CN115894328A - Compounds as P53 modulators and/or HDAC inhibitors - Google Patents
Compounds as P53 modulators and/or HDAC inhibitors Download PDFInfo
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- CN115894328A CN115894328A CN202111165274.2A CN202111165274A CN115894328A CN 115894328 A CN115894328 A CN 115894328A CN 202111165274 A CN202111165274 A CN 202111165274A CN 115894328 A CN115894328 A CN 115894328A
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Abstract
The invention provides a compound serving as a P53 regulator and/or an HDAC 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 conditions associated with the activity or amount of expression of P53 and/or HDAC.
Description
Technical Field
The present invention relates to the field of pharmaceutical chemistry; in particular to a novel tricyclic heteroaryl-containing derivative, a synthesis method thereof and application of the derivative as a P53 regulator and/or an HDAC inhibitor in preparation of medicines for treating various related diseases such as tumors.
Background
In human tumors, the most common mutation is the mutation of the TP53 gene, which encodes the P53 protein. TP53 mutations are closely associated with poor prognosis in a variety of tumors, and germline TP53 mutations can lead to a rare familial cancer-prone disease: li Fraumeni syndrome. P53 is used as a cancer suppressor and provides an important barrier for the transformation and the progression of tumors. P53 is very sensitive to cellular stress and can coordinate a complex signaling pathway to maintain cellular homeostasis and genomic stability. Most of the TP53 mutations are missense mutations, and codons encoding one amino acid are changed into codons encoding another amino acid after base substitution. Such mutations usually result in the inactivation of the cancer-suppressing function of the p53 protein and the loss of the function of activating the downstream genes, and some mutations may in turn suppress the normal p53 protein from functioning and thus play a dominant role in suppression. In addition, mutated p53 may support tumor progression by promoting an adaptive response to tumor-associated stress. In a growing tumor, cancer cells are exposed to a variety of internal and external stresses. The mutant p53 can induce various cellular stresses and induce adaptive mechanisms of cells to exert a cancer promotion effect.
The P53Y 220C mutation is one of the common missense mutation types of the P53, the mutation exists in the cancer types such as breast cancer, lung cancer, colon cancer, gastric cancer, head and neck cancer, and about 10 million cancer patients with the mutation are newly added in the whole world every year. Therefore, the development of compounds directed against this mutation, which reactivate the function of wild-type p53, is crucial for cancer therapy.
HDACs (Histone deacetylases) are a class of Histone deacetylases and play an important role in structural modification of chromosomes, regulation of gene expression, and post-translational modification of proteins. HDACs deacetylate the lysine side chain at the amino terminus of histones, enhancing the interaction between positively charged histones and negatively charged DNA, and allowing relaxed nucleosomes to become sufficiently compact to be detrimental to the expression of specific genes, including some tumor suppressor genes. HDACs also deacetylate and modify some non-histones, such as transcription factors E2F, c-Myc and NF-. Kappa.B, and some signaling factors, such as Stat3, smad7 and β -catenin, etc., to regulate cellular homeostasis. The HDAC inhibitor can improve histone acetylation in specific chromatin region, regulate and control the expression and stability of apoptosis and differentiation related protein, induce tumor cell cycle arrest and apoptosis, inhibit the generation of tumor angiogenesis, promote the immunogenicity of tumor cells, and inhibit the growth of various tumor cells.
The same small molecule is used for simultaneously regulating p 53Y 220C and HDACs to play a better anti-tumor effect, and no report is found at present. It is thought that the simultaneous regulation and control of these two targets will improve the microenvironment of tumor cells, raise immunity, promote cell cycle arrest and apoptosis of tumor cells and produce effective anticancer effect.
Disclosure of Invention
It is an object of the present invention to provide a novel class of P53 modulators and/or HDAC inhibitors.
In a first aspect of the present invention, there is provided 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:
in formula (I):
ring A is selected from aryl or heteroaryl;
ring B is selected from aryl or heteroaryl;
c ring is selected from C 3-8 Cycloalkyl or 4-to 12-membered heterocyclyl;
d is selected from the group consisting of a chemical bond, -C.ident.C-, -CR a ＝CR a -, or C 3-6 A cyclic group;
e is selected from the group consisting of a bond, - (CR) a R a ) q -、-O-、-NR b -、C 3-6 A cyclic group, or a 3-to 6-membered heterocyclic group;
f is selected from the group consisting of a bond, -NR b -, -O-, or- (CR) a R a ) q -；
U is selected from the group consisting of a bond, -NR c -、-O-、-NR c C(O)R c -、-NR c C(O)-；
Each of the above R a Each independently selected from hydrogen, halogen, C 1-4 Alkyl, OR b 、CN、NR b R b (ii) a Each R is b And R c Each independently selected from hydrogen and C 1-4 Alkyl, or C 1-4 A haloalkyl group; or two R b Together with the nitrogen atom to which they are attached form an optionally substituted 4-to 8-membered cyclic structure which may additionally contain 0-1 heteroatoms optionally selected from N, O, S;
R 1 selected from hydrogen, C 1-4 Alkyl radical, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, 3-to 8-membered heterocyclyl, aryl, heteroaryl, C (O) R d Or S (O) 2 R d (ii) a Said alkyl, cycloalkyl, heterocyclyl is optionally substituted by one or more groups selected from: halogen, CN, OR b 、SR b 、NR b R b (ii) a Or said cycloalkyl, heterocyclyl is optionally substituted by C = M; m is selected from O or CR e R e (ii) a Each R is e Each independently selected from hydrogen, fluorine, or C 1-4 An alkyl group; said R is e Wherein the alkyl group is optionally substituted with a substituent of the group: CN, OR b 、SR b 、NR b R b 、C(O)OR b ；R d Is selected from C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-to 8-membered heterocyclyl, aryl, or heteroaryl; r b Is as defined above;
each R is 2 Each independently selected from hydrogen, halogen, C 1-4 Alkyl radical, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-to 6-membered heterocyclyl, CN, OR b 、SR b Or NR b R b ；R b Is as defined above;
R 3 selected from hydrogen, halogen, C 1-4 Alkyl radical, C 1-4 Haloalkyl, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-to 8-membered heterocyclyl, aryl, heteroaryl, CN, OR b 、SR b 、NR b R b 、C(O)R d 、C(O)OR b 、C(O)NR b R b 、C(O)N(OR b )R b 、NR b C(O)R d 、NR b S(O) 2 R d 、S(O) 2 R d 、S(O)(NR b )R d 、S(O)R d 、NR b S(O) 2 R d 、S(O) 2 NR b R b 、NR b S(O) 2 NR b R b 、P(O)R f R f 、P(O)(NR b R b )R f OR P (O) (OR) b )R f (ii) a Each R is b And R d Is as defined above; or two R b Together with the nitrogen atom to which they are attached form an optionally substituted 4-to 8-membered cyclic structure which may additionally contain 0-1 heteroatoms optionally selected from N, O, S; each R is f Each independently selected from C 1-4 Alkyl radical, C 3-6 Cycloalkyl, 3-to 8-membered heterocyclyl, aryl, heteroaryl, OR b 、NR b R b (ii) a Or two R f Together with the phosphorus atom to which they are attached form an optionally substituted 4-to 8-membered cyclic structure which may additionally contain 0-1 heteroatoms optionally selected from N, O, S; r f The alkyl, cycloalkyl, heterocyclyl, or cyclic structure recited in (1) is optionally substituted with a substituent of the group: hydrogen, halogen, C 1-4 Alkyl radical, C 1-4 Haloalkyl, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-to 6-membered heterocyclyl, CN, OR b 、SR b 、NR b R b 、＝O；R b Is as defined above;
each R is 4 Each independently selected from hydrogen, halogen, C 1-4 Alkyl radical, C 1-4 Haloalkyl, hydroxy, C 1-4 Alkoxy radical, C 1-4 Haloalkoxy, C 2-4 Alkenyl radical, C 2-4 Haloalkenyl, C 2-4 Alkynyl, C 2-4 Halogenated alkynyl, C 3-6 Cycloalkyl, 3-to 8-membered heterocyclyl, C 2-4 alkenyl-O-, C 2-4 haloalkenyl-O-, C 2-4 alkynyl-O-, C 2-4 Halogenated alkynyl-O-, C 3-6 cycloalkyl-O-, 3-to 8-membered heterocyclyl-O-, CN, SR b 、NR b R b 、C(O)R d 、C(O)OR b 、C(O)NR b R b (ii) a Said alkyl, alkoxy, cycloalkyl, heterocyclyl is optionally substituted with one or more groups selected from: halogen, CN, OR b 、SR b 、NR b R b (ii) a Or said cycloalkyl, heterocyclyl is optionally substituted by C = M; m is selected from O or CR e R e (ii) a Each R is e Each independently selected from hydrogen, fluorine, or C 1-4 An alkyl group; said R is e Is optionally substituted with the following group of substituents: CN, OR b 、SR b 、NR b R b 、C(O)OR b (ii) a Each R is b And R d Is as defined above;
or R 4 And R in E a Together with F and B to which they are attached form an optionally substituted 6-to 8-membered cyclic structure;
or R 4 And R in F b Taken together with the B ring to which it is attached to form an optionally substituted 6-to 8-membered cyclic structure;
R 5 selected from hydrogen, halogen, C 1-4 Alkyl radical, C 1-4 Haloalkyl, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-to 6-membered heterocyclyl, CN, OR b 、SR b 、NR b R b 、C(O)R d 、C(O)OR b 、C(O)NR b R b 、C(O)NR b (OR b )、NR b C(O)R d 、NR b S(O) 2 R d 、S(O) 2 R d 、S(O)(NR b )R d 、S(O)R d 、NR b S(O) 2 R d 、S(O) 2 NR b R b (ii) a Each R is b Each independently selected from hydrogen and C 1-4 Alkyl, or C 1-4 A haloalkyl group; or two R b Together with the nitrogen atom to which they are attached form an optionally substituted 4-to 8-membered cyclic structure which may additionally contain 0-1 heteroatoms optionally selected from N, O, S; r d Is selected from C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-to 6-membered heterocyclyl; r is as defined above 5 、R b 、R d The alkyl, cycloalkyl, heterocyclyl group in (a) is optionally substituted with one or more groups selected from the group consisting of: halogen, C 1-4 Alkyl radical, C 3-6 Cycloalkyl, 3-to 6-membered heterocyclyl, CN, OR b 、SR b 、NR b R b (ii) a Or the above R 5 The cycloalkyl, heterocyclyl in (a) is optionally substituted with C = M; m is selected from O or CR e R e (ii) a Each R is e Each independently selected from hydrogen, fluorine, or C 1-4 An alkyl group; the R is e Is optionally substituted with a substituent of the group: CN, OR b 、SR b 、NR b R b 、C(O)OR b (ii) a Each R is b Is as defined above;
each R is 6 Each independently selected from hydrogen, halogen, C 1-4 Alkyl radical, C 1-4 Haloalkyl, hydroxy, C 1-4 Alkoxy radical, C 1-4 Haloalkoxy, C 3-6 Cycloalkyl, 3-to 6-membered heterocyclyl, CN, SR b 、NR b R b (ii) a Each R is b Is as defined above;
m is selected from 0, 1,2,3, or 4;
n is selected from 0, 1,2,3, or 4;
p is selected from 0, 1,2,3, or 4;
q is selected from 0, 1,2, or 3;
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, C 1-4 Alkyl radical, C 1-4 Haloalkyl, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-to 8-membered heterocyclyl, aryl, heteroaryl, CN, NO 2 、OR b 、SR b 、NR b R b 、C(O)R d 、C(O)OR b 、C(O)NR b R b 、NR b C(O)R d 、NR b S(O) 2 R d Or S (O) 2 R d Provided that the chemical structure formed is stable and meaningful; wherein each R is b Each independently selected from hydrogen, C 1-4 Alkyl, or C 1-4 A haloalkyl group; or two R b Together with the nitrogen atom to which they are attached form an optionally substituted 4-to 8-membered cyclic structure which may additionally contain 0-1 heteroatoms optionally selected from N, O, S; each R is d Each independently selected from C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-to 6-membered heterocyclyl, aryl, or heteroaryl;
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 monocyclic, bicyclic, fused or heterocyclic ring, which may be saturated or partially unsaturated (but not aromatic)
In a second aspect of the present invention, there is provided a pharmaceutical composition comprising a compound according to the first aspect of the present invention, or an optical isomer, a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrate, a solvate, and a pharmaceutically acceptable carrier thereof.
In a third aspect of the present invention, there is provided a use of a compound according to the first aspect of the present invention, or an optical isomer, a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrate, a solvate thereof, for the preparation of a pharmaceutical composition for the treatment of a disease, disorder or condition associated with P53 modulator and/or HDAC activity or expression.
