CN117510513A - Heterocyclic compounds having biological activity - Google Patents

Heterocyclic compounds having biological activity Download PDF

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CN117510513A
CN117510513A CN202210888300.2A CN202210888300A CN117510513A CN 117510513 A CN117510513 A CN 117510513A CN 202210888300 A CN202210888300 A CN 202210888300A CN 117510513 A CN117510513 A CN 117510513A
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alkyl
membered
ring
substituted
cycloalkyl
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刘志华
陈坤成
袁保昆
张凯
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Capital Pharmaceutical Holdings Beijing Co ltd
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Capital Pharmaceutical Holdings Beijing Co ltd
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Priority to PCT/CN2023/108603 priority patent/WO2024022244A1/en
Publication of CN117510513A publication Critical patent/CN117510513A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • C07F9/65615—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing a spiro condensed ring system of the formula where at least one of the atoms X or Y is a hetero atom, e.g. S

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Abstract

The present application relates to biologically active heterocyclic compounds of formula (I), methods for their preparation, pharmaceutical compositions thereof, and to the use of such compounds and pharmaceutical compositions thereof, for example in the treatment of cancer. In the preparation process, the compound of the formula I is obtained through substitution, coupling, deprotection and other reactions.

Description

Heterocyclic compounds having biological activity
Technical Field
The present invention relates generally to novel substituted pyridyl heterocyclic compounds having SHP2 inhibitory activity, processes for their preparation, pharmaceutical compositions thereof, and to the use of such compounds and pharmaceutical compositions thereof for the treatment of diseases benefiting from SHP2 enzyme inhibition, such as for the treatment of cancer.
Background
Cancer is a serious disease which seriously threatens human health and life, especially the incidence and death rate of cancer in recent years are rapidly rising, and cardiovascular diseases are the first killers of human health. In these signaling pathways, the phosphorylation and dephosphorylation of proteins are important, and this reversible process is regulated by both kinases and phosphatases. Phosphorylation of Protein Tyrosine Kinases (PTKs) and dephosphorylation of Protein Tyrosine Phosphatases (PTPs) are a pair of reversible processes that maintain dynamic equilibrium between themselves to maintain normal physiological functions of cells whereas abnormal phosphorylation can lead to the development of cancer, inflammation, diabetes and other diseases.
The SHP2 protein is a non-receptor protein tyrosine phosphatase coded by the ptpn11 gene, is widely expressed in various tissues, and participates in important physiological and pathological processes such as embryo development, metabolism, immune response, tumorigenesis and the like.
The SHP2 protein consists of two N-terminal SH2 domains in tandem (N-SH 2 and C-SH 2), a PTP catalytic domain and a C-terminal tail with regulatory effects the SH2 domain is a conformational switch that mediates the interaction of the SHP2 protein with phosphotyrosine-containing activators (e.g., insulin receptor substrate 1-IRS1 and GRB 2-associated binding protein 1-GAB 1) and the intramolecular interaction of the SH2 domain with the PTP catalytic domain. In the unstimulated state, the SHP2 domain binds to the PTP domain, blocking the catalytically active site, leaving the SHP2 phosphatase activity in a self-inhibiting state. The nature of this shift in activity of SHP2 allows for various mutations in SHP2 to disrupt the self-inhibiting state of SHP2, leading to over-activation of SHP2 protein phosphatase activity and thus cancer, when SH2 domain binding activators, and the inhibitory intramolecular interactions are released, the SHP2 phosphatase is in an open conformation, allowing the SHP2 substrate to localize to the catalytically active site and exert phosphatase function. Both experimental and clinical data confirm that SHP2 plays a promoting role in most cancers, as the first tyrosine phosphatase discovered to promote cancer progression, which has received great attention in the cancer field, its phosphatase activity plays an important role in intracellular signal regulation.
SHP2 is involved in regulating cell signal transduction pathways activated by cytokines, growth factors and hormones, including RAS/ERK, JAK/STAT, PI3K/AKT and NF- κB signal pathways, thereby regulating physiological functions such as cell proliferation, differentiation, cell cycle maintenance and migration, and the like, while SHP2 also mediates compensatory activation pathways after MEK and other kinases are inhibited, thereby promoting the occurrence of tumor resistance. SHP2 has been shown to be a downstream molecule of PD-1 signaling that not only inhibits T cell activation but also promotes T cell disability. In addition, SHP2 can inhibit IFN-gamma mediated immune responses by inactivating signal transduction and transcriptional activator STAT 1.
In recent years, SHP2 activating mutations and high expression have been continuously found in leukemia, solid tumor, melanoma, glioblastoma, lung cancer, breast cancer and knoop-male syndrome, and are closely related to the occurrence, development and prognosis of tumors. However, because of the high conservation, polarity and charged environment of various phosphatase PTP catalytic domains, the traditional SHP2 inhibitors have larger defects in specificity and bioavailability, and limit the clinical application, therefore, the development of SHP2 inhibitors with high specificity, high safety and strong cell membrane permeability is a key for determining whether SHP2 can become a novel tumor intervention target, and the SHP2 protein allosteric inhibitors become the main direction of current research. In summary, SHP2 allosteric inhibitors are rapidly starting, competing increasingly at home and abroad, and these drugs will become a further heavy weapon for tumor treatment.
Disclosure of Invention
In one aspect, the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, metabolite or prodrug thereof,
wherein,
ring A isOr alternatively
Wherein carbon is linked to Y, X 3 And X 4 Each independently is N or CR 10 ；
R 3 、R 20 、R 21 And R is 22 Each independently is H, halogen, -CN, -NH 2 、-OH、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -O-R 5 、-NR-R 5 、C 3-8 Cycloalkyl, or 3-8 membered heterocycloalkyl,
the alkyl, cycloalkyl and heterocycloalkyl groups may be optionally substituted with one or more halogen, -CN, -NH 2 、-OH、C 1-6 Alkyl, -O-C 1-6 Alkyl, or-NH-C 1-6 Alkyl substitution;
the B ring is a 6-10 membered aromatic ring or a 5-12 membered heteroaromatic ring, or
The B ring is a bicyclic or tricyclic ring system comprising a 6-10 membered aromatic ring or a 5-12 membered heteroaromatic ring attached to N, and a 3-8 membered alicyclic ring or a 3-8 membered heteroalicyclic ring fused to said aromatic ring or heteroaromatic ring, said alicyclic ring and heteroalicyclic ring optionally being oxo,
X 1 and X 2 Each independently is N or CR 7 ，
R 7 And R is 10 Each independently is H, halogen, -CN, -NH 2 、-OH、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -O-R 5 、-NR-R 5 、C 3-8 Cycloalkyl, or 3-8 membered heterocycloalkyl, which alkyl, cycloalkyl and heterocycloalkyl may optionally be substituted with one or more halo, -CN, -NH 2 、-OH、C 1-6 Alkyl, -O-C 1-6 Alkyl, or-NH-C 1-6 An alkyl group is substituted and a substituent is substituted,
R 2 is H or C 1-6 An alkyl group, a hydroxyl group,
R 1 is halogen, -CN, -NH 2 、-OH、-NO 2 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -O-R 5 、-NR-R 5 、C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, -O- (6-10 membered aryl), -NR- (6-10 membered aryl), 5-12 membered heteroaryl, -O- (5-12 membered heteroaryl), -NR- (5-12 membered heteroaryl), -P (O) R 8 R 9 、-(SO 2 )-R 6 、-COOH、-(CO)-O-R 6 Or- (CO) -NR-R 6 The alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups can optionally be substituted with one or more R 4 Instead of the above-mentioned,
R 4 each independently selected from halogen, -CN, -NH 2 、-OH、-NO 2 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -O-R 5 、-NR-R 5 、C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, -P (O) R 8 R 9 、-(SO 2 )-R 6 、-COOH、-(CO)-O-R 6 Or- (CO) -NR-R 6 The alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups may optionally be substituted with one or more halo, -CN, -NH 2 、-OH、-NO 2 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -O-R 5 、-NR-R 5 、C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, -P (O) R 8 R 9 、-(SO 2 )-R 6 、-COOH、-(CO)-O-R 6 Or- (CO) -NR-R 6 Instead of the above-mentioned,
R 5 and R is 6 Each independently selected from C 1-6 Alkyl and C 3-8 Cycloalkyl, said alkyl and cycloalkyl optionally being substituted with one or more halogens, -CN, -NH 2 、-OH、C 1-6 Alkyl, -O-C 1-6 Alkyl or-NH-C 1-6 An alkyl group is substituted and a substituent is substituted,
R 8 and R is 9 Each independently selected from C 1-6 Alkyl and C 3-8 A cycloalkyl group,
r is each independently selected from H and C 1-6 An alkyl group, a hydroxyl group,
y is selected from C 6-10 Aryl, 5-12 membered heteroaryl, 3-12 membered heteroalicyclic, and 5-15 membered spirocyclic groups, said aryl, heteroaryl, heteroalicyclic, and spirocyclic groups optionally being substituted with one or more halogen, -OH, -O-C 1-6 Alkyl, -NH 2 、-NH-C 1-6 Alkyl, C 1-6 Alkyl, or C 3-8 Cycloalkyl, said alkyl or cycloalkyl optionally being substituted by halogen, -OH, -O-C 1-6 Alkyl, -NH 2 or-NH-C 1-6 Alkyl-substituted, said heteroalicyclic and spirocyclic groups optionally being substituted with C 6-10 Aryl or 5-10 membered heteroaryl, aryl or heteroaryl fused to a heteroalicyclic and spirocyclic group, optionally substituted with one or more halo, -OH, -O-C 1-6 Alkyl, -NH 2 、-NH-C 1-6 Alkyl, C 1-6 Alkyl, or C 3-8 Cycloalkyl substitution;
n is 0, 1, 2 or 3.
