WO2024222680A1

WO2024222680A1 - Map4k4 inhibitor and preparation method and application thereof

Info

Publication number: WO2024222680A1
Application number: PCT/CN2024/089337
Authority: WO
Inventors: 陈晖�; 廖学斌
Original assignee: 北京宇繁科技有限责任公司
Priority date: 2023-04-24
Filing date: 2024-04-23
Publication date: 2024-10-31
Also published as: CN118834206A

Abstract

Disclosed in the present invention are a MAP4K4 inhibitor formula (I), and a preparation method and an application thereof. In the present invention, a series of compounds having good MAP4K4 (HGK) inhibitory activity are prepared, and expected to be used for the prevention and treatment of diseases related to MAP4K4 (HGK) activity.

Description

A MAP4K4 inhibitor and its preparation method and application

Technical Field

The present invention relates to the field of chemical medicine technology, and in particular to a MAP4K4 inhibitor and a preparation method and application thereof.

Background Art

Mitogen-activated protein kinase MAP4K4 (Mitogen-activated protein kinase 4), also known as HGK (Hepatocyte progenitor kinase-like/germinal center kinase-like kinase), is a member of the serine/threonine kinase subfamily STE20 (MAP4K). It is widely expressed and affects many physiological processes such as embryonic development and inflammation. In 1995, HGK was discovered as a key kinase in the conjugation pathway of Saccharomyces cerevisiae, and was subsequently found to be involved in the regulation of various cellular functions and physiological and pathological processes. In 2001, HGK was named MAP4K4 because it can activate MAP3K molecules (such as TAK, MEKK) in the MAPK molecular pathway through phosphorylation, thereby regulating the signal transduction of the MAPK molecular pathway.

It has been reported that MAP4K4 is associated with diseases such as immunity, inflammation, metabolism and cardiovascular diseases, tumors (especially malignant tumors) (see, for example, Chuang HC, Wang X, Tan TH. MAP4K Family Kinases in Immunity and Inflammation. Adv Immunol. 2016; 129: 277-314.; Virbasius JV, Czech MP. Map4k4 Signaling Nodes in Metabolic and Cardiovascular Diseases. vascular Diseases.Trends Endocrinol Metab.2016Jul；27(7):484-492.；Gao X,Gao C,Liu G,Hu J.MAP4K4:an emerging therapeutic target in cancer.Cell Biosci.2016Oct 28；6:56.), for example, it is highly expressed in many tumors and participates in tumor cell migration, etc., and is expected to become a new target for tumor treatment or prevent the occurrence, development and metastasis of certain tumors.

However, there are few reports on MAP4K4 inhibitors.

Summary of the invention

In order to overcome the deficiencies of the prior art, the present invention provides a MAP4K4 inhibitor and a preparation method and application thereof.

In the first aspect of the present invention, a compound is provided, which can regulate (especially inhibit) MAP4K4 activity and has the following structure:

in,

X ₁ is CR ₂ or N; wherein R ₂ is selected from the group consisting of H, halogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, -CN, -NO ₂ , -OR ^2a , -COR ^2a , -C(O)OR ^2a , -C(O)NR ^2a R ^2b , -OC(O)R ^2a , -SR ^2a , -S(O)-R ^2a , -S(O) ₂ -R ^2a , -NR ^2a R ^2b , -NR ^2a C(O)R ^2b , -NR ^2a -S(O)-R ^2b , -NR ^2a -S(O) ₂ -R ^2b , -S(O)-NR ^2a R ^2b , -S(O) ₂ -NR ^2a R ^2b , R ^2a and R R 2a and R ^2b are independently selected from: H, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, or R ^2a and R ^2b together with the nitrogen atom to which they are attached form a heterocyclyl; wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl is optionally substituted with one or more R ^2c groups;

X ₂ is CR ₃ or N; wherein R ₃ is selected from the group consisting of H, halogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, -CN, -NO ₂ , -OR ^3a , -COR ^3a , -C(O)OR ^3a , -C(O)NR ^3a R ^3b , -OC(O)R ^3a , -SR ^3a , -S(O)-R ^3a , -S(O) ₂ -R ^3a , -NR ^3a R ^3b , -NR ^3a C(O)R ^3b , -NR ^3a -S(O)-R ^3b , -NR ^3a -S(O) ₂ -R ^3b , -S(O)-NR ^3a R ^3b , -S(O) ₂ -NR ^3a R ^3b , R ^3a and R ^3b is independently selected from: H, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycle R ^3a and R ^3b together with the nitrogen atom to which they are attached form a heterocyclyl group; wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl is optionally substituted with one or more R ^3c groups;

Ring A is an aromatic ring or a heteroaromatic ring;

R _1a is one or more substituents on ring A, each of which is independently selected from the group consisting of H, halogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, -CN, -NO ₂ , -OR ^1a , -COR ^1a , -C(O)OR ^1a , -C(O)NR ^1a R ^1b , -OC(O)R ^1a , -SR ^1a , -S(O)-R ^1a , -S(O) ₂ -R ^1a , -NR ^1a R ^1b , -NR ^1a C(O)R ^1b , -NR ^1a -S(O)-R ^1b , -NR ^1a -S(O) ₂ -R ^1b , -S(O)-NR ^1a R ^1b , -S(O) ₂ -NR ^1a R ^1b , R ^1a and R R 1a and R ^1b are independently selected from: H, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, or R ^1a and R ^1b together with the nitrogen atom to which they are attached form a heterocyclyl; or, two R ₁ groups together with the carbon atom to which they are attached form a carbocyclic or heterocyclic ring; wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, carbocyclic ring, heterocyclic ring is optionally substituted with one or more R ^1c groups;

L ₁ is selected from the group consisting of a single bond, C _1-6 alkylene, N(R ₄ ), O, S, C(O), N(R ₄ )C(O), C(O)N(R ₄ ), C(O)O, OC(O), SO, SO ₂ , N(R ₄ )SO ₂ , SO ₂ N(R ₄ ); wherein R ₄ is selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl;

_Y1 is selected from: substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, substituted or unsubstituted alkenylene, substituted or unsubstituted alkynylene;

L ₂ is selected from the group consisting of a single bond, C _1-6 alkylene, C _1-6 heteroalkylene, C _3-6 cycloalkylene, heterocyclylene, N(R ₅ ), O, S, C(O), C(O)N(R ₅ ), N(R ₅ )C(O), C(O)O, OC(O), SO, SO ₂ , N(R ₅ )SO ₂ , SO ₂ N(R ₅ ); wherein R ₅ is selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl;

_Y2 is selected from: H, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl; optionally, wherein each of the alkyl, heteroalkyl, heterocyclyl, heterocyclylalkyl is optionally substituted with one or more _R6 groups;

_R is selected from the group consisting of H, (=O), halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, -CN, -NO2, _-OR6a , ^-COR6a , ^-C (O) ^OR6a , -C(O) ^NR6aR6b , -OC(O) ^R6a , ^-SR6a , -S(O) ^-R6a , ^-S (O) ₂ ^- ^R6a , -NR6aR6b, -NR6aC(O ^)R6b ^, ^-NR6a - ^S (O) ^-R6b , ^-NR6a -S(O) ₂ ^- ^R6b , -S(O) ^-NR6aR6b , -S(O) _2- ^NR6aR6b ^, ^R6a and R R 6a and R ^6b are independently selected from: H, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, or R ^6a and R ^6b together with the nitrogen atom to which they are attached form a heterocyclyl; wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, carbocycle, heterocycle is optionally substituted with one or more R ^6c groups;

R ^1c , R ^2c , R ^3c , R ^6c are independently selected from the group consisting of: H, (═O), halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, -CN, -NO ₂ , -CF ₃ , -OCF ₃ , -OR′, -COR′, -C(O)OR′, -C(O)NR′R″, -OC(O)R′, -S(O) _p -R′, -NR′R″, -NR′C(O)R″, -NR′-S(O) _p -R″, -S(O) _p -NR′R″, -C(═NH)NR′R″, p is selected from the group consisting of 0, 1 and 2;

Each R' and R" is independently selected from the group consisting of H, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl.

In some embodiments of the present invention, X ₁ is CH; in other embodiments of the present invention, X ₁ is N.

In some embodiments of the present invention, _X2 is CH; in other embodiments of the present invention, _X2 is N.

In some preferred embodiments of the present invention, the compound is a pyrazolo[3,4-b]pyridine derivative having the following structure:

In other embodiments of the present invention, the compound is a pyrrolo[2,3-b]pyrazine derivative having the following structure:

Specifically, R ^1a and R ^1b are independently selected from: H, C _1-6 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl), C _3-6 cycloalkyl (e.g., ), C _4-8 cycloalkylalkyl (e.g. ), 4 to 6 membered saturated heterocycloalkyl (e.g. ), saturated heterocycloalkylalkyl (e.g. ); More specifically, R ^1a and R ^1b are independently selected from: H, C _1-3 alkyl.

In some embodiments of the present invention, R ₁ is selected from: H, halogen (eg, F, Cl), -CN, -NO ₂ , -OH, -NH ₂ , C _1-6 alkyl (eg, -CH ₃ , ), C _1-6 haloalkyl (e.g., -CHF ₂ , -CH ₂ F, -CH ₂ Cl, -CF ₃ , -CH ₂ CF ₃ , -CH ₂ CH ₂ F), C _1-6 hydroxyalkyl (e.g., C _1-6 alkoxy (e.g. ), C _1-6 haloalkoxy (e.g. -OCF ₃ ), C _1-6 aminoalkyl (e.g. ), C _1-6 alkylamino (e.g. ), C _1-6 alkylaminoalkyl (e.g. ), -C(O)N(C _0-6 alkyl)(C _0-6 alkyl)(e.g. ), -N(C _0-6 alkyl)C(O)(C _0-6 alkyl) (e.g. ), -SO ₂ (C _0-6 alkyl) (e.g. ), -SO ₂ (C _3-6 cycloalkyl) (e.g. ), -NH-SO ₂ (C _0-6 alkyl) (e.g. ), -NH-SO ₂ (C _3-6 cycloalkyl) (e.g. ), -SO ₂ -N(C _0-6 alkyl)(C _0-6 alkyl)(e.g. ), substituted or unsubstituted 4- to 6-membered heterocyclic group (e.g. ), saturated heterocycloalkylalkyl (e.g. ), substituted or unsubstituted phenyl (e.g. ),

In some embodiments of the present invention, ring A is a benzene ring, that is, Part of

In other embodiments of the present invention, ring A is a 5-6 membered heteroaromatic ring, for example Specifically, Some can be

In some embodiments of the present invention, two _R1 groups together with the carbon atoms to which they are attached form a 4-6 membered carbocyclic or heterocyclic ring, which forms a fused bicyclic ring with the A ring, for example, For example Some can be

In some embodiments of the present invention, L ₁ is a single bond; in other embodiments of the present invention, L ₁ is N(R ₄ ), such as NH.

In one embodiment of the present invention, Y ₁ is a substituted or unsubstituted arylene group, in particular a substituted or unsubstituted phenylene group, for example * represents the position connected to L ₁ , R ₇ is one or more independent substituents on the benzene ring, each of which is independently selected from the group consisting of H, halogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, -CN, -NO ₂ , -OR ^7a , -COR ^7a , -C(O)OR ^7a , -C(O)NR ^7a R ^7b , -OC(O)R ^7a , -S(O) _q -R ^7a , -NR ^7a R ^7b , -NR ^7a C(O)R ^7b , -NR ^7a -S(O) _q -R ^7b , -S(O) _q -NR ^7a R ^7b , q is selected from the group consisting of 0, 1 and 2, R ^7a and R ^7b are independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl; or, two R The _7c group together with the carbon atom to which it is attached forms a carbocycle or a heterocycle; wherein the alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, carbocycle, heterocycle are each optionally substituted by one or more R ^7c groups; each R ^7c is independently selected from: halogen, -CN, -NO ₂ , -CF ₃ , -OCF ₃ , -OR', -COR', -C(O)OR', -C(O)NR'R", -OC(O)R', -S(O) _p -R', -NR'R", -NR'C(O)R", -NR'-S(O) _p -R", -S(O) _p -NR'R", p is selected from 0, 1 and 2.

