MHz,DMSO-d6)δ7.06(d,J＝3.8Hz,1H),7.00(d,J＝8.0Hz,1H),6.86(dd,J＝3.8,1.0Hz,1H),5.86(s,1H),5.55(t,J＝7.2Hz,1H),4.07(m,2H),3.90(m,2H),3.71(s,2H),3.59(s,3H),2.34(s,3H),1.55(d,J＝6.9Hz,3H)。
Step two: an aqueous solution (1 mL) of lithium hydroxide (190 mg,4.52 mmol) was added dropwise to a solution of the above intermediate compound (250 mg,0.56 mmol) in tetrahydrofuran (4 mL), and the reaction was carried out at room temperature for 2 hours, and the disappearance of starting material was detected by TLC. The solvent was removed under reduced pressure to give a crude intermediate (220 mg) as a pale yellow solid. LCMS (ESI) m/z 429.8[ M+H ]] + .
Step three: HATU (665 mg,1.75 mmol) was added to the above intermediateThe compound (220 mg,0.58 mmol), 4-aminomethyltetrahydropyran (200 mg,1.75 mmol) and N, N-diisopropylethylamine (300 mg,2.3 mmol) were reacted at 70℃for 12 hours in tetrahydrofuran. The solvent was removed by concentration under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: ethyl acetate/methanol=10:1) to give the intermediate compound (180 mg) as a yellow solid. LCMS (ESI) m/z 526.9[ M+H ] ] + 。 1 H NMR(400MHz,DMSO-d6)δ7.94(d,J＝5.4Hz,1H),7.06(d,J＝3.8Hz,1H),6.85(dd,J＝3.8,1.0Hz,1H),6.80(d,J＝7.9Hz,1H),5.91(s,1H),5.53(m,1H),4.10(m,2H),3.91(m,2H),3.85-3.80(m,2H),3.50(s,2H),3.22(m,2H),2.94(m,2H),2.69(m,1H),2.33(s,3H),1.68-1.58(m,1H),1.55(m,4H),1.20-1.07(m,2H)。
Step four: aqueous hydrochloric acid (5M, 1.5mL,7.5 mmol) was added to a solution of the above intermediate compound (170 mg,0.32 mmol) in isopropanol (8 mL). The reaction mixture was reacted at 80℃for 1 hour. LCMS detected complete reaction of starting material. The reaction mixture was diluted with dichloromethane (100 mL) and washed with brine. The separated organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: dichloromethane/methanol=10:1) to give an intermediate compound (150 mg) as a pale yellow solid. LCMS (ESI) m/z 463.1[ M+H ]] + 。
Step five: tetratriphenylphosphine palladium (13 mg,0.017 mmol) was added to the above simplified compound (80 mg,0.173 mmol), 4, 5-difluoro-2- (pinacol borate) benzaldehyde (27 mg,0.207 mmol), potassium carbonate (30 mg,0.34 mmol) and water (1 mL) in 1, 4-dioxane (5 mL) under nitrogen. The reaction mixture was heated to 100℃and reacted at this temperature for 2 hours. LCMS detects disappearance of starting material. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with brine (20 mL). The separated organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=10:1) to give a pale yellow solid compound (50 mg). LCMS (ESI) m/z 525.2[ M+H ] ] + 。
Step six: a drop of glacial acetic acid was added to the above intermediate compound (50 mg,0.1 mmol) and tetrahydropyrrole (21 mg,0.3 mmol) in methanol (5 mL) at room temperature, and the reaction mixture was reacted at 20℃for 2 hours. Sodium cyanoborohydride (19 mg,0.3 mmol) was addedThe reaction was continued for 12 hours in the above reaction solution, and LCMS detected no starting material and most was converted to the desired product. The reaction mixture was diluted with ethyl acetate (50 mL), washed with brine (30 mL), and the separated organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product obtained was prepared by HPLC to give the compound of example 32 (4.82 mg) as a pale yellow solid. LC-MS (rt= 1.955 min); (ESI) m/z 580.2[ M+H ]] + . 1 H NMR(400MHz,DMSO-d6)δ9.06(s,1H),8.66(d,J＝8.0Hz,1H),7.51-7.43(m,2H),7.19(m,1H),7.12-7.10(m,1H),6.12(s,1H),5.88(t,J＝7.1Hz,1H),3.95-3.81(m,4H),3.52(s,2H),3.23(m,2H),2.39(s,4H),2.31(s,3H),2.07(s,1H),1.69(d,J＝6.9Hz,3H),1.62(s,4H),1.43(m,2H),1.27(m,2H)。
Example 33: (R) -4- ((1- (4-chloro-5- (2- (pyrrol-1-ylmethyl) phenyl) thiophen-2-yl) ethyl) amino) -2-methyl-6- ((tetrahydro-2H-pyran-4-yl) methyl) pyrido [4,3-d ] pyrimidin-7 (6H) -one
Step one: liquid bromine (6.72 g,42.0 mmol), aluminum trichloride (11.2 g,84.0 mmol) were added to chloroform (50 mL) of 1- (4-chlorothiophene-2-yl) ethyl-1-one (4.5 g,28.016 mmol) at room temperature, and the reaction mixture was reacted at 60℃for 1 hour. LCMS detects no starting material and most is converted to the desired product. The reaction mixture was diluted with ethyl acetate (100 mL), the organic phase was washed with a sodium chloride solution, the organic phase was separated, dried over anhydrous sodium sulfate, concentrated, and purified to give an intermediate compound (5.0 g) as a white solid. LCMS (ESI) m/z 240.9[ M+H ] ] + 。 1 H NMR(400MHz,DMSO)δ8.05(s,1H),2.53(s,3H)。
Step two: tetraethyltitanate (8.57 g,37.58 mmol), (R) - (+) tert-butylsulfinamide (2.28 g,18.8 mmol) was added to tetrahydrofuran (80 mL) of the above intermediate compound (5.0 g,20.88 mmol) at room temperature. The reaction mixture was reacted at 70℃for 16 hours. LC-MS detection reaction was complete. Water (150 mL) was added, extracted three times with ethyl acetate (80 mL), and the combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (elution)The preparation method comprises the following steps: petroleum ether/ethyl acetate=4:1) to afford intermediate compound (3.7 g) as a pale yellow solid. LCMS (ESI) m/z 343.9[ M+H ]] + 。 1 H NMR(400MHz,DMSO-d6)δ7.87(s,1H),2.65(s,3H),1.19(s,9H)。