In some embodiments, the a ring isWherein R is 20 And R is 22 As defined above.
In some embodiments, X 1 And X 2 Each independently is CR 7 ，R 7 Each independently is H, halogen, -CN, -NH 2 -OH, or C 1-6 Alkyl, preferably H or C 1-6 Alkyl, more preferably X 1 And X 2 CH.
In some embodiments, X 3 And X 4 Each independently is CR 10 ，R 10 Each independently is H, halogen, -CN, -NH 2 -OH, or C 1-6 Alkyl, preferably H or C 1-6 Alkyl, more preferably X 3 And X 4 CH.
In some embodiments, R 2 H.
In some embodiments, R 3 Halogen, preferably F.
In some embodiments, R 5 And R is 6 Each independently selected from C 1-6 Alkyl and C 3-8 Cycloalkyl groups.
In some embodiments, n is 0, 1, or 2, preferably 0 or 1.
In some embodiments of the present invention, in some embodiments,
y is a 5-15 membered spirocycloalkyl or a 5-15 membered heterospirocycloalkyl, which spirocycloalkyl or heterospirocycloalkyl may optionally be substituted by one or more halogens, C 1-6 Alkyl, -OH or-NH 2 And (3) substitution. .
In some preferred embodiments, Y is a 5-15 membered oxazaspirocycloalkyl group, optionally substituted with one or more halogens, C 1-6 Alkyl, -OH or-NH 2 And (3) substitution.
In some more preferred embodiments, Y isThe radicals may optionally be substituted with one or more halogens, C 1-6 Alkyl, -OH, or-NH 2 And (3) substitution.
In some embodiments, the B ring is a pyridine ring or pyrimidine ring, or
Ring B is a bicyclic or tricyclic ring system comprising a pyridine or pyrimidine ring attached to N, and a 5-6 membered alicyclic or 5-6 membered heteroalicyclic ring fused to said pyridine or pyrimidine ring, said alicyclic and heteroalicyclic ring optionally being oxo.
In some embodiments, the invention provides the following compounds, or pharmaceutically acceptable salts, solvates, polymorphs, tautomers, metabolites, or prodrugs thereof:
in another aspect, the invention provides a pharmaceutical composition comprising a compound of the invention, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, metabolite, or prodrug thereof, and optionally a pharmaceutically acceptable adjuvant.
In another aspect, the invention provides a method of treating a disorder associated with SHP2 comprising administering to a mammal, preferably a human, in need of such treatment a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, metabolite, or prodrug thereof, or a pharmaceutical composition thereof.
In another aspect, the invention provides the use of a compound of the invention, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, metabolite or prodrug thereof, or a pharmaceutical composition thereof, or any of the foregoing, in combination with an inhibitor of SHP2 or an inhibitor of KRAS or an EGFR inhibitor, for the manufacture of a medicament for the treatment of a disorder associated with SHP2 and/or KRAS and/or EGFR.
In some embodiments of the invention, the SHP2 and/or KRAS and/or EGFR-associated disease is leukemia, melanoma, glioblastoma, lung cancer, breast cancer, or knoop-male syndrome.
On the other hand, SHP2 acts upstream of KRAS, hana Algul team (Mutant KRAS-driven cancers depend on PTPN/SHP 2 phosphotase, nature Medicine 2018) demonstrates that small molecule inhibitors of SHP2 have significant efficacy against invasive KRAS tumors such as Pancreatic Ductal Adenocarcinoma (PDAC) and non-small cell lung carcinoma (NSCLC), protein tyrosine phosphatase SHP2 has become a key drug target for invasive KRAS tumors, and furthermore, schneeberger, v.e. team (Inhibition of Shp suppresses Mutant EGFR-induced lung tumors in transgenic mouse model of lung adenocarcinoma. Oncotarget 2015) demonstrates that SHP2 promotes RAS-RAF-MEK-ERK signaling in EGFR mutated non-small cell lung carcinoma, therefore, small molecule inhibitors of SHP2 of the present invention, alone or in combination with prior art KRAS inhibitors (AMG 510, etc.), EGFR inhibitors (Iressa, tarceva, etc.), can both effectively inhibit tumor development and progression.
Structures that function the same biology in a drug molecule are called bioisosteres, which are structures that do not affect the primary biological activity of the drug by replacing the original functional group in the drug with another functional group.
Certain chemical terms
Unless otherwise indicated, all stereoisomers, including, for example, enantiomers and diastereomers, the compounds of the invention containing asymmetric carbon atoms may be isolated in optically pure or racemic form. Optically pure forms can be resolved from the racemic mixture or synthesized by using chiral starting materials or chiral reagents.
The compounds of the invention also include tautomeric forms, which originate from the exchange of one single bond with an adjacent double bond and are accompanied by the migration of one proton.
The invention also includes all isotopic atoms, whether in intermediates or final compounds. Isotopes of hydrogen include, for example, tritium and deuterium.
The term "fused" or "fused ring" as used herein, alone or in combination, refers to a cyclic structure in which two or more rings share one or more bonds.
The term "spiro" or "spiro" as used herein, alone or in combination, refers to a cyclic structure in which two or more rings share one or more atoms.
The term "halogen" refers to fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine.
