KR20250135234A - Novel ALPK1 inhibitors - Google Patents

Abstract

The present invention relates to a novel ALPK1 inhibitor having the structure of formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug, or crystalline form thereof. The present invention also relates to a pharmaceutical composition comprising the novel ALPK1 inhibitor; and to its use in treating inflammation-related diseases, such as ROSAH syndrome, inflammatory bowel disease (IBD), NASH, gout, diabetes, chronic kidney disease, pancreatitis, Kawasaki disease, inflammatory skin diseases, and neurodegenerative diseases, including Alzheimer's disease.

Description

Novel ALPK1 inhibitors

The present invention relates to a novel ALPK1 inhibitor, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug, or crystalline form thereof. The present invention also relates to a pharmaceutical composition comprising the novel ALPK1 inhibitor; and its use in treating inflammation-related diseases, such as ROSAH syndrome, inflammatory bowel disease (IBD), NASH, gout, diabetes, chronic kidney disease, pancreatitis, Kawasaki disease, inflammatory skin diseases, and neurodegenerative diseases, including Alzheimer's disease.

Innate immunity plays a crucial role in host defense against infections. The mammalian cytoplasmic protein ALPK1 (alpha-kinase 1) has been identified as a novel member of the innate immune sensory system that acts as a receptor for ADP-heptose, a bacterial sugar metabolite in the LPS biosynthetic pathway ( Nature . 2018, 561(7721): 122-126). ADP-heptose is widely present in bacteria. ALPK1 consists of an N-terminal domain (NTD) and a C-terminal kinase domain (KD), which are connected by an extended unstructured region. ADP-heptose directly binds to the NTD and activates the KD, which then phosphorylates its substrate, TIFA (TRAF-interacting protein with a forkhead-associated domain). The phosphorylated TIFA oligomerizes and binds to and activates TRAF6, resulting in downstream NF-κB activation and induction of the innate immune response.

Dysregulated activation of ALPK1 can lead to many diseases and disorders. Gain-of-function mutations in ALPK1 cause the NF-κB-mediated autoinflammatory disorder ROSAH (retinal dystrophy, optic edema, splenomegaly, anhidrosis, and headache) syndrome ( Genet. Med. 2019, 21 (9): 2103-2115; J. Clin. Immunol . 2020, 40 (2): 350-358; Ann. Rheum . Dis. 2022, 81 (10): 1453-1464). Another ALPK1 gain-of-function mutation is associated with a rare skin adnexal tumor called hidradenoma or sweat gland carcinoma ( Nat. Commun . 2019, 10 (1): 2213). A rare missense variant found in the ALPK1 gene has also been reported to predispose to the development of PFAPA (periodic fever, aphthous stomatitis, pharyngitis, and cervicitis) syndrome ( Eur. J. Hum. Genet. . 2019, 27(9): 1361-1368). Genetic and bioinformatic analyses have revealed that ALPK1 is associated with various inflammatory diseases such as inflammatory bowel disease (IBD), NASH, gout, diabetes, chronic kidney disease, pancreatitis, Kawasaki disease, inflammatory skin diseases, and neurodegenerative diseases including Alzheimer's disease ( Nat.Commun. 2018, 9 (1): 3797; ; Int.J.Epidemiol. 2013, 42 (2): 466-474; Biomed.Rep . 2013, 1 (6): 940-944; Biomed.Rep . 2015, 3 (3): 347-354; Sci.Rep . 2016, 6: 25740; J.Med.Genet . 2013, 50 (6): 410-418; Front.Immunol . 2021, 12: 705751; Nat.Commun . 2019, 10 (1): 2213; J.Bone.Miner.Res . 2022, 37 (10): 1973-1985; Int.Immunopharmacol . 2022, 113 (Pt A): 109330). The association between ALPK1 and cancer has been actively studied in relation to the development or progression of gastric cancer, breast cancer, oral cancer, lung cancer, colon cancer, as well as lymphoblastic leukemia ( Sci.Rep . 2016, 6: 27350; Oncotarget . 2016, 7 (50): 83278-83293; Am.J.Pathol . 20199, 189 (1): 190-199; Gut.Microbes . 2022, 144 (1): 2038852).

Currently, there are no approved ALPK1 inhibitors. While other immunosuppressants and kinase inhibitors have been approved for clinical use in the diseases listed above, new treatment options remain urgently needed.

The present invention provides compounds of formula (I) and subformulae (II), (II-1), (II-2), (III-1), (III-2), (III-3) and (IV) described herein, which are inhibitors of ALPK1 activity, and compositions and methods thereof for treating inflammation-related diseases.

In one aspect, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug, or crystalline form thereof:

In the above chemical formula,

M ₁ is selected from CR ₁ and N;

M ₂ is selected from CR ₂ and N;

M ₃ is selected from CR ₃ and N;

M ₄ is selected from CR ₄ and N;

L is selected from chemical bonds, -O-, -S-, and -NH-;

Y is -C(O)-, -C(S)-, -C(N-OH)-, -S(O)-, -S(O) ₂ - and is selected from;

Z is -C(R _2s )(R _3s )- or -N(R _2s )-;

Ring A is selected from C _3-6 cycloalkyl, 4-6 membered heterocyclyl, phenyl and 5-10 membered heteroaryl, preferably phenyl or 5-9 membered heteroaryl;

