CN113200981A - Heterocyclic compounds as SOS1 inhibitors - Google Patents

Heterocyclic compounds as SOS1 inhibitors Download PDF

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Publication number
CN113200981A
CN113200981A CN202110535285.9A CN202110535285A CN113200981A CN 113200981 A CN113200981 A CN 113200981A CN 202110535285 A CN202110535285 A CN 202110535285A CN 113200981 A CN113200981 A CN 113200981A
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group
compound
formula
radical
cycloalkyl
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张汉承
贾薇
蔡聪聪
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Hangzhou Innogate Pharma Co Ltd
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Hangzhou Innogate Pharma Co Ltd
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Priority to PCT/CN2022/075934 priority patent/WO2022171184A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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

Abstract

The invention provides a compound serving as an SOS1 inhibitor, and particularly provides a compound with a structure shown as a formula (I) below, or an optical isomer, a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrate and a solvate thereof. The compounds may be used to treat or prevent diseases or disorders associated with the activity or expression of SOS 1.

Description

Heterocyclic compounds as SOS1 inhibitors
Technical Field
The present invention relates to the field of pharmaceutical chemistry; in particular to a novel tricyclic heteroaryl-containing derivative, a synthetic method thereof and application of the derivative serving as an SOS1 inhibitor in preparation of medicines for treating various related diseases such as tumors.
Background
RAS (rat Sarcoma Viral Oncogene homolog) protein plays an important role in the development of carcinogenesis, RAS mutations occur in 20-30% of human tumors, and are key factors in promoting carcinogenesis, especially in cancer species such as lung cancer, colon cancer and pancreatic cancer. There are three RAS genes known today, HRAS, NRAS and KRAS, where the KRAS gene encodes two isoform proteins, KRAS-4A and KRAS4B, respectively. RAS functions as a molecular switch, and by binding gtp (guanosine triphosphate) or gdp (guanosine diphosphate), an activated (on) or inactivated (off) state is exhibited in a cell, respectively, thereby regulating a downstream signaling pathway. RAS family proteins are highly conserved in the GTP binding domain with large differences at the C-terminus. RAS protein has weak GTP enzyme hydrolysis function and slow nucleotide exchange rate, and can enhance the GTP hydrolysis function of RAS protein by combining with GTPase Activating Proteins (GAP), such as NF1, RASA1-3, and the like. SOS1(Son of seven less 1) is a class of Guanine Nucleotide Exchange Factors (GEF). SOS1 binds to RAS, promoting RAS proteins to release GDP, binding GTP. In GTP binding state, RAS protein is in an activated state, recruits downstream effector proteins, activates signal pathways such as Raf-MEK-ERK and PI3K-AKT-mTOR, and promotes growth, proliferation, survival, metabolism, angiogenesis and the like of cells.
Under normal physiological conditions, RAS activity is regulated by upstream growth factor signals, such as receptor tyrosine kinases, integrins, G-protein coupled receptors, and the like. When RAS is mutated, its intrinsic or GAP-induced gtpase activity is inhibited, RAS is always in GTP-bound state, and the molecular switch is continuously opened, thereby causing various downstream signaling pathways to be in continuously activated state, and the cell to proliferate and grow abnormally. KRAS mutations (G12, G13, Q61, a146, and the like) occur at a relatively high frequency, and are frequently found in lung cancer, colon cancer, pancreatic cancer, and the like, and HRAS mutations (G12, G13, Q61, and the like) and NRAS mutations (G12, G13, Q61, a146, and the like) occur at a relatively low frequency, and mainly occur in cancer types such as melanoma, leukemia, thyroid cancer, and the like. In addition, abnormal activation of RAS proteins (such as gene mutation, amplification and overexpression) and drug resistance of some antitumor drugs, such as EGFR monoclonal antibody and EGFR small molecule inhibitor, are closely related. Therefore, RAS-related signaling pathways are important anti-tumor targets.
There are three major classes of guanine nucleotide exchange factors of the RAS family, SOS proteins (SOS1 and SOS2), RAS guanine nucleotide releasing protein (RAS-GRP1-4), and RAS guanine nucleotide releasing factor (RAS-GRF1 and RAS-GRF 2). SOS is widely expressed in various tissues of the human body and is recruited and activated by growth factors. RAS-GPR is expressed primarily in the nervous system and is involved in calcium ion-dependent RAS activation. GRF is expressed primarily in hematopoietic cells and is involved in the non-receptor tyrosine kinase signaling pathway. Guanine nucleotide exchange factors involved in cancer-associated signaling pathways are primarily SOS proteins, and in particular SOS1, and decreasing the expression of SOS1 significantly inhibits the proliferation and survival of KRAS mutated cancer cells. In addition, the signaling pathway that SOS1 participates in activation plays an important role in other mutant types of cancer. SOS1 can interact with the adaptor protein Grb2 to form a SOS1/Grb2 complex, which binds to activated receptor tyrosine kinases (e.g., EGFR, HER2, Erbb4, TRKA, TRKB, TRKC, RET, and AXL, etc.). SOS1 may also be recruited to phosphorylated cell surface receptors, such as T cell receptors, B cell receptors, and monocyte colony stimulating factor receptors. The positioning of SOS1 on the cell membrane makes SOS1 better promote the activation of RAS family proteins and activate downstream signaling pathways. SOS1 is also involved in the activation of other GTP hydrolases, such as RAC 1. RAC1 is also implicated in the pathogenesis of a variety of human cancers and other diseases. Furthermore, the SOS1 mutation was found in cancer types such as lung cancer, embryonal rhabdomyosarcoma, and cutaneous granulocytic tumor, and the overexpression of SOS1 was found in cancer types such as bladder cancer and prostate cancer. In addition to cancer, inherited SOS1 mutations have also been associated with the pathogenesis of RAS lesions, including noonan's syndrome, heart-face-skin syndrome, and inherited gingival fibromas type i.
Based on the above background, we developed a class of structurally novel SOS1 inhibitors. The inhibitor binds to the catalytic site of SOS1, blocks the mutual binding of SOS1 and RAS protein, and inhibits the activation of RAS protein by SOS 1. The scope of application of the compounds includes various cancer types such as cancers with altered RAS family signaling pathways (gene mutation, amplification, overexpression, etc.), cancer types with abnormally activated receptor tyrosine kinases, and cancer types with abnormally activated SOS1, etc. In addition, based on the important role played by SOS1 in RAC1 activation, RAC 1-dependent cancer types would also be more sensitive to this class of compounds. Other diseases associated with SOS1, such as noonan's syndrome, the heart-face-skin syndrome mentioned above, as well as type one hereditary gingival fibroma, and the like, may also benefit from such inhibitors.
Disclosure of Invention
The invention aims to provide a novel SOS1 inhibitor, which is a compound with a structure shown as the following formula (I), or an optical isomer, a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrate and a solvate thereof:
Figure BDA0003069583300000021
in formula (I):
R1、R2and R3Each independently selected from the group consisting of: hydrogen, deuterium, halogen, C1-6Alkyl radical, C1-6Haloalkyl, C2-6Alkenyl radical, C2-6Haloalkenyl, C2-6Alkynyl, C2-6Halogenated alkynyl, C1-6Alkoxy radical, C1-4Haloalkoxy, C1-4Halogenoalkoxy radical C1-4Alkyl radical, C1-4Alkoxy radical C1-4Haloalkyl, C3-6Cycloalkyl radical C1-4Haloalkyl, or C3-6cycloalkyl-O-C1-4Haloalkyl, NRiRi(ii) a Wherein said cycloalkyl group may be optionally substituted with a substituent selected from the group consisting of: halogen, C1-4Alkyl radical, C1-4Haloalkyl, C1-4Alkoxy, or hydroxy; each R isiEach independently of the other being hydrogen, or C1-4An alkyl group;
R4selected from the group consisting of: hydrogen, C1-4Alkyl radical, C1-4Haloalkyl, C1-4Alkoxy radical, C1-4Haloalkoxy, C2-4Alkenyl radical, C2-4Haloalkenyl, C2-4Alkynyl, C3-6Cycloalkyl radical, C3-6Cycloalkyl radical C1-4Alkyl, or 4-to 8-membered heterocyclyl; said cycloalkyl or heterocyclyl is optionally substituted with one or more substituents selected from the group consisting of: halogen, C1-4Alkyl radical, C1-4Haloalkyl, C1-4Alkoxy, or "═ M", where M is selected from O or CRjRk(ii) a Wherein R isjAnd RkEach independently selected from the group consisting of: hydrogen, halogen, or C1-4An alkyl group;
z is selected from the group consisting of: o, NH, NCH3；
U is selected from the group consisting of: key, CReRf、NRg(ii) a Wherein R iseAnd RfEach independently selected from hydrogen or C1-4An alkyl group; or ReAnd RfTogether with the carbon atom to which they are attached form C ═ O; rgSelected from hydrogen, C1-4Alkyl radical, C1-4Haloalkyl, C3-6Cycloalkyl, 4-to 8-membered heterocyclyl, aryl, or heteroaryl, C (O) Rt；
A is selected from the following group: hydrogen, C1-4Alkyl radical, C1-4Haloalkyl, saturated or unsaturated C3-10Cycloalkyl, or a saturated or unsaturated 4-to 12-membered heterocyclyl; said cycloalkyl or heterocyclyl may optionally be substituted with 0-4R5Substitution; when U is a bond and A is a saturated or unsaturated 4-to 12-membered heterocyclic group containing an N atom, A may optionally be linked to the remainder of the structure of formula (I) via an N-N bond;
each R is5Each independently selected from the group consisting of: hydrogen, halogen, C1-4Alkyl radical, C1-4Haloalkyl, C2-4Alkenyl radical, C2-4Haloalkenyl, C2-4Alkynyl, C2-4Halogenated alkynyl, C3-6Cycloalkyl, 4-to 8-membered heterocyclyl, aryl, heteroaryl, CN, NO2、 ORh、SRh、NRhRh、C(O)Rt、C(O)ORh、OC(O)Rt、C(O)NRhRh、NRhC(O)Rt、S(O)2Rt、NRhS(O)2RtOr NRhS(O)2NRhRh(ii) a Said alkyl group may be optionally substituted with a substituent selected from the group consisting of: CN, NO2、ORh、SRh、 NRhRh、C(O)Rt、C(O)ORh、OC(O)Rt、C(O)NRhRh、NRhC(O)Rt、S(O)2Rt、NRhS(O)2RtOr NRhS(O)2NRhRh(ii) a Wherein each R ishEach independently of the other being hydrogen, or C1-4An alkyl group; or two RhTogether with the nitrogen atom to which they are attached form a 3-to-8-membered heterocyclic group containing 1 or 2N atoms and 0 or 1 heteroatom selected from O, S; rtIs C1-4Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C3-8Cycloalkyl, 4-to 8-membered heterocyclyl, aryl, or heteroaryl;
or two R5Together with the carbon atom to which they are attached form C ═ M, where M is selected from O or CRaRb(ii) a Wherein R isaAnd RbEach independently selected from the group consisting of: hydrogen, deuterium, halogen, or C1-4An alkyl group; wherein said alkyl group may be optionally substituted with 0 to more groups selected from: halogen, C1-4Alkyl radical, C1-4Haloalkyl, C1-4Alkoxy radical, C1-4Haloalkoxy, NRcRd、 C3-6Cycloalkyl, 3-to 8-membered heterocyclyl, aryl, or heteroaryl; or RaAnd RbTogether with the carbon atom to which they are attached form a 3-to-6-membered cycloalkyl groupOr a 4-to 8-membered heterocyclyl containing 1 or 2 heteroatoms selected from N, O, S; wherein R iscAnd RdEach independently selected from the group consisting of: hydrogen, C1-4Alkyl radical, C3-6Cycloalkyl, 4-to 8-membered heterocyclyl;
wherein each of the above alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is optionally and each independently substituted with 1 to 3 substituents each independently selected from the group consisting of: halogen, C1-4Alkyl radical, C1-4Haloalkyl, C2-4Alkenyl radical, C2-4Alkynyl, C3-8Cycloalkyl, 3-to 8-membered heterocyclyl, aryl, heteroaryl, CN, NO2、ORh、SRh、NRhRh、 C(O)Rt、C(O)ORh、C(O)NRhRh、NRhC(O)Rt、NRhS(O)2RtOr S (O)2RtProvided that the chemical structure formed is stable and meaningful; wherein R ishAnd RtIs as defined above;
the above-mentioned aryl group is an aromatic group having 6 to 12 carbon atoms unless otherwise specified; heteroaryl is a 5-to 15-membered (preferably 5-to 12-membered) heteroaromatic group; the cyclic structure is a saturated or unsaturated, heteroatom-containing or heteroatom-free cyclic group.
The compound of formula (I) is selected from the group consisting of:
Figure BDA0003069583300000041
Figure BDA0003069583300000051
Figure BDA0003069583300000061
Figure BDA0003069583300000071
Detailed Description
The inventor has conducted extensive and intensive research for a long time and unexpectedly found a new class of SOS1 inhibitors containing tricyclic aryl compounds, and a preparation method and application thereof. The compounds of the invention may be used in the treatment of various diseases associated with the activity of said kinases. Based on the above findings, the inventors have completed the present invention.
Term(s) for
Unless otherwise indicated, reference to "or" herein has the same meaning as "and/or" (meaning "or" and ").
Unless otherwise specified, each chiral carbon atom (chiral center) in all compounds of the invention may optionally be in the R configuration or the S configuration, or a mixture of the R configuration and the S configuration.
As used herein, the term "alkyl", alone or as part of another substituent, refers to a straight-chain (i.e., unbranched) or branched-chain saturated hydrocarbon group containing only carbon atoms, or a combination of straight-chain and branched-chain groups. When the alkyl group is preceded by a carbon atom number limitation (e.g. C)1-10) When used, it means that the alkyl group contains 1 to 10 carbon atoms. E.g. C1-8Alkyl refers to an alkyl group having 1 to 8 carbon atoms, and includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, or the like.
As used herein, the term "alkenyl", alone or as part of another substituent, refers to a straight or branched chain carbon chain radical having at least one carbon-carbon double bond. Alkenyl groups may be substituted or unsubstituted. When the alkenyl radical is preceded by a carbon atom number limitation (e.g. C)2-8) When used, it means that the alkenyl group has 2 to 8 carbon atoms. E.g. C2-8Alkenyl means alkenyl having 2 to 8 carbon atoms and includes ethenyl, propenyl, 1, 2-butenyl, 2, 3-butenyl, butadienyl, or the like.