The term "alkyl" refers to a straight or branched saturated hydrocarbon group consisting of carbon and hydrogen atoms, e.g. C 1-20 Alkyl, preferably C 1-6 Alkyl groups such as methyl, ethyl, propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, sec-butyl or tert-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl), n-hexyl, 2-methylhexyl, and the like, which may be unsubstituted or substituted, including but not limited to alkyl, alkyloxy, cyano, carboxyl, aryl, heteroaryl, amino, halogen, sulfonyl, sulfinyl, phosphoryl, and hydroxyl.
The term "C 1-6 Alkyl "refers to a straight or branched saturated aliphatic hydrocarbon group consisting of carbon and hydrogen atoms attached to the remainder of the molecule by a single bond having from 1 to 6 carbon atoms, which alkyl may be unsubstituted or substituted with one or more substituents selected from the group consisting of alkyl, alkoxy, amino, halogen and hydroxy.
The term "alkenyl" as used herein, alone or in combination, refers to an optionally substituted straight or optionally substituted branched monovalent hydrocarbon radical having one or more c=c double bonds and having from 2 to about 10 carbon atoms, more preferably from 2 to about 6 carbon atoms, the double bonds in these radicals may be in cis or trans configuration and should be understood to encompass both isomers examples include, but are not limited to, vinyl (ch=ch 2 ) 1-propenyl (CH) 2 CH＝CH 2 ) Isopropenyl (C (CH) 3 )＝CH 2 ) Butenyl, and 1, 3-butadienyl, and the like. Alkenyl groups as defined herein are present in the numerical range, e.g. "C 2 -C 6 Alkenyl "or" C 2-6 Alkenyl "refers to alkenyl groups that may be composed of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, and alkenyl groups herein are also intended to cover instances where no numerical range is specified.
The term "cycloalkyl" refers to an all-carbon monocyclic, fused-ring, or spiro saturated hydrocarbon group consisting of carbon atoms and hydrogen atoms, having 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 ring atoms, preferably 3, 4, 5, 6, 7, or 8 ring atoms, more preferably 3, 4, 5, or 6 ring atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
The term "heterocycloalkyl" refers to a monocyclic, fused or spiro saturated hydrocarbon group consisting of carbon atoms, hydrogen atoms, and at least 1 heteroatom, having 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 ring atoms, preferably 3, 4, 5, 6, 7, or 8 ring atoms, more preferably 3, 4, 5, or 6 ring atoms, wherein 1 or more ring atoms are selected from N, O, S (O) n (wherein n is 0, 1 or 2) and the remaining ring atoms are c. The heterocycloalkyl group may be unsubstituted or substituted, and the substituents include, but are not limited to, alkyl, alkyloxy, cyano, carboxyl, aryl, heteroaryl, amino, halogen, sulfonyl, sulfinyl, phosphoryl and hydroxyl.
The term "aryl" refers to an all-carbon monocyclic or fused ring having a fully conjugated pi-electron system, which has 6 to 14 carbon atoms, preferably 6 to 12 carbon atoms, and most preferably 6 carbon atoms. Non-limiting examples of unsubstituted aryl groups include, but are not limited to, phenyl, naphthyl, and anthracenyl.
The term "heteroaryl" refers to a monocyclic or fused ring of 5 to 12 ring atoms having 5, 6, 7, 8, 9, 10, 11 or 12 ring atoms containing 1, 2, 3 or 4 ring atoms selected from N, O, S, the remaining ring atoms being C and having a fully conjugated pi-electron system. Non-limiting examples of unsubstituted heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, tetrazolyl, triazinyl.
The term "alicyclic" refers to a monocyclic, fused or spiro carbocyclic ring having 3 to 12 ring atoms, having 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 ring atoms, such rings may be saturated or unsaturated (e.g., having one or more double bonds), but not have a fully conjugated pi-electron system.
The term "cycloaliphatic" refers to the group which remains after 1 hydrogen atom has been removed from the "cycloaliphatic" molecule. The heteroalicyclic may be unsubstituted or the hydrogen atom thereof may be optionally substituted with substituents including, but not limited to, alkyl, alkoxy, =o, aryl, aralkyl, -COOH, -CN, amino, halogen and hydroxy.
The term "heteroalicyclic" refers to a single, fused or spiro ring having 3-12 ring atoms, with 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 ring atoms, where 1 or 2 ring atoms are selected from N, O, S (O) n (wherein n is 0, 1 or 2) and the remaining ring atoms are C. Examples of 3-membered saturated heteroalicyclic rings that may be saturated or unsaturated (e.g., have one or more double bonds), but do not have a fully conjugated pi-electron system include, but are not limited to4-membered fullAnd examples of heteroalicyclic include, but are not limited to +.>Examples of 5-membered saturated heteroalicyclic rings include, but are not limited to Examples of 6-membered saturated heteroalicyclic rings include, but are not limited to Examples of 7-membered saturated heteroalicyclic rings include, but are not limited to Examples of 5-membered unsaturated heteroalicyclic rings include, but are not limited to Examples of 6-membered unsaturated heteroalicyclic rings include, but are not limited to
The term "heteroalicyclic" refers to the group that remains after 1 hydrogen atom has been removed from the "heteroalicyclic" molecule, which may be unsubstituted or in which a hydrogen atom is optionally replaced by a substituent including, but not limited to, alkyl, alkoxy, =o, aryl, aralkyl, -COOH, -CN, amino, halogen, and hydroxy.
The term "spirocyclic group" refers to the group remaining after 1 hydrogen atom has been removed from a polycyclic compound in which two monocyclic rings share one carbon atom; the types of the atoms included may be classified into a carbocyclic screw group and a heterocyclic screw group, and when the carbon atoms constituting the carbocyclic screw group are substituted with other hetero atoms such as O, N and S, the heterocyclic screw group is formed.
The term "spirocycloalkyl" refers to a saturated carbocyclic ring that forms two rings, wherein both rings share one carbon atom as part of the ring.
The term "heterospirocycloalkyl" refers to a spirocycloalkyl group as described above containing at least one heteroatom selected from O, N and S.
The term "oxaspiro-cycloalkyl" refers to a heterospiro-cycloalkyl as described above containing at least one O and at least one N.
The compounds of the present invention or salts thereof may be administered alone as the active substance, preferably in the form of a pharmaceutical composition thereof.
"pharmaceutical composition" refers to a formulation of one or more compounds of the invention or salts thereof with a carrier commonly accepted in the art for delivery of biologically active compounds to an organism (e.g., a human). The purpose of the pharmaceutical composition is to facilitate the administration of the compounds of the invention to an organism.
The term "pharmaceutically acceptable carrier" refers to those carriers that do not significantly stimulate the organism and that do not impair the biological activity and performance of the active compound, "pharmaceutically acceptable carrier" refers to inert substances that are administered with the active ingredient and that facilitate administration of the active ingredient, including, but not limited to, any glidants, sweeteners, diluents, preservatives, dyes/colorants, flavoring enhancers, surfactants, wetting agents, dispersants, disintegrants, suspending agents, stabilizers, isotonic agents, solvents or emulsifiers that are approved by the U.S. food and drug administration for use in humans or animals (e.g., livestock).
The administration of the compounds of the invention or pharmaceutically acceptable salts thereof, either in pure form or in the form of a suitable pharmaceutical composition, may be carried out by any acceptable mode of administration providing a medicament of similar use the pharmaceutical compositions of the invention may be prepared by combining the compounds of the invention with suitable pharmaceutically acceptable carriers, diluents or excipients.
Typical routes of administration of the compounds of the invention or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, transmucosal, enteral administration, or topical, transdermal, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration.
The pharmaceutical composition of the present invention can be manufactured by a method known in the art, such as a conventional mixing method, a dissolution method, a granulation method, a sugar coating pill method, a milling method, an emulsification method, a freeze-drying method, etc.
