CN115466263A - Tricyclic compound and use thereof - Google Patents

Tricyclic compound and use thereof Download PDF

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CN115466263A
CN115466263A CN202210652494.6A CN202210652494A CN115466263A CN 115466263 A CN115466263 A CN 115466263A CN 202210652494 A CN202210652494 A CN 202210652494A CN 115466263 A CN115466263 A CN 115466263A
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alkyl
pharmaceutically acceptable
compound
formula
acceptable salt
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张雁
杨圣伟
周峰
杨桂梅
王峰
唐锋
唐任宏
任晋生
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Nanjing Zaiming Pharmaceutical Co ltd
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Jiangsu Simcere Pharmaceutical Co Ltd
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    • 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
    • C07D471/12—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 three hetero rings
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Abstract

The invention relates to a tricyclic compound and application thereof, in particular to a compound shown in a formula (I) or pharmaceutically acceptable salt thereof,

Description

Tricyclic compound and use thereof
The invention requires the priority of the prior application with patent application number of 202110649480.4 entitled "tricyclic compound and application thereof" submitted to the intellectual property office of China in 2021, 6 months and 10 days. The entire contents of the above-mentioned prior application are incorporated herein by reference.
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a tricyclic compound or a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the tricyclic compound or the pharmaceutically acceptable salt thereof, and application of the tricyclic compound or the pharmaceutically acceptable salt thereof as an SOS1 inhibitor in prevention or treatment of related diseases.
Background
RAS family proteins including KRAS (V-Ki-RAS 2 Kirsten rat sarcoma virus oncogene homolog), NRAS (neuroblastoma RAS virus oncogene homolog), HRAS (Harvey murine sarcoma virus oncogene), and the like, are small gtpases present in cells in either GTP-bound or GDP-bound states (McCormick et al, j.mol.med. (Berl.) 2016,94 (3): 253-8 nimnual et al, sci.stke.,2002 (145): pe 36).
RAS family proteins play an important role in human cancers. Tumors caused by RAS protein mutations account for 20-30% of all tumors in humans and are considered as tumorigenic drivers, particularly in lung, colorectal and pancreatic cancers (Malumbres & Barbacid 2002Nature Reviews Cancer, pylayeva-Gupta et al, 2011Nature Reviews Cancer).
SOS1 (son of seven homology 1) protein is a regulatory protein widely expressed in cells, and plays an important role in regulating RAS and RAC signal transduction pathways in cells as a guanine nucleotide exchange factor of RAS and RAC proteins. SOS1 has two binding sites for RAS family proteins: a catalytic site that binds a GDP-bound RAS family protein to facilitate guanine nucleotide exchange; an allosteric site that binds to a GTP-bound RAS family protein, which results in a further increase in the catalytic GEF function of SOS1 (Freedman et al, proc. Natl.Acad.Sci.USA.,2006,103 (4): 16692-7, pierre et al, biochem. Pharmacol.,2011,82 (9): 1049-56). Published data indicate that SOS1 is involved in mutant KRAS activation and oncogenic signaling in cancer (Jeng et al, nat. Commun.,2012, 3. Consumption of SOS1 levels decreased the proliferation rate and survival of tumor cells carrying KRAS mutations, whereas no effect was observed in KRAS wild-type cell lines. The effect of loss of SOS1 was not compensated by SOS1 with the introduction of a catalytic site mutation, further demonstrating the important role of SOS1 GEF activity in KRAS mutant cancer cells.
In recent decades, RAS family protein-SOS 1 protein interactions have been increasingly studied. Small activating molecules have been identified that bind to the lipophilic pocket of SOS1 in close proximity to the RAS binding site (Burns et al, proc. Natl. Acad. Sci.2014,111 (9): 3401-6). However, the binding of these molecules appears to result in an increase in nucleotide exchanges, thereby activating, rather than inactivating, the RAS.
Although some small molecule inhibitors of SOS1 are reported in the prior literature (for example, patent document WO2018/115380 A1), a large number of patients still cannot obtain satisfactory clinical treatment effects, so that there is still a need to develop SOS1 inhibitors with better activity, selectivity and safety.
Disclosure of Invention
The invention provides a compound shown in a formula (I) and a pharmaceutically acceptable salt thereof. These compounds can inhibit the activity of SOS1, thereby affecting biological functions.
The invention provides a compound shown in a formula (I) or a pharmaceutically acceptable salt thereof,
Figure BDA0003685226970000021
wherein the content of the first and second substances,
x is selected from CH or N;
y is selected from CH or N;
z is selected from CH or N;
l is selected from the group consisting of a bond, NR 6 Or O;
R 6 is selected from H orC 1 -C 6 An alkyl group;
R 1 selected from H, halogen, hydroxy, cyano, amino, C 1 -C 6 Alkyl radical, C 1 -C 3 Haloalkyl, C 1 -C 3 Deuterated alkyl, -O-C 1 -C 6 Alkyl or C 3 -C 6 A cycloalkyl group;
R 2 is selected from C 3 -C 10 Cycloalkyl, C 6 -C 10 Aryl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl, said C 3 -C 10 Cycloalkyl radical, C 6 -C 10 Aryl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl optionally substituted with R 2b And/or R 2c Substitution;
R 2b independently selected from halogen, cyano, -OR 2c 、-N(R 2c ) 2 、-C(O)R 2c 、-C(O)N(R 2c ) 2 、-C(O)OR 2c 、-S(O) 2 R 2c 、-S(O) 2 N(R 2c ) 2 、-NHC(O)R 2c or-N (C) 1 -C 3 Alkyl) C (O) R 2c ；
Each R 2c Independently selected from H, deuterium, C 1 -C 3 Deuterated alkyl, C 1 -C 6 Alkyl radical, C 3 -C 10 Cycloalkyl, C 6 -C 10 Aryl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl, said C 1 -C 6 Alkyl radical, C 3 -C 10 Cycloalkyl radical, C 6 -C 10 Aryl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl optionally substituted with R 2d Substitution;
R 2d selected from independently halogen, hydroxy, cyano, amino, -C (O) R 2f 、-C(O)N(R 2f ) 2 、-C(O)OR 2f 、-S(O) 2 R 2f 、-S(O) 2 N(R 2f ) 2 、-N(C 1 -C 3 Alkyl) R 2f 、-NHC(O)R 2f or-N (C) 1 -C 3 Alkyl) C (O) R 2f ；
Each R 2f Independently selected from H or C 1 -C 6 An alkyl group;
R 3 、R 4 independently selected from H, deuterium, C 1 -C 3 Deuterated alkyl, C 1 -C 6 Alkyl or C 1 -C 3 A haloalkyl group;
R 5 selected from halogen, hydroxy, cyano, amino, C 1 -C 6 Alkyl radical, C 3 -C 6 Cycloalkyl, -O-C 1 -C 6 Alkyl, -O-C 3 -C 6 Cycloalkyl, -O- (4-7 membered heterocyclyl), -S (O) 2 -C 1 -C 3 Alkyl, -P (O) (R) 5b ) 2 、-C(O)R 5b 、-C(O)N(R 5b ) 2 、-C(O)OR 5b 、
Figure BDA0003685226970000031
4-7 membered heterocyclic group or 5-10 membered heteroaryl group, said C 1 -C 6 Alkyl radical, C 3 -C 6 Cycloalkyl, -O-C 1 -C 6 Alkyl, -O-C 3 -C 6 Cycloalkyl, -O- (4-7 membered heterocyclyl), -S (O) 2 -C 1 -C 3 Alkyl, 4-7 membered heterocyclyl or 5-10 membered heteroaryl optionally substituted with R 5a Substitution;
R 5a selected from halogen, hydroxy, cyano or amino;
each R 5b Independently selected from H or C 1 -C 6 An alkyl group;
n is selected from 0, 1,2,3 or 4;
ring A is selected from C 6 -C 10 Aryl, 5-10 membered heterocyclyl or 5-10 membered heteroaryl.