Step three: diisobutylaluminum hydride (33 mL) was added to tetrahydrofuran (80 mL) of the above intermediate compound (3.7 g,10.8 mmol) at-60℃or lower. The reaction mixture was gradually warmed to room temperature and reacted at this temperature for 16 hours. LCMS detects no starting material and most is converted to the desired product. Methanol (10 mL) was added to the reaction solution, the reaction solution was then diluted with ethyl acetate (100 mL), the reaction solution was concentrated under reduced pressure after filtration through celite, and the obtained crude product was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=4:1) to give a pale yellow solid intermediate compound (3.1 g). LCMS (ESI) m/z 345.9[ M+H ] ] + 。 1 H NMR(400MHz,DMSO-d6)δ7.08(s,1H),6.01(d,J＝7.5Hz,1H),4.60-4.55(m,1H),1.47(d,J＝6.8Hz,3H),1.13(s,9H)。
Step four: a methanol solution (30 mL) of HCl (g) was added to methanol (30 mL) of the above intermediate compound (3.1 g,8.99 mmol) at room temperature, and the reaction mixture was reacted at room temperature for 3 hours. LCMS reaction was complete, the reaction was directly spin-dried, and the resulting crude product was purified by silica gel column chromatography (eluent: dichloromethane/methanol=10:1) to give intermediate compound (2.2 g) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ8.74(br.s,2H),7.35(s,1H),4.65(q,J＝6.8Hz,1H),1.57(d,J＝6.8Hz,3H)。
Step five: potassium fluoride (254 mg,14.7 mmol) was added to methyl 2- (6-chloro-5- (1, 3-dioxolan-2-yl) -2-methylpyrimidin-4-yl) acetate (400 mg,1.47 mmol) and dimethyl sulfoxide (10 mL) of the above intermediate compound (530 mg,2.21 mmol). The reaction mixture was then sealed at 100℃for 16 hours. After the reaction solution was diluted with ethyl acetate (50 mL), the organic phase was washed with water (20 mL), and the separated organic phase was dried over anhydrous sodium sulfate. After the filtrate was concentrated under reduced pressure, the obtained crude product was purified by HPLC to give a white solid intermediate compound (350 mg). LCMS (ESI) m/z 477.8[ M+H ]] + 。 1 H NMR(400MHz,DMSO-d6)δ7.06-7.03(m,2H),5.87(s,1H),5.53(m,1H),4.09(m,2H),3.91(m,2H),3.72(s,2H),3.59(s,3H),2.35(s,3H),1.56(d,J＝6.9Hz,3H)。
Step six, an aqueous solution (2 mL) of lithium hydroxide (350 mg,0.73 mmol) was added to tetrahydrofuran (3 mL) of the above intermediate compound (350 mg,0.73 mmol) at room temperature, and the reaction mixture was reacted at this temperature for 2 hours, and the completion of the reaction was detected by LCMS. The solvent was removed by concentration under reduced pressure to give the crude intermediate compound (350 mg) as a pale yellow solid.
Step seven, the above intermediate compound (350 mg,0.73 mmol) was dissolved in tetrahydrofuran (80 mL) and (tetrahydropyran-4-yl) methylamino (254 mg,2.20 mmol), HATU (837 mg,2.20 mmol) and N, N-diisopropylethylamine (380 mg,2.94 mmol) were added sequentially and the reaction mixture reacted at 70℃for 2 hours. After completion of LCMS detection, the reaction was diluted with ethyl acetate (150 mL) and washed twice with water (50 mL), and the separated organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by HPLC to give a pale yellow solid intermediate compound (110 mg). LCMS (ESI) m/z 560.9[ M+H ]] + 。
Step eight: aqueous hydrochloric acid (5M, 1.5 mL) was added to isopropyl alcohol (8 mL) of the above intermediate compound (110 mg,0.2 mmol) at room temperature, and the reaction mixture was reacted at 80℃for 2 hours. LCMS detected completion of the reaction, and dichloromethane (100 mL) diluted the reaction. The reaction mixture was washed with brine (80 mL), and the separated organic phase was separated, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure, and the obtained crude product was purified by HPLC to give a white solid intermediate compound (85 mg). LCMS (ESI) m/z 499.1[ M+H ]] + 。
Step nine: palladium tetraphenylphosphine (19 mg,0.0161 mmol) was added to 2- (pyrrol-1-ylmethyl) phenylboronic acid (43 mg,0.21 mmol), the above intermediate compound (80 mg,0.1607 mmol), potassium carbonate (45 mg,0.32 mmol), water (3 mL) and 1, 4-dioxane (16 mL) at room temperature. The reaction mixture was reacted at 100℃for 2 hours. LCMS detected complete reaction of starting material. The reaction mixture was diluted with ethyl acetate (80 mL), filtered through celite, and the filtrate was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: dichloromethane/methanol=10:1) to give the compound (20.2 mg) of example 33 as a white solid. LC-MS (rt=0.996 min); (ESI) m/z 578.3[ M+H ] ] + . 1 H NMR(400MHz,DMSO-d6)δ9.05(br.s,1H),8.67(br.s,1H),7.51(d,J＝7.5Hz,1H),7.40(m,1H),7.31(m,1H),7.24(d,J＝6.7Hz,1H),7.13(s,1H),6.12(s,1H),5.81(m,1H),3.92(m,2H),3.83(m,2H),3.43(s,2H),3.23(m,2H),2.28(m,7H),2.07(m,1H),1.68(d,J＝6.8Hz,3H),1.55(m,4H),1.43(m,2H),1.34-1.21(m,2H)。
Example 34: (R) -4- ((1- (4-methyl-5- (2- (pyrrol-1-ylmethyl) phenyl) thiophen-2-yl) ethyl) amino) -2-methyl-6- ((tetrahydro-2H-pyran-4-yl) methyl) pyrido [4,3-d ] pyrimidin-7 (6H) -one
Step one: n-bromosuccinimide NBS (12.69 g,71.3 mmol) was added to 1- (4-methylthiophene-2-yl) ethyl-1-one (2 g,14.3 mmol) in ethanol (30 mL) at room temperature, and the reaction mixture was reacted at 20℃for 2 hours. LCMS detected complete reaction. The reaction was diluted with ethyl acetate (100 mL) and the organic phase was washed with sodium chloride solution (50 mL). The separated organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=20:1) to obtain an intermediate compound (2.5 g) as a white solid. LCMS (ESI) m/z 220.8[ M+H ]] + 。 1 H NMR(400MHz,DMSO-d6)δ7.78(s,1H),2.48(s,3H),2.19(s,3H)。