In another preferred embodiment, the disease, disorder or condition is selected from the group consisting of: non-small cell lung cancer, lung adenocarcinoma, lung squamous carcinoma, pancreatic cancer, colon cancer, thyroid cancer, embryonal rhabdomyosarcoma, cutaneous granulocytic tumor, melanoma, hepatocellular carcinoma, intrahepatic bile duct cancer, rectal cancer, bladder cancer, throat cancer, breast cancer, vaginal cancer, prostate cancer, testicular cancer, brain tumor, glioma, ovarian cancer, head and neck squamous cancer, cervical cancer, osteosarcoma, esophageal cancer, kidney cancer, skin cancer, stomach cancer, myeloid leukemia, lymphoid leukemia, myelofibrosis, B-cell lymphoma, T-cell lymphoma, hodgkin's lymphoma, non-hodgkin's lymphoma, monocytic leukemia, polycythemia splenomegaly, hypereosinophilic syndrome, bone marrow cancer and other solid tumors and hematological tumors.
Detailed Description
The inventors have conducted extensive and intensive studies for a long time and unexpectedly found a novel class of P53 modulators and/or HDAC inhibitors, as well as methods for their preparation and use. The compounds of the present invention may be used in the treatment of various diseases associated with the activity of the transcription factor and/or acetyltransferase. 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. For example, C 1-8 Alkyl 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 contains 2 to 8 carbon atoms. For example, C 2-8 Alkenyl refers to alkenyl groups containing 2 to 8 carbon atoms and includes ethenyl, propenyl, 1,2-butenyl, 2,3-butenyl, butadienyl, or the like.
As used herein, in the context ofThe term "alkynyl", alone or as part of another substituent, refers to an aliphatic hydrocarbon group having at least one carbon-carbon triple 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) 2-8 Alkynyl) means that the alkynyl group contains 2 to 8 carbon atoms. For example, the term "C 2-8 Alkynyl "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 radical having a saturated or partially saturated monocyclic, bicyclic or polycyclic (fused, bridged or spiro) ring system. 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 "C 3-8 Cycloalkyl "refers to a saturated or partially unsaturated 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-ring 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, and in which 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. "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.
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.
"heteroaryl" refers to a monocyclic or polycyclic group having aromatic character containing one to more heteroatoms (optionally selected from nitrogen, oxygen, and sulfur), or a polycyclic group containing a heterocyclic group (containing one to more heteroatoms selected from nitrogen, oxygen, and sulfur) fused to an aryl group at a site of attachment to 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.
"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.
“C 3-6 The cyclic group "means a saturated or partially unsaturated monocyclic or bicyclic cyclic group having 3 to 6 carbon atoms.
"heterocyclic group" means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon group (non-aromatic) in which one or more ring atoms are selected from nitrogen, oxygen or sulfur and the remaining ring atoms are carbon.
"Cyclic structure" refers to a ring system group having saturated or partially saturated unit rings, bicyclic or polycyclic rings (fused, bridged or spiro rings), and no heteroatoms in the ring backbone. The cyclic group may be a monovalent, divalent, trivalent or other valency group, preferably a divalent or trivalent group. When a cyclic 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.
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 "Substitution (with or without "optionally" modifying) means that one or more hydrogen atoms on a particular group are replaced with a particular substituent. Particular substituents are those described correspondingly in the preceding text or as present 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): c 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, C 3-8 Cycloalkyl, 3-to 12-membered heterocyclyl, aryl, heteroaryl, halogen, hydroxy, alkoxy, carboxy (-COOH), C 1-8 Aldehyde group, C 2-10 Acyl radical, C 2-10 Ester 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, isomers (enantiomers or diastereomers, if present), hydrates, pharmaceutically acceptable carriers or excipients, for modulating P53 and/or HDAC.
The compounds of the invention are useful as a P53 modulator and/or HDAC inhibitor.
The invention relates to a P53 regulator and/or an HDAC inhibitor, which achieves the purpose of preventing, alleviating or curing diseases by regulating the activity of P53 and/or HDAC. Diseases referred to include, but are not limited to: non-small cell lung cancer, lung adenocarcinoma, lung squamous carcinoma, pancreatic cancer, colon cancer, thyroid cancer, embryonal rhabdomyosarcoma, cutaneous granulocytic tumor, melanoma, hepatocellular carcinoma, intrahepatic bile duct cancer, rectal cancer, bladder cancer, throat cancer, breast cancer, vaginal cancer, prostate cancer, testicular cancer, brain tumor, glioma, ovarian cancer, head and neck squamous cancer, cervical cancer, osteosarcoma, esophageal cancer, kidney cancer, skin cancer, stomach cancer, myeloid leukemia, lymphoid leukemia, myelofibrosis, B-cell lymphoma, T-cell lymphoma, hodgkin's lymphoma, non-hodgkin's lymphoma, monocytic leukemia, polycythemia splenomegaly, hypereosinophilic syndrome, bone marrow cancer and other solid tumors and hematological tumors.
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.
Pharmaceutical compositions and methods of administration
Since the compound of the present invention has excellent activity for regulating P53 and/or inhibiting HDAC, the compound of the present invention and various crystalline forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates thereof, and a pharmaceutical composition containing the compound of the present invention as a main active ingredient can be used for treating, preventing and alleviating diseases related to P53 and/or HDAC 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 "compatibility" is meant herein the ability of the components of the composition to interact withThe compounds of the present invention and their intermingling without significantly reducing the efficacy of the compounds. Examples of pharmaceutically acceptable carrier moieties are cellulose and its derivatives (e.g. sodium carboxymethylcellulose, sodium ethylcellulose, cellulose 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, glycerol, mannitol, sorbitol, etc.), emulsifiers (e.g. propylene glycol, glycerol, mannitol, sorbitol, etc.)
) 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, hydroxymethyl cellulose, 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 a composition 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, especially 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 of the compounds of the present invention for topical administration 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 using pharmaceutical compositions, a safe and effective amount of a compound of the present invention is administered to a mammal (e.g., a human) in need of treatment, wherein the administration is a pharmaceutically acceptable and effective dose, and the daily dose for a human of 60kg body weight is usually 1 to 2000mg, preferably 5 to 500mg. Of course, the particular dosage will also take into account such factors as the route of administration, the health of the patient, and the like, which are 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 novel P53 modulators and/or HDAC inhibitors that inhibit the activity of P53 and/or HDAC at very low concentrations, and their preparation and use.
3. Pharmaceutical compositions for the treatment of diseases associated with P53 and/or HDAC 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.
Some representative compounds of the present invention can be prepared by the following synthetic methods, and in each reaction formula, reagents and conditions of each step can be selected from those conventional in the art for such preparation methods, and after the structure of the compound of the present invention is disclosed, the above selection can be performed by those skilled in the art according to the knowledge in the art.
General synthetic method of compound
Abbreviations
Boc 2 O = di-tert-butyl dicarbonate
Cs 2 CO 3 = cesium carbonate
DCM = dichloromethane
DIPEA = N, N-diisopropylamine
DMAP = 4-dimethylaminopyridine
DMF = N, N-dimethylformamide
DMSO = dimethyl sulfoxide
e.e. = enantiomeric excess percentage
EtOAc or EA = ethyl acetate
HATU = (1- [ bis (dimethylamino) methylene ] -1H-1,2,3-triazolo [4,5-b ] pyridinium 3-oxidohexafluorophosphate)
MgCl 2 = magnesium chloride
NH 4 HCO 3 = ammonium hydrogen carbonate
Pd(OAc) 2 = Palladium acetate (II)
Pd 2 dba 3 = tris (dibenzylideneacetone) palladium (0)
PE = petroleum ether
RT = room temperature
TEA = triethylamine
TFA = trifluoroacetic acid
Part of the compounds of the invention can be prepared by the following method:
scheme 1:
the partial compound of the formula (II) can be prepared by the following method.
The compound IIa-1 is prepared by the method in the patent WO 2021061643. Compound IIa-2 can be prepared by a suitable method. The compound IIa-1 and the compound IIa-2 are subjected to metal-catalyzed coupling reaction to obtain a compound IIa-3, and then subjected to deprotection reaction to obtain a target compound IIa. Compounds 2 and 3 of the present invention were prepared using the method of scheme 1.
Scheme 2:
the compound of formula (III) can be prepared by the following method.
The compound III-1 is prepared by the method in patent WO 2021061643. The compound III-1 is hydrolyzed to obtain a compound III-2, and then the compound III-2 is condensed to obtain the compound shown in the formula (III).
Example (b):
EXAMPLE 1 preparation of Compound 1
5-chloro-2-nitrobenzyl ether (100mg, 0.534mmol) was dissolved in DMF (2 mL) under a nitrogen atmosphere, and K was added sequentially 3 PO 4 (125mg，0.586mmol)、Pd(OAc) 2 (6mg, 0.0026mmol), 4,5-bis-diphenylphosphine-9,9-dimethyl xanthene (18.4 mg, 0.032mmol) and dimethyl phosphine oxide (46mg, 0.586mmol), and the reaction mixture is heated to 150 ℃ for microwave reaction for 50 minutes. The reaction was cooled to room temperature, water (5 mL) was added, extraction was performed with ethyl acetate (3X 5 mL), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was isolated and purified by silica gel column chromatography (dichloromethane: methanol = 20). MS (ES) + ,m/z):230.3[M+H] + 。 1 H NMR(500MHz,CDCl 3 )δ7.86(dd,J＝8.1,3.2Hz,1H),7.66(dd,J＝12.6,1.0Hz,1H),7.17(m 1H),4.02(s,3H),1.78(s,3H),1.76(s,3H)。
Compound 1-b (500mg, 2.18mmol) and Pd/C (50 mg) were added to methanol (30 mL), and the reaction mixture was reacted at 25 ℃ for 4 hours under a hydrogen atmosphere of 1 atm. Methanol (20 mL) was added to dilute the reaction, and after filtration, the filtrate was concentrated under reduced pressure to give a crude product. The crude product was isolated and purified by silica gel column chromatography (dichloromethane: methanol =20 = 1-15). MS (ES) + ,m/z):200.3[M+H] + 。 1 H NMR(500MHz,CD 3 OD)δ7.16-7.09(m,2H),6.80(m,1H),3.90(s,3H),1.72(s,3H),1.69(s,3H)。
Compounds 1-c (8mg, 0.067mmol) were dissolved in (Boc) 2 In O (1 mL), the reaction mixture was heated to 80 ℃ and stirred for three hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the crude product was isolated and purified by silica gel column chromatography (dichloromethane: methanol = 10). MS (ES) + ,m/z):300.4[M+H] + 。 1 H NMR(500MHz,CDCl 3 )δ8.20(bs,1H),7.37(dd,J＝12.3,1.1Hz,1H),7.23(s,1H),7.09(m,1H),3.94(s,3H),1.72(s,3H),1.69(s,3H),1.52(s,9H)。
