CN116903609A

CN116903609A - Compound, pharmaceutical composition containing same and application of compound

Info

Publication number: CN116903609A
Application number: CN202111308674.4A
Authority: CN
Inventors: 李京; 陈旭星; 陈艳红
Original assignee: Shanghai Youli Huisheng Pharmaceutical Co ltd
Current assignee: Shanghai Youli Huisheng Pharmaceutical Co ltd
Priority date: 2021-11-05
Filing date: 2021-11-05
Publication date: 2023-10-20
Also published as: TW202319386A; WO2023078426A1; CN117980306A; TWI846135B

Abstract

The invention provides a compound, a pharmaceutical composition containing the same and application thereof. The compounds interfere with interactions between the mentin proteins and MLL1 or MLL2 or MLL-fusion oncoproteins and are expected to be drugs for the treatment of tumors, diabetes and other diseases that depend on the activity of the MLL1, MLL2, MLL fusion proteins, and/or the menin proteins.

Description

Compound, pharmaceutical composition containing same and application of compound

Technical Field

The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a compound, a pharmaceutical composition containing the compound and application of the compound.

Background

Mixed-lineage leukemia (MLL) protein is a histone methyltransferase that plays an important role in the regulation of gene transcription. Most acute leukemias, including acute myelogenous leukemia (acute myeloblastic leukemia, AML), acute lymphoblastic leukemia (acute lymphoblastic leukemia, ALL) and mixed leukemia, are found to be translocated by the MLL gene located at the q23 band position of chromosome 11, forming a MLL fusion (MLL-r) protein with one of about 80 proteins (e.g., AF4, AF9, ENL, AF10, ELL, AF6, AF1p, GAS7, etc.). The MLL-r protein retains approximately 1400 amino acid sequences at the N-terminus of the MLL protein, lacks the C-terminal methyltransferase active region, and is capable of abnormally regulating transcription of various oncogenes including HOX and MEIS1, promoting cell proliferation, and ultimately leading to the occurrence of cancer. Leukemia patients with chromosomal translocation of the MLL gene generally have a poor prognosis and a survival rate of less than 40% in 5 years.

The Menin protein, encoded by the multiple endocrine gland tumor (Multiple Endocrine Neoplasia, MEN) gene, is a widely expressed nuclear protein that interacts with DNA replication and repair proteins, chromatin modification proteins, and multiple transcription factors. The Menin protein binds to the N-terminus of MLL proteins including MLL1, MLL2 and MLL-r proteins, which binding is necessary for the oncogenic activity of the MLL proteins. Interference between the menin and MLL-r protein can selectively inhibit proliferation of MLL-r leukemia cells in vitro and in vivo.

In specific hematological neoplasms, there are certain specific gene abnormalities or mutations, such as nuclear pore protein 98 (NUP 98) gene fusion, nuclear phosphoprotein (NPM 1) gene mutation, DNA methyltransferase 3A (DNMT 3A) mutation, MLL gene amplification, etc., which are often accompanied by high levels of HOX gene expression. The backward HOXD gene, especially HOXD13, is abnormally over-expressed in ewing's sarcoma, accompanied by high levels of meinin and MLL1 proteins, while HOXD13 is a downstream gene regulated by menin and MLL 1.

Thus, interfering with the interaction between the gin and the MLL protein, especially by covalent binding, is a very promising strategy for treating tumors.

There is an urgent need in the art to develop effective drugs that interfere with the interaction of the men and MLL proteins.

Disclosure of Invention

It is an object of the present invention to provide effective drugs capable of interfering with the interaction of the men and MLL proteins.

In a first aspect of the present invention, there is provided a compound, or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, cis-trans isomer, solvate, polymorph, deuterate or combination thereof, of formula I:

wherein,,

R ¹ selected from the group consisting of: -C (O) (NR) ^a R ^b ) Phenyl and 5-6 membered heteroaryl; wherein said phenyl or heteroaryl may optionally be R ^1a Substitution;

R ^a and R is ^b Each independently selected from the group consisting of: H. optionally substituted C1-C6 alkyl, optionally substituted 3-8 membered cycloalkyl or optionally substituted 4-8 membered heterocyclyl; or R is ^a And R is R ^b And together with the N atom to which they are attached form an optionally substituted 4-8 membered heterocyclic ring; wherein the heterocyclic ring comprises 0-2 heteroatoms selected from N, O, S and P in addition to the attached N atom; wherein, the substitution refers to that H in the group is substituted by one or more R;

each R is ^1a Independently selected from the group consisting of: H. cyano, halogen, C1-C3 alkyl, halogenated C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C3 alkoxy A group, a halogenated C1-C3 alkoxy group and a C3-C5 cycloalkyl group;

R ² selected from the group consisting of: H. halogen, methyl and trifluoromethyl;

R ³ none, or represents 1, 2 or 3 groups each independently selected from the group consisting of: H. halogen, C1-C3 alkyl, and halogenated C1-C3 alkyl;

R ⁴ selected from the group consisting of: H. optionally substituted C1-C6 alkyl, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 alkylamino, optionally substituted (C1-C4 alkyl) ₂ Amino, halogen, -NH ₂ 、-NO ₂ -COOH, -CN, -OH, optionally substituted C1-C6 alkyl sulphonyl, optionally substituted C1-C6 alkyl sulphoxide, optionally substituted C1-C6 alkylthio, -NHCOCR ^4a ＝CH ₂ 、-NHCOCHR ^4a R ^4b 、-SO ₂ C(R ^4a )＝CH ₂ 、-NHSO ₂ CR ^4a ＝CH ₂ or-NHSO ₂ CHR ^4a R ^4b The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is ^4a Each independently selected from the group consisting of: H. methyl and fluoro; r is R ^4b Each independently is a chlorine or bromine atom; wherein, said substitution means that H in the group is substituted with one or more (e.g. 1, 2 or 3) R;

x is selected from N or CR ^X The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is ^X Selected from the group consisting of: H. halogen, -CN, -OH, -NH ₂ Optionally substituted C1-C4 alkyl, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 alkylamino, and optionally substituted (C1-C4 alkyl) ₂ An amino group; wherein, the substitution refers to that H in the group is substituted by one or more R;

the ring A is piperazine ring or homopiperazine ring; the A ring may optionally be R ^A Substitution; each R is ^A Independently selected from deuterium, C1-C4 alkyl, halogenated C1-C4 alkyl, C3-C6 cycloalkyl, 3-8 membered heterocyclyl, oxo, halogen, C1-C4 alkoxy, hydroxy and amino, or two R's on adjacent carbon atoms or on the same carbon atom ^A Together with the carbons to which they are attached, form a 3-8 membered carbocyclic ring or a 4-8 membered heterocyclic group;

ring B is a 4-12 membered saturated or partially saturated nitrogen containing heterocycle; wherein the nitrogen-containing heterocycle may optionallyQuilt R ^B Substitution;

each R is ^B Independently selected from the group consisting of: deuterium, halogen, oxo, C1-C3 alkyl, halogenated C1-C3 alkyl or cyano;

L ¹ and L ² Each independently selected from: absence (i.e. single bond), -CR ^La R ^Lb -、-CO-、-SO ₂ -or-SO-; wherein R is ^La And R is ^Lb Each independently selected from the group consisting of: H. deuterium, optionally substituted C1-C4 alkyl and halogen, or R ^La And R is ^Lb And together with the carbon atoms to which they are attached form an optionally substituted 3-8 membered saturated or unsaturated carboalkyl group, an optionally substituted 4-8 membered saturated or unsaturated heterocyclyl group; wherein the heterocycle comprises 1-3 heteroatoms selected from N, O, S, and P;

y is optionally substituted saturated or unsaturated 3-8 membered carbocyclyl, optionally substituted saturated or unsaturated 4-12 membered heterocyclyl, optionally substituted 6-10 membered aryl or optionally substituted 5-10 membered heteroaryl, optionally substituted saturated or unsaturated 3-8 membered carbocyclyl and 6-10 membered aryl, optionally substituted saturated or unsaturated 3-8 membered carbocyclyl and 5-10 membered heteroaryl, optionally substituted saturated or unsaturated 3-8 membered carbocyclyl and 6-10 membered aryl, or optionally substituted saturated or unsaturated 3-8 membered carbocyclyl and 5-10 membered heteroaryl; wherein said substitution means by one or more R ^Y And/or R substitution;

each R is ^Y Selected from the group consisting of: r is R ^Y’ 、R ^Y” 、-S(O) ₂ R ^Y” 、-NHC(O)R ^Y” 、-NHS(O) ₂ R ^Y” 、R ^Y”’ And R;

R ^Y’ selected from the group consisting of: H. halogen, C1-C3 alkyl, halogenated C1-C3 alkyl, C1-C3 alkoxy, cyano, C3-C8 cycloalkyl;

R ^Y” selected from the group consisting of: C1-C3 alkyl, halogenated C1-C3 alkyl, C1-C3 alkylamino, C3-C8 cycloalkyl, 4-8 membered heterocyclyl;

R ^Y”’ selected from H, C1-C4 alkyl; wherein said alkyl is optionally further substituted with one or more substituents selected from the group consisting of: halogen, -OH, oxo (= O), -NH ₂ C3-C8 cycloalkyl, 3-8A membered heterocyclyl, 5-to 10-membered heteroaryl, -O-C1-C4-alkyl, -C1-C4-alkyl-OH, -C1-C4-alkyl-O-C1-C4-alkyl, -OC 1-C4-haloalkyl, cyano, nitro, -C (O) -OH, -C (O) OC 1-C6-alkyl, -CON (C1-C6-alkyl) ₂ -CONH (C1-C6 alkyl), -CONH ₂ -NHC (O) (C1-C6 alkyl), -NH (C1-C6 alkyl) C (O) (C1-C6 alkyl), -SO ₂ (C1-C6 alkyl), -SO ₂ (phenyl) -SO ₂ (C1-C6 haloalkyl), -SO ₂ NH ₂ 、-SO ₂ NH (C1-C6 alkyl), -SO ₂ NH (phenyl) -NHSO ₂ (C1-C6 alkyl), -NHSO ₂ (phenyl) and-NHSO ₂ (C1-C6 haloalkyl); r is R ^Y”’ In which the cycloalkyl, heterocyclyl, and heteroaryl groups can also be optionally substituted with substituents selected from the group consisting of: C1-C4 alkyl, C1-C4 haloalkyl;

each R is independently selected from the group consisting of: deuterium, halogen, -OH, oxo, mercapto, cyano, -CD ₃ -C1-C6 alkyl, alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 6-10 membered aryl, 4-12 membered heterocyclyl, 5-10 membered heteroaryl, 6-10 membered aryl-C1-C6 alkylene-, 5-10 membered heteroaryl-C1-C6 alkylene-, C3-C8 cycloalkyl-C1-C6 alkylene-, 4-12 membered heterocyclyl-C1-C6 alkylene-, C1-C6 haloalkyl-, -OC1-C6 alkyl, -OC2-C6 alkenyl, C3-C8 cycloalkyl-O-, 4-12 membered heterocyclyl-O-, 6-10 membered aryl-O-, 5-10 membered heteroaryl-O-, -OC1-C6 alkylphenyl, -C1-C6 alkyl-OH, -C1-C6 alkyl-SH, -C1-C6 alkyl-O-C1-C6 alkyl, -OC1-C6 haloalkyl, -NH ₂ -C1-C6 alkyl-NH ₂ -N (C1-C6 alkyl) ₂ -NH (C1-C6 alkyl), -N (C1-C6 alkyl) (C1-C6 alkylphenyl), -NH (C1-C6 alkylphenyl), -N (C1-C6 alkyl) (6-10 membered aryl), -NH (6-10 membered aryl), nitro, -C (O) -OH, -C (O) OC1-C6 alkyl, -CONR ⁱ R ⁱⁱ -NHC (O) (C1-C6 alkyl), -NHC (O) (phenyl), -N (C1-C6 alkyl) C (O) (C1-C6 alkyl), -N (C1-C6 alkyl) C (O) (phenyl), -C (O) C1-C6 alkyl, 5-10 membered heteroaryl C (O) -, -C (O) C1-C6 alkylphenyl, -C (O) C1-C6 haloalkyl, -OC (O) C1-C6 alkyl, -S (O) ₂ -C1-C6 alkyl, -S (O) ₂ -phenyl, -S (O) ₂ -C1-C6 haloalkyl, -S (O) ₂ NH ₂ 、-S(O) ₂ NH (C1-C6 alkyl), -S (O) ₂ NH (phenyl), -NHS (O) ₂ (C1-C6 alkyl), -NHS (O) ₂ (phenyl) and-NHS (O) ₂ (C1-C6 haloalkyl); wherein each hydrogen of said alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, aryl, heterocyclyl and heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of: halogen, -OH, oxo (= O), -NH ₂ C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C1-C4 alkyl, C1-C4 haloalkyl-, -OC1-C4 alkyl, -C1-C4 alkyl-OH, -C1-C4 alkyl-O-C1-C4 alkyl, -OC1-C4 haloalkyl, cyano, nitro, -C (O) -OH, -C (O) OC1-C6 alkyl, -CON (C1-C6 alkyl) ₂ -CONH (C1-C6 alkyl), -CONH ₂ -NHC (O) (C1-C6 alkyl), -NH (C1-C6 alkyl) C (O) (C1-C6 alkyl), -SO ₂ (C1-C6 alkyl), -SO ₂ (phenyl) -SO ₂ (C1-C6 haloalkyl), -SO ₂ NH ₂ 、-SO ₂ NH (C1-C6 alkyl), -SO ₂ NH (phenyl) -NHSO ₂ (C1-C6 alkyl), -NHSO ₂ (phenyl) and-NHSO ₂ (C1-C6 haloalkyl); r is R ⁱ And R is ⁱⁱ Each independently is H, deuterium, or C1-C6 alkyl.

In another preferred embodiment, the nitrogen-containing heterocycle is a monocyclic, fused, bridged or spiro ring.

In another preferred embodiment, ring B is a nitrogen-containing monocyclic, fused, bridged or spiro heterocycle.