In some embodiments of the present invention, _Y1 is

More specifically, R ₇ is selected from: H, halogen (eg, F, Cl), -CN, -NO ₂ , -OH, -NH ₂ , C _1-6 alkyl (eg, -CH ₃ , ), C _1-6 haloalkyl (e.g., -CHF ₂ , -CH ₂ F, -CH ₂ Cl, -CF ₃ , -CH ₂ CF ₃ , -CH ₂ CH ₂ F), C _1-6 alkoxy (e.g., ), C _1-6 haloalkoxy (e.g. -OCF ₃ ), C _1-6 alkylamino (e.g. ), -C(O)N(C _0-6 alkyl)(C _0-6 alkyl)(e.g. ), -N(C _0-6 alkyl)C(O)(C _0-6 alkyl) (e.g. ), -SO ₂ (C _0-6 alkyl) (e.g. ), -SO ₂ (C _3-6 cycloalkyl) (e.g. ), -NH-SO ₂ (C _0-6 alkyl) (e.g. ), -NH-SO ₂ (C _3-6 cycloalkyl) (e.g. ), -SO ₂ -N(C _0-6 alkyl)(C _0-6 alkyl)(e.g. ).

In some embodiments of the present invention, R ₇ is H; in other embodiments of the present invention, R ₇ is selected from: halogen (eg, F, Cl), -CN, -NO ₂ , -OH, -NH ₂ , -CHF ₂ , -CH ₂ F, -CH ₂ Cl, -CF ₃ , -OCF ₃ , -CH ₃ .

In one embodiment of the present invention, Y ₁ is a substituted or unsubstituted heteroarylene group, in particular a 5-6 membered heteroarylene group, for example Wherein * represents the position of connection with _L1 , _R7 is one or more independent substituents on the ring, having the above definition; in some embodiments of the present invention, _R7 is H.

In one embodiment of the present invention, Y ₁ is an alkynylene group, for example Where * indicates the position of connection with _L1 .

In some embodiments of the present invention, _L2 is a single bond.

In other embodiments of the present invention, L ₂ is selected from: C _1-3 alkylene, C _1-3 heteroalkylene, N(R ₅ ), O, S, C(O), C(O)N(R ₅ ), SO ₂ , SO ₂ N(R ₅ ), in particular: methylene, ethylene, NH, O, C(O), C(O)NH, SO ₂ ,

In one embodiment of the present invention, _Y2 is H.

In one embodiment of the present invention, Y ₂ is a C _1-6 alkyl group, such as methyl, ethyl, n-propyl, isopropyl.

In one embodiment of the present invention, _Y2 is _C1-6 heteroalkyl, for example

In one embodiment of the present invention, _Y2 is a substituted or unsubstituted cycloalkyl or saturated heterocyclic group having the following structure: Wherein, Z ₁ is C or N, Z ₂ is selected from: O, S, N, C, SO ₂ , e is 0, 1 or 2, f is 0, 1 or 2, g is 0, 1 or 2, and R ₆ is one or more independent substituents on the ring, which are defined as above.

More specifically, _Y2 can be selected from:

In some embodiments of the present invention, e is 1, f is 1, and g is 1; in other embodiments of the present invention, e is 2, f is 1, and g is 1; in other embodiments of the present invention, e is 0, f is 1, and g is 1; in other embodiments of the present invention, e is 0, f is 1, and g is 0; in other embodiments of the present invention, e is 0, f is 0, and g is 0.

Specifically, R ₆ can be selected from: H, (=O), halogen (such as F, Cl), -CN, -NO ₂ , -OH, -NH ₂ , C _1-6 alkyl (such as -CH ₃ , ), C _1-6 haloalkyl (e.g., -CHF ₂ , -CH ₂ F, -CH ₂ Cl, -CF ₃ , -CH ₂ CF ₃ , -CH ₂ CH ₂ F), C _1-6 hydroxyalkyl (e.g., ), C _1-6 alkoxy (e.g. ), C _1-6 haloalkoxy (e.g. -OCF ₃ ), C _1-6 aminoalkyl (e.g. ), C _1-6 alkylamino (e.g. ), C _1-6 alkylaminoalkyl (e.g. ), -C(O)N(C _0-6 alkyl)(C _0-6 alkyl)(e.g. ), -N(C _0-6 alkyl)C(O)(C _0-6 alkyl) (e.g. ), -SO ₂ (C _0-6 alkyl) (e.g. ), -NH-SO ₂ (C _0-6 alkyl) (e.g. ), -SO ₂ -N(C _0-6 alkyl)(C _0-6 alkyl)(e.g. ), C _3-6 cycloalkyl (e.g. ), C _4-8 cycloalkylalkyl (e.g. ), substituted or unsubstituted 4- to 6-membered heterocyclic group (e.g. ), saturated heterocycloalkylalkyl (e.g.

More specifically, _R6 can be selected from: H, (=O), halogen (e.g., F, Cl), -CN, _-NO2 , -OH, _-NH2 , _C1-3 alkyl, _C1-3 haloalkyl, _C1-3 hydroxyalkyl, _C1-3 alkoxy, _C1-3 haloalkoxy, _C1-3 aminoalkyl, _C1-3 alkylamino, substituted or unsubstituted 6-membered saturated heterocyclic group.

In some embodiments of the present invention, _Y2 is selected from:

In other embodiments of the present invention, _Y2 is selected from:

In one embodiment of the present invention, Y ₂ is a heteroaryl group, in particular a 5-, 6- or 7-membered heteroaryl group, such as a pyrrolyl group, a pyridyl group, a pyrimidyl group, a pyrazolyl group, an oxazolyl group, a triazolyl group, a tetrazolyl group; for example, Y ₂ can be _R6 is one or more independent substituents on the ring, and their definition is as above.

More specifically, _R6 can be selected from: H, halogen (e.g., F, Cl), -CN, _-NO2 , -OH, _-NH2 , _C1-3 alkyl, _C1-3 haloalkyl, _C1-3 hydroxyalkyl, _C1-3 alkoxy, _C1-3 haloalkoxy, _C1-3 aminoalkyl, _C1-3 alkylamino.

In some embodiments of the present invention, _Y2 is selected from:

In some embodiments of the present invention, the compound has the following structure:

In the second aspect of the present invention, provided are pharmaceutically acceptable salts, stereoisomers, esters, prodrugs, solvates, and deuterated compounds of the compounds described in the first aspect.

In the third aspect of the present invention, a pharmaceutical composition is provided, which comprises the compound described in the first aspect, or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, deuterated compound thereof, and one or more pharmaceutically acceptable excipients.

Specifically, the pharmaceutically acceptable excipients may be selected from one or more of: disintegrants, binders, lubricants, suspending agents, stabilizers, fillers, absorption enhancers, surfactants, flavoring agents, antioxidants, preservatives, and the like.

Specifically, in the pharmaceutical composition, the compound described in the first aspect, or its pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, deuterated compound, can be used alone or in combination with other types of active ingredients.

Specifically, the pharmaceutical composition can be administered by any suitable route, such as enteral administration (e.g., oral) or parenteral administration (e.g., intravenous, intramuscular, subcutaneous, intraorgan, intranasal, intradermal, instillation, intracerebral, intrarectal, etc.).

Specifically, the pharmaceutical composition can be in any suitable dosage form, such as a dosage form for gastrointestinal administration, for example, including, but not limited to, tablets, pills, powders, granules, capsules, lozenges, syrups, liquids, emulsions, suspensions, etc.; a dosage form for non-gastrointestinal administration, for example, an injectable dosage form: such as an injection (for example, for subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection), a dosage form for respiratory administration: such as a spray, an aerosol, a powder aerosol, etc., a dosage form for skin administration, such as an external solution, a lotion, an ointment, a plaster, a paste, a patch, etc., a dosage form for mucosal administration: such as eye drops, eye ointments, nasal drops, gargles, sublingual tablets, etc., a dosage form for cavity administration: such as suppositories, aerosols, effervescent tablets, drops, pills, etc., for use in the vagina, urethra, nasal cavity, ear canal, etc.

Specifically, various dosage forms of the above-mentioned pharmaceutical composition can be prepared according to conventional production methods in the pharmaceutical field, such as mixing the active ingredient with one or more pharmaceutically acceptable excipients and then preparing the mixture into the desired dosage form.

Specifically, in the above-mentioned pharmaceutical composition, the weight percentage of the compound described in the first aspect, or its pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate can be 0.1-99.5%, for example, 0.5%, 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%.

In the fourth aspect of the present invention, there is provided the use of the compound described in the first aspect, or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, or deuterated compound thereof, in the preparation of a drug for preventing and/or treating a disease associated with MAP4K4 (HGK) activity.

Specifically, the disease associated with MAP4K4 (HGK) activity is a disease that can be beneficially prevented and/or treated by inhibiting MAP4K4 (HGK), such as tumors, metabolic diseases, cardiovascular diseases, inflammatory diseases, autoimmune diseases, and the like.

Specifically, tumors include, but are not limited to, lymphoma, blastoma, medulloblastoma, retinoblastoma, sarcoma, liposarcoma, synovial cell sarcoma, neuroendocrine tumors, carcinoid tumors, gastrinoma, islet cell carcinoma, mesothelioma, schwannoma, acoustic neuroma, meningioma, adenocarcinoma, melanoma, squamous cell carcinoma, epithelial squamous cell carcinoma, lung cancer (including small cell lung cancer, non-small cell lung cancer, adenocarcinoma lung cancer, lung squamous cell carcinoma), peritoneal cancer, hepatocellular carcinoma, gastric cancer, intestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, liver cancer, breast cancer, colon cancer, rectal cancer, colorectal cancer, uterine cancer, salivary gland cancer, kidney cancer, prostate cancer, vulvar cancer, thyroid cancer, liver cancer, anal cancer, penile cancer, Merkel cell carcinoma, esophageal cancer, biliary tract tumors, head and neck cancer, and hematological malignancies.

More specifically, the above tumor is a hematological malignancy, such as leukemia, lymphoma, multiple myeloma (MM).

Specifically, the leukemia can be chronic lymphocytic leukemia, chronic myeloid leukemia, acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), acute monocytic leukemia, especially acute myeloid leukemia. Specifically, the leukemia can be relapsed, refractory or drug-resistant.

Specifically, the lymphoma may be a B-cell lymphoma (e.g., diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, Mucosa-associated lymphoid tissue lymphoma (MALT), small lymphocytic lymphoma/chronic lymphocytic leukemia, mantle cell lymphoma (MCL), T/NK cell lymphoma, especially diffuse large B-cell lymphoma (DLBCL).

More specifically, the tumor is ovarian cancer, liver cancer, lung cancer, pancreatic cancer, prostate cancer, etc.

Specifically, metabolic diseases include, but are not limited to, type I diabetes, type II diabetes, insulin resistance, hyperglycemia, obesity, lipid metabolism disorders, etc.

Specifically, cardiovascular diseases include, but are not limited to, coronary heart disease, arrhythmia, heart failure, etc.

In some embodiments of the present invention, the above application is the use of the compound, or its pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, deuterated compound, in the preparation of a drug for preventing and/or treating myocardial infarction (commonly known as "heart attack" caused by atherosclerosis, coronary thrombosis, coronary artery abnormalities or other interferences with blood flow or oxygen and nutrient delivery to the heart).

In particular, the cardiovascular disease is selected from the group consisting of: cardiomyocyte damage, cardiomyocyte damage due to cardiopulmonary bypass, chronic forms of cardiomyocyte damage, hypertrophic cardiomyopathy, dilated cardiomyopathy, mitochondrial cardiomyopathy, cardiomyopathy due to genetic conditions; cardiomyopathy due to high blood pressure; cardiomyopathy due to damage to heart tissue caused by a previous heart attack; cardiomyopathy due to a chronic rapid heart rate; cardiomyopathy due to heart valve problems; cardiomyopathy due to metabolic disorders; cardiomyopathy due to nutritional deficiencies of essential vitamins or minerals; cardiomyopathy due to alcohol use; cardiomyopathy due to the use of cocaine, amphetamines or anabolic steroid-induced cardiomyopathy; cardiomyopathy due to radiation therapy for cancer; cardiomyopathy due to certain infections that may damage the heart and trigger cardiomyopathy; cardiomyopathy due to hemochromatosis; cardiomyopathy due to sarcoidosis; cardiomyopathy due to amyloidosis; cardiomyopathy due to connective tissue disorders; drug- or radiation-induced cardiomyopathy; idiopathic or cryptogenic cardiomyopathy; other forms of ischemic injury, including but not limited to ischemia-reperfusion injury, ischemic stroke, renal artery occlusion, and global ischemia-reperfusion injury (cardiac arrest); cardiomyocyte necrosis; or cardiomyocyte apoptosis.

Specifically, inflammatory diseases include, but are not limited to, osteoarthritis, inflammatory bowel syndrome, ulcerative colitis, Crohn's disease, chronic obstructive pulmonary disease (COPD), emphysema, Kawasaki's disease, hemophagocytic syndrome (macrophage activation syndrome), multicentric reticulohistiocytosis, atherosclerosis, etc.