Compound 1-d (50mg, 0.167mmol) was dissolved in DMF (4 mL), and cesium carbonate (162.9mg, 0.5mmol) and propynylbromide (60mg, 0.5mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. Water (5 mL) was added, extraction was performed with ethyl acetate (3X 5 mL), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was isolated and purified by silica gel column chromatography (dichloromethane: methanol = 20). MS (ES) + ,m/z):338.4[M+H] + 。 1 H NMR(500MHz,CDCl 3 )δ8.01(s,1H),7.42(m,2H),7.11(m,1H),4.27(bs,2H),3.90(s,3H),2.17(s,1H),1.75(s,3H),1.73(s,3H),1.35(m,9H)。
Compound 1-e (150mg, 0.44mmol) was dissolved in DMF (3 mL) and triethylamine (3 mL) under a nitrogen atmosphere, and cuprous iodide (12.56mg, 0.066 mmol), (Ph) was added 3 P) 2 PdCl 2 (15mg, 0.022mmol) and compound 1-f (227mg, 0.533mmol, see WO 2021/061643 for synthesis), the reaction mixture was stirred at room temperature for 2 hours. Water (10 mL) was added, extraction was performed with ethyl acetate (3X 10 mL), and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was isolated and purified by silica gel column chromatography (dichloromethane: methanol = 20). MS (ES) + ,m/z):615.4[M+H] + 。 1 H NMR(500MHz,CDCl 3 )δ7.48(d,J＝13.1Hz,1H),7.38(s,1H),7.33(d,J＝7.5Hz,1H),7.23(d,J＝8.3Hz,1H),7.17-7.08(m,2H),6.79(s,1H),4.64(q,J＝8.4Hz,4H),3.92(s,3H),1.76(s,3H),1.73(s,3H),1.46(m,9H)。
Under a nitrogen atmosphere, 1-g (80mg, 0.13mmol) of the compound was dissolved in anhydrous 1,4-dioxane, and 2- (dicyclohexylphosphine) 3,6-dimethoxy-2 ',4',6' -triisopropyl-1,1 ' -biphenyl (8.37mg, 0.0091mmol), 2-dicyclohexylphosphine-2 ',6' -diisopropoxy-1,1 ' -biphenyl (8.5mg, 0.018mmol), cesium carbonate (1699 mg, 0.52mmol) and the compound 1-h (35mg, 0.17mmol) were added in this order. The temperature of the reaction mixture is raised to 100 ℃, and the reaction mixture is stirred for 16 hours. Water (10 mL) was added, extraction was performed with ethyl acetate (3X 10 mL), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was isolated and purified by silica gel column chromatography (dichloromethane: methanol = 20) and then by silica gel thin layer chromatography (dichloromethane: methanol = 20). MS (ES) + ,m/z):665.8[M+H] + 。
Compound 1-i (6mg, 0.009mmol) was dissolved in 4M HCl 1,4-dioxane (3 mL) and stirred at 25 ℃ for 0.5 h. The reaction solution is decompressed and concentrated, and NH is dripped 3 MeOH (0.5 mL) to pH 8, water (5 mL), ethyl acetate (5 mL. Times.3) extraction, saturated brine washing of the organic phase, drying over anhydrous sodium sulfate, filtration and vacuum concentration of the filtrate to give the crude product. The crude product was isolated and purified by silica gel column chromatography (dichloromethane: methanol = 15. Purification by silica gel thin layer chromatography (dichloromethane: methanol = 20) gave compound 1 (1.6 mg, yield 31.5%) as a pale yellow solid + ,m/z):565.7[M+H] + 。 1 H NMR(500MHz,DMSO-d 6 )δ7.21(m,1H),7.17(s,1H),7.13(dd,J＝11.9,1.4Hz,1H),7.00(t,J＝8.0Hz,1H),6.84(m,1H),6.73(d,J＝8.3Hz,1H),6.23(d,J＝7.9Hz,1H),6.04(t,J＝6.4Hz,1H),5.50(d,J＝8.7Hz,1H),4.90(q,J H,F ＝8.8Hz,2H),4.80(d,J＝50.1Hz,1H),4.31(d,J＝6.4Hz,2H),3.84(s,3H),3.61-3.50(m,1H),3.02(m,1H),2.80(d,J＝10.6Hz,1H),2.18(s,3H),2.07(m,1H),2.01(m,1H),1.92(m,1H),1.69(m,1H),1.59(s,3H),1.56(s,3H)。
EXAMPLE 2 preparation of Compound 2
t-BuOK (168mg, 1.5 mmol) was dissolved in DMF (2 mL) under a nitrogen atmosphere, the temperature was reduced to-55 ℃ and the compound 2-a (213mg, 1mmol) and the compound 2- [ (difluoromethyl) sulfonyl group were added in that order]Pyridine (61mg, 0.83mmol). The reaction mixture was stirred at-55 ℃ for 15 minutes, and a saturated aqueous solution of ammonium chloride (0.5 mL) was added to the mixture, followed by addition of a 3M aqueous solution of hydrochloric acid (1.3 mL). Water (5 mL) was added, extraction was performed with methyl tert-butyl ether (5 mL. Times.3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was isolated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 8:1) to give compound 2-b as a white solid (100 mg, yield 40%). MS (ES) + ,m/z):247.4[M+H] + 。 1 H NMR(500MHz,CDCl 3 )δ4.43(s,1H),3.52(s,1H),2.41(dt,J＝15.1,4.0Hz,2H),1.99(dd,J＝11.9,2.8Hz,2H),2.00-1.80(m,2H),1.44(s,9H),1.24-1.12(m,2H). 19 F NMR(471MHz,CDCl 3 )δ-97.85(s)。
Compound 2-b (100mg, 0.4 mmol) was dissolved in 4M HCl 1,4-dioxane (5 mL) and stirred for 1 hour at 25 ℃. The reaction mixture was concentrated under reduced pressure to give compound 2-c as a white solid (73 mg, yield 99%). 1 H NMR(500MHz,DMSO-d 6 )δ8.25(s,3H),3.10(s,1H),2.40(d,J＝14.5Hz,2H),2.01(d,J＝12.1Hz,2H),1.96-1.84(m,2H),1.42-1.30(m,2H)。
Compound 2-d (50mg, 0.08mmol, see for synthesis WO 2021/061643), compound 2-c (17.9mg, 0.096mmol), cesium carbonate (106mg, 0.32mmol), brettphos Pd G4 (7.3mg, 0.008mmol), and 2-bicyclohexylphosphine-2 ',6' -diisopropoxybiphenyl (7.3mg, 0.016mmol) were added in this order to a microwave reaction tube, followed by addition of anhydrous 1,4-dioxane solution (2 mL) and reaction at 110 ℃ for 16 hours under a nitrogen atmosphere. Water (2 mL) and ethyl acetate (3X 5 mL) were added for extraction, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product. The crude product was purified by Prep-TLC separation (dichloromethane: methanol = 15. Compound 2-e was obtained as a pale yellow solid (40mg, 72.2%). MS (ES) + ,m/z):682.8[M+H] + 。 1 H NMR(500MHz,DMSO-d 6 )δ7.53(d,J＝8.0Hz,1H),7.32-7.50(m,2H),7.15(t,J＝8.0Hz,1H),6.65(d,J＝8.2Hz,1H),6.62(s,1H),6.31(d,J＝7.8Hz,1H),4.95-4.36(m,4H),3.93(s,3H),3.89-3.63(m,1H),3.57-3.44(m,1H),3.08(s,3H),2.56-2.44(m,2H),2.22-2.15(m,2H),2.05-1.97(m,2H),1.44-1.28(m,11H)。
Compound 2-e (20mg, 0.029mmol) was dissolved in 4M HCl solution of 1,4-dioxane (2 mL), and stirred at 25 ℃ for 0.5 h. TLC monitored the reaction completion, and the reaction was concentrated under reduced pressure. After lyophilization, compound 2 hydrochloride was obtained as a pale yellow solid (1695g, 85.7%). MS (ES) + ,m/z):582.7[M+H] + 。 1 H NMR(500MHz,DMSO-d 6 )δ7.39(dd,J＝8.4,1.9Hz,1H),7.26(d,J＝1.9Hz,1H),7.23-7.16(m,1H),7.16-7.12(m,1H),6.90(d,J＝8.4Hz,1H),6.82-6.43(m,2H),5.09-5.01(m,2H),4.38(s,2H),4.32(s,1H),3.90(s,3H),3.82(m,2H),3.39(s,1H),3.10(s,3H),2.44-2.39(m,2H),2.05-1.99(m,2H),1.98-1.89(m,2H),1.47-1.38(m,2H)。
EXAMPLE 3 preparation of Compound 3
Sodium hydride (60%, 48mg,1.2 mmol) was dispersed in THF (3 mL) under a nitrogen atmosphere, the temperature was lowered to-78 deg.C, triethyl phosphonoacetate (250mg, 1.2 mmol) was slowly added dropwise thereto, and after the addition was completed, the mixture was warmed to room temperature and stirred for 0.5 hour. The reaction mixture was cooled to zero, compound 3-a (213mg, 1mmol) was added thereto, stirred at room temperature for 2 hours, added with saturated aqueous sodium bicarbonate (5 mL), extracted with ethyl acetate (5 mL × 3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was isolated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1). Compound 3-b was obtained as a white solid (260 mg, yield 92%). 1 H NMR(500MHz,CDCl 3 )δ5.62(s,1H),4.45(s,1H),4.13(m,2H),3.68(s,1H),3.62(d,J＝14.1Hz,1H),2.27(dd,J＝18.7,14.7Hz,2H),2.17(dd,J＝22.0,9.3Hz,1H),2.07(t,J＝11.8Hz,2H),1.43(s,9H),1.35-1.28(m,2H),1.25(d,J＝7.1Hz,3H)。
Under nitrogen atmosphere, compound 3-b (347mg, 1.225mmol) was dissolved in anhydrous tetrahydrofuran (5 mL), cooled to-78 deg.CDiisobutylaluminum hydride (2.55mL, 2.55mmol) was slowly added dropwise, and the reaction mixture was stirred at-78 ℃ for 1 hour. The reaction solution was warmed to zero degrees, water (0.15 mL), 15% aqueous sodium hydroxide solution (0.15 mL), and water (0.3 mL) were added dropwise in this order, the reaction mixture was warmed to room temperature and stirred for 15 minutes, an appropriate amount of anhydrous sodium sulfate was added, stirring was carried out for 15 minutes, filtration was carried out, the filtrate was concentrated under reduced pressure, and the resulting crude product was separated and purified by silica gel column chromatography to give compound 3-c (250mg, 85%). 1 H NMR(500MHz,CDCl 3 )δ5.40(t,J＝7.0Hz,1H),4.43(s,1H),4.14(d,J＝3.0Hz,2H),3.62(s,1H),2.60-2.51(m,1H),2.23(m,1H),2.14(t,J＝12.7Hz,1H),2.06-1.97(m,2H),1.97-1.89(m,1H),1.44(s,9H),1.24-1.19(m,2H)。
Compound 3-c (242mg, 1.0 mmol) was dissolved in dichloromethane (8 mL), diisopropylethylamine (390mg, 3mmol) and methanesulfonyl chloride (173mg, 1.5 mmol) were added dropwise under ice-cooling, and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was added with saturated brine, extracted with dichloromethane (20mL × 3), the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude compound 3-d (319 mg) which was used directly in the next reaction.
Compound 3-d (319mg, 1.0mmol), sodium iodide (15mg, 0.1mmol), dimethylamine (1.0M in THF,5.5mL, 5.5mmol) were dissolved in acetonitrile (6 mL). The reaction mixture was heated and stirred in a sealed tube at 60 ℃ for 3 hours. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane: methanol = 15. MS (ES) + ,m/z):269.5[M+H] + 。 1 H NMR(500MHz,DMSO-d 6 )δ6.79(d,J＝7.7Hz,1H),5.27(t,J＝7.7Hz,1H),3.64(d,J＝7.7Hz,2H),2.65(s,6H),2.59(d,J＝14.3Hz,1H),2.25(d,J＝13.6Hz,1H),2.10(t,J＝12.5Hz,1H),1.88(t,J＝13.2Hz,1H),1.82(d,J＝8.8Hz,2H),1.37(s,10H),1.27-1.16(m,2H)。
Compound 3-e (20mg, 0.074mmol) was dissolved in 4M HCl solution of 1,4-dioxane (3 mL) and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and lyophilized to give compound 3-f (10 mg, yield 66%) as a white solid. 1 H NMR(500MHz,DMSO-d 6 )δ10.81(s,1H),δ8.31(s,3H),5.34(t,J＝7.7Hz,1H),3.66(d,J＝5.2Hz,2H),3.56(s,1H),3.24-3.12(m,1H),2.69(m,1H),2.65(s,6H),2.32(m,1H),2.14(m,1H),2.04(m,2H),1.95-1.85(m,1H),1.50-1.34(m,2H)。
Under a nitrogen atmosphere, compound 2-d (15mg, 0.024mmol), compound 3-f (6mg, 0.029mmol), cesium carbonate (31.8mg, 0.097mmol), brettphos Pd G4 (2.2 mg, 0.0024mmol), 2-dicyclohexylphosphorus-2 ',6' -diisopropoxy-1,1 ' -biphenyl (2.2 mg, 0.0048mmol), and 1,4-dioxane solution (1 mL) were reacted at 110 ℃ for 16 hours in a sealed tube. After the reaction mixture was cooled, water (2 mL) was added, and extraction was performed with ethyl acetate (3X 5 mL), and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was isolated and purified by preparative thin layer chromatography (dichloromethane: methanol = 15). MS (ES) + ,m/z):703.8[M+H] + 。 1 H NMR(500MHz,DMSO-d 6 )δ7.58(s,1H),7.53(s,2H),7.09(s,1H),7.03(t,J＝8.0Hz,1H),6.70(d,J＝8.4Hz,1H),6.22(d,J＝7.9Hz,1H),5.50(d,J＝8.0Hz,1H),5.20(t,J＝7.2Hz,1H),4.93-4.83(m,2H),4.80-4.50(m,2H),3.92(s,3H),3.62-3.51(m,1H),3.27(s,3H),3.01-2.88(m,2H),2.32-2.12(m,8H),2.10-2.03(m,2H),1.96-1.88(m,1H),1.46-1.24(m,12H)。
Compound 3-g (8mg, 0.011mmol) was dissolved in dichloromethane (0.5 mL) and a solution of 4M hydrochloric acid in 1,4-dioxane (0.1mL, 0.4 mmol) was added. The mixture was stirred at 25 ℃ for 2 hours. Concentrating the reaction solution, adjusting pH with methanol solution of ammonia>7. Purification by preparative thin layer chromatography (dichloromethane: methanol = 15) gave compound 3 as a brown solid (1.3mg, 19%). MS (ES) + ,m/z):603.7[M+H] + 。 1 H NMR(500MHz,DMSO-d 6 )δ8.26(s,1H),7.39(dd,J＝8.3,1.8Hz,1H),7.25(d,J＝1.8Hz,1H),7.08(s,1H),7.01(t,J＝8.0Hz,1H),6.89(d,J＝8.4Hz,1H),6.68(d,J＝8.2Hz,1H),6.50(t,J＝6.2Hz,1H),6.20(d,J＝7.9Hz,1H),5.48(d,J＝8.0Hz,1H),5.19(t,J＝7.0Hz,1H),4.93(q,J＝9.0Hz,2H),4.36(d,J＝6.2Hz,2H),3.90(s,3H),3.10(s,3H),2.87(d,J＝7.1Hz,2H),2.15(s,6H),2.05-1.95(m,4H),1.94-1.86(m,2H),1.34-1.27(m,2H)。
Example 4 preparation of Compound 4
Compound 4-a (171mg, 1mmol) was dissolved in DMF (2.5 mL), and NaSMe (140mg, 2mmol) was added. The reaction mixture was stirred at 25 ℃ for 2 hours. After the reaction was monitored by TLC, water (5 mL) was added to the reaction mixture, MTBE (5 mL. Times.3) was extracted, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was isolated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10) to obtain compound 4-b as a yellow solid (150 mg, yield 75%). MS (ES) + ,m/z):200.3[M+H] + 。 1 H NMR(500MHz,MeOD)δ7.83(d,J＝8.6Hz,1H),7.04(d,J＝1.8Hz,1H),6.91(dd,J＝8.6,1.9Hz,1H),3.96(s,3H),2.57(s,3H).