In some embodiments, R 1 Selected from H, C 1 -C 6 Alkyl or C 1 -C 3 A deuterated alkyl group.
In some embodiments, R 1 Selected from H, C 1 -C 3 Alkyl or C 1 -C 3 A deuterated alkyl group.
In some embodiments, R 1 Selected from H, CH 3 Or CD 3 。
In some embodiments, R 1 Is selected from CH 3 。
In some embodiments, R 2 Selected from 3-10 membered heterocyclyl or 5-10 membered heteroaryl, said 3-10 membered heterocyclyl or 5-10 membered heteroaryl optionally substituted with R 2b And/or R 2c And (4) substitution.
In some embodiments, R 2 Selected from 4-6 membered heterocyclyl or 5-6 membered heteroaryl, said 4-6 membered heterocyclyl or 5-6 membered heteroaryl optionally substituted with R 2b And/or R 2c And (4) substitution.
In some embodiments, R 2 Selected from the following groups: piperidinyl, dihydropyranyl, tetrahydropyridinyl, azetidinyl, morpholinyl or pyrazolyl optionally substituted by R 2b And/or R 2c And (4) substitution.
In some embodiments, R 2 Selected from the following groups:
Figure BDA0003685226970000032
Figure BDA0003685226970000033
in some embodiments, R 2b Independently selected from halogen, cyano, -OR 2c 、-N(R 2c ) 2 、-C(O)R 2c 、-C(O)N(R 2c ) 2 、-C(O)OR 2c 、-NHC(O)R 2c or-N (C-C) 3 Alkyl) C (O) R 2c 。
In some embodiments, R 2b Independently selected from-OR 2c 、-C(O)R 2c or-C (O) N (R) 2c ) 2 。
In some embodiments, R 2b Independently selected from-OH, -O-CH 3 、-C(O)CH 3 、-C(O)CD 3 or-C (O) NHCH 3 。
In some embodiments, R 2b Selected from the group consisting of-C (O) R 2c 。
In some embodiments, each R is 2c Independently selected from H, deuterium, C 1 -C 3 Deuterated alkyl, C 1 -C 6 Alkyl radical, C 3 -C 10 Cycloalkyl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl, said C 1 -C 6 Alkyl radical, C 3 -C 10 Cycloalkyl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl optionally substituted with R 2d And (4) substitution.
In some embodiments, each R is 2c Independently selected from H, deuterium, C 1 -C 3 Deuterated alkyl or C 1 -C 6 Alkyl radical, said C 1 -C 6 Alkyl is optionally substituted by R 2d And (4) substitution.
In some embodiments, each R is 2c Independently selected from H, deuterium, CD 3 Or CH 3 。
In some embodiments, R 2c Is selected from C 1 -C 6 An alkyl group.
In some embodiments, R 3 、R 4 Independently selected from H, deuterium, C 1 -C 3 Deuterated alkyl or C 1 -C 6 An alkyl group.
In some embodiments, R 3 、R 4 Independently selected from H, deuterium, CH 3 Or CD 3 。
In some embodiments, R 3 Selected from H or deuterium, R 4 Is selected from CH 3 Or CD 3 。
In some embodiments, R 3 Selected from H, R 4 Is selected from CH 3 。
In some embodiments, R 5 Selected from halogen, hydroxy, cyano, amino, C 1 -C 6 Alkyl radical, C 3 -C 6 Cycloalkyl, -O-C 1 -C 6 Alkyl, -S (O) 2 -C 1 -C 3 Alkyl, -P (O) (R) 5b ) 2 、
Figure BDA0003685226970000041
4-7 membered heterocyclic group or 5-10 membered heteroaryl group, said C 1 -C 6 Alkyl radical, C 3 -C 6 Cycloalkyl, -O-C 1 -C 6 Alkyl, -S (O) 2 -C 1 -C 3 Alkyl, 4-7 membered heterocyclyl or 5-10 membered heteroaryl optionally substituted with R 5a And (4) substitution.
In some embodiments, R 5 Selected from halogen, hydroxy, cyano, amino, C 1 -C 6 Alkyl, -O-C 1 -C 6 Alkyl, -S (O) 2 -C 1 -C 3 Alkyl, -P (O) (R) 5b ) 2 、
Figure BDA0003685226970000042
Or 4-7 membered heterocyclic group, said C 1 -C 6 Alkyl, -O-C 1 -C 6 Alkyl, -S (O) 2 -C 1 -C 3 Alkyl or 4-7 membered heterocyclyl is optionally substituted by R 5a And (4) substitution.
In some embodiments, R 5 Selected from halogen, amino, C 1 -C 6 Alkyl, -S (O) 2 -C 1 -C 3 Alkyl, -P (O) (R) 5b ) 2 Or
Figure BDA0003685226970000043
Said C is 1 -C 6 Alkyl or-S (O) 2 -C 1 -C 3 Alkyl is optionally substituted by R 5a And (4) substitution.
In some embodiments, R 5 Is selected from F and CH 3 Amino, -S (O) 2 -CH 3 or-P (O) (CH) 3 ) 2 Said CH 3 or-S (O) 2 -CH 3 Optionally substituted with R 5a And (4) substitution.
In some embodiments, R 5 Selected from halogen, amino or C 1 -C 6 Alkyl radical, said C 1 -C 6 Alkyl is optionally substituted by R 5a And (4) substitution.
In some embodiments, R 5 Selected from F and CH 3 Or amino group, said CH 3 Optionally substituted by R 5a And (4) substitution.
In some embodiments, R 5 Selected from halogen or C 1 -C 6 Alkyl radical, said C 1 -C 6 Alkyl is optionally substitutedIs covered with R 5a And (4) substitution.
In some embodiments, R 5 Is selected from F or CH 3 Said CH 3 Optionally substituted by R 5a And (4) substitution.
In some embodiments, R 5 Selected from F or CHF 2 。
In some embodiments, R 5a Selected from halogens.
In some embodiments, n is selected from 0, 1 or 2.
In some embodiments, n is selected from 2.
In some embodiments, ring a is selected from C 6-10 Aryl, 9-10 membered heterocyclyl or 9-10 membered heteroaryl.
In some embodiments, ring a is selected from C 6-10 And (3) an aryl group.
In some embodiments, ring a is selected from phenyl.