At this time, R _a is selected from H, D, halo, oxo, CN, NO ₂ , NH ₂ , -C _0-6 alkylene-OH, -C(O)OR _x , -C(O)NR _{y R z ,} -S ₍ O)NR _y R _z , -S(O) ₂ NR y R z , C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, C _2-6 haloalkynyl, C _3-6 cycloalkyl, 4-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl and amino protecting group, which is optionally substituted with 1, 2 or 3 halo, oxo, OR _x , NR _y R _z , C _1-6 alkyl or C _1-6 haloalkyl. m=0, 1, 2, 3, 4 or 5; or two adjacent _{R a} form phenyl or a 5- to 6-membered heteroaryl together with the atoms to which they are connected;

R ₁ is selected from H, D, halo, CN, OR _x , NR _y R _z , C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxyl, C _1-6 haloalkoxyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, C _2-6 haloalkynyl, C _3-8 cycloalkyl and 4- to 10-membered heterocyclyl;

R ₂ is selected from H, D, halo, CN, -C _0-6 alkylene-OH, -C _0-6 alkylene-NH ₂ , -C(O)C _1-6 alkyl, -C(O)C _1-6 haloalkyl, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxyl, C _1-6 haloalkoxyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, C _2-6 haloalkynyl, -TC _3-8 cycloalkyl, -T-4 to 10 membered heterocyclyl, -TC _6-10 aryl and -T-5 to 10 membered heteroaryl, which is optionally selected from 1, 2, 3, 4 or 5 CN, halo, oxo, -C _1-6 alkylene-OH, C Substituted with _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl or 5-6 membered heterocyclyl;

Here, T is a chemical bond, -O-, -S- or -NH-;

R ₃ is selected from H, D, halo, CN, -C _0-6 alkylene-OH, -C _0-6 alkylene-NH ₂ , C _1-6 alkyl and C _1-6 haloalkyl;

R ₄ is selected from H, D, halo, C _1-6 alkyl and C _1-6 haloalkyl;

Alternatively, R ₁ and R ₂ together with the carbon atom to which they are connected form C _5-6 cycloalkyl, 5-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, which optionally comprises 1, 2 or 3 halo, CN, C _1-6 alkyl, C _1-6 haloalkyl, -C(O)H, -C(O)C _1-6 alkyl, -C(O)C _1-6 haloalkyl, C _2-6 alkenyl, C 2-6 haloalkenyl, C _2-6 alkynyl, C _2-6 haloalkynyl or C _2-6 alkynyl-substituted phenyl, preferably 1, 2 or 3 halo, CN, C _1-6 alkyl, C _1-6 haloalkyl, -C(O)C _1-6 alkyl, -C(O)C _{1-6 haloalkyl} , substituted with C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, C _2-6 haloalkynyl, or C _2-6 alkynyl-substituted phenyl;

Alternatively, R ₂ and R ₃ together with the carbon atoms to which they are connected form C _5-6 cycloalkyl, 5-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, which are optionally substituted with 1, 2, 3 or 4 halo, C _1-6 alkyl, C _1-6 haloalkyl, -C _1-6 alkylene-C _1-6 alkoxyl, -C _{1-6 alkylene-C 1-6 haloalkoxyl} , -C(O)C _1-6 alkyl or -C(O)C _1-6 haloalkyl;

R _1s is selected from H, D, -C _0-6 alkylene-OR _x , -C _0-6 alkylene-NR _y R _z , C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _{2-6 alkynyl, C 2-6 haloalkynyl} , C _3-6 cycloalkyl and phenyl;

R _2s is selected from H, D, C _1-6 alkyl, C _1-6 haloalkyl and C(R _2s1 )(R _2s2 )(R _2s3 );

At this time, R _2s1 is selected from H, D, -C _0-6 alkylene-OR _x , -C _0-6 alkylene-NR _y R _z , C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, C _2-6 haloalkynyl and C _3-6 cycloalkyl;

R _2s2 is selected from H, D, -C _0-6 alkylene-OH, C _1-6 alkyl and C _1-6 haloalkyl;

R _2s3 is C _1-6 alkyl or C _1-6 haloalkyl;

Alternatively, R _2s1 and R _2s2 together with the carbon atoms to which they are connected form a C _3-6 cycloalkyl;

Alternatively, R _2s2 and R _2s3 together with the atoms to which they are connected form a C _3-6 cycloalkyl or a 4- to 6-membered heterocyclyl, which is optionally substituted with 1 or 2 halo;

Alternatively, R _2s1 , R _2s2 and R _2s3 together with the atoms to which they are connected form a C _4-8 bridged bicycloalkyl (optionally substituted with 1 or 2 halo, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl and C _2-6 haloalkynyl), or a 4- to 8-membered bridged heterocyclyl;

or R _1s and R _2s3 are linked to form C _2-6 alkylene, which is optionally substituted with 1, 2 or 3 halo, OR _x , NR _y R _z , C _1-6 alkyl or C _1-6 haloalkyl;

R _3s is selected from H, D, C _1-6 alkyl and C _1-6 haloalkyl;

Alternatively, R _2s and R _3s together with the carbon atoms to which they are connected form a C _3-6 cycloalkyl or a 4- to 6-membered heterocyclyl, which is optionally substituted with 1 or 2 halo, C _1-6 alkyl or C _1-6 haloalkyl;

Alternatively, R _1s and R _2s together with the nitrogen atom to which they are connected form a 4- to 6-membered heterocyclyl, which is optionally substituted with 1 or 2 halo, C _1-6 alkyl or C _1-6 haloalkyl;

Alternatively, R _1s , R _2s and R _3s together with the carbon atoms to which they are connected form a C _4-8 bridged bicycloalkyl (which is optionally substituted with 1 or 2 halo, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl and C _2-6 haloalkynyl), or to form;

At this time, Y ₁ is CR ₁₁ or N;

Y ₂ is CR ₁₂ or N;

R ₁₁ and R ₁₃ are independently selected from H, D, C _1-6 alkyl and C _1-6 haloalkyl;

R ₁₂ is selected from H and D;

R _x , R _y and R _z are independently selected from H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, C _2-6 haloalkynyl, C _3-8 cycloalkyl and 4- to 6-membered heterocyclyl; or R _y and R _z together with the nitrogen atom to which they are connected form a 4- to 6-membered heterocyclyl;

The above-mentioned atoms may be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated.