Compound 4-b (40mg, 0.2mmol) was dissolved in methanol (3 mL), and NaIO was added 4 (35mg, 0.16mmol) in water (1 mL). The reaction mixture was stirred at 25 ℃ for 16 hours. After the reaction was monitored by TLC, water (5 mL) was added to the reaction mixture, ethyl acetate (5 mL × 3) was extracted, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was isolated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:2) to give compound 4-c as a yellow solid (25 mg, yield 58%). MS (ES) + ,m/z):216.3[M+H] + 。 1 H NMR(500MHz,MeOD)δ7.97(d,J＝8.3Hz,1H),7.62(d,J＝1.6Hz,1H),7.37(dd,J＝8.3,1.7Hz,1H),4.04(s,3H),2.87(s,3H)。
Compound 4-c (30mg, 0.14mmol) was dissolved in dichloromethane (2 mL) under a nitrogen atmosphere, mgO (23mg, 0.56mmol) was added, and after stirring for two minutes, trifluoroacetamide (32mg, 0.28mmol), phI (OAc) were added in this order 2 (68mg,0.21mmol),Rh 2 (OAc) 4 (1.6mg, 0.035mmol). The reaction mixture was stirred at 25 ℃ for 16 hours. TLC monitoring reaction is finished, water (5 mL) is added into reaction liquid, dichloromethane (5 mL x 3) is used for extraction, organic phase is washed by saturated saline solution, anhydrous sodium sulfate is used for drying, and after filtration, filtrate is decompressed and concentrated to obtain crude product. The crude product was isolated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1). Compound 4-d was obtained as a yellow solid (24 mg, yield 52%). MS (ES) + ,m/z):327[M+H] + 。 1 H NMR(500MHz,CDCl 3 )δ7.99(d,J＝8.4Hz,1H),7.72(d,J＝1.8Hz,1H),7.61(dd,J＝8.4,1.8Hz,1H),4.07(s,3H),3.49(s,3H).
Compound 4-d (30mg, 0.1mmol) was dissolved in methanol (10 mL) under a hydrogen atmosphere, and Pd/C (5 mg) was added. The reaction mixture was stirred at 25 ℃ for 4 hours. After the reaction was monitored by TLC, methanol (2 mL) was added to dilute the reaction solution, and after filtration the filtrate was concentrated under reduced pressure to give the crude product. The crude product was isolated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1). Compound 4-e was obtained as a gray solid (20 mg, yield 67%). MS (ES) + ,m/z):297.3[M+H] + 。 1 H NMR(500MHz,CDCl 3 )δ7.39(dd,J＝8.4,2.1Hz,1H),7.25(d,J＝2.1Hz,1H),6.74(d,J＝8.4Hz,1H),4.54(s,2H),3.90(s,3H),3.40(s,3H).
Compound 4-e (150mg, 0.5mmol) was dissolved in (Boc) 2 In O (2 mL), the reaction mixture was heated to 90 ℃ and stirred for 16 hours. TLC was used to monitor the completion of the reaction, and the reaction mixture was cooled to room temperature and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1). Compound 4-f was obtained as a white solid (160 mg, yield 81%). MS (ES) + ,m/z):397.4[M+H] + 。 1 H NMR(500MHz,CDCl 3 )δ8.38(d,J＝8.7Hz,1H),7.54(dd,J＝8.7,2.1Hz,1H),7.40(d,J＝2.1Hz,1H),7.34(s,1H),3.97(s,3H),3.43(s,3H),1.53(s,9H).
Compound 4-f (600mg, 1.5 mmol) was dissolved in DMF (20 mL), and cesium carbonate (975mg, 3mmol) and bromopropyne (360mg, 3mmol) were added. The reaction mixture was stirred at room temperature for 16 hours. TLC monitoring reaction, water (20 mL), ethyl acetate (10 mL x 3) extraction, organic phase by saturated saline water washing, anhydrous sodium sulfate drying, filtering, filtrate decompression concentration to obtain crude product. The crude product was isolated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1). Yield 4-g (420 mg, yield 82.8%) of compound as a colorless liquid. MS (ES) + ,m/z):339.5[M+H] + 。 1 H NMR(500MHz,CDCl 3 ) δ 7.63-7.57 (m, 1H), 7.54 (t, J =2.2hz, 1h), 7.46 (bs, 1H), 7.29 (d, J =8.1hz, 1h), 4.29 (bs, 2H), 3.90 (m, 3H), 3.11 (m, 3H), 2.18 (t, J =2.3hz, 1h), 1.42 (s, 9H). Compound 4-g (280mg, 0.83mmol) was dissolved in (Boc) 2 In O (3 mL), the reaction mixture roseThe mixture was warmed to 90 ℃ and stirred for 16 hours. TLC was used to monitor the completion of the reaction, and the reaction mixture was cooled to room temperature and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1). Compound 4-i was obtained as a white solid (350 mg, yield 94%). MS (ES) + ,m/z):439.5[M+H] + 。 1 H NMR(500MHz,CDCl 3 )δ7.57-7.53(m,1H),7.49(d,J＝1.7Hz,1H),7.32(d,J＝8.2Hz,1H),4.32(bs,2H),3.91(s,3H),3.25(s,3H),2.18(t,J＝2.3Hz,1H),1.40(s,9H),1.39(s,9H).
Under a nitrogen atmosphere, compound 4-i (200mg, 0.456 mmol) was dissolved in DMF (3 mL) and triethylamine (3 mL), and CuI (13mg, 0.68mmol), (Ph) was added 3 P) 2 PdCl 2 (1695g, 0.023mmol), compound 1-f (240mg, 0.5636 mmol), and the reaction mixture was stirred at room temperature for 2 hours. TLC to monitor the reaction, add water (10 mL), extract with ethyl acetate (10mL x 3), wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the crude product. The crude product was isolated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:2). Compound 4-J was obtained as a pale yellow solid (250 mg, yield 71.5%). MS (ES) + ,m/z):716.7[M+H] + 。 1 H NMR(500MHz,CDCl 3 )δ7.54-7.49(m,3H),7.33(d,J＝7.8Hz,1H),7.23(d,J＝8.4Hz,1H),7.14(t,J＝7.9Hz,1H),6.79(s,1H),5.04-4.37(m,4H),3.92(d,J＝11.7Hz,3H),3.25(d,J＝8.4Hz,3H),1.43-1.36(m,18H).
Under a nitrogen atmosphere, compound 4-J (50mg, 0.07mmol) was dissolved in anhydrous dioxane, and Brettphos (4.5mg, 0.0049mmol), ruphos (4.5mg, 0.0098mmol), cesium carbonate (91mg, 0.28mmol), and compound 1-h (17mg, 0.085mmol) were added in this order. The temperature of the reaction mixture is raised to 100 ℃, and the reaction mixture is stirred for 16 hours. TLC to monitor the reaction, add water (10 mL), extract with ethyl acetate (10mL x 3), wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the crude product. The crude product was isolated and purified by silica gel column chromatography (dichloromethane: methanol = 20. Purification again by silica gel thin layer chromatography (dichloromethane: methanol = 20) gave compound 4-k (15 mg, yield 28%) as a pale yellow solid. MS (ES) + ,m/z):766.9[M+H] + 。 1 H NMR(500MHz,CDCl 3 )δ7.59-7.44(m,3H),7.14(t,J＝8.0Hz,1H),6.71-6.69(m,2H),6.29(d,J＝7.7Hz,1H),4.87(d,J＝48.6Hz,1H),4.64-4.56(m,4H),4.19(s,1H),3.93(s,3H),3.61-3.56(m,1H),3.33-3.26(m,1H),3.23(s,3H),2.99(m,1H),2.40(s,3H),2.32-2.23(m,1H),2.12-1.90(m,3H),1.38(s,18H).
Compound 4-k (15mg, 0.019mmol) was dissolved in 4M HCl/dioxane (2 mL) and stirred at 25 ℃ for 1h. TLC monitoring reaction is finished, the reaction solution is decompressed and concentrated, and NH is dripped 3 Adjusting pH to 8 with MeOH (0.5 mL), adding water (5 mL), extracting with ethyl acetate (5 mL. Times.3), washing the organic phase with saturated brine, drying over anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure to obtain the crude product. The crude product was isolated and purified by silica gel column chromatography (dichloromethane: methanol = 15. Purification by silica gel thin layer chromatography (dichloromethane: methanol =15 = 1) gave compound 4 (8 mg, yield 72.1%) as a pale yellow solid after lyophilization. MS (ES) + ,m/z):566.6[M+H] + 。 1 HNMR(500MHz,DMSO-d 6 )δ7.42(dd,J＝8.3,2.0Hz,1H),7.30(d,J＝2.0Hz,1H),7.19(s,1H),7.01(t,J＝8.0Hz,1H),6.87(d,J＝8.4Hz,1H),6.74(d,J＝8.2Hz,1H),6.33(t,J＝6.3Hz,1H),6.24(d,J＝7.8Hz,1H),5.52(d,J＝8.7Hz,1H),4.93(q,J＝9.2Hz,2H),4.82(d,J＝49.3Hz,1H),4.35(d,J＝6.3Hz,2H),3.88(s,3H),3.82(bs,1H),3.60-3.51(m,1H),3.05(m,1H),2.99(s,3H),2.82(d,J＝10.8Hz,1H),2.20(s,3H),2.11(m,1H),1.95-1.91(m,2H),1.70(d,J＝12.6Hz,1H).