Step two: tetraethyltitanate (4.5 g,19.7 mmol), (R) - (+) tert-butylsulfinamide (1.19 g,9.86 mmol) was added to tetrahydrofuran (20 mL) of the above intermediate compound (2.4 g,10.9 mmol) at room temperature. The reaction mixture was reacted at 70℃for 16 hours. LCMS detected the reaction was essentially complete and brine (80 mL) was added. After diluting the reaction solution with ethyl acetate (100 mL), the separated organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=4:1) to obtain a pale yellow solid intermediate compound (2.5 g). LCMS (ESI) m/z 323.9[ M+H ] ] + 。 1 H NMR(400MHz,DMSO-d6)δ7.63(s,1H),2.62(s,3H),2.16(s,3H),1.18(s,9H)。
Step three: at a temperature below-60 ℃ to the above-mentioned middle partTo a solution of the intermediate compound (2.5 g,7.74 mmol) in tetrahydrofuran (50 mL) was slowly added DIBAL-H (24 mL). The reaction mixture was gradually warmed to room temperature and reacted at this temperature for 16 hours. LCMS detected substantial reaction complete. Methanol (10 mL) was added to the reaction solution, diluted with ethyl acetate (100 mL), filtered through celite, and the filtrate was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=4:1) to give a pale yellow solid intermediate compound (2.0 g). LCMS (ESI) m/z 325.9[ M+H ]] + 。
Step four: a methanol solution (20 mL) of HCl (g) was added to methanol (20 mL) of the above intermediate compound (2.0 g,7.71 mmol) at room temperature, and the reaction mixture was reacted at room temperature for 3 hours. LCMS detected the reaction was essentially complete. The solvent was removed by concentration under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: dichloromethane/methanol=10:1) to give intermediate compound (1.4 g) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ8.70(br.s,2H),7.09(s,1H),4.60(s,1H),2.12(s,3H),1.55(d,J＝6.6Hz,3H).
Step five: n, N-diisopropylethylamine (750 mg,12.3 mmol) was added to dimethyl sulfoxide (6 mL) of the above intermediate compound (500 mg,4.09 mmol), methyl 2- (6-chloro-5- (1, 3-dioxolan-2-yl) -2-methylpyrimidin-4-yl) acetate (900 mg,4.09 mmol). The reaction mixture was then sealed at 100℃for 16 hours. LCMS detects disappearance of starting material. The reaction solution was diluted with ethyl acetate (100 mL), brine (50 mL) was washed twice, the combined organic phases were dried over anhydrous sodium sulfate, the filtrate was concentrated under reduced pressure, and the obtained crude product was prepared by HPLC to give a white solid intermediate compound (240 mg). LCMS (ESI) m/z 458.3[ M+H ] ] + 。
Step six: an aqueous solution (2 mL) of lithium hydroxide (176 mg,4.20 mmol) was added to tetrahydrofuran (3 mL) of the above intermediate compound (240 mg,0.53 mmol) at room temperature, and the reaction mixture was reacted at this temperature for 2 hours, and the complete conversion of the starting material into product was detected by LCMS. The solvent tetrahydrofuran and water were swirled off under reduced pressure to give a white solid compound (240 mg). LCMS (ESI) m/z 444.0[ M+H ]] + 。
Step seven: the intermediate compound (240 mg,0.53 mmol) was dissolved in tetrahydrofuran (50 mL) at room temperature(tetrahydropyran-4-yl) methylamino (182 mg,1.575 mmol), HATU (599 mg,1.58 mmol) and N, N-diisopropylethylamine (272 mg,2.1 mmol) were added in a short time and the reaction mixture was reacted at 70℃for 2 hours. LCMS detected the reaction product as the predominant product. The reaction mixture was diluted with ethyl acetate (100 mL), washed twice with brine (50 mL), the separated organic phase was dried over anhydrous sodium sulfate, the filtrate was concentrated under reduced pressure, and the obtained crude product was purified by HPLC to give a pale yellow solid compound (160 mg). LCMS (ESI) m/z 541.1[ M+H ]] + 。
Step eight: aqueous hydrochloric acid (5M, 1.5 mL) was added to isopropyl alcohol (8 mL) of the above intermediate compound (160 mg,0.3 mmol) at room temperature, and the reaction mixture was reacted at 80℃for 2 hours. LCMS detected a substantially complete reaction. The reaction mixture was diluted with dichloromethane (100 mL) and washed with brine (50 mL). The separated organic phase was dried over anhydrous sodium sulfate, the filtrate was concentrated under reduced pressure, and the obtained crude product was purified by HPLC to give an intermediate compound (85 mg) as a white solid. LCMS (ESI) m/z 479.0[ M+H ] ] + 。
Step nine: palladium tetraphenylphosphine (20 mg,0.017 mmol) was added to 2-formylphenylboronic acid (33 mg,0.22 mmol), the above intermediate compound (80 mg,0.17 mmol), potassium carbonate (46 mg,0.34 mmol) and water (1 mL) in 1, 4-dioxane (5 mL) at room temperature. The reaction mixture was reacted at 100℃for 2 hours. Ethyl acetate (30 mL) was diluted, filtered through celite, and the filtrate was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: dichloromethane/methanol=10:1) to give intermediate compound (80 mg) as a white solid. LCMS (ESI) m/z 503.2[ M+H ]] + 。