In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from a compound of formula (II) or a pharmaceutically acceptable salt thereof:
Figure BDA0003685226970000051
wherein, ring A, L, R 1 ，R 2 ，R 3 ，R 4 ，R 5 And n is as defined above.
In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from a compound of formula (III) or a pharmaceutically acceptable salt thereof,
Figure BDA0003685226970000052
wherein, ring A, L, R 1 ，R 2 ，R 3 ，R 4 ，R 5 And n is as defined above.
In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from a compound of formula (IV) or a pharmaceutically acceptable salt thereof,
Figure BDA0003685226970000061
wherein, ring A, L, R 1 ，R 2 ，R 3 ，R 4 ，R 5 And n is as defined above.
In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from a compound of formula (V) or a pharmaceutically acceptable salt thereof,
Figure BDA0003685226970000062
wherein, ring A, L, R 1 ，R 2 ，R 3 ，R 4 ，R 5 And n is as defined above.
In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of a compound of formula (I), or a pharmaceutically acceptable salt thereof,
Figure BDA0003685226970000063
Figure BDA0003685226970000071
further, the invention also provides a pharmaceutical composition, which comprises the compound shown in the formula (I) or pharmaceutically acceptable salt thereof and pharmaceutically acceptable auxiliary materials.
Further, the invention relates to application of the compound shown in the formula (I) or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in preparing a medicament for preventing or treating SOS1 related diseases.
Further, the invention relates to application of the compound shown as the formula (I) or pharmaceutically acceptable salts thereof or a pharmaceutical composition thereof in preventing or treating SOS1 related diseases.
Further, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for preventing or treating SOS 1-related diseases.
The present invention also relates to a method of treating SOS 1-related disorders comprising administering to a patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, as described herein.
Further, the SOS 1-associated disease is selected from cancer.
Unless otherwise indicated, the terms used in the present invention have the following meanings, and the group and term definitions described in the present invention, including definitions thereof as examples, exemplary definitions, preferred definitions, definitions described in tables, definitions of specific compounds in examples, and the like, may be arbitrarily combined and combined with each other. A particular term should not be considered as ambiguous or unclear without special definition, but rather construed according to ordinary meaning in the art. When a trade name appears herein, it is intended to refer to its corresponding commodity or its active ingredient.
In this context
Figure BDA0003685226970000081
Indicates the attachment site.
The illustrations of racemic or enantiomerically pure compounds herein are from Maehr, j.chem.ed.1985, 62. Using wedge and virtual wedge keys, unless otherwise indicated
Figure BDA0003685226970000082
Representing an absolute configuration of a solid center, with black solid and dotted bonds
Figure BDA0003685226970000083
Indicates the relative configuration of a stereocenter (e.g., cis-trans configuration of an alicyclic compound).
The term "tautomer" refers to an isomer of a functional group resulting from the rapid movement of an atom in a molecule at two positions. The compounds of the invention may exhibit tautomerism. Tautomeric compounds may exist in two or more interconvertible species. Tautomers generally exist in equilibrium, and attempts to isolate a single tautomer usually result in a mixture whose physicochemical properties are consistent with the mixture of the compounds. The position of equilibrium depends on the chemical properties within the molecule. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the keto form predominates; whereas in phenol the enol type predominates. The present invention encompasses all tautomeric forms of the compounds.
The term "stereoisomer" refers to isomers resulting from the different arrangement of atoms in a molecule, including cis-trans isomers, enantiomers, and diastereomers.
The compounds of the present invention may have asymmetric atoms such as carbon atom, sulfur atom, nitrogen atom, phosphorus atom or asymmetric double bond, and thus the compounds of the present invention may exist in a specific geometric or stereoisomeric form. The particular geometric or stereoisomeric forms may be the cis and trans isomers, the E and Z geometric isomers, the (-) -and (+) -enantiomers, (R) -and (S) -enantiomers, diastereomers, (D) -isomers, (L) -isomers, as well as racemic or other mixtures thereof, e.g., enantiomerically or diastereomerically enriched mixtures, all of which, as well as mixtures thereof, are within the definition of the compounds of the present invention. The presence of additional asymmetric carbon, sulfur, nitrogen or phosphorus atoms in substituents such as alkyl groups is also within the definition of the compounds of the invention as regards all such isomers and mixtures thereof. The compounds of the invention containing asymmetric atoms can be isolated in optically pure form or in racemic form, the optically pure form can be resolved from a racemic mixture, or synthesized by using chiral starting materials or chiral reagents.
The term "substituted" means that any one or more hydrogen atoms on a particular atom is replaced with a substituent, so long as the valence of the particular atom is normal and the substituted compound is stable. When the substituent is oxo (i.e = O), meaning that two hydrogen atoms are substituted, oxo does not occur on the aromatic group.
The terms "optional" or "optionally" mean that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. For example, ethyl is "optionally" substituted with halo, meaning that ethyl may be unsubstituted (CH) 2 CH 3 ) Monosubstituted (CH) 2 CH 2 F、CH 2 CH 2 Cl, etc.), polysubstituted (CHFCH) 2 F、CH 2 CHF 2 、CHFCH 2 Cl、CH 2 CHCl 2 Etc.) or completely substituted (CF) 2 CF 3 、CF 2 CCl 3 、CCl 2 CCl 3 Etc.). It will be appreciated by those skilled in the art that any group containing one or more substituents will not incorporate any substitution or substitution patterns which are sterically impossible and/or synthetically impossible.
When any variable (e.g. R) a 、R b ) When a compound occurs more than one time in its composition or structure, its definition in each case is independent. For example, if a group is substituted by 2R b Substituted, then each R b There are separate options.
When the number of one linking group is 0, e.g. - (CH) 2 ) 0 -, denotes that the linking group is a bond.
When one of the variables is selected from a chemical bond or is absent, it indicates that the two groups to which it is attached are directly linked, e.g., L in A-L-Z represents a bond, indicating that the structure is actually A-Z.
When referring to a linking group herein, the direction of attachment is arbitrary unless it is indicated. For example as a structural element
Figure BDA0003685226970000091
L in (1) 1 Is selected from "C 1 -C 3 alkylene-O', when L is 1 The rings Q and R can be connected in the direction from left to right 1 Form "Ring Q-C 1 -C 3 alkylene-O-R 1 ", the rings Q and R may be connected in the right-to-left direction 1 Form "ring Q-O-C 1 -C 3 alkylene-R 1 ”。
When a substituent's bond is cross-linked to two atoms on a ring, such substituent may be bonded to any atom on the ring. For example, a structural unit
Figure BDA0003685226970000092
Represents R 5 The substitution may occur at any position on the phenyl ring.
Herein C m -C n Refers to having an integer number of carbon atoms in the range of m-n. For example "C 1 -C 10 By "is meant that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms, or 10 carbon atoms.
The term "C 1 -C 3 Haloalkyl "comprises monohalogenated C 1 -C 3 Alkyl or polyhalogenated C 1 -C 3 Specific examples of alkyl groups include, but are not limited to, trifluoromethyl, 2-trichloroethyl, or 3-fluoropropyl, and the like.
The term "C 1 -C 3 Deuterated alkyl "C containing mono-deuteration 1 -C 3 Alkyl or deuterated C 1 -C 3 Alkyl, specific examples include but are not limited to CD 3 、CH 2 CD 3 And so on.