EXAMPLE 5 preparation of Compound 5
Cyclopropanol (200mg, 3.42mmol) was dissolved in tetrahydrofuran (10 mL), sodium hydride (140mg, 3.42mmol) was added in portions at 0 deg.C, stirred at 0 deg.C for 30 minutes, then compound 5-a (500mg, 2.28mmol) in tetrahydrofuran was added, and the reaction was monitored by TLC to be complete. The reaction was quenched with ice water, extracted with ethyl acetate (3 × 10 mL), the organic phase washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The crude product was isolated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to give compound 5-b as a yellow solid (450mg, 76.7%). 1 HNMR(500MHz,CDCl 3 )δ8.02(d,J＝1.8Hz,1H),7.92(d,J＝8.3Hz,1H),7.62(dd,J＝8.3,1.8Hz,1H),4.00-3.97(m,1H),3.12(s,3H),0.97-0.92(m,4H)
Compound 5-b (450mg, 1.75mmol) was dissolved in ethyl acetate (20 mL) under a nitrogen atmosphere, pd/C (100 mg) was added, and the flask was replaced with nitrogen as hydrogen. The reaction mixture was stirred at 25 ℃ for 4 hours. And monitoring the reaction by TLC, adding kieselguhr and ethyl acetate, filtering, and concentrating the filtrate under reduced pressure to obtain a crude product. The crude product was isolated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) to yield compound 5-c as a gray solid (350mg, 88.1%). MS (ES) + ,m/z):228.3[M+H] + 。 1 H NMR(500MHz,CDCl 3 )δ7.61(d,J＝2.1Hz,1H),7.39(dd,J＝8.2,2.0Hz,1H),6.73(d,J＝8.2Hz,1H),4.25(s,2H),3.85-3.81(m,1H),3.03(s,3H),0.90-0.82(m,2H),0.84-0.77(m,2H)
Compound 5-c (320mg, 1.47mmol) was dissolved in anhydrous tetrahydrofuran (5 mL) under a nitrogen atmosphere, and di-tert-butyl dicarbonate (642mg, 2.94mmol) and DMAP (180mg, 1.47mmol) were added in this order. The reaction mixture was stirred at 70 ℃ for 4 hours. After the reaction was cooled by LCMS, water (5 mL) was added, ethyl acetate (10mL × 3) was extracted, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was isolated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) to give compound 5-d as a white solid (520mg, 86.4%). MS (ES) + ,m/z):428.4[M+H] + 。 1 HNMR(500MHz,CDCl 3 )δ7.81(d,J＝2.0Hz,1H),7.54(dd,J＝8.1,2.0Hz,1H),7.29(d,J＝8.1Hz,1H),3.85(m,1H),3.08(s,3H),1.41(s,18H),0.88-0.84(m,2H),0.80-0.75(m,2H)
Compound 5-d (320mg, 0.75mmol) was dissolved in a methanol solution (30 mL), and anhydrous potassium carbonate (518mg, 3.75mmol) was added thereto, followed by stirring at room temperature overnight. LCMS check reaction complete. The methanol solution was distilled under reduced pressure and extracted by the addition of water (10 mL) and ethyl acetate (3X 20 mL). Washing the organic phase with saturated saline solution, drying with anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 4:1) to give a colorless oily compound5-e(230mg，93.9％)。MS(ES + ,m/z):272.3[M-(t-Bu)+H] + 。 1 HNMR(500MHz,CDCl 3 )δ8.30(d,J＝8.6Hz,1H),7.71(d,J＝2.1Hz,1H),7.55(dd,J＝8.5,2.0Hz,1H),7.13(s,1H),3.88-3.83(m,1H),3.05(s,3H),1.53(s,9H),0.94-0.89(m,2H),0.88-0.85(m,2H)
Compound 5-e (230mg, 0.7 mmol) was dissolved in anhydrous DMF (5 mL) under a nitrogen atmosphere, and cesium carbonate (682mg, 2.1mmol) and bromopropyne (250mg, 2.1mmol) were added in this order. The reaction mixture was stirred at room temperature for 3h. After completion of the reaction, LCMS was used to monitor that water (5 mL) and ethyl acetate (3X 10mL) were added to the reaction solution for extraction, and the organic phase was washed with saturated brine for 3 times, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was isolated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 4:1). Compound 5-f was obtained as a yellow solid (250mg, 97.3%). MS (ES) + ,m/z):310.3[M-(t-Bu)+H] + 。 1 HNMR(500MHz,CDCl 3 )δ7.81(d,J＝1.9Hz,1H),7.54(dd,J＝8.2,2.0Hz,1H),7.45(s,1H),4.24(s,2H),3.84(s,1H),3.09(s,3H),2.17(s,1H),1.41(s,9H),0.88-0.85(m,2H),0.81-0.78(m,2H)
Compound 5-f (100mg, 0.27mmol), compound 1-f (128mg, 0.3mmol), cuprous iodide (10mg, 0.05mmol), bis (triphenylphosphine) palladium dichloride (10mg, 0.014mmol) were dissolved in DMF (2 mL) and triethylamine (1 mL) under a nitrogen atmosphere, the mixture was stirred at room temperature for 1 hour, LCMS monitored for completion of the reaction, the reaction solution was extracted with water (3 mL) and ethyl acetate (3X 5 mL), the organic phase was washed three times with saturated brine, then dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product, which was isolated and purified by silica gel column chromatography (petroleum ether: ethyl acetate 3:1). This gave 5-g (95mg, 54.8%) of compound as a yellow solid. LCMS (ES, m/z): MS (ES) + ,m/z):585.4,587.4[M-(t-Bu)+H] + 。 1 HNMR (500MHz, DMSO-d 6) delta 7.85-7.82 (m, 1H), 7.64 (d, J =8.3Hz, 1H), 7.56 (s, 2H), 7.37 (d, J =7.5Hz, 1H), 7.26-7.20 (m, 1H), 6.77 (s, 1H), 5.09 (d, J =9.2Hz, 2H), 4.62 (s, 2H), 4.06 (s, 1H), 3.27 (s, 3H), 1.37 (s, 9H), 0.85 (m, 2H), 0.67 (m, 2H). The compound 5-g (40mg, 0.062mmol) compound 1-H (16mg, 0.074mmol), cesium carbonate (60mg, 0.186mmol), bretphos (4mg, 0.004mmol), rutphos (4mg, 0.080.084 mmol) in turnAdded to the microwave tube, followed by addition of anhydrous dioxane solution (2 mL), stirring with nitrogen gas for 10 minutes using a long needle, and sealing the microwave tube. The reaction mixture was stirred at 110 ℃ for 16 hours. LCMS monitor reaction completion. Water (2 mL) and ethyl acetate (3 × 5 mL) were added for extraction, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product which was isolated and purified by silica gel column chromatography (dichloromethane: methanol = 20. This gave 5-h (10mg, 23.1%) as a yellow solid. MS (ES) + ,m/z):693.8[M+H] + 。 1 HNMR(500MHz,CDCl 3 )δ7.84(s,1H),7.54(d,J＝7.8Hz,1H),7.44(s,1H),7.14(t,J＝8.0Hz,1H),6.74-6.66(m,2H),6.29(d,J＝7.8Hz,1H),4.85(d,J＝48.9Hz,1H),4.60-4.54(m,4H),3.85(s,1H),3.56(dd,J＝28.4,11.6Hz,1H),3.29-3.20(m,1H),3.08(s,3H),2.97(d,J＝12.0Hz,1H),2.35(s,3H),2.28-2.13(m,2H),1.94-1.88(m,2H),1.37(s,9H),0.87-0.86(m,2H),0.84-0.76(m,2H).
Compound 5-h (10mg, 0.014mmol) was dissolved in a hydrogen chloride dioxane solution, stirred at room temperature for 1 hour, and the reaction was monitored by LCMS to be completed. The reaction mixture was concentrated, ethyl acetate and triethylamine were added, and separation was performed by Prep-TLC to obtain Compound 5 (3mg, 35.1%). MS (ES) + ,m/z):593.7[M+H] + 。 1 HNMR(500MHz,CDCl 3 )δ7.62(d,J＝2.0Hz,1H),7.53(dd,J＝8.4,2.0Hz,1H),7.14(t,J＝8.0Hz,1H),6.80(d,J＝8.4Hz,1H),6.76(s,1H),6.70(d,J＝8.2Hz,1H),6.29(d,J＝7.7Hz,1H),5.02(t,J＝6.3Hz,1H),4.89(d,J＝46.7Hz,2H),4.59(q,J H,F ＝8.5Hz,2H),4.32(d,J＝6.3Hz,2H),3.88-3.81(m,1H),3.66-3.61(m,1H),3.31-3.28(m,1H),3.04(s,3H),2.44(s,3H),3.03-3.01(m,1H),2.08-1.97(m,4H),0.89-0.85(m,2H),0.84-0.80(m,2H).
Example 6 preparation of Compound 6
Compound 6-a (507mg, 6.84mmol) was dissolved in THF (20 mL) under nitrogen, naH (280mg, 6.84mmol) was added, the mixture was stirred in an ice-water bath for ten minutes, and oxetan-3-ol (1g, 4.56mmol) was added. Reaction(s) ofThe mixture was stirred at room temperature for sixteen hours. TLC to monitor the reaction, add water (10 mL), extract with ethyl acetate (10mL x 3), wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the crude product. The crude product was isolated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1). Compound 6-b was obtained as a white solid (1 g, yield 80%). MS (ES) + ,m/z):274[M+H] + 。 1 H NMR(500MHz,CDCl 3 )δ7.99(d,J＝8.3Hz,1H),7.66(dd,J＝8.3,1.7Hz,1H),7.20(d,J＝1.6Hz,1H),5.45-5.39(m,1H),5.07-5.02(m,2H),4.83(m,2H),3.09(s,3H).
Compound 6-b (30mg, 0.109mmol) was dissolved in methanol (5 mL) under hydrogen atmosphere, and Pd/C (10 mg) was added. The reaction mixture was stirred at 25 ℃ for 4 hours. After the reaction was monitored by TLC, methanol (10 mL) was added to dilute the reaction solution, and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was isolated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1). Compound 6-c was obtained as a white solid (22 mg, yield 74%). MS (ES) + ,m/z):244[M+H] + 。 1 H NMR(500MHz,CDCl 3 )δ7.40(dd,J＝8.3,1.9Hz,1H),6.83(d,J＝1.8Hz,1H),6.78(m,1H),5.32-5.25(m,1H),5.03(m,2H),4.76(m,2H),4.44(s,2H),2.99(s,3H).
Compound 6-c (350mg, 1.44mmol) was dissolved in (Boc) 2 O (10 mL), the reaction mixture was heated to 80 ℃ and stirred for three hours. After the reaction was monitored by TLC, it was cooled to room temperature and purified by wet column chromatography on silica gel (petroleum ether: ethyl acetate = 1:1). Compound 6-d was obtained as a white solid (300 mg, yield 61%). MS (ES) + ,m/z):344[M+H] + 。 1 H NMR(500MHz,CDCl 3 )δ7.99(d,J＝7.8Hz,1H),7.48(d,J＝2.1Hz,1H),7.44(dd,J＝8.7,2.2Hz,1H),4.33-4.27(m,1H),4.16(m,1H),3.88-3.80(m,2H),3.59(m,1H),3.03(s,3H),1.55(s,9H).
Compound 6-d (270mg, 0.786 mmol) was dissolved in DMF (5 mL), and cesium carbonate (770 mg, 2.36mmol) and bromopropyne (290mg, 2.36mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. TLC to monitor the reaction, water (10 mL) was added, ethyl acetate (10mL. Times.3) was extracted, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressureTo obtain a crude product. The crude product was isolated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1). Compound 6-e was obtained as a pale yellow solid (100 mg, yield 33%). MS (ES) + ,m/z):326[M+H] + 。 1 H NMR(500MHz,CDCl 3 )δ8.01(d,J＝8.8Hz,1H),7.48(d,J＝2.3Hz,1H),7.44(dd,J＝8.7,2.3Hz,1H),4.37(m,1H),4.24(t,J＝1.9Hz,2H),4.20(m,1H),3.80(m,1H),3.73(m,1H),3.54(m,1H),3.02(s,3H),2.48(t,J＝2.4Hz,1H),1.56(s,9H).