Step ten: tetrahydropyrrole (106 mg,1.4921 mmol) was added to methanol (3 mL) of the above intermediate compound (75 mg,0.15 mmol) at room temperature, and after reacting at 20℃for 1 hour, sodium cyanoborohydride (33 mg,0.52 mmol) was added, and the reaction mixture was reacted at 20℃for 1 hour. LCMS detected complete reaction. The reaction was diluted with ethyl acetate (100 mL) and the organic phase was washed twice with aqueous sodium chloride (30 mL). The separated organic phase was dried over anhydrous sodium sulfate, the filtrate was concentrated under reduced pressure, and the obtained crude product was purified by HPLC to give the compound of example 34 (5.3 mg) as a white solid. LC-MS (rt=1.067 min); (ESI) m/z 558.3[ M+H ]] + . 1 H NMR(400MHz,DMSO-d6)δ9.08(s,1H),8.64(s,1H),8.17(s,2H),7.53(d,J＝7.5Hz,1H),7.37(t,J＝7.0Hz,1H),7.27(t,J＝7.0Hz,1H),7.17(d,J＝7.4Hz,1H),6.94(s,1H),6.11(s,1H),5.84(d,J＝6.8Hz,1H),3.97(m,1H),3.84(m,3H),3.43(s,2H),3.23(s,2H),2.31(d,J＝6.7Hz,7H),2.12–2.01(m,1H),1.93(s,3H),1.66(d,J＝6.8Hz,3H),1.60(m,4H),1.43(d,J＝12.2Hz,2H),1.27(m,2H)。
Example 35: (R) -4- ((1- (3-fluoro-5- (2- (pyrrol-1-ylmethyl) phenyl) thiophen-2-yl) ethyl) amino) -2-methyl-6- ((tetrahydro-2H-pyran-4-yl) methyl) pyrido [4,3-d ] pyrimidin-7 (6H) -one
Step one: 1-Ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (13.85 g,72.3 mmol) was added to a solution of 3-fluorothiophene-2-carboxylic acid (4.8 g,32.85 mmol) and N, O-dimethylhydroxylamine hydrochloride (7.05 g,72.3 mmol) in pyridine (30 mL) at room temperature, and the reaction mixture was reacted at room temperature for 16 hours. The solvent of the reaction solution was removed by concentration under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=4:1) to give an intermediate compound (6.1 g) as a yellow solid. LCMS (ESI) m/z 190.0[ M+H ]] + 。
Step two: n-bromosuccinimide (17.5 g,98.31 mmol) was added to N, N-dimethylformamide (100 mL) of the above intermediate compound (6.1 g,32.8 mmol) under nitrogen atmosphere, and the reaction mixture was heated to 60℃and reacted at this temperature for 16 hours. Ethyl acetate (500 mL) was added to the mixture to dilute the mixture, the mixture was then washed with saturated brine (100 mL) three times, the separated organic phase was dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure, and the obtained crude product was subjected to silica gel column chromatography (detergent: ethyl acetate/petroleum ether=4:1) to give a brown solid intermediate compound (3.5 g). LCMS (ESI) m/z 269.8[ M+H ]] + 。 1 H NMR(400MHz,DMSO-d6)δ7.42(s,1H),3.74(s,3H),3.22(s,3H)。
Step three: methyl magnesium bromide (30 mL,31.7 mmol) was added to tetrahydrofuran (50 mL) of the above intermediate compound (3.4 g,12.7 mmol) at 0deg.C under nitrogen atmosphere to react The reaction was continued at 0℃for 1 hour. After LCMS detects complete reaction of starting material, the reaction was quenched by addition of ammonium chloride solution (200 mL). The reaction solution was extracted twice with ethyl acetate (150 ml), and the combined organic phases were dried over anhydrous sodium sulfate, and after concentration of the filtrate under reduced pressure, the obtained crude product was prepared as a brown oily intermediate compound (2.2 g) by HPLC. LCMS (ESI) m/z 224.8[ M+H ]] + 。 1 H NMR(400MHz,DMSO-d6)δ8.23(s,1H),2.54(s,3H)。
Step four: tetraethyltitanate (3.94 g,17.2 mmol) was added to tetrahydrofuran (30 mL) of the above compound (2.2 g,9.5 mmol), (R) - (+) tert-butylsulfinamide (1.05 g,8.64 mmol) under nitrogen, and the reaction mixture was heated to 70 ℃ and reacted at this temperature for 16 hours. After the reaction solution was cooled to room temperature, brine (50 ml) was added thereto, stirring was continued for 10 minutes, the reaction mixture was filtered through celite, the filtrate was extracted twice with ethyl acetate (100 ml), the combined organic phases were dried over anhydrous sodium sulfate, the filtrate was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=4:1) to give a brown solid intermediate compound (1.8 g). LCMS (ESI) m/z 326.0[ M+H ]] + 。 1 H NMR(400MHz,DMSO-d6)δ7.47(s,1H),2.65(d,J＝2.4Hz,3H),1.18(s,9H)。
Step five: DIBAL-H (15 mL,14.1 mmol) was added to tetrahydrofuran (30 mL) of the above intermediate compound (1.8 g,5.5 mmol) at-78deg.C cooled, and the reaction mixture was slowly warmed to room temperature and reacted at this temperature for 16 hours, and the reaction was substantially complete as determined by LCMS. The reaction was quenched with methanol (20 ml), concentrated under reduced pressure to remove most of the solvent, the residue was diluted with methanol (200 ml), filtered through celite, and the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=4:1) to give brown solid compound (1.4 g). LC-MS (ESI) m/z 329.9[ M+H ] ] + . 1 H NMR(400MHz,DMSO-d6)δ7.19(s,1H),5.89(d,J＝6.6Hz,1H),4.66(m,1H),1.45(d,J＝6.8Hz,3H),1.10(s,9H)。
Step six: a solution of HCl (g) in methanol (10 mL,30 mmol) was added to the intermediate compound (1.8 g,5.48 mmol) in methanol (10 mL). The reaction was allowed to react at room temperature for 2 hours. LCMS reaction was essentially complete. Concentrating under reduced pressure to remove solventThe crude product obtained was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=10:1) to give intermediate compound (1.4 g) as a brown solid. LC-MS (ESI) m/z 206.9[ M+H ]] + . 1 H NMR(400MHz,DMSO-d6)δ8.76(s,3H),7.33(s,1H),4.70(d,J＝6.6Hz,1H),1.56(d,J＝6.8Hz,3H).