In another preferred embodiment, the compound is of formula Ia or Ib

Wherein R is ¹ 、R ² 、R ³ 、R ⁴ X, A ring, B ring, L ¹ And L ² Defined in formula I.

In another preferred embodiment, R ^Y Selected from the group consisting of: cyano, -C1-C6 alkyl, 4-12 membered heterocyclyl-C1-C6 alkylene-, and-NHS (O) ₂ (C1-C6 alkyl).

In another preferred embodiment, R ¹ is-C (O) (NR) ^a R ^b )。

In another preferred embodiment, R ^a And R is ^b Each independently selected from the group consisting of: optionally substituted C1-C6 alkyl, optionally substituted 3-8 membered cycloalkyl or optionally substituted 4-8 membered heterocyclyl; or R is ^a And R is R ^b And together with the N atom to which they are attached form an optionally substituted 4-8 membered heterocyclic ring; wherein the heterocyclic ring contains 1-2 heteroatoms selected from N, O, S, and P in addition to the attached N atom.

In another preferred embodiment, R ^a And R is ^b Wherein said substitution means that H in the group is substituted with one or more substituents selected from the group consisting of: from deuterium, halogen, C1-C3 alkyl, halogenated C1-C3 alkyl and C1-C3 alkoxy.

In another preferred embodiment, each R ^1a Independently selected from the group consisting of: H. cyano, halogen, C1-C3 alkyl, halogenated C1-C3 alkyl and C3-C5 cycloalkyl.

In another preferred embodiment, R ⁴ Selected from the group consisting of: H. C1-C6 alkyl, C1-C4 alkoxy, C1-C4 alkylamino, halogen, -NH ₂ 、-NO ₂ -COOH, -CN and-OH.

In another preferred embodiment, R ^X Is H, halogen, -CN, -OH or-NH ₂ 。

In another preferred embodiment, L ¹ And L ² Each independently is absent, -CR ^La R ^Lb -or-CO-.

In another preferred embodiment, wherein R ^La 、R ^Lb Each independently selected from the group consisting of: H. deuterium, optionally substituted C1-C4 alkyl and halogen.

In a further preferred embodiment of the present invention,

R ¹ selected from-C (O) (NR) ^a R ^b ) Phenyl and 5-6 membered heteroaryl, said phenyl or heteroaryl optionally being substituted with R ^1a Substitution; preferably, R ¹ is-C (O) (NR) ^a R ^b )

R ^a And R is ^b Each independently selected from the group consisting of: optionally substituted C1-C6 alkyl, optionally substituted 3-8 membered cycloalkyl or optionally substituted 4-8 membered heterocyclyl; or R is ^a And R is R ^b And together with the N atom to which they are attached form an optionally substituted 4-8 membered heterocyclic ring; wherein the heterocyclic ring comprises 1-2 heteroatoms selected from N, O, S, and P in addition to the attached N atom; wherein, the substitution means that H in the group is substituted with one or more substituents selected from the group consisting of: from deuterium, halogen, C1-C3 alkyl, halogenated C1-C3 alkyl and C1-C3 alkoxy;

each R is ^1a Independently selected from the group consisting of: H. cyano, halogen, C1-C3 alkyl, halogenated C1-C3 alkyl and C3-C5 cycloalkyl;

R ⁴ selected from the group consisting of: H. C1-C6 alkyl, C1-C4 alkoxy, C1-C4 alkylamino, halogen, -NH ₂ 、-NO ₂ -COOH, -CN and-OH;

x is selected from N or CR ^X Wherein R is ^X Is H, halogen, -CN, -OH or-NH ₂ ；

L ¹ And L ² Each independently is absent, -CR ^La R ^Lb -or-CO-; wherein R is ^La 、R ^Lb Each independently selected from the group consisting of: H. deuterium, optionally substituted C1-C4 alkyl and halogen.

In another preferred embodiment, the B ring is selected from the group shown below:

preferably, the B ring is +.>

The B ring may optionally be R ^B Substitution;

each R is ^B Independently deuterium, halogen, oxo, C1-C3 alkyl, halo-C1-C3 alkyl or cyano.

In another preferred embodiment, Y is selected from the group shown below:

R ^Y”’ selected from H, C1-C4 alkyl; wherein said alkyl is optionally further substituted with one or more substituents selected from the group consisting of: halogen, -OH, oxo (= O), -NH ₂ C3-C8 cycloalkyl, 3-8 membered heterocyclyl, 5-10 membered heteroaryl, -O-C1-C4 alkyl, -C1-C4 alkyl-OH, -C1-C4 alkyl-O-C1-C4 alkyl, -OC1-C4 haloalkyl, cyano, nitro, -C (O) -OH, -C (O) OC1-C6 alkyl, -CON (C1-C6 alkyl) ₂ -CONH (C1-C6 alkyl), -CONH ₂ -NHC (O) (C1-C6 alkyl), -NH (C1-C6 alkyl) C (O) (C1-C6 alkyl), -SO ₂ (C1-C6 alkyl), -SO ₂ (phenyl) -SO ₂ (C1-C6 haloalkyl), -SO ₂ NH ₂ 、-SO ₂ NH (C1-C6 alkyl), -SO ₂ NH (phenyl) -NHSO ₂ (C1-C6 alkyl), -NHSO ₂ (phenyl) and-NHSO ₂ (C1-C6 haloalkyl); r is R ^Y”’ In which the cycloalkyl, heterocyclyl, and heteroaryl groups can also be optionally substituted with substituents selected from the group consisting of: C1-C4 alkyl, C1-C4 haloalkyl;

R ^c and R is ^d Each independently selected from the group consisting of: H. C1-C4 alkyl, halogen, -OH, oxo (= O), -NH ₂ C3-C8 cycloalkyl, 3-8 membered heterocyclyl, 5-10 membered heteroaryl, -O-C1-C4 alkyl, -C1-C4 alkyl-OH, -C1-C4 alkyl-O-C1-C4 alkyl, -OC1-C4 haloalkyl, cyano, nitro, -C (O) -OH, -C (O) OC1-C6 alkyl, -CON (C1-C6 alkyl) ₂ -CONH (C1-C6 alkyl), -CONH ₂ -NHC (O) (C1-C6 alkyl), -NH (C1-C6 alkyl) C (O) (C1-C6 alkyl),-SO ₂ (C1-C6 alkyl), -SO ₂ (phenyl) -SO ₂ (C1-C6 haloalkyl), -SO ₂ NH ₂ 、-SO ₂ NH (C1-C6 alkyl), -SO ₂ NH (phenyl) -NHSO ₂ (C1-C6 alkyl), -NHSO ₂ (phenyl) and-NHSO ₂ (C1-C6 haloalkyl); or R is ^c And R is ^d And the carbons to which they are attached together form a C3-C8 carbocyclic ring, a 4-12 membered heterocyclic ring, wherein said carbocyclic or heterocyclic ring is optionally further substituted with one or more substituents selected from the group consisting of: halogen, -OH, oxo (= O), -NH ₂ C3-C8 cycloalkyl, 3-8 membered heterocyclyl, 5-10 membered heteroaryl, -O-C1-C4 alkyl, -C1-C4 alkyl-OH, -C1-C4 alkyl-O-C1-C4 alkyl, -OC1-C4 haloalkyl, cyano, nitro, -C (O) -OH, -C (O) OC1-C6 alkyl, -CON (C1-C6 alkyl) ₂ -CONH (C1-C6 alkyl), -CONH ₂ -NHC (O) (C1-C6 alkyl), -NH (C1-C6 alkyl) C (O) (C1-C6 alkyl), -SO ₂ (C1-C6 alkyl), -SO ₂ (phenyl) -SO ₂ (C1-C6 haloalkyl), -SO ₂ NH ₂ 、-SO ₂ NH (C1-C6 alkyl), -SO ₂ NH (phenyl) -NHSO ₂ (C1-C6 alkyl), -NHSO ₂ (phenyl) and-NHSO ₂ (C1-C6 haloalkyl).

In another preferred embodiment, X is N.

In another preferred embodiment, R ¹ 、R ² 、R ³ 、R ⁴ X, A ring, B ring, L ¹ And L ² Y is each independently a group corresponding to a specific compound in Table A or in the examples.

In another preferred embodiment, the compound is selected from the group consisting of:

table A

In a second aspect of the present invention, there is provided a pharmaceutical composition comprising a compound as claimed in any one of claims 1 to 5 and a pharmaceutically acceptable carrier.

In a third aspect of the present invention there is provided the use of a compound as described in the first aspect or a pharmaceutical composition as described in the second aspect, the use being selected from any one or more of the following (a) - (c):

(a) Preparing a medicament for preventing or treating a disease associated with the activity of MLL1, MLL2, MLL fusion proteins, and/or grin proteins;

(b) Preparing an inhibitor for in vitro non-therapeutic association with the activity of MLL1, MLL2, MLL fusion proteins, and/or grin proteins;

(c) Preparing proliferation inhibitor for in vitro non-therapeutic tumor cells.

In another preferred embodiment, the disease associated with MLL1, MLL2, MLL fusion protein, and/or the activity of the mentin protein is selected from the group consisting of: tumors, diabetes, and other diseases related to MLL1, MLL2, MLL fusion proteins, and/or the activity of the mentin protein.

In another preferred embodiment, the tumor associated with MLL1, MLL2, MLL fusion protein, and/or the activity of the grin protein is selected from the group consisting of: leukemia, ewing's sarcoma, breast cancer, prostate cancer, T-cell lymphoma, B-cell lymphoma, malignant rhabdomyoma, synovial sarcoma, colorectal cancer, endometrial tumor, gastric cancer, liver cancer, renal cancer, lung cancer, melanoma, ovarian cancer, pancreatic cancer, brain glioma, cholangiocarcinoma, nasopharyngeal cancer, cervical cancer, head and neck cancer, esophageal cancer, thyroid cancer, and bladder cancer.

In another preferred embodiment, the other disease associated with MLL1, MLL2, MLL fusion protein, and/or the activity of the mentin protein is selected from the group consisting of: autoimmune disease, non-alcoholic hepatitis.

In another preferred embodiment, the pharmaceutical composition further comprises other therapeutic agents. ,

in another preferred embodiment, the other therapeutic agent is an other anti-tumor drug.

In another preferred embodiment, the other therapeutic agent comprises: antitumor drugs acting on the chemical structure of DNA such as cisplatin, antitumor drugs affecting nucleic acid synthesis such as Methotrexate (MTX), 5-fluorouracil (5 FU) and the like, antitumor drugs affecting nucleic acid transcription such as doxorubicin, epirubicin, aclacinomycin, mithramycin and the like, antitumor drugs acting on tubulin synthesis such as paclitaxel, vinorelbine and the like, aromatase inhibitors such as aminoglutethimide, orchiron, letrozole, ryanodine and the like, cell signal pathway inhibitors such as epidermal growth factor receptor inhibitors Imatinib (Imatinib), gefitinib (Gefitinib), erlotinib (Erlotinib) and Lapatinib (Lapatinib).

It is understood that within the scope of the present invention, the above-described technical features of the present invention and technical features specifically described below (e.g., in the examples) may be combined with each other to constitute new or preferred technical solutions. And are limited to a space, and are not described in detail herein.

Detailed Description

Based on extensive and intensive studies, the inventors have unexpectedly found a class of compounds having a novel structure that have excellent ability to interfere with the interaction between the mentin protein and the MLL1 or MLL2 or MLL-fusion oncoprotein. Based on this, the inventors completed the present invention.

Description of the terms

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

As used herein, the term "comprising" or "including" can be open, semi-closed, and closed. In other words, the term also includes "consisting essentially of …," or "consisting of ….

The invention will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. The experimental methods, in which specific conditions are not noted in the following examples, are generally conducted under conventional conditions or under conditions recommended by the manufacturer. Percentages and parts are by weight unless otherwise indicated.

Definition of groups

The definition of standard chemical terms can be found in references (including Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY4TH ED." vols.a (2000) and B (2001), plenum Press, new York). Conventional methods within the skill of the art, such as mass spectrometry, NMR, IR and UV/VIS spectroscopy, and pharmacological methods are employed unless otherwise indicated. Unless specifically defined otherwise, the terms used herein in the description of analytical chemistry, organic synthetic chemistry, and pharmaceutical chemistry are known in the art. Standard techniques may be used in chemical synthesis, chemical analysis, pharmaceutical preparation, formulation and delivery, and treatment of patients. For example, the reaction and purification can be carried out using the manufacturer's instructions for the kit, or in a manner well known in the art or in accordance with the teachings of the present invention. The techniques and methods described above may generally be practiced according to conventional methods well known in the art, based on a number of general and more specific descriptions in the literature cited and discussed in this specification. In this specification, groups and substituents thereof can be selected by one skilled in the art to provide stable moieties and compounds.

When substituents are described by conventional formulas written from left to right, the substituents also include chemically equivalent substituents obtained when writing formulas from right to left. For example, -CH ₂ O-is equivalent to-OCH ₂ -。

The section headings used herein are for purposes of organizing articles only and should not be construed as limiting the subject matter. All documents or portions of documents cited in this disclosure, including but not limited to patents, patent applications, articles, books, operating manuals, and treatises, are hereby incorporated by reference in their entirety.

Certain chemical groups defined herein are preceded by a simplified symbol to indicate the total number of carbon atoms present in the group. For example, C1-C6 alkyl refers to an alkyl group as defined below having a total of 1 to 6 carbon atoms. The total number of carbon atoms in the reduced notation does not include carbon that may be present in a substituent of the group.

In addition to the foregoing, when used in the specification and claims of the present application, the following terms have the meanings indicated below, unless otherwise specified.