In another aspect, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof.

In the above chemical formula,

M ₁ is selected from CR ₁ and N;

M ₂ is selected from CR ₂ and N;

M ₃ is selected from CR ₃ and N;

M ₄ is selected from CR ₄ and N;

L is selected from chemical bonds, -O-, -S-, and -NH-;

Y is -C(O)-, -C(S)-, -C(N-OH)-, -S(O)-, -S(O) ₂ - and is selected from;

Z is -C(R _2s )(R _3s )- or -N(R _2s )-;

Ring A is selected from phenyl and 5- to 9-membered heteroaryl;

wherein R _a is selected from H, D, halo, CN, NO ₂ , NH ₂ , -C _0-6 alkylene-OH, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C 2-6 haloalkenyl, C _2-6 alkynyl, _{C 2-6 haloalkynyl} and amino protecting group, and m=0, 1, 2, 3, 4 or 5; or two adjacent R _a together with the atoms to which they are connected form phenyl or a 5- to 6-membered heteroaryl;

R ₁ is selected from H, D, halo, OR _x , NR _y R _z , C _1-6 alkyl, C _1-6 haloalkyl, C 1-6 alkoxyl, C _1-6 haloalkoxyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, C _2-6 haloalkynyl, C _3-8 cycloalkyl and 4- to 10-membered heterocyclyl _;

R ₂ is selected from H, D, halo, CN, -C _0-6 alkylene-OH, -C _0-6 alkylene-NH ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxyl, C _1-6 haloalkoxyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, C _2-6 haloalkynyl, -TC _3-8 cycloalkyl, -T-4 to 10 membered heterocyclyl, -TC _6-10 aryl and -T-5 to 10 membered heteroaryl, which is optionally selected from 1, 2, 3, 4 or 5 CN, halo, oxo, -C _1-6 alkylene-OH, C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl or 5 membered substituted with a 6-membered heterocyclyl;

Here, T is a chemical bond, -O-, -S- or -NH-;

R ₃ is selected from H, D, halo, CN, -C _0-6 alkylene-OH, -C _0-6 alkylene-NH ₂ , C _1-6 alkyl and C _1-6 haloalkyl;

R ₄ is selected from H, D, halo, C _1-6 alkyl and C _1-6 haloalkyl;

Alternatively, R ₁ and R ₂ together with the carbon atoms to which they are connected form a C _5-6 cycloalkyl, a 5-6 membered heterocyclyl, phenyl or a 5-6 membered heteroaryl, which is optionally substituted with 1, 2 or 3 halo, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _{2-6 haloalkenyl, C 2-6 alkynyl} , C _2-6 haloalkynyl, or C _2-6 alkynyl-substituted phenyl;

Alternatively, R ₂ and R ₃ together with the carbon atoms to which they are connected form a C _5-6 cycloalkyl or a 5- to 7-membered heterocyclyl, which is optionally substituted with 1, 2, 3 or 4 halo, C _1-6 alkyl, C _1-6 haloalkyl, -C _1-6 alkylene-C _1-6 alkoxyl, -C _1-6 alkylene-C _1-6 haloalkoxyl, -C(O)C _1-6 alkyl or -C(O)C _1-6 haloalkyl;

R _1s is selected from H, D, -C _0-6 alkylene-OR _x , -C _0-6 alkylene-NR _y R _z , C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _{2-6 alkynyl, C 2-6 haloalkynyl} , C _3-6 cycloalkyl and phenyl;

R _2s is selected from H, D, C _1-6 alkyl, C _1-6 haloalkyl and C(R _2s1 )(R _2s2 )(R _2s3 );

At this time, R _2s1 is selected from H, D, -C _0-6 alkylene-OR _x , -C _0-6 alkylene-NR _y R _z , C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, C _2-6 haloalkynyl and C _3-6 cycloalkyl;

R _2s2 is selected from H, D, -C _0-6 alkylene-OH, C _1-6 alkyl and C _1-6 haloalkyl;

R _2s3 is C _1-6 alkyl or C _1-6 haloalkyl;

Alternatively, R _2s2 and R _2s3 together with the atoms to which they are connected form a C _3-6 cycloalkyl or a 4- to 6-membered heterocyclyl, which is optionally substituted with 1 or 2 halo;

Alternatively, R _2s1 and R _2s3 together with the atoms to which they are connected form a C _4-8 bridged bicycloalkyl or a 4- to 8-membered bridged heterocyclyl; or

or R _1s and R _2s3 are linked to form C _2-6 alkylene, which is optionally substituted with 1, 2 or 3 halo, OR _x , NR _y R _z , C _1-6 alkyl or C _1-6 haloalkyl;

R _3s is selected from C _1-6 alkyl and C _1-6 haloalkyl;

Alternatively, R _2s and R _3s together with the carbon atoms to which they are connected form a C _3-6 cycloalkyl or a 4- to 6-membered heterocyclyl, which is optionally substituted with 1 or 2 halo, C _1-6 alkyl or C _1-6 haloalkyl;