Compound 6-e (95mg, 0.25mmol), compound 1-f (128mg, 0.3mmol), cuprous iodide (9.5mg, 0.05mmol), bis (triphenylphosphine) palladium dichloride (9mg, 0.013mmol) were dissolved in DMF (2 mL) and triethylamine (2 mL) under nitrogen atmosphere, the mixture was stirred at room temperature for 2 hours, LCMS monitored for completion of the reaction, the reaction solution was extracted with water (3 mL) and ethyl acetate (3x10 mL), the organic phase was washed three times with saturated brine, then dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product, which was isolated and purified by silica gel column chromatography (petroleum ether: ethyl acetate 4:1). Compound 6-f was obtained as a yellow solid (130mg, 79.4%). MS (ES, m/z) 601.3,603.3[ M-tBu + H] + 。 1 HNMR(500MHz,CDCl 3 )δ7.49(d,J＝2.3Hz,1H),7.44(dd,J＝8.7,2.2Hz,1H),7.35(d,J＝7.6Hz,1H),7.26(s,2H),7.18(t,J＝7.9Hz,1H),6.91(s,1H),4.77(q,J＝8.4Hz,2H),4.56(d,J＝1.6Hz,2H),4.40(m,1H),4.24(m,1H),3.88(m,1H),3.81(m,1H),3.55(m,1H),3.00(s,3H),1.54(s,9H)。
Compounds 6-f (115mg, 0.175mmol), compounds 1-h (43mg, 0.21mmol), cesium carbonate (228mg, 0.7mmol), brettphos (11.3mg, 0.012mmol), ruphos (11.4mg, 0.024mmol) were added to a microwave tube in this order, followed by addition of anhydrous dioxane solution (2 mL), stirring with nitrogen gas using a long needle deep into the solution for 10 minutes, and the microwave tube was sealed. The reaction mixture was stirred at 110 ℃ for 16 hours. LCMS monitor reaction complete. Water (2 mL), ethyl acetate (3 × 10 mL) was added, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product which was isolated and purified by silica gel column chromatography (dichloromethane: methanol = 20. Yield 6-g (34mg, 27.4%) as a yellow solid. MS (ES, m/z) 709.8[ M + H ]] + 。 1 HNMR(500MHz,CDCl 3 )δ8.02(d,J＝8.7Hz,1H),7.50(d,J＝2.2Hz,1H),7.44(dd,J＝8.8,2.2Hz,1H),7.17(t,J＝8.0Hz,1H),6.83(s,1H),6.73(d,J＝8.3Hz,1H),6.31(d,J＝7.7Hz,1H),4.86(d,J＝49.1Hz,1H),4.72(q,J＝8.5Hz,2H),4.55(s,2H),4.42-4.38(m,1H),4.23(d,J＝13.7Hz,1H),3.88(m,1H),3.81(m,1H),3.63-3.51(m,2H),3.30-3.21(m,1H),3.01(s,3H),2.35(s,3H),2.28-2.12(m,2H),2.02-1.87(m,2H),1.54(s,9H)。
6-g (10mg, 0.014mmol) of the compound was dissolved in methylene chloride (0.5 mL), and trifluoroacetic acid was added dropwise thereto (0.5 mL), followed by stirring at room temperature for 1 hour and completion of the reaction was monitored by LCMS. The reaction solution was adjusted to pH =8 by dropwise addition of methanolic ammonia solution, and after concentration, it was fractionated by Prep-TLC to obtain Compound 6 (3mg, 35.1%). MS (ES, m/z) 609.7[ m + H ]] + 。 1 HNMR(500MHz,CDCl 3 )δ7.37(s,1H),7.33(d,J＝8.4Hz,1H),7.17(t,J＝8.0Hz,1H),6.83(s,1H),6.73(d,J＝8.3Hz,1H),6.63(d,J＝8.3Hz,1H),6.31(d,J＝7.7Hz,1H),4.87(d,J＝49.1Hz,1H),4.70(q,J＝8.5Hz,2H),4.55(s,2H),4.36-4.34(m,2H),4.24(bs,1H),3.87(m,1H),3.80(m,1H),3.64-3.55(m,1H),3.52(d,J＝12.0Hz,1H),3.40(m,1H),3.26(t,J＝11.2Hz,1H),2.97(s,3H),2.36(s,3H),2.33-2.23(m,1H),2.18(t,J＝11.4Hz,1H),2.05-2.03(m,1H),1.93(q,J＝12.1Hz,1H)。
Example 7 preparation of Compound 7
Compound 7-a (2.53g, 13.96mmol, 1.0eq) was dissolved in (Boc) 2 O (30 mL), stirred at 110 ℃ for 3 hours. TLC monitored the reaction was complete and column chromatography purification (petroleum ether: ethyl acetate = 10) gave compound 7-b-1/7-b-2 (4.74 g) as a white solid which was used directly in the next reaction step.
The compound 7-b-1/7-b-2 (3.74g, 1.0 eq), K 2 CO 3 (3.86g, 27.92mmol,2.0 eq) was dissolved in methanol (30 mL) and reacted at 41 ℃ for 16h. DCM extraction and combining the organic phases, washing with saturated brine, drying over anhydrous sodium sulfate, filtration and concentration. Column chromatography separation and purification (petroleum ether: ethyl acetate = 10) gave compound 7-c (3.74g, 95%). LC-MS (ES) + ,m/z):282.1[M+H] + 。 1 H NMR(500MHz,CDCl 3 )δ8.16(d,J＝8.4Hz,1H)7.67(dd,J＝8.5,1.5Hz,1H),7.52(d,J＝1.5Hz,1H),7.26(s,1H),3.93(s,3H),3.89(s,3H),1.35(s,9H)。
Mixing the compounds 7-c (2.74g, 9.74mmol, 1.0eq), cs 2 CO 3 (9.52g, 29.22mmol, 3.0eq), 3-bromopropyne (3.48g, 29.22mmol, 3.0eq) was dissolved in DMF (50 mL), and the mixture was stirred at room temperature for 2 hours. TLC monitored the reaction was complete, water/MTBE extracted, spin dried, and column chromatography purified (petroleum ether: ethyl acetate = 10). LC-MS (ES) + ,m/z):319.2[M+H] + 。 1 H NMR(500MHz,CDCl3)δ7.63(dd,J＝8.0,1.55Hz,1H),7.58(s,1H),7.33(s,1H),4.27(s,2H),3.91(s,3H),3.87(s,3H),2.15(s,1H),1.38(s,9H)。
Compounds 7-d (400mg, 1.25mmol, 1.0eq), 1-f (640mg, 1.50mmol, 1.2eq), cuI (36mg, 0.188mmol, 0.15eq), (PPh) 3 ) 2 PdCl 2 (44mg, 0.063mmol, 0.05eq) was dissolved in a mixed solvent of triethylamine (10 mL) and DMF (5 mL) and reacted at room temperature under nitrogen atmosphere for 16h. TLC monitoring of the reaction was complete, triethylamine was spin dried, water/MTBE extracted spin dried, and purified by column chromatography (petroleum ether: ethyl acetate = 5:1) to afford compound 7-e as a yellow solid (398mg, 54%). LC-MS (ES) + ,m/z):539.4 541.3[M+H-56] + 。 1 H NMR(500MHz,CDCl3)δ7.66(d,J＝8.1Hz,1H),7.63(s,1H),7.34-7.29(m,2H),7.22(d,J＝8.2Hz,1H),7.14(t,J＝7.9Hz,1H),6.78(s,1H),4.73(bs,2H),4.60(q,J＝8.5Hz,2H),3.93(s,3H),3.91(s,3H),1.39(s,9H)。
Compounds 7-e (300mg, 0.504mmol, 1.0eq), 1-h (205mg, 0.68mmol, 1.3eq), cs were added 2 CO 3 (654mg, 2.02mmol, 4eq), bretPhos (44mg, 0.063mmol, 0.05eq), ruPhos (33mg, 0.07mmol, 0.14eq) were dissolved in dioxane (5 mL) and reacted at 110 ℃ for 16h under nitrogen. TLC monitored the reaction was complete, water/MTBE extracted and dried, and column chromatography purified (DCM: meOH = 50). LC-MS (ES) + ,m/z):647.6[M+H] + . Directly used for the next reaction.
The compound 7-f (100mg, 0.155mmol, 1.0eq) was dissolvedTo methanol (10 mL) was added LiOH (H) 2 Compound O) (32mg, 0.77mmol,5.0 eq). The reaction was stirred at 45 ℃ for 16 hours. TLC monitored the completion of the reaction, methanol was spun off and purified on a C-18 column to give 7-g (48mg, 48%) of the compound as a yellow solid. LC-MS (ES) + ,m/z):633.3[M-Li+2H] + 。
7-g (10.2mg, 0.016mmol, 1.0eq) of the compound was dissolved in DMF (2 mL), HATU (25mg, 0.080mmol, 5eq), methoxyamine hydrochloride (7 mg,0.080mmol, 5eq), DIPEA (21mg, 0.16mmol, 110eq) were added, and the reaction was carried out at room temperature for 16 hours. TLC reaction was complete, THF extracted, organic phase dried, filtered, concentrated under reduced pressure, and PTLC purified (DCM: meOH = 20) to afford 7-h (6.3mg, 60%) as a yellow solid.
Under nitrogen atmosphere, 7-h (6.2mg, 00094mmol, 1.0eq) was stirred in DCM (1 mL) and TFA (1 mL), reacted for 30min after completion of the reaction monitored by LC-MS, and the reaction solution was spin-dried. NH 3 free/MeOH (5 mL), purified by PTLC isolation (DCM: meOH =15 1) to give 7 as a yellow solid (2.6 mg, 49%). LC-MS (ES) + ,m/z):562.5[M+H] + 。 1 H NMR(500MHz,CDCl3)δ8.57(s,1H),7.32(s,1H),7.24(d,J＝8.6Hz,1H),7.14(t,J＝8.0Hz,1H),6.75(s,1H),6.70(t,J＝8.3Hz,2H),6.29(d,J＝7.7Hz,1H),5.00(m,1H),4.86(d,J＝48.5Hz,1H),4.57(q,J＝8.5Hz,2H),4.32(d,J＝6.1Hz,2H),4.18(m,1H),3.82(s,3H),3.88(s,3H).3.57(m,1H),3.28(t,J＝11.0Hz,1H),3.00(d,J＝10.0Hz,1H),2.39(s,3H),1.91-2.07(m,3H).
Example 8 preparation of Compound 8
7-g (33mg, 0.052mmol, 1.0eq) of the compound was dissolved in DMF (2 mL), and HATU (80mg, 0.258mmol, 5eq), O- (tetrahydro-2H-pyran-2-yl) hydroxylamine (30mg, 0.258mmol, 5eq), DIPEA (67mg, 0.52mmol, 10eq) were added to react at room temperature for 16 hours. TLC reaction was complete, THF extracted, organic phase dried, filtered, concentrated under reduced pressure, and PTLC separation purified (DCM: meOH = 20) to afford 8-a (27mg, 71%) as a yellow solid. LC-MS (ES) + ,m/z):732.4[M+H] + 。
Under nitrogen atmosphere, 8-a (27mg, 0.0368mmol, 1.0 eq) was stirred in DCM (5 mL) and TFA (2 mL) for 30min. NH 3 free/MeOH (5 mL), purified by PTLC isolation (DCM: meOH =15 1) to give 8 as a yellow solid (3.0 mg, 14%).
LC-MS(ES + ,m/z):548.30[M+H] + 。
Example 9 preparation of Compound 9
Compound 9-a (232mg, 1mmol) was dissolved in DMF (3.5 mL) under a nitrogen atmosphere, and K was added sequentially 3 PO 4 (255mg,1.2mmol)，Pd(OAc) 2 (12mg，0.05mmol)，Xantphos(58mg，0.1mmol),POEt 2 (160mg, 1.5mmol), and the reaction mixture was heated to 150 ℃ for fifty minutes by microwave reaction. TLC monitoring reaction is finished, the reaction liquid is cooled to room temperature, water (5 mL) is added, ethyl acetate (5 mL x 3) is used for extraction, the organic phase is washed by saturated saline solution, anhydrous sodium sulfate is used for drying, and after filtration, the filtrate is decompressed and concentrated to obtain a crude product. The crude product was isolated and purified by silica gel column chromatography (dichloromethane: methanol = 15. Compound 9-b was obtained as a black liquid (200 mg, yield 77.8%). MS (ES) + ,m/z):258.4[M+H] + 。 1 H NMR(500MHz,CDCl 3 )δ7.86(dd,J＝8.1,3.1Hz,1H),7.64(d,J＝11.5Hz,1H),7.10(dd,J＝13.0,4.6Hz,1H),4.03(s,3H),2.11-1.98(m,2H),1.92-1.81(m,2H),1.15(t,J＝7.7Hz,3H),1.11(t,J＝7.7Hz,3H).
Compound 9-b (1.3g, 5.054mmol) was dissolved in methanol (50 mL) under a hydrogen atmosphere, and Pd/C (300 mg) was added. The reaction mixture was stirred at 25 ℃ for 4 hours. After the reaction was monitored by TLC, methanol (20 mL) was added to dilute the reaction solution, and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was isolated and purified by silica gel column chromatography (dichloromethane: methanol = 20. Compound 9-c was obtained as a black liquid (1.1 g, 96% yield). MS (ES) + ,m/z):228.44[M+H] + 。 1 H NMR(500MHz,CDCl 3 )δ7.17(d,J＝11.4Hz,1H),6.94-6.88(m,1H),6.72(dd,J＝7.8,3.3Hz,1H),4.41-3.95(m,2H),3.87(s,3H),1.97-1.85(m,2H),1.85-1.74(m,2H),1.09(t,J＝7.9Hz,3H),1.06(t,J＝7.8Hz,3H)。
Compound 9-c (1.1g, 4.84mmol) was dissolved in (Boc) 2 O (10 mL), the reaction mixture was heated to 80 ℃ and stirred for three hours. The reaction was monitored by TLC, cooled to room temperature, and purified by wet column chromatography on silica gel (dichloromethane: methanol = 20. Compound D was obtained as a black liquid (1.5 g,95% yield).