For oral administration, the pharmaceutical compositions may be formulated by mixing the active compounds with pharmaceutically acceptable carriers well known in the art, which enable the compounds of the present invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, slurries, suspensions and the like for oral administration to a patient.
Solid oral pharmaceutical compositions may be prepared by conventional mixing, filling or tabletting methods. For example, it can be obtained by the following method: the active compound is admixed with solid excipients, the resulting mixture is optionally milled, if desired, with other suitable adjuvants, and the mixture is then processed into granules to give tablets or dragee cores: binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, and the like. Such as microcrystalline cellulose, dextrose solution, acacia syrup, gelatin solution, sucrose and starch paste; talc, starch, magnesium stearate, calcium stearate or stearic acid; lactose, sucrose, starch, mannitol, sorbitol or dicalcium phosphate; silicon dioxide; the cores of the dragees may optionally be coated according to methods well known in usual pharmaceutical practice, in particular with enteric coatings.
The pharmaceutical compositions may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in suitable unit dosage forms. Suitable excipients, for example fillers, buffers or surfactants, can be used.
In yet another aspect, the invention relates to the use of a compound of formulas I through VI, or a pharmaceutically acceptable salt, solvate, polymorph, metabolite, or the like, in a medicament for treating a disease benefiting from SHP2 inhibition, wherein the disease benefiting from SHP2 inhibition is selected from cancers.
The substituted alkynyl heterocyclic compound provided by the invention has very good SHP2 inhibition activity, and is expected to become an efficient SHP2 inhibitor drug.
Detailed Description
The following specific examples are put forth so as to enable those skilled in the art to more clearly understand and practice the present invention. They should not be considered as limiting the scope of the invention, but merely as being illustrative and representative thereof: there are other synthetic routes to form the compounds of the present invention, and the following non-limiting examples are provided.
Unless otherwise indicated, all procedures involving readily oxidizable or hydrolyzable starting materials were carried out under nitrogen protection.
Column chromatography is performed by silica gel (200-300 mesh) produced by Qingdao chemical Co., ltd.) thin layer chromatography is performed by prefabricated plate (silicon) produced by E.Merck companyGlue 60 PF 254 0.25 mm.) chiral compound separation and enantiomeric excess value (ee) determination using Agilent LC 1200 series (column: CHIRALPAK AD-H, the amino acid sequence of which is defined as, millimeter, 5 microns, 30 ℃). Nuclear magnetic data [ ] 1 H NMR) was run at 400MHz using a Varian apparatus. The solvent used in the nuclear magnetic data is CDCl 3 、CD 3 OD、D 2 O, DMSO-d6, etc., based on tetramethylsilane (0.00 ppm) or on residual solvent (CDCl) 3 ：7.26ppm；CD 3 OD：3.31ppm；D 2 O:4.79ppm; d6—dmso:2.50 ppm) when peak shape diversity is indicated, the following abbreviations represent the different peak shapes: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad), dd (doublet), dt (doublet). If the coupling constant is given, then in Hertz (Hz); liquid chromatography-mass spectrometry (LC/MS) using FINNIGAN Thermo LCQ Advantage MAX Agilent LC 1200 series (column: waters Symmetry C, 18,)>Millimeter, 5 microns, 35 ℃) using ESI (+) ion mode.
Abbreviations:
experimental part
Intermediate 1: (R) -N- (3S, 4S) -8- (5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -3-methyl-2-oxo-8-azaspiro [4.5] dec-4-yl) -2-methylpropan-2-sulfinamide
Step 1: (R) -2-methyl-N- (3S, 4S) -3-methyl-2-oxo-8-azaspiro [4.5] dec-4-yl) propane-2-sulfinamide trifluoroacetate salt
To a solution of tert-butyl (3 s,4 s) -tert-butyl 4- ((R) -1, 1-dimethylethylsulfonamido) -3-methyl-2-oxa-8-azaspiro [4.5] decane-8-carboxylic acid ester (3.74 g) in methylene chloride (50 mL) at room temperature was added dropwise trifluoroacetic acid (10 mL), and stirred at room temperature for 5 hours.
Step 2: (R) -N- (3S, 4S) -8- (5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -3-methyl-2-oxo-8-azaspiro [4.5] dec-4-yl) -2-methylpropan-2-sulfinamide
The product of the above step (3.88 g) and 3-chloro-4- (5-chloropyrazin-2-yl) thio) pyridin-2-amine (2.73 g) (synthesized by reference patent WO 2016/203406) were dissolved in DMF (100 mL), DIEA (10 mL) was added thereto and heated to 100 ℃ and stirred for 12 hours, cooled to room temperature, poured into cold water (300 mL) and extracted with ethyl acetate (100 mL x 2), the extract was washed with saturated brine (200 mL x 2) and dried over anhydrous sodium sulfate, filtered, the filtrate concentrated under reduced pressure, and the residue was purified by silica gel chromatography (dichloromethane: methanol, 20:1) to give the title compound (4.0 g).
1 H NMR(400MHz，CDCl3)，8.23(s，1H)，8.28(s，1H)，7.69(d，J＝5.6Hz，1H)，6.00(d，J＝5.6Hz，1H)，4.88(s，2H)，4.12-4.28(m，3H)，3.59(d，J＝9.2Hz，1H)，3.67(d，J＝9.2Hz，1H)，3.49-3.53(m，1H)，3.41-3.44(m，1H)，3.13-3.24(m，2H)，1.94-2.08(m，2H)，1.58-1.76(m，2H)，1.24(s，9H)，1.21(d，J＝6.8Hz，3H)。
Example 1: (3S, 4S) -8- (5- ((3-chloro-2- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) pyridin-4-yl) thio) pyrazin-2-yl) -3-methyl-2-oxo-8-azaspiro [4.5] decan-4-amine hydrochloride
Step 1: (R) -N- ((3S, 4S) -8- (5- ((3-chloro-2- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) pyridin-4-yl) thio) pyrazin-2-yl) -3-methyl-2-oxo-8-azaspiro [4.5] dec-4-yl) -2-methylpropan-2-sulfinamide
The intermediate 1 (R) -N- (3S, 4S) -8- (5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -3-methyl-2-oxo-8-azaspiro [4.5] dec-4-yl) -2-methylpropan-2-sulfinamide (51 mg), 3- (2-chloropyrimidin-4-yl) -1-methylindole (24 mg) (synthesized in reference to WO 2013/14448), ruPhos-Pd-G3 (8 mg) and cesium carbonate (100 mg) were dissolved in dioxane (10 mL) under nitrogen, the reaction flask was replaced three times with nitrogen and heated to 100℃and stirred for 12 hours. Cooled to room temperature, filtered, and the filtrate concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography (developer: dichloromethane: methanol=20:1 (V: V)) to give the objective compound (20 mg).
Step 2: (3S, 4S) -8- (5- ((3-chloro-2- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) pyridin-4-yl) thio) pyrazin-2-yl) -3-methyl-2-oxo-8-azaspiro [4.5] decan-4-amine hydrochloride
To a solution of (R) -N- (3S, 4S) -8- (5- ((3-chloro-2- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) pyridin-4-yl) thio) pyrazin-2-yl) -3-methyl-2-oxo-8-azaspiro [4.5] decan-4-yl) -2-methylpropan-2-sulfinamide (20 mg) in THF (10 mL) was added dropwise 6N dioxane hydrochloride (1 mL) at room temperature and stirred at room temperature for 12 hours after the completion of the reaction, the reaction mixture was concentrated under reduced pressure to give the title compound (15 mg).