In the present application, unless specified otherwise, the term "halogen" means fluorine, chlorine, bromine or iodine; "hydroxy" refers to an-OH group; "hydroxyalkyl" refers to an alkyl group as defined below substituted with a hydroxy (-OH); "carbonyl" refers to a-C (=o) -group; "nitro" means-NO ₂ The method comprises the steps of carrying out a first treatment on the surface of the "cyano" refers to-CN; "amino" means-NH ₂ The method comprises the steps of carrying out a first treatment on the surface of the "alkylamino" or "alkylamino" refers to an amino group in which one or two hydrogens are replaced with an alkyl group as defined below (e.g., -NH (CH) ₃ ) or-N (CH) ₃ ) ₂ ) The method comprises the steps of carrying out a first treatment on the surface of the "Alkylsulfonyl" refers to-SO ₂ -an alkyl group; "Alkylsulfoxide" refers to an-SO-alkyl group; "carboxy" refers to-COOH.

"substituted amino" refers to an amino group substituted with one or two alkyl, alkylcarbonyl, arylalkyl, heteroarylalkyl groups as defined below, e.g., mono-alkylamino, di-alkylamino, alkylamido, arylalkylamino, heteroarylalkylamino.

In the present application, as a single group or as part of another group (e.g., as used in halogen substituted alkyl groups and the like), the term "alkyl" refers to a straight or branched hydrocarbon chain radical that is fully saturated, consisting of only carbon and hydrogen atoms, having, for example, from 1 to 12 (preferably from 1 to 8, more preferably from 1 to 6, such as 1, 2, 3, or 4) carbon atoms, and being attached to the remainder of the molecule by one or more single bonds, including, for example, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2-dimethylpropyl, n-hexyl, heptyl, 2-methylhexyl, 3-methylhexyl, octyl, nonyl, decyl, and the like. For the purposes of the present application, the term "alkyl" preferably denotes an alkyl group containing from 1 to 6 carbon atoms.

In the present application, the term "alkenyl" means, as part of a single group or other groups, a straight or branched hydrocarbon chain group consisting of only carbon and hydrogen atoms, containing at least one double bond, having, for example, 2 to 14 (preferably 2 to 10, more preferably 2 to 6, such as 2,3, or 4) carbon atoms and linked to the remainder of the molecule by one or more single bonds, such as, but not limited to, vinyl, propenyl, allyl, but-1-enyl, but-2-enyl, pent-1, 4-dienyl, and the like.

The term "alkynyl" as used herein, alone or as part of another group, means a straight or branched hydrocarbon chain group consisting of only carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, having, for example, from 2 to 14 (preferably from 2 to 10, more preferably from 2 to 6, such as 2,3, or 4) carbon atoms, and attached to the remainder of the molecule by one or more single bonds, such as, but not limited to, ethynyl, 1-propynyl, 1-butynyl, heptynyl, octynyl, and the like.

In the present application, the term "carbocyclic (group)" means, as part of a single group or other group, a stable, non-aromatic, mono-or polycyclic hydrocarbon group consisting of only carbon and hydrogen atoms, which may include fused ring systems, bridged ring systems, or spiro ring systems, having 3 to 15 carbon atoms, preferably having 3 to 10 carbon atoms, more preferably having 3 to 8 carbon atoms, more preferably 3 to 6 carbon atoms, and which is a saturated or unsaturated ring (i.e., cycloalkyl, cycloalkenyl, etc.) and may be attached to the remainder of the molecule by 1 or more single bonds via any suitable carbon atom. Unless otherwise specifically indicated in the present specification, carbon atoms in a carbocyclyl group may optionally be oxidized. Examples of carbocyclyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, 2, 3-indanyl, octahydro-4, 7-methylene-1H-indenyl, 1,2,3, 4-tetrahydro-naphthyl, 5,6,7, 8-tetrahydro-naphthyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, 1H-indenyl, 8, 9-dihydro-7H-benzocyclohepten-6-yl, 6,7,8, 9-tetrahydro-5H-benzocycloheptenyl, 5,6,7,8,9, 10-hexahydro-benzocyclooctenyl, fluorenyl, bicyclo [1.1.1] pentane, bicyclo [2.2.1] heptyl, 7-dimethyl-bicyclo [2.2.1] heptyl, bicyclo [2.2.1] heptenyl, bicyclo [ 2.2.2.2 ] octyl, bicyclo [3.1 ] cycloheptyl, bicyclo [1.1.1] octanyl, bicyclo [ 2.2.1.1 ] octanyl, and the like.

In the present application, the term "heterocyclic (group)" means a stable 3-to 20-membered non-aromatic cyclic group consisting of 2 to 14 carbon atoms and 1 to 6 hetero atoms selected from nitrogen, phosphorus, oxygen and sulfur as a part of a separate group or other groups. Unless specifically indicated otherwise in the present specification, a heterocyclyl group may be a monocyclic, bicyclic, tricyclic or more cyclic ring system, which may include fused, bridged or spiro ring systems; the nitrogen, carbon or sulfur atoms in the heterocyclyl may optionally be oxidized; the nitrogen atom may optionally be quaternized; and the heterocyclyl may be partially or fully saturated. The heterocyclic group may be attached to the remainder of the molecule via a carbon atom or heteroatom and through 1 or more single bonds. In heterocyclyl groups containing fused rings, one or more of the rings may be aryl or heteroaryl as defined below, provided that the point of attachment to the remainder of the molecule is a non-aromatic ring atom. For the purposes of the present application, heterocyclyl groups are preferably stable 4-to 11-membered non-aromatic monocyclic, bicyclic, bridged or spiro groups comprising 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably stable 4-to 8-membered non-aromatic monocyclic, bicyclic, bridged or spiro groups comprising 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. Examples of heterocyclyl groups include, but are not limited to: pyrrolidinyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, thiomorpholinyl, 2-azabicyclo [2.2.2] octanyl, 2, 7-diaza-spiro [3.5] nonan-7-yl, 2-oxa-6-aza-spiro [3.3] heptan-6-yl, 2, 5-diaza-bicyclo [2.2.1] heptan-2-yl, azetidinyl, pyranyl, tetrahydropyranyl, thiopyranyl, tetrahydrofuranyl, oxazinyl, dioxacyclopentyl, tetrahydroisoquinolyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, quinozinyl, thiazolidinyl, isothiazolidinyl, isoxazolidinyl, indolinyl, octahydroindolyl, octahydroisoindolyl, pyrrolidinyl, pyrazolidinyl, phthalimidyl, and the like.

In the present application, the term "aryl" means a conjugated hydrocarbon ring system group having 6 to 18 carbon atoms (preferably having 6 to 10 carbon atoms) as part of a separate group or other groups. For the purposes of the present application, aryl groups may be monocyclic, bicyclic, tricyclic or more ring systems, and may also be fused to a carbocyclyl or heterocyclyl group as defined above, provided that the aryl groups are linked to the remainder of the molecule via 1 or more single bonds via atoms on the aromatic ring. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthryl, phenanthryl, fluorenyl, 2, 3-dihydro-1H-isoindolyl, 2-benzoxazolinone, 2H-1, 4-benzoxazin-3 (4H) -one-7-yl, and the like.

In the present application, the term "arylalkyl" refers to an alkyl group as defined above substituted with an aryl group as defined above.

In the present application, the term "heteroaryl" as part of a single group or other group means a 5-to 16-membered conjugated ring system group having 1 to 15 carbon atoms (preferably 1 to 10 carbon atoms) and 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur within the ring. Unless otherwise specifically indicated in the present specification, heteroaryl groups may be monocyclic, bicyclic, tricyclic or more ring systems, and may also be fused to a carbocyclyl or heterocyclyl group as defined above, provided that the heteroaryl groups are attached to the remainder of the molecule via 1 or more single bonds via an atom on a heteroaromatic ring. The nitrogen, carbon, or sulfur atoms in the heteroaryl group may optionally be oxidized; the nitrogen atom may optionally be quaternized. For the purposes of the present application, heteroaryl groups are preferably stable 5-to 12-membered aromatic groups comprising 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably stable 5-to 10-membered aromatic groups comprising 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur or 5-to 6-membered aromatic groups comprising 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. Examples of heteroaryl groups include, but are not limited to, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzimidazolyl, benzopyrazolyl, indolyl, furanyl, pyrrolyl, triazolyl, tetrazolyl, triazinyl, indolizinyl, isoindolyl, indazolyl, isoindazolyl, purinyl, quinolinyl, isoquinolinyl, naphthyridinyl, quinoxalinyl, pteridinyl, carbazolyl, carbolinyl, phenanthridinyl, phenanthrolinyl, acridinyl, phenazinyl, isothiazolyl, benzothiazolyl, benzothienyl, oxatriazolyl, cinnolinyl, quinazolinyl, thiophenyl, indolizinyl, phenanthroline, isoxazolyl, phenoxazinyl, phenothiazinyl, 4,5,6, 7-tetrahydrobenzo [ b ] thienyl, naphthyridinyl, [1,2,4] triazolo [4, 3-triazolo [1, 4] pyridazine, 3-1, 4-imidazo [1, 4] triazolo [1, 4, 3-triazolo [1, 4] pyridazine, 3-1, 4-imidazo [ 2,4] a ] 1, 4-imidazo [ 2, 4-a ] and the like.

In the present application, the term "heteroarylalkyl" refers to an alkyl group as defined above substituted with a heteroaryl group as defined above.

In the present application, the term "absent" means that both sides of the groups defined above are directly connected by chemical bonds. For example, the absence of B in "A-B-C" means "A-C".

In the present application, the term "- [ CH ] ₂ ] _n "means that the two sides of the groups defined above are linked by a number n of methylene groups. When n is 0, it means that both sides of the group defined above are directly connected by a chemical bond.

In the present application,is->Represents the attachment position of the group R.

In the present application, unless otherwise indicated, "optionally," "optionally," and "optionally" mean that the subsequently described event or condition may or may not occur, and that the description includes both instances where the event or condition occurs and does not occur. For example, "optionally substituted aryl" means that a hydrogen on the aryl is substituted or unsubstituted, and the description includes both substituted and unsubstituted aryl. For example, where substituents are not explicitly listed, as used hereinThe term "optionally substituted", "substituted" or "substituted with … …" means that one or more hydrogen atoms on a given atom or group are independently substituted with one or more, e.g., 1, 2, 3 or 4 substituents independently selected from: deuterium (D), halogen, -OH, -oxo (=o), mercapto, cyano, -CD ₃ -C1-C6 alkyl (preferably-C1-3 alkyl), C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl (preferably-C3-C8 cycloalkyl), aryl, heterocyclyl (preferably 3-8 membered heterocyclyl), heteroaryl, aryl-C1-C6 alkyl-, heteroaryl-C1-C6 alkyl-, C1-C6 haloalkyl-, -OC1-C6 alkyl (preferably-OC 1-C3 alkyl), -OC2-C6 alkenyl, -Ocycloalkyl, -Oheterocyclyl, -Oaryl, -Oheteroaryl, -OC1-C6 alkylphenyl, -C1-C6 alkyl-OH (preferably-C1-C4 alkyl-OH), -C1-C6 alkyl-SH, -C1-C6 alkyl-O-C1-C6 alkyl, -OC1-C6 haloalkyl, -NH ₂ -C1-C6 alkyl-NH ₂ (preferably-C1-C3 alkyl-NH) ₂ ) -N (C1-C6 alkyl) ₂ (preferably-N (C1-C3 alkyl) ₂ ) -NH (C1-C6 alkyl) (preferably-NH (C1-C3 alkyl)), -N (C1-C6 alkyl) (C1-C6 alkylphenyl), -NH (C1-C6 alkylphenyl), -N (C1-C6 alkyl) (aryl), -NH (aryl), nitro, -C (O) -OH, -C (O) OC1-C6 alkyl (preferably-C (O) OC1-C3 alkyl), -CONR ⁱ R ⁱⁱ (wherein R is ⁱ And R is ⁱⁱ Is H, D and C1-6 alkyl, preferably C1-3 alkyl), -NHC (O) (C1-C6 alkyl), -NHC (O) (phenyl), -N (C1-C6 alkyl) C (O) (C1-C6 alkyl), -N (C1-C6 alkyl) C (O) (phenyl), -C (O) C1-C6 alkyl, -C (O) heteroaryl (preferably-C (O) -5-7 membered heteroaryl), -C (O) C1-C6 alkylphenyl, -C (O) C1-C6 haloalkyl, -OC (O) C1-C6 alkyl (preferably-OC (O) C1-C3 alkyl), -S (O) ₂ -C1-C6 alkyl, -S (O) ₂ -phenyl, -S (O) ₂ -C1-C6 haloalkyl, -S (O) ₂ NH ₂ 、-S(O) ₂ NH (C1-C6 alkyl), -S (O) ₂ NH (phenyl), -NHS (O) ₂ (C1-C6 alkyl), -NHS (O) ₂ (phenyl) and-NHS (O) ₂ (C1-C6 haloalkyl), wherein each of said alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, aryl, heterocyclyl, and heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of: halogen, -OH, oxo (= O), -NH ₂ Cycloalkyl, 3-8 membered heterocyclyl, C1-C4 alkyl, C1-C4 haloalkyl-, -OC1-C4 alkyl, -C1-C4 alkyl-OH, -C1-C4 alkyl-O-C1-C4 alkyl, -OC1-C4 haloalkyl, cyano, nitro, -C (O) -OH, -C (O) OC1-C6 alkyl, -CON (C1-C6 alkyl) ₂ -CONH (C1-C6 alkyl), -CONH ₂ -NHC (O) (C1-C6 alkyl), -NH (C1-C6 alkyl) C (O) (C1-C6 alkyl), -SO ₂ (C1-C6 alkyl), -SO ₂ (phenyl) -SO ₂ (C1-C6 haloalkyl), -SO ₂ NH ₂ 、-SO ₂ NH (C1-C6 alkyl), -SO ₂ NH (phenyl) -NHSO ₂ (C1-C6 alkyl), -NHSO ₂ (phenyl) and-NHSO ₂ (C1-C6 haloalkyl). When an atom or group is substituted with multiple substituents, the substituents may be the same or different. The terms "moiety", "structural moiety", "chemical moiety", "group", "chemical group" as used herein refer to a particular fragment or functional group in a molecule. Chemical moieties are generally considered to be chemical entities that are embedded or attached to a molecule.