Specifically, autoimmune diseases include, but are not limited to, organ-specific autoimmune diseases and systemic autoimmune diseases, for example, achalasia, Addison's disease, adult-onset Still's disease, agammaglobulinemia, alopecia areata, amyloidosis, ankylosing spondylitis, anti-glomerular basement membrane antibody nephritis, antiphospholipid syndrome, autoimmune angioedema, autoimmune dysautonomia, autoimmune encephalomyelitis, autoimmune hepatitis, autoimmune inner ear disease, autoimmune Myocarditis, autoimmune oophoritis, autoimmune orchitis, autoimmune pancreatitis, autoimmune retinopathy, autoimmune urticaria, acute motor sensory axonal neuropathy, Barlow's disease (also known as concentric sclerosis), Behcet's disease, benign mucous membrane pemphigoid (also known as cicatricial pemphigoid), bullous pemphigoid, giant lymphadenopathy, celiac disease, Chagas disease, chronic inflammatory demyelinating polyneuropathy, chronic relapsing multifocal osteomyelitis, Churg-S Trauss syndrome (also known as allergic granulomatous vasculitis or eosinophilic granulomatosis with polyangiitis), Cogan syndrome, cold agglutinin disease, congenital heart block, coxsackievirus myocarditis, CREST syndrome, Crohn's disease, dermatitis herpetiformis, dermatomyositis, Devic's disease (also known as neuromyelitis optica), discoid lupus, Dressler syndrome, endometriosis, eosinophilic esophagitis, eosinophilic fasciitis, erythema nodosum, mixed cryoglobulinemia, Evans syndrome, fibromyalgia, fibrosing alveolitis, giant cell arteritis, giant cell myocarditis, glomerulonephritis, Goodpasture syndrome, granulomatosis with polyangiitis, Graves' disease, Guillain-Barré syndrome, Hashimoto's thyroiditis, hemolytic anemia, Henoch-Schonlein purpura (also known as Henoch-Schonlein purpura), herpes pregnancy or pemphigoid gestationis, hidradenitis suppurativa, hypogammaglobulinemia, I gA nephropathy, IgG4-related sclerosing disease (also known as IgG4-related systemic disease, high IgG4 disease, and IgG4-related disease), immune thrombocytopenic purpura, inclusion body myositis, interstitial cystitis, juvenile arthritis, juvenile myositis, Kawasaki disease, Lambert-Eaton syndrome, leukocytic vasculitis (also known as allergic vasculitis), lichen planus, atrophic lichen sclerosus, woody conjunctivitis, linear IgA disease, chronic Lyme disease, Meniere's disease, microscopic polyangiitis, mixed connective tissue disease, Mooren's corneal ulcer, Mucha-Habermann disease (also known as acute pityriasis lichenoides), multifocal motor neuropathy, multiple sclerosis, myasthenia gravis, myositis, narcolepsy, neonatal lupus, neutropenia, ocular cicatricial pemphigoid, optic neuritis, relapsing rheumatic disease, PANDAS, paraneoplastic cerebellar degeneration, paroxysmal nocturnal hemoglobinuria, Parr y-Romberg syndrome, pars planitis (also known as peripheral uveitis), Parsonage-Turner syndrome (also known as brachial neuritis), pemphigus, peripheral neuropathy, perivenous encephalomyelitis, pernicious anemia, POEMS syndrome, polyarteritis nodosa, polyglandular syndrome type I, II, III, polymyalgia rheumatica, polymyositis, post-myocardial infarction syndrome, postpericardiotomy syndrome, primary biliary cirrhosis, primary sclerosing cholangitis, progestogen dermatitis, psoriasis, psoriatic arthritis, pure red cell aplasia, pyoderma gangrenosum, Raynaud's phenomenon, reactive arthritis, reflex sympathetic dystrophy (also known as pain syndrome), relapsing polychondritis, restless legs syndrome, retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis, sarcoidosis, Schmidt syndrome (also known as polyglandular autoimmune syndrome type 2), scleritis, scleroderma, Sjögren's syndrome, sperm and testicular autoimmunity, stiff-man syndrome Syndrome, subacute bacterial endocarditis, Susac's syndrome, sympathetic ophthalmia, systemic lupus erythematosus, Takayasu's arteritis, temporal arteritis, thyroid eye disease, Tolosa-Hunt syndrome, type 1 diabetes mellitus (also known as autoimmune diabetes mellitus, insulin-dependent diabetes mellitus), ulcerative colitis, undifferentiated connective tissue disease, uveitis, vasculitis, vitiligo, Koyanagi-Harada disease; especially systemic lupus erythematosus, type 1 diabetes mellitus, rheumatoid arthritis, multiple sclerosis, ankylosing spondylitis, psoriasis, ulcerative colitis, Crohn's disease.

In the fifth aspect of the present invention, a method for preventing and/or treating diseases associated with MAP4K4 (HGK) activity is provided, which comprises the step of administering to a subject in need thereof the compound of the first aspect, or its pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, deuterated compound, or the pharmaceutical composition of the third aspect.

Specifically, the subject is a mammal, such as a human.

Specifically, the disease has the disease definition in the fourth aspect of the present invention.

Specifically, in the method, the compound described in the first aspect, or its pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, deuterated compound, can be used alone or in combination with other types of pharmaceutical preparations and/or treatment methods.

In the sixth aspect of the present invention, a method for regulating (inhibiting) MAP4K4 (HGK) activity is provided, which comprises the step of administering the compound described in the first aspect, or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, deuterated compound thereof, or the pharmaceutical composition described in the third aspect.

Specifically, the administration may be in vitro administration or in vivo administration.

The present invention prepares a series of compounds, which have better MAP4K4 (HGK) inhibitory activity and are expected to be used for the prevention and treatment of diseases related to MAP4K4 (HGK) activity.

DETAILED DESCRIPTION

Unless otherwise defined, all scientific and technical terms used in the present invention have the same meanings as commonly understood by one of ordinary skill in the art to which the present invention relates.

In the present invention, the term "aliphatic group" refers to a straight or branched hydrocarbon chain (e.g., "alkyl", "alkenyl", "alkynyl") that is completely saturated or contains one or more unsaturated units, or a cyclic hydrocarbon group (also referred to herein as "carbocycle", "aliphatic ring", "cycloalkyl") that is completely saturated or contains one or more unsaturated units, which is connected to the rest of the molecule by a single bond. Suitable aliphatic groups include, but are not limited to, straight or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl, and mixtures thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, (cycloalkyl)alkenyl, etc.

The term "alkyl" refers to a straight or branched hydrocarbon chain radical that does not contain an unsaturated bond, and the hydrocarbon chain radical is connected to the rest of the molecule by a single bond. Typical alkyl groups contain 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) carbon atoms, particularly 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl, isohexyl, etc. If the alkyl is substituted by a cycloalkyl, it is correspondingly a "cycloalkylalkyl", such as cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, etc. If the alkyl is substituted by an aryl, it is correspondingly an "aralkyl", such as benzyl, diphenylmethyl or phenethyl. If the alkyl is substituted by a heterocyclyl, it is correspondingly a "heterocyclylalkyl".

The term "heteroalkyl" refers to an alkyl group in which one or more heteroatom carbon atoms are replaced by heteroatoms, wherein the definition of alkyl is as described above, wherein the heteroatom is selected from N, O, S or oxidized forms thereof (eg, SO, SO ₂ ).

The term "alkylene" refers to a hydrocarbon group (divalent alkyl group) formed by losing two hydrogen atoms from an alkane molecule, which may be a straight chain or branched chain and is connected to the rest of the molecule by a single bond. In this context, a typical alkylene group has 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, ₁₀ ) carbon atoms, preferably 1 to 6 carbon atoms, and examples of alkylene groups include methylene ( _-CH2- ₎ , _ethylene ( _-CH2CH2- ), propylene ( _-CH2CH2CH2- , -CH( _CH3 ) _CH2- , or _-CH2- CH( _CH3 )-), and the like.

The term "cycloalkyl" refers to an alicyclic hydrocarbon, which may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may be a fused, spirocyclic, or bridged ring system. The cycloalkyl may contain 3-18 carbon atoms, preferably 3-10 (e.g., 3, 4, 5, 6, 7, 8, 9, 10) carbon atoms, especially a monocyclic, 3-6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or adamantyl, etc.

The term "alkoxy" refers to a substituent formed by replacing the hydrogen in a hydroxy group with an alkyl group, such as an alkoxy group containing 1 to 10 carbon atoms, for example, methoxy, ethoxy, propoxy, butoxy, and the like.

The term "alkylamino" refers to an amino group ( _-NH2 ) in which one or both hydrogen atoms are replaced by an alkyl group, such as an alkylamino group containing 1 to 10 carbon atoms, for example

The term "halogen" refers to fluorine, chlorine, bromine or iodine.

The term "haloalkyl" refers to a group in which one or more hydrogen atoms in an alkyl group are replaced by a halogen atom (e.g., fluorine, chlorine, bromine or iodine). groups, for example _-CHF2 , _-CH2F , _-CH2Cl , _-CF3 _, _-CH2 - _CF3 , _-CH2CH2 _- _CF3 , _-CH2CH2CH2 - _CF3 . In particular, methyl and ethyl groups substituted by one, two or three halogen atoms (F, Cl, Br, _I ).

The term "aryl" refers to a monocyclic or polycyclic free radical, including a polycyclic free radical containing a monoaryl group and/or a condensed aromatic group, such as a radical containing 1-3 monocyclic or condensed rings and 6-18 (e.g., 6, 8, 10, 12, 14, 16, 18) carbon ring atoms, such as phenyl, naphthyl, biphenyl, indenyl, etc.

The term "heterocyclyl" refers to a 3- to 18-membered non-aromatic ring group containing 2 to 17 carbon atoms and 1 to 10 heteroatoms. The heterocyclyl group may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may contain fused, spirocyclic or bridged ring systems. The heterocyclyl group may be partially saturated (heteroaryl) or fully saturated (heterocycloalkyl). Suitable heteroaryl groups in the compounds of the present invention contain 1, 2 or 3 heteroatoms selected from N, O, S or their oxidized forms (e.g. SO, SO ₂ ), the heteroaryl group includes, for example, coumarin (including 8-coumarin), quinolyl (including 8-quinolyl), isoquinolyl, pyridinyl, pyrazinyl, pyrazolyl, pyrimidinyl, furanyl, pyrrolyl, thienyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl, isoxazolyl, oxazolyl, imidazolyl, indolyl, isoindolyl, indazolyl, indolizinyl, phthalazinyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, pyridazinyl, triazinyl, cinnolinyl, benzimidazolyl, benzofuranyl, benzofurazanyl, benzothienyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl and furopyridinyl. Suitable heterocycloalkyl groups in the compounds of the present invention contain 1, 2 or 3 heteroatoms selected from N, O or S atoms, and include, for example, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, oxathiolanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxirane, thiirane, azepine, oxazepine, diazepine, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, dihydroindolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothiolanyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, 3H-indolyl and quinolizinyl.

In the present invention, "D" refers to deuterium; "substituted by deuterium" means replacing one or more hydrogen atoms with a corresponding number of deuterium atoms.

It should be recognized that, depending on the source of the chemical materials used in the synthesis, there is some variation in the natural isotopic abundance in the synthesized compounds. Therefore, the compounds of the present invention will inherently contain small amounts of deuterated isotopologues. Despite this variation, the concentrations of such naturally abundant stable hydrogen and carbon isotopes are low and insignificant compared to the degree of stable isotopic substitution in the compounds of the present invention. See, for example, Wada, E et al., Seikagaku, 1994, 66:15; Gannes, LZ et al., Comp Biochem Physiol Mol Integr Physiol, 1998, 119:725.

In the compounds of the present invention, any atom not designated as deuterium is present at its natural isotopic abundance. Unless otherwise specified, when a position is specifically designated as "H" or "hydrogen", the position is understood to have hydrogen according to its natural abundance isotopic composition. Similarly, unless otherwise specified, when a position is specifically designated as "D" or "deuterium", the position is understood to have deuterium at an abundance of at least 3000 times greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 45% deuterium incorporation).

As used herein, the term "isotopic enrichment factor" refers to the ratio between the isotopic abundance and the natural abundance of a particular isotope.

In other embodiments, the compounds of the invention have an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).

The term "isotopologue" refers to species wherein the chemical structure differs from a specific compound of the present invention only in its isotopic composition.

The term "pharmaceutically acceptable salts" includes acid addition salts and base addition salts.

The term "acid addition salt" includes, but is not limited to, salts from inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic and phosphonic acids, and salts from organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids and aliphatic and aromatic sulfonic acids. Therefore, these salts include but are not limited to sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, hydrochloride, hydrobromide, iodate, acetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, tartrate and mesylate, also comprising amino acid salts such as arginate, gluconate, galacturonate etc. Acid addition salts can be prepared by contacting the free alkali form with a sufficient amount of the required acid to form a salt in a conventional manner. The free alkali form can be regenerated by contacting the salt form with an alkali, and the free alkali is separated in a conventional manner.