The term "alkyl" refers to a group of formula C n H 2n+1 The alkyl group may be linear or branched. The term "C 1 -C 10 Alkyl "is understood to mean a straight-chain or branched saturated hydrocarbon radical having 1,2,3, 4,5, 6,7,8, 9 or 10 carbon atoms. Specific examples of the alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-ethylpropyl, 1, 2-dimethylpropyl, neopentyl, 1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3-dimethylbutyl, 2-dimethylbutyl, 1-dimethylbutyl, 2, 3-dimethylbutyl, 1, 3-dimethylbutyl or 1, 2-dimethylbutyl, etc.; the term "C 1 -C 6 Alkyl "is understood to mean an alkyl group having from 1 to 6 carbon atoms, specific examples including, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl and the like. The term "C 1 -C 3 Alkyl "is understood to mean a straight-chain or branched saturated alkyl group having from 1 to 3 carbon atoms. Said "C" is 1 -C 10 Alkyl groups "may contain" C 1 -C 6 Alkyl "or" C 1 -C 3 Alkyl radicals ", said" C 1 -C 6 The alkyl group "may further comprise" C 1 -C 3 Alkyl groups ".
The term "cycloalkyl" refers to a carbon ring that is fully saturated and exists as a single ring, a bicyclic ring, a bridged ring, or a spiro ring, among others. Unless otherwise indicated, the carbocycle is typically a 3 to 10 membered ring. The term "C 3 -C 10 Cycloalkyl "is understood to mean a saturated monocyclic, bicyclic, spirocyclic or bridged ring having from 3 to 10 carbon atoms. Specific examples of such cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, norbornyl (bicyclo [2.2.1 ] s)]Heptyl), bicyclo [2.2.2]Octyl, adamantyl, spiro [4.5 ]]Decyl, and the like. The term "C 3 -C 10 Cycloalkyl "may contain" C 3 -C 6 Cycloalkyl radical ", the term" C 3 -C 6 Cycloalkyl "is understood to mean a saturated monocyclic or bicyclic hydrocarbon ring having from 3 to 6 carbon atoms, specific examples including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, and the like.
The term "heterocyclyl" refers to a fully or partially saturated (not heteroaromatic with aromatic character as a whole) monocyclic, fused, spiro or bridged ring group containing 1 to 5 heteroatoms or heteroatom groups in ring atoms (i.e., containing heteroatoms)The "heteroatom or heteroatom group" includes, but is not limited to, a nitrogen atom (N), an oxygen atom (O), a sulfur atom (S), a phosphorus atom (P), a boron atom (B), -S (= O) 2 -、-S(＝O)-、-P(＝O) 2 -, -P (= O) -, -NH-, -S (= O) (= NH) -, and-C (= O) NH-, or-NHC (= O) NH-, or the like. The term "3-10 membered heterocyclyl" refers to heterocyclyl groups having a ring atom number of 3,4, 5,6,7,8, 9 or 10 and having 1-5 heteroatoms or groups of heteroatoms in the ring atoms independently selected from those described above. "3-10 membered heterocyclic group" includes "4-7 membered heterocyclic group", wherein specific examples of the 4 membered heterocyclic group include, but are not limited to, azetidinyl or oxetanyl; specific examples of 5-membered heterocyclic groups include, but are not limited to, tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, 4, 5-dihydrooxazolyl, or 2, 5-dihydro-1H-pyrrolyl; specific examples of 6-membered heterocyclyl include, but are not limited to, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, tetrahydropyridinyl, or 4H- [1,3,4]Thiadiazinyl; specific examples of 7-membered heterocyclic groups include, but are not limited to, diazepanyl. The heterocyclic group may also be a bicyclic group, wherein specific examples of the 5,5-membered bicyclic group include, but are not limited to, hexahydrocyclopenta [ c ] group]Pyrrol-2 (1H) -yl; specific examples of 5,6-membered bicyclic groups include, but are not limited to, hexahydropyrrolo [1,2-a ]]Pyrazin-2 (1H) -yl, 5,6,7,8-tetrahydro- [1,2,4]Triazolo [4,3-a]Pyrazinyl or 5,6,7,8-tetrahydroimidazo [1,5-a ]]A pyrazinyl group. Optionally, the heterocyclic group may be a benzo-fused ring group of the above-mentioned 4-7 membered heterocyclic group, and specific examples include, but are not limited to, dihydroisoquinolinyl and the like. "4-to 10-membered heterocyclic group" may include ranges of "5-to 10-membered heterocyclic group", "4-to 7-membered heterocyclic group", "5-to 6-membered heterocyclic group", "6-to 8-membered heterocyclic group", "4-to 10-membered heterocycloalkyl group", "5-to 10-membered heterocycloalkyl group", "4-to 7-membered heterocycloalkyl group", "5-to 6-membered heterocycloalkyl group", "6-to 8-membered heterocycloalkyl group" and the like, and "4-to 7-membered heterocyclic group" may further include ranges of "4-to 6-membered heterocyclic group", "5-to 6-membered heterocyclic group", "4-to 7-membered heterocycloalkyl group", "4-to 6-membered heterocycloalkyl group", "5-to 6-membered heterocycloalkyl group" and the like. Although some bicyclic heterocyclic groups of the present invention contain, in part, a benzene ring or a heterocycleAromatic rings, but the heterocyclic group as a whole is still non-aromatic.
The term "aryl" refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated pi-electron system. The aryl group can have 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbon atoms. The term "C 6 -C 20 Aryl "is understood to mean aryl having from 6 to 20 carbon atoms. In particular a ring having 6 carbon atoms ("C) 6 Aryl "), such as phenyl; or a ring having 9 carbon atoms ("C) 9 Aryl "), such as indanyl or indenyl; or a ring having 10 carbon atoms ("C) 10 Aryl), such as tetralinyl, dihydronaphthyl, or naphthyl; or a ring having 13 carbon atoms ("C) 13 Aryl "), such as fluorenyl; or a ring having 14 carbon atoms ("C) 14 Aryl), such as anthracyl. The term "C 6 -C 10 Aryl "is understood to be an aryl group having from 6 to 10 carbon atoms. In particular a ring having 6 carbon atoms ("C) 6 Aryl "), such as phenyl; or a ring having 9 carbon atoms ("C) 9 Aryl "), such as indanyl or indenyl; or a ring having 10 carbon atoms ("C) 10 Aryl), such as tetralinyl, dihydronaphthyl, or naphthyl. The term "C 6 -C 20 Aryl "may contain" C 6 -C 10 Aryl radicals "
The term "heteroaryl" refers to a monocyclic or fused polycyclic aromatic ring system containing at least one ring atom selected from N, O, S, the remaining ring atoms being C. The term "5-to 10-membered heteroaryl" is understood to include monocyclic or bicyclic aromatic ring systems: it has 5,6,7,8, 9 or 10 ring atoms, in particular 5 or 6 or 9 or 10 ring atoms, and it contains 1 to 5, preferably 1 to 3 heteroatoms independently selected from N, O and S. In particular, heteroaryl is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl or thiadiazolyl and the like and their benzo derivatives, such as benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl or isoindolyl and the like; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and the like, and benzo derivatives thereof, such as quinolyl, quinazolinyl, isoquinolyl, and the like; or azocinyl, indolizinyl, purinyl and the like and benzo derivatives thereof; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl or phenoxazinyl, and the like. The term "5-6 membered heteroaryl" refers to an aromatic ring system having 5 or 6 ring atoms and which contains 1-3, preferably 1-2 heteroatoms independently selected from N, O and S.