In the present invention, (C1-C4 alkyl) ₂ Amino, representing 2 identical or different C1-C4-alkyl-substituted amines, may be, for exampleEtc.

Unless otherwise indicated, herein "plurality" means 2, 3 or 4.

Active ingredient

As used herein, "inventive compound" or "active ingredient" refers to a compound represented by formula I, and further comprises a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, cis-trans isomer, solvate, polymorph, deuterate, or combination thereof.

"stereoisomers" refer to compounds that consist of the same atoms, are bonded by the same bonds, but have different three-dimensional structures. The present invention is intended to cover various stereoisomers and mixtures thereof.

When an olefinic double bond is contained in the compounds of the present invention, the compounds of the present invention are intended to include both E-and Z-geometric isomers unless otherwise specified.

"tautomer" refers to an isomer formed by the transfer of a proton from one atom of a molecule to another atom of the same molecule. All tautomeric forms of the compounds of the invention are also intended to be included within the scope of the invention.

The compounds of the invention or pharmaceutically acceptable salts thereof may contain one or more chiral carbon atoms and thus may be produced in enantiomers, diastereomers and other stereoisomeric forms. Each chiral carbon atom may be defined as (R) -or (S) -, based on stereochemistry. The present invention is intended to include all possible isomers, as well as racemates and optically pure forms thereof. The compounds of the invention may be prepared by selecting racemates, diastereomers or enantiomers as starting materials or intermediates. Optically active isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as crystallization and chiral chromatography.

Conventional techniques for preparing/separating individual isomers include chiral synthesis from suitable optically pure precursors, or resolution of racemates (or racemates of salts or derivatives) using, for example, chiral high performance liquid chromatography, see, for example, gerald gabiz and Martin g.schmid (eds.), chiral Separations, methods and Protocols, methods in Molecular Biology, vol.243,2004; m.stalcup, chiral Separations, annu.rev.animal.chem.3:341-63, 2010; fumigs et al (EDs.), VOGEL' S ENCYCLOPEDIA OF PRACTICAL ORGANIC CHEMISTRY.sup.TH ED, longman Scientific and Technical Ltd., essex,1991,809-816; heller, acc.chem.Res.1990,23,128.

In the present application, the term "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

By "pharmaceutically acceptable acid addition salt" is meant a salt with an inorganic or organic acid that retains the biological effectiveness of the free base without other side effects. Inorganic acid salts include, but are not limited to, hydrochloride, hydrobromide, sulfate, nitrate, phosphate, and the like; organic acid salts include, but are not limited to, formate, acetate, 2-dichloroacetate, trifluoroacetate, propionate, hexanoate, octanoate, decanoate, undecylenate, glycolate, gluconate, lactate, sebacate, adipate, glutarate, malonate, oxalate, maleate, succinate, fumarate, tartrate, citrate, palmitate, stearate, oleate, cinnamate, laurate, malate, glutamate, pyroglutamate, aspartate, benzoate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, alginate, ascorbate, salicylate, 4-aminosalicylate, naphthalenedisulfonate, and the like. These salts can be prepared by methods known in the art.

By "pharmaceutically acceptable base addition salt" is meant a salt formed with an inorganic or organic base that is capable of maintaining the bioavailability of the free acid without other side effects. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Preferred inorganic salts are ammonium, sodium, potassium, calcium and magnesium salts. Salts derived from organic bases include, but are not limited to, the following: primary, secondary and tertiary amines, substituted amines including natural substituted amines, cyclic amines and basic ion exchange resins such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. These salts can be prepared by methods known in the art.

Pharmaceutical compositions and methods of administration

In the present application, "pharmaceutical composition" refers to a formulation of a compound of the present application with a medium commonly accepted in the art for delivery of biologically active compounds to a mammal (e.g., a human). The medium includes a pharmaceutically acceptable carrier. The purpose of the pharmaceutical composition is to promote the administration of organisms, facilitate the absorption of active ingredients and further exert biological activity.

The term "pharmaceutically acceptable" as used herein refers to a material (e.g., carrier or diluent) that does not affect the biological activity or properties of the compounds of the present application, and is relatively non-toxic, i.e., the material can be administered to an individual without causing an adverse biological reaction or interacting in an adverse manner with any of the components contained in the composition.

In the present application, "pharmaceutically acceptable carrier" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye/colorant, flavoring agent, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonizing agent, solvent, or emulsifying agent that is approved by the relevant government regulatory agency as acceptable for human or livestock use.

The "tumor" of the present application includes, but is not limited to, lung cancer, pancreatic cancer, colorectal cancer, leukemia, ewing's sarcoma, breast cancer, prostate cancer, T-cell lymphoma, B-cell lymphoma, malignant rhabdomyoma, synovial sarcoma, endometrial tumor, gastric cancer, liver cancer, renal cancer, melanoma, ovarian cancer, brain glioma, bile duct cancer, nasopharyngeal cancer, cervical cancer, head and neck cancer, esophageal cancer, thyroid cancer, bladder cancer, and the like.

In a preferred embodiment, the tumor associated with MLL1, MLL2, MLL fusion protein, and/or the activity of the grin protein is selected from the group consisting of: leukemia, ewing's sarcoma, breast cancer, prostate cancer, T-cell lymphoma, B-cell lymphoma, malignant rhabdomyoma, synovial sarcoma, colorectal cancer, endometrial tumor, gastric cancer, liver cancer, renal cancer, lung cancer, melanoma, ovarian cancer, pancreatic cancer, brain glioma, cholangiocarcinoma, nasopharyngeal cancer, cervical cancer, head and neck cancer, esophageal cancer, thyroid cancer, and bladder cancer; related "other diseases" include, but are not limited to, autoimmune diseases, non-alcoholic hepatitis, and the like.

The terms "prevent", "preventing" and "preventing" as used herein include reducing the likelihood of a patient from developing or worsening a disease or condition.

The term "treatment" and other similar synonyms as used herein include the following meanings:

(i) Preventing the occurrence of a disease or disorder in a mammal, particularly when such mammal is susceptible to the disease or disorder, but has not been diagnosed as having the disease or disorder;

(ii) Inhibiting the disease or disorder, i.e., inhibiting its progression;

(iii) Alleviating a disease or condition, i.e., causing the state of the disease or condition to subside; or alternatively

(iv) Alleviating symptoms caused by the disease or condition.

The term "effective amount," "therapeutically effective amount," or "pharmaceutically effective amount" as used herein refers to an amount of at least one agent or compound that is sufficient to alleviate one or more symptoms of the disease or disorder being treated to some extent after administration. The result may be a reduction and/or alleviation of signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an "effective amount" for treatment is the amount of a composition comprising a compound disclosed herein that is required to provide clinically significant relief from a disorder. Effective amounts suitable in any individual case can be determined using techniques such as a dose escalation test.

The terms "administering," "administering," and the like as used herein refer to a method capable of delivering a compound or composition to a desired site for biological action. These methods include, but are not limited to, oral routes, duodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration, and rectal administration. Application techniques useful in the compounds and methods described herein are well known to those skilled in the art, for example, at Goodman and Gilman, the Pharmacological Basis of Therapeutics, current ed.; pergamon; and Remington's, pharmaceutical Sciences (current edition), mack Publishing co., easton, pa. In preferred embodiments, the compounds and compositions discussed herein are administered orally.

The terms "pharmaceutical combination", "co-administration", "administration of other treatments", "administration of other therapeutic agents" and the like as used herein refer to a pharmaceutical treatment obtained by mixing or combining more than one active ingredient, which includes both fixed and non-fixed combinations of active ingredients. The term "fixed combination" refers to the simultaneous administration of at least one compound described herein and at least one synergistic agent to a patient in the form of a single entity or single dosage form. The term "ambulatory combination" refers to the simultaneous administration, co-administration, or sequential administration of at least one compound described herein and at least one synergistic formulation as separate entities to a patient at variable intervals. These also apply to cocktail therapies, for example, administration of three or more active ingredients.

Preferably, the pharmaceutical composition further comprises other pharmaceutically acceptable therapeutic agents, in particular other antitumor agents. Such therapeutic agents include, but are not limited to: antitumor drugs acting on the chemical structure of DNA such as cisplatin, antitumor drugs affecting nucleic acid synthesis such as Methotrexate (MTX), 5-fluorouracil (5 FU) and the like, antitumor drugs affecting nucleic acid transcription such as doxorubicin, epirubicin, aclacinomycin, mithramycin and the like, antitumor drugs acting on tubulin synthesis such as paclitaxel, vinorelbine and the like, aromatase inhibitors such as aminoglutethimide, orchiron, letrozole, ryanodine and the like, cell signal pathway inhibitors such as epidermal growth factor receptor inhibitors Imatinib (Imatinib), gefitinib (Gefitinib), erlotinib (Erlotinib), lapatinib (Lapatinib) and the like.

Compared with the prior art, the invention has the following beneficial effects:

(1) The invention provides a compound shown as a formula I or pharmaceutically acceptable salt thereof;

(2) The invention provides a compound shown as a formula I for preparing a pharmaceutical composition for preventing and treating diseases related to MLL1, MLL2, MLL fusion protein and/or menin protein activity.

The invention will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. The experimental methods, in which specific conditions are not noted in the following examples, are generally conducted under conventional conditions or under conditions recommended by the manufacturer. Percentages and parts are weight percentages and parts unless otherwise indicated.

The experimental materials and reagents used in the following examples were obtained from commercial sources unless otherwise specified.

In the context of the various embodiments of the present invention, ¹ h NMR was recorded by BRUKER AVANCE NEO 400.400 MHz NMR and chemical shifts were expressed as δ (ppm); LC-MS (LCMS) was recorded by Shimadzu LC-20AD, SIL-20A, CTO-20AC, SPD-M20A, CBM-20A, LCMS-2020 type mass spectrometer; preparative HPLC separation was performed using a Gilson-281 model liquid chromatograph.

Preparation of intermediates

1. Preparation of intermediate A

The synthetic route for intermediate a is shown below:

(1) To a solution of compound A-1 (1.00 g,5.91 mmol) in methanol (10.0 mL) was added acetic acid (35.5 mg, 591. Mu. Mol), sodium cyanoborohydride (1.11 g,17.7 mmol) and compound A-2 (1.13 g,7.09 mmol), and the reaction was stirred at 25℃for 1 hour. Ethyl acetate (30.0 mL) was added, the mixture was extracted with water (30.0 mL. Times.2), and the organic phases were combined, washed with saturated brine (30.0 mL. Times.1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Separating the crude product by silica gel column chromatography (petroleum ether/ethyl acetate=1:0 to 10:1) to obtain compound a-3;

MS-ESI[M+H] ⁺ calculated 313, measured 313.

¹ H NMR(400MHz,CDCl ₃ )δ7.59(dd,J＝9.6,3.2Hz,1H),7.12(ddd,J＝9.2,7.6,3.2Hz,1H),6.71(dd,J＝9.2,4.4Hz,1H),4.80(s,1H),3.86(s,3H),3.32-3.40(m,4H),1.45(s,9H)。

(2) To a solution of Compound A-3 (1.50 g,4.80 mmol) in dichloromethane (15.0 mL) was added trifluoroacetic acid (5.0 mL), and the reaction was stirred at 20℃for 1 hour. Concentrating the reaction solution under reduced pressure to obtain trifluoroacetate of the compound A-4;

MS-ESI[M+H] ⁺ calculated 213, measured 213.

(3) To a solution of the trifluoroacetate salt of compound A-4 (5.30 g,16.2 mmol) in methanol (50.0 mL) was added triethylamine (5.09 g,50.3 mmol), sodium cyanoborohydride (3.10 g,49.3 mmol) and compound A-5 (6.02 g,32.5 mmol), and the reaction was stirred at 25℃for 1 hour. The reaction was quenched with water (20.0 mL), extracted with dichloromethane (20.0 mL. Times.3), and the combined organic phases were washed with saturated brine (30.0 mL. Times.1), dried over anhydrous sodium sulfate, filtered, and the organic phase concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (dichloromethane/methanol=1:0 to 30:1) to give compound a-6;

MS-ESI[M+H] ⁺ Calculated 382, measured 382.

(4) To a solution of compound A-6 (6.90 g,14.3 mmol) and compound A-7 (11.1 g,57.2 mmol) in N-methylpyrrolidone (50.0 mL) was added diisopropylethylamine (5.72 g,44.2 mmol), and the reaction was stirred under nitrogen at 110℃for 8 hours. Ethyl acetate (300 mL) was added, washed with water (100 ml×5), the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate=1:0 to 4:1) to give compound a-8;

MS-ESI[M+H] ⁺ calculated 538, measured 538.

¹ H NMR(400MHz,CDCl ₃ )δ8.66(s,1H),8.47(s,1H),7.59(dd,J＝2.8,9.6Hz,1H),7.07-7.17(m,1H),6.66(dd,J＝4.4,9.2Hz,1H),5.03-5.15(m,1H),3.88-3.94(m,2H),3.86(s,3H),3.56-3.72(m,2H),3.45(t,J＝6.4Hz,2H),3.27-3.39(m,2H),2.17-2.27(m,1H),2.10-2.16(m,1H),1.46(s,9H)。

(5) Compound A-8 (500 mg, 929. Mu. Mol), cesium carbonate (328 mg,2.79 mmol), 2-di-tert-butylphosphine-2 ',4',6' -triisopropylbiphenyl (90.0 mg, 189. Mu. Mol) and methanesulfonic acid (2-dicyclohexylphosphino-2, 4, 6-triisopropyl-1, 1-biphenyl) (2-amino-1, 1-biphenyl-2-yl) palladium (80.0 mg, 94.5. Mu. Mol) were dissolved in dioxane (10.0 mL). The reaction solution was stirred for 4 hours at 110℃under nitrogen. The reaction solution was concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (dichloromethane/methanol=1:0 to 25:1) to give compound a-9.

MS-ESI[M+H] ⁺ Calculated 458, measured 458.