The term "base addition salt" refers to salts formed with metals or amines, such as hydroxides of alkali metals and alkaline earth metals, or with organic amines. Examples of metals used as cations include, but are not limited to, sodium, potassium, magnesium, and calcium. Examples of suitable amines include, but are not limited to N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine (ethane-1,2-diamine), N-methylglucamine and procaine. Base addition salts can be prepared by contacting the free acid form with a sufficient amount of the desired base to form the salt in a conventional manner. The free acid form can be regenerated by contacting the salt form with an acid and isolating the free acid in a conventional manner.

The term "stereoisomer" includes the presence of enantiomers, diastereomers and geometric isomers. Some compounds of the present invention have cyclic hydrocarbon groups that can be substituted on more than one carbon atom, in which case all geometric forms, including cis and trans, and mixtures thereof, are within the scope of the present invention.

The term "solvate" refers to a physical association of a compound of the invention with one or more solvent molecules. The physical association includes various degrees of ionic and covalent bonding, including hydrogen bonding. In some cases, the solvate can be isolated, for example when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. Solvates include solution phases and separable solvates. Representative solvates include ethanolates, methanolates, and the like.

The term "prodrug" refers to a form of the compound of formula I which is suitable for administration to patients without undue toxicity, irritation, allergic response, etc. and is effective for its intended use, including acetal, ester and zwitterion forms. The prodrug is transformed in vivo, such as by hydrolysis in the blood, to yield the parent compound.

The term "patient" or "subject" and the like are used interchangeably herein and refer to any animal or cell thereof treated according to the methods described herein, whether in vitro or in situ. Specifically, the aforementioned animal includes mammals, e.g., rats, mice, guinea pigs, rabbits, dogs, monkeys or humans, particularly humans.

The terms "treat" and "treat" refer to preventing, curing, reversing, alleviating, lessening, minimizing, inhibiting, suppressing and/or halting one or more clinical symptoms of a disease after onset of the disease.

The term "prevent" refers to avoiding, minimizing or making the onset or development of a disease difficult by treating it before it occurs.

The terms "MAP4K4 (HGK) inhibitor", "MAP4K4 (HGK) antagonist" have the same meaning and refer to a molecule that reduces, inhibits or otherwise decreases one or more biological activities of MAP4K4 (HGK). Inhibition using a MAP4K4 (HGK) inhibitor does not necessarily indicate complete elimination of MAP4K4 (HGK) activity. MAP4K4 (HGK) activity may be reduced by a significant amount compared to a control, for example, MAP4K4 (HGK) activity is reduced by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100%.

[00136] Various publications, patents, and published patent specifications are cited herein, the disclosures of which are incorporated by reference in their entireties.

The present invention provides a compound which can be used as a MAP4K4 inhibitor and has the following structure:

In one embodiment of the present invention, Part of The compound has the following structure:

Wherein, R ₁ ' is one or more independent substituents on the benzene ring, which have the definition of R ₁ as described above; L ₁ , Y ₁ , L ₂ , and Y ₂ have the corresponding definitions of the present invention as described above.

More specifically, Y ₁ is a substituted or unsubstituted arylene group (particularly a substituted or unsubstituted phenylene group, such as ) or a substituted or unsubstituted heteroarylene group (particularly a 5-6 membered heteroarylene group, for example ), as defined above in the present invention.

More specifically, R ₁ ′ is H.

More specifically, the compound has the following structure:

More specifically, _Y2 is selected from: H, methyl, ethyl, n-propyl, isopropyl,

Specifically, the compound has the following structure:

In one embodiment of the present invention, Y ₁ is an alkynylene group, for example In particular, the compound has the following structure:

Wherein, Ring A, R ₁ , L ₂ and Y ₂ have the above corresponding definitions of the present invention.

More specifically, ring A is a benzene ring or a 5-6 membered heteroaromatic ring, Some can be

More specifically, the compound has the following structure:

More specifically, L ₂ is selected from: a single bond, C _1-3 alkylene, C _1-3 heteroalkylene, N(R ₅ ), O, S, C(O), C(O)N(R ₅ ), SO ₂ , SO ₂ N(R ₅ ), in particular: methylene, ethylene, NH, O, C(O), C(O)NH, SO ₂ ,

More specifically, _Y2 is selected from: H, methyl, ethyl, n-propyl, isopropyl, in particular:

Specifically, the compound has the following structure:

In one embodiment of the present invention, the compound has the following structure:

Wherein, Ring A, R ₁ , R ₆ , and R ₇ have the above-mentioned corresponding definitions of the present invention.

More specifically, ring A is a benzene ring or a 5-6 membered heteroaromatic ring, Some can be in particular But for some considerations, Partly not (in particular ).

More specifically, R ₁ is selected from: H, halogen (eg, F, Cl), -CN, -NO ₂ , -OH, -NH ₂ , -CH ₃ , -CHF ₂ , -CH ₂ F, -CH ₂ Cl, -CF ₃ , -OCF ₃ ,

More specifically, Part of in particular

More specifically, the compound has the following structure:

More specifically, _R6 can be selected from: H, _C1-3 alkyl, _C1-3 haloalkyl, _C1-3 hydroxyalkyl, _C1-3 haloalkoxy, _C1-3 aminoalkyl, substituted or unsubstituted 6-membered saturated heterocyclic group, in particular: H, _C1-3 alkyl, _C1-3 haloalkyl; in some embodiments of the present invention, _R6 is methyl.

More specifically, ring A is a benzene ring or a 5-6 membered heteroaromatic ring, Some can be in particular

More specifically, Part of in particular

More specifically, the compound has the following structure:

The technical solution of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

Preparation Example

Example 1

Sodium hydride (1.2 equivalents) was slowly added to a tetrahydrofuran solution containing 5-bromo-3-iodo-1H-pyrazolo[3,4-B]pyrimidine (1 equivalent) at 0°C. After stirring at 0°C for 30 minutes, a tetrahydrofuran solution containing 2-(trimethylsilyl)ethoxymethyl chloride (SEMCl) was slowly added dropwise to the reaction solution. The mixture was then heated to room temperature and stirred overnight. After the reaction was complete, a saturated ammonium chloride solution was added to quench the reaction. The reaction solution was extracted with ethyl acetate, and the ethyl acetate containing the product was washed with saturated brine. Drying over anhydrous sodium sulfate, vacuum concentration, and column chromatography gave compound 3a. The yield was 78%.

Step 1: 3a (1.0 equivalent), 4-chlorophenylboronic acid 4a (1.1 equivalent), palladium catalyst (0.05 equivalent), sodium carbonate (3.0 equivalent), 1,4-dioxane aqueous solution (V ₁ :V ₂ =5:1) were added to the reaction flask in sequence. The air in the reaction flask was replaced by argon three times. The reaction was placed in an oil bath at 35°C. Stir overnight, then the reaction solution was poured into a large amount of ethyl acetate solution, and washed twice with pure water and saturated brine. Drying over anhydrous sodium sulfate, vacuum concentration, and column chromatography to obtain product 5a with a yield of 82%.

Step 2: 5a (1.0 equivalent), 4-(4-methyl-1-piperazinemethyl)phenylboronic acid pinacol ester 6a (2.0 equivalent), palladium catalyst (0.05 equivalent), sodium carbonate (3.0 equivalent), 1,4-dioxane aqueous solution (V ₁ :V ₂ =5:1) were added to the reaction bottle in sequence. The air in the reaction bottle was replaced by argon three times. The reaction was placed in an oil bath at 80°C. After stirring overnight, the reaction solution was poured into a large amount of ethyl acetate solution, and washed twice with pure water and saturated brine. Drying over anhydrous sodium sulfate, vacuum concentration, and column chromatography gave the product 7a with a yield of 68%.

Step 3: Slowly drop an equal volume of trifluoroacetic acid into a dichloromethane solution containing 7a at 0°C. After the addition is completed, the reaction solution is stirred at room temperature for 6 hours. Vacuum concentrate to remove dichloromethane and trifluoroacetic acid. Then add a small amount of methanol to the reaction flask to dissolve the product, and place the solution in a low-temperature reaction bath at 0°C. Slowly drop ammonia methanol solution. Stir at room temperature overnight. After the reaction is completed, vacuum concentrate and reverse column chromatography to obtain product 8a with a yield of 90%.

The NMR data are as follows:

¹ H NMR (400MHz, MeOD) δ8.84(d,J＝3.6Hz,1H),8.64(d,J＝7.8Hz,1H),8.06(dd,J＝8.2,6.2Hz,2H),7.75( t,J＝7.4Hz,2H),7.55(ddd,J＝12.0,8.1,4.4Hz,4H),3.70(s,2H),3.09–2.23(m,11H).

The mass spectrometry data are as follows:

HRMS m/z calculated for[M+H] ⁺ 418.1798,fund 418.1784

Example 2

The reaction conditions for preparing compound 9a are the same as those in Example 1, and specific reference is made to the method in Example 1.

The NMR data are as follows:

¹ H NMR (400MHz, MeOD) δ9.07–8.74(m,1H),8.69–8.46(m,1H),8.18–7.90(m,2H),7.75(t,J＝8.2Hz,2H),7.59 –7.39(m,4H),3.72(s,2H),3.03(s,4H),2.68(s,7H).

The mass spectrometry data are as follows:

HRMS m/z calculated for[M+H] ⁺ 418.1798,fund 418.1784

Example 3

The reaction conditions for preparing compound 10a are the same as those in Example 1, and specific reference is made to the method in Example 1.

The NMR data are as follows:

¹ H NMR (400MHz, MeOD) δ8.84 (dd, J＝8.8, 4.1Hz, 1H), 8.64 (dd, J＝14.2, 6.9Hz, 1H), 7.92 (dd, J＝15.6, 11.7Hz, 2H ),7.80–7.70(m,2H),7.68–7.59(m,1H),7.53(d,J＝4.9Hz,2H),3.71(s,2H),3.00(s,4H),2.72(s, 3H),2.66(s,4H).

The mass spectrometry data are as follows:

HRMS m/z calculated for[M+H] ⁺ 436.1704,fund 436.169

Example 4

The reaction conditions for preparing compound 11a are the same as those in Example 1, and specific reference is made to the method in Example 1.

The NMR data are as follows:

¹ H NMR (400MHz, MeOD) δ8.81(d,J＝1.9Hz,1H),8.57(t,J＝10.9Hz,1H),7.86(d,J＝7.7Hz,1H),7.79–7.67( m,3H),7.58(dd,J＝7.9,6.0Hz,1H),7.50(d,J＝8.0Hz,2H),7.19(t,J＝8.5Hz,1H),3.69(s,2H), 2.98(s,4H),2.83–2.51(m,7H).

The mass spectrometry data are as follows:

HRMS m/z calculated for[M+H] ⁺ 402.2094,fund 402.2088

Example 5

The reaction conditions for preparing compound 12a are the same as those in Example 1, and specific reference is made to the method in Example 1.

The mass spectrometry data are as follows:

MS m/z calculated for[M+H] ⁺ 399.23,fund 399.50

Example 6

The reaction conditions for preparing compound 13a are the same as those in Example 1, and specific reference is made to the method in Example 1.

The mass spectrometry data are as follows:

MS m/z calculated for[M+H] ⁺ 399.23,fund 399.45

Example 7

The reaction conditions for preparing compound 14a are the same as those in Example 1, and specific reference is made to the method in Example 1.

The NMR data are as follows:

¹ H NMR (400MHz, Acetone) δ8.85 (s, 1H), 8.69 (s, 1H), 8.18 (s, 1H), 7.94 (d, J = 6.9Hz, 1H), 7.72 (d, J = 7.6 Hz,2H),7.63–7.32(m,3H),3.74(s,1H),3.39(s,3H),3.10(s,3H),2.92(s,5H).

The mass spectrometry data are as follows:

HRMS m/z calculated for[M+H] ⁺ 477.2073,fund 477.2079

Example 8

The reaction conditions for preparing compound 15a are the same as those in Example 1, and specific reference is made to the method in Example 1.

The NMR data are as follows:

¹ H NMR (400MHz, Acetone) δ8.82(d,J＝2.1Hz,1H),8.63(d,J＝2.1Hz,1H),8.34(s,1H),7.74(d,J＝8.2Hz, 2H),7.63(dd,J＝8.4,2.1Hz,1H),7.58(d,J＝2.0Hz,1H),7.49(d,J＝8.2Hz,2H),6.99(d,J＝8.3Hz, 1H), 4.34 (s, 4H), 3.65 (s, 2H), 3.06 (s, 4H), 2.71 (d, J = 21.6Hz, 7H).