Alternatively, R _1s and R _2s together with the nitrogen atom to which they are connected form a 4- to 6-membered heterocyclyl, which is optionally substituted with 1 or 2 halo, C _1-6 alkyl or C _1-6 haloalkyl;

Alternatively, R _1s , R _2s and R _3s together with the carbon atoms to which they are connected may be C _4-8 bridged bicycloalkyl or to form;

At this time, Y ₁ is CR ₁₁ or N;

Y ₂ is CR ₁₂ or N;

R ₁₁ and R ₁₃ are independently selected from H, D, C _1-6 alkyl and C _1-6 haloalkyl;

R ₁₂ is selected from H and D;

R _x , R _y and R _z are independently selected from H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, C _2-6 haloalkynyl, C _3-8 cycloalkyl and 4- to 6-membered heterocyclyl; or R _y and R _z together with the nitrogen atom to which they are connected form a 4- to 6-membered heterocyclyl;

The above-mentioned atoms may be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated.

In another aspect, the present invention provides a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotopic variant, prodrug, or crystalline form thereof; a pharmaceutically acceptable excipient(s); and optionally, one or more other therapeutic agents.

In another aspect, the present invention provides a kit comprising a first container comprising a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug, or crystalline form thereof; and optionally, a second container comprising one or more other therapeutic agents; and optionally, a third container comprising pharmaceutically acceptable excipient(s) for diluting or suspending the compound and/or other therapeutic agent(s).

In another aspect, the present invention provides the use of a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotopic variant, prodrug or crystalline form thereof, in the manufacture of a medicament for treating an immune and/or inflammatory disease, disorder or condition associated with excessive or inappropriate ALPK1-dependent inflammatory signaling.

In another aspect, the present invention provides a compound as described herein, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, for use in treating an immune and/or inflammatory disease, disorder or condition associated with excessive or inappropriate ALPK1-dependent inflammatory signaling.

In another aspect, the present invention provides a method of treating an immune and/or inflammatory disease, disorder or condition associated with excessive or inappropriate ALPK1-dependent inflammatory signaling, the method comprising administering to a subject in need thereof a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof.

In another aspect, the disease, disorder or condition is selected from sepsis, cancer (including lung cancer, colon cancer and oral squamous cell carcinoma), systemic lupus erythematosus, hidradenoma, hidradenomatosis, Kawasaki disease, ROSAH (retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis and migraine) syndrome, PFAPA (periodic fevers, aphthous stomatitis, pharyngitis and adenitis) syndrome.

Chemical definition

Definitions and chemical terms for specific functional groups are explained in more detail below.

When a range of values is listed, it is intended to include each value and any subranges within that range. For example, "C _1-6 alkyl" is intended to include C ₁ , C ₂ , C ₃ , C ₄ , C ₅ , C ₆ , C _1-6 , C _1-5 , C _1-4 , C _1-3 , C _1-2 , C _2-6 , C _2-5 , C _2-4 , C _2-3 , C _3-6 , C _3-5 , C _3-4 , C _4-6 , C _4-5 , and C _5-6 alkyl.

"C _1-6 alkyl" refers to a radical of a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms. In some embodiments, C _1-4 alkyl is preferred. Examples of C _1-6 alkyl include methyl (C ₁ ), ethyl (C ₂ ), n-propyl (C ₃ ), iso-propyl (C ₃ ), n-butyl (C ₄ ), tert-butyl (C ₄ ), sec-butyl (C ₄ ), iso-butyl (C ₄ ), n-pentyl (C ₅ ), 3-pentyl (C ₅ ), pentyl (C ₅ ), neopentyl (C ₅ ), 3-methyl-2-butyl (C ₅ ), tert-pentyl (C ₅ ), and n-hexyl (C ₆ ). The term "C _1-6 alkyl" also includes heteroalkyl groups in which one or more (e.g., one, two, three, or four) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, and phosphorus). The alkyl group may be optionally substituted with one or more substituents, e.g., one to five substituents, one to three substituents, or one substituent. Common abbreviations for alkyl include Me(-CH ₃ ), Et(-CH ₂ CH ₃ ), iPr(-CH(CH ₃ ) ₂ ), nPr(-CH ₂ CH ₂ CH ₃ ), n-Bu(-CH ₂ CH ₂ CH ₂ CH ₃ ), or i-Bu(-CH ₂ CH(CH ₃ ) ₂ ).

"C _2-6 alkenyl" means a radical of a straight or branched chain hydrocarbon group having 2 to 6 carbon atoms and at least one carbon-carbon double bond. In some embodiments, C _2-4 alkenyl is preferred. Examples of C _2-6 alkenyl include vinyl (C ₂ ), 1-propenyl (C ₃ ), 2-propenyl (C ₃ ), 1-butenyl (C ₄ ), 2-butenyl (C ₄ ), butadienyl (C ₄ ), pentenyl (C ₅ ), pentadienyl (C ₅ ), hexenyl (C ₆ ), and the like. The term "C _2-6 alkenyl" also includes heteroalkenyl, wherein one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by a heteroatom (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). The alkenyl group may be optionally substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