(6) To a solution of Compound A-9 (120 mg, 262. Mu. Mol) in methanol (1.50 mL) were added lithium hydroxide monohydrate (33.0 mg, 787. Mu. Mol) and water (0.50 mL), and the reaction mixture was stirred at 20℃for 2 hours. Adding aqueous hydrochloric acid (1 mol/L) to the reaction solution to adjust the pH value to 6, extracting with dichloromethane (10.0 mL×3), drying the organic phase with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain a compound A-10;

MS-ESI[M+H] ⁺ Calculated 444, found 444.

(7) To a solution of compound A-10 (100 mg, 225. Mu. Mol) in methylene chloride (3.0 mL) were added compound A-11 (57.6 mg, 661. Mu. Mol), diisopropylethylamine (120. Mu.L, 689. Mu. Mol) and 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (130 mg, 342. Mu. Mol), and the reaction mixture was stirred at 25℃for 1 hour. The reaction was quenched with water (10.0 mL), extracted with methylene chloride (10.0 mL. Times.1), and the combined organic phases were washed with saturated brine (10.0 mL. Times.1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give Compound A-12.

MS-ESI[M+H] ⁺ Calculated 513, measured 513.

(8) To a solution of Compound A-12 (65.0 mg, 127. Mu. Mol) in methylene chloride (5.0 mL) was added a dioxane solution of hydrogen chloride (4 mol/L,0.50 mL), and the reaction mixture was stirred at 20℃for 2 hours. Concentrating the reaction solution under reduced pressure to obtain hydrochloride of the compound A;

MS-ESI[M+H] ⁺ calculated 413, measured 413.

2. Preparation of intermediate B

The synthetic route for intermediate B is shown below:

(1) Compound B-1 (20.0 mg,108 mmol), cesium carbonate (70.1 g,215 mmol), 2-bis (diphenylphosphino) -1, 1-binaphthyl (26.8 mg,43.0 mmol), compound B-2 (20.0 mg,118 mmol) and tris (dibenzylideneacetone) dipalladium (19.7 g,21.5 mmol) were dissolved in toluene (250 mL). The reaction solution was stirred at 110℃for 10 hours under nitrogen. Water (500 mL) was added, extracted with ethyl acetate (500 mL. Times.2), the organic phase was washed with saturated brine (500 mL. Times.4), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (petroleum ether/ethyl acetate=1:0 to 0:1) to give compound B-3.

MS-ESI[M+H] ⁺ Calculated 275, measured 275.

(2) To a solution of compound B-3 (20.0 g,72.9 mmol) in methanol (400 mL) was added acetic acid (4.49 g,74.7 mmol), sodium cyanoborohydride (9.17 g,146 mmol) and compound B-4 (17.1 g,72.9 mmol), and the reaction was stirred at 25℃for 16 hours. Water (80.0 mL) was added, extraction was performed with ethyl acetate (80.0 mL. Times.3), and the combined organic phases were washed with saturated brine (80.0 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. Separating the crude product by silica gel column chromatography (dichloromethane/methanol=1:0 to 10:1) to obtain compound B-5;

MS-ESI[M+H] ⁺ calculated 493, found 493.

¹ H NMR(400MHz,CDCl ₃ )δ8.50(s,1H),8.19(d,J＝5.2Hz,1H),7.72(d,J＝9.2Hz,1H),7.63(s,1H),7.34-7.36(m,5H),7.24(s,2H),5.11(s,2H),4.30(s,2H),3.89(s,5H),3.46(t,J＝6.8Hz,2H),2.89(t,J＝6.8Hz,2H),2.74(s,3H),2.09(s,2H),1.92(s,2H)。

(3) To a solution of compound B-5 (4.70 g,9.54 mmol) in methanol (100 mL) was added acetic acid (17.2 g, 284 mmol), sodium cyanoborohydride (9.17 g,28.6 mmol), 4A molecular sieve (30.0 g) and compound B-6 (18.8 g,95.8 mmol), and the reaction was stirred under nitrogen for 16 hours at 25 ℃. The reaction solution was filtered, ethyl acetate (500 mL) was added, the mixture was washed with saturated brine (500 mL. Times.1), dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. Separating the crude product by silica gel column chromatography (petroleum ether/ethyl acetate=1:0 to 3:2) to obtain a compound B-7;

MS-ESI[M+H] ⁺ calculated 555, measured 555.

¹ H NMR(400MHz,CDCl ₃ )δ8.51-8.55(m,1H),8.33-8.38(m,1H),7.66-7.71(m,1H),7.52-7.56(m,1H),7.34(s,5H),7.15-7.22(m,1H),6.89-6.94(m,1H),5.12-5.13(m,2H),4.03-4.07(m,2H),3.87-3.92(m,3H),2.97-3.09(m,2H),2.87-2.95(m,3H),1.98-2.03(m,4H)。

(4) To a solution of compound B-7 (1.00 g,1.80 mmol) in N, N-dimethylformamide (40.0 mL) was added potassium carbonate (746 mg,5.40 mmol), and the reaction was stirred under nitrogen at 110℃for 2 hours. Ethyl acetate (100 mL) was added, washed with saturated brine (100 ml×5), and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (dichloromethane/methanol=1:0 to 32:1) to give compound B-8;

MS-ESI[M+H] ⁺ Calculated 519, measured 519.

¹ H NMR(400MHz,CDCl ₃ )δ8.10(d,J＝4.8Hz,1H),7.73(s,1H),7.51(d,J＝7.6Hz,1H),7.34-7.38(m,5H),7.24(d,J＝5.6Hz,2H),7.07(d,J＝4.4Hz,1H),5.13(s,2H),4.25(s,2H),4.07(d,J＝18.0Hz,2H),3.60-3.75(m,5H),3.11(s,2H),2.80(s,3H),1.92(s,2H),1.46-1.53(m,2H)。

(5) To a solution of Compound B-8 (90.0 mg, 174. Mu. Mol) in methanol (6.0 mL) were added lithium hydroxide monohydrate (43.7 mg,1.04 mmol) and water (2.0 mL), and the reaction was stirred at 20℃for 2 hours. Adding aqueous hydrochloric acid (1 mol/L) to the reaction solution to adjust the pH value to 6, extracting with dichloromethane (10.0 mL×3), drying the organic phase with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain a compound B;

MS-ESI[M+H] ⁺ calculated 505, measured 505.

3. Preparation of intermediate C

The synthetic route for intermediate C is shown below:

(1) To a solution of trifluoroacetate salt of Compound A-4 (1.37 g,4.20 mmol) in methanol (15.0 mL) was added triethylamine (1.27 g,12.6 mmol), sodium cyanoborohydride (792 mg,12.6 mmol) and Compound C-1 (1.00 g,5.04 mmol), and the reaction was stirred under nitrogen at 25℃for 1 hour. The reaction was quenched with water (20.0 mL), extracted with dichloromethane (20.0 mL. Times.3), and the combined organic phases were washed with saturated brine (30.0 mL. Times.1), dried over anhydrous sodium sulfate, filtered, and the organic phase concentrated under reduced pressure. Separating the crude product by silica gel column chromatography (dichloromethane/methanol=1:0 to 49:1) to obtain compound C-2;

MS-ESI[M+H] ⁺ calculated 396, found 396.

¹ H NMR(400MHz,CDCl ₃ )δ7.58(dd,J＝9.6,3.2Hz,1H),7.14(ddd,J＝9.2,7.6,3.2Hz,1H),6.69(dd,J＝9.2,4.4Hz,1H),4.11-4.19(m,2H),3.85(s,3H),3.57(t,J＝6.0Hz,2H),3.08-3.13(m,2H),2.97-3.03(m,1H),2.75(t,J＝12.0Hz,2H),2.01(d,J＝11.6Hz,2H),1.50-1.60(m,2H),1.44-1.46(m,9H)。

(2) To a solution of compound C-2 (900 mg,2.28 mmol) and compound A-7 (640 mg,4.55 mmol) in N-methylpyrrolidone (15.0 mL) was added diisopropylethylamine (882 mg,6.82 mmol), and the reaction was stirred under nitrogen at 110℃for 8 hours. Ethyl acetate (30.0 mL) was added, extraction was performed with water (30.0 ml×2), the organic phase was washed with saturated brine (30.0 ml×2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate=1:0 to 9:1) to give compound C-3;

MS-ESI[M+H] ⁺ Calculated 552, measured 552.

¹ H NMR(400MHz,CDCl ₃ )δ8.53(s,1H),8.45(s,1H),7.51(dd,J＝9.6,3.2Hz,1H),7.08-7.18(m,1H),6.81(dd,J＝9.2,4.4Hz,1H),4.32-4.41(m,1H),4.12-4.19(m,2H),3.83(s,3H),3.76(t,J＝6.0Hz,2H),3.43(t,J＝6.0Hz,2H),2.79(s,2H),1.78-1.84(m,2H),1.71(d,J＝8.4Hz,2H),1.45(s,9H)。

(3) Compound C-3 (463 mg, 843. Mu. Mol), cesium carbonate (823 mg,2.53 mmol), 2-di-tert-butylphosphine-2 ',4',6' -triisopropylbiphenyl (161 mg, 337. Mu. Mol) and methanesulfonic acid (2-dicyclohexylphosphino-2, 4, 6-triisopropyl-1, 1-biphenyl) (2-amino-1, 1-biphenyl-2-yl) palladium (143 mg, 169. Mu. Mol) were dissolved in dioxane (25.0 mL). The reaction solution was stirred for 4 hours at 110℃under nitrogen. Ethyl acetate (30.0 mL) was added to the reaction solution, extraction was performed with water (30.0 ml×2), and the organic phase was washed with saturated brine (30.0 ml×2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (dichloromethane/methanol=1:0 to 30:1) to give compound C-4.

MS-ESI[M+H] ⁺ Calculated value 472, measured value 472.

¹ H NMR(400MHz,CDCl ₃ )δ7.96(s,1H),7.60(d,J＝8.4Hz,1H),7.43(dd,J＝6.4,1.6Hz,2H),6.95(s,1H),4.91-5.03(m,2H),4.25(d,J＝12.8Hz,2H),3.72(s,3H),3.61(s,4H),2.93(s,1H),1.73-1.79(m,4H),1.48(s,9H)。

(4) To a solution of Compound C-4 (210 mg, 445. Mu. Mol) in methylene chloride (3.0 mL) was added trifluoroacetic acid (1.0 mL), and the reaction mixture was stirred at 20℃for 1 hour. Filtering the reaction solution, and concentrating under reduced pressure to obtain trifluoroacetate of the compound C;

MS-ESI[M+H] ⁺ calculated 372, measured 372.

4. Preparation of intermediate D

The synthetic route for intermediate D is shown below:

(1) To a solution of the trifluoroacetate salt of compound A-4 (2.20 g,6.74 mmol) in methanol (20.0 mL) were added triethylamine (682 mg,6.74 mmol) and compound D-1 (1.61 g,8.09 mmol), and the reaction was stirred under nitrogen at 25℃for 2 hours. Sodium cyanoborohydride (1.27 g,20.2 mmol) was added, stirring was continued for 12 hours, the reaction was quenched by the addition of water (20.0 mL), extracted with ethyl acetate (20.0 mL. Times.3), the combined organic phases were washed with saturated brine (30.0 mL. Times.1), dried over anhydrous sodium sulfate, filtered, and the organic phase concentrated under reduced pressure. Separating the crude product by silica gel column chromatography (dichloromethane/methanol=1:0 to 10:1) to obtain compound D-2;

MS-ESI[M+H] ⁺ Calculated 396, found 396.

(2) To a solution of compound D-2 (1.00 g,2.53 mmol) and compound A-7 (1.96 mg,10.1 mmol) in N-methylpyrrolidone (15.0 mL) was added diisopropylethylamine (480 mg,7.59 mmol), and the reaction was stirred under nitrogen at 110℃for 6 hours. Ethyl acetate (30.0 mL) was added, extraction was performed with water (30.0 ml×2), the organic phase was washed with saturated brine (30.0 ml×2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate=1:0 to 3:1) to give compound D-3;

MS-ESI[M+H] ⁺ calculated 552, measured 552.

(3) Compound D-3 (300 mg, 543. Mu. Mol), cesium carbonate (530 mg,1.63 mmol), 2-di-tert-butylphosphine-2 ',4',6' -triisopropylbiphenyl (103 mg, 217. Mu. Mol) and methanesulfonic acid (2-dicyclohexylphosphino-2, 4, 6-triisopropyl-1, 1-biphenyl) (2-amino-1, 1-biphenyl-2-yl) palladium (91.9 mg, 108. Mu. Mol) were dissolved in dioxane (15.0 mL). The reaction solution was stirred for 3 hours at 110℃under nitrogen. Ethyl acetate (30.0 mL) was added to the reaction solution, extraction was performed with water (15.0 ml×2), and the organic phase was washed with saturated brine (30.0 ml×2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate=1:0 to 5:1) to give compound D-4.

MS-ESI[M+H] ⁺ Calculated value 472, measured value 472.

(4) To a solution of compound D-4 (200 mg, 424. Mu. Mol) in methylene chloride (5.0 mL) was added trifluoroacetic acid (1.0 mL), and the reaction mixture was stirred at 20℃for 1 hour. Filtering the reaction solution, and concentrating under reduced pressure to obtain trifluoroacetate of the compound D;

MS-ESI[M+H] ⁺ calculated 372, measured 372.

5. Preparation of intermediate E

The synthetic route for intermediate E is shown below:

(1) To a solution of the trifluoroacetate salt of Compound A-4 (3.52 g,4.75 mmol) in methanol (50.0 mL) were added triethylamine (882 mg,8.71 mmol) acetic acid (262 mg,4.37 mmol) Compound E-1 (930 mg,4.36 mmol) and magnesium sulfate (1.50 g), and the reaction was stirred under nitrogen at 35℃for 3 hours. Sodium cyanoborohydride (268 g,8.72 mmol) was added, stirring was continued for 2 hours, the reaction was quenched by addition of water (20.0 mL), extracted with dichloromethane (20.0 mL. Times.3), the combined organic phases were washed with saturated brine (30.0 mL. Times.1), dried over anhydrous sodium sulfate, filtered, and the organic phase concentrated under reduced pressure. Separating the crude product by silica gel column chromatography (dichloromethane/methanol=1:0 to 10:1) to obtain compound E-2;

MS-ESI[M+H] ⁺ calculated value 410, measured value 410.