1 H NMR(400MHz，DMSO)，8.69(s，1H)，8.57(s，1H)，8.55(d，J＝7.6Hz，1H)，8.39(s，1H)，8.32(d，J＝6.8Hz，1H)，8.18-8.26(brs，3H)，8.17(d，J＝5.6Hz，1H)，8.57(d，J＝8.0Hz，1H)，8.52(d，J＝6.4Hz，1H)，7.32(t，J＝7.6Hz，1H)，7.27(t，J＝7.6Hz，1H)，6.64(d，J＝5.6Hz，1H)，4.17-4.36(m，3H)，3.91(s，3H)，3.47(d，J＝4.4Hz，1H)，3.44(d，J＝4.4Hz，1H)，3.35-3.39(m，1H)，3.12-3.22(m，2H)，1.77-1.88(m，2H)，1.67-1.74(m，1H)，1.57-1.64(m，1H)，1.22(d，J＝6.4Hz，3H).
Example 2: (3S, 4S) -8- (5- (3-chloro-2- (6, 7-dimethoxy-2-methylquinazolin-4-yl) amino) pyridin-4-yl) thio) pyrazin-2-yl) -3-methyl-2-oxo-8-azaspiro [4.5] decan-4-amine hydrochloride
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With reference to the procedure in example 1, the title compound was obtained using 4-chloro-6, 7-dimethoxy-2-methylquinazoline (synthesized with reference to patent WO 2018/172250) as starting material.
1 H NMR(400MHz，CD 3 OD)，8.46(s，1H)，8.37(s，1H)，8.21(d，J＝5.2Hz，1H)，7.93(s，1H)，7.19(s，1H)，6.86(d，J＝5.2Hz，1H)，4.40-4.46(m，1H)，4.28-4.38(m，2H)，4.07(s，3H)，4.04(s，3H)，4.02(d，J＝9.2Hz，1H)，3.89(d，J＝9.2Hz，1H)，3.47(d，J＝4.0Hz，1H)，3.20-3.33(m，2H)，2.62(s，3H)，1.85-1.96(m，3H)，1.72-1.79(m，1H)，1.33(d，J＝6.4Hz，3H)。
Example 3: (3S, 4S) -8- (5- ((2- (6, 7-bis (2-methoxyethoxy) quinazolin-4-yl) amino) -3-chloropyridin-4-yl) thio) pyrazin-2-yl) -3-methyl-2-oxo-8-azaspiro [4.5] decan-4-amine hydrochloride
With reference to the procedure in example 1, the title compound was obtained using 4-chloro-6, 7-bis (2-methoxyethoxy) quinazoline (synthesized with reference to patent WO 2009/7984) as starting material.
1 H NMR(400MHz，CD 3 OD)，8.66(s，1H)，8.43(s，1H)，8.37(d，J＝1.2Hz，1H)，8.16(d，J＝5.6Hz，1H)，7.97(s，1H)，7.28(s，1H)，6.79(d，J＝5.6Hz，1H)，4.39-4.46(m，3H)，4.29-4.37(m，4H)，4.00(d，J＝9.2Hz，1H)，3.86-3.91(m，5H)，3.45-3.47(m，7H)，3.18-3.33(m，2H)，1.82-1.93(m，3H)，1.70-1.78(m，1H)，1.32(d，J＝6.4Hz，3H).
Example 4: (3S, 4S) -8- (5- ((3-chloro-2- ((6- (2, 6-dichloro-3, 5-dimethoxyphenyl) quinazolin-2-yl) amino) pyridin-4-yl) thio) pyrazin-2-yl) -3-methyl-2-oxo-8-azaspiro [4.5] decan-4-amine hydrochloride
With reference to the procedure in example 1, 2-chloro-6- (2, 6-dichloro-3, 5-dimethoxyphenyl) quinazoline (synthesized in reference to patent WO 2014/11900) was used as a starting material to give the title compound.
1 H NMR(400MHz，DMSO)，9.40(s，1H)，8.56(s，1H)，8.39(s，1H)，8.13-8.26(brs，4H)，7.87(d，J＝2.0Hz，1H)，7.76(d，J＝8.4Hz，1H)，7.65(dd，J＝8.4Hz，1.6Hz，1H)，7.01(s，1H)，6.61(d，J＝5.6Hz，1H)，4.16-4.34(m，3H)，3.95(s，6H)，3.47(d，J＝4.4Hz，1H)，3.44(d，J＝4.4Hz，1H)，3.35-3.41(m，1H)，3.12-3.22(m，2H)，1.75-1.86(m，2H)，1.66-1.74(m，1H)，1.56-1.64(m，1H)，1.22(d，J＝6.4Hz，3H)。
Example 5:2- ((4- ((5- ((3S, 4S) -4-amino-3-methyl-2-oxo-8-azaspiro [4.5] dec-8-yl) pyrazin-2-yl) thio) -3-chloropyridin-2-yl) amino) -7-methyl-9- (tetrahydro-2H-pyran-4-yl) -7, 9-dihydro-8H-purin-8-one hydrochloride
Referring to the procedure in example 1, 2-chloro-7-methyl-9- (tetrahydro-2H-pyran-4-yl) -7, 9-dihydro-8H-purin-8-one (synthesized in reference to patent WO 2011/157397) was used as starting material to give the title compound. 1 H NMR(400MHz，CD 3 OD)，8.43(s，1H)，8.36(s，1H)，8.22(s，1H)，8.14(s，1H)，6.69(s，1H)，4.62-4.72(m，1H)，4.26-4.48(m，3H)，4.08-4.12(m，2H)，4.01(d J＝9.2Hz，1H)，3.89(d，J＝9.2Hz，1H)，3.70-3.74(m，1H)，3.63-3.67(m，2H)，3.46(s，3H)，3.18-3.32(m，2H)，2.66-2.78(m，2H)，1.69-1.97(m，6H)，1.32(d，J＝6.0Hz，3H)。
Example 6: (6- ((2- ((4- ((5- ((3S, 4S) -4-amino-3-methyl-2-oxo-8-azaspiro [4.5] dec-8-yl) pyrazin-2-yl) thio) -3-chloropyridin-2-yl) -amino) -5-bromopyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine hydrochloride
Referring to the procedure in example 1, (6- ((5-bromo-2-chloropyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide (synthesized as described in reference to patent WO 2022/12622) was used as starting material to give the title compound.
1 H NMR(400MHz，CD 3 OD)，9.24(dd，J＝9.6Hz，4.0Hz，1H)，8.91-8.92(m，2H)，8.54(s，1H)，8.44(d，J＝1.2Hz，1H)，8.36(d，J＝1.2Hz，1H)，8.34(d，J＝9.6Hz，1H)，8.10(d，J＝6.0Hz，1H)，6.73(d，J＝6.0Hz，1H)，4.39-4.46(m，1H)，4.24-4.37(m，2H)，4.01(d，J＝8.8Hz，1H)，3.89(d，J＝8.8Hz，1H)，3.46(d，J＝3.6Hz，1H)，3.08-3.28(m，2H)，2.18(d，J＝14.4Hz，6H)，1.82-1.92(m，3H)，1.70-1.77(m，1H)，1.32(d，J＝6.0Hz，3H)。
Example 7: n (N) 2 - (4- ((5- ((3S, 4S) -4-amino-3-methyl-2-oxo-8-azaspiro [ 4.5)]Dec-8-yl) pyrazin-2-yl) thio) -3-chloropyridin-2-yl) -5-chloro-N 4 - (2- (isopropylsulfonyl) phenyl) pyrimidine-2, 4-diamine hydrochloride
Referring to the procedure in example 1, 2, 5-dichloro-N- (2- (isopropylsulfonyl) phenyl) pyrimidin-4-amine (synthesized with reference to patent WO 2011/140338) was used as a starting material to give the title compound.