The mass spectrometry data are as follows:

HRMS m/z calculated for[M+H] ⁺ 442.2243,fund 442.2257

Example 9

The reaction conditions for preparing compound 16a are the same as those in Example 1, and specific reference is made to the method in Example 1.

The NMR data are as follows:

¹ H NMR (400MHz, Acetone) δ8.90 (s, 1H), 8.77 (d, J = 1.7Hz, 1H), 8.44–8.18 (m, 2H), 7.83 (d, J = 8.2Hz, 2H), 7.62(d,J＝8.1Hz,2H),7.57–7.45(m,2H),4.00(s,2H),3.51(s,3H),3.16(s,4H),2.94(s,3H).

The mass spectrometry data are as follows:

HRMS m/z calculated for[M+H] ⁺ 468.2011,fund 468.2004

Example 10

The reaction conditions for preparing compound 17a are the same as those in Example 1, and specific reference is made to the method in Example 1.

The mass spectrometry data are as follows:

MS m/z calculated for[M+H] ⁺ 423.23,fund 423.55

Embodiment 11

The reaction conditions for preparing compound 18a are the same as those in Example 1, and specific reference is made to the method in Example 1.

The mass spectrometry data are as follows:

MS m/z calculated for[M+H] ⁺ 450.24,fund 450.55

Example 12

The reaction conditions for preparing compound 19a are the same as those in Example 1, and specific reference is made to the method in Example 1.

The mass spectrometry data are as follows:

MS m/z calculated for[M+H] ⁺ 418.18,fund 418.25

Example 13

The reaction conditions for preparing compound 20a are the same as those in Example 1, and specific reference is made to the method in Example 1.

The mass spectrometry data are as follows:

MS m/z calculated for[M+H] ⁺ 452.21,fund452.54

Embodiment 14

The reaction conditions for preparing compound 21a are the same as those in Example 1, and specific reference is made to the method in Example 1.

The NMR data are as follows:

¹ H NMR (400MHz, MeOD) δ8.83(d,J＝2.0Hz,1H),8.66(d,J＝2.0Hz,1H),8.17–8.11(m,1H),8.05(d,J＝7.8 Hz,1H),7.81(d,J＝8.2Hz,2H),7.70(t,J＝8.0Hz,1H),7.65–7.54(m,3H),4.21(s,2H),3.54(s,4H ),3.33(s,10H),2.97(s,3H).

The mass spectrometry data are as follows:

MS m/z calculated for[M+H] ⁺ 427.26,fund 427.25

Embodiment 15

The reaction conditions for preparing compound 22a are the same as those in Example 1, and specific reference is made to the method in Example 1.

The NMR data are as follows:

¹ H NMR (400MHz, Acetone) δ8.86 (s, 1H), 8.75 (d, J = 1.6Hz, 1H), 8.26 (dd, J = 2.7, 1.2Hz, 1H), 7.87 (dd, J = 5.0 ,1.1Hz,1H),7.81(d,J＝8.1Hz,2H),7.65(dd,J＝5.0,2.9Hz,1H),7.57(d,J＝8.0Hz,2H),3.90(s,2H ),3.46(s,4H),3.06(s,4H),2.93(s,4H).

The mass spectrometry data are as follows:

HRMS m/z calculated for[M+H] ⁺ 390.1752,fund 390.1751

Example 16

The reaction conditions for preparing compound 23a are the same as those in Example 1, and specific reference is made to the method in Example 1.

The NMR data are as follows:

¹ H NMR (400MHz, Acetone) δ9.50 (s, 1H), 8.92 (s, 1H), 8.84 (s, 1H), 8.78 (s, 1H), 8.71 (d, J = 8.0Hz, 1H), 7.87(d,J＝8.0Hz,2H),7.74(s,1H),7.66(d,J＝8.0Hz,2H),4.15(s,2H),3.61(s,4H),3.33(s,4H ),2.97(s,3H).

The mass spectrometry data are as follows:

HRMS m/z calculated for[M+H] ⁺ 385.2141,fund 385.213

Embodiment 17

The reaction conditions for preparing compound 24a are the same as those in Example 1, and specific reference is made to the method in Example 1.

The NMR data are as follows:

¹ H NMR (400MHz, Acetone) δ8.91 (s, 1H), 8.79 (s, 1H), 8.65 (s, 1H), 8.32 (d, J = 7.7Hz, 1H), 8.03 (d, J = 7.8 Hz,1H),7.89(d,J＝8.0Hz,2H),7.75(d,J＝8.0Hz,2H),7.66(t,J＝7.7Hz,1H),4.49(s,2H),3.83( s,4H),3.70(s,4H),3.05(s,3H).

The mass spectrometry data are as follows:

HRMS m/z calculated for[M+H] ⁺ 427.2246,fund 427.2256

Embodiment 18

The reaction conditions for preparing compound 25a are the same as those in Example 1, and specific reference is made to the method in Example 1.

The NMR data are as follows:

¹ H NMR (400MHz, DMSO) δ13.92(s,1H),8.92(dd,J＝14.3,2.0Hz,2H),8.73(s,1H),8.40(dd,J＝8.6,2.4Hz,1H ),7.87(d,J＝7.8Hz,2H),7.47(d,J＝7.4Hz,2H),7.00(d,J＝8.7Hz,1H),3.95(s,3H),3.64(s,2H ),3.34(s,8H),2.78(s,3H).

The mass spectrometry data are as follows:

HRMS m/z calculated for[M+H] ⁺ 415.2246,fund 415.2245

Embodiment 19

The reaction conditions for preparing compound 26a are the same as those in Example 1, and specific reference is made to the method in Example 1.

The NMR data are as follows:

¹ H NMR (400MHz, MeOD) δ8.82(d,J＝1.9Hz,1H),8.68–8.53(m,2H),8.27(d,J＝7.6Hz,1H),8.06(d,J＝7.5 Hz,1H),7.76(d,J＝8.0Hz,2H),7.68(t,J＝7.8Hz,1H),7.55(d,J＝8.0Hz,2H),3.97(s,2H),3.38( s,3H),3.01-2.91(m,8H),2.69(s,3H).

The mass spectrometry data are as follows:

MS m/z calculated for[M+H] ⁺ 426.23,fund 426.54

Embodiment 20

The reaction conditions for preparing compound 27a are the same as those in Example 1, and specific reference is made to the method in Example 1.

The NMR data are as follows:

¹ H NMR (400MHz, MeOD) δ9.63 (d, J = 1.9 Hz, 1H), 9.35 ( d, J = 1.7 Hz, 1H), 8.74 ( dd, J = 10.0, 1.9 Hz, 2H), 8.24 ( d,J＝8.1Hz,1H),8.09(d,J＝8.5Hz,1H),8.01–7.90(m,1H),7.85–7.69(m,3H),7.52(d,J＝8.2Hz,2H ),4.13(s,2H),3.46(s,4H),3.27(s,3H),2.87(s,3H).

The mass spectrometry data are as follows:

MS m/z calculated for[M+H] ⁺ 435.23,fund 435.35

Embodiment 21

The reaction conditions for preparing compound 28a are the same as those in Example 1, and specific reference is made to the method in Example 1.

The NMR data are as follows:

¹ H NMR (400MHz, MeOD) δ8.67 (d, J = 1.9 Hz, 1H), 8.42 (dd, J = 7.8, 2.2 Hz, 2H), 8.06 (dd, J = 9.0, 2.5 Hz, 1H), 7.90(t,J＝1.7Hz,1H),7.86(d,J＝7.7Hz,1H),7.45(t,J＝7.8Hz,1H),7.41–7.33(m,1H),7.14(s,1H ),5.00(s,4H),3.47(s,4H),3.01(s,3H).

The mass spectrometry data are as follows:

MS m/z calculated for[M+H] ⁺ 405.16,fund 405.30

Embodiment 22

The reaction conditions for preparing compound 29a are the same as those in Example 1, and specific reference is made to the method in Example 1.

The NMR data are as follows:

¹ H NMR (400MHz, MeOD) δ8.78 (s, 1H), 8.53 (s, 1H), 8.24 (s, 2H), 7.76 (d, J = 7.9Hz, 2H), 7.70 (d, J = 4.7 Hz,2H),7.61(d,J＝8.1Hz,2H),4.27(s,2H),3.58–3.42(m,8H),2.98(s,3H).

The mass spectrometry data are as follows:

MS m/z calculated for[M+H] ⁺ 452.21,fund 452.35

Embodiment 23

The reaction conditions for preparing compound 30a are the same as those in Example 1, and specific reference is made to the method in Example 1.

The NMR data are as follows:

¹ H NMR (400MHz, MeOD) δ8.82(d,J＝2.0Hz,1H),8.61(d,J＝2.0Hz,1H),8.17(d,J＝6.3Hz,2H),7.80(d, J＝8.2Hz,2H),7.65(dt,J＝10.4,8.0Hz,4H),6.90(t,J＝56.2Hz,1H),4.23(s,2H),3.55–3.36(m,8H), 2.97(s,3H).

The mass spectrometry data are as follows:

MS m/z calculated for[M+H] ⁺ 434.22,fund 434.20

Embodiment 24

The reaction conditions for preparing compound 31a are the same as those in Example 1, and specific reference is made to the method in Example 1.

¹ H NMR (400MHz, MeOD) δ8.81(s,1H),8.57(s,1H),7.99(d,J＝7.4Hz,2H),7.71(d,J＝7.9Hz,2H),7.63– 7.50(m,4H),7.45(t,J＝7.4Hz,1H),3.87(s,2H),3.33(s,4H),2.96(s,4H),2.89(s,3H).

HRMS m/z calculated for[M+H] ⁺ 384.2188,fund 384.2184

Embodiment 25

Step 1: 3a (1.0 equivalent), 3-cyanophenylboronic acid 4b (1.1 equivalent), palladium catalyst (0.05 equivalent), sodium carbonate (3.0 equivalent), 1,4-dioxane aqueous solution (V ₁ :V ₂ =5:1) were added to the reaction flask in sequence. The air in the reaction flask was replaced by argon three times. The reaction was placed in an oil bath at 35°C. Stir overnight, then the reaction solution was poured into a large amount of ethyl acetate solution, and washed twice with pure water and saturated brine. Drying over anhydrous sodium sulfate, vacuum concentration, and column chromatography to obtain product 5b with a yield of 77%.

Step 2: 5b (1.0 equivalent), 4-(4-methyl-1-piperazinemethyl)phenylboronic acid pinacol ester 6a (2.0 equivalent), palladium catalyst (0.05 equivalent), sodium carbonate (3.0 equivalent), 1,4-dioxane aqueous solution (V ₁ :V ₂ =5:1) were added to the reaction bottle in sequence. The air in the reaction bottle was replaced by argon three times. The reaction was placed in an oil bath at 80°C. After stirring overnight, the reaction solution was poured into a large amount of ethyl acetate solution, and washed twice with pure water and saturated brine. Drying over anhydrous sodium sulfate, vacuum concentration, and column chromatography gave the product 7b with a yield of 72%.

Step 3: Slowly drop an equal volume of trifluoroacetic acid into a dichloromethane solution containing 7b at 0°C. After the addition is completed, the reaction solution is stirred at room temperature for 6 hours. Vacuum concentrate to remove dichloromethane and trifluoroacetic acid. Then add a small amount of methanol to the reaction flask to dissolve the product, and place the solution in a low-temperature reaction bath at 0°C. Slowly drop ammonia methanol solution. Stir at room temperature overnight. After the reaction is completed, vacuum concentrate and reverse column chromatography to obtain product 8b with a yield of 82%.

The NMR data are as follows:

¹ H NMR (400MHz, MeOD) δ8.85(d,J＝1.9Hz,1H),8.67(d,J＝1.9Hz,1H),8.51–8.25(m,2H),7.93–7.68(m,4H ),7.53(d,J＝8.1Hz,2H),3.70(s,2H),2.93(s,4H),2.65(d,J＝37.7Hz,7H).

The mass spectrometry data are as follows:

HRMS m/z calculated for[M+H] ⁺ 409.2141,fund 409.2157

Embodiment 26

The reaction conditions for the preparation of compound 9b are the same as those in Example 25, and specific reference is made to the method in Example 25.

The NMR data are as follows:

¹ H NMR (400MHz, DMSO) δ14.03 (s, 1H), 8.86 (d, J = 2.0Hz, 1H), 8.72 (d, J = 1.8Hz, 1H), 8.51 (s, 1H), 8.46 ( d,J＝8.0Hz,1H),7.89(d,J＝7.7Hz,1H),7.74(dd,J＝13.9,8.2Hz,3H),7.08(d,J＝8.7Hz,2H),3.36( s,4H),3.27–3.10(m,4H),2.25(s,3H).