As used herein, the term "alkynyl", alone or as part of another substituent, refers to a compound having at least one carbon-carbon tripleAliphatic hydrocarbon groups of the bond. The alkynyl group can be linear or branched, or a combination thereof. When alkynyl is preceded by a carbon atom number limitation (e.g. C)2-8Alkynyl) means that the alkynyl group contains 2 to 8 carbon atoms. For example, the term "C2-8Alkynyl "refers to straight or branched chain alkynyl groups having 2 to 8 carbon atoms and includes ethynyl, propynyl, isopropynyl, butynyl, isobutynyl, sec-butynyl, tert-butynyl, or the like.
As used herein, the term "cycloalkyl", alone or as part of another substituent, refers to a monocyclic, bicyclic, or polycyclic (fused, bridged, or spiro) ring system group having saturated or partially unsaturated units. When a cycloalkyl group is preceded by a carbon atom number limitation (e.g. C)3-10) When used, means that the cycloalkyl group contains 3 to 10 carbon atoms. In some preferred embodiments, the term "C3-8Cycloalkyl "refers to a saturated or partially saturated monocyclic or bicyclic alkyl group having 3 to 8 carbon atoms, including cyclopropyl, cyclobutyl, cyclopentyl, cycloheptyl, or the like. "spirocycloalkyl" refers to a bicyclic or polycyclic group having a single ring with a common carbon atom (called the spiro atom) between them, which may contain one or more double bonds, but none of the rings have a completely conjugated pi-electron system. "fused cyclic alkyl" refers to an all-carbon bicyclic or polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system. "bridged cycloalkyl" refers to an all-carbon polycyclic group in which any two rings share two carbon atoms not directly connected, and these may contain one or more double bonds, but none of the rings have a completely conjugated pi-electron system. The cycloalkyl groups contain all carbon atoms. Some examples of cycloalkyl groups are given below, and the present invention is not limited to only the cycloalkyl groups described below.
Figure BDA0003069583300000081
Unless stated to the contrary, the following terms used in the specification and claims have the following meanings. "aryl" refers to an all-carbon monocyclic or fused polycyclic (i.e., rings which share adjacent pairs of carbon atoms) groups having a conjugated pi-electron system, such as phenyl and naphthyl. The aryl ring may be fused to other cyclic groups (including saturated and unsaturated rings) but must not contain heteroatoms such as nitrogen, oxygen, or sulfur, and the point of attachment to the parent must be at a carbon atom on the ring which has a conjugated pi-electron system. The aryl group may be substituted or unsubstituted. Some examples of aryl groups are given below, and the present invention is not limited to only the aryl groups described below.
Figure BDA0003069583300000082
"heteroaryl" refers to a monocyclic or polycyclic group having aromaticity comprising one to more heteroatoms (optionally selected from nitrogen, oxygen, and sulfur), or a polycyclic group comprising a heterocyclic group (comprising one to more heteroatoms optionally selected from nitrogen, oxygen, and sulfur) fused to an aryl group with the attachment site being on the aryl group. Heteroaryl groups may be optionally substituted or unsubstituted. Some examples of heteroaryl groups are given below, to which the present invention is not limited.
Figure BDA0003069583300000083
"Heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent in which one or more ring atoms are selected from nitrogen, oxygen, or sulfur and the remaining ring atoms are carbon. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl. Polycyclic heterocyclic groups refer to heterocyclic groups including spiro rings, fused rings, and bridged rings. "Spirocyclic heterocyclyl" refers to polycyclic heterocyclic groups in which each ring in the system shares one atom (referred to as a spiro atom) with other rings in the system, where one or more ring atoms are selected from nitrogen, oxygen, or sulfur, and the remaining ring atoms are carbon. "fused ring heterocyclyl" refers to a polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, one or more of the rings may contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system, and in which one or more of the ring atoms is selected from nitrogen, oxygen or sulfur, and the remaining ring atoms are carbon. "bridged heterocyclyl" means a polycyclic heterocyclic group in which any two rings share two atoms not directly attached, which may contain one or more double bonds, but none of the rings have a completely conjugated pi-electron system, and in which one or more ring atoms are selected from nitrogen, oxygen, or sulfur, and the remaining ring atoms are carbon. If both saturated and aromatic rings are present in the heterocyclyl (e.g., the saturated and aromatic rings are fused together), the point of attachment to the parent moiety must be at the saturated ring. Note: when the point of attachment to the parent is on the aromatic ring, it is referred to as heteroaryl and not as heterocyclyl. The following are some examples of heterocyclic groups, and the present invention is not limited to only the heterocyclic groups described below.
Figure BDA0003069583300000091
As used herein, the term "halogen", alone or as part of another substituent, refers to F, Cl, Br, and I.
As used herein, the term "substituted" (with or without "optionally" modifying) means that one or more hydrogen atoms on a particular group is replaced with a particular substituent. Particular substituents are those described correspondingly in the foregoing, or as appearing in the examples. Unless otherwise specified, an optionally substituted group may have a substituent selected from a specific group at any substitutable site of the group, and the substituents may be the same or different at each position. A cyclic substituent, such as a heterocyclic group, may be attached to another ring, such as a cycloalkyl group, to form a spiro bicyclic ring system, i.e., the two rings have a common carbon atom. It will be understood by those skilled in the art that the combinations of substituents contemplated by the present invention are those that are stable or chemically achievable. Such substituents are for example (but not limited to): c1-8Alkyl radical, C2-8Alkenyl radical, C2-8Alkynyl, C3-8Cycloalkyl, 3-to 12-membered heterocyclyl, aryl,Heteroaryl, halogen, hydroxy, carboxy (-COOH), C1-8Aldehyde group, C2-10Acyl radical, C2-10Ester group and amino group.
For convenience and in accordance with conventional understanding, the terms "optionally substituted" or "optionally substituted" are only applicable to sites which can be substituted by substituents, and do not include those substitutions which are not chemically achievable.
As used herein, unless otherwise specified, the term "pharmaceutically acceptable salt" refers to a salt that is suitable for contact with the tissues of a subject (e.g., a human) without undue side effects. In some embodiments, pharmaceutically acceptable salts of a certain compound of the invention include salts of a compound of the invention having an acidic group (e.g., potassium, sodium, magnesium, calcium) or a basic group (e.g., sulfate, hydrochloride, phosphate, nitrate, carbonate).
The application is as follows:
the present invention provides the use of a class of compounds of formula (I), or deuterated derivatives thereof, salts thereof, isomers (enantiomers or diastereomers, if present), hydrates, pharmaceutically acceptable carriers, or excipients, for inhibiting SOS 1.
The compounds of the present invention are useful as SOS1 inhibitors.
The invention is a single inhibitor of SOS1, and achieves the purpose of preventing, relieving or curing diseases by regulating the enzyme activity of SOS 1. The diseases include non-small cell lung cancer, lung adenocarcinoma, squamous cell lung cancer, pancreatic cancer, colon cancer, thyroid cancer, embryonal rhabdomyosarcoma, cutaneous granular cell tumor, melanoma, liver cancer, rectal cancer, bladder cancer, throat cancer, breast cancer, prostate cancer, glioma, ovarian cancer, head and neck squamous cancer, cervical cancer, esophageal cancer, kidney cancer, skin cancer, lymphoma, gastric cancer, acute myeloid leukemia, myelofibrosis, B-cell lymphoma, monocytic leukemia, splenomegaly, hypereosinophilic syndrome, myelocarcinoma and other solid tumors and hematological tumors, and various diseases related to SOS1 genetic mutation, including but not limited to neurofibroma I, Noonas syndrome, multiple-freckle-like Noonas syndrome, capillary malformation-arteriovenous malformation syndrome, Cardio-facio-cutaneous syndrome, costello's syndrome, reji's syndrome, and hereditary gingival fibroma type i, and the like.
The compounds of the present invention and deuterated derivatives thereof, as well as pharmaceutically acceptable salts or isomers thereof (if present) or hydrates thereof and/or compositions can be formulated together with pharmaceutically acceptable excipients or carriers and the resulting compositions can be administered to mammals, such as men, women and animals, in vivo for the treatment of conditions, symptoms and diseases. The composition may be: tablets, pills, suspensions, solutions, emulsions, capsules, aerosols, sterile injections. Sterile powders, and the like. In some embodiments, pharmaceutically acceptable excipients include microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate, mannitol, hydroxypropyl- β -cyclodextrin, β -cyclodextrin (plus), glycine, disintegrants (such as starch, croscarmellose sodium, complex silicates, and polymeric polyethylene glycols), granulation binders (such as polyvinylpyrrolidone, sucrose, gelatin, and acacia), and lubricants (such as magnesium stearate, glycerol, and talc). In a preferred embodiment, the pharmaceutical composition is in a dosage form suitable for oral administration, including but not limited to tablets, solutions, suspensions, capsules, granules, powders. The amount of a compound or pharmaceutical composition of the present invention administered to a patient is not fixed and is generally administered in a pharmaceutically effective amount. Also, the amount of the compound actually administered can be determined by a physician, in the light of the actual circumstances, including the condition being treated, the chosen route of administration, the actual compound administered, the individual condition of the patient, and the like. The dosage of the compounds of the invention will depend on the particular use being treated, the mode of administration, the state of the patient, and the judgment of the physician. The proportion or concentration of the compounds of the invention in the pharmaceutical composition will depend on a variety of factors including dosage, physicochemical properties, route of administration and the like.
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments.
General synthetic method of compound
The compound of formula (I) of the invention can be prepared by the following method:
reaction formula 1:
Figure BDA0003069583300000111
hydrolyzing the compound I-a in an inert solvent under the alkaline condition to obtain I-b, condensing the compound I-b and the compound I-c by a proper method to obtain a compound I-d, and then performing ring closure under the acidic condition to obtain the target compound I.
R in the reaction formula 11、R2、R3、R4U and A are the same as in claim 1.
The compound of formula (VIII) of the present invention can be prepared by the following method:
reaction formula 2:
Figure BDA0003069583300000112
in an inert solvent, a compound VIII-a and diethyl malonate are subjected to ring closure under an alkaline condition to obtain a compound VIII-b, the compound VIII-b is subjected to substitution and acylation reactions in a mixture of phosphorus oxychloride and N, N-dimethylformamide to obtain a compound VIII-c, an aldehyde group is protected by ethylene glycol to obtain a compound VIII-d, then the compound VIII-d and dimethyl malonate are subjected to substitution reactions to obtain a compound VIII-e, one methyl carboxylate is removed by heating to obtain a compound VIII-f, the compound VIII-f and substituted amine are subjected to substitution reactions to obtain an intermediate VIII-g, the intermediate VIII-g is hydrolyzed under an alkaline condition to obtain a compound VIII-h, and then the target compound VIII is obtained through condensation reactions and ring closure reactions.
R in reaction formula 21、R2、R3、R10T, q, U and a are the same as those in claim 10.
In the above formulae, the groups are as defined above. Reagents and conditions for each step may be selected from those conventional in the art for carrying out such preparation methods, and such selection may be made by those skilled in the art after the structure of the compound of the present invention is disclosed, according to the knowledge in the art.
The conditions of the method, such as reactants, solvent, base, acid, amount of the compound used, reaction temperature, time required for the reaction, and the like are not limited to the following explanation. The compounds of the present invention may also be conveniently prepared by optionally combining various synthetic methods described in the present specification or known in the art, and such combinations may be readily carried out by those skilled in the art to which the present invention pertains.
Pharmaceutical compositions and methods of administration
Because the compound has excellent inhibitory activity on a series of protein kinases, the compound and various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates thereof, and a pharmaceutical composition containing the compound as a main active ingredient can be used for treating, preventing and relieving diseases related to SOS1 activity or expression level.
The pharmaceutical composition of the present invention comprises the compound of the present invention or a pharmacologically acceptable salt thereof in a safe and effective amount range and a pharmacologically acceptable excipient or carrier. Wherein "safe and effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000mg of a compound of the invention per dose, more preferably, 5-200mg of a compound of the invention per dose. Preferably, said "dose" is a capsule or tablet.
"pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. By "compatible" is meant herein that the components of the composition are capable of intermixing with and with the compounds of the present invention without significantly diminishing the efficacy of the compounds. Examples of pharmaceutically acceptable carrier moieties are cellulose and its derivatives (e.g. sodium carboxymethyl cellulose, sodium ethyl cellulose, cellophaneVitamin acetate, etc.), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), and water
Figure BDA0003069583300000122
Figure BDA0003069583300000121
) Wetting agents (e.g., sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like.
The mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, for example, glycerol; (d) disintegrating agents, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) absorption accelerators, e.g., quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glycerol monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.
Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shells such as enteric coatings and other materials well known in the art. They may contain opacifying agents and the release of the active compound or compounds in such compositions may be delayed in release in a certain part of the digestive tract. Examples of embedding components which can be used are polymeric substances and wax-like substances. If desired, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly employed in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, in particular, cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of such materials and the like.
In addition to these inert diluents, the compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols and suitable mixtures thereof.
Dosage forms for topical administration of the compounds of the present invention include ointments, powders, patches, sprays, and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required if necessary.
The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
When the pharmaceutical composition is used, a safe and effective amount of the compound of the present invention is suitable for mammals (such as human beings) to be treated, wherein the administration dose is a pharmaceutically-considered effective administration dose, and for a human body with a weight of 60kg, the daily administration dose is usually 1 to 2000mg, preferably 5 to 500 mg. Of course, the particular dosage will depend upon such factors as the route of administration, the health of the patient, and the like, and is within the skill of the skilled practitioner.
The main advantages of the invention include:
1. provides a compound shown as a formula I.
2. Provided are SOS1 inhibitors of novel structure that inhibit the activity of SOS1 at very low concentrations, and their preparation and use.
3. Pharmaceutical compositions for treating disorders associated with SOS1 activity are provided.
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are by weight.
EXAMPLE 1 preparation of Compound 1
Figure BDA0003069583300000131
Compound 1a was synthesized using the method in patent WO 2019122129.
Compound 1a (14mg,0.03mmol) was dissolved in a mixture of acetonitrile (1.5mL) and water (3 drops), followed by addition of sodium hydroxide (6mg,0.15 mmol). The reaction mixture was stirred at room temperature overnight. After the reaction is finished, the reaction mixed solution is directly dried by anhydrous sodium sulfate and then filtered to obtain a filtrate containing the compound 1 b. The filtrate was used directly in the next reaction.