The term "halo" or "halogen" refers to fluorine, chlorine, bromine or iodine.
The term "hydroxy" refers to an-OH group.
The term "cyano" refers to the group — CN.
The term "amino" refers to the group-NH 2 A group.
The term "nitro" means-NO 2 A group.
The term "therapeutically effective amount" refers to an amount of a compound of the invention that (i) treats a particular disease, condition, or disorder, (ii) reduces, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein. The amount of a compound of the present invention that constitutes a "therapeutically effective amount" varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by those skilled in the art with their own knowledge and this disclosure.
The term "pharmaceutically acceptable" is intended to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
The term "pharmaceutically acceptable salt" refers to salts of pharmaceutically acceptable acids or bases, including salts of compounds with inorganic or organic acids, and salts of compounds with inorganic or organic bases.
The term "pharmaceutical composition" refers to a mixture of one or more compounds of the invention or salts thereof with pharmaceutically acceptable excipients. The purpose of the pharmaceutical composition is to facilitate administration of the compounds of the invention to an organism.
The term "pharmaceutically acceptable adjuvants" refers to those adjuvants which do not have a significant irritating effect on the organism and do not impair the biological activity and properties of the active compound. Suitable adjuvants are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.
The word "comprising" or "comprises" and variations thereof such as "comprises" or "comprising", will be understood to have an open, non-exclusive meaning, i.e., "including but not limited to".
The invention also includes isotopically-labeled compounds of the present invention, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine, such as respectively 2 H、 3 H、 11 C、 13 C、 14 C、 13 N、 15 N、 15 O、 17 O、 18 O、 31 P、 32 P、 35 S、 18 F、 123 I、 125 I and 36 cl, and the like.
Certain isotopically-labelled compounds of the invention (e.g. by 3 H and 14 c-label) can be used in compound and/or substrate tissue distribution assays. Tritiated (i.e. by tritiation) 3 H) And carbon-14 (i.e. 14 C) Isotopes are particularly preferred for their ease of preparation and detectability. Positron emitting isotopes, such as 15 O、 13 N、 11 C and 18 f for positronsEmission Tomography (PET) studies to determine substrate occupancy. Isotopically labeled compounds of the present invention can generally be prepared by following procedures analogous to those disclosed in the schemes and/or in the examples below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
The pharmaceutical composition of the present invention can be prepared by combining the compound of the present invention with suitable pharmaceutically acceptable excipients, and can be formulated, for example, into solid, semisolid, liquid or gaseous preparations such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres, aerosols, and the like.
Typical routes of administration of the compounds of the present invention or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration.
The pharmaceutical compositions of the present invention may be manufactured by methods well known in the art, such as conventional mixing, dissolving, granulating, emulsifying, lyophilizing, and the like.
In some embodiments, the pharmaceutical composition is in an oral form. For oral administration, the pharmaceutical compositions may be formulated by mixing the active compounds with pharmaceutically acceptable excipients well known in the art. These adjuvants 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 compositions may be prepared by conventional mixing, filling or tableting methods. For example, it can be obtained by the following method: the active compounds are mixed with solid adjuvants, optionally the mixture obtained is milled, if desired with further suitable adjuvants, and the mixture is then processed to granules, to give tablets or dragee cores. Suitable excipients include, but are not limited to: binders, diluents, disintegrants, lubricants, glidants or flavoring agents, and the like.
The pharmaceutical compositions may also be adapted for parenteral administration, as sterile solutions, suspensions or lyophilized products in suitable unit dosage forms.
In all methods of administration of the compounds of general formula (I) described herein, the daily dose is from 0.01mg/kg to 200mg/kg body weight, preferably from 0.05mg/kg to 50mg/kg body weight, more preferably from 0.1mg/kg to 30mg/kg body weight, in single or divided doses.
Detailed Description
The following examples illustrate the technical solutions of the present invention in detail, but the scope of the present invention includes but is not limited thereto.
The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) and/or Mass Spectrometry (MS). NMR shift in units of 10 -6 (ppm). Solvents for NMR determination are deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol and the like, and internal standard is Tetramethylsilane (TMS); ' IC 50 "half inhibitory concentration" means the concentration at which half of the maximum inhibitory effect is achieved.
Abbreviation:
NBS: n-bromosuccinimide; DMF: n, N-dimethylformamide; THF: tetrahydrofuran; ethanol: ethanol; pyAOP: triazolo [4,5-b]Pyridine-3-oxy) tri-1-pyrrolidinylhexafluorophosphate; DBU 1, 8-diazabicyclo [5.4.0]-7-undecene; pd (dppf) Cl 2 1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride; dioxane, dioxane; formic acid: formic acid; pd/C: palladium on carbon; acOH: acetic acid; methanol: methanol; NH (NH) 2 NH 2 Hydrazine hydrate.
Example 1: (R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -6- (3, 6-dihydro-2H-pyran-4-yl) -2-methyl- [1,2,4] triazolo [4',3':1,6] pyrido [2,3-d ] pyrimidin-4-amine
Figure BDA0003685226970000141
Step 1: synthesis of 2-amino-5-bromo-6-chloropyridine-3-carboxylic acid
Figure BDA0003685226970000142
2-amino-6-chloropyridine-3-carboxylic acid (25.0 g) was dissolved in 150mL of N, N-dimethylformamide, and N-bromosuccinimide (28.4 g) was added in portions, and the reaction was completed after heating to 70 ℃ and stirring for 2 hours. The reaction mixture was cooled to room temperature, poured into 500mL of ice-water mixture, filtered, the filter cake was washed three times with water and the filter cake was dried to give the title compound.
Step 2: synthesis of 6-bromo-7-chloro-2-methyl-pyrido [2,3-d ] [1,3] oxazin-4-one
Figure BDA0003685226970000143
2-amino-5-bromo-6-chloropyridine-3-carboxylic acid (36.0 g) was dissolved in 500mL of acetic anhydride, heated to 130 ℃ and stirred for 36 hours, after completion of the reaction, the reaction mixture was cooled to room temperature, concentrated and dried, and then directly fed to the next step.
And 3, step 3: synthesis of 6-bromo-7-chloro-2-methyl-3H-pyrido [2,3-d ] pyrimidin-4-one
Figure BDA0003685226970000144
And (3) dissolving the crude product obtained in the step 2 in 1L of tetrahydrofuran, dropwise adding ammonia methanol (7.0 mol/L,415 mL) into the reaction solution at the temperature of-30 ℃, and after dropwise adding, heating the reaction system to room temperature to react for 12 hours and then finishing the reaction. Pouring the reaction liquid into 1L of ice water, adding 4N diluted hydrochloric acid to adjust the pH value to 8-9, separating out light yellow solid, filtering, washing a filter cake with water for three times, drying, and then adding petroleum ether: ethyl acetate =3:1 (V: V) slurried and purified to give the title compound.