¹ H NMR(400MHz,CDCl ₃ )δ7.57-7.62(m,1H),7.18-7.27(m,1H),6.83-6.88(m,1H),3.87(s,3H),3.62(t,J＝4.0Hz,2H),3.35(s,1H),3.19-3.26(m,3H),2.93(d,J＝8.0Hz,2H),2.70-2.86(m,2H),1.77(d,J＝12.0Hz,2H),1.45(s,10H),1.12-1.22(m,2H)。

(2) To a solution of compound E-2 (1.80 g,4.40 mmol) and compound A-7 (850 mg,4.40 mmol) in N-methylpyrrolidone (20.0 mL) was added diisopropylethylamine (1.70 g,13.2 mmol), and the reaction was stirred under nitrogen at 90℃for 5 hours. Ethyl acetate (50.0 mL) was added, extraction was performed with water (30.0 ml×2), the organic phase was washed with saturated brine (30.0 ml×2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate=1:0 to 1:1) to give compound E-3;

MS-ESI[M+H] ⁺ Calculated 566, measured 566.

(3) Compound E-3 (900 mg,1.59 mmol), cesium carbonate (1.56 mg,4.78 mmol), 2-di-tert-butylphosphine-2 ',4',6' -triisopropylbiphenyl (151 mg, 317. Mu. Mol) and methanesulfonic acid (2-dicyclohexylphosphino-2, 4, 6-triisopropyl-1, 1-biphenyl) (2-amino-1, 1-biphenyl-2-yl) palladium (135 mg, 160. Mu. Mol) were dissolved in dioxane (20.0 mL). The reaction solution was stirred for 3 hours at 100℃under nitrogen. The reaction solution was added with water (50.0 mL), extracted with ethyl acetate (100 ml×3), washed with saturated brine (50.0 ml×2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (dichloromethane/methanol=1:0 to 10:1) to give compound E-4.

MS-ESI[M+H] ⁺ Calculated 486, measured 486.

¹ H NMR(400MHz,CDCl ₃ )δ8.12(s,1H),7.60-7.67(m,1H),7.28-7.32(m,2H),7.06(s,1H),4.08-4.17(m,2H),3.78(s,3H),3.53-3.73(m,6H),2.67-2.78(m,2H),1.69(br d,J＝12.0Hz,2H),1.46(s,10H),1.23-1.27(m,2H)。

(4) To a solution of Compound E-4 (50.0 mg, 103. Mu. Mol) in methylene chloride (5.0 mL) was added trifluoroacetic acid (1.0 mL), and the reaction mixture was stirred at 20℃for 1 hour. Filtering the reaction solution, and concentrating under reduced pressure to obtain trifluoroacetate of the compound E;

MS-ESI[M+H] ⁺ calculated 386, measured 386.

6. Preparation of intermediate F

The synthetic route for intermediate F is shown below:

(1) To a solution of the hydrochloride salt of Compound F-1 (5.00 g,25.8 mmol) in methylene chloride (400 mL) was added triethylamine (7.84 g,77.5 mmol), followed by methanesulfonyl chloride (5.91 g,51.6 mmol) at 0℃and the reaction was stirred under nitrogen at 0℃for 1 hour. Water (100 mL) was added, extracted with dichloromethane (100 mL. Times.1), the combined organic phases were washed with saturated brine (80.0 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure to give Compound F-2;

¹ H NMR(400MHz,CDCl ₃ )δ3.67-3.69(m,3H),3.22-3.34(m,1H),2.96-3.00(m,3H),2.20-2.29(m,1H),2.10-2.17(m,2H),2.01-2.08(m,2H),1.48-1.61(m,2H),1.22-1.35(m,2H)。

(2) To a solution of compound F-2 (6.00 g, 25.5. Mu. Mol) in toluene (200 mL) was added diisobutylaluminum hydride (51 mL,1 mol/L), and the reaction was stirred under nitrogen protection at-78℃for 4 hours. Methanol (30.0 mL) and aqueous hydrochloric acid (30.0 mL,1 mol/L) were added to the reaction solution, extracted with ethyl acetate (500 ml×3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (dichloromethane/methanol=1:0 to 10:1) to give compound F;

¹ H NMR(400MHz,CDCl ₃ )δ9.62-9.65(s,1H),4.34-4.43(m,1H),3.25-3.33(m,1H),2.99(s,3H),2.11-2.24(m,4H),1.31-1.45(m,4H)。

example 1

The present embodiment provides a compound 1 shown in formula I, wherein the structural formula of the compound 1 is as follows:

the synthetic route for compound 1 is shown below:

(1) To a solution of intermediate B (50.0 mg, 99.1. Mu. Mol) in N, N-dimethylformamide (3.0 mL) were added ethyldiisopropylamine (38.4 mg, 297. Mu. Mol) and 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (75.4 mg, 198. Mu. Mol), and the reaction mixture was stirred at 25℃for 0.5 hours. Isopropyl methyl amine (36.2 mg, 495. Mu. Mol) was then added and the reaction stirred at 25℃for 0.5 hours. The reaction was quenched by addition of water (10.0 mL), extracted with ethyl acetate (10.0 ml×1), the combined organic phases were washed with saturated brine (10.0 ml×3), dried over anhydrous sodium sulfate, filtered, and the organic phase concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (ethyl acetate/methanol=10:1) to give compound 1-1; .

MS-ESI[M+H] ⁺ Calculated value 560, measured value 560。

(2) To a solution of compound 1-1 (40.0 mg, 71.5. Mu. Mol) in methanol (3.0 mL) was added palladium on carbon (20.0 mg, 10%), and the reaction mixture was stirred under a hydrogen atmosphere at 25℃for 2 hours. Filtering the reaction solution, and concentrating under reduced pressure to obtain a compound 1-2;

MS-ESI[M+H] ⁺ calculated 426, measured 426.

(3) To a solution of compound 1-2 (40.0 mg, 94.0. Mu. Mol) in methylene chloride (5.0 mL) was added acetic acid (565. Mu.g, 9.4. Mu. Mol), compound F (38.6 mg, 188. Mu. Mol) and sodium triacetoxyborohydride (59.8 mg, 282. Mu. Mol), and the reaction solution was stirred at 25℃for 1 hour. The reaction was quenched by the addition of water (20.0 mL), extracted with dichloromethane (20.0 mL. Times.1), the organic phase was washed with saturated brine (10.0 mL. Times.3), dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure, and the crude product was isolated by preparative high performance liquid chromatography (Phenomnex Luna C18,100 mm. Times.30 mm 3 μm, A: water (0.225% formic acid; B: acetonitrile, 0% -30%:8 min) to give formate of Compound 1;

MS-ESI[M+H] ⁺ calculated 615, measured 615.

¹ H NMR(400MHz,MeOD)δ8.00-8.08(m,1H),7.73(d,J＝13.2Hz,1H),7.48-7.58(m,1H),7.25-7.35(m,2H),7.01-7.15(m,1H),4.33-4.74(m,1H),3.90-4.10(m,2H),3.66-3.89(m,1H),3.33-3.65(m,4H),3.07-3.25(m,3H),2.95(s,3H),2.86-2.92(m,3H),2.83(s,1H),2.76(s,1H),2.46(s,2H),2.00-2.15(m,4H),1.88(d,J＝12.0Hz,4H),1.76(s,1H),1.28-1.41(m,2H),1.13-1.24(m,2H),1.11(d,J＝6.4Hz,3H),0.44-0.77(m,3H)。

Example 2

The present embodiment provides a compound 2 shown in formula I, wherein the structural formula of the compound 2 is as follows:

the synthetic route for compound 2 is shown below:

(1) To a solution of intermediate B (90.0 mg, 178. Mu. Mol) in N, N-dimethylformamide (5.0 mL) was added ethyldiisopropylamine (69.1 mg, 535. Mu. Mol) and 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (136 mg, 358. Mu. Mol), and the reaction was stirred at 25℃for 0.5 hours. Isopropyl methyl amine (156 mg,1.79 mmol) was then added and the reaction stirred at 25℃for 0.5 h. The reaction was quenched by addition of water (20.0 mL), extracted with ethyl acetate (20.0 ml×1), the combined organic phases were washed with saturated brine (20.0 ml×3), dried over anhydrous sodium sulfate, filtered, and the organic phase concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (ethyl acetate/methanol=6:1) to give compound 2-1; .

MS-ESI[M+H] ⁺ Calculated 574, measured 574.

(2) To a solution of Compound 1-1 (50.0 mg, 87.5. Mu. Mol) in methanol (3.0 mL) was added palladium on carbon (20.0 mg, 10%), and the reaction mixture was stirred under a hydrogen atmosphere at 25℃for 2 hours. Filtering the reaction solution, and concentrating under reduced pressure to obtain a compound 2-2;

MS-ESI[M+H] ⁺ calculated 440, measured 440.

(3) To a solution of compound 2-2 (40.0 mg, 91.0. Mu. Mol) in methylene chloride (5.0 mL) was added acetic acid (548. Mu.g, 9.1. Mu. Mol), compound F (28.0 mg, 136. Mu. Mol) and sodium triacetoxyborohydride (58.0 mg, 274. Mu. Mol), and the reaction solution was stirred at 25℃for 1 hour. The reaction was quenched by the addition of water (20.0 mL), extracted with dichloromethane (20.0 mL. Times.1), the organic phase was washed with saturated brine (10.0 mL. Times.3), dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure, and the crude product was isolated by preparative high performance liquid chromatography (Phenomenex Gemini-NX C18,100 mm. Times.30 mm. 3 μm, A: water (10 mmol/L ammonium bicarbonate; B: acetonitrile, 15% -45%:10 min) to give Compound 2;

MS-ESI[M+H] ⁺ calculated 629, measured 629.

¹ H NMR(400MHz,MeOD)δ7.99-8.08(m,1H),7.65(s,1H),7.50-7.59(m,1H),7.26-7.36(m,2H),7.03-7.13(m,1H),3.88-3.99(m,2H),3.59-3.71(m,2H),3.54(dt,J＝13.2,6.8Hz,1H),3.36-3.44(m,1H),3.13-3.20(m,2H),3.06-3.12(m,2H),2.97(d,J＝5.2Hz,1H),2.94(s,3H),2.51(d,J＝8.0Hz,1H),2.10-2.20(m,2H),2.02(d,J＝9.2Hz,2H),1.83-1.96(m,6H),1.55-1.72(m,2H),1.47(s,1H),1.24-1.36(m,3H),1.11-1.18(m,2H),1.09-1.11(m,3H),1.03-1.09(m,2H),0.96-1.03(m,2H),0.56(d,J＝5.6Hz,2H)。

Example 3

The present embodiment provides a compound 3 shown in formula I, wherein the structural formula of the compound 3 is as follows:

the synthetic route for compound 3 is shown below:

to a solution of intermediate A hydrochloride (57.0 mg, 127. Mu. Mol) in methanol (5.0 mL) was added triethylamine to adjust the pH to 8. Compound F (52.0 mg, 253. Mu. Mol) was then added and the reaction stirred under nitrogen at 25℃for 12 hours. Sodium cyanoborohydride (25.0 mg, 398. Mu. Mol) was added and stirring was continued for 2 hours. The reaction was quenched with water (5.0 mL), extracted with dichloromethane (10.0 mL. Times.3), and the combined organic phases were washed with saturated brine (10.0 mL. Times.1), dried over anhydrous sodium sulfate, filtered, and the organic phase concentrated under reduced pressure. Preparation of crude product high performance liquid chromatography (Xtimate C18,100 mm. Times.30 mm 10 μm, A: water (0.225% formic acid; B: acetonitrile, 0% -30%:10 min) afforded the formate salt of Compound 3.

MS-ESI[M+H] ⁺ Calculated 602, measured 602.

¹ H NMR(400MHz,MeOD)δ8.43(brs,1H),8.06(brs,1H),7.42-7.54(m,1H),7.29-7.38(m,1H),7.08-7.27(m,2H),3.63-3.93(m,5H),3.34-3.63(m,4H),3.08-3.28(m,4H),2.92-3.07(m,5H),2.55(brs,1H),2.15-2.35(m,1H),1.98-2.13(m,3H),1.63-1.92(m,4H),1.26-1.39(m,3H),1.24(d,J＝3.6Hz,1H),1.11-1.21(m,5H),0.91-1.10(m,3H)。

Example 4

The present embodiment provides a compound 4 shown in formula I, wherein the structural formula of the compound 4 is as follows:

the synthetic route for compound 4 is shown below:

to a solution of intermediate A hydrochloride (41.0 mg, 91.1. Mu. Mol) in methanol (3.0 mL) was added triethylamine to adjust the pH to 8. Compound 4-1 (34.1 mg, 185. Mu. Mol) was then added and the reaction stirred under nitrogen at 25℃for 12 hours. Sodium cyanoborohydride (8.0 mg, 127. Mu. Mol) was added and stirring was continued for 2 hours. The reaction was quenched with water (5.0 mL), extracted with dichloromethane (10.0 mL. Times.3), and the combined organic phases were washed with saturated brine (10.0 mL. Times.1), dried over anhydrous sodium sulfate, filtered, and the organic phase concentrated under reduced pressure. Preparation of crude product high performance liquid chromatography (Phenomenex C18,75 mm. Times.30 mm 3 μm, A: water (10 mmol/L ammonium bicarbonate; B: acetonitrile, 40% -70%:14 min) afforded Compound 4.

MS-ESI[M+H] ⁺ Calculated 581, measured 581.