To a mixture of Compound 1b (theoretical mass: 13mg,0.03mmol) in acetonitrile (1.5mL) was added in sequenceThe compound 1c (4mg,0.04mmol), N, N, N ', N' -tetramethyl-O- (7-azabenzotriazol-1-yl) hexafluorophosphate urea (19mg,0.05mmol) and diisopropylethylamine (13mg,0.09mmol) were added. The reaction mixture was stirred at room temperature for 30 minutes under nitrogen. After the reaction is finished, the reaction solution is decompressed and concentrated to obtain a crude product. The crude product was purified by preparative thin layer chromatography (dichloromethane: methanol ═ 20:1) to give compound 1d (12mg, yield 71%) as a colorless oil. MS M/z 494.5[ M + H ]]+。
Compound 1d (12mg,0.02mmol) was dissolved in isopropanol (2mL) and concentrated hydrochloric acid (2 drops) was added. The reaction mixture was stirred at 60 ℃ for 3 hours. After the reaction is finished, the reaction liquid is cooled to room temperature. Adding a proper amount of ammonia water into the reaction solution to adjust the pH value to about 7, and then concentrating the mixed solution under reduced pressure. The crude product was purified by preparative thin layer chromatography (dichloromethane: methanol ═ 15:1, 2% aqueous ammonia) to give compound 1 as a pale yellow solid (5mg, yield 49%).1H NMR(500MHz,CD3OD)δ9.22(s,1H),7.60(t,J＝7.0Hz,1H),7.50(t,J＝ 7.0Hz,1H),7.26(t,J＝7.7Hz,1H),7.00(t,J＝54.8Hz,1H),6.35(s,1H),5.86-5.75(m, 1H),3.92-3.68(m,2H),3.24-2.98(m,2H),2.29(s,3H),1.91-1.70(m,4H),1.65(d,J＝7.0 Hz,3H),1.61-1.38(m,2H)ppm。MS m/z 432.6[M+H]+。
EXAMPLE 2 preparation of Compound 2
Figure BDA0003069583300000141
Potassium tert-butoxide (1.10g,9.74mmol) was dissolved in DMF (10mL), cooled to-50 to-40 ℃ and a mixed solution of compound 2a (1.00g,5.41mmol) and compound 2b (940mg,4.87mmol) in DMF (10mL) was added dropwise under a nitrogen atmosphere at which temperature stirring was continued for 0.5 h. The reaction mixture was warmed to 0 ℃, and saturated ammonium chloride solution (5mL), 6M hydrochloric acid (10mL) were added, followed by stirring at room temperature for 3 hours. TLC monitored the reaction was complete. The mixture was extracted with ethyl acetate (3 × 50 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Separating and purifying the crude product by silica gel column chromatography (petroleum ether: ethyl acetate: 20:1) to obtain a white solid compound2c (384mg, yield 32%).1H NMR(500MHz,CDCl3)δ4.79(br,1H),4.23(br,1H), 3.13-2.99(m,2H),2.60-2.48(m,2H),1.44(s,9H)ppm。19F NMR(470MHz,CDCl3)δ- 95.03(s)ppm。
Compound 2c (50mg,0.23mmol) was dissolved in dichloromethane (3mL) and dioxane hydrochloride solution (4M,1mL) was added. The reaction mixture was stirred at room temperature overnight. After the reaction was completed, the reaction mixture was filtered, and the filter cake was a white solid product 2d (14mg, yield 40%) which was directly used in the next reaction.
Figure BDA0003069583300000151
From compound 1a (22mg,0.05mmol) by the method in example 1, a reaction solution containing compound 1b was obtained and used as it is for the next reaction.
From the above reaction mixture of Compound 1b, Compound 2d (16mg,0.10mmol), N, N, N ', N' -tetramethyl-O- (7-azabenzotriazol-1-yl) urea hexafluorophosphate (29mg,0.08mmol) and diisopropylethylamine (20mg,0.15mmol), compound 2e (9mg, yield 34%) was obtained as a white solid by the method in example 2. MS M/z 513.4 [ M + H ]]+。
From compound 2e (9mg,0.02mmol), compound 2(7mg, yield 88%) was obtained as a pale yellow solid by the method in example 1.1H NMR(500MHz,CDCl3)δ9.36(s,1H),9.04(s,1H),7.53(t,J＝7.0Hz, 1H),7.41(t,J＝7.0Hz,1H),7.08(t,J＝7.7Hz,1H),6.85(t,J＝55.0Hz,1H),6.40(s,1H), 5.88-5.84(m,1H),5.51-5.45(m,1H),3.23-3.06(m,2H),3.06-2.94(m,2H),2.39(s,3H), 1.60(d,J＝7.0Hz,3H)ppm。MS m/z 451.6[M+H]+。
EXAMPLE 3 preparation of Compound 3
Figure BDA0003069583300000152
White light was obtained from compound 3a (300mg,1.62mmol), compound 2b (281mg,1.49 mmol) and potassium tert-butoxide (327mg,2.92mmol) by the method in example 2Compound 3b (134mg, yield 38%) was obtained as a colored solid.1H NMR(500MHz,CDCl3)δ5.01(br,1H),4.54(d,J＝24.5Hz,1H),1.44(s,9H),0.98-0.90 (m,2H)ppm。19F NMR(470MHz,CDCl3)δ(-85.98)-(-86.11)(m,1F),-86.68(d,J＝40.0 Hz,1F)ppm。
From compound 3b (134mg,0.05mmol), compound 3c (60mg, yield 63%) was obtained as a white solid by the method in example 2.
Figure BDA0003069583300000153
From compound 1a (24mg,0.06mmol) by the method in example 1, a reaction solution containing compound 1b was obtained and used as it is for the next reaction.
Using the method in example 1, from the reaction mixture of Compound 1b, Compound 3c (19mg,0.12mmol), N, N, N ', N' -tetramethyl-O- (7-azabenzotriazol-1-yl) urea hexafluorophosphate (34mg,0.09mmol) and diisopropylethylamine (23mg,0.18mmol), Compound 3d (8mg, yield 34%) was obtained as a white solid. MS M/z 513.4 [ M + H ]]+。
From compound 3d (8mg,0.02mmol) by the method of example 1, compound 3(4mg, yield 57%) was obtained as a pale yellow solid.1H NMR(500MHz,CDCl3)δ8.76(s,1H),7.60(t,J＝7.0Hz,1H),7.49(t,J ＝7.0Hz,1H),7.19(t,J＝7.7Hz,1H),6.89(t,J＝55.0Hz,1H),6.46(s,1H),5.84(dd,J＝13.9,6.9Hz,1H),4.95(dd,J＝25.0,1.0Hz,1H),2.39(s,3H),1.71(d,J＝7.0Hz,3H), 1.48-1.32(m,4H)ppm。MS m/z 451.6[M+H]+。
Example 4 preparation of Compound 4
Figure BDA0003069583300000161
From compound 4a (1.00g,4.69mmol), compound 2b (815mg,4.22 mmol) and potassium tert-butoxide (946mg,8.44mmol), compound 4b was obtained as a white solid (878mg, yield 76%) by the method in example 2.1H NMR(500MHz,CDCl3)δ4.42(br,1H),3.53(br,1H),2.49-2.37(m,2H),2.05-1.96(m, 2H),1.94-1.84(m,2H),1.45(s,9H),1.25-1.12(m,2H)ppm。
From compound 4b (200mg,0.05mmol), compound 4c (92mg, yield 62%) was obtained as a white solid by the method in example 2.
Figure BDA0003069583300000162
From compound 1a (18mg,0.04mmol) by the method in example 1, a reaction solution containing compound 1b was obtained and used as it is for the next reaction.
Using the method in example 1, from the reaction mixture of Compound 1b, Compound 4c (15mg,0.08mmol), N, N, N ', N' -tetramethyl-O- (7-azabenzotriazol-1-yl) urea hexafluorophosphate (23mg,0.06mmol) and diisopropylethylamine (16mg,0.12mmol), Compound 4d (8mg, yield 34%) was obtained as a white solid. MS M/z 541.7 [ M + H ]]+。
From compound 4d (8mg,0.015mmol) by the method in example 1, compound 4(2mg, yield 30%) was obtained as a pale yellow solid.1H NMR(500MHz,CDCl3)δ8.99(s,1H),8.43(s,1H),7.57(t,J＝7.0 Hz,1H),7.44(t,J＝7.0Hz,1H),7.12(t,J＝7.7Hz,1H),6.87(t,J＝55.0Hz,1H), 6.45(s,1H),5.85(q,J＝7.0Hz,1H),5.19-5.08(m,1H),2.56-2.43(m,2H),2.39(s, 3H),2.04-1.91(m,4H),1.69-1.64(m,2H),1.64(d,J＝7.0Hz,3H)ppm。MS m/z 479.4[M+H]+。
EXAMPLE 5 preparation of Compound 5
Figure BDA0003069583300000171
From compound 5a (100mg,0.47mmol), compound 2b (82mg,0.42 mmol) and potassium tert-butoxide (95mg,0.85mmol), compound 5b was obtained as a white solid (62mg, yield 53%) by the method in example 2.1H NMR(500MHz,CDCl3)δ4.72(br,1H),4.43(br,1H),2.32-2.22(m,1H),2.00-1.90(m, 1H),1.86-1.77(m,1H),1.75-1.66(m,1H),1.66-1.51(m,3H),1.45(s,9H),1.41-1.31(m, 1H)ppm。
Compound 5b (62mg,0.25mmol) was dissolved in dichloromethane (3mL) and dioxane hydrochloride solution (4M,1mL) was added. The reaction mixture was stirred at room temperature overnight. After the reaction was completed, the reaction mixture was distilled under reduced pressure to give crude white solid product 5c (46mg, yield 100%) which was used directly in the next reaction.
Figure BDA0003069583300000172
From compound 1a (21mg,0.05mmol) by the method in example 1, a reaction solution containing compound 1b was obtained and used as it is for the next reaction.
Using the method in example 1, from the reaction mixture of Compound 1b, Compound 5c (18mg,0.10mmol), N, N, N ', N' -tetramethyl-O- (7-azabenzotriazol-1-yl) urea hexafluorophosphate (30mg,0.08mmol) and diisopropylethylamine (19mg,0.15mmol), Compound 5d (11mg, yield 41%) was obtained as a white solid. MS M/z 541.7 [ M + H ]]+。
From compound 5d (11mg,0.02mmol) by the method in example 1, compound 5(8mg, yield 82%) was obtained as a pale yellow solid.1H NMR(500MHz,CDCl3)δ8.88(br,1H),7.65-7.55(m,1H),7.50(t, J＝7.0Hz,1H),7.16(t,J＝7.6Hz,1H),6.88(t,J＝55.0Hz,1H),6.48(s,1H),5.90- 5.79(m,1H),5.66-5.56(m,1H),2.53-2.44(m,1H),2.39(d,J＝7.0Hz,3H),2.18- 2.03(m,2H),1.98-1.89(m,1H),1.82-1.73(m,1H),1.72-1.66(m,1H),1.67(t,J＝ 7.0Hz,3H),1.58-1.49(m,1H),1.41-1.32(m,1H)ppm。MS m/z 479.7[M+H]+。
Example 6 preparation of Compound 6
Figure BDA0003069583300000181
From compound 6a (100mg,0.50mmol), compound 2b (87mg,0.45 mmol) and potassium tert-butoxide (101mg,0.90mmol), compound 6b was obtained as a white solid (75mg, yield 64%) by the method in example 2.1H NMR(500MHz,CDCl3)δ4.49(br,1H),4.04(br,1H),2.71-2.60(m,1H),2.41-2.25 (m,2H),2.16-2.06(m,1H),2.04-1.96(m,1H),1.64-1.55(m,1H),1.45(s,9H)ppm。
Compound 6b (75mg,0.32mmol) was dissolved in dichloromethane (3mL) and dioxane hydrochloride solution (4M,1mL) was added. The reaction mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was distilled under reduced pressure to give crude product 6c as a white solid (54mg, yield 100%).
Figure BDA0003069583300000182
From compound 1a (27mg,0.06mmol) by the method in example 1, a reaction solution containing compound 1b was obtained and used as it is for the next reaction.
Using the method in example 1, from the reaction mixture of Compound 1b, Compound 6c (20mg,0.12mmol), N, N, N ', N' -tetramethyl-O- (7-azabenzotriazol-1-yl) urea hexafluorophosphate (34mg,0.09mmol) and diisopropylethylamine (23mg,0.18mmol), Compound 6d (14mg, yield 42%) was obtained as a white solid. MS M/z 527.7 [ M + H ]]+。
From compound 6d (14mg,0.03mmol) by the method in example 1, compound 6(10 mg, yield 81%) was obtained as a pale yellow solid.1H NMR(500MHz,CDCl3)δ9.03(br,1H),8.31(br,1H),7.65-7.53(m, 1H),7.51-7.42(m,1H),7.16-7.11(m,1H),6.87(dt,J＝55.0,5.7Hz,1H),6.46(s,1H), 5.91-5.83(m,1H),5.48-5.40(m,1H),2.90-2.79(m,1H),2.56-2.45(m,1H),2.41(d,J＝ 1.5Hz,3H),2.38-2.29(m,2H),2.26-2.14(m,1H),2.14-1.97(m,1H),1.66(d,J＝7.0Hz, 3H)ppm。MS m/z 465.6[M+H]+。
Example 7 preparation of Compound 7
Figure BDA0003069583300000191
Compound 7a (550mg,2.5mmol) was dissolved in toluene (2mL) and placed in a sealed tube, triphenylphosphine (655 mg,2.5mmol) was added, and the mixture was stirred at 80 ℃ for 16 hours. The reaction mixture was cooled to room temperature, filtered, and the solid was washed with a small amount of petroleum ether. The resulting filter cake was dried to give crude product 7b (900mg) which was used directly in the next reaction.