1 H NMR(400MHz，CD 3 OD)，8.62(d，J＝8.0Hz，1H)，8.40-8.46(m，2H)，8.35(s，1H)，8.05-8.12(brs，1H)，8.00(d，J＝7.6Hz，1H)，7.87(t，J＝7.6Hz，1H)，7.54(t，J＝7.6Hz，1H)，6.68-6.75(brs，1H)，4.26-4.46(m，3H)，4.00(d，J＝8.8Hz，1H)，3.88(d，J＝8.8Hz，1H)，3.37-3.49(m，2H)，3.18-3.30(m，2H)，1.82-1.96(m，3H)，1.70-1.78(m，1H)，1.32(d，J＝6.0Hz，3H)，1.26(d，J＝6.4Hz，6H).
Example 8: (3S, 4S) -8- (5- (3-chloro-2- ((5-fluoro-4- (4-fluoro-2-methoxyphenyl) pyridin-2-yl) amino) pyridin-4-yl) thio) pyrazin-2-yl) -3-methyl-2-oxo-8-azaspiro [4.5] decan-4-amine hydrochloride
With reference to the procedure in example 1, 2-chloro-5-fluoro-4- (4-fluoro-2-methoxyphenyl) pyridine (synthesized in reference to patent WO 2014/60375) was used as a starting material to give the objective compound.
1 H NMR(400MHz，CD 3 OD)，8.45(s，1H），8.34-8.40(m，2H)，8.09(s，1H)，7.72(d，J＝5.2Hz，1H)，7.38-7.41(m，1H)，7.00(dd，J＝10.8Hz，2.4Hz，1H)，6.87(td，J＝8.0Hz，2.4Hz，1H)，6.72(s，1H)，4.25-4.48(m，3H)，4.02(d，J＝8.8Hz，1H)，3.89(d，J＝8.8Hz，1H)，3.85(s，3H)，3.44-3.51(m，1H)，3.19-3.35(m，2H)，1.84-1.97(m，3H)，1.71-1.79(m，1H)，1.33(d，J＝5.6Hz，3H).
Example 9: (3S, 4S) -8- (5- (3-chloro-2- ((4- (1-cyclopropyl-1H-indol-3-yl) pyrimidin-2-yl) amino) pyridin-4-yl) thio) pyrazin-2-yl) -3-methyl-2-oxo-8-azaspiro [4.5] decan-4-amine hydrochloride
Referring to the procedure in example 1, 3- (2-chloropyrimidin-4-yl) -1-cyclopropyl-1H-indole (synthesized in reference to patent CN 109761960) was used as a starting material to give the title compound.
1 H NMR(400MHz，CD 3 OD)，8.73-8.76(m，1H)，8.58(s，1H)，8.42(s，1H)，8.36(s，1H)，8.27(d，J＝6.8Hz，1H)，8.12(d，J＝5.6Hz，1H)，7.74-7.76(m，1H)，7.71(d，J＝6.8Hz，1H)，7.37-7.43(m，2H)，6.64(d，J＝5.6Hz，1H)，4.38-4.45(m，1H)，4.27-4.36(m，2H)，4.00(d，J＝8.8Hz，1H)，3.90(d，J＝8.8Hz，1H)，3.60-3.66(m，1H)，3.45(d，J＝4.0Hz，1H)，3.18-3.30(m，2H)，1.80-1.96(m，3H)，1.70-1.78(m，1H)，1.32(d，J＝6.4Hz，3H)，1.24-1.28(m，2H)，1.11-1.16(m，2H).
Example 10: (3S, 4S) -8- (5- (3-chloro-2- (6, 7-dimethoxyquinazolin-4-yl) amino) pyridin-4-yl) thio) pyrazin-2-yl) -3-methyl-2-oxo-8-azaspiro [4.5] decan-4-amine hydrochloride
With reference to the procedure in example 1, the title compound was obtained using 4-chloro-6, 7-dimethoxyquinazoline (synthesized with reference to patent CN 114105890) as starting material.
1 H NMR(400MHz，DMSO)，8.82(s，1H)，8.56(s，1H)，8.41(s，1H)，8.26(d，J＝5.2Hz，1H)，8.14-8.24(m，4H)，7.38(s，1H)，6.78(d，J＝5.6Hz，1H)，4.27-4.35(m，1H)，4.16-4.26(m，2H)，3.99(s，3H)，3.98(s，3H)，3.47(d，J＝4.8Hz，1H)，3.44(d，J＝4.8Hz，1H)，3.36-3.39(m，1H)，3.12-3.22(m，2H)，1.76-1.87(m，2H)，1.67-1.74(m，1H)，1.57-1.64(m，1H)，1.22(d，J＝6.8Hz，3H).
Example 11: (2- ((2- ((4- ((5- ((3S, 4S) -4-amino-3-methyl-2-oxo-8-azaspiro [4.5] dec-8-yl) pyrazin-2-yl) thio) -3-chloropyridin-2-yl) amino) -5-chloropyrimidin-4-yl) amino) phenyl) dimethylphosphine hydrochloride
Referring to the procedure in example 1, (2- ((2, 5-dichloropyrimidin-4-yl) amino) phenyl) dimethylphosphine oxide (synthesized with reference to patent CN 111138492) was used as starting material to give the title compound.
1 H NMR(400MHz，DMSO)，11.59(s，1H)，9.72-10.02(brs，1H)，8.57(s，1H)，8.47(dd，J＝8.4Hz，4.0Hz，1H)，8.37(d，J＝1.2Hz，1H)，8.22(s，1H)，8.11-8.19(m，4H)，7.53(dd，J＝10.0Hz，7.2Hz，1H)，7.43(t，J＝8.0Hz，1H)，7.11(t，J＝8.0Hz，1H)，6.55(d，J＝5.6Hz，1H)，4.16-4.35(m，3H)，3.48(d，J＝4.4Hz，1H)，3.44(d，J＝4.8Hz，1H)，3.36-3.40(m，1H)，3.12-3.22(m，2H)，1.68-1.86(m，9H)，1.56-1.64(m，1H)，1.22(d，J＝6.8Hz，3H)。
Example 12: (3S, 4S) -8- (5- (3-chloro-2- ((4-morpholinpyrimidin-2-yl) amino) pyridin-4-yl) thio) pyrazin-2-yl) -3-methyl-2-oxo-8-azaspiro [4.5] decan-4-amine hydrochloride
With reference to the procedure in example 1, 4- (2-chloropyrimidin-4-yl) morpholine (synthesized with reference to patent WO 2020/6497) was used as a starting material to give the title compound.
1 H NMR(400MHz，CD 3 OD)，8.41(d，J＝1.2Hz，1H)，8.33(d，J＝1.2Hz，1H)，8.07(d，J＝5.6Hz，1H)，7.99(d，J＝7.6Hz，1H)，6.79(d，J＝7.6Hz，1H)，6.57(d，J＝5.6Hz，1H)，4.38-4.44(m，1H)，4.28-4.35(m，2H)，4.05-4.11(m，2H)，4.00(d，J＝9.2Hz，1H)，3.89(d，J＝9.2Hz，1H)，3.72-3.82(m，6H)，3.46(d，J＝4.0Hz，1H)，3.18-3.32(m，2H)，1.83-1.92(m，3H)，1.70-1.77(m，1H)，1.32(d，J＝6.0Hz，3H).