MS(ES + ,m/z):328.45[M+H] + 。 1 H NMR(500MHz,CDCl 3 )δ8.19(d,J＝6.0Hz,1H),7.35(d,J＝11.4Hz,1H),7.23(s,1H),7.02(t,J＝9.3Hz,1H),3.93(s,3H),1.95(m,2H),1.84(m,2H),1.51(s,9H),1.11(t,J＝7.8Hz,3H),1.08(t,J＝8.0Hz,3H)。
Compound 9-d (1.2g, 3.65mmol) was dissolved in DMF (20 mL), and cesium carbonate (3.6g, 10.97mmol) and bromopropyne (1.4 g, 10.97mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. TLC to monitor the reaction, add water (10 mL), extract with ethyl acetate (10mL x 3), wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the crude product. The crude product was isolated and purified by silica gel column chromatography (dichloromethane: methanol = 20. Compound 9-e was obtained as a pale yellow solid (1.3 g, yield 97%). MS (ES) + ,m/z):366.46[M+H] + 。 1 H NMR(500MHz,CDCl 3 )δ7.40(d,J＝11.4Hz,1H),7.36(s,1H),7.08-7.00(m,1H),4.25(bs,2H),3.88(s,3H),2.17(s,1H),1.99(m,2H),1.87(m,2H),1.56-1.20(m,9H),1.13(t,J＝8.0Hz,3H),1.09(d,J＝7.6Hz,3H)。
Under a nitrogen atmosphere, compound 9-e (50mg, 0.137mmol) was dissolved in DMF (1 mL) and triethylamine (2 mL), and CuI (4mg, 0.02mmol), (Ph) was added 3 P) 2 PdCl 2 (5mg, 0.0068mmol), compound 1-f (70mg, 0.164mmol), and the reaction mixture was stirred at room temperature for 2 hours. TLC to monitor the reaction, add water (10 mL), extract with ethyl acetate (10mL x 3), wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the crude product. The crude product was isolated and purified by silica gel column chromatography (dichloromethane: methanol = 25. Compound 9-f was obtained as a pale yellow solid (60 mg, yield 68%). MS (ES) + ,m/z):641.6[M+H] + 。 1 H NMR(500MHz,CDCl 3 )δ7.46(dd,J＝7.6,4.4Hz,1H),7.36(d,J＝8.0Hz,1H),7.32(d,J＝7.7Hz,1H),7.23(d,J＝8.2Hz,1H),7.14(t,J＝7.9Hz,1H),7.05(t,J＝9.0Hz,1H),6.78(s,1H),4.66(m,4H),3.92(s,3H),2.00(m,2H),1.93-1.84(m,2H),1.34(m,9H),1.13(t,J＝8.1Hz,3H),1.10(t,J＝7.9Hz,3H)。
Under a nitrogen atmosphere, compound 9-f (100mg, 0.156mmol) was dissolved in anhydrous dioxane, and Brettphos (10mg, 0.011mmol), ruphos (10mg, 0.02184mmol), cesium carbonate (202mg, 0.624mmol), and compound 1-h (45mg, 0.202mmol) were added in this order. The temperature of the reaction mixture is raised to 100 ℃, and the reaction mixture is stirred for 16 hours. TLC to monitor the reaction, add water (10 mL), extract with ethyl acetate (10mL x 3), wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the crude product. The crude product was isolated and purified by silica gel column chromatography (dichloromethane: methanol = 15. Purification by silica gel thin layer chromatography (dichloromethane: methanol = 15) gave compound 9-g (25 mg, yield 23%) as a pale yellow solid. MS (ES) + ,m/z):693.6[M+H] + 。 1 H NMR(500MHz,CDCl 3 )δ7.46(d,J＝9.0Hz,1H),7.36(s,1H),7.14(t,J＝8.0Hz,1H),7.09-7.00(m,1H),6.69(m,2H),6.29(d,J＝7.7Hz,1H),4.84(d,J＝49.0Hz,1H),4.61(m,4H),4.19(bs,1H),3.92(s,3H),3.55(m,1H),3.24(t,J＝10.6Hz,1H),2.95(d,J＝11.0Hz,1H),2.33(s,3H),2.32-2.20(m,1H),2.15(t,J＝11.6Hz,1H),2.06-1.86(m,6H),1.58-1.31(m,9H),1.16-1.12(m,3H),1.12-1.07(m,3H)。
Compound 9-g (10mg, 0.0144mmol) was dissolved in DCM/TFA (1 mL/1 mL), and stirred at 25 ℃ for 1h. TLC monitoring reaction is finished, the reaction solution is decompressed and concentrated, and NH is dripped 3 Adjusting pH to 8 with MeOH (0.5 mL), adding water (5 mL), extracting with ethyl acetate (5 mL. Times.3), washing the organic phase with saturated brine, drying over anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure to obtain the crude product. The crude product was isolated and purified by silica gel column chromatography (dichloromethane: methanol = 12. Purification by silica gel thin layer chromatography (dichloromethane: methanol = 12). MS (ES) + ,m/z):593.6[M+H] + 。 1 H NMR(500MHz,CDCl 3 )δ7.23(d,J＝11.4Hz,1H),7.13(t,J＝8.0Hz,1H),7.10-7.04(m,1H),6.82(dd,J＝8.0,3.1Hz,1H),6.76(s,1H),6.68(d,J＝8.2Hz,1H),6.29(d,J＝7.8Hz,1H),4.93(t,J＝6.1Hz,1H),4.85(d,J＝49.0Hz,1H),4.57(dd,J＝17.1,8.6Hz,2H),4.32(d,J＝6.2Hz,2H),4.19(s,1H),3.93(s,3H),3.53(s,1H),3.25(s,1H),2.95(s,1H),2.36(s,3H),2.24-1.78(m,8H),1.14(t,J＝8.0Hz,3H),1.10(d,J＝7.7Hz,3H)。
EXAMPLE 10 preparation of Compound 10
Compound 10-a (3.90g, 26.32mmol, 1.0eq) was dissolved in (Boc) 2 O (40 mL), stirred at 100 ℃ for 48 hours. TLC monitored the completion of the reaction and column chromatography separation and purification (petroleum ether: ethyl acetate = 30) yielded compound 10-b as a white solid (5.38g, 83%). LC-MS (ES) + ,m/z):249.3[M+H] +
The compound 10-b (4.07g, 16.39mmol, 1.0eq), naN was added 3 (5.33g，81.96mmol，5.0eq)，NH 4 Cl (4.38g, 81.96mmol,5.0 eq) was dissolved in DMF (50 mL) and reacted at 120 ℃ for 16h. TLC, diluted with water, adjusted to pH =1 with 1M HCl, extracted with thf, combined organic phases, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography isolation and purification (DCM: THF = 5:1) yielded compound 10-c (3.86g, 81%). LC-MS (ES) + ,m/z):292.4[M+H] + ； 1 H NMR(500MHz,DMSO)δ8.23(s,1H),7.98(d,J＝8.3Hz,1H),7.64(s,1H),7.61(d,J＝8.4Hz,1H),3.92(s,3H),1.48(s,9H)。
Compound 10-c (720mg, 2.56mmol, 1.0eq), DHP (323mg, 3.8mmol, 1.5eq), PPTS (65mg, 0.256mmol, 0.1eq) were dissolved in THF (15 mL) and reacted at room temperature for 16 hours. TLC monitoring the reaction was complete and concentrated. Column chromatography isolation and purification (PE: EA = 5:1) gave compound 10-d (800mg, 83%) as a colorless liquid. LC-MS (ES) + ,m/z):376.2[M+H] + ； 1 H NMR(500MHz,CDCl 3 ),δ8.20(s,1H),7.80(dd,J＝8.4,1.25Hz,1H),7.67(d,J＝1.3Hz,1H),7.22(s,1H),6.03(dd,J＝8.0,2.45Hz,1H),4.05(m,1H),3.97(s,3H),3.83(m,1H),2.51(m,1H),2.18(m,2H),1.71-1.83(m,3H),1.54(s,9H)。
The compound 10-d (400mg, 1.06mmol, 1.0eq), cs 2 CO 3 (1.0g, 3.2mmol, 3.0eq), 3-bromopropyne (380mg, 3.2mmol, 3.0eq) was dissolved in DMF (5 mL), and the mixture was stirred at room temperature for 16 hours. TLC monitored the completion of the reaction, water/MTBE extraction spin-dried, and purified by column chromatography (PE: EA = 5:1) to give compound 10-e (400mg, 91%) as a colorless liquid. LC-MS (ES) + ,m/z):430.2[M+H] + ； 1 H NMR(500MHz,CDCl 3 )δ7.78(d,J＝8.0Hz,1H),7.74(s,1H),7.37(s,1H),6.05(dd,J＝7.8,2.6Hz,1H),4.04(m,1H),3.92(s,3H),3.83(m,1H),4.3(bs,2H)2.51(m,1H),2.18(m,3H),1.71-1.83(m,3H),1.54(s,2H)1.34(s,7H)。
The compounds 10-e (80mg, 0.188mmol, 1.0eq), 1-f (124mg, 0.288mmol, 1.2eq), cuI (6mg, 0.029mmol, 0.15eq), (PPh) 3 ) 2 PdCl 2 (7mg, 0.010mmol, 0.05eq) was dissolved in a mixed solvent of triethylamine (2 mL) and DMF (1 mL) and reacted at room temperature under nitrogen for 16 hours. TLC monitoring of the reaction completion, rotary drying of triethylamine, water/MTBE extraction, rotary drying, prep-TLC separation and purification (petroleum ether: ethyl acetate = 2:1) gave LC-MS (ES) 10-f (42mg, 32%) as a yellow solid compound + ,m/z):689.5[M+H] + ,691.6[M+H+2] + ；1H NMR(500MHz,CDCl3)δ7.80(d,J＝8.0Hz,1H),7.39(t,J＝7.8Hz,1H),7.27-7.33(m,2H),7.22(d,J＝8.2Hz,1H),7.13(t,J＝7.9Hz,1H),6.79(s,1H)6.07(dd,J＝7.7,2.4Hz,1H),4.23-5.19(s,2H)4.61(q,J＝8.5Hz,2H),4.04(m,1H),3.94(s,3H),3.83(m,1H),2.52(m,1H),2.19(m,3H),1.71-1.82(m,3H),1.34(s,9H)
The compound 10-f (69mg, 0.10mmol, 1.0eq), 1-h (27mg, 0.13mmol, 1.3eq), cs 2 CO 3 (130mg，0.40mmol，4eq)，BrettPhos(7mg，0.007mmol，0.07eq)，RuPhos(7mg, 0.014mmol, 0.14eq) was dissolved in dioxane (2 mL) and reacted at 110 ℃ for 16h under nitrogen. TLC monitoring the reaction was complete, water/MTBE extraction spin dried, column chromatography purification (DCM: meOH = 50. LC-MS (ES) + ,m/z):741.6[M+H] + 。
10-g (3mg, 0.0041mmol, 1.0eq) was stirred in DCM (2 mL) and TFA (1 mL) under a nitrogen atmosphere, and reacted30min, LC-MS monitors the reaction and spin-dry the reaction solution. NH 3 free/MeOH (5 mL), purified by Prep-TLC separation (DCM: meOH = 10. LC-MS (ES) + ,m/z):557.5[M+H] + 。
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes or modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the appended claims of the present application.