"C _2-6 alkynyl" refers to a radical of a straight or branched chain hydrocarbon group having 2 to 6 carbon atoms, at least one carbon-carbon triple bond, and optionally one or more carbon-carbon double bonds. In some embodiments, C _2-4 alkynyl is preferred. Examples of C _2-6 alkynyl include, but are not limited to, ethynyl (C ₂ ), 1-propynyl (C ₃ ), 2-propynyl (C ₃ ), 1-butynyl (C ₄ ), 2-butynyl (C ₄ ), pentynyl (C ₅ ), hexynyl (C ₆ ), and the like. The term "C _2-6 alkynyl" also includes heteroalkynyl, wherein one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by a heteroatom (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). The alkynyl group may be substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

"C _1-6 alkylene" means a divalent group of "C _1-6 alkyl" as defined above. In particular, "C _1-6 alkylene" means a divalent group formed by removing another hydrogen of C _1-6 alkyl, and may be substituted or unsubstituted alkylene. In some embodiments, C _2-6 alkylene, C _1-4 alkylene, and C _2-3 alkylene are particularly preferred. Unsubstituted alkylene groups include, but are not limited to, methylene (-CH ₂ -), ethylene (-CH ₂ CH ₂ -), propylene (-CH ₂ CH ₂ CH ₂ -), butylene (-CH ₂ CH ₂ CH ₂ CH ₂ -), pentylene (-CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ -), hexylene (-CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ -), and the like. Examples of substituted alkylene groups, such as those substituted with one or more alkyl (methyl) groups, include, but are not limited to, substituted methylene (-CH(CH ₃ )-, -C(CH ₃ ) ₂ -), substituted ethylene (-CH(CH ₃ )CH ₂ -, -CH _{2 CH} (CH ₃ )-, -C(CH ₃ ) 2 CH ₂ -, -CH ₂ C(CH ₃ ) ₂ -), substituted propylene (-CH(CH ₃ )CH ₂ CH ₂ -, -CH ₂ CH(CH _{3 )} CH _{2 -} , -CH ₂ CH ₂ CH(CH _{3 ) -} , -C(CH ₃ ) ₂ CH ₂ CH ₂ -, -CH ₂ C(CH 3 ) 2 CH 2 -, -CH 2 CH ₂ C(CH ₃ ) ₂ -).

"C _0-6 alkylene" includes a chemical bond and "C _1-6 alkylene". Similarly, "C _0-4 alkylene" includes a chemical bond and "C _1-4 alkylene".

"Halo" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).

"C _1-6 haloalkyl" means a "C _1-6 alkyl" as defined above substituted with one or more halogen groups. Examples include monohalogenated, dihalogenated, and polyhalogenated alkyls, as well as perhalogenated alkyls. A monohalogen substituent within such a group can have an iodine, bromine, chlorine, or fluorine atom; dihalogen substituents and polyhalogen substituents can have two or more of the same halogen atoms or a combination of different halogen atoms. In some embodiments, C _1-4 haloalkyl is particularly preferred. Examples of preferred haloalkyl groups include monofluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, and dichloropropyl. A haloalkyl group may be substituted at any available attachment point, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

Similarly, "C _2-6 haloalkenyl" and "C _2-4 haloalkenyl" refer to the aforementioned "C _2-6 alkenyl" and "C _2-4 alkenyl" substituted with one or more halogen groups. "C _2-6 haloalkynyl" and "C _2-4 haloalkynyl" refer to the aforementioned "C _2-6 alkynyl" and "C _2-4 alkynyl" substituted with one or more halogen groups.

"C _1-6 alkoxy" refers to a -OC _1-6 alkyl radical, and "C _1-4 alkoxy" refers to a -OC _1-4 alkyl radical (e.g., -OCH ₃ ). "C _1-6 haloalkoxy" refers to a -OC _1-6 haloalkyl radical, and "C _1-4 haloalkoxy" refers to a -OC _1-4 haloalkyl radical (e.g., -OCF ₃ ).

"C _3-8 cycloalkyl" refers to a radical of a non-aromatic cyclic hydrocarbon group having 3 to 8 ring carbon atoms and 0 heteroatoms. The term cycloalkyl may include one or more double bonds or triple bonds, as long as it is non-aromatic. In some embodiments, C _3-6 cycloalkyl is particularly preferred. In some embodiments, C _5-6 cycloalkyl is particularly preferred. In some embodiments, C _4-6 cycloalkyl is particularly preferred. In some embodiments, C _3-5 cycloalkyl is particularly preferred. In some embodiments, C _3-4 cycloalkyl is particularly preferred. Cycloalkyl also includes ring systems in which a cycloalkyl as described herein is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the cycloalkyl ring, and even in such cases, the number of carbon atoms represents the number of carbon atoms in the cycloalkyl system. Cycloalkyl may be substituted with one or more substituents, for example, with 1 to 5 substituents, with 1 to 3 substituents, or with 1 substituent.

Exemplary cycloalkyl groups include, but are not limited to, cyclopropyl (C ₃ ), cyclopropenyl (C ₃ ), cyclobutyl (C ₄ ), cyclobutenyl (C ₄ ), cyclopentyl (C ₅ ), cyclopentenyl (C ₅ ), cyclohexyl (C ₆ ), cyclohexenyl (C ₆ ), cyclohexadienyl (C ₆ ), cycloheptyl (C ₇ ), cycloheptenyl (C ₇ ), cycloheptadienyl (C ₇ ), cycloheptatrienyl (C ₇ ). Examples of cycloalkyl groups further include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Cycloalkyls may include multiple fused rings and/or bridged rings. Non-limiting examples of fused/bridged cycloalkyls include _C4-8 bridged bicycloalkyls, for example, bicyclo[1.1.0]butanyl, bicyclo[2.1.0]pentanyl, bicyclo[1.1.1]pentanyl, bicyclo[3.1.0]hexanyl, bicyclo[2.1.1]hexanyl, bicyclo[3.2.0]heptanyl, bicyclo[4.1.0]heptanyl, bicyclo[2.2.1]heptanyl, bicyclo[3.1.1]heptanyl, bicyclo[4.2.0]octanyl, bicyclo[3.2.1]octanyl, bicyclo[2.2.2]octanyl. Cycloalkyl also includes spirocyclic rings (e.g., a spirocyclic bicycle in which the two rings are linked by only one atom). Non-limiting examples of spirocyclic cycloalkyls include spiro[2.2]fentanyl, spiro[2.5]octanyl, spiro[3.5]nonanyl, spiro[3.5]nonanyl, spiro[3.5]nonanyl, spiro[4.4]nonanyl, spiro[2.6]nonanyl, spiro[4.5]decanyl, spiro[3.6]decanyl, spiro[5.5]undecanyl, and the like.