And 4, step 4: synthesis of 6-bromo-7-hydrazino-2-methylpyrido [2,3-d ] pyrimidin-4 (3H) -one
Figure BDA0003685226970000145
6-bromo-7-chloro-2-methyl-3H-pyrido [2,3-d ] pyrimidin-4-one (1.10 g) and hydrazine hydrate (927 ul) were dissolved in 10ml of ethanol, and after the reaction was completed with stirring at 70 ℃ for 3 hours, the reaction was filtered, the filter cake was washed with ethanol, and the filter cake was dried to give the title compound.
And 5: synthesis of 6-bromo-2-methyl- [1,2,4] triazolo [4',3':1,6] pyrido [2,3-d ] pyrimidin-4 (3H) -one
Figure BDA0003685226970000151
6-bromo-7-hydrazino-2-methylpyrido [2,3-d ] pyrimidin-4 (3H) -one (990 mg) was dissolved in 12ml of formic acid, and the reaction was completed at 100 ℃ for 4 hours, followed by concentration under reduced pressure to obtain the title compound.
Step 6: synthesis of (R) -6-bromo-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methyl- [1,2,4] triazolo [4',3':1,6] pyrido [2,3-d ] pyrimidin-4-amine
Figure BDA0003685226970000152
6-bromo-2-methyl- [1,2,4] triazolo [4',3':1,6] pyrido [2,3-d ] pyrimidin-4 (3H) -one (200 mg), (3H-1, 2, 3-triazolo [4,5-b ] pyridin-3-yloxy) tri-1-pyrrolidinyl hexafluorophosphate (558 mg) was dissolved in 5ml of N, N-dimethylformamide, and 1, 8-diazabicyclo [5.4.0] -7-undecene (320 uL) was added, followed by stirring at room temperature for 30 minutes, followed by addition of (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethane-1-amine hydrochloride (193 mg) and reaction at room temperature overnight. After the reaction, ethyl acetate is added for dilution, water washing, saturated salt water washing, organic phase anhydrous sodium sulfate drying, filtration, concentration and column chromatography (petroleum ether/ethyl acetate gradient elution) are carried out to obtain the title compound.
And 7: synthesis of (R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -6- (3, 6-dihydro-2H-pyran-4-yl) -2-methyl- [1,2,4] triazolo [4',3':1,6] pyrido [2,3-d ] pyrimidin-4-amine
Figure BDA0003685226970000153
Reacting (R) -6-bromo-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methyl- [1,2,4] triazolo [4',3':1,6] pyridine [2,3-d ] pyrimidin-4-amine (100 mg), 3, 6-dihydro-2H-pyran-4-boronic acid pinacol ester (69.9 mg), [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (16.2 mg), sodium carbonate (47.0 mg) dissolved in 2mL dioxane and 0.5mL water, argon replaced, and stirred at 100 ℃ for 2 hours. After the reaction, ethyl acetate is added for dilution, water washing, saturated salt water washing, organic phase anhydrous sodium sulfate drying, filtration, concentration and column chromatography (petroleum ether/ethyl acetate gradient elution) are carried out to obtain the title compound.
1 H NMR(400MHz,DMSO-d 6 )δ H 9.59(s,1H),8.78(d,J＝7.2Hz,1H),8.06(s,1H),7.74-7.66(m,2H),7.52(t,J＝7.1Hz,1H),7.32(t,J＝7.7Hz,1H),7.25(t,J＝54.4Hz,1H),5.83(p,J＝7.0Hz,1H),4.40-4.38(m,2H),3.95(t,J＝5.5Hz,2H),2.78-2.61(m,2H),2.45(s,3H),1.64(d,J＝7.1Hz,3H).
LC/MS(m/z,MH + ):455.2.
Example 2: (R) -1- (4- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl- [1,2,4] triazolo [4',3':1,6] pyrido [2,3-d ] pyrimidin-6-yl) piperidin-1-yl) ethan-1-one
Figure BDA0003685226970000161
Step 1: synthesis of (R) -1- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl- [1,2,4] triazolo [4',3':1,6] pyrido [2,3-d ] pyrimidin-6-yl) -3, 6-dihydropyridin-1 (2H) -yl) ethan-1-one
Figure BDA0003685226970000162
Reacting (R) -6-bromo-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methyl- [1,2,4] triazolo [4',3":1,6] pyridine [2,3-d ] pyrimidin-4-amine (100 mg), 1-acetyl-5, 6-dihydro-2H-pyridine-4-boronic acid pinacol ester (83.6 mg), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (16.2 mg), sodium carbonate (47.0 mg) dissolved in 2mL dioxane and 0.5mL water, argon replaced, and stirred at 100 ℃ for 2 hours. After the reaction, ethyl acetate is added for dilution, water washing, saturated salt water washing, organic phase anhydrous sodium sulfate drying, filtration, concentration and column chromatography (petroleum ether/ethyl acetate gradient elution) are carried out to obtain the title compound.
And 2, step: synthesis of (R) -1- (4- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl- [1,2,4] triazolo [4',3':1,6] pyrido [2,3-d ] pyrimidin-6-yl) piperidin-1-yl) ethan-1-one
Figure BDA0003685226970000171
(R) -1- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl- [1,2,4] triazolo [4',3':1,6] pyrido [2,3-d ] pyrimidin-6-yl) -3, 6-dihydropyridin-1 (2H) -yl) ethan-1-one (30.0 mg) was dissolved in 5ml of methanol, palladium on carbon (6.00 mg) was added, one drop of acetic acid was added, hydrogen was replaced, and the mixture was stirred at room temperature overnight. After the reaction, the mixture was diluted with ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate for the organic phase, filtered, concentrated, and subjected to column chromatography (dichloromethane/methanol gradient elution) to obtain the title compound.
1 H NMR(400MHz,DMSO-d 6 )δ H 9.57(s,1H),8.63(d,J＝7.1Hz,1H),7.99(s,1H),7.69(t,J＝7.4Hz,1H),7.52(t,J＝7.0Hz,1H),7.32(t,J＝7.7Hz,1H),7.25(t,J＝54.4Hz,1H),5.80(p,J＝7.0Hz,1H),4.67-4.64(m,1H),4.04-4.01(m,1H),3.49-3.38(m,1H),3.30-3.23(m,1H),2.74-2.64(m,1H),2.44(s,3H),2.15-2.00(m,5H),1.86-1.72(m,2H),1.63(d,J＝7.0Hz,3H).
LC/MS(m/z,MH + ):498.
Experimental example 1 Effect of Compounds of the invention on the p-ERK pathway in H358 cells
The effect of the compounds of the invention on the p-ERK pathway of H358 cells was assessed by the Advanced phosphor-ERK (Thr 202/Tyr 204) cellular kit method.