Step seven: methyl 2- (6-chloro-5- (1, 3-dioxolan-2-yl) -2-methylpyrimidin-4-yl) acetate (500 mg,1.84 mmol), the above intermediate compound (494 mg,2.2 mmol) and potassium fluoride (1.06 g,18.3 mmol) were dissolved in dimethyl sulfoxide (5 mL), and the reaction was heated to 100℃overnight in a sealed tube. LCMS checked the reaction to be substantially complete, ethyl acetate (100 mL) was used to dilute the reaction solution, washed three times with water (50 mL), the combined organic phases were dried over anhydrous sodium sulfate, the filtrate was concentrated under reduced pressure, and the resulting crude product was purified by HPLC to give the intermediate compound (500 mg) as a white solid. LC-MS (ESI) m/z 462.1[ M+H ]] + 。 1 H NMR(400MHz,DMSO-d6)δ7.18(s,1H),7.08(d,J＝7.5Hz,1H),5.88(s,1H),5.55(m,1H),4.09(m,2H),3.96-3.91(m,2H),3.71(s,2H),3.59(s,3H),2.56-2.55(m,1H),2.33(s,3H),1.55(d,J＝6.9Hz,3H)。
Step eight: an aqueous solution (2 mL) of lithium hydroxide (365 mg,8.69 mmol) was added dropwise to a solution of the above intermediate compound (500 mg,1.08 mmol) in tetrahydrofuran (10 mL), and the reaction was carried out at room temperature for 2 hours. LC-MS detected complete reaction of the starting materials. The solvent was removed by concentration under reduced pressure to give the crude intermediate product (450 mg) as a pale yellow solid. LC-MS (ESI) m/z 447.8[ M+H ] ] + 。
Step nine: HATU (665 mg,1.75 mmol) was added to a solution of the above intermediate compound (220 mg,0.58 mmol), (tetrahydropyran-4-yl) methylamino (200 mg,1.75 mmol) and N, N-diisopropylethylamine (300 mg,2.3 mmol) in tetrahydrofuran, and the reaction was heated to 70℃for 2 hours. The solvent was removed by concentration under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: ethyl acetate/methanol=10:1) to give the intermediate compound (180 mg) as a yellow solid. LC-MS (ESI) m/z 545.0[ M+H ]] + 。
Step ten: aqueous hydrochloric acid (5M, 1.5mL,7.5 mmol) was added to a solution of the above intermediate compound (350 mg,0.52 mmol) in isopropanol (8 mL). The reaction mixture was reacted at 80℃for 1 hour. LCMS detectionThe raw materials react completely. The reaction was diluted with dichloromethane (100 mL), washed twice with brine (30 mL), the separated organic phase was dried over anhydrous sodium sulfate, the filtrate was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: dichloromethane/methanol=10:1) to give a pale yellow solid compound (180 mg). LC-MS (ESI) m/z 483.1[ M+H ]] + 。
Step eleven: tetratriphenylphosphine palladium (58 mg,0.05 mmol) was added to 1, 4-dioxane (5 mL) of 2-formylphenylboronic acid (98 mg,0.65 mmol), the above intermediate compound (250 mg,0.5 mmol), potassium carbonate (138 mg,0.1 mmol) and water (1 mL) under nitrogen. The reaction mixture was heated to 100℃and reacted at this temperature for 16 hours. LCMS detected the reaction was essentially complete. The reaction mixture was diluted with ethyl acetate (50 mL), washed twice with brine (10 mL), and the separated organic phase was dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: dichloromethane/methanol=10:1) to give a pale yellow solid compound (180 mg). LC-MS (ESI) m/z 507.2[ M+H ] ] + 。
Step twelve: a drop of glacial acetic acid was added to the intermediate compound (180 mg,0.37 mmol) and tetrahydropyrrole (81 mg,1.13 mmol) in methanol (5 mL) at room temperature, and the reaction mixture was stirred at room temperature for 2 hours. Sodium cyanoborohydride (71 mg,1.13 mmol) was added to the above reaction solution, and the reaction was continued for 12 hours, whereby the LC-MS detection reaction was substantially complete. The reaction mixture was diluted with ethyl acetate (50 mL), washed twice with brine (20 mL), and the separated organic phase was dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, and the obtained crude product was prepared by HPLC to give a pale yellow solid, example 35 compound (11.2 mg). LC-MS (rt= 1.962 min); (ESI) m/z 562.2[ M+H ]] + 。 1 H NMR(400MHz,DMSO-d6)δ9.09(s,1H),8.64(d,J＝8.0Hz,1H),7.44-7.40(m,2H),7.35-7.33(m,2H),7.24(s,1H),6.12(s,1H),5.88-5.85(m,1H),4.00-3.95(m,1H),3.91-3.82(m,3H),3.54(s,2H),3.26-3.21(m,2H),2.38(m,7H),2.30(s,3H),2.08(m,1H),1.68(d,J＝6.8Hz,3H),1.61(m,4H),1.33-1.30(m,2H),1.27-1.24(m,2H)。
Referring to the methods of examples 1 and 19, the synthesis of examples 36-41 was carried out using commercially available different amines as starting materials instead of (tetrahydro-2H-pyran-4-yl) -methylamine and different boric acids as starting materials instead of 4- ((2- (dimethylamino) ethyl) carbonic acyl) phenyl) boronic acid:
example 42: (R) -N, N-dimethyl-4 '- (1- ((2-methyl-7-oxo-6- ((tetrahydro-2H-pyran-4-yl) methyl) -6, 7-dihydropyridin [4,3-d ] pyrimidin-4-yl) amino) ethyl) - [1,1' -diphenyl ] -2-carbonic acid amide
Step one: potassium fluoride (4.26 g,73.51 mmol) was added to methyl 2- (6-chloro-5- (1, 3-dioxolan-2-yl) -2-methylpyrimidin-4-yl) acetate (2.0 g,7.351 mmol), (R) -1- (4-bromophenyl) ethyl-1-amine hydrochloride (2.073 g,8.82 mmol) in dimethyl sulfoxide (40 mL) at room temperature. The reaction mixture was then sealed at 100℃for 16 hours. LCMS detected the reaction was essentially complete. The reaction mixture was diluted with ethyl acetate (200 mL), washed twice with brine (50 mL), the combined organic phases were dried over anhydrous sodium sulfate, the filtrate was concentrated under reduced pressure, and the resulting crude product was purified by HPLC to give the intermediate compound (2.4 g) as a pale yellow solid. LCMS (ESI) m/z 438.1[ M+H ] ] + 。
Step two: an aqueous solution (8 mL) of lithium hydroxide (1.19 g,49.6 mmol) was added to tetrahydrofuran (40 mL) of the above intermediate compound (2.7 g,6.21 mmol) at room temperature, and the reaction mixture was reacted at this temperature for 2 hours. LCMS detected the reaction was essentially complete. The solvent was removed by concentration under reduced pressure to give an intermediate product (2.5 g) as a pale yellow solid. LCMS (ESI) m/z 422.1[ M+H-Li] + 。