"4- to 10-membered heterocyclyl" refers to a radical of a 4- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. In heterocyclyls containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, as long as the valence permits. The term heterocyclyl may include one or more double bonds or triple bonds, so long as it is non-aromatic. In some embodiments, 5- to 10-membered heterocyclyls are preferred, which are radicals of a 5- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms. In some embodiments, a 5- to 7-membered heterocyclyl is preferred, which is a radical of a 5- to 7-membered non-aromatic ring system having a ring carbon atom and 1 to 5 ring heteroatoms. In some embodiments, a 5- to 6-membered heterocyclyl is more preferred, which is a radical of a 5- to 6-membered non-aromatic ring system having a ring carbon atom and 1 to 3 ring heteroatoms. In some embodiments, a 4- to 6-membered heterocyclyl is preferred, which is a radical of a 4- to 6-membered non-aromatic ring system having a ring carbon atom and 1 to 3 ring heteroatoms. Heterocyclyl also includes ring systems wherein the aforementioned heterocyclyl is fused with one or more cycloalkyl groups, wherein the point of attachment is on the cycloalkyl ring, or wherein the aforementioned heterocyclyl is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring; Even in these cases, the number of ring members represents the number of ring members in the heterocyclyl ring system. Examples of 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, aziridinyl, oxiranyl, and thiorenyl. Examples of 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Examples of 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Examples of 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Examples of 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Examples of 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidyl, tetrahydropyranyl, dihydropyridyl, and thianyl. Examples of 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Examples of 6-membered heterocyclyl groups containing 3 heteroatoms include, but are not limited to, triazinanyl. Examples of 7-membered heterocyclyl groups containing 1 heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Examples of 5-membered heterocyclyl groups fused to a _C6 aryl (also referred to herein as 5,6-bicyclic heterocyclyl) include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazolinonyl, and the like. Examples of 6-membered heterocyclyl groups fused to a _C6 aryl (also referred to herein as 6,6-bicyclic heterocyclyl) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like. The heterocyclyl may be substituted with one or more substituents, for example, with 1 to 5 substituents, with 1 to 3 substituents, or with 1 substituent.

Specific examples of preferred heterocyclyl groups include pyrrolinyl, imidazolidinyl, pyrazolidinyl, tetrahydropyranyl, dihydropyranyl, dihydrofuranyl, thiazolidinyl, dihydrothiazolyl, 2,3-dihydro-benzo[1,4]dioxole, indolinyl, isoindolinyl, dihydrobenzothiophene, dihydrobenzofuranyl, isodihydrobenzopyranyl, dihydrobenzopyranyl, 1,2-dihydroisoquinoline, 1,2,3,4-tetrahydroisoquinoline, 1,2,3,4-tetrahydroquinoline, 2,3,4,4a,9,9a-hexahydro-1H-3-azafluorene, 5,6,7-Trihydro-1,2,4-triazolo[3,4-a]isoquinolyl, 3,4-dihydro-2H-benzo[l,4]oxazinyl, benzo[l,4]dioxole, 2,3-dihydro-lH-lk'-benzo[d]isothiazol-6-yl, 2,3-di-benzo[l,4]dioxinyl, dihydrobenzofuran, 2-oxoaziridin-1-yl, 2-oxoazetidin-1-yl, 2-oxopyrrolidin-1-yl, 2-oxopiperidin-1-yl, 2-oxoazepan-1-yl, 2-oxoazocan-1-yl, 2-oxoazonan-1-yl, 2-oxoazecan-1-yl, aziridine, azetidine, pyrrolidinyl, Includes piperidine, azepane, ajocan, azonane, azecan, piperidyl, piperazinyl, morpholinyl, diazaspiro[3.3]heptane, diazaspiro[3.4]octane, diazaspiro[3.5]nonane, diazaspiro[4.4]nonane, diazaspiro[4.5]decane and diazaspiro[5.5]undecane.