¹ H NMR(400MHz,MeOD)δ7.90-7.97(m,1H),7.36-7.49(m,1H),7.24-7.32(m,3H),7.14-7.24(m,2H),6.95-7.08(m,1H),5.54(s,1H),4.60(s,1H),3.57-3.93(m,5H),3.38-3.56(m,3H),3.07-3.20(m,1H),2.92-3.04(m,1H),2.65-2.77(m,1H),2.52-2.64(m,4H),2.35-2.47(m,1H),2.18-2.33(m,1H),1.77-1.94(m,,1H),1.64-1.64(m,1H),1.07-1.19(m,3H),0.93-1.03(m,3H),0.88(d,J＝6.4Hz,2H)。

Example 5

The present embodiment provides a compound 5 shown in formula I, wherein the structural formula of the compound 5 is as follows:

the synthetic route for compound 5 is shown below:

to a solution of intermediate A hydrochloride (57.0 mg, 127. Mu. Mol) in methanol (5.0 mL) was added triethylamine to adjust the pH to 8. Then, compound 5-1 (40.0 mg, 247. Mu. Mol) was added thereto, and the reaction mixture was stirred under nitrogen at 25℃for 12 hours. Sodium cyanoborohydride (30.0 mg, 477. Mu. Mol) was added and stirring was continued for 2 hours. The reaction was quenched with water (5.0 mL), extracted with dichloromethane (10.0 mL. Times.3), and the combined organic phases were washed with saturated brine (10.0 mL. Times.1), dried over anhydrous sodium sulfate, filtered, and the organic phase concentrated under reduced pressure. Preparation of crude product high performance liquid chromatography (Xtimate C18,100 mm. Times.30 mm 10 μm, A: water (0.2% formic acid; B: acetonitrile, 0% -30%:10 min) afforded the formate salt of Compound 5.

MS-ESI[M+H] ⁺ Calculated 559, measured 559.

¹ H NMR(400MHz,MeOD)δ8.49(s,1H),8.03(s,1H),7.38-7.51(m,1H),7.26-7.35(m,1H),7.01-7.25(m,5H),4.33(brs,1H),4.00(d,J＝12.4Hz,1H),3.41-3.81(m,6H),3.10-3.27(m,3H),2.88-3.10(m,2H),2.49(brs,1H),2.17(brs,1H),0.77-1.38(m,10H。

Example 6

This example provides a compound 6 of formula I wherein the structural formula of compound 6 is as follows:

the synthetic route for compound 6 is shown below:

(1) To a solution of compound D in trifluoroacetic acid salt (220 mg, 453. Mu. Mol) in dichloromethane (10.0 mL) was added triethylamine to adjust the pH to 8. Then, compound F (111 mg, 544. Mu. Mol) and acetic acid (27.2 mg, 453. Mu. Mol) were added, and the reaction solution was stirred under nitrogen at 25℃for 2 hours. Sodium cyanoborohydride (288 mg,1.36 mmol) was added and stirring was continued for 2 hours. The reaction was quenched with water (30.0 mL), extracted with dichloromethane (30.0 ml×3), the combined organic phases were washed with saturated brine (30.0 ml×1), dried over anhydrous sodium sulfate, filtered, and the organic phase concentrated under reduced pressure to give compound 6-1 by separation of crude silica gel column chromatography (dichloromethane/methanol=1:0 to 10:1).

MS-ESI[M+H] ⁺ Calculated 561, measured 561.

(2) To a solution of compound 6-1 (92.0 mg, 164. Mu. Mol) in methanol (4.5 mL) were added lithium hydroxide monohydrate (20.6 mg, 492. Mu. Mol) and water (1.5 mL), and the reaction solution was stirred at 25℃for 3 hours. Adding aqueous hydrochloric acid (1 mol/L) to the reaction solution to adjust the pH value to 6, extracting with ethyl acetate (20.0 mL×3), mixing organic phases, washing with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain a compound 6-2;

MS-ESI[M+H] ⁺ Calculated 547 actual measured 547.

(3) To a solution of compound 6-2 (100 mg, 182. Mu. Mol) in N, N-dimethylformamide (4.0 mL) were added diisopropylethylamine (70.9 mg, 268 mmol) and 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (104 mg, 274. Mu. Mol), and the reaction mixture was stirred at 25℃for 0.5 hours. Ethyl isopropyl amine (75.5 mg, 866. Mu. Mol) was added thereto, and the reaction mixture was stirred at 25℃for 0.5 hours. Ethyl acetate (20.0 mL. Times.1) was added, the mixture was extracted with water (15.0 mL. Times.2), the organic phase was washed with saturated brine (15.0 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. Crude silica gel column chromatography (dichloromethane/methanol=1:0 to 10:1) gives compound 9-2. Preparation of crude product high performance liquid chromatography (Phenomenex C18,75 mm. Times.30 mm 3 μm, A: water (10 mmol/L ammonium bicarbonate; B: acetonitrile, 33% -63%:10 min) afforded Compound 6.

MS-ESI[M+H] ⁺ Calculated 616, measured 616.

¹ H NMR(400MHz,MeOD)δ8.00(s,1H),7.49-7.51(m,1H),7.30-7.32(m,1H),7.19-7.21(m,1H),7.09-7.16(m,1H),3.75-3.78(m,1H),3.46-3.70(m,6H),3.08-3.27(m,4H),2.94(s,5H),1.98-2.08(m,2H),1.65-1.96(m,8H),1.28-1.48(m,4H),1.15-1.23(m,5H),0.98-1.06(m,2H),0.85-0.95(m,2H)。

Example 7

This example provides a compound 7 of formula I wherein the structural formula of compound 7 is as follows:

the synthetic route for compound 7 is shown below:

(1) To a solution of compound E in trifluoroacetic acid salt (100 mg, 102. Mu. Mol) in ethanol (10.0 mL) was added triethylamine to adjust the pH to 8. Then, compound 7-1 (109 mg, 511. Mu. Mol) and acetic acid (18.4 mg, 306. Mu. Mol) were added, and the reaction solution was stirred under nitrogen at 90℃for 15 hours. Sodium cyanoborohydride (51.3 mg, 817. Mu. Mol) was added thereto and stirring was continued at 60℃for 2 hours. The reaction was quenched with water (30.0 mL), extracted with ethyl acetate (30.0 ml×3), the combined organic phases were washed with saturated brine (30.0 ml×1), dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure, and crude silica gel column chromatography (petroleum ether/ethyl acetate=1:0 to 10:1) was separated to give compound 7-2.

MS-ESI[M+H] ⁺ Calculated 583, measured 583.

(2) To a solution of compound 7-2 (60.0 mg, 103. Mu. Mol) in methylene chloride (5.0 mL) was added trifluoroacetic acid (1.0 mL), and the reaction mixture was stirred at 20℃for 1 hour. Filtering the reaction solution, and concentrating under reduced pressure to obtain trifluoroacetate salt of the compound 7-3;

MS-ESI[M+H] ⁺ calculated 483, measured 483.

(3) To a solution of trifluoroacetate salt (108 mg, 102. Mu. Mol) of compound 7-3 in methylene chloride (10.0 mL) were added triethylamine (20.7 mg, 204. Mu. Mol) and methylsulfonyl chloride (60.0 mg, 524. Mu. Mol), and the reaction solution was stirred under nitrogen at 0℃for 1 hour. The reaction was quenched by the addition of water (10.0 mL), the pH was adjusted to 8 with saturated aqueous sodium bicarbonate, extracted with dichloromethane (30.0 ml×3), the combined organic phases were washed with saturated brine (30.0 ml×1), dried over anhydrous sodium sulfate, filtered, the organic phases concentrated under reduced pressure and the crude silica gel column chromatography (dichloromethane/methanol=1:0 to 10:1) separated to give compound 7-4.

MS-ESI[M+H] ⁺ Calculated 561, measured 561.

(4) To a solution of compound 7-4 (50.0 mg, 89.2. Mu. Mol) in tetrahydrofuran (6.0 mL) were added lithium hydroxide monohydrate (6.41 mg, 268. Mu. Mol) and water (3.0 mL), and the reaction solution was stirred at 25℃for 3 hours. Adding aqueous hydrochloric acid (1 mol/L) to the reaction solution to adjust the pH value to 6, extracting with dichloromethane (50.0 mL×3), mixing organic phases, washing with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain a compound 7-5;

MS-ESI[M+H] ⁺ Calculated 547 actual measured 547.

(5) To a solution of compound 7-5 (60.0 mg, 87.8. Mu. Mol) in N, N-dimethylformamide (10.0 mL) were added diisopropylethylamine (34.1 mg,263 mmol) and 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (50.1 mg, 263. Mu. Mol), and the reaction was stirred at 25℃for 0.5 hours. Ethyl isopropyl amine (9.18 mg, 105. Mu. Mol) was added thereto, and the reaction mixture was stirred at 25℃for 0.5 hours. Ethyl acetate (10.0 mL. Times.1) was added, extraction was performed with water (20.0 mL. Times.3), and the organic phase was washed with saturated brine (15.0 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Crude silica gel column chromatography (dichloromethane/methanol=1:0 to 10:1) gives compound 9-2. Preparation of crude product high performance liquid chromatography (Xtimate C18,100 mm. Times.30 mm 3 μm, A: water (0.225% formic acid; B: acetonitrile, 0% -30%:10 min) gives compound 7.

MS-ESI[M+H] ⁺ Calculated 616, measured 616.

¹ H NMR(400MHz,MeOD)δ7.86-8.07(m,1H),7.42-7.52(m,1H),7.28-7.37(m,1H),6.96-7.24(m,2H),3.75-3.85(m,1H),3.62-3.74(m,4H),3.44-3.61(m,5H),3.10-3.28(m,3H),3.00-3.08(m,2H),2.94-2.99(m,3H),1.92-2.28(m,7H),1.52-1.92(m,6H),1.36-1.49(m,1H),1.28-1.32(m,1H),1.12-1.27(m,6H),1.02-1.11(m,1H)。

Example 8

The present embodiment provides a compound 8 shown in formula I, wherein the structural formula of the compound 8 is as follows:

the synthetic route for compound 8 is shown below:

(1) To a solution of compound C in trifluoroacetic acid salt (200 mg, 412. Mu. Mol) in dichloromethane (5.0 mL) was added triethylamine (125 mg, 1.24. Mu. Mol), compound F (169 mg, 823. Mu. Mol) and sodium triacetoxyborohydride (262 mg,1.24 mmol), and the mixture was stirred at 25℃for 3 hours. Dichloromethane (20.0 mL) was added, extraction was performed with 1mol/L aqueous sodium hydroxide solution (10.0 ml×1), the organic phase was washed with saturated brine (50.0 ml×2), dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (dichloromethane/methanol=1:0 to 7:1) to give compound 8-1;

MS-ESI[M+H] ⁺ Calculated 561, measured 561.

¹ H NMR(400MHz,CDCl ₃ )δ7.96(s,1H),7.61(d,J＝8.8Hz,1H),7.41-7.45(m,2H),6.96(s,1H),3.73(s,3H),3.64(s,4H),3.15-3.22(m,1H),2.95(s,3H),2.53(d,J＝6.0Hz,4H),2.02-2.09(m,4H),1.96(s,2H),1.85-1.93(m,4H),

1.61-1.67(m,1H),1.28-1.34(m,4H),1.06-1.16(m,2H)。

(2) To a solution of compound 8-1 (170 mg, 303. Mu. Mol) in methanol (6.0 mL) were added lithium hydroxide monohydrate (76.4 mg,1.82 mmol) and water (2.0 mL), and the reaction mixture was stirred at 25℃for 1 hour. Adding aqueous hydrochloric acid solution (1 mol/L) into the reaction solution to adjust the pH value to 6, and freeze-drying to obtain a compound 8-2;

MS-ESI[M+H] ⁺ calculated 547 actual measured 547.

(3) To a solution of compound 8-2 (70 mg, 128. Mu. Mol) in N, N-dimethylformamide (3.0 mL) were added diisopropylethylamine (49.7 mg, 384. Mu. Mol) and 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (97.3 mg, 256. Mu. Mol), and the reaction was stirred at 25℃for 0.5 hours. Ethyl isopropyl amine (33.5 mg, 384. Mu. Mol) was added thereto, and the reaction mixture was stirred at 25℃for 0.5 hour. Ethyl acetate (20.0 ml×1) was added to the solution, the organic phases were combined, washed with saturated brine (20.0 ml×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Preparation of crude product high performance liquid chromatography (Phenomenex luna C18,75 mm. Times.30 mm 3 μm, A: water (0.225% formic acid; B: acetonitrile, 30% -55%:8 min) afforded the formate salt of Compound 8.

MS-ESI[M+H] ⁺ Calculated 616, measured 616.

¹ H NMR(400MHz,MeOD)δ7.93-7.99(m,1H),7.42-7.51(m,1H),7.31(td,J＝8.4,2.8Hz,1H),7.19(dd,J＝8.4,2.8Hz,1H),7.02-7.13(m,1H),4.76-4.81(m,1H),3.68-3.83(m,1H),3.58-3.63(m,2H),3.48-3.54(m,2H),3.13-3.25(m,2H),3.03(d,J＝10.8Hz,2H),2.94(s,3H),2.21(d,J＝6.8Hz,2H),2.11(t,J＝10.4Hz,2H),2.04(d,J＝10.4Hz,2H),1.86-1.96(m,4H),1.56-1.82(m,3H),1.49(dd,J＝7.2,3.6Hz,1H),1.25-1.34(m,2H),1.22(d,J＝6.4Hz,1H),1.09-1.17(m,5H),0.98-1.09(m,3H),0.93(s,2H)。

Example 9

This example provides a compound 9 of formula I, the structural formula of the compound 9 is shown below:

The synthetic route for compound 9 is shown below:

(1) To a solution of Compound C-4 (350 mg, 742. Mu. Mol) in methanol (6.0 mL) were added lithium hydroxide monohydrate (93.5 mg,2.23 mmol) and water (2.0 mL), and the reaction was stirred at 25℃for 3 hours. Adding aqueous hydrochloric acid (1 mol/L) to the reaction solution to adjust the pH value to 6, extracting with dichloromethane (20.0 mL multiplied by 3), mixing organic phases, washing with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain a compound 9-1;

MS-ESI[M+H] ⁺ calculated value 458 is measured value 458.