Step three: the intermediate compound (2.41 g,5.64 mmol) was dissolved in tetrahydrofuran (100 mL) at room temperature, and (tetrahydropyran-4-yl) methylamino (1.95 g,16.9 mmol), HA was added sequentiallyTU (8.58 g,22.6 mmol) and N, N-diisopropylethylamine (2.92 g,22.6 mmol) were reacted by heating the reaction mixture to 70℃for 2 hours. LCMS detected the reaction was essentially complete. After concentrating under reduced pressure to remove most of the solvent, the reaction mixture was diluted with ethyl acetate (200 mL) and washed twice with water (50 mL). The combined organic phases were dried over anhydrous sodium sulfate, the filtrate was concentrated under reduced pressure, and the resulting crude product was subjected to silica gel column chromatography (eluent: ethyl acetate/methanol=20:1) to give intermediate compound (2.08 g) as a pale yellow solid. LCMS (ESI) m/z 521.2[ M+H ]] + 。
Step four: aqueous hydrochloric acid (5M, 7.0 mL) was added to tetrahydrofuran (32 mL) of the above intermediate compound (2.08 g,4.01 mmol) at room temperature, and the reaction mixture was reacted at 80℃for 2 hours. LCMS detected the reaction was essentially complete. The reaction was diluted with dichloromethane (200 mL), washed twice with brine (50 mL) and the combined organic phases were dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: dichloromethane/methanol=10:1) to give an intermediate compound (1.6 g) as a pale yellow solid. LCMS (ESI) m/z 459.1[ M+H ] ] + 。 1 H NMR(400MHz,DMSO-d6)δ9.11(s,1H),8.55(d,J＝7.4Hz,1H),7.63-7.45(m,2H),7.38(d,J＝8.4Hz,2H),6.10(s,1H),5.54(m,1H),4.00(m,1H),3.92-3.77(m,3H),3.23(m,2H),3.17(m,1H),2.23(s,3H),2.10(m,1H),1.54(d,J＝7.0Hz,3H),1.44(m,2H),1.34-1.22(m,2H)。
Step four: palladium tetraphenylphosphine (33 mg,0.03 mmol) was added to the above intermediate compound (130 mg, 0.284 mmol), (2- (dimethylformamide) phenyl) boric acid (72 mg,0.37 mmol), potassium carbonate (79 mg,0.57 mmol), and water (2 mL) under nitrogen as a 1, 4-dioxane (12 mL). The reaction mixture was heated to 100℃and reacted at this temperature for 2 hours. The reaction was diluted with ethyl acetate (200 mL), washed twice with brine (50 mL), the combined organic phases were dried over anhydrous sodium sulfate, the filtrate was concentrated under reduced pressure, and the resulting crude product was purified by HPLC to give the compound of example 42 as a pale yellow solid (20.2 mg). LC-MS (rt=1.493 min); (ESI) m/z 526.3[ M+H ]] + . 1 H NMR(400MHz,DMSO-d6)δ9.13(s,1H),8.53(d,J＝7.7Hz,1H),7.70(m,4H),7.53(d,J＝8.2Hz,2H),7.48(d,J＝8.2Hz,2H),6.10(s,1H),5.66(m,1H),4.01(m,1H),3.93-3.81(m,3H),3.25(m,2H),2.97(m,6H),2.25(s,3H),2.11(m,1H),1.60(d,J＝7.0Hz,3H),1.45(m,2H),1.34-1.23(m,2H)。
Referring to the procedure of example 42, the synthesis of (tetrahydropyran-4-yl) methylamino was replaced with a different amine and (2- (dimethylformamide) phenyl) boronic acid was replaced with a different boronic acid, which was commercially available, gave examples 43-47:
referring to the methods of examples 1 and 19, the synthesis of examples 48-50 was carried out using commercially available different amines as starting materials instead of (tetrahydro-2H-pyran-4-yl) -methylamine and different boric acids as starting materials instead of 4- ((2- (dimethylamino) ethyl) carbonic acyl) phenyl) boronic acid:
referring to the method of example 35, examples 52 to 56 were obtained by the synthesis method using various amines commercially available as raw materials instead of (tetrahydropyran-4-yl) methylamino and various boric acids as raw materials instead of 2-formylphenylboric acid;
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Referring to the method of example 35, examples 71 to 80 were obtained by a synthetic method using commercially available different amines as a raw material instead of (tetrahydropyran-4-yl) methylamino and different boric acids as a raw material instead of 2-formylphenylboric acid;
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referring to the method of example 42, examples 81-86 were obtained by a synthetic method using commercially available different amines as raw materials instead of (tetrahydropyran-4-yl) methylamino and different boric acids as raw materials instead of (2- (dimethylformamide) phenyl) boronic acid;
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test example 1 inhibition Activity test of enzyme
KRAS using CisBio G12C SOS1 kit for testing compound inhibition SOS1 and KRAS by using Binding assay method G12C Efficacy of protein-protein interactions between them, as a result of IC 50 The value represents.
The testing method comprises the following steps: (1) Test compounds were tested at 1000nM, 100% DMSO solution diluted to 200-fold final concentration in 384well plates 3-fold diluted compound, 10 concentrations.50nL of compound at 200-fold final concentration was transferred to the 384well plate of interest using a dispenser Echo 550. 50nL of 100% DMSO is added to each of the negative control well and the positive control well; (2) Preparing Tag1 SOS1 solution with 4 times of final concentration by using a reagent buffer; (3) 2.5. Mu.L of a 4-fold final concentration of Tag1 SOS1 solution was added to 384-well plates; (4) Tag2 KRAS was formulated at 4-fold final concentration with a Diluent buffer G12C A solution; (5) Tag2 KRAS was added at a final concentration of 4-fold of 2.5. Mu.L to each of the compound well and positive control well G12C A solution; 2.5. Mu.L of a reagent buffer was added to the negative control well; (6) Centrifuging the 384-well plate at 1000rpm for 30 seconds, shaking and uniformly mixing, and incubating for 15 minutes at room temperature; (7) Preparing an Anti Tag1Tb3+ solution with a 1-time final concentration and an Anti Tag2XL665 solution with a 1-time final concentration by using a Detection buffer, uniformly mixing the two solutions, and adding 5 mu L of mixed solution into each hole; (8) Centrifuging the 384-well plate at 1000rpm for 30 seconds, shaking and uniformly mixing, and incubating for 120 minutes at room temperature; (9) reading Em665/620 with an Envision microplate reader; (10) Data analysis, calculation formulaWherein Min signal negative control Kong Junzhi; max signal positive control Kong Junzhi; compound Kong Junzhi. The log value of concentration is taken as an X-axis of the fit-up dose-response curve, the percentage inhibition rate is taken as a Y-axis, and log (inhibitor) vs. response Variable slope fit-up dose-response curve of analysis software GraphPad Prism 5 is adopted, so that the IC of each compound on enzyme activity is obtained 50 Values. The fitting formula is: y=bottom+ (Top Bottom)/(1+10 ((log ic) 50 X)*Hill Slope))。
Results: most example Compounds of the invention against KRAS G12C SOS1 enzyme showed high inhibitory activity, IC 50 Less than 100nM. (specific IC) 50 The values are expressed as follows: a is that<50nM；50nM≤B<200nM；C≥200nM).