Claims (13)
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:
in formula (I):
ring A is selected from aryl or heteroaryl;
ring B is selected from aryl or heteroaryl;
c ring is selected from C 3-8 Cycloalkyl or 4-to 12-membered heterocyclyl;
d is selected from the group consisting of a chemical bond, -C.ident.C-, -CR a ＝CR a -, or C 3-6 A cyclic group;
e is selected from the group consisting of a chemical bond, - (CR) a R a ) q -、-O-、-NR b -、C 3-6 A cyclic group, or a 3-to 6-membered heterocyclic group;
f is selected from the group consisting of a bond, -NR b -, -O-, or- (CR) a R a ) q -；
U is selected from the group consisting of a bond, -NR c -、-O-、-NR c C(O)R c -、-NR c C(O)-；
Each of the above R a Each independently selected from hydrogen, halogen, C 1-4 Alkyl, OR b 、CN、NR b R b (ii) a Each R is b And R c Each independently selected from hydrogen and C 1-4 Alkyl, or C 1-4 A haloalkyl group; or two R b Together with the nitrogen atom to which they are attached form an optionally substituted 4-to 8-membered cyclic structure which may additionally contain 0-1 heteroatoms optionally selected from N, O, S;
R 1 selected from hydrogen, C 1-4 Alkyl radical, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, 3-to 8-membered heterocyclyl, aryl, heteroaryl, C (O) R d Or S (O) 2 R d (ii) a Said alkyl, cycloalkyl, heterocyclyl is optionally substituted with one or more groups selected from: halogen, CN, OR b 、SR b 、NR b R b (ii) a Or said cycloalkyl, heterocyclyl is optionally substituted with C = M; m is selected from O or CR e R e (ii) a Each R is e Each independently selected from hydrogen, fluorine, or C 1-4 An alkyl group; the R is e Wherein the alkyl group is optionally substituted with a substituent of the group: CN, OR b 、SR b 、NR b R b 、C(O)OR b ；R d Is selected from C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-to 8-membered heterocyclyl, aryl, or heteroaryl; r is b Is as defined above;
each R is 2 Each independently selected from hydrogen, halogen, C 1-4 Alkyl radical, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-to 6-membered heterocyclyl, CN, OR b 、SR b Or NR b R b ；R b Is as defined above;
R 3 selected from hydrogen, halogen, C 1-4 Alkyl radical, C 1-4 Haloalkyl, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-to 8-membered heterocyclyl, aryl, heteroaryl, CN, OR b 、SR b 、NR b R b 、C(O)R d 、C(O)OR b 、C(O)NR b R b 、C(O)N(OR b )R b 、NR b C(O)R d 、NR b S(O) 2 R d 、S(O) 2 R d 、S(O)(NR b )R d 、S(O)R d 、NR b S(O) 2 R d 、S(O) 2 NR b R b 、NR b S(O) 2 NR b R b 、P(O)R f R f 、P(O)(NR b R b )R f OR P (O) (OR) b )R f (ii) a Each R is b And R d Is as defined above; or two R b Together with the nitrogen atom to which they are attached form an optionally substituted 4-to 8-membered cyclic structure which may additionally contain 0-1 heteroatoms optionally selected from N, O, S; each R is f Each independently selected from C 1-4 Alkyl radical, C 3-6 Cycloalkyl, 3-to 8-membered heterocyclyl, aryl, heteroaryl, OR b 、NR b R b (ii) a Or two R f Together with the phosphorus atom to which they are attached form an optionally substituted 4-to 8-membered cyclic structure which may additionally contain 0-1 heteroatoms optionally selected from N, O, S; r f The alkyl, cycloalkyl, heterocyclyl, or cyclic structure recited in (1) is optionally substituted with a substituent of the group: hydrogen, halogen, C 1-4 Alkyl radical, C 1-4 Haloalkyl, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-to 6-membered heterocyclyl, CN, OR b 、SR b 、NR b R b 、＝O；R b Is as defined above;
each R is 4 Each independently selected from hydrogen, halogen, C 1-4 Alkyl radical, C 1-4 Haloalkyl, hydroxy, C 1-4 Alkoxy radical, C 1-4 Haloalkoxy, C 2-4 Alkenyl radical, C 2-4 Halogenated alkenyl group, C 2-4 Alkynyl, C 2-4 Halogenated alkynyl, C 3-6 Cycloalkyl, 3-to 8-membered heterocyclyl, C 2-4 alkenyl-O-, C 2-4 haloalkenyl-O-, C 2-4 alkynyl-O-, C 2-4 Halogenated alkynyl-O-, C 3-6 cycloalkyl-O-, 3-to 8-membered heterocyclyl-O-, CN, SR b 、NR b R b 、C(O)R d 、C(O)OR b 、C(O)NR b R b (ii) a Said alkyl, alkoxy, cycloalkyl, heterocyclyl is optionally substituted with one or more groups selected from: halogen, CN, OR b 、SR b 、NR b R b (ii) a Or said cycloalkyl, heterocyclyl is optionally substituted with C = M; m is selected from O or CR e R e (ii) a Each R is e Each independently selected from hydrogen, fluorine, or C 1-4 An alkyl group; the R is e Is optionally substituted with a substituent of the group: CN, OR b 、SR b 、NR b R b 、C(O)OR b (ii) a Each R is b And R d Is as defined above;
or R 4 And R in E a Together with F and B to which they are attached form an optionally substituted 6-to 8-membered cyclic structure;
or R 4 And R in F b Taken together with the B ring to which it is attached to form an optionally substituted 6-to 8-membered ring structure;
R 5 selected from hydrogen, halogen, C 1-4 Alkyl radical, C 1-4 Haloalkyl, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-to 8-membered heterocyclyl, CN, OR b 、SR b 、NR b R b 、C(O)R d 、C(O)OR b 、C(O)NR b R b 、C(O)NR b (OR b )、NR b C(O)R d 、NR b S(O) 2 R d 、S(O) 2 R d 、S(O)(NR b )R d 、S(O)R d 、NR b S(O) 2 R d 、S(O) 2 NR b R b (ii) a Each R is b Each independently selected from hydrogen and C 1-4 Alkyl, or C 1-4 A haloalkyl group; or two R b Together with the nitrogen atom to which they are attached form an optionally substituted 4-to 8-membered cyclic structure which may additionally contain 0-1 heteroatoms optionally selected from N, O, S; r d Is selected from C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-toA 6-membered heterocyclic group; r is as defined above 5 、R b 、R d The alkyl, cycloalkyl, heterocyclyl group in (a) is optionally substituted with one or more groups selected from the group consisting of: halogen, C 1-4 Alkyl radical, C 3-6 Cycloalkyl, 3-to 6-membered heterocyclyl, CN, OR b 、SR b 、NR b R b (ii) a Or the above R 5 The cycloalkyl, heterocyclyl in (a) is optionally substituted with C = M; m is selected from O or CR e R e (ii) a Each R is e Each independently selected from hydrogen, fluorine, or C 1-4 An alkyl group; the R is e Is optionally substituted with a substituent of the group: CN, OR b 、SR b 、NR b R b 、C(O)OR b (ii) a Each R is b Is as defined above;
each R is 6 Each independently selected from hydrogen, halogen, C 1-4 Alkyl radical, C 1-4 Haloalkyl, hydroxy, C 1-4 Alkoxy radical, C 1-4 Haloalkoxy, C 3-6 Cycloalkyl, 3-to 6-membered heterocyclyl, CN, SR b 、NR b R b (ii) a Each R is b Is as defined above;
m is selected from 0, 1,2,3, or 4;
n is selected from 0, 1,2,3, or 4;
p is selected from 0, 1,2,3, or 4;
q is selected from 0, 1,2, or 3;
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, C 1-4 Alkyl radical, C 1-4 Haloalkyl, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-to 8-membered heterocyclyl, aryl, heteroaryl, CN, NO 2 、OR b 、SR b 、NR b R b 、C(O)R d 、C(O)OR b 、C(O)NR b R b 、NR b C(O)R d 、NR b S(O) 2 R d Or S (O) 2 R d Provided that the chemical structure formed is stable and meaningful;wherein each R is b Each independently selected from hydrogen and C 1-4 Alkyl, or C 1-4 A haloalkyl group; or two R b Together with the nitrogen atom to which they are attached form an optionally substituted 4-to 8-membered cyclic structure which may additionally contain 0-1 heteroatoms optionally selected from N, O, S; each R is d Each independently selected from C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-to 8-membered heterocyclyl, aryl, or heteroaryl;
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 single ring, fused ring or heterocyclic ring, which may be saturated or partially unsaturated (but not aromatic).
2. The compound of claim 1,
R 3 selected from C (O) NR b (OR b )、P(O)R f R f 、P(O)(NR b R b )R f OR P (O) (OR) b )R f (ii) a Each R is f Each independently selected from C 1-4 Alkyl radical, C 3-6 Cycloalkyl, 3-to 8-membered heterocyclyl, aryl, heteroaryl, OR b 、NR b R b (ii) a Or two R f Together with the phosphorus atom to which they are attached form an optionally substituted 4-to 8-membered cyclic structure which may additionally contain 0-1 heteroatoms optionally selected from N, O, S; each R is b Each independently selected from hydrogen, C 1-4 Alkyl, or C 1-4 A haloalkyl group; or two R b Together with the nitrogen atom to which they are attached form an optionally substituted 4-to 8-membered cyclic structure which may additionally contain 0-1 heteroatoms optionally selected from N, O, S;
wherein R is f The alkyl, cycloalkyl, heterocyclyl, or cyclic structure described in (1) is optionally substituted with a group selected from the group consisting of: hydrogen, halogen, C 1-4 Alkyl radical, C 1-4 Haloalkyl, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-to 6-membered heterocyclyl, CN, OR b 、SR b 、NR b R b 、＝O；R b Is as defined above;
or R 3 Selected from:
wherein "-" represents R 3 A site of attachment to the other moiety of the compound of formula (I); r is b Is as defined above.
3. The compound of claim 1, wherein formula (I) is formula (II):
wherein the content of the first and second substances,
R 1 selected from the group consisting of:
wherein the content of the first and second substances,
represents R 1 A site of attachment to the other moiety of the compound of formula (II);
each R is 2 Each independently selected from hydrogen, halogen, C 1-4 Alkyl radical, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, C 2-4 Alkenyl radical, C 2-4 Alkynyl, CN, OR b 、SR b Or NR b R b (ii) a m is selected from 0, 1, or 2; r b Is as defined in claim 1;
R 3 selected from the group consisting of:
wherein "-" represents R 3 A site of attachment to the other moiety of the compound of formula (II); r b And R d Is as defined in claim 2;
R 4 selected from the group consisting of:
wherein "- - -" represents R 4 A site of attachment to the other moiety of the compound of formula (II);
fragments
Selected from the group consisting of:
wherein "+" denotes a chiral center;
f is selected from-NH-, -NMe-, or-O-.
4. A compound according to claim 3,
R 3 selected from the group consisting of:
wherein "-" represents R 3 A site of attachment to the other moiety of the compound of formula (II); r is b And R d Is defined as in claim 2.
5. A compound according to claim 3,
fragments
Selected from the group consisting of>
Wherein "+" denotes a chiral center;
6. A compound according to claim 3,
R 1 selected from the group consisting of:
wherein the content of the first and second substances,
represents R 1 A site of attachment to the other moiety of the compound of formula (II).
7. A compound according to claim 3,
R 4 selected from the group consisting of:
wherein "- - - -" represents R 4 A site of attachment to the other moiety of the compound of formula (II).
8. The compound of claim 1, wherein formula (I) is formula (III):
wherein each X is independently selected from C or N, provided that at least two X are selected from C and the structure formed is stable; wherein one C atom is bonded to C (O) NH (OR) in formula (III) b ) To which other C atoms are optionally substituted by R 4 Substitution; r b Selected from hydrogen or C 1-4 An alkyl group;
R 1 、R 2 m, F, C ring, R 5 、R 6 P is as defined in claim 1.
9. The compound of claim 1, wherein formula (I) is formula (IV):
wherein each X is independently selected from C or N, provided that at least two X are selected from C and the structure formed is stable; wherein one C atom is bonded to P (O) R in formula (IV) f R f To which other C atoms are optionally substituted by R 4 Substitution; each R is f Each independently selected from C 1-4 Alkyl radical, C 3-6 A cycloalkyl group, a,3-to 8-membered heterocyclyl, aryl, heteroaryl, OR b 、NR b R b (ii) a Or two R f Together with the phosphorus atom to which they are attached form an optionally substituted 4-to 8-membered cyclic structure which may additionally contain 0-1 heteroatoms optionally selected from N, O, S; r f The alkyl, cycloalkyl, heterocyclyl, or cyclic structure recited in (1) is optionally substituted with a substituent of the group: hydrogen, halogen, C 1-4 Alkyl radical, C 1-4 Haloalkyl, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-to 6-membered heterocyclyl, CN, OR b 、SR b 、NR b R b 、＝O；
R 1 、R 2 M, F, C ring, R 5 、R 6 、p、R b Is defined as in claim 1.
10. The compound of claim 1, wherein the compound of formula (I) is selected from the group consisting of:
the structural formula is shown as "+" represents a chiral center, and can be in an R configuration or an S configuration or a mixture of the R configuration and the S configuration optionally; by using
The carbon atoms to which the bonds are attached may optionally be in the R configuration or S configuration, or optionally be in the cis or trans configuration.
11. A pharmaceutical composition comprising a compound of any one of claims 1 to 10, or an optical isomer, a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrate, a solvate, and a pharmaceutically acceptable carrier thereof.
12. Use of a compound according to any one of claims 1 to 10, 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 P53 modulator and/or HDAC activity or expression.
13. The use of claim 12, wherein the disease, disorder or condition is selected from the group consisting of: non-small cell lung cancer, lung adenocarcinoma, lung squamous carcinoma, pancreatic cancer, colon cancer, thyroid cancer, embryonal rhabdomyosarcoma, cutaneous granulocytic tumor, melanoma, hepatocellular carcinoma, intrahepatic bile duct cancer, rectal cancer, bladder cancer, throat cancer, breast cancer, vaginal cancer, prostate cancer, testicular cancer, brain tumor, glioma, ovarian cancer, head and neck squamous cancer, cervical cancer, osteosarcoma, esophageal cancer, kidney cancer, skin cancer, stomach cancer, myeloid leukemia, lymphoid leukemia, myelofibrosis, B-cell lymphoma, T-cell lymphoma, hodgkin's lymphoma, non-hodgkin's lymphoma, monocytic leukemia, polycythemia splenomegaly, hypereosinophilic syndrome, bone marrow cancer and other solid tumors and hematological tumors.
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| CN202111165274.2A CN115894328A (en) | 2021-09-30 | 2021-09-30 | Compounds as P53 modulators and/or HDAC inhibitors |
| CN202280058585.5A CN117916230A (en) | 2021-08-27 | 2022-08-29 | Compounds as p53 modulators |
| PCT/CN2022/115635 WO2023025324A1 (en) | 2021-08-27 | 2022-08-29 | Compound serving as p53 regulator |
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