Additional examples of heterocyclyl groups include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, and the like. Heterocyclyl groups may contain multiple fused and bridged rings. Non-limiting examples of fused/bridged heterocyclyls include: 2-azabicyclo[1.1.0]butanyl, 2-azabicyclo[2.1.0]fentanyl, 2-azabicyclo[1.1.1]fentanyl, 3-azabicyclo[3.1.0]hexanyl, 5-azabicyclo[2.1.1]hexanyl, 3-azabicyclo[3.2.0]heptanyl, octahydrocyclopenta[c]pyrrolyl, 3-azabicyclo[4.1.0]heptanyl, 7-azabicyclo[2.2.1]heptanyl, 6-azabicyclo[3.1.1]heptanyl, 7-azabicyclo[4.2.0]octanyl, 2-Azabicyclo[2.2.2]octanyl, 3-Azabicyclo[3.2.1]octanyl, 2-oxabicyclo[1.1.0]butanyl, 2-oxabicyclo[2.1.0]fentanyl, 2-oxabicyclo[1.1.1]fentanyl, 3-oxabicyclo[3.1.0]hexanyl, 5-oxabicyclo[2.1.1]hexanyl, 3-oxabicyclo[3.2.0]heptanyl, 3-oxabicyclo[4.1.0]heptanyl, 7-oxabicyclo[2.2.1]heptanyl, 6-oxabicyclo[3.1.1]heptanyl, 7-oxabicyclo[4.2.0]octanyl, 2-Oxabicyclo[2.2.2]octanyl, 3-oxabicyclo[3.2.1]octanyl, etc. Heterocyclyl also includes spirocyclic rings (e.g., a spirocyclic bicyclic ring in which the two rings are connected by a single atom). Non-limiting examples of spirocyclic heterocyclyls include 2-azaspiro[2.2]fentanyl, 4-azaspiro[2.5]octanyl, 1-azaspiro[3.5]nonanyl, 2-azaspiro[3.5]nonanyl, 7-azaspiro[3.5]nonanyl, 2-azaspiro[4.4]nonanyl, 6-azaspiro[2.6]nonanyl, 1,7-diazaspiro[4.5]decanyl, 7-azaspiro[4.5]decanyl, 2,5-diazaspiro[3.6]decanyl, 3-azaspiro[5.5]undecanyl, 2-oxaspiro[2.2]fentanyl, 4-oxaspiro[2.5]octanyl, 1-Oxaspiro[3.5]nonanyl, 2-oxaspiro[3.5]nonanyl, 7-oxaspiro[3.5]nonanyl, 2-oxaspiro[4.4]nonanyl, 6-oxaspiro[2.6]nonanyl, 1,7-dioxaspiro[4.5]decanyl, 2,5-dioxaspiro[3.6]decanyl, 1-oxaspiro[5.5]undecanyl, 3-oxaspiro[5.5]undecanyl, 3-oxa-9-azaspiro[5.5]undecanyl, etc. The term "saturated" as used herein means that there are only single bonds between ring constituent atoms, and the remaining available valencies are occupied by hydrogen and/or other substituents as defined herein.

"C _6-10 aryl" means a radical of a monocyclic or polycyclic (e.g., bicyclic) 4n+2 aromatic ring system (e.g., having 6 or 10 shared π electrons in a cyclic arrangement) having 6 to 10 ring carbon atoms and 0 heteroatoms. In some embodiments, an aryl group has 6 ring carbon atoms ("C ₆ aryl"; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C ₁₀ aryl"; e.g., naphthyl, such as 1-naphthyl and 2-naphthyl). An aryl group includes ring systems in which the above-described aryl ring is fused to one or more cycloalkyl or heterocyclyl groups, wherein the point of attachment is on the aryl ring, even in this case the number of carbon atoms represents the number of carbon atoms in the aryl ring system. An aryl may be substituted with one or more substituents, for example, with 1 to 5 substituents, with 1 to 3 substituents, or with 1 substituent.

"5- to 10-membered heteroaryl" refers to a radical of a 5- to 10-membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms (e.g., having 6 or 10 shared π electrons in a cyclic arrangement), wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, as long as the valence permits. Heteroaryl bicyclic systems may contain one or more heteroatoms in one or both rings. Heteroaryl also includes ring systems in which the aforementioned heteroaryl rings are fused to one or more cycloalkyl or heterocyclyl groups, and the point of attachment is on the heteroaryl ring. Even in such cases, the number of carbon atoms represents the number of carbon atoms in the heteroaryl ring system. In some embodiments, a 5-9 membered heteroaryl group that is a radical of a 5-9 membered monocyclic or bicyclic 4n+2 aromatic ring system having a ring carbon atom and 1 to 4 ring heteroatoms is particularly preferred. In some embodiments, a 5-6 membered heteroaryl group that is a radical of a 5-6 membered monocyclic or bicyclic 4n+2 aromatic ring system having a ring carbon atom and 1 to 4 ring heteroatoms is particularly preferred. In some embodiments, a 5-membered heteroaryl group that is a radical of a 5-6 membered monocyclic or bicyclic 4n+2 aromatic ring system having a ring carbon atom and 1 to 4 ring heteroatoms is particularly preferred. Examples of 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furyl, and thienyl. Examples of 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Examples of 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl), and thiadiazolyl. Examples of 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Examples of 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridyl. Examples of 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Examples of 6-membered heteroaryl groups containing 3 or 4 heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Examples of 7-membered heteroaryl groups containing 1 heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Examples of 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl. Examples of 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolyl, isoquinolyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. The heteroaryl may be substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

Specific examples of preferred heteroaryl groups include pyrrolyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl (4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, pyranyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, oxazolyl, isoxazolyl, oxazolyl (1,2,4-oxazolyl, 1,3,4-oxazolyl, 1,2,5-oxazolyl, thiazolyl, thiadiazolyl (1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl).