Test example 2: effect of example Compounds on MiaPaca-2 cell proliferation
Test method one (2D) MiaPaca-2 cells (pancreatic cancer) cells (100. Mu.L/well, 20000 cells/mL) were seeded in 96-well plates and supplemented with 10% fetal bovine serum and 1% penicillin/streptomycin sulfate. Cells were treated with a 10. Mu.M solution of test compound diluted three times in eight gradients at an initial concentration of 0.5% dimethyl sulfoxide as a blank and treated with 5% CO 2 Incubate in incubator for a certain period of time (5 days). At the end of incubation, 10. Mu.L of MTT stock solution (5 mg/mL) was added to each well. The plates were incubated at 37℃for 4 hours, after which the medium was removed. Dimethyl sulfoxide (100 μl) was added to each well, followed by shaking well. The absorbance of the formazan product was measured at 570nm on a Thermo Scientific Varioskan Flash multimode reader. IC was obtained by fitting dose response data to a three-parameter nonlinear regression model using GraphPad Prism 6.0 software 50 Values.
As a result, the compounds of the present invention provided example have proliferation-inhibiting activity on MiaPaca-2 cells, IC 50 Values were all less than 15uM; some of the example compounds were shown to have value-added inhibitory activity on MiaPaca-2 cells, IC, as in examples 2, 6, 9, 10, 15 50 Values less than 5uM show excellent in vitro antitumor effect. As shown in table (two). List of data for inhibitory activity of the compounds of the examples of the present application on MiaPaca-2 cell proliferation.
Examples numbering IC 50 /uM Examples numbering IC 50 /uM
Comparative compound BI3406 7.85 2 4.42
5 7.4 6 1.67
7 11.6 9 2.51
10 1.67 15 1.98
16 6.12
Test example 3: ADMET test of example Compounds
(1) Metabolic stability test: metabolic stability incubation was performed with 150 μl of liver microsomes (final concentration 0.5 mg/mL) containing NADPH (final concentration 1 mM), 1 μl of test compound and positive control midazolam or negative control atenolol, and the reaction was stopped with tinidazole-containing acetonitrile at 0min, 5min, 10min, 20min and 30min, vortexed for 10min, centrifuged at 15000rmp for 10min, and 50 μl of supernatant was sampled in 96 well plates. The metabolic stability of the compounds was calculated by measuring the relative decrease in the drug substance.
Results: the compounds of some embodiments of the present application have better stability to liver microsomes of various species (rat, mouse, dog, human), showing higher metabolic potency.
All documents mentioned in this disclosure are incorporated by reference in this disclosure as if each were individually incorporated by reference. Further, it will be appreciated that various changes and modifications may be made by those skilled in the art after reading the above teachings, and such equivalents are intended to fall within the scope of the application as defined in the appended claims.

Claims (22)

1. A pyrimidoheterocyclic compound shown in a general formula I or pharmaceutically acceptable salt thereof,
wherein:
R 1 selected from C 3 -C 12 Cycloalkyl, 3-12 membered heterocycloalkyl, - (C1-C6 alkylene) -C 3 -C 6 Cycloalkyl group,- (C1-C6 alkylene) -5-8 membered heterocycloalkyl, optionally substituted by 1-3 Rn; said Rn is selected from deuterium, halogen, C 1 -C 6 Alkyl, C 1 -C 6 An alkoxy group; and when R is 1 Selected from- (C1-C6 alkylene) -C 3 -C 6 Cycloalkyl, - (C1-C6 alkylene) -5-8 membered heterocycloalkyl, with Rn being halogen or C1-C3 alkyl;
R 2a is hydrogen, R 2b Methyl, said R is 2a And R is 2b The commonly attached carbon atoms are R configuration carbon atoms;
R 3 is C 1 -C 3 An alkyl group;
m is C-H;
Ar 1 selected from phenyl or thienyl, optionally substituted with one or more deuterium, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, or halo substitution;
Ar 2 selected from phenyl, pyridyl, pyrazolyl,Optionally substituted with one or more groups R selected from the group consisting of m The substitution is as follows: deuterium, halogen, -CONH (C) 1 -C 3 Alkyl group, C 1 -C 8 Sulfonamide, hydroxy, amino, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 1 -C 3 monoalkylamino-C 1 -C 6 Alkyl-, C 1 -C 3 dialkylamino-C 1 -C 6 Alkyl-, C 2 -C 6 Alkenyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, 3-8 membered cycloalkyl-C 1 -C 6 Alkyl-, 3-8 membered heterocycloalkyl-C 1 -C 6 Alkyl-,Wherein when R is m Is 3-8 membered cycloalkyl, 3-8 membered cycloalkyl-C 1 -C 6 Alkyl, 3-8 membered heterocycloalkyl-C 1 -C 6 Alkyl-at the time of said R m Optionally further substituted with amino, C 1 -C 3 Alkyl, hydroxy substitution; when R is m is-CONH (C) 1 -C 3 Alkyl), the R m Further by C 1 -C 3 Monoalkylamino, C 1 -C 3 A dialkylamino substitution;
wherein said heterocycloalkyl comprises 1 to 3 heteroatoms selected from the group consisting of: n, O or S, optionally the carbon atom in the cycloalkyl group is oxidized, and optionally the nitrogen, carbon or sulfur atom in the heterocycloalkyl group is oxidized.
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof,
Ar 1 selected from phenyl or thienyl, optionally substituted with 1-3C 1 -C 6 Alkyl or halogen substitution.
3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Ar 2 Selected from phenyl, pyridyl, pyrazolyl,
Wherein the phenyl, pyridinyl groups are optionally substituted with one or more groups R selected from the group m The substitution is as follows: deuterium, halogen, -CONH- (C) 1 -C 3 Alkylene) - (C 1 -C 3 Dialkylamino group, C 1 -C 6 Sulfonamide, hydroxy, amino, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 1 -C 3 monoalkylamino-C 1 -C 6 Alkyl-, C 1 -C 3 dialkylamino-C 1 -C 6 Alkyl-, C 2 -C 6 Alkenyl, 3-8 membered cycloalkyl-C 1 -C 6 Alkyl-, 3-8 membered heterocycloalkyl-C 1 -C 6 Alkyl-,Wherein when R is m Is 3-8 membered cycloalkyl-C 1 -C 6 Alkyl, 3-8 membered heterocycloalkyl-C 1 -C 6 Alkyl-at the time of said R m Optionally further substituted with amino, C 1 -C 3 Alkyl, hydroxy substitution;
optionally substituted with one or more C1-C6 alkyl groups.