Crude 7b (486mg,1.0mmol) was placed in tetrahydrofuran (5mL), cooled to 0 deg.C, and a solution of n-BuLi (2.5M in Hexane,0.4mL) was slowly added dropwise, after all the solid had dissolved, a solution of Compound 7c (213mg,1.0mmol) in tetrahydrofuran (2mL) was added dropwise, and stirred for 16 hours. The mixture was quenched into ice and extracted with ethyl acetate (2 × 5mL), and the combined organic phases were washed with saturated sodium bicarbonate, saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product was purified by column separation (petroleum ether: ethyl acetate 85:15) to give compound 7d (120mg, yield 40%) as a colorless liquid.1H NMR(500MHz,CDCl3)δ5.16(t,J＝7.5Hz,1H),4.44(s,1H), 3.65(m,1H),2.8-2.69(m,2H),2.48(m,1H),2.28(m,1H),2.17(m,1H),2.04(m,2H), 1.94(m,1H),1.46(s,9H),1.28-1.22(m,2H)ppm。
Figure BDA0003069583300000192
Compound 7d (30mg,0.24mmol) was dissolved in dichloromethane (3mL) and a solution of hydrogen chloride in 1, 4-dioxane (4M,1mL) was added. The reaction mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was directly concentrated under reduced pressure to give 7e (22mg, yield 100%) as a white solid.1H NMR(500MHz,CD3OD) δ5.27(t,J＝7.4Hz,1H),3.30-3.25(m,1H),3.00-2.86(m,2H),2.75-2.69(m,1H),2.43- 2.37(m,1H),2.28-2.19(m,1H),2.16-2.08(m,2H),2.01-1.92(m,1H),1.48-1.33(m,2H) ppm。
To a mixture of compound 1b (13mg,0.03mmol) in acetonitrile (1.5mL) was added compound 7e (12mg,0.05mmol), N, N, N ', N' -tetramethyl-O- (7-azabenzotriazol-1-yl) urea hexafluorophosphate (19mg,0.05mmol), and diisopropylethylamine (13mg,0.10mmol) in that order. The reaction mixture was stirred at room temperature for 30 minutes under nitrogen. After the reaction is finished, the reaction solution is decompressed and concentrated to obtain a crude product. The crude product was purified by preparative thin layer chromatography (dichloromethane: methanol 15:1) to give compound 7f as a white solid (10mg, yield 49%). MS M/z 587.5[ M + H ]]+。
Compound 7f (10mg,0.02mmol) was dissolved inTo isopropanol (2mL) was added concentrated hydrochloric acid (3 drops). The reaction mixture was stirred at 60 ℃ for 2.5 hours. After the reaction is finished, the reaction liquid is cooled to room temperature. Adding a proper amount of ammonia water into the reaction solution to adjust the pH value to about 7, and then concentrating the mixed solution under reduced pressure. The crude product was purified by preparative thin layer chromatography (dichloromethane: methanol ═ 15:1) to give compound 7 as a pale yellow solid (7.5mg, yield 84%).1H NMR(500MHz,CD3OD)δ9.06(s,1H),7.59(t,J＝7.5Hz,1H),7.50(t,J＝7.0Hz, 1H),7.26(t,J＝7.5Hz,1H),7.00(t,J＝55.0Hz,1H),6.40(s,1H),5.81(q,J＝7.0Hz, 1H),5.32(t,J＝7.5Hz,1H),5.29-5.19(m,1H),3.06-2.91(m,2H),2.88-2.85(m,1H), 2.57-2.51(m,1H),2.44-2.39(m,1H),2.29(s,3H),2.17-2.08(m,3H),1.96-1.87(m,1H), 1.84-1.77(m,1H),1.66(d,J＝7.0Hz,3H)ppm。MS m/z 525.4[M+H]+。
Example 8 preparation of Compound 8
Figure BDA0003069583300000201
Compound 8a (100mg,0.54mmol) was dissolved in dichloromethane (5mL) and additional benzylamine (64mg, 0.59mmol), sodium cyanoborohydride (68mg,1.08mmol) and acetic acid (1 drop) were added. The reaction mixture was stirred at room temperature for 3 hours. TLC monitored the reaction was complete. The mixture was quenched with water and extracted with dichloromethane (3 × 20 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was isolated and purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 20:1) to give compound 8b (85mg, yield 57%).
Compound 8b (85mg,0.31mmol) was dissolved in methanol (5mL) and palladium on carbon (10%, 20mg) was added. The reaction mixture was heated to 60 ℃ under hydrogen atmosphere and stirred overnight. TLC monitored the reaction was complete. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the crude compound 8c was used directly in the next reaction.
Compound 8c (57mg,0.31mmol) was dissolved in dichloromethane (5mL), diisopropylethylamine (120mg, 0.93mmol) was added, and methanesulfonyl chloride (52mg,0.46mmol) was added dropwise under ice bath. The reaction mixture was stirred in an ice bath for 1 hour. TLC monitoring of the reactionAnd (6) finishing. The mixture was quenched with water and extracted with dichloromethane (3 × 20 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was isolated and purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 20:1) to give compound 8d (50mg, yield 62%).1H NMR(500MHz,CDCl3)δ3.22(s,2H),2.95(s,3H),1.44(s,9H),0.90-0.83(m,4H) ppm。
Compound 8d (50mg,0.19mmol) was dissolved in dichloromethane (3mL), and a solution of hydrochloric acid in methanol (4M,0.5mL) was added dropwise and the reaction mixture was stirred at room temperature overnight. TLC monitored the reaction was complete. The reaction mixture was concentrated under reduced pressure and the crude compound 8e was used directly in the next reaction.
Figure BDA0003069583300000202
Compound 1a (34mg,0.08mmol) was dissolved in a mixture of acetonitrile (3mL) and water (3 drops) and then sodium hydroxide (16mg,0.4mmol) was added. The reaction mixture was stirred at room temperature overnight. After the reaction is finished, the reaction mixed solution is directly dried by anhydrous sodium sulfate and then filtered to obtain a filtrate containing the compound 1 b. The filtrate was used directly in the next reaction.
To a mixture of compound 1b (theoretical mass: 16mg,0.04mmol) in acetonitrile (1.5mL) were added compound 8e (8mg,0.05mmol), N, N, N ', N' -tetramethyl-O- (7-azabenzotriazol-1-yl) urea hexafluorophosphate (23mg,0.06mmol), and diisopropylethylamine (15mg,0.12mmol) in that order. The reaction mixture was stirred at room temperature for 30 minutes under nitrogen. After the reaction is finished, the reaction solution is decompressed and concentrated to obtain a crude product. The crude product was purified by preparative thin layer chromatography (dichloromethane: methanol ═ 15:1) to give compound 8f (13mg, yield 63%) as a colorless oil. MS M/z 558.6[ M + H ]]+。
Compound 8f (13mg,0.02mmol) was dissolved in isopropanol (2mL) and concentrated hydrochloric acid (2 drops) was added. The reaction mixture was stirred at 60 ℃ for 3 hours. After the reaction is finished, the reaction liquid is cooled to room temperature. Adding a proper amount of ammonia water into the reaction solution to adjust the pH value to about 7, and then concentrating the mixed solution under reduced pressure. What is needed isThe crude product was purified by preparative thin layer chromatography (dichloromethane: methanol ═ 15:1, 2% ammonia) to give compound 8 as a pale yellow solid (4.71mg, yield 41%).1H NMR(500MHz,DMSO-d6)δ9.18(s,1H),7.68(t,J＝7.2Hz,1H),7.53(t,J ＝7.1Hz,1H),7.33(d,J＝7.9Hz,1H),7.27(t,J＝6.4Hz,1H),7.17(t,J＝54.3Hz,1H), 6.06(s,1H),5.86-5.79(m,1H),3.33(s,2H)2.81(s,3H),2.23(s,3H),1.61(d,J＝7.0Hz, 3H),1.30-1.22(m,4H)ppm。MS m/z 496.4[M+H]+。
Example 9 preparation of Compound 9
Figure BDA0003069583300000211
Compound 9a (CAS:871014-19-6,37mg,0.20mmol) and triethylamine (60mg, 0.60mmol) were dissolved in tetrahydrofuran (2mL) in an ice-water bath, and a solution of methanesulfonyl chloride 9b (34mg,0.30mmol) in tetrahydrofuran was slowly added dropwise. The reaction mixture was stirred at room temperature for 1 hour. After the reaction is finished, the reaction solution is quenched by water. The mixture was extracted with dichloromethane (3X15 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was isolated and purified by silica gel column chromatography (dichloromethane: ethyl acetate ═ 3:1) to give compound 9c (48mg, yield 91%) as a white solid.1H NMR(500MHz,CD3OD)δ4.05-3.96 (m,2H),2.88(s,3H),2.36-2.26(m,4H),1.43(s,9H)ppm。
Compound 9c (46mg,0.17mmol) was dissolved in dichloromethane (5mL) and a solution of hydrogen chloride in 1, 4-dioxane (4M,1mL) was added. The reaction mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was directly concentrated under reduced pressure to give the product 9d as a white solid (37mg, yield 100%).1H NMR(500MHz,CD3OD) δ4.25-4.16(m,1H),3.85-3.79(m,1H),2.91(s,3H),2.57-2.47(m,4H)ppm。
Compound 1a (29mg,0.07mmol) was dissolved in a mixture of acetonitrile (1.5mL) and water (3 drops), followed by addition of sodium hydroxide (8mg,0.20 mmol). The reaction mixture was stirred at room temperature overnight. After the reaction is finished, the reaction mixed solution is directly dried by anhydrous sodium sulfate and then filtered to obtain a filtrate containing the compound 1 b. The filtrate was used directly in the next reaction.
To a mixture of compound 1b (theoretical mass: 28mg,0.07mmol) and acetonitrile (1.5mL) were added compound 9d (20mg,0.10mmol), N, N, N ', N' -tetramethyl-O- (7-azabenzotriazol-1-yl) urea hexafluorophosphate (39mg,0.10mmol), and diisopropylethylamine (26mg,0.20mmol) in that order. The reaction mixture was stirred at room temperature for 30 minutes under nitrogen. After the reaction is finished, the reaction solution is decompressed and concentrated to obtain a crude product. The crude product was purified by preparative thin layer chromatography (dichloromethane: methanol ═ 12:1) to give compound 9e (37mg, yield 97%) as a colorless oil. MS M/z 558.6[ M + H ]]+。
Compound 9e (37mg,0.07mmol) was dissolved in isopropanol (2mL) and concentrated hydrochloric acid (3 drops) was added. The reaction mixture was stirred at 60 ℃ for 3 hours. After the reaction is finished, the reaction liquid is cooled to room temperature. Adding a proper amount of ammonia water into the reaction solution to adjust the pH value to about 7, and then concentrating the mixed solution under reduced pressure. The crude product was purified by preparative thin layer chromatography (dichloromethane: methanol ═ 10:1, 2% aqueous ammonia) to give compound 9(20mg, yield 61%) as a pale yellow solid.1H NMR(500MHz,CD3OD)δ9.14(s,1H),7.63(t,J＝7.0Hz,1H),7.50(t,J＝ 7.0Hz,1H),7.27(t,J＝7.7Hz,1H),7.01(t,J＝54.8Hz,1H),6.35(s,1H),5.88-5.82(m, 1H),5.41-5.33(m,1H),4.18-4.11(m,1H),2.96(s,3H),2.94-2.88(m,2H),2.78-2.70(m, 2H),2.31(s,3H),1.69(d,J＝7.0Hz,3H)ppm。MS m/z 496.5[M+H]+。
EXAMPLE 10 preparation of Compound 10
Figure BDA0003069583300000221
Compound 10a (100mg,0.53mmol) was dissolved in dichloromethane (3mL) and dioxane hydrochloride solution (4M,1mL) was added. The reaction mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was distilled under reduced pressure to give crude product 10b as a white solid (66mg, yield 100%).
Figure BDA0003069583300000222
From compound 1a (25mg,0.06mmol) by the method in example 1, a reaction solution containing compound 1b was obtained and used as it is for the next reaction.
Using the method in example 1, from the reaction mixture of Compound 1b, Compound 10b (15mg,0.12mmol), N, N, N ', N' -tetramethyl-O- (7-azabenzotriazol-1-yl) urea hexafluorophosphate (34mg,0.09mmol) and diisopropylethylamine (23mg,0.18mmol), Compound 10c (23mg, yield 76%) was obtained as a white solid. MS M/z 481.4[ M + H ]]+。
From compound 10c (23mg,0.05mmol), compound 10 (12mg, yield 60%) was obtained as a pale yellow solid by the method in example 1.1H NMR(500MHz,DMSO-d6)δ9.13(s,1H),8.90(s,1H),7.66 (t,J＝7.0Hz,1H),7.52(t,J＝7.0Hz,1H),7.33(d,J＝7.5Hz,1H),7.22(t,J＝46.8Hz, 1H),6.04(s,1H),5.84-5.72(m,1H),5.02(t,J＝5.0Hz,1H),3.75-3.51(m,2H),2.18(s, 3H),1.58(d,J＝7.0Hz,3H),1.18-1.05(m,4H)ppm。MS m/z 419.3[M+H]+。
Example 11 preparation of Compound 11
Figure BDA0003069583300000231
Compound 10(9mg,0.02mmol) was dissolved in dichloromethane (2mL), diisopropylethylamine (8mg,0.06mmol) was added dropwise, and trifluoroacetic anhydride (6mg,0.03mmol) was added dropwise under ice bath. The reaction was stirred for 1 hour in an ice bath. TLC monitored the reaction was complete. The reaction was quenched with methanol, the mixture was concentrated under reduced pressure, and separated and purified on preparative thin-layer plates to give compound 11 as a white solid (1mg, yield 9%).1H NMR(500MHz,DMSO-d6) δ9.17(s,1H),7.72(t,J＝7.2Hz,1H),7.54(t,J＝6.9Hz,1H),7.37-7.34(m,1H),7.23(t, J＝52.7Hz,1H),6.18(s,1H),5.80-5.72(m,1H),5.05(t,J＝5.7Hz,1H),3.67-3.52(m, 2H),1.62(d,J＝7.1Hz,3H),1.24(s,3H),1.17-1.07(m,4H)ppm。MS m/z 515.5[M+H]+。
EXAMPLE 12 preparation of Compound 12
Figure BDA0003069583300000232
Compound 1a (25mg,0.06mmol) was dissolved in a mixture of acetonitrile (1.5mL) and water (3 drops), followed by the addition of sodium hydroxide (8mg,0.20 mmol). The reaction mixture was stirred at room temperature overnight. After the reaction is finished, the reaction mixed solution is directly dried by anhydrous sodium sulfate and then filtered to obtain a filtrate containing the compound 1 b. The filtrate was used directly in the next reaction.