The mass spectrometry data are as follows:

HRMS m/z calculated for[M+H] ⁺ 395.1984,fund 395.1974

Embodiment 27

The reaction conditions for preparing compound 10b are the same as those in Example 25, and specific reference is made to the method in Example 25.

The NMR data are as follows:

¹ H NMR (400MHz, DMSO) δ8.86(d,J＝1.9Hz,1H),8.72(d,J＝1.9Hz,1H),8.50(s,1H),8.46(d,J＝7.9Hz, 1H),7.88(d,J＝7.7Hz,1H),7.75(dd,J＝8.1,5.7Hz,3H),7.08(d,J＝8.7Hz,2H),3.97–3.68(m,4H), 3.22–3.02(m,4H).

The mass spectrometry data are as follows:

HRMS m/z calculated for[M+H] ⁺ 382.1668,fund 382.1663

Embodiment 28

The reaction conditions for preparing compound 11b are the same as those in Example 25, and specific reference is made to the method in Example 25.

The NMR data are as follows:

¹ H NMR (400MHz, DMSO) δ14.03 (s, 1H), 8.90 (d, J = 2.0Hz, 1H), 8.74 (d, J = 1.8Hz, 1H), 8.50–8.40 (m, 3H), 8.17(s,1H),7.96–7.85(m,1H),7.75(t,J＝7.8Hz,1H),4.36(s,2H),3.62(s,4H),2.88(s,2H).

The mass spectrometry data are as follows:

HRMS m/z calculated for[M+H] ⁺ 400.1886,fund 400.1905

Embodiment 29

The reaction conditions for the preparation of compound 12b are the same as those in Example 25, and specific reference is made to the method in Example 25.

The NMR data are as follows:

¹ H NMR (400MHz, DMSO) δ14.18(s,1H),8.97(d,J＝2.0Hz,1H),8.92(d,J＝2.0Hz,1H),8.54(s,2H),8.48( d,J＝8.0Hz,1H),8.00(s,4H),7.91(d,J＝7.8Hz,1H),7.76(t,J＝7.8Hz,1H),3.43(dd,J＝12.2,6.3 Hz, 3H), 2.55 (t, J = 6.8Hz, 2H), 2.29 (s, 6H).

The mass spectrometry data are as follows:

HRMS m/z calculated for[M+H] ⁺ 411.1933,fund 411.1944

Embodiment 30

The reaction conditions for the preparation of compound 13b are the same as those in Example 25, and specific reference is made to the method in Example 25.

The NMR data are as follows:

¹ H NMR (400MHz, DMSO) δ14.26(s,1H),8.99(dd,J＝8.8,1.9Hz,2H),8.55(s,1H),8.48(d,J＝8.0Hz,1H), 8.21(d,J＝8.4Hz,2H),7.92(t,J＝7.0Hz,3H),7.76(t,J＝7.8Hz,1H),3.12(s,8H),2.64(s,3H).

The mass spectrometry data are as follows:

HRMS m/z calculated for[M+H] ⁺ 459.1603,fund 459.1605

Embodiment 31

The reaction conditions for the preparation of compound 14b are the same as those in Example 25, and specific reference is made to the method in Example 25.

The NMR data are as follows:

¹ H NMR (400MHz, DMSO) δ14.18(s,1H),8.98–8.83(m,2H),8.51(s,1H),8.48–8.35(m,1H),7.99(s, 1H), 7.91 (d, J = 7.7Hz, 1H), 7.76 (t, J = 7.8Hz, 1H), 7.07 (d, J = 9.1Hz, 1H).

The mass spectrometry data are as follows:

HRMS m/z calculated for[M+H] ⁺ 313.1202,fund 313.1222

Embodiment 32

The reaction conditions for the preparation of compound 15b are the same as those in Example 25, and specific reference is made to the method in Example 25.

The NMR data are as follows:

¹ H NMR (400MHz, DMSO) δ14.05 (s, 1H), 8.93 (d, J = 1.9Hz, 1H), 8.78 (d, J = 1.9Hz, 1H), 8.48 (d, J = 2.5Hz, 2H),8.44(d,J＝8.0Hz,1H),8.21(s,1H),7.91(d,J＝7.7Hz,1H),7.76(t,J＝7.8Hz,1H),4.55(td, J＝10.9,5.4Hz,1H),3.46(d,J＝12.9Hz,2H),3.14(dd,J＝21.6,10.9Hz,2H),2.39–1.94(m,4H).

The mass spectrometry data are as follows:

HRMS m/z calculated for[M+H] ⁺ 370.1654,fund 370.1790

Embodiment 33

The reaction conditions for the preparation of compound 16b are the same as those in Example 25, and specific reference is made to the method in Example 25.

The NMR data are as follows:

¹ H NMR (400MHz, CDCl ₃ ) δ8.72 (s, 1H), 8.42–8.30 (m, 1H), 8.29–8.15 (m, 1H), 7.86 (t, J = 3.7Hz, 2H), 7.75– 7.50(m,2H),7.30(s,1H),4.35(dd,J＝8.5,4.7Hz,2H),3.78(dd,J＝8.5,4.8Hz,2H),3.39–3.32(m,3H) .

The mass spectrometry data are as follows:

HRMS m/z calculated for[M+H] ⁺ 345.1464,fund 345.1465

Embodiment 34

The reaction conditions for the preparation of compound 17b are the same as those in Example 25, and specific reference is made to the method in Example 25.

The NMR data are as follows:

¹ H NMR (400MHz, DMSO) δ14.17(s,1H),8.95(d,J＝2.0Hz,1H),8.90(d,J＝2.0Hz,1H),8.54(s,1H),8.49( d,J＝1.1Hz,1H),7.96(d,J＝8.3Hz,2H),7.91(dd,J＝6.5,1.3Hz,1H),7.75(t,J＝7.8Hz,1H),7.56( d,J＝8.3Hz,2H),4.07–3.18(m,8H),2.33(s,3H).

The mass spectrometry data are as follows:

HRMS m/z calculated for[M+H] ⁺ 423.1933,fund 423.1964

Embodiment 35

The reaction conditions for the preparation of compound 18b are the same as those in Example 25, and specific reference is made to the method in Example 25.

The NMR data are as follows:

¹ H NMR (400MHz, MeOD) δ8.88(d,J＝2.0Hz,1H),8.71(d,J＝2.0Hz,1H),8.42–8.33(m,2H),7.92(d,J＝8.1 Hz,2H),7.80(d,J＝7.8Hz,1H),7.77–7.64(m,3H),4.39(s,2H),3.92(s,4H),3.29(s,4H).

The mass spectrometry data are as follows:

HRMS m/z calculated for[M+H] ⁺ 396.1824,fund 396.1807

Embodiment 36

The reaction conditions for the preparation of compound 19b are the same as those in Example 25, and specific reference is made to the method in Example 25.

The NMR data are as follows:

¹ H NMR (400MHz, DMSO) δ14.12(s,1H),8.91(d,J＝1.9Hz,1H),8.85(d,J＝1.9Hz,1H),8.54(s,1H),8.47( d,J＝8.0Hz,1H),7.91(d,J＝7.8Hz,1H),7.85(d,J＝8.1Hz,2H),7.75(t,J＝7.8Hz,1H),7.50(d, J＝8.1Hz,2H),3.76(s,2H),3.14(d,J＝5.0Hz,4H),2.93(s,4H).

The mass spectrometry data are as follows:

HRMS m/z calculated for[M+H] ⁺ 444.1494,fund 444.1473

Embodiment 37

The reaction conditions for the preparation of compound 20b are the same as those in Example 25, and specific reference is made to the method of Example 25.

HRMS m/z calculated for[M+H] ⁺ 313.1202,fund 313.1196

Embodiment 38

The reaction conditions for the preparation of compound 21b are the same as those in Example 25, and specific reference is made to the method in Example 25.

The NMR data are as follows:

¹ H NMR (400MHz, DMSO) δ14.20 (s, 1H), 9.09–8.90 (m, 2H), 8.56 (s, 1H), 8.50 (d, J = 8.1Hz, 1H), 8.18 (dd, J ＝21.6,8.5Hz,3H),7.92(d,J＝7.7Hz,1H),7.77(t,J＝7.8Hz,1H).

The mass spectrometry data are as follows:

HRMS m/z calculated for[M+H] ⁺ 365.1263,fund 365.1274

Embodiment 39

The reaction conditions for the preparation of compound 22b are the same as those of Example 25, and specific reference is made to the method of Example 25.

The NMR data are as follows:

¹ H NMR (400MHz, DMSO) δ14.11 (s, 1H), 8.87 (d, J = 2.3Hz, 1H), 8.80 (s, 1H), 8.53 (s, 1H), 8.48 (d, J = 8.0 Hz,1H),7.90(d,J＝7.7Hz,1H),7.75(t,J＝7.8Hz,1H),6.98(s,1H).

The mass spectrometry data are as follows:

HRMS m/z calculated for[M+H] ⁺ 314.1154,fund 314.115

Embodiment 40

The reaction conditions for the preparation of compound 23b are the same as those of Example 25, and specific reference is made to the method of Example 25.

The NMR data are as follows:

¹ H NMR (400MHz, DMSO) δ14.10 (s, 1H), 8.90 (d, J = 2.1Hz, 1H), 8.82 (d, J = 2.1Hz, 1H), 8.53 (t, J = 1.4Hz, 1H),8.50–8.35(m,1H),7.95–7.88(m,1H),7.83(dd,J＝12.8,2.3Hz,1H),7.75(t,J＝7.8Hz,1H),7.63(dd ,J＝8.5,1.2Hz,1H),7.31(t,J＝8.8Hz,1H),4.72(dt,J＝12.1,6.0Hz,1H),1.33(d,J＝6.0Hz,6H).

HRMS m/z calculated for[M+H] ⁺ 373.1465,fund 373.1459

Embodiment 41

The reaction conditions for the preparation of compound 24b are the same as those of Example 25, and specific reference is made to the method of Example 25.

The NMR data are as follows:

¹ H NMR (400MHz, DMSO) δ14.14(s,1H),8.90(s,1H),8.82(s,1H),8.53(s,1H),8.47(d,J＝7.8Hz,1H),7.90(d,J＝7.7Hz,1H),7.84(d,J＝8.0Hz,2H),7.75(t,J＝7. 8Hz,1H),7.41(d,J＝8.1Hz,2H),3.56(d,J＝11.3Hz,2H),3.24–3.09(m,2H),2.93(dd,J＝20.6,8.6Hz,1H),2.84(s,3H),2.07(d,J＝13.3Hz,2H),1.92(dd,J =23.8,11.9Hz,2H).

The mass spectrometry data are as follows:

HRMS m/z calculated for[M+H] ⁺ 394.2032,fund 394.2019

Embodiment 42

The reaction conditions for the preparation of compound 25b are the same as those of Example 25, and specific reference is made to the method of Example 25.

The NMR data are as follows:

¹ H NMR (400MHz, DMSO) δ14.08(s,1H),8.88(s,1H),8.78(s,1H),8.53(s,1H),8.47(d,J＝8.1Hz,1H), 7.91(s,1H),7.81(d,J＝8.6Hz,2H),7.75(t,J＝7.8Hz,1H),7.10(d,J＝8.6Hz,2H),4.91(t,J＝5.4 Hz, 1H), 4.07 (t, J = 4.9 Hz, 2H), 3.76 (dd, J = 10.0, 5.0 Hz, 2H).

The mass spectrometry data are as follows:

HRMS m/z calculated for[M+H] ⁺ 357.1352,fund 357.1342

Embodiment 43

The reaction conditions for the preparation of compound 26b are the same as those of Example 25, and specific reference is made to the method of Example 25.

The NMR data are as follows:

¹ H NMR (400MHz, DMSO) δ14.18(s,1H),9.18(s,1H),8.94(d,J＝2.0Hz,1H),8.86(d,J＝2.0Hz,1H),8.53( s,1H),8.47(d,J＝8.1Hz,1H),7.96(d,J＝8.1Hz,2H),7.91(d,J＝7.8Hz,1H),7.75(t,J＝7.8Hz, 1H), 7.62 (d, J = 8.0Hz, 2H), 4.17 (s, 2H), 3.32 -3.18 (m, 8H).

The mass spectrometry data are as follows:

HRMS m/z calculated for[M+H] ⁺ 395.1984,fund 395.2008

Embodiment 44

The reaction conditions for the preparation of compound 27b are the same as those in Example 25, and specific reference is made to the method in Example 25.