4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Ar 1 Selected from phenyl or thienyl, optionally substituted with one or more groups independently selected from deuterium, halogen, C 1 -C 6 Alkyl, C 1 -C 6 The group of the alkoxy group is substituted;
alternatively, R m Selected from halogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 2 -C 6 Alkenyl, hydroxy, -CONH (C) 1 -C 3 Alkyl), 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, 3-8 membered cycloalkyl-C 1 -C 6 Alkyl-, 3-8 membered heterocycloalkyl-C 1 -C 6 Alkyl-, C 1 -C 3 dialkylamino-C 1 -C 6 Alkyl-, wherein, when R m is-CONH (C) 1 -C 3 Alkyl), the R m Further by C 1 -C 3 Monoalkylamino, C 1 -C 3 Dialkylamino substitution.
5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R m Selected from halogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, hydroxy, C 1 -C 3 monoalkylamino-C 1 -C 6 Alkyl-, C 1 -C 3 dialkylamino-C 1 -C 6 Alkyl-, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl-C 1 -C 6 Alkyl-.
6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 3 Is methyl.
7. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, whereinAr is thus 2 Is phenyl, pyridyl or pyrazolyl.
8. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is of the formula:wherein R is 1 、M、Ar 2 The scope of (c) is as defined in claim 1.
9. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is of the formula:wherein R is 1 、M、Ar 2 The scope of (c) is as defined in claim 1.
10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R m Selected from halogen, C 1 -C 6 Alkyl, C 1 -C 4 Alkoxy, -CONH (C) 1 -C 3 Alkyl group, C 2 -C 4 Alkenyl, hydroxy, amino, 3-6 membered heterocycloalkyl- (C1-C3 alkyl) -, C 1 -C 3 dialkylamino-C 1 -C 6 Alkyl-, wherein when R m is-CONH (C) 1 -C 3 Alkyl), the R m Further selected from C 1 -C 3 Monoalkylamino, C 1 -C 3 Substituents of the dialkylamino group.
11. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R m Selected from halogen, -CONH (C) 1 -C 3 Alkyl), 3-6 membered heterocycloalkyl- (C1-C3 alkyl) -, C 1 -C 3 dialkylamino-C 1 -C 6 Alkyl-, wherein, when R m is-CONH (C) 1 -C 3 Alkyl), the R m Further by C 1 -C 3 Monoalkylamino, C 1 -C 3 Dialkylamino substitution.
12. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from C 3 -C 8 Cycloalkyl, 3-8 membered heterocycloalkyl, optionally substituted with 1-3 Rn, said Rn being as defined in claim 1.
13. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from C 3 -C 6 Cycloalkyl, 5-8 membered heterocycloalkyl, - (C1-C6 alkylene) -C 3 -C 6 Cycloalkyl, - (C1-C6 alkylene) -5-8 membered heterocycloalkyl, optionally substituted by 1-3 Rn, said Rn being halogen or C1-C3 alkyl.
14. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from 5-6 membered heterocycloalkyl, - (C1-C3 alkylene) -5-6 membered heterocycloalkyl.
15. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from the following groups:
wherein one or more R c Are each independently selected from hydrogen, deuterium, halogen, -C 1 -C 6 An alkyl group; r is R d Independently selected from hydrogen, -C 1 -C 6 An alkyl group.
16. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from the following groups:wherein R is c As defined in claim 15.
17. The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein R c Selected from hydrogen, halogen, -C 1 -C 3 An alkyl group; r is R d Selected from hydrogen, -C 1 -C 3 An alkyl group.
18. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:
19. a compound, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:
20. the use of a compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, and/or a compound according to claim 19, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a disease associated with Ras protein activity or expression or mutation.
21. The use according to claim 20 for the preparation of a medicament for the treatment of tumors independently selected from lung cancer, pancreatic cancer, liver cancer, colorectal cancer, cholangiocarcinoma, brain cancer, leukemia, lymphoma, melanoma, thyroid cancer, and nasopharyngeal carcinoma.
22. A pharmaceutical composition, said pharmaceutical composition comprising:
(i) An effective amount of a compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof and/or a compound according to claim 19, or a pharmaceutically acceptable salt thereof; and
(ii) A pharmaceutically acceptable carrier.
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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103842364A (en) * 2011-09-30 2014-06-04 奇尼塔公司 Anti-viral compounds
CN110167928A (en) * 2016-12-22 2019-08-23 勃林格殷格翰国际有限公司 The quinazoline and derivative that Novel warp benzylamino as SOS1 inhibitor replaces
CN111372932A (en) * 2017-12-21 2020-07-03 勃林格殷格翰国际有限公司 Novel benzylamino-substituted pyridopyrimidinones and derivatives as SOS1 inhibitors
CN114456165A (en) * 2022-02-14 2022-05-10 上海翰森生物医药科技有限公司 Nitrogen-containing fused ring derivative regulator, preparation method and application thereof
CN114685487A (en) * 2020-12-27 2022-07-01 上海凌达生物医药有限公司 Pyrimidine heterocyclic compound, preparation method and application

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US5654307A (en) * 1994-01-25 1997-08-05 Warner-Lambert Company Bicyclic compounds capable of inhibiting tyrosine kinases of the epidermal growth factor receptor family
US8383635B2 (en) * 2008-08-12 2013-02-26 Glaxosmithkline Llc Chemical compounds

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103842364A (en) * 2011-09-30 2014-06-04 奇尼塔公司 Anti-viral compounds
CN110167928A (en) * 2016-12-22 2019-08-23 勃林格殷格翰国际有限公司 The quinazoline and derivative that Novel warp benzylamino as SOS1 inhibitor replaces
CN111372932A (en) * 2017-12-21 2020-07-03 勃林格殷格翰国际有限公司 Novel benzylamino-substituted pyridopyrimidinones and derivatives as SOS1 inhibitors
CN114685487A (en) * 2020-12-27 2022-07-01 上海凌达生物医药有限公司 Pyrimidine heterocyclic compound, preparation method and application
CN114456165A (en) * 2022-02-14 2022-05-10 上海翰森生物医药科技有限公司 Nitrogen-containing fused ring derivative regulator, preparation method and application thereof

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