To an acetonitrile mixture containing compound 1b were added compound 12a (14mg,0.12mmol), N' -tetramethyl-O- (7-azabenzotriazol-1-yl) urea hexafluorophosphate (34mg,0.09mmol), and diisopropylethylamine (23mg,0.18mmol) in that order. The reaction mixture was stirred at room temperature for 30 minutes under nitrogen. After the reaction is finished, the reaction solution is decompressed and concentrated to obtain a crude product. The crude product was purified by preparative thin layer chromatography (dichloromethane: methanol ═ 12:1) to give compound 12b (9mg, yield 32%) as a colorless oil. MS M/z 479.3[ M + H ]]+。
Compound 12b (37mg,0.07mmol) was dissolved in isopropanol (2mL) and concentrated HCl (3 drops) was added. The reaction mixture was stirred at 60 ℃ for 3 hours. After the reaction is finished, the reaction liquid is cooled to room temperature. Adding a proper amount of ammonia water into the reaction solution to adjust the pH value to about 7, and then concentrating the mixed solution under reduced pressure. The crude product was purified by preparative thin layer chromatography (dichloromethane: methanol ═ 10:1, 2% aqueous ammonia) to give compound 12 as a pale yellow solid (1.41mg, yield 17%).1H NMR(500MHz,CDCl3)δ10.08(s,1H),7.77(t,J＝7.0Hz,1H),7.43 (t,J＝7.0Hz,1H),7.13(t,J＝7.7Hz,1H),6.86(t,J＝55.0Hz,1H),6.49(s,1H), 6.03(q,J＝7.0Hz,1H),5.44-5.36(m,1H),3.91-3.80(m,2H),3.56-3.45(m,2H), 2.50(s,3H),1.79(d,J＝7.0Hz,3H)ppm。MS m/z 417.6[M+H]+。
Example 13 preparation of Compound 13
Figure BDA0003069583300000241
Will combine withSubstance 13a (1.0g,2.5mmol) and 40% aqueous dimethylamine solution (281mg,2.5mmol) were stirred in a sealed tube at 60 ℃ for 4 hours. The reaction mixture was cooled to room temperature, a small amount of water (2mL) was added, and the mixture was extracted with dichloromethane isopropanol (3:1, v: v) (3X20mL), and the combined organic phases were washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting crude 13b (600mg) was used directly in the next reaction. LCMS M/z 334.2[ M + H ]]+。
Crude 13b (600mg,1.4mmol) and compound 13c (310mg,1.4mmol) were dissolved in tetrahydrofuran (10mL), cooled to 0 deg.C, and a solution of potassium tert-butoxide (191mg, 1.68mmol) in THF (5mL) was added and the compound reacted at 0 deg.C for 2 hours. The reaction was quenched with water (5mL) and extracted with ethyl acetate (2 × 15mL), and the combined organic phases were washed with saturated sodium bicarbonate, saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product was purified by column chromatography (dichloromethane: methanol ═ 85:15, 2% aqueous ammonia) to give compound 13d (50mg, yield 13%) as a pale yellow liquid.1H NMR(500MHz,DMSO-d6)δ6.69(d,J＝7.0Hz,1H),5.13(t,J＝7.0Hz,1H),3.45- 3.33(m,1H),2.80(d,J＝7.0Hz,2H),2.19-1.99(m,9H),1.79-1.75(m,3H),1.37(s,9H), 1.24-1.20(m,2H)ppm。
Figure BDA0003069583300000242
Compound 13d (10mg,0.04mmol) was dissolved in dichloromethane (3mL) and a solution of hydrogen chloride in 1, 4-dioxane (4M,0.5mL) was added. The reaction mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was directly concentrated under reduced pressure to give 13e (11mg, yield 100%) as a yellow solid.
To a mixture of compound 1b (12mg,0.03mmol) in acetonitrile (1.5mL) was added compound 13e (11mg,0.04mmol), N, N, N ', N' -tetramethyl-O- (7-azabenzotriazol-1-yl) urea hexafluorophosphate (16mg,0.04mmol), and diisopropylethylamine (11mg,0.08mmol) in that order. The reaction mixture was stirred at room temperature for 30 minutes under nitrogen. After the reaction is finished, the reaction solution is decompressed and concentrated to obtain a crude product. The crude product is purified by preparative thin-layer chromatography (dichloromethane: A)Alcohol 15:1, 2% ammonia) to give compound 13f as a white solid (15mg, 96% yield). MS M/z 562.5[ M + H ]]+。
Compound 13f (15mg,0.03mmol) was dissolved in isopropanol (2mL) and concentrated hydrochloric acid (3 drops) was added. The reaction mixture was stirred at 60 ℃ for 2.5 hours. After the reaction is finished, the reaction liquid is cooled to room temperature. Adding a proper amount of ammonia water into the reaction solution to adjust the pH value to about 7, and then concentrating the mixed solution under reduced pressure. The crude product was purified by preparative thin layer chromatography (dichloromethane: methanol ═ 10:1, 2% aqueous ammonia) to give compound 13 as a pale yellow solid (7.23mg, yield 54%).1H NMR(500MHz,CD3OD)δ9.47(d,J＝4.5Hz,1H),7.76(t,J＝7.0Hz,1H), 7.54(t,J＝7.0Hz,1H),7.34-7.28(m,1H),7.00(t,J＝54.8Hz,1H),6.30(s,1H),6.04- 5.97(m,1H),5.72(s,1H),5.24-5.15(m,1H),2.93(s,6H),2.55-2.48(m,4H),2.46(d,J＝ 2.0Hz,3H),2.44-2.30(m,3H),2.09-2.02(m,1H),1.75(d,J＝7.0Hz,3H),1.37-1.30(m, 2H)ppm。MS m/z 500.5[M+H]+。
EXAMPLE 14 preparation of Compound 14
Figure BDA0003069583300000251
Triethyl phosphonoacetate (1.68g,7.5mmol) was dissolved in tetrahydrofuran (20mL) under nitrogen, cooled to 0 deg.C, and a solution of potassium tert-butoxide (1.12g, 10mmol) in tetrahydrofuran (20mL) was added and the reaction was carried out until a large amount of solid precipitated. A solution of compound 14a (1.05g,5mmol) in tetrahydrofuran (5ml) was added and reacted at 0 ℃ for 3 hours. The reaction was quenched with water (5mL) and extracted with ethyl acetate (2 × 30mL), and the combined organic phases were washed with saturated sodium bicarbonate, saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product was purified by column chromatography (dichloromethane: methanol ═ 85:15, 2% aqueous ammonia) to give compound 14b (900mg, yield 75%) as a colorless liquid. The resulting compound was used directly in the next reaction.
Compound 14b (400mg,1.4mmol) is dissolved in tetrahydrofuran (5mL) under nitrogen, cooled to 0 deg.C, lithium aluminum hydride (119mg, 3.22mmol) is added and the reaction mixture is slowly warmed to room temperatureAnd reacted for 3 hours. Quenched by the addition of 30% aqueous NaOH (0.5g) and stirred until a large amount of solid precipitated. Anhydrous magnesium sulfate is added for drying and concentration to obtain a crude product, and the crude product is directly used for the next reaction. The resulting crude product was purified by column separation (petroleum ether: ethyl acetate 85:15) to give compound 14c (300mg, yield 85%) as a colorless liquid.1H NMR(500MHz,DMSO- d6)δ6.77(d,J＝8.0Hz,1H),5.21(t,J＝6.5Hz,1H),4.46(t,J＝5.0Hz,1H),3.92-3.88 (m,2H),3.45-3.38(m,1H),2.19-2.11(m,1H),2.04-1.97(m,2H),1.77-1.72(m,3H),1.37 (s,9H),1.23-1.21(m,2H)ppm。
Compound 14c (100mg,0.4mmol), anhydrous acetonitrile (2mL), silver oxide (462mg,2mmol) and iodomethane (564mg,4mmol) were added to a sealed tube and heated to 40 ℃ for reaction for 16 hours. The solid was removed by filtration, and the resulting crude product was concentrated under reduced pressure and purified by column chromatography to give compound 14d (50mg, yield 45%).1H NMR(500MHz,CDCl3)δ5.26(t,J＝6.7Hz,1H),4.42-4.39(m,1H),3.85- 3.82(m,2H),3.59-3.51(m,1H),3.24(s,3H),2.49-2.47(m,1H),2.19-2.16(m,1H),2.10- 2.08(m,1H),1.96-1.85(m,3H),1.37(s,9H),1.19-1.10(m,2H)ppm。
Figure BDA0003069583300000261
Compound 14d (17mg,0.07mmol) was dissolved in dichloromethane (3mL) and a solution of hydrogen chloride in 1, 4-dioxane (4M,1mL) was added. The reaction mixture was stirred at room temperature overnight. After the reaction is finished, the reaction solution is directly decompressed and concentrated to obtain a white solid product 14 e.
To a mixture of compound 1b (15mg,0.03mmol) in acetonitrile (1.5mL) was added compound 14e (10mg,0.05mmol), N, N, N ', N' -tetramethyl-O- (7-azabenzotriazol-1-yl) urea hexafluorophosphate (19mg,0.05mmol), and diisopropylethylamine (13mg,0.10mmol) in that order. The reaction mixture was stirred at room temperature for 30 minutes under nitrogen. After the reaction is finished, the reaction solution is decompressed and concentrated to obtain a crude product. The crude product was purified by preparative thin layer chromatography (dichloromethane: methanol ═ 20:1) to give compound 14f as a white solid (11mg, yield 58%). MS M/z 549.7[ M + H ]]+。
Compound 14f (11mg,0.02mmol) was dissolved in isopropanol (2mL) and concentrated hydrochloric acid (3 drops) was added. The reaction mixture was stirred at 60 ℃ for 2 hours. After the reaction is finished, the reaction liquid is cooled to room temperature. Adding a proper amount of ammonia water into the reaction solution to adjust the pH value to about 7, and then concentrating the mixed solution under reduced pressure. The crude product was purified by preparative thin layer chromatography (dichloromethane: methanol ═ 20:1) to give compound 14 as a pale yellow solid (4.0mg, yield 41%).1H NMR(500MHz,CD3OD)δ9.08(s,1H),7.60(t,J＝7.0Hz,1H),7.50(t,J＝7.0 Hz,1H),7.26(t,J＝7.7Hz,1H),7.00(t,J＝54.9Hz,1H),6.39(s,1H),5.85-5.78 (m,1H),5.46(t,J＝6.9Hz,1H),5.28-5.19(m,1H),4.06-3.94(m,2H),3.35(s,3H), 2.91(d,J＝13.9Hz,1H),2.51-2.46(m,1H),2.44-2.36(m,1H),2.30(s,3H),2.14- 1.98(m,3H),1.94-1.86(m,1H),1.86-1.79(m,1H),1.66(d,J＝7.0Hz,3H)ppm。 MS m/z 487.5[M+H]+。
Example 15 preparation of Compound 15
Figure BDA0003069583300000262
Compound 1a (20mg,0.05mmol) was dissolved in a mixture of acetonitrile (1.5mL) and water (2 drops), followed by addition of sodium hydroxide (10mg,0.25 mmol). The reaction mixture was stirred at room temperature overnight. After the reaction is finished, the reaction mixed solution is directly dried by anhydrous sodium sulfate and then filtered to obtain a filtrate containing the compound 1 b. The filtrate was used directly in the next reaction.
To a mixture of compound 1b (theoretical mass: 19mg,0.04mmol) and acetonitrile (1.5mL) were added compound 15a (8mg,0.06mmol), N, N, N ', N' -tetramethyl-O- (7-azabenzotriazol-1-yl) urea hexafluorophosphate (23mg,0.06mmol), and diisopropylethylamine (15mg,0.12mmol) in that order. The reaction mixture was stirred at room temperature for 30 minutes under nitrogen. After the reaction is finished, the reaction solution is decompressed and concentrated to obtain a crude product. The crude product was purified by preparative thin layer chromatography (dichloromethane: methanol ═ 15:1) to give compound 15b (14mg, yield 63%) as a colorless oil. MS M/z 509.6[ M + H ]]+。
Compound 15b (14mg, 0)03mmol) was dissolved in isopropanol (2mL) and concentrated hydrochloric acid (2 drops) was added. The reaction mixture was stirred at 60 ℃ for 3 hours. After the reaction is finished, the reaction liquid is cooled to room temperature. Adding a proper amount of ammonia water into the reaction solution to adjust the pH value to about 7, and then concentrating the mixed solution under reduced pressure. The crude product was purified by preparative thin layer chromatography (dichloromethane: methanol 10:1, 2% ammonia) to give compound 15(8.60mg, yield 70%) as a pale yellow solid.1H NMR(500MHz,CD3OD)δ9.20(s,1H),7.60(t,J＝7.0Hz,1H),7.50(t,J＝ 7.0Hz,1H),7.26(t,J＝7.7Hz,1H),7.00(t,J＝54.8Hz,1H),6.34(s,1H),5.84-5.77(m, 1H),4.24-3.93(m,2H),3.24-2.99(m,2H),2.96-2.71(m,2H),2.68-2.46(m,2H),2.36(s, 3H),2.29(s,3H),1.65(d,J＝7.0Hz,3H)ppm。MS m/z 447.4[M+H]+。
EXAMPLE 16 preparation of Compound 16
Figure BDA0003069583300000271
Compound 1a (40mg,0.09mmol) was dissolved in a mixture of acetonitrile (1.5mL) and water (2 drops), followed by addition of sodium hydroxide (19mg,0.47 mmol). The reaction mixture was stirred at room temperature overnight. After the reaction is finished, the reaction mixed solution is directly dried by anhydrous sodium sulfate and then filtered to obtain a filtrate containing the compound 1 b. The filtrate was used directly in the next reaction.