The NMR data are as follows:

¹ H NMR (400MHz, DMSO) δ14.18(s,1H),8.93(d,J＝1.9Hz,1H),8.85(d,J＝1.9Hz,1H),8.53(s,1H),8.47( d,J＝8.1Hz,1H),7.96–7.85(m,2H),7.76(t,J＝7.8Hz,1H),7.58(t,J＝7.6Hz,1H),7.48(d,J＝7.5 Hz, 1H), 4.06 (s, 1H), 3.35 (d, J = 83.7Hz, 4H), 2.82 (s, 3H).

The mass spectrometry data are as follows:

HRMS m/z calculated for[M+H] ⁺ 409.2141,fund 300.1253

Embodiment 45

Step 1: Add 5b (1.0 equivalent), 4-(4-methyl-1-piperazinemethyl)aniline (2.0 equivalent), palladium catalyst (0.05 equivalent), phosphorus ligand (0.1 equivalent), cesium carbonate (3.0 equivalent), and toluene to the reaction bottle in sequence. Replace the air in the reaction bottle with argon three times. Place the reaction in an oil bath. After reflux and stirring overnight, pour the reaction solution into a large amount of ethyl acetate solution, and wash twice with pure water and saturated brine. Dry over anhydrous sodium sulfate, concentrate in vacuo, and obtain product 7c after column chromatography with a yield of 56%.

Step 2: Slowly drop an equal volume of trifluoroacetic acid into a dichloromethane solution containing 7c at 0°C. After the addition is completed, the reaction solution is stirred at room temperature for 6 hours. Vacuum concentrate to remove dichloromethane and trifluoroacetic acid. Then add a small amount of methanol to the reaction flask to dissolve the product, and place the solution in a low-temperature reaction bath at 0°C. Slowly drop ammonia methanol solution. Stir at room temperature overnight. After the reaction is completed, vacuum concentrate and reverse column chromatography to obtain product 8c with a yield of 82%.

The NMR data are as follows:

¹ H NMR (400MHz, Acetone) δ8.52(d,J＝2.3Hz,1H),8.38(dd,J＝7.5,1.3Hz,2H),8.32(d,J＝2.4Hz,1H),7.85– 7.79(m,1H),7.74(d,J＝8.5Hz,1H),7.60(s,1H),7.27(d,J＝8.4Hz,2H),7.10(dd,J＝8.5,1.6Hz,2H ),3.60(s,2H),3.02-2.74(m,8H),2.66–2.56(m,3H).

The mass spectrometry data are as follows:

HRMS m/z calculated for[M+H] ⁺ 424.2250,fund 424.2259

Embodiment 46

The reaction conditions for the preparation of compound 9c are the same as those in Example 45, and specific reference is made to the method of Example 45.

The mass spectrometry data are as follows:

HRMS m/z calculated for[M+H] ⁺ 523.2934,fund 523.2951

Embodiment 47

The reaction conditions for preparing compound 10c are the same as those in Example 45, and specific reference is made to the method in Example 45.

The NMR data are as follows:

¹ H NMR (400MHz, DMSO) δ13.85 (s, 1H), 9.66 (s, 1H), 8.39 (d, J = 2.4Hz, 1H), 8.30 (s, 1H), 8.25 (d, J = 8.2 Hz,1H),8.03(d,J＝2.4Hz,1H),7.86(d,J＝7.7Hz,1H),7.72(t,J＝7.8Hz,1H),7.06(d,J＝8.8Hz, 1H),6.96(d,J＝9.0Hz,2H),3.68(d,J＝12.5Hz,2H),3.52(d,J＝12.5Hz,2H),3.18(d,J＝10.8Hz,3H) ,2.87(s,4H).

The mass spectrometry data are as follows:

HRMS m/z calculated for[M+H] ⁺ 410.2093,fund 410.2076

Embodiment 48

Step 1: Add 3a (1.0 equivalent), 3-cyanophenylboronic acid 4b (1.1 equivalent), palladium catalyst (0.05 equivalent), sodium carbonate (3.0 equivalent), and 1,4-dioxane aqueous solution (V ₁ :V ₂ =5:1) to the reaction flask in sequence. Replace the air in the reaction flask with argon three times. Place the reaction in an oil bath at 35°C. Stir overnight, pour the reaction solution into a large amount of ethyl acetate solution, and wash twice with pure water and saturated brine. Dry over anhydrous sodium sulfate, concentrate in vacuo, and obtain product 5b by column chromatography with a yield of 77%.

Step 2: Add 5b (1.0 equivalent), 6d (2.0 equivalent), palladium catalyst (0.05 equivalent), cuprous iodide (0.1 equivalent), triethylamine (3.0 equivalent), and N,N-dimethylformamide to the reaction flask in sequence. Replace the air in the reaction flask with argon three times. Place the reaction in an oil bath at 110°C. After stirring overnight, pour the reaction solution into a large amount of ethyl acetate solution, and wash twice with pure water and saturated brine. Dry over anhydrous sodium sulfate, concentrate in vacuo, and obtain product 7d after column chromatography with a yield of 76%.

Step 3: Slowly drop an equal volume of trifluoroacetic acid into a dichloromethane solution containing 7d at 0°C. After the addition is completed, the reaction solution is stirred at room temperature for 6 hours. Vacuum concentrate to remove dichloromethane and trifluoroacetic acid. Then add a small amount of methanol to the reaction flask to dissolve the product, and place the solution in a low-temperature reaction bath at 0°C. Slowly drop ammonia methanol solution. Stir at room temperature overnight. After the reaction is completed, vacuum concentrate and reverse column chromatography to obtain product 8d with a yield of 66%.

The NMR data are as follows:

¹ H NMR (400MHz, DMSO) δ14.27(s,1H),8.85(s,1H),8.65(d,J＝1.6Hz,1H),8.46(s,1H),8.39(d,J＝7.9 Hz,1H),7.90(d,J＝7.7Hz,1H),7.73(t,J＝7.8Hz,1H),3.84(s,2H),3.23(d,J＝4.4Hz,4H),3.16( s,4H).

The mass spectrometry data are as follows:

HRMS m/z calculated for[M+H] ⁺ 392.1181,fund 392.1181

Embodiment 49

The reaction conditions for the preparation of compound 9d are the same as those in Example 48, and specific reference is made to the method in Example 48.

The NMR data are as follows:

¹ H NMR (400MHz, DMSO) δ14.28(s,1H),8.91(s,1H),8.67(d,J＝1.6Hz,1H),8.49(s,1H),8.41(d,J＝8.0 Hz,1H),7.91(d,J＝7.8Hz,1H),7.74(t,J＝7.8Hz,1H),6.70(s,1H),4.84(d,J＝6.3Hz,1H),4.65( d,J＝6.4Hz,1H).

The mass spectrometry data are as follows:

HRMS m/z calculated for[M+H] ⁺ 317.1039,fund 317.1033

Embodiment 50

The reaction conditions for preparing compound 10d are the same as those in Example 48, and specific reference is made to the method in Example 48.

The NMR data are as follows:

¹ H NMR (400MHz, DMSO) δ13.94(s,1H),8.77(d,J＝1.5Hz,1H),8.59(d,J＝1.6Hz,1H),8.45(s,1H),8.38( d,J＝8.0Hz,1H),7.89(d,J＝7.7Hz,1H),7.72(t,J＝7.8Hz,1H),4.98(s,1H),3.65(t,J＝6.8Hz, 2H),2.63(t,J＝6.8Hz,2H).

The mass spectrometry data are as follows:

HRMS m/z calculated for[M+H] ⁺ 289.1089,fund 289.1101

Embodiment 51

The reaction conditions for the preparation of compound 11d are the same as those in Example 48, and specific reference is made to the method in Example 48.

The NMR data are as follows:

¹ H NMR (400MHz, DMSO) δ14.30 (s, 1H), 8.86 (s, 1H), 8.68 (s, 1H), 8.46 (s, 1H), 8.39 (d, J = 7.9Hz, 1H), 7.91(d,J＝7.3Hz,1H),7.73(s,1H),3.82(s,2H),3.51-3.16(m,8H),2.83(s,3H).

The mass spectrometry data are as follows:

HRMS m/z calculated for[M+H] ⁺ 357.1828,fund 357.1844

Embodiment 52

The reaction conditions for the preparation of compound 12d are the same as those in Example 48, and specific reference is made to the method in Example 48.

The NMR data are as follows:

¹ H NMR (400MHz, MeOD) δ8.57 (d, J = 13.6 Hz, 2H), 8.04 (d, J = 8.2 Hz, 2H), 7.59 (d, J = 8.2 Hz, 2H), 4.03 (s, 2H),3.52(s,4H),3.33(d,J＝1.4Hz,4H),3.15(s,3H),3.07(s,3H),2.97(s,3H).

The mass spectrometry data are as follows:

MS m/z calculated for[M+H] ⁺ 403.22,fund 403.35

Embodiment 53

Sodium hydride (1.2 equivalents) was slowly added to a tetrahydrofuran solution containing 2-bromo-7-iodo-5H-pyrrolo[2,3-B]pyrazine (1 equivalent) at 0°C. After stirring at 0°C for 30 minutes, a tetrahydrofuran solution containing 2-(trimethylsilyl)ethoxymethyl chloride (SEMCl) was slowly added dropwise to the reaction solution. The mixture was then heated to room temperature and stirred overnight. After the reaction was complete, a saturated ammonium chloride solution was added to quench the reaction. The reaction solution was extracted with ethyl acetate, and the ethyl acetate containing the product was washed with saturated brine. Drying over anhydrous sodium sulfate, vacuum concentration, and column chromatography gave the target molecule 3e. The yield was 66%.

Step 1: Add 3e (1.0 equivalent), 4-chlorophenylboronic acid 4e (1.1 equivalent), palladium catalyst (0.05 equivalent), sodium carbonate (3.0 equivalent), and 1,4-dioxane aqueous solution (V ₁ :V ₂ =5:1) to the reaction flask in sequence. Replace the air in the reaction flask with argon three times. Place the reaction in an oil bath at 35°C. Stir overnight, pour the reaction solution into a large amount of ethyl acetate solution, and wash twice with pure water and saturated brine. Dry over anhydrous sodium sulfate, concentrate in vacuo, and obtain product 5e by column chromatography with a yield of 79%.

Step 2: 5e (1.0 equivalent), 4-(4-methyl-1-piperazinemethyl)phenylboronic acid pinacol ester 6a (2.0 equivalent), palladium catalyst (0.05 equivalent), sodium carbonate (3.0 equivalent), 1,4-dioxane aqueous solution (V ₁ :V ₂ =5:1) were added to the reaction bottle in sequence. The air in the reaction bottle was replaced by argon three times. The reaction was placed in an oil bath at 80°C. After stirring overnight, the reaction solution was poured into a large amount of ethyl acetate solution, and washed twice with pure water and saturated brine. Drying over anhydrous sodium sulfate, vacuum concentration, and column chromatography gave the product 7e with a yield of 56%.

Step 3: Slowly drop an equal volume of trifluoroacetic acid into a dichloromethane solution containing 7e at 0°C. After the addition is completed, the reaction solution is stirred at room temperature for 6 hours. Vacuum concentrate to remove dichloromethane and trifluoroacetic acid. Then add a small amount of methanol to the reaction flask to dissolve the product, and place the solution in a low-temperature reaction bath at 0°C. Slowly drop ammonia methanol solution. Stir at room temperature overnight. After the reaction is completed, vacuum concentrate and reverse column chromatography to obtain product 8e with a yield of 77%.

The NMR data are as follows:

¹ H NMR (400MHz, Acetone) δ11.46(s,1H),8.90(s,1H),8.42(d,J＝8.5Hz,3H),8.21(d,J＝7.3Hz,2H),7.52( dd,J＝20.8,7.9Hz,4H),3.83(d,J＝96.4Hz,8H),3.22(s,3H),2.10(s,1H).

The mass spectrometry data are as follows:

HRMS m/z calculated for[M+H] ⁺ 418.1798,fund 418.1784

Activity Test Example

Example 1: ADP-Glo method to detect the inhibitory effect of compounds on the activity of protein MAP4K4

1. Experimental purpose: Determine the half-inhibition constant _IC50 of the compound on protein MAP4K4

2. Experimental materials:

ATP, purchased from Promega, catalog number: V915B

MBP, purchased from MEMD Millipore Crop, catalog number: 13-104

ADP-Glo ^TM Reagent, purchased from Promega, catalog number: V912B

Kinase Detection Reagent, purchased from Promega, catalog number: V913B

384-well plate, purchased from PE, item number: 6007680

3. Reaction system:

Plate 1: MAP4K4

MAP4K4: 3 ng/well; ATP: 1 μM; MBP: 0.1 μg/μL

MAP4K4 Kinase Buffer: 40mM Tris-HCl, pH7.5; 20mM MgCl ₂ ; 0.1mg/ml BSA; 50μM DTT.