(2) To a solution of compound 9-1 (330 mg, 721. Mu. Mol) in methylene chloride (10.0 mL) were added diisopropylethylamine (280 mg,2.16 mmol) and 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (411 mg, 1.08. Mu. Mol), and the reaction mixture was stirred at 25℃for 0.5 hours. Ethyl isopropyl amine (75.5 mg, 866. Mu. Mol) was added thereto, and the reaction mixture was stirred at 25℃for 0.5 hours. Ethyl acetate (20.0 ml×1) was added to the solution, the organic phases were combined, washed with saturated brine (20.0 ml×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Crude silica gel column chromatography (dichloromethane/methanol=1:0 to 10:1) gives compound 9-2.

MS-ESI[M+H] ⁺ Calculated 527, measured 527.

¹ H NMR(400MHz,CDCl ₃ )δ8.14(s,1H),7.31-7.42(m,1H),7.20-7.25(m,1H),7.00-7.12(m,2H),5.01-5.11(m,1H),4.29(s,2H),3.65-3.78(m,2H),3.43-3.63(m,4H),3.11-3.25(m,1H),2.87(s,2H),1.66-1.79(m,4H),1.39-1.51(m,12H),1.11-1.20(m,6H)。

(3) To a solution of compound 9-2 (100 mg, 190. Mu. Mol) in methylene chloride (3.0 mL) was added trifluoroacetic acid (1.0 mL), and the reaction mixture was stirred at 20℃for 1 hour. Filtering the reaction solution, and concentrating under reduced pressure to obtain trifluoroacetate salt of the compound 9-3;

MS-ESI[M+H] ⁺ Calculated 427, measured 427.

(4) To a solution of trifluoroacetate salt of compound 9-3 (100 mg, 92.5. Mu. Mol) in methanol (10.0 mL) was added triethylamine to adjust the pH to 8. Then, compound 9-4 (17.9 mg, 97.1. Mu. Mol) was added thereto, and the reaction solution was stirred under nitrogen at 25℃for 15 hours. Sodium cyanoborohydride (17.4 mg, 278. Mu. Mol) was added and stirring was continued for 2 hours. The reaction was quenched with water (30.0 mL), extracted with ethyl acetate (50.0 mL. Times.3), and the combined organic phases were washed with saturated brine (50.0 mL. Times.1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Preparation of crude product high performance liquid chromatography (Xtimate C18,100 mm. Times.30 mm 3 μm, A: water (0.225% formic acid; B: acetonitrile, 0% -40%:10 min) afforded the formate salt of Compound 9.

MS-ESI[M+H] ⁺ Calculated 595, measured 595.

¹ H NMR(400MHz,MeOD)δ8.00(s,1H),7.42-7.51(m,1H),7.26-7.40(m,4H),7.17-7.22(m,1H),7.05-7.12(m,1H),3.83-4.04(m,2H),3.73-3.82(m,1H),3.39-3.72(m,6H),3.17-3.29(m,3H),3.04-3.16(m,1H),2.61(s,4H),1.73-2.04(m,4H),1.01-1.22(m,7H),0.85-0.96(m,2H)。

Example 10

The present embodiment provides a compound 10 shown in formula I, wherein the structural formula of the compound 10 is as follows:

the synthetic route for compound 10 is shown below:

to a solution of the trifluoroacetate salt of compound 9-3 (80.0 mg, 92.5. Mu. Mol) in methanol (10.0 mL) was added triethylamine to adjust the pH to 8. Then, compound 10-1 (122 mg, 750. Mu. Mol), acetic acid (11.3 mg, 188. Mu. Mol) was added, and the reaction mixture was stirred under nitrogen at 85℃for 15 hours. Sodium cyanoborohydride (35.4 mg, 563. Mu. Mol) was added thereto, and stirring was continued for 2 hours. The reaction was quenched with water (30.0 mL), extracted with dichloromethane (50.0 mL. Times.3), and the combined organic phases were washed with saturated brine (50.0 mL. Times.1), dried over anhydrous sodium sulfate, filtered, and the organic phase concentrated under reduced pressure. The crude product was isolated by thin layer chromatography (dichloromethane/methanol=1:0 to 10:1) and preparative high performance liquid chromatography (Phenomenex C18,70mm×30mm3μm, a: water (10 mmol/L ammonium bicarbonate; B: acetonitrile, 0% -40%:10 min) to give compound 10.

MS-ESI[M+H] ⁺ Calculated 573, measured 573. ¹ H NMR(400MHz,MeOD)δ7.96-7.98(m,1H),7.44-7.49(m,1H),7.27-7.33(m,1H),7.18(dd,J＝4.0,8.0Hz,1H),7.08(s,2H),6.99-7.04(m,2H),3.72-3.81(m,1H),3.57(s,5H),3.47-3.53(m,2H),3.15-3.24(m,1H),3.00-3.07(m,2H),2.16-2.24(m,2H),1.84-1.94(m,2H),1.65-1.73(m,2H),1.17-1.24(m,1H),1.07-1.17(m,6H),1.03(t,J＝8.0Hz,1H),0.86-0.96(m,2H)。

Test examples

Determination of the antiproliferative effect of the Compounds on MV-4-11 cells (CTG method):

1. the experimental principle is that MV-4-11 is a human leukemia cell line with MLL translocation and expresses MLL fusion protein MLL-AF4. The compounds of the present invention inhibit MV-4-11 proliferation by interfering with the binding of the menin/MLL proteins/protein interactions.

2. Experimental materials CellTiter-Glo was purchased from Promega (cat# G7571); IMDM medium was purchased from Gibco (cat# 12440061); fetal bovine serum was purchased from excel (cat# FND 500); dimethyl sulfoxide (DMSO) was purchased from Sigma (cat#d2650); 384 well cell culture plates were purchased from Corning (cat# 3756); automatic cytometer is available from Life technologies (model Countess II); the microplate reader was purchased from PerkinElmer (model EnVisionMultilabel Reader).

3. Experimental methods cells in the logarithmic growth phase were resuspended in growth medium (IMDM+10% FBS) and diluted to the target density (50000/mL). Inoculating 50 mu L of the cell suspension into a 384-well plate; at 37 ℃,5% CO ₂ Incubate overnight in incubator.

Test compounds were dissolved in DMSO to prepare a stock solution at a concentration of 10 mM. Stock was first diluted to 2mmol/L with DMSO and then diluted 3-fold in a gradient for a total of 10 concentrations. 5.5. Mu.L of the above solution was taken at each concentration, and diluted with 94.5. Mu.L of growth medium, respectively. Then 5. Mu.L/well was added to 384 well plates inoculated with cells.

Placing the cells added with the compound to be tested at 37 ℃ and 5% CO ₂ Incubate in incubator for 72 hours. 384 well plates were equilibrated at room temperature, 15 μl CellTiter-Glo reagent was added to each well, mixed on a vortexing device for 2 min, incubated at room temperature for 60 min, enVisionMultilabel Reader read luminescence, and the IC of the compound was calculated using GraphPad Prism 5.0software ₅₀ 。

4. Experimental data:

the specific test results are shown in table 1:

TABLE 1

Test compounds	MV 4-11IC ₅₀ (nM)
		Formate salt of example 1	5543
Example 2	5561
		Formate salt of example 3	293.1
Example 4	800
		Formate salt of example 5	784.3
Example 6	8580
		Formate salt of example 7	>10000
Formate salt of example 8	166.1
		Formate salt of example 9	40.87
Formate salt of example 10	3095

As shown in the test data of Table 1, the spiro compound shown in the formula I has a better inhibition effect on the growth of human myelomonocytic leukemia MV-4-11 cells, and has potential for preparing medicines for treating and preventing leukemia.

The applicant states that the thienopyrimidines, pharmaceutical compositions containing them and their use are illustrated by the examples described above, but the invention is not limited to, i.e. it does not mean that the invention has to be practiced in dependence on the examples described above. It should be apparent to those skilled in the art that any modification of the present invention, equivalent substitution of raw materials for the product of the present invention, addition of auxiliary components, selection of specific modes, etc., falls within the scope of the present invention and the scope of disclosure.

All documents mentioned in this disclosure are incorporated by reference in this disclosure as if each were individually incorporated by reference. Further, it will be appreciated that various changes and modifications may be made by those skilled in the art after reading the above teachings, and such equivalents are intended to fall within the scope of the application as defined in the appended claims.

Claims

1. A compound, or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, cis-trans isomer, solvate, polymorph, deuterate, or combination thereof, wherein the compound is represented by formula I:

wherein,,

Each R is ^1a Independently selected from the group consisting of: H. cyano, halogen, C1-C3 alkyl, halogenated C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C3 alkoxy, halogenated C1-C3 alkoxy and C3-C5 cycloalkyl;

ring B is a 4-12 membered saturated or partially saturated nitrogen containing heterocycle; wherein the nitrogen-containing heterocycle may optionally be substituted with R ^B Substitution;

each R is ^Y Selected from the group consisting of: r is R ^Y’ 、R ^Y” 、-S(O) ₂ R ^Y” 、-NHS(O) ₂ R ^Y” 、R ^Y”’ And R;

2. A compound as claimed in claim 1,

R ^a And R is ^b Each independently selected from the group consisting of: optionally substituted C1-C6 alkyl, optionally substituted 3-8 membered cycloalkyl or optionally substituted 4-8 membered heterocyclyl; or R is ^a And R is R ^b And together with the N atom to which they are attached form an optionally substituted 4-8 membered heterocyclic ring; wherein the heterocyclic ring comprises 1-2 heteroatoms selected from N, O, S, and P in addition to the attached N atom; wherein, the substitution means that H in the group is substituted with one or more substituents selected from the group consisting of: from deuterium, halogenC1-C3 alkyl, halogenated C1-C3 alkyl and C1-C3 alkoxy;

3. A compound as claimed in claim 1 or 2,

the B ring is selected from the group shown below:

preferably, the B ring is +.>

The B ring may optionally be R ^B Substitution;

4. A compound according to any one of claims 1 to 3,

y is selected from the group shown below:

R ^c and R is ^d Each independently selected from the group consisting of: H. C1-C4 alkyl, halogen, -OH, oxo (= O), -NH ₂ C3-C8 cycloalkyl, 3-8 membered heterocyclyl, 5-10 membered heteroaryl, -O-C1-C4 alkyl, -C1-C4 alkyl-OH, -C1-C4 alkyl-O-C1-C4 alkyl, -OC1-C4 haloalkyl, cyano, nitro, -C (O) -OH, -C (O) OC1-C6 alkyl, -CON (C1-C6 alkyl) ₂ -CONH (C1-C6 alkyl), -CONH ₂ -NHC (O) (C1-C6 alkyl), -NH (C1-C6 alkyl) C (O) (C1-C6 alkyl), -SO ₂ (C1-C6 alkyl), -SO ₂ (phenyl) -SO ₂ (C1-C6 haloalkyl), -SO ₂ NH ₂ 、-SO ₂ NH (C1-C6 alkyl), -SO ₂ NH (phenyl), -NHSO ₂ (C1-C6 alkyl), -NHSO ₂ (phenyl) and-NHSO ₂ (C1-C6 haloalkyl); or R is ^c And R is ^d And the carbons to which they are attached together form a C3-C8 carbocyclic ring, a 4-12 membered heterocyclic ring, wherein said carbocyclic or heterocyclic ring is optionally further substituted with one or more substituents selected from the group consisting of: halogen, -OH, oxo (= O), -NH ₂ C3-C8 cycloalkyl, 3-8 membered heterocyclyl, 5-10 membered heteroaryl, -O-C1-C4 alkyl, -C1-C4 alkyl-OH, -C1-C4 alkyl-O-C1-C4 alkyl, -OC1-C4 haloalkyl, cyano, nitro, -C (O) -OH, -C (O) OC1-C6 alkyl, -CON (C1-C6 alkyl) ₂ -CONH (C1-C6 alkyl), -CONH ₂ -NHC (O) (C1-C6 alkyl), -NH (C1-C6 alkyl) C (O) (C1-C6 alkyl), -SO ₂ (C1-C6 alkyl), -SO ₂ (phenyl) -SO ₂ (C1-C6 haloalkyl), -SO ₂ NH ₂ 、-SO ₂ NH (C1-C6 alkyl), -SO ₂ NH (phenyl) -NHSO ₂ (C1-C6 alkyl), -NHSO ₂ (phenyl) and-NHSO ₂ (C1-C6 haloalkyl).

5. A compound according to any one of claims 1 to 4 wherein X is N.

6. A compound according to any one of claims 1 to 4, wherein the compound is selected from the group consisting of:

table A

7. A pharmaceutical composition comprising a compound according to any one of claims 1-5 and a pharmaceutically acceptable carrier.

8. Use of a compound according to any one of claims 1 to 5 or a pharmaceutical composition according to claim 6, wherein the use is selected from any one or more of the following (a) - (c):

(c) Preparing proliferation inhibitor for in vitro non-therapeutic tumor cells.

9. The use according to claim 8, wherein the disease associated with MLL1, MLL2, MLL fusion proteins, and/or the activity of the men protein is selected from the group consisting of: tumors, diabetes, and other diseases related to MLL1, MLL2, MLL fusion proteins, and/or the activity of the mentin protein.

10. The use according to claim 9, wherein,

the tumor associated with MLL1, MLL2, MLL fusion protein, and/or the menin protein activity is selected from the group consisting of: leukemia, ewing's sarcoma, breast cancer, prostate cancer, T-cell lymphoma, B-cell lymphoma, malignant rhabdomyoma, synovial sarcoma, colorectal cancer, endometrial tumor, gastric cancer, liver cancer, renal cancer, lung cancer, melanoma, ovarian cancer, pancreatic cancer, brain glioma, cholangiocarcinoma, nasopharyngeal cancer, cervical cancer, head and neck cancer, esophageal cancer, thyroid cancer, and bladder cancer; and/or

The other diseases associated with MLL1, MLL2, MLL fusion proteins, and/or the activity of the mentin protein are selected from the group consisting of: autoimmune disease, non-alcoholic hepatitis.