To a mixture of compound 1b (theoretical mass: 19mg,0.04mmol) and acetonitrile (1.5mL) were added compound 16a (7mg,0.06mmol), N, N, N ', N' -tetramethyl-O- (7-azabenzotriazol-1-yl) urea hexafluorophosphate (23mg,0.06mmol), and diisopropylethylamine (15mg,0.12mmol) in that order. The reaction mixture was stirred at room temperature for 30 minutes under nitrogen. After the reaction is finished, the reaction solution is decompressed and concentrated to obtain a crude product. The crude product was purified by preparative thin layer chromatography (dichloromethane: methanol ═ 15:1) to give compound 16b (8mg, yield 37%) as a colorless oil. MS M/z 496.5[ M + H ]]+。
Compound 16b (8mg,0.02mmol) was dissolved in isopropanol (2mL) and concentrated hydrochloric acid (2 drops) was added. The reaction mixture was stirred at 60 ℃ for 3 hours. After the reaction is finished, the reaction solution is added,the reaction solution was cooled to room temperature. Adding a proper amount of ammonia water into the reaction solution to adjust the pH value to about 7, and then concentrating the mixed solution under reduced pressure. The crude product was purified by preparative thin layer chromatography (dichloromethane: methanol ═ 10:1, 2% aqueous ammonia) to give compound 16 as a pale yellow solid (4.56mg, yield 65%).1H NMR(500MHz,CD3OD)δ9.24(s,1H),7.61(t,J＝7.0Hz,1H),7.50(t,J＝ 7.0Hz,1H),7.26(t,J＝7.7Hz,1H),7.00(t,J＝54.8Hz,1H),6.35(s,1H),5.87-5.76(m, 1H),4.14-3.47(m,8H),2.30(s,3H),1.65(d,J＝7.0Hz,3H).ppm。MS m/z 434.5[M+H]+。
Example 17 preparation of Compound 17
Figure BDA0003069583300000281
Compound 17a (200mg, 1.27mmol) was dissolved in water (3mL), and sodium hydroxide solution (2M, 0.70mL) was added and stirred at room temperature for one hour, and sodium nitrite (175mg, 2.54mmol) and acetic acid solution (0.1mL) were added to the reaction mixture in portions under ice-bath and stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was extracted with saturated sodium bicarbonate solution, extracted with dichloromethane, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to dryness under reduced pressure, and then separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate 4:1) to obtain compound 17b (190mg, yield 94%) as a pale yellow solid. MS M/z 151.4[ M + H ]]+。
Compound 17b (50mg, 0.33mmol) was dissolved in tetrahydrofuran (1mL), lithium aluminum hydride (22mg, 0.58mmol) was slowly added under ice bath and heated under reflux for one hour, cooled to room temperature, water (1 drop) was added dropwise under ice bath, heated under reflux for half an hour, after completion of the reaction, quenched with saturated sodium bicarbonate solution, dichloromethane extracted, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to dryness under reduced pressure, and separated and purified by silica gel column chromatography (dichloromethane: methanol ═ 10:1) to obtain compound 17c (10mg, yield 22%).1H NMR(500 MHz,CDCl3)δ2.85-2.66(m,4H),2.64-2.28(br,2H),2.14-2.00(m,4H)ppm。
Figure BDA0003069583300000282
To a mixture of compound 1b (theoretical mass: 18mg,0.04mmol) in acetonitrile (2mL) was added compound 17c (9mg,0.06mmol), N, N, N ', N' -tetramethyl-O- (7-azabenzotriazol-1-yl) urea hexafluorophosphate (23mg,0.06mmol), and diisopropylethylamine (15mg,0.12mmol) in that order. The reaction mixture was stirred at room temperature for 30 minutes under nitrogen. After the reaction is finished, the reaction solution is decompressed and concentrated to obtain a crude product. The crude product was purified by preparative thin layer chromatography (dichloromethane: methanol 25:1) to give compound 17d as a colorless oil (3mg, yield 14%). MS M/z 530.5[ M + H ]]+。
Compound 17d (3mg,0.01mmol) was dissolved in isopropanol (2mL) and concentrated hydrochloric acid (2 drops) was added. The reaction mixture was stirred at 60 ℃ for 3 hours. After the reaction is finished, the reaction liquid is cooled to room temperature. Adding a proper amount of ammonia water into the reaction solution to adjust the pH value to about 7, and then concentrating the mixed solution under reduced pressure. The crude product was purified by preparative thin layer chromatography (dichloromethane: methanol ═ 15:1, 2% aqueous ammonia) to give compound 17(1.40mg, yield 55%) as a pale yellow solid.1H NMR(500MHz,CD3OD)δ9.25(s,1H),7.61(t,J＝7.0Hz,1H),7.50(t,J＝ 7.0Hz,1H),7.26(t,J＝7.7Hz,1H),7.00(t,J＝54.8Hz,1H),6.35(s,1H),5.85-5.77(m, 1H),4.13-3.83(m,2H),3.28-3.10(m,2H),2.29(s,3H),2.28-2.05(m,4H),1.65(d,J＝7.1 Hz,3H)ppm。MS m/z 468.6[M+H]+。
EXAMPLE 18 preparation of Compound 18
Figure BDA0003069583300000291
Compound 18a (3g, 23.16mmol) was dissolved in water (10mL), and sodium nitrite (3.2g, 46.32mmol) and acetic acid (2.27mL) were added to the reaction mixture in portions under ice-bath and stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was filtered to obtain compound 18b (2.8g, yield 100%) as a solid.
Compound 18b (200mg, 1.64mmol) was dissolved in a mixed solution of methanol (1mL) and acetic acid (0.3mL), zinc powder (1.07g, 16.38mmol) was slowly added under ice-cooling to react at room temperature for 5 hours, and after completion of the reaction, the reaction solution was separated and purified by preparative thin layer chromatography silica gel plate (dichloromethane: methanol ═ 8:1), 4M hydrogen chloride methanol solution (0.5mL) was added to the product-containing fraction, and stirred at room temperature for 5 minutes, and concentrated under reduced pressure to give compound 18c (70 mg, yield 40%) as a white solid.
Figure BDA0003069583300000292
To a mixture of compound 1b (theoretical mass: 15mg,0.03mmol) in acetonitrile (2mL) were added compound 18c (6mg,0.04mmol), N, N, N ', N' -tetramethyl-O- (7-azabenzotriazol-1-yl) urea hexafluorophosphate (23mg,0.06mmol), and diisopropylethylamine (12mg,0.09mmol) in that order. The reaction mixture was stirred at room temperature for 30 minutes under nitrogen. After the reaction is finished, the reaction solution is decompressed and concentrated to obtain a crude product. The crude product was purified by preparative thin layer chromatography (dichloromethane: methanol 25:1) to give compound 18d (12mg, yield 69%) as a colorless oil. MS M/z 502.6[ M + H ]]+。
Compound 18d (12mg,0.02mmol) was dissolved in isopropanol (2mL) and concentrated hydrochloric acid (2 drops) was added. The reaction mixture was stirred at 60 ℃ for 3 hours. After the reaction is finished, the reaction liquid is cooled to room temperature. Adding a proper amount of ammonia water into the reaction solution to adjust the pH value to about 7, and then concentrating the mixed solution under reduced pressure. The crude product was isolated and purified by preparative thin layer chromatography (dichloromethane: methanol ═ 15:1, 2% aqueous ammonia) to give compound 18 as a pale yellow solid (4.40mg, yield 42%).1H NMR(500MHz,CD3OD)δ9.15(s,1H),7.59(t,J＝7.3Hz,1H),7.49(t,J＝ 7.0Hz,1H),7.25(t,J＝7.7Hz,1H),7.00(t,J＝54.8Hz,1H),6.36(s,1H),5.84-5.75(m, 1H),4.79(t,J＝12.1Hz,4H),2.30(s,3H),1.64(d,J＝7.1Hz,3H)ppm。MS m/z 440.5 [M+H]+。
EXAMPLE 19 preparation of Compound 19
Figure BDA0003069583300000301
Compound 19a (10mmol,2.16g) was dissolved in thionyl chloride (10mL), a catalytic amount of DMF was added, and the mixture was heated under reflux for 4 hours. After the reaction was completed, the thionyl chloride solvent was removed by concentration under reduced pressure, and the residue was dissolved in acetonitrile (10mL), and a 2M hexane solution (10mL) of trimethylsilyldiazomethane was added and allowed to react at room temperature for 16 hours. After the reaction was completed, the reaction was quenched with saturated aqueous sodium bicarbonate, the aqueous phase was extracted with ethyl acetate, the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate, and the crude product was purified by silica gel column chromatography to give compound 19b (1.5g, yield 63%).1H NMR(500MHz,DMSO-d6)δ7.94- 7.91(m,1H),7.75(t,J＝6.8Hz,1H),7.30(t,J＝7.9Hz,1H),6.66(s,1H)ppm。
Compound 19b (720mg,3mmol) was dissolved in toluene (5mL), indium trifluoromethanesulfonate (300mg) was added, and the reaction mixture was stirred at room temperature for 4 hours. The reaction was quenched with saturated aqueous ammonium chloride, the organic phase was washed with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography to give pure 19c (420 mg, yield 60%).1H NMR(500MHz,CDCl3)δ7.91-7.88(m,1H),7.78-7.75(m,1H), 7.17(t,J＝7.9Hz,1H),4.64(d,J＝3.6Hz,2H),3.52(s,3H)ppm。
Compound 19c (200mg,0.74mmol) was dissolved in diethylaminosulfur trifluoride (2mL), and after addition of a catalytic amount of methanol, the reaction was stirred at 50 ℃ for 16 hours. Slowly dropping the reaction solution into ice cubes, extracting with ethyl acetate, washing an organic layer with a saturated sodium bicarbonate solution, washing with a saturated saline solution, drying with anhydrous sodium sulfate, and concentrating to obtain a crude product. The crude product was purified by silica gel chromatography (ethyl acetate: petroleum ether ═ 10:90) to give product 19d (140mg, yield 65%).1H NMR(500MHz,CDCl3)δ7.67-7.64(m,1H),7.56-7.48(m,1H),7.11(t,J＝7.9Hz, 1H),3.95(td,J＝13.3,1.2Hz,2H)ppm。
Pd (PPh)3)2Cl2(105mg,0.16mmol) and compound 19d (140mg,0.52mmol) were dissolved in 1, 4-dioxane (3mL), triethylamine (150mg,1.5mmol) and 19e (273mg, 0.77mmol) were added under nitrogen, and the reaction was stirred at 100 ℃ for 16 h. After the reaction solution is cooled, 4M chlorine is dropwise addedStirring aqueous hydrogen (2mL), monitoring by TLC until the intermediate is completely converted into the target product, dropwise adding an equal ratio mixed solution of saturated potassium fluoride aqueous solution and saturated sodium carbonate aqueous solution until a large amount of solid is separated out, filtering the solid with diatomite, adding ethyl acetate for extraction, neutralizing an organic layer with saturated sodium bicarbonate solution, washing with saturated saline solution, drying with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate 85:15) to give the product (100mg, yield 82%).1H NMR(500MHz,CDCl3)δ7.96(m,1H),7.75(m,1H),7.31(t,J＝ 7.8Hz,1H),3.98(t,J＝13.2Hz,2H),3.44(s,3H),2.67(d,J＝5.2Hz,3H)ppm。
Compound 19f (100mg,0.43mmol) and (R) - (+) -tert-butylsulfinamide (78mg,0.65mmol) were dissolved in tetrahydrofuran (2mL), tetraethyltitanate (269mg,1.30mmol) was added, and the mixture was heated to 70 ℃ for 16 hours. After the reaction solution was cooled, saturated sodium chloride solution was added dropwise until a large amount of solid precipitated, ethyl acetate (30mL) was added to dilute the mixture, the solid was filtered off with celite, the organic layer was washed with saturated sodium bicarbonate solution, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate 50:50) to give 19g (100mg, yield 70%) of the product. MS M/z 336.2[ M + H ]]+。
Compound 19g (100mg,0.30mmol) was dissolved in tetrahydrofuran (1mL), cooled to-70 deg.C and lithium tri-sec-butylborohydride (1M in hexane, 0.6mL) was added and stirring continued at this temperature for 2 h. Adding saturated ammonium chloride aqueous solution to quench reaction, extracting the aqueous phase with ethyl acetate, washing the combined organic phases with saturated saline solution, drying with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain a crude product. The crude product was purified on preparative thin layer plates (dichloromethane: methanol ═ 90:10) to give the product 19h (80mg, 80% yield). MS M/z 338.2[ M + H ]]+。
Compound 19h (150mg,0.3mmol) was dissolved in 4M hydrogen chloride in methanol (2mL) and reacted at room temperature for 1 hour. Adding 1M sodium hydroxide solution to adjust the pH value to 7, diluting with ethyl acetate, separating a water layer, drying an organic layer through anhydrous sodium sulfate, and concentrating under reduced pressure to obtain a crude product. The crude product was chromatographed on silica gel column (dichloromethane: methanol 85:15,v: v) purification gave 19i (65mg, 63% yield).1H NMR(500MHz,CDCl3)δ7.57(t,J＝ 6.9Hz,1H),7.48–7.42(m,1H),7.20(t,J＝7.7Hz,1H),4.46(q,J＝6.7Hz,1H),3.96(td, J＝13.5,0.9Hz,2H),3.44(s,3H),1.42(d,J＝6.7Hz,3H)ppm。
Compound 19i (30mg,0.13mmol) and compound 19j (35mg,0.13mmol) were dissolved in dimethyl sulfoxide (0.2mL), and N, N-diisopropylethylamine (50mg,0.39mmol) was added. The reaction mixture was stirred at 100 ℃ for 3 hours. After cooling to room temperature, the reaction mixture was extracted with ethyl acetate (15 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was isolated and purified by silica gel column chromatography (dichloromethane: methanol ═ 20:1) to give 19k (31mg, yield 51%) as a yellow oil. MS M/z 470.4[ M + H ]]+。
Compound 19k (15mg,0.03mmol) was dissolved in a mixture of acetonitrile (2mL) and water (3 drops) and sodium hydroxide (4mg,0.09mmol) was added. The reaction mixture was stirred at room temperature overnight. After the reaction is finished, the reaction mixed solution is directly dried by anhydrous sodium sulfate and then filtered to obtain mixed solution containing 19l of the product. The resulting mixture was used directly in the next reaction. MS M/z 456.6[ M + H ]]+。
To a mixture of 19l (theoretical yield: 15mg,0.03mmol) of the compound in acetonitrile (1.5mL) were added in the order of compound 19m (8mg,0.05mmol), N, N, N ', N' -tetramethyl-O- (7-azabenzotriazol-1-yl) urea hexafluorophosphate (19mg,0.05mmol) and N, N-diisopropylethylamine (12mg,0.09 mmol). The reaction mixture was stirred at room temperature for 1 hour under nitrogen. After the reaction is finished, the reaction solution is decompressed and concentrated to obtain a crude product. The crude product was purified by preparative thin layer chromatography (dichloromethane: methanol ═ 20:1) to give compound 19n (7mg, purity 50%, two-step yield 20%) as a yellow solid. MS M/z 545.4[ M + H ]]+。