The experimental methods are summarized as follows:
h358 cells (ATCC, CRL-5807) containing 10% FBS (fetal bovine serum) (Gibco, 10100147) and 100U/mL of complete medium RPMI1640 (ThermoFisher, A1049101) of a mixed solution of penicillin and streptomycin (Gibco, 15140163) were cultured, and when the coverage of the cells in the culture vessel reached 80-90%, the cells were blown out and seeded in a 96-well plate (Corning, 3599) with 50000 cells per well (90. Mu.L of complete medium RPMI 1640), left to stand for 5 minutes, placed at 37 ℃ and 5 CO for 5 minutes 2 The cells were cultured in the incubator of (1) for 6 hours, and then starved overnight with serum-free RPMI 1640.
After overnight, 10. Mu.L of the diluted compound was added to each well using a line gun, and the 96-well plate was incubated at 37 ℃ and 5% CO 2 The culture box of (2) for 1h. The supernatant was decanted and washed once with PBS buffer, 50. Mu.L of lysate (Advanced phosphor-ERK (Thr 202/Tyr 204) cellular kit,64 AERPEH) was added to each well, shaken at 450rpm for 1h at room temperature, after the cells were completely lysed, 16. Mu.L of supernatant was added to 384 wells (PE, 6007299), mixed antibody (d 2/Eu = 1), incubated for 4h at room temperature, the microplate reader selected HTRF read plates, ratio = Signal 665nm/Signal 620nm x 10, and Ratio = Signal 665nm/Signal 620nm x 10 4 . In this experiment, the cell-free group (replaced with 1640 medium) was used as the 100% inhibition group, and the cell-free but compound-free group was used as the 0% inhibition group.
The percent inhibition of the H358 cell p-ERK pathway by the compound can be calculated by the following formula:
percent inhibition =100 (0% inhibition group signal value-signal value at specific concentration of test compound)/(0% inhibition group signal value-100% inhibition group signal value).
Compound IC 50 Values were calculated from 8 concentration points using XLfit (ID Business Solutions ltd., UK) software by the following formula:
Y＝Bottom+(Top-Bottom)/(1+10^((logIC 50 -X)×slope factor))
wherein Y is the inhibition percentage, X is the logarithm value of the concentration of the compound to be detected, bottom is the minimum inhibition percentage, top is the maximum inhibition percentage, and slope factor is the curve slope coefficient. Fitting sigmoidal curve slope using default fitting curve to determine IC 50 The value is obtained. The results of the inhibition tests for compounds of the invention are detailed in table 1.
TABLE 1 test results for p-ERK inhibition by compounds of the present examples
Examples IC 50 (nM)
1 203
2 313
Experimental example 2: determination of inhibitory Activity on binding of SOS1 to KRAS G12D in examples of the present invention
The effect of the compounds of the invention on KRASG12D:: SOS1 BINDING inhibition was evaluated using KRAS-G12D/SOS1 BINDING ASSAY KITS (Cisbio, cat # 63ADK000CB21 PEH).
The experimental method comprises the following steps:
the positive control BAY-293 and test compound (10 mM stock) were diluted 5-fold to 0.1mM with 100% DMSO, and diluted 11 concentrations at 1. 0.1. Mu.L of the compound solution diluted in a gradient was transferred to 384-well plates using Echo, 2 replicates per compound, 1000rpm/min, and centrifuged for 1min. Transfer 5. Mu.L of 4X KRAS G12D (final concentration 1X) and GTP solution (final concentration 10. Mu. M, sigma, cat # V900868) to 384 reaction plates, 1000rpm/min, centrifuge for 1min, and incubate at 25 ℃ for 15min. Transfer 5. Mu.L of 4X SOS1 solution (final concentration 1X) to 384 reaction plates, 1000rpm/min, centrifuge for 1min, and incubate for 45min at 25 ℃. The final concentration of BAY-293 compound was 10,3.33,1.11,0.37,0.12,0.04,0.014,0.0046,0.0015,0.0005,0.00017,0uM. The final concentrations of the compounds to be tested were 10,3.33,1.11,0.37,0.12,0.04,0.014,0.0046,0.0015,0.0005,0.00017, and 0uM. The final concentration of DMSO was 0.5%. Transfer 10. Mu.L of 2X assay reagent solution to 384 reaction plates, 1000rpm/min, centrifuge for 1min, incubate for 180min at 4 ℃. The excitation wavelength was 665nm and the emission wavelength 615nm were read using an Envision multifunctional microplate reader. 665/615Ratio signal intensity is used to characterize the degree of activity of the enzyme.
The data processing method comprises the following steps: fitting Compound IC by Graphpad Prism 8 nonlinear regression equation 50 ：
Negative control: DMSO (dimethylsulfoxide)
Positive control: 10 μ M BAY-293
The IC of the compound was obtained using the following non-linear fit equation 50 (median inhibitory concentration):
Y＝Bottom+(Top-Bottom)/(1+10^((LogIC 50 -X)×HillSlope))
x log value of concentration of test compound
Y percent inhibition
Bottom is the minimum inhibition percentage, top is the maximum inhibition percentage, and HillSlope is Hill slope;
and (3) test results: under the experimental conditions, the test compound has good inhibitory activity on KRASG12D SOS1 binding. The results of the corresponding activity tests for the compounds tested are specified in table 2.
TABLE 2 test results of inhibitory Activity of Compounds of the present examples on KRAS G12D SOS1 binding
Examples IC 50 (nM)
1 5.8
2 6.2

Claims (13)

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof,
Figure FDA0003685226960000011
wherein, the first and the second end of the pipe are connected with each other,
x is selected from CH or N;
y is selected from CH or N;
z is selected from CH or N;
l is selected from the group consisting of a bond, NR 6 Or O;
R 6 is selected from H or C 1 -C 6 An alkyl group;
R 1 selected from H, halogen, hydroxy, cyano, amino, C 1 -C 6 Alkyl radical, C 1 -C 3 Haloalkyl, C 1 -C 3 Deuterated alkyl, -O-C 1 -C 6 Alkyl or C 3 -C 6 A cycloalkyl group;
R 2 is selected from C 3 -C 10 Cycloalkyl radical, C 6 -C 10 Aryl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl, said C 3 -C 10 Cycloalkyl radical, C 6 -C 10 Aryl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl optionally substituted with R 2b And/or R 2c Substitution;
R 2b independently selected from halogen, cyano, -OR 2c 、-N(R 2c ) 2 、-C(O)R 2c 、-C(O)N(R 2c ) 2 、-C(O)OR 2c 、-S(O) 2 R 2c 、-S(O) 2 N(R 2c ) 2 、-NHC(O)R 2c or-N (C) 1 -C 3 Alkyl) C (O) R 2c ；
Each R 2c Independently selected from H, deuterium, C 1 -C 3 Deuterated alkyl, C 1 -C 6 Alkyl radical, C 3 -C 10 Cycloalkyl, C 6 -C 10 Aryl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl, said C 1 -C 6 Alkyl radical, C 3 -C 10 Cycloalkyl radical, C 6 -C 10 Aryl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl is optionally substituted with R 2d Substitution;
R 2d selected from independently halogen, hydroxy, cyano, amino, -C (O) R 2f 、-C(O)N(R 2f ) 2 、-C(O)OR 2f 、-S(O) 2 R 2f 、-S(O) 2 N(R 2f ) 2 、-N(C 1 -C 3 Alkyl) R 2f 、-NHC(O)R 2f or-N (C) 1 -C 3 Alkyl) C (O) R 2f ；
Each R 2f Independently selected from H or C 1 -C 6 An alkyl group;
R 3 、R 4 independently selected from H, deuterium, C 1 -C 3 Deuterated alkyl, C 1 -C 6 Alkyl or C 1 -C 3 A haloalkyl group;
R 5 selected from halogen, hydroxy, cyano, amino, C 1 -C 6 Alkyl radical, C 3 -C 6 Cycloalkyl, -O-C 1 -C 6 Alkyl, -O-C 3 -C 6 Cycloalkyl, -O- (4-7 membered heterocyclyl), -S (O) 2 -C 1 -C 3 Alkyl, -P (O) (R) 5b ) 2 、-C(O)R 5b 、-C(O)N(R 5b ) 2 、-C(O)OR 5b 、
Figure FDA0003685226960000012
4-7 membered heterocyclic group or 5-10 membered heteroaryl group, said C 1 -C 6 Alkyl radical, C 3 -C 6 Cycloalkyl, -O-C 1 -C 6 Alkyl, -O-C 3 -C 6 Cycloalkyl, -O- (4-7 membered heterocyclyl), -S (O) 2 -C 1 -C 3 Alkyl, 4-7 membered heterocyclyl or 5-10 membered heteroaryl optionally substituted with R 5a Substitution;
R 5a selected from halogen, hydroxy, cyano or amino;
each R 5b Independently selected from H or C 1 -C 6 An alkyl group;
n is selected from 0, 1,2,3 or 4;
ring A is selected from C 6 -C 10 Aryl, 5-10 membered heterocyclyl or 5-10 membered heteroaryl.