Example 13:2- (6- (2- ((4- ((5- ((3S, 4S) -4-amino-3-methyl-2-oxo-8-azaspiro [4.5] dec-8-yl) pyrazin-2-yl) thio) -3-chloropyridin-2-yl) amino) -6-cyclopropyl-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) pyridin-2-yl) propan-2-ol hydrochloride
Referring to the procedure in example 1, 2- (6- (2-chloro-6-cyclopropyl-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) pyridin-2-yl) propan-2-ol (synthesized with reference to patent CN 111718348) was used as starting material to give the title compound, MS m/z [ LC-MS ]:699.29[ M+1].
Example 14: (3S, 4S) -8- (5- ((3-chloro-2- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) pyridin-4-yl) thio) pyrazin-2-yl) -3-methyl-2-oxo-8-azaspiro [4.5] decan-4-amine hydrochloride
With reference to the procedure in example 1, 2-chloro-4- (pyridin-3-yl) pyrimidine (synthesized with reference to patent WO 2021/74138) was used as starting material to give the title compound. MS m/z [ LC-MS ]:562.19[ M+1].
Example 15: n (N) 2 - (4- ((5- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [ 4.5)]Dec-8-yl) pyrazin-2-yl) thio) -3-chloropyridin-2-yl) -N4- (2, 3-dimethyl-2H-indazol-6-yl) -N 4 -methylpyrimidine-2, 4-diamine hydrochloride
Referring to the procedure in example 1, N- (2-chloropyrimidin-4-yl) -N,2, 3-trimethyl-2H-indazol-6-amine (synthesized in reference to patent WO 2021/162647) was used as starting material to give the title compound: 658.26[ M+1].
Example 16: (R) -2- ((4- ((5- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] dec-8-yl) pyrazin-2-yl) thio) -3-chloropyridin-2-yl) amino) -8-cyclopentyl-7-ethyl-5-methyl-7, 8-dihydropterin-6 (5H) -one hydrochloride
Referring to the procedure in example 1, (R) -2-chloro-8-cyclopentyl-7-ethyl-5-methyl-7, 8-dihydropterin-6 (5H) -one (synthesized as described in reference to WO 2011/79114) was used as a starting material to give the title compound, MS m/z [ LC-MS ]:665.30[ M+1].
Example 17: (3S, 4S) -8- (5- ((3-chloro-2- ((6, 7-dimethoxyquinolin-4-yl) amino) pyridin-4-yl) thio) pyrazin-2-yl) -3-methyl-2-oxo-8-azaspiro [4.5] decan-4-amine hydrochloride
With reference to the procedure in example 1, 4-chloro-6, 7-dimethoxyquinoline (synthesized with reference to patent WO 2005/121125) was used as a starting material to give the target compound. MS m/z [ LC-MS ]:594.22[ M+1].
Biological testing
Determination of the inhibition of the in vitro enzymatic Activity of SHP2 by Compounds
The enzymatic activity detection of SHP2 in this patent is performed using a rapid fluorescence method, using DiFMUP as an alternative substrate for reaction and optimizing the establishment of a high throughput screening platform where the detection of the inhibitory activity of compounds on SHP2 operates: SHP2 at a final concentration of 1nM was pre-incubated with 2.5. Mu.M of a mixture of phosphorylated IRS1 peptide fragments (sequence: H2N-LN (pY) IDLDLV (dPEG 8) LST (pY) ASINFQK-amide) for 30 min at 23 ℃. The compound was diluted 5-fold in a gradient from 0.2mM (total of 7 concentrations) with 100% DMSO, and 2. Mu.L of the compound was added to 48. Mu.L of reaction buffer (60mM HEPES,pH 7.2, 75mM NaCl,75mM KCl,1mM EDTA,0.05%Tween 20,5mM DTT) for dilution and mixing. mu.L of the diluted compound was added to a black 384-well plate (OptiPlate-384, cat. No. 6007270, purchased from Perkinelmer), followed by 10. Mu.L of a pre-incubated mixture of SHP2 and IRS1 peptide fragments, centrifuged and mixed, and incubated at 23℃for 30 minutes. Add 5. Mu.L of surrogate substrate DiFMUP (final concentration 50. Mu.M, cat. No. D6567, purchased from Invitrogen) to the reaction and incubate at 23℃for 60 minutes then add 5. Mu.L of 1. Mu.M bpV (Phen) solution (SC-22137, purchased from Santa) termination of the reaction immediately after termination of the reaction, detection of fluorescent signals at excitation and emission wavelengths of 340nm and 450nm, respectively, using a microplate reader (Perkin-Elmer), data calculation using GraphPad Prism software to obtain the IC of the compound 50 Values. The specific compounds in the embodiment of the invention have SHP2 in-vitro enzymatic inhibition activity and IC 50 Values lie in the interval 0.1nM to 1uM, with activity of exemplary partial compounds as shown in Table 1:
TABLE 1 inhibitory Activity of middle differentiation Compounds on SHP2 enzyme
The compounds in the embodiment of the invention have the inhibiting activity to the SHP2 protease within 10nM, which indicates that the compounds have good inhibiting activity to the SHP2 protease.
Determination of the inhibition of SHP 2-positive cell proliferation by Compounds
Human non-small cell lung carcinoma cell line NCI-H358 cells were cultured using RPMI-1640 medium (accession number C11875500BT, purchased at Biological Industries) plus 10% fetal bovine serum (FBS, accession number 04-001-1ACS, purchased at Biological Industries, BI) and 1% penicillin/streptomycin diab (P/S, accession number 15070-063, purchased at Gibco) under culture conditions of 37 ℃,5% CO2. The day prior to compound detection, NCI-H358 cells were plated at a concentration of 2000 cells/195. Mu.L/well in 196 well plates (accession number 3917, purchased at comin.) after 24 hours, the compound was 3-fold gradient diluted with 100% DMSO starting at 10mM (10 total concentrations), then 2. Mu.L of each compound was added to 48. Mu.L of serum-and diab-free medium, 5. Mu.L of each diluted compound was added to the plated cells, the compound and cells were incubated in culture chambers and medium was added at a total of 72 days after cell suction (3 days) mu.L Cell-Titer Glo (G7570, purchased from Promega) reagent was incubated for another 5-10 min after which fluorescence values were read on Envision and data were calculated using GraphPad Prism software to obtain IC's for inhibition of Cell proliferation by the compound 50 Values. Human acute myeloblastic leukemia cell line Kasumi-1 cells were cultured using RPMI-1640 medium (cat# C11875500BT, purchased at Biological Industries) plus 20% fetal bovine serum (FBS, cat# 04-001-1ACS, purchased at Biological Industries, BI) and 1% penicillin/streptomycin diab (P/S, cat# 15070-063, purchased at Gibco) at 37℃and 5% CO2. Kasumi-1 cells were plated in 196 well plates (cat# 3599, purchased at doming) at a concentration of 3000 cells/195. Mu.L/well the day prior to compound detection. After 24 hours, the compounds were diluted 3-fold in 100% dmso starting at 10mM (total 10 concentrations), and then 2 μl of the compound was added to 48 μl of serum-free and double antibody-free medium for dilution at each concentration. mu.L of the diluted compound was added to the plated Cell suspension at each concentration, the compound was incubated with the cells in a Cell incubator for 72 hours (3 days), 35. Mu.L of Cell-Titer Blue (G8082, purchased from Promega) was added and incubated again for 4 hours, after which the fluorescence values were read on Flexstation III (560 nm excitation, 590nm detection) and the data were calculated using GraphPad Prism software to obtain IC for inhibition of Cell proliferation by the compound 50 Values. The results of partial compound detection are shown in Table 2.