Compound 19n (7mg, 50% pure, 0.006mmol) was dissolved in isopropanol (2.5mL) and concentrated hydrochloric acid (3 drops) was added. The reaction mixture was stirred at 60 ℃ for 1 hour. After the reaction is finished, the reaction liquid is cooled to room temperature. Adding a proper amount of ammonia water into the reaction solution to adjust the pH value to about 7, and then concentrating the mixed solution under reduced pressure. The crude product obtainedPurification by preparative thin layer chromatography (dichloromethane: methanol ═ 20:1) gave compound 19(1.57mg, yield 51%) as a yellow solid.1H NMR(500MHz,CD3OD)δ9.22(s,1H),7.59(t,J＝7.2Hz,1H),7.49- 7.45(m,1H),7.24(t,J＝7.8Hz,1H),6.34(s,1H),6.25(t,J＝57.5Hz,1H),5.87-5.81(m, 1H),3.96(t,J＝13.5Hz,2H),3.37(s,3H),2.31(s,3H),1.66(d,J＝7.1Hz,3H),1.61- 1.57(m,2H),1.47-1.41(m,2H)ppm。MS m/z 483.4[M+H]+。
EXAMPLE 20 preparation of Compound 20
Figure BDA0003069583300000321
Compound 20i was synthesized according to the method of example 19.1H NMR(500MHz,CDCl3)δ7.56(t,J＝7.1 Hz,1H),7.50-7.40(m,1H),7.20(t,J＝7.7Hz,1H),4.47(q,J＝6.7Hz,1H),4.05(t,J＝ 13.7Hz,2H),3.45-3.42(m,1H),2.60(s,2H),1.45(d,J＝6.7Hz,3H),0.57-0.55(m,2H), 0.48-0.45(m,2H)ppm。
Compound 20i (31mg,0.12mmol) and compound 20j (33mg,0.12mmol) were dissolved in dimethyl sulfoxide (0.2mL), and N, N-diisopropylethylamine (47mg,0.36mmol) was added. The reaction mixture was stirred at 100 ℃ for 3 hours. After cooling to room temperature, the reaction mixture was extracted with ethyl acetate (3 × 15 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was isolated and purified by silica gel column chromatography (dichloromethane: methanol ═ 20:1) to give 20k (13mg, yield 22%) as a yellow oil. MS M/z 496.5[ M + H ]]+。
Compound 20k (13mg,0.03mmol) was dissolved in a mixture of acetonitrile (2mL) and water (3 drops), and sodium hydroxide (3mg,0.08mmol) was added. The reaction mixture was stirred at room temperature overnight. After the reaction is finished, the reaction mixed solution is directly dried by anhydrous sodium sulfate and then filtered to obtain the mixed solution containing 20l of the product. The resulting mixture was used directly in the next reaction. MS M/z 482.6[ M + H ]]+。
To a mixture of compound 20l (theoretical yield: 13mg,0.03mmol) in acetonitrile (1.5mL) was added compound 20m (8)mg,0.05mmol), N, N, N ', N' -tetramethyl-O- (7-azabenzotriazol-1-yl) hexafluorophosphate urea (19mg,0.05mmol) and N, N-diisopropylethylamine (12mg,0.09 mmol). The reaction mixture was stirred at room temperature for 30 minutes under nitrogen. After the reaction is finished, the reaction solution is decompressed and concentrated to obtain a crude product. The crude product was purified by preparative thin layer chromatography (dichloromethane: methanol ═ 20:1) to give compound 20n (6mg, purity 60%, yield 24%) as a yellow solid. MS M/z 571.4[ M + H ]]+。
Compound 20n (6mg, 60% pure, 0.006mmol) was dissolved in isopropanol (2mL) and concentrated hydrochloric acid (3 drops) was added. The reaction mixture was stirred at 60 ℃ for 1 hour. After the reaction is finished, the reaction liquid is cooled to room temperature. Adding a proper amount of ammonia water into the reaction solution to adjust the pH value to about 7, and then concentrating the mixed solution under reduced pressure. The crude product was purified by preparative thin layer chromatography (dichloromethane: methanol ═ 20:1) to give compound 20 (1.53mg, yield 48%) as a yellow solid.1H NMR(500MHz,CD3OD)δ9.23(s,1H),7.59(t,J＝ 6.8Hz,1H),7.48-7.43(m,1H),7.24(t,J＝7.8Hz,1H),6.34(s,1H),6.25(t,J＝ 57.5Hz,1H),5.86-5.80(m,1H),4.06(t,J＝13.6Hz,2H),3.41-3.37(m,1H),2.31 (s,3H),1.67(d,J＝7.1Hz,3H),1.62-1.57(m,2H),1.47-1.41(m,2H),0.43-0.39 (m,4H)ppm。MS m/z 509.5[M+H]+。
Example 21: synthesis of Compound 21
Figure BDA0003069583300000331
Phosphorus oxychloride (880 mg, 5.74mmol) was added dropwise to N, N-dimethylformamide (192mg, 2.63mmol) at 0 ℃ and stirring was continued at this temperature for 1 h. Compound 21a (200mg, 1.31 mmol; synthesized using the method described in patent WO 2011/58478) was then added portionwise at 0 ℃. The reaction solution was allowed to warm to room temperature and stirred overnight. The reaction was warmed to reflux and stirred for 16 hours. The reaction solution was cooled to room temperature, poured into ice water, and extracted with dichloromethane (40 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound 21b (168mg, yield 59%) as a brown solid.1H NMR(500MHz,CDCl3)δ10.40(s,1H),2.32-2.27(m, 1H),1.34-1.27(m,4H)ppm。
A mixture of compound 21b (93mg, 0.43mmol), p-toluenesulfonic acid (7.9mg, 0.04mmol), ethylene glycol (34mg, 0.55mmol) and benzene (2mL) was heated under reflux for 3 hours. After the reaction solution was concentrated, the residue was diluted with ethyl acetate (20mL), washed with water (5mL) and saturated sodium chloride solution (5mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography to give compound 21c as a white solid (80mg, yield 71%).1H NMR(500MHz,CDCl3)δ6.35(s,1H),4.43-4.32(m,2H),4.11-4.10 (m,2H),2.25-2.21(m,1H),1.28-1.14(m,4H)ppm。
A mixture of compound 21c (100mg, 0.38mmol), dimethyl malonate (73mg, 0.55mmol), cesium carbonate (300mg, 0.92mmol) and dimethyl sulfoxide (5mL) was heated to 80 ℃ for reaction for 8 hours. The reaction was cooled to room temperature and dispersed with ethyl acetate (50mL), washed with water (5mL) and saturated sodium chloride solution (5mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography to give compound 21d (108mg, yield 79%) as a white solid.1H NMR(500MHz,CDCl3)δ6.08(s,1H),5.29(s, 1H),4.19-4.16(m,2H),4.01-3.99(m,2H),3.76(s,6H),2.24-2.19(m,1H),1.18-1.07(m, 4H)ppm。MS m/z 357.3[M+H]+。
A mixture of compound 21d (100mg, 0.28mmol), lithium chloride (64mg, 1.51mmol) and dimethyl sulfoxide (1mL) was heated to 120 ℃ and reacted for 2 hours. The reaction was cooled to room temperature and dispersed with ethyl acetate (20mL), washed with saturated sodium chloride solution (5mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether: acetone ═ 3:1) to give compound 21e (36mg, yield 43%) as a white solid.
A mixture of compound 21e (30mg, 0.10mmol), compound 21f (22.5mg, 0.12mmol, purchased), N-diisopropylethylamine (40mg, 0.31mmol) and dimethyl sulfoxide (0.1mL) was heated to 110 ℃ for reaction for 3 hours. The reaction was cooled to room temperature and dispersed with ethyl acetate (50mL), washed with water (5mL) and saturated sodium chloride solution (5mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product. The crude product is chromatographed by silica gel column (petroleum)Ether ethyl acetate ═ 5:1) purification afforded 21g (21mg, yield 46.5%) of the compound as a yellow solid. MS M/z 452.4 [ M + H ]]+。
From 21g (15mg,0.03mmol) of the compound obtained in example 16, a reaction solution containing 21h of the compound was used as it was in the next reaction.
Figure BDA0003069583300000341
Using the method in example 16, from the reaction mixture of compound 21h, compound 21i (10mg,0.07 mmol; synthesized by the method in patent WO 2019122129), N, N, N ', N' -tetramethyl-O- (7-azabenzotriazol-1-yl) urea hexafluorophosphate (19mg,0.05mmol) and diisopropylethylamine (13mg,0.10mmol), compound 21j (7mg, yield 40%) was obtained as a white solid. MS M/z 527.3[ M + H ]]+。
From compound 21j (7mg,0.01mmol) by the method in example 16, compound 21(3mg, yield 49%) was prepared as a pale yellow solid. MS M/z 465.4[ M + H ]]+。
EXAMPLE 22 preparation of Compound 22
Figure BDA0003069583300000351
Compound 22a (1g, 5.24mmol), sodium difluorochloroacetate (2.39g, 15.71mmol) and cesium carbonate (5.07g, 15.71mmol) were dissolved in DMF (10mL) and the compound was heated to 100 ℃ for 2 hours. After the reaction was completed, water was added to quench, extraction was performed twice with ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude 22b (1.26g, yield 100%). MS m/z 241.0
[M+H]+。
Compound 22f was obtained from 22b using the procedure in example 19.1H NMR(500MHz,CDCl3)δ7.31- 7.27(m,1H),7.15-7.08(m,2H),6.54(t,J＝73.6Hz,1H),4.43(q,J＝6.7Hz,1H),2.20- 1.80(brs,2H),1.43(d,J＝6.7Hz,3H)ppm。
Figure BDA0003069583300000352
22f (40mg,0.19mmol), 22g (53mg, 0.19mmol) and N, N-diisopropylethylamine (43mg,0.39mmol) were dissolved in dimethyl sulfoxide (0.3mL), heated to 100 ℃ and reacted for 2.5 hours. After most of the raw materials are reacted, adding water for quenching, extracting the water phase twice by using ethyl acetate, combining organic phases, washing by using saturated saline solution, drying by using anhydrous sodium sulfate, and concentrating under reduced pressure to obtain a crude product. Purification of the crude product on a silica gel column afforded the product 22h (40mg, 46% yield). MS M/z 442.2[ M + H ]]+。
From compound 22h (17mg,0.04mmol) by the method in example 16, a reaction solution containing compound 22i was obtained and used as it is for the next reaction. MS M/z 428.3[ M + H ]]+。
Figure BDA0003069583300000361
Using the method of example 16, from the reaction mixture of compound 22i, compound 21i (11mg,0.08mmol), N, N, N ', N' -tetramethyl-O- (7-azabenzotriazol-1-yl) urea hexafluorophosphate (22mg,0.06mmol) and diisopropylethylamine (15mg,0.12mmol), compound 22j (12mg, yield 60%) was obtained as a white solid. MS M/z 517.5 [ M + H ]]+。
From compound 22j (12mg,0.02mmol), compound 22 (6mg, yield 57%) was obtained as a pale yellow solid by the method described in example 16.1H NMR(500MHz,CD3OD)δ9.21(s,1H),7.33-7.28(m,1H),7.22- 7.12(m,2H),6.83(t,J＝73.5Hz,1H),6.34(s,1H),6.25(t,J＝57.6Hz,1H),5.82(q,J＝ 7.1Hz,1H),2.31(s,3H),1.66(d,J＝7.1Hz,3H),1.62-1.57(m,2H),1.48-1.40(m,2H)。 MS m/z 455.4[M+H]+。
Example 23 investigation of the inhibition of the SOS1 Activity of the Compound
Positive drug and test compound (10mM stock) were diluted in a 3-fold gradient with 100% DMSO and 0.1uL of compound was transferred to 384-well plates using a dispenser ECHO. 5ul of Tag2-KRAS G12D was added&GTP was centrifuged in 384 well plates at 1000rpm for 1 min.5uL of Tag 1-SOS 1 was added to a 384 well plate and centrifuged at 1000rpm for 1 min. Incubate at 25 ℃ for 15min, add 10uL of anti-Tag1-Tb and anti-Tag2-XL665 mixture to 384 well plates, centrifuge at 1000rpm for 1min, incubate at 4 ℃ for 3 h. Envision was used to read 665nM and 615nM values. The log values of the concentrations are taken as an X axis, 665nM/615nM is taken as a Y axis, and an assay effect curve is fitted by adopting the Y ═ Bottom + (Top-Bottom)/(1+10^ ((LogIC50-X) × HillSlope)) of the GraphPad Prism 8 of the analysis software, so that the IC of each compound to the enzyme activity is obtained50The value is obtained. The activity of some representative compounds is shown in table 1.
Table 1: results of inhibition of Compound SOS1 Activity
Figure BDA0003069583300000362
Figure BDA0003069583300000371
Example 24 pharmacokinetic Studies in rats
The instrument comprises the following steps: XEVO TQ-S LC Mass spectrometer manufactured by Waters, all measured data were collected and processed by Masslynx V4.1 software, and data were calculated and processed using Microsoft Excel. And calculating pharmacokinetic parameters by using WinNonLin 8.0 software and a statistical moment method. Mainly comprising a kinetic parameter Tmax、T1/2、Cmax、AUClastAnd the like. A chromatographic column: ACQUITY UPLC BEH C18(2.1 mm. times.50 mm, 1.7 μm); the column temperature is 40 ℃; mobile phase a was water (0.1% formic acid), mobile phase B was acetonitrile, flow rate was 0.350 ml/min, gradient elution was used, elution gradient was 0.50 min: 10% of B; 1.50 min: 10% of B; 2.30 min: 95% of B; 2.31 min: 10% of B; 3.00 min: and (7) stop. Sample introduction amount: 5 μ L.
Animals: SD male rats 3 in the weight range of 200-220g were used after being raised in the laboratory of the center of the experimental animals for 2 days after purchase, fasted for 12 hours before and 4 hours after administration, and had free water during the experiment. Blood samples were taken at established time points after gavage.
Solvent: 0.5% Methylcellulose (0.4% Tween 80 in 1% ethanol in water). Preparing a gastric lavage administration solution: precisely weighing the compound, adding into solvent, and performing ultrasonic treatment at room temperature for 5min to completely dissolve the medicine to obtain 0.3 mg/ml medicinal liquid.
Drug samples: the representative compound of the structure shown in the formula (I) of the invention is generally prepared by taking a plurality of samples with similar structures (the molecular weight difference is more than 2 units), accurately weighing and dosing together (cassette PK). This allows for the simultaneous screening of multiple compounds and comparison of their oral absorption rates. Single dosing was also used to study the pharmacokinetics of the drug samples in rats.
After gavage, blood was collected from the orbit at 0.25, 0.5, 1,2, 4, 9, 12 and 24 hours, respectively, placed in heparin sodium treated tubes and centrifuged to collect supernatant plasma for LC-MS/MS analysis.
Accurately weighing the compounds to prepare different concentrations, carrying out quantitative analysis on a mass spectrum so as to establish a standard curve, and then testing the concentrations of the compounds in the plasma to obtain the concentrations of the compounds at different time points. All the measured data are collected and processed by relevant software, and pharmacokinetic parameter calculation (mainly including kinetic parameter T) is carried out by adopting a statistical moment methodmax、T1/2、Cmax、AUClastEtc.). The kinetic parameters of some representative compounds are shown in table 2.