2. The compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 1, wherein: r 1 Selected from H, C 1 -C 6 Alkyl or C 1 -C 3 A deuterated alkyl group.
3. The compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 1 or 2, wherein: r 2 Selected from 3-10 membered heterocyclyl or 5-10 membered heteroaryl, said 3-10 membered heterocyclyl or 5-10 membered heteroaryl being optionally substituted with R 2b And/or R 2c Substitution; preferably, R 2 Selected from 4-6 membered heterocyclyl or 5-6 membered heteroaryl, said 4-6 membered heterocyclyl or 5-6 membered heteroaryl optionally substituted with R 2b And/or R 2c And (4) substitution.
4. A compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-3, wherein: r 2b Independently selected from halogen, cyano, -OR 2c 、-N(R 2c ) 2 、-C(O)R 2c 、-C(O)N(R 2c ) 2 、-C(O)OR 2c 、-NHC(O)R 2c or-N (C) 1 -C 3 Alkyl) C (O) R 2c (ii) a Preferably, R 2b Independently selected from-OR 2c 、-C(O)R 2c or-C (O) N (R) 2c ) 2 (ii) a More preferably, R 2b Independently selected from-OH, -O-CH 3 、-C(O)CH 3 、-C(O)CD 3 or-C (O) NHCH 3 。
5. The compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-4, wherein: each R 2c Independently selected from H, deuterium, C 1 -C 3 Deuterated alkyl, C 1 -C 6 Alkyl radical, C 3 -C 10 Cycloalkyl, 3-to 10-membered heterocyclyl or 5-to 10-membered heteroaryl, or a pharmaceutically acceptable salt thereofC is 1 -C 6 Alkyl radical, C 3 -C 10 Cycloalkyl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl optionally substituted with R 2d Substitution; preferably, R 2c Independently selected from H, deuterium, C 1 -C 3 Deuterated alkyl or C 1 -C 6 Alkyl radical, said C 1 -C 6 Alkyl is optionally substituted by R 2d Substitution; more preferably, each R 2c Independently selected from H, deuterium, CD 3 Or CH 3 。
6. The compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any one of claims 1-5, wherein: r is 3 、R 4 Independently selected from H, deuterium, C 1 -C 3 Deuterated alkyl or C 1 -C 6 An alkyl group; preferably, R 3 Selected from H or deuterium, R 4 Is selected from CH 3 Or CD 3 。
7. The compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-6, wherein: r 5 Selected from halogen, hydroxy, cyano, amino, C 1 -C 6 Alkyl radical, C 3 -C 6 Cycloalkyl, -O-C 1 -C 6 Alkyl, -S (O) 2 -C 1 -C 3 Alkyl, -P (O) (R) 5b ) 2 、
Figure FDA0003685226960000021
4-7 membered heterocyclic group or 5-10 membered heteroaryl group, said C 1 -C 6 Alkyl radical, C 3 -C 6 Cycloalkyl, -O-C 1 -C 6 Alkyl, -S (O) 2 -C 1 -C 3 Alkyl, 4-7 membered heterocyclyl or 5-10 membered heteroaryl optionally substituted with R 5a Substitution; preferably, R 5 Selected from halogen, amino, C 1 -C 6 Alkyl, -S (O) 2 -C 1 -C 3 Alkyl, -P (O) (R) 5b ) 2 Or
Figure FDA0003685226960000022
Said C is 1 -C 6 Alkyl or-S (O) 2 -C 1 -C 3 Alkyl is optionally substituted by R 5a And (4) substitution.
8. The compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any one of claims 1-7, wherein: n is selected from 0, 1 or 2.
9. The compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any one of claims 1-8, wherein: ring A is selected from C 6-10 And (4) an aryl group.
10. The compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-9, wherein: the compound shown in the formula (I) or pharmaceutically acceptable salt thereof is selected from the compound shown in the formula (II), the compound shown in the formula (III), the compound shown in the formula (IV), the compound shown in the formula (V) or pharmaceutically acceptable salt thereof,
Figure FDA0003685226960000031
Figure FDA0003685226960000041
wherein, ring A, L, R 1 ，R 2 ，R 3 ，R 4 ，R 5 N is as defined in any one of claims 1 to 9.
11. The compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 1, wherein: the compound shown in the formula (I) or the pharmaceutically acceptable salt thereof is selected from the following compounds or the pharmaceutically acceptable salts thereof:
Figure FDA0003685226960000042
Figure FDA0003685226960000051
12. a pharmaceutical composition comprising a compound of formula (I) as claimed in any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
13. Use of a compound of formula (I) according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 12, for the manufacture of a medicament for the prevention or treatment of a disease associated with SOS 1.
CN202210652494.6A 2021-06-10 2022-06-09 Tricyclic compound and use thereof Pending CN115466263A (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115677699A (en) * 2021-07-23 2023-02-03 武汉誉祥医药科技有限公司 Tricyclic compound, pharmaceutical composition and application thereof
WO2023138691A1 (en) * 2022-01-21 2023-07-27 Shenzhen Ionova Life Science Co., Ltd. Fused heterocyclic compounds as modulators of ras signalling

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115677699A (en) * 2021-07-23 2023-02-03 武汉誉祥医药科技有限公司 Tricyclic compound, pharmaceutical composition and application thereof
WO2023138691A1 (en) * 2022-01-21 2023-07-27 Shenzhen Ionova Life Science Co., Ltd. Fused heterocyclic compounds as modulators of ras signalling

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