TABLE 2 inhibitory Activity of example Compounds against proliferation of cells (NCI-H358)
Examples IC 50 (nM)
1 323
The proliferation inhibition activity of the compound in the embodiment of the invention on SHP2 positive expression cells is within 1 mu M, and the test data in Table 2 show the specific data of part of the compounds in the embodiment, which shows that the compound provided by the invention has good inhibition activity on the proliferation of SHP2 positive expression cells.
The invention also predicts that the compounds of the invention also have certain inhibitory effects on EGFR and VEGFR targets, and that specific enzymatic activity inhibition and cell proliferation inhibition assays are underway.

Claims (10)

1. A compound of formula (I) or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, metabolite or prodrug thereof,
wherein,
ring A isOr alternatively
Wherein carbon is linked to Y, X 3 And X 4 Each independently is N or CR 10 ；
R 3 、R 20 、R 21 And R is 22 Each independently is H, halogen, -CN, -NH 2 、-OH、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -O-R 5 、-NR-R 5 、C 3-8 Cycloalkyl, or 3-8 membered heterocycloalkyl,
the alkyl, cycloalkyl and heterocycloalkyl groups may be optionally substituted with one or more halogen, -CN, -NH 2 、-OH、C 1-6 Alkyl, -O-C 1-6 Alkyl, or-NH-C 1-6 Alkyl substitution;
the B ring is a 6-10 membered aromatic ring or a 5-12 membered heteroaromatic ring, or
The B ring is a bicyclic or tricyclic ring system comprising a 6-10 membered aromatic ring or a 5-12 membered heteroaromatic ring attached to N, and a 3-8 membered alicyclic ring or a 3-8 membered heteroalicyclic ring fused to said aromatic ring or heteroaromatic ring, said alicyclic ring and heteroalicyclic ring optionally being oxo,
X 1 and X 2 Each independently is N or CR 7 ，
R 7 And R is 10 Each independently is H, halogen, -CN, -NH 2 、-OH、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -O-R 5 、-NR-R 5 、C 3-8 Cycloalkyl, or 3-8 membered heterocycloalkyl, which alkyl, cycloalkyl and heterocycloalkyl may optionally be substituted with one or more halo, -CN, -NH 2 、-OH、C 1-6 Alkyl, -O-C 1-6 Alkyl, or-NH-C 1-6 An alkyl group is substituted and a substituent is substituted,
R 2 is H or C 1-6 An alkyl group, a hydroxyl group,
R 1 is halogen, -CN, -NH 2 、-OH、-NO 2 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -O-R 5 、-NR-R 5 、C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, -O- (6-10 membered aryl), -NR- (6-10 membered aryl), 5-12 membered heteroaryl, -O- (5-12 membered heteroaryl), -NR- (5-12 membered heteroaryl), -P (O) R 8 R 9 、-(SO 2 )-R 6 、-COOH、-(CO)-O-R 6 Or- (CO) -NR-R 6 The alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups can optionally be substituted with one or more R 4 Instead of the above-mentioned,
R 4 each independently selected from halogen, -CN, -NH 2 、-OH、-NO 2 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -O-R 5 、-NR-R 5 、C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, -P (O) R 8 R 9 、-(SO 2 )-R 6 、-COOH、-(CO)-O-R 6 Or- (CO)-NR-R 6 The alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups may optionally be substituted with one or more halo, -CN, -NH 2 、-OH、-NO 2 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -O-R 5 、-NR-R 5 、C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, -P (O) R 8 R 9 、-(SO 2 )-R 6 、-COOH、-(CO)-O-R 6 Or- (CO) -NR-R 6 Instead of the above-mentioned,
R 5 and R is 6 Each independently selected from C 1-6 Alkyl and C 3-8 Cycloalkyl, said alkyl and cycloalkyl optionally being substituted with one or more halogens, -CN, -NH 2 、-OH、C 1-6 Alkyl, -O-C 1-6 Alkyl or-NH-C 1-6 An alkyl group is substituted and a substituent is substituted,
R 8 and R is 9 Each independently selected from C 1-6 Alkyl and C 3-8 A cycloalkyl group,
r is each independently selected from H and C 1-6 An alkyl group, a hydroxyl group,
y is selected from C 6-10 Aryl, 5-12 membered heteroaryl, 3-12 membered heteroalicyclic, and 5-15 membered spirocyclic groups, said aryl, heteroaryl, heteroalicyclic, and spirocyclic groups optionally being substituted with one or more halogen, -OH, -O-C 1-6 Alkyl, -NH 2 、-NH-C 1-6 Alkyl, C 1-6 Alkyl, or C 3-8 Cycloalkyl, said alkyl or cycloalkyl optionally being substituted by halogen, -OH, -O-C 1-6 Alkyl, -NH 2 or-NH-C 1-6 Alkyl-substituted, said heteroalicyclic and spirocyclic groups optionally being substituted with C 6-10 Aryl or 5-10 membered heteroaryl, aryl or heteroaryl fused to a heteroalicyclic and spirocyclic group, optionally substituted with one or more halo, -OH, -O-C 1-6 Alkyl, -NH 2 、-NH-C 1-6 Alkyl, C 1-6 Alkyl, or C 3-8 Cycloalkyl substitution;
n is 0, 1, 2 or 3.
2. The method according to claim 1A compound or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, metabolite or prodrug thereof, wherein Y is a 5-15 membered spirocycloalkyl or a 5-15 membered heterospirocycloalkyl, said spirocycloalkyl or heterospirocycloalkyl optionally being substituted with one or more halogens, C 1-6 Alkyl, -OH or-NH 2 And (3) substitution.
3. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, metabolite, or prodrug thereof, wherein ring B is a pyridine or pyrimidine ring, or
Ring B is a bicyclic or tricyclic ring system comprising a pyridine or pyrimidine ring attached to N, and a 5-6 membered alicyclic or 5-6 membered heteroalicyclic ring fused to said pyridine or pyrimidine ring, said alicyclic and heteroalicyclic ring optionally being oxo.
4. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, metabolite, or prodrug thereof, wherein R 21 And R is 22 Each independently is H or C 1-6 Alkyl, R 20 Is H,Or trifluoromethyl, R 3 Is halogen or C 1-6 An alkyl group.
5. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, metabolite, or prodrug thereof, wherein X 1 、X 2 、X 3 And X 4 Is CH, R 2 Is H, R 3 Is halogen.
6. A compound according to claim 1, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, metabolite or prodrug thereof, wherein Y is a 5-15 membered oxazaspirocycloalkyl group, optionally substituted with one or moreMultiple halogens, C 1-6 Alkyl, -OH or-NH 2 And (3) substitution.
7. The compound of claim 1 or 6, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, metabolite, or prodrug thereof, wherein Y isThe radicals may optionally be substituted with one or more halogens, C 1-6 Alkyl, -OH, or-NH 2 And (3) substitution.
8. The following compounds, or pharmaceutically acceptable salts, solvates, polymorphs, tautomers, metabolites or prodrugs thereof:
9. a pharmaceutical composition comprising a compound according to any one of claims 1-8, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, metabolite or prodrug thereof, and optionally a pharmaceutically acceptable adjuvant.
10. Use of a compound according to any one of claims 1-8, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, metabolite or prodrug thereof, or a pharmaceutical composition according to claim 9, or any of the foregoing in combination with an inhibitor of SHP2 or KRAS or an EGFR inhibitor, for the manufacture of a medicament for the treatment of a disorder associated with SHP2 and/or KRAS and/or EGFR; preferably, the SHP2 and/or KRAS and/or EGFR related disease is leukemia, melanoma, glioblastoma, lung cancer, breast cancer or knoop-male syndrome.
CN202210888300.2A 2022-07-26 2022-07-26 Heterocyclic compounds having biological activity Pending CN117510513A (en)

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