4. Detection method:

(1) Add 2 μL kinase (MAP4K4) and 1 μL compound to the 384 plate;

(2) Add 2 μL of substrate/ATP mixture and incubate at room temperature in the dark for 60 min;

(3) Add 5 μL ADP-Glo ^™ Reagent and incubate at room temperature for 40 minutes;

(4) Add 10 μL Kinase Detection Reagent and incubate at room temperature for 30 minutes;

(5) Read the plate on an ELISA reader and record the luminescence (set the integration time to 0.10 s).

5. Data processing:

Inhibition rate calculation:

Among them, Ratio _cpd is the test compound reading;

Ratio _pc is the positive control reading;

Ratio _vc is the blank reading.

The results are shown in Table 1.

Table 1 Activity test results

The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

The aforementioned embodiments and methods described in the present invention may be varied based on the ability, experience and preference of those skilled in the art.

In the present invention, merely listing the steps of the method in a certain order does not constitute any limitation on the order of the method steps.

Claims

A compound or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, or deuterated compound thereof, wherein the compound has the following structure:

in,

X 1 is CR 2 or N; wherein R 2 is selected from the group consisting of H, halogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, -CN, -NO 2 , -OR 2a , -COR 2a , -C(O)OR 2a , -C(O)NR 2a R 2b , -OC(O)R 2a , -SR 2a , -S(O)-R 2a , -S(O) 2 -R 2a , -NR 2a R 2b , -NR 2a C(O)R 2b , -NR 2a -S(O)-R 2b , -NR 2a -S(O) 2 -R 2b , -S(O)-NR 2a R 2b , -S(O) 2 -NR 2a R 2b , R 2a and R R 2a and R 2b are independently selected from: H, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, or R 2a and R 2b together with the nitrogen atom to which they are attached form a heterocyclyl; wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl is optionally substituted with one or more R 2c groups;

X 2 is CR 3 or N; wherein R 3 is selected from the group consisting of H, halogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, -CN, -NO 2 , -OR 3a , -COR 3a , -C(O)OR 3a , -C(O)NR 3a R 3b , -OC(O)R 3a , -SR 3a , -S(O)-R 3a , -S(O) 2 -R 3a , -NR 3a R 3b , -NR 3a C(O)R 3b , -NR 3a -S(O)-R 3b , -NR 3a -S(O) 2 -R 3b , -S(O)-NR 3a R 3b , -S(O) 2 -NR 3a R 3b , R 3a and R R 3a and R 3b are independently selected from: H, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, or R 3a and R 3b together with the nitrogen atom to which they are attached form a heterocyclyl; wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl is optionally substituted with one or more R 3c groups;

Ring A is an aromatic ring or a heteroaromatic ring;

R 1a is one or more substituents on ring A, each of which is independently selected from the group consisting of H, halogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, -CN, -NO 2 , -OR 1a , -COR 1a , -C(O)OR 1a , -C(O)NR 1a R 1b , -OC(O)R 1a , -SR 1a , -S(O)-R 1a , -S(O) 2 -R 1a , -NR 1a R 1b , -NR 1a C(O)R 1b , -NR 1a -S(O)-R 1b , -NR 1a -S(O) 2 -R 1b , -S(O)-NR 1a R 1b , -S(O) 2 -NR 1a R 1b , R 1a and R R 1a and R 1b are independently selected from: H, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, or R 1a and R 1b together with the nitrogen atom to which they are attached form a heterocyclyl; or, two R 1 groups together with the carbon atom to which they are attached form a carbocyclic or heterocyclic ring; wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, carbocyclic ring, heterocyclic ring is optionally substituted with one or more R 1c groups;

L 1 is selected from the group consisting of a single bond, C 1-6 alkylene, N(R 4 ), O, S, C(O), N(R 4 )C(O), C(O)N(R 4 ), C(O)O, OC(O), SO, SO 2 , N(R 4 )SO 2 , SO 2 N(R 4 ); wherein R 4 is selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl;

Y1 is selected from: substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, substituted or unsubstituted alkenylene, substituted or unsubstituted alkynylene;

L 2 is selected from the group consisting of a single bond, C 1-6 alkylene, C 1-6 heteroalkylene, C 3-6 cycloalkylene, heterocyclylene, N(R 5 ), O, S, C(O), C(O)N(R 5 ), N(R 5 )C(O), C(O)O, OC(O), SO, SO 2 , N(R 5 )SO 2 , SO 2 N(R 5 ); wherein R 5 is selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl;

Y2 is selected from: H, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl; optionally, wherein each of the alkyl, heteroalkyl, heterocyclyl, heterocyclylalkyl is optionally substituted with one or more R6 groups;

R is selected from the group consisting of H, (=O), halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, -CN, -NO2, -OR6a , -COR6a , -C (O) OR6a , -C(O) NR6aR6b , -OC(O) R6a , -SR6a , -S(O) -R6a , -S (O) 2 - R6a , -NR6aR6b, -NR6aC(O )R6b , -NR6a - S (O) -R6b , -NR6a -S(O) 2 - R6b , -S(O) -NR6aR6b , -S(O) 2- NR6aR6b , R6a and R 6b is independently selected from the group consisting of: H, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, hetero cyclyl, heterocyclylalkyl, or R 6a and R 6b together with the nitrogen atom to which they are attached form a heterocyclyl; wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, carbocycle, heterocycle is optionally substituted with one or more R 6c groups;

R 1c , R 2c , R 3c , R 6c are independently selected from the group consisting of: H, (═O), halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, -CN, -NO 2 , -CF 3 , -OCF 3 , -OR′, -COR′, -C(O)OR′, -C(O)NR′R″, -OC(O)R′, -S(O) p -R′, -NR′R″, -NR′C(O)R″, -NR′-S(O) p -R″, -S(O) p -NR′R″, -C(═NH)NR′R″, p is selected from the group consisting of 0, 1 and 2;

Each R' and R" is independently selected from the group consisting of H, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl;

Preferably, X1 is CH and X2 is N; or, X1 is N and X2 is CH.
The compound according to claim 1, characterized in that ring A is a benzene ring or a 5-6 membered heteroaromatic ring;

Preferably, Part of
The compound according to claim 1 or 2, characterized in that R 1 is selected from: H, halogen (such as F, Cl), -CN, -NO 2 , -OH, -NH 2 , C 1-6 alkyl (such as -CH 3 , ), C 1-6 haloalkyl (e.g., -CHF 2 , -CH 2 F, -CH 2 Cl, -CF 3 , -CH 2 CF 3 , -CH 2 CH 2 F), C 1-6 hydroxyalkyl (e.g., ), C 1-6 alkoxy (e.g. ), C 1-6 haloalkoxy (e.g. -OCF 3 ), C 1-6 aminoalkyl (e.g. ), C 1-6 alkylamino (e.g. ), C 1-6 alkylaminoalkyl (e.g. ), -C(O)N(C 0-6 alkyl)(C 0-6 alkyl)(e.g. ), -N(C 0-6 alkyl)C(O)(C 0-6 alkyl) (e.g. ), -SO 2 (C 0-6 alkyl) (e.g. ), -SO 2 (C 3-6 cycloalkyl) (e.g. ), -NH-SO 2 (C 0-6 alkyl) (e.g. ), -NH-SO 2 (C 3-6 cycloalkyl) (e.g. ), -SO 2 -N(C 0-6 alkyl)(C 0-6 alkyl)(e.g. ), substituted or unsubstituted 4- to 6-membered heterocyclic group (e.g. ), saturated heterocycloalkylalkyl (e.g. ), substituted or unsubstituted phenyl (e.g. ),
The compound according to any one of claims 1 to 3, characterized in that L 1 is a single bond or N(R 4 ), such as NH.
The compound according to any one of claims 1 to 4, characterized in that Y 1 is or alkynylene (e.g. ), wherein * represents the position connected to L 1 , R 7 is one or more independent substituents on the ring, each of which is independently selected from: H, halogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, -CN, -NO 2 , -OR 7a , -COR 7a , -C(O)OR 7a , -C(O)NR 7a R 7b , -OC(O)R 7a , -S(O) q -R 7a , -NR 7a R 7b , -NR 7a C(O)R 7b , -NR 7a -S(O) q -R 7b , -S(O) q -NR 7a R 7b , q is selected from 0, 1 and 2, R 7a and R 7b are independently selected from: H, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl; or, two R R 7c group and the carbon atom to which it is attached form a carbocycle or heterocycle; wherein the alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, carbocycle, heterocycle are each optionally substituted by one or more R 7c groups; each R 7c is independently selected from: halogen, -CN, -NO 2 , -CF 3 , -OCF 3 , -OR', -COR', -C(O)OR', -C(O)NR'R", -OC(O)R', -S(O) p -R', -NR'R", -NR'C(O)R", -NR'-S(O) p -R", -S(O) p -NR'R", p is selected from 0, 1 and 2;

Preferably, R 7 is selected from: H, halogen (eg, F, Cl), -CN, -NO 2 , -OH, -NH 2 , -CHF 2 , -CH 2 F, -CH 2 Cl, -CF 3 , -OCF 3 , -CH 3 .
The compound according to any one of claims 1 to 5, characterized in that L 2 is a single bond, or L 2 is selected from: C 1-3 alkylene, C 1-3 heteroalkylene, N(R 5 ), O, S, C(O), C(O)N(R 5 ), SO 2 , SO 2 N(R 5 ), preferably selected from: methylene, ethylene, NH, O, C(O), C(O)NH, SO 2 ,
The compound according to any one of claims 1 to 6, characterized in that Y 2 is selected from: H, C 1-6 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl), C 1-6 heteroalkyl (e.g., ).
The compound according to any one of claims 1 to 6, characterized in that Y 2 has the following structure: Wherein, Z 1 is C or N, Z 2 is selected from: O, S, N, C, SO 2 , e is 0, 1 or 2, f is 0, 1 or 2, g is 0, 1 or 2, and R 6 is one or more independent substituents on the ring;

Preferably, Y2 is selected from:

Preferably, e is 1, f is 1, and g is 1; or, e is 2, f is 1, and g is 1; or, e is 0, f is 1, and g is 1; or, e is 0, f is 1, and g is 0; or, e is 0, f is 0, and g is 0;

Preferably, R 6 is selected from: H, (=O), halogen (eg, F, Cl), -CN, -NO 2 , -OH, -NH 2 , C 1-6 alkyl (eg, -CH 3 , ), C 1-6 haloalkyl (e.g., -CHF 2 , -CH 2 F, -CH 2 Cl, -CF 3 , -CH 2 CF 3 , -CH 2 CH 2 F), C 1-6 hydroxyalkyl (e.g., ), C 1-6 alkoxy (e.g. ), C 1-6 haloalkoxy (e.g., -OCF 3 ), C 1-6 Aminoalkyl (e.g. ), C 1-6 alkylamino (e.g. ), C 1-6 alkylaminoalkyl (e.g. ), -C(O)N(C 0-6 alkyl)(C 0-6 alkyl)(e.g. ), -N(C 0-6 alkyl)C(O)(C 0-6 alkyl) (e.g. ), -SO 2 (C 0-6 alkyl) (e.g. ), -NH-SO 2 (C 0-6 alkyl) (e.g. ), -SO 2 -N(C 0-6 alkyl)(C 0-6 alkyl)(e.g. ), C 3-6 cycloalkyl (e.g. ), C 4-8 cycloalkylalkyl (e.g. ), substituted or unsubstituted 4- to 6-membered heterocyclic group (e.g. ), saturated heterocycloalkylalkyl (e.g. ),

More preferably, Y2 is selected from:
The compound according to any one of claims 1 to 6, characterized in that Y 2 is

Preferably, R 6 is selected from: H, halogen (e.g., F, Cl), -CN, -NO 2 , -OH, -NH 2 , C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 aminoalkyl, C 1-3 alkylamino;

More preferably, Y2 is selected from:
The compound according to claim 1, characterized in that the compound has the following structure:

Wherein, R 1 ' is one or more independent substituents on the benzene ring, which have the definition of R 1 ;

Y1 is a substituted or unsubstituted arylene group or a substituted or unsubstituted heteroarylene group;

Preferably, the compound has the following structure:

or,

The compound has the following structure:

Preferably, the compound has the following structure:

or,

The compound has the following structure:

The compound has the following structure:

or,

The compound has the following structure:

Preferably, the compound has the following structure:
The compound according to claim 1, characterized in that the compound is selected from the following structures:
A pharmaceutical composition comprising the compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, deuterated compound thereof, and one or more pharmaceutically acceptable excipients.
Use of the compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, or deuterated compound thereof in the preparation of a medicament for preventing and/or treating a disease associated with MAP4K4 activity;

Preferably, the disease is selected from the group consisting of: tumors, metabolic diseases, cardiovascular diseases, inflammatory diseases, and autoimmune diseases.