TABLE 2 pharmacokinetic parameters in rats
Figure BDA0003069583300000372

Claims (17)

1. A compound having a structure represented by the following formula (I), or an optical isomer, a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrate, a solvate thereof:
Figure FDA0003069583290000011
in formula (I):
R1、R2and R3Each independently selected from the group consisting of: hydrogen, deuterium, halogen, C1-6Alkyl radical, C1-6Haloalkyl, C2-6Alkenyl radical, C2-6Haloalkenyl, C2-6Alkynyl, C2-6Halogenated alkynyl, C1-6Alkoxy radical, C1-4Haloalkoxy, C1-4Halogenoalkoxy radical C1-4Alkyl radical, C1-4Alkoxy radical C1-4Haloalkyl, C3-6Cycloalkyl radical C1-4Haloalkyl, or C3-6cycloalkyl-O-C1-4Haloalkyl, NRiRi(ii) a Wherein said cycloalkyl group may be optionally substituted with a substituent selected from the group consisting of: halogen, C1-4Alkyl radical, C1-4Haloalkyl, C1-4Alkoxy, or hydroxy; each R isiEach independently of the other being hydrogen, or C1-4An alkyl group;
R4selected from the group consisting of: hydrogen, C1-4Alkyl radical, C1-4Haloalkyl, C1-4Alkoxy radical, C1-4Haloalkoxy, C2-4Alkenyl radical, C2-4Haloalkenyl, C2-4Alkynyl, C3-6Cycloalkyl radical, C3-6Cycloalkyl radical C1-4Alkyl, or 4-to 8-membered heterocyclyl; said cycloalkyl or heterocyclyl is optionally substituted with one or more substituents selected from the group consisting of: halogen, C1-4Alkyl radical, C1-4Haloalkyl, C1-4Alkoxy, or "═ M", where M is selected from O or CRjRk(ii) a Wherein R isjAnd RkEach independently selected from the group consisting of: hydrogen, halogen, or C1-4An alkyl group;
z is selected from the group consisting of: o, NH, NCH3；
U is selected from the group consisting of: key, CReRf、NRg(ii) a Wherein R iseAnd RfEach independently selected from hydrogen or C1-4An alkyl group; or ReAnd RfTogether with the carbon atom to which they are attached form C ═ O; rgSelected from hydrogen, C1-4Alkyl radical, C1-4Haloalkyl, C3-6Cycloalkyl, 4-to 8-membered heterocyclyl, aryl, or heteroaryl, C (O) Rt；
A is selected from the following group: hydrogen, C1-4Alkyl radical, C1-4Haloalkyl, saturated or unsaturated C3-10Cycloalkyl, or a saturated or unsaturated 4-to 12-membered heterocyclyl; said cycloalkyl or heterocyclyl may optionally be substituted with 0-4R5Substitution; when U is a bond and A is a saturated or unsaturated 4-to 12-membered heterocyclic group containing an N atom, A may optionally be linked to the remainder of the structure of formula (I) via an N-N bond;
each R is5Each independently selected from the group consisting of: hydrogen, halogen, C1-4Alkyl radical, C1-4Haloalkyl, C2-4Alkenyl radical, C2-4Haloalkenyl, C2-4Alkynyl, C2-4Halogenated alkynyl, C3-6Cycloalkyl, 4-to 8-membered heterocyclyl, aryl, heteroaryl, CN, NO2、ORh、SRh、NRhRh、C(O)Rt、C(O)ORh、OC(O)Rt、C(O)NRhRh、NRhC(O)Rt、S(O)2Rt、NRhS(O)2RtOr NRhS(O)2NRhRh(ii) a Said alkyl group may be optionally substituted with a substituent selected from the group consisting of: CN, NO2、ORh、SRh、NRhRh、C(O)Rt、C(O)ORh、OC(O)Rt、C(O)NRhRh、NRhC(O)Rt、S(O)2Rt、NRhS(O)2RtOr NRhS(O)2NRhRh(ii) a Wherein each R ishEach independently of the other being hydrogen, or C1-4An alkyl group; or two RhTogether with the nitrogen atom to which they are attached form a 3-to-8-membered heterocyclic group containing 1 or 2N atoms and 0 or 1 heteroatom selected from O, S; rtIs C1-4Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C3-8Cycloalkyl, 4-to 8-membered heterocyclyl, aryl, or heteroaryl;
or two R5Together with the carbon atom to which they are attached form C ═ M, where M is selected from O or CRaRb(ii) a Wherein R isaAnd RbEach independently selected from the group consisting of: hydrogen, deuterium, halogen, or C1-4An alkyl group; wherein said alkyl group may be optionally substituted with 0 to more groups selected from: halogen, C1-4Alkyl radical, C1-4Haloalkyl, C1-4Alkoxy radical, C1-4Haloalkoxy, NRcRd、C3-6Cycloalkyl, 3-to 8-membered heterocyclyl, aryl, or heteroaryl; or RaAnd RbTogether with the carbon atom to which they are attached form a 3-to-6-membered cycloalkyl group, or a 4-to 8-membered heterocyclyl group containing 1 or 2 heteroatoms selected from N, O, S; wherein R iscAnd RdEach independently selected from the group consisting of: hydrogen, C1-4Alkyl radical, C3-6Cycloalkyl, 4-to 8-membered heterocyclyl;
wherein each of the above alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is optionally and each independently substituted with 1 to 3 substituents each independently selected from the group consisting of: halogen, C1-4Alkyl radical, C1-4Haloalkyl, C2-4Alkenyl radical, C2-4Alkynyl, C3-8Cycloalkyl, 3-to 8-membered heterocyclyl, aryl, heteroaryl, CN, NO2、ORh、SRh、NRhRh、C(O)Rt、C(O)ORh、C(O)NRhRh、NRhC(O)Rt、NRhS(O)2RtOr S (O)2RtProvided that the chemical structure formed is stable and meaningful; wherein R ishAnd RtIs as defined above;
the above-mentioned aryl group is an aromatic group having 6 to 12 carbon atoms unless otherwise specified; heteroaryl is a 5-to 15-membered (preferably 5-to 12-membered) heteroaromatic group; the cyclic structure is a saturated or unsaturated, heteroatom-containing or heteroatom-free cyclic group.
2. The compound of claim 1, or an optical isomer, pharmaceutically acceptable salt, prodrug, deuterated derivative, hydrate, solvate thereof, wherein formula (I) is formula (II):
Figure FDA0003069583290000021
t is selected from CR6Or N;
y is selected from CR7R8、NR9、O；
m and n are each independently 0, 1,2, or 3; provided that m and n cannot be 0 at the same time;
p is 0, 1,2, 3, or 4;
R6selected from the group consisting of: hydrogen, C1-4Alkyl radical, C1-4Haloalkyl, C2-4Alkenyl radical, C2-4Haloalkenyl, C2-4An alkynyl group; said alkyl group may be optionally substituted with a substituent selected from the group consisting of: CN, NO2、ORh、SRh、NRhRh、C(O)Rt、C(O)ORh、OC(O)Rt、C(O)NRhRh、NRhC(O)Rt、S(O)2Rt、NRhS(O)2RtOr NRhS(O)2NRhRh；
Each R is7And R8Each independently selected from the group consisting of: hydrogen, halogen, C1-4Alkyl radical, C1-4Haloalkyl, C2-4Alkenyl radical, C2-4Haloalkenyl, C2-4Alkynyl, CN, NO2、ORh、SRh、NRhRh、C(O)Rt、C(O)ORh、OC(O)Rt、C(O)NRhRh、NRhC(O)Rt、S(O)2RtOr NRhS(O)2RtOr NRhS(O)2NRhRh(ii) a Said alkyl group may be optionally substituted with a substituent selected from the group consisting of: halogen, CN, NO2、ORh、SRh、NRhRh、C(O)Rt、C(O)ORh、OC(O)Rt、C(O)NRhRh、NRhC(O)Rt、S(O)2Rt、NRhS(O)2RtOr NRhS(O)2NRhRh；
Or R7And R8Together with the carbon atom to which they are attached form C ═ M, where M is selected from O or CRaRb；
R9Selected from the group consisting of: hydrogen, C1-4Alkyl radical, C1-4Haloalkyl, C3-6Cycloalkyl, 4-to 8-membered heterocyclyl, aryl, heteroaryl, C (O) Rt、C(O)ORh、C(O)NRhRh、S(O)2RtOr S (O)2NRhRh；
R1、R2、R3、R4、R5、Ra、Rb、Rh、RtIs as defined in claim 1.
3. The compound of claim 1, or an optical isomer, pharmaceutically acceptable salt, prodrug, deuterated derivative, hydrate, solvate thereof, wherein formula (I) is formula (III):
Figure FDA0003069583290000031
the definition of each group in the formula (III) is as defined in claim 2.
4. The compound of claim 1, or an optical isomer, pharmaceutically acceptable salt, prodrug, deuterated derivative, hydrate, solvate thereof, wherein formula (I) is formula (IV):
Figure FDA0003069583290000032
the definition of each group in the formula (IV) is as defined in claim 1.
5. The compound of claim 1, or an optical isomer, pharmaceutically acceptable salt, prodrug, deuterated derivative, hydrate, solvate thereof, wherein formula (I) is formula (V):
Figure FDA0003069583290000033
the radicals in formula (V) are as defined in claim 2.
6. The compound of claim 2, or an optical isomer, pharmaceutically acceptable salt, prodrug, deuterated derivative, hydrate, solvate thereof, wherein formula (I) is formula (VI):
Figure FDA0003069583290000041
the radicals in the formula (VI) are as defined in claim 2.
7. The compound of claim 1, or an optical isomer, a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrate, a solvate thereof, wherein formula (I) is formula (VII):
Figure FDA0003069583290000042
the definitions of the radicals in the formula (VII) are stated in claim 2.
8. The compound of claim 1, or an optical isomer, pharmaceutically acceptable salt, prodrug, deuterated derivative, hydrate, solvate thereof,
R4selected from the group consisting of: methyl, acetyleneA phenyl group, or a cyclopropyl group.
9. The compound of claim 7, or an optical isomer, a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrate, a solvate thereof, wherein in formula (VII):
R4selected from the group consisting of: ethynyl group, C3-6Cycloalkyl radical, C3-6Cycloalkyl radical C1-4Alkyl, or 4-to 8-membered heterocyclyl;
the remaining groups of formula (VII) are as defined in claim 2.
10. The compound of claim 1, or an optical isomer, pharmaceutically acceptable salt, prodrug, deuterated derivative, hydrate, solvate thereof, wherein formula (I) is formula (VIII):
Figure FDA0003069583290000043
in formula (VIII):
each R is10Each independently selected from halogen or C1-4An alkyl group; t is 0, 1, or 2; q is 1,2, 3, or 4;
R1、R2、R3u, and A are as defined in claim 1.
11. The compound of claim 1, or an optical isomer, pharmaceutically acceptable salt, prodrug, deuterated derivative, hydrate, solvate thereof, wherein formula (I) is formula (IX):
Figure FDA0003069583290000051
in formula (IX):
each R is10Each independently selected from halogen or C1-4An alkyl group; t is 0, 1, or 2; q is 1,2, 3, or 4;
R1、R2、R3and R6Is defined as in claim 2.
12. The compound of claim 1, or an optical isomer, pharmaceutically acceptable salt, prodrug, deuterated derivative, hydrate, solvate thereof, wherein formula (I) is formula (X):
Figure FDA0003069583290000052
in the formula (X):
R1、R2and R3Each independently selected from the group consisting of: hydrogen, deuterium, halogen, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Alkoxy radical, C1-4Haloalkoxy, C2-6Halogenated alkynyl, C3-6Cycloalkyl radical C1-4Haloalkyl, or NRiRi；
R6Selected from the group consisting of: hydrogen, C1-4Alkyl radical, C1-4Haloalkyl, C2-4Alkenyl radical, C2-4Haloalkenyl, C2-4An alkynyl group; said alkyl group may be optionally substituted with a substituent selected from the group consisting of: CN, NO2、ORh、SRh、NRhRh、C(O)Rt、C(O)ORh、OC(O)Rt、NRhC(O)RtOr NRhS(O)2Rt；
Each R isiEach independently of the other being hydrogen, or C1-4An alkyl group; each R ishEach independently of the other being hydrogen, or C1-4An alkyl group.
13. The compound of claim 1, or an optical isomer, pharmaceutically acceptable salt, prodrug, deuterated derivative, hydrate, solvate thereof,
structural fragment in formula (I)
Figure FDA0003069583290000053
Selected from the group consisting of:
Figure FDA0003069583290000061
Figure FDA0003069583290000062
represents the linking site of the above structural fragment with other parts of the structure of formula (I).
14. The compound of claim 1, wherein the compound of formula (I) is selected from the group consisting of:
Figure FDA0003069583290000071
Figure FDA0003069583290000081
Figure FDA0003069583290000091
Figure FDA0003069583290000101
15. a pharmaceutical composition comprising a compound of any one of claims 1 to 14, or an optical isomer, a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrate, a solvate, and a pharmaceutically acceptable carrier thereof.
16. Use of a compound of any one of claims 1 to 14, or an optical isomer, pharmaceutically acceptable salt, prodrug, deuterated derivative, hydrate, solvate thereof, for the preparation of a pharmaceutical composition for the treatment of a disease, disorder or condition associated with the activity or expression of SOS 1.
17. The use of claim 16, wherein the disease, disorder or condition is selected from the group consisting of:
non-small cell lung cancer, lung adenocarcinoma, squamous cell lung carcinoma, pancreatic cancer, colon cancer, thyroid cancer, melanoma, embryonal rhabdomyosarcoma, cutaneous granulocytic tumors, liver cancer, rectal cancer, bladder cancer, throat cancer, breast cancer, prostate cancer, glioma, ovarian cancer, head and neck squamous cell carcinoma, cervical cancer, esophageal cancer, kidney cancer, skin cancer, lymphoma, gastric cancer, acute myeloid leukemia, myelofibrosis, B-cell lymphoma, monocytic leukemia, splenomegaly, hypereosinophilic syndrome, myelogenous syndrome, various solid and hematologic tumors such as myeloid cancer, and various diseases associated with SOS1 genetic mutation including but not limited to neurofibroma I, Noonas syndrome, multiple freckle-like Noonas syndrome, capillary malformation-arteriovenous malformation syndrome, cardio-facio-cutaneous syndrome, Costilux syndrome, rengiles' syndrome, and hereditary gingival fibroma type i, among others.
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