Additional examples of heteroaryl include thienyl, pyridinyl, furyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl, benzothienyl, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl, cinnolinyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, purinyl, thienopyridinyl, pyrido[2,3- d ]pyrimidinyl, pyrrolo[2,3- b ]pyridinyl, quinazolinyl, quinolinyl, thieno[2,3- c ]pyridinyl, pyrazolo[3,4- b ]pyridinyl, pyrazolo[3,4- c ]pyridinyl, pyrazolo[4,3- c ]pyridinyl, pyrazolo[4,3- b ]pyridinyl, tetrazolyl, chromanyl, 2,3-dihydrobenzo[ b ][1,4]dioxinyl, benzo[ d ][1,3]dioxolyl, benzo[ d ]thiazolyl, 2,3-dihydrobenzofuran, tetrahydroquinolinyl, 2,3-dihydrobenzo[ b ][1,4]oxathinyl, indolinyl, isoindolinyl, etc. In some embodiments, heteroaryl is selected from thienyl, pyridinyl, furyl, pyrazolyl, imidazolyl, isoindolinyl, pyranyl, pyrazinyl, and pyrimidinyl.

In this application, when a ring is described as "aromatic", it means that the ring has a continuous and delocalized π-electron system. Typically, the number of π-electrons present out of the plane is given by Hückel's rule (H It conforms to the ckel rule (4n+2).

"Oxo" is represented by =O.

To avoid confusion, unless otherwise specified, for rings and cyclic groups (e.g., aryls, heteroaryls, heterocyclyls, heterocycloalkenyls, cycloalkenyls, cycloalkyls, etc., as described herein) containing a sufficient number of ring atoms to form bicyclic or higher-order ring systems (e.g., tricyclic, polycyclic ring systems), such rings and cyclic groups are defined as those in which the point of fusion is (i) located on adjacent ring atoms (e.g., a [xx0] ring system, where 0 indicates 0 atomic bridging (e.g., )); (ii) located on a single ring atom (spiro-fused ring system) (e.g. ), or (iii) a bridged ring system (where all bridge lengths are > 0) located on the ring atoms of a continuous array (e.g., ) encompasses those with fusion rings, including fusion rings.

Additionally, the atoms constituting the compounds of the embodiments of the present invention are intended to include all isotopic forms of such atoms. As used herein, isotopes include atoms having the same atomic number but different mass numbers. As general examples, but not limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include ^13C and ^14C .

Additionally, the compounds disclosed herein, generally or specifically, are intended to include all tautomeric forms. Thus, for example, Compounds containing a portion Also included are tautomeric forms containing a moiety. Similarly, a pyridinyl or pyrimidinyl moiety described as optionally substituted with a hydroxyl moiety includes a pyridone or pyrimidone tautomeric form.

An "amino protecting group" is used to prevent an amino group from undergoing undesirable reactions. The selection of an appropriate protecting group for a specific functional group and the appropriate conditions for protection and deprotection are well known in the art. For example, various protecting groups and their introduction and removal are described in T.W. Greene and P.G.M. Wuts, Protecting Groups in Organic Synthesis, Second Edition, Wiley, New York, 1991, and references cited herein. Representative amino protecting agents include Cbz, Boc, Fmoc, Alloc, and Teoc.

Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl as defined herein are optionally substituted groups.

Examples of substituents on a carbon atom include halogens, -CN, -NO ₂ , -N ₃ , -SO ₂ H, -SO ₃ H, -OH, -OR ^aa , -ON(R ^bb ) ₂ , -N(R ^bb ) ₂ , -N(R ^bb ) ₃ ⁺ X ^- , -N(OR ^cc )R ^bb , -SH, -SR ^aa , -SSR ^cc , -C(=O)R ^aa , -CO ₂ H, -CHO, -C(OR ^cc ) ₂ , -CO ₂ R ^aa , -OC(=O)R ^aa , -OCO ₂ R ^aa , -C(=O)N(R ^bb ) ₂ , -OC(=O)N(R ^bb ) ₂ , -NR ^bb C(=O)R ^aa , -NR ^bb CO ₂ R ^aa , -NR ^bb C(=O)N(R ^bb ) ₂ , -C(=NR ^bb )R ^aa , -C(=NR ^bb )OR ^aa , -OC(=NR ^bb )R ^aa , -OC(=NR ^bb )OR ^aa , -C(=NR ^bb )N(R ^bb ) ₂ , -OC(=NR ^bb )N(R ^bb ) ₂ , -NR ^bb C(=NR ^bb )N(R ^bb ) ₂ , -C(=O)NR ^bb SO ₂ R ^aa , -NR ^bb SO ₂ R ^aa , -SO ₂ N(R ^bb ) ₂ , -SO ₂ R ^aa , -SO ₂ OR ^aa , -OSO ₂ R ^aa , -S(=O)R ^aa , -OS(=O)R ^aa , -Si(R ^aa ) ₃ , -OSi(R ^aa ) ₃ , -C(=S)N(R ^bb ) ₂ , -C(=O)SR ^aa , -C(=S)SR ^aa , -SC(=S)SR ^aa , -SC(=O)SR ^aa , -OC(=O)SR ^aa , -SC(=O)OR ^aa , -SC(=O)R ^aa , -P(=O) ₂ R ^aa , -OP(=O) ₂ R ^aa , -P(=O)(R ^aa ) ₂ , -OP(=O)(R ^aa ) ₂ , -OP(=O)(OR ^cc ) ₂ , -P(=O) ₂ N(R ^bb ) ₂ , -OP(=O) ₂ N(R ^bb ) ₂ , -P(=O)(NR ^bb ) ₂ , -OP(=O)(NR ^bb ) ₂ , -NR ^bb P(=O)(OR ^cc ) ₂ , -NR ^bb P(=O)(NR ^bb ) ₂ , -P(R ^cc ) ₂ , -P(R ^cc ) ₃ , -OP(R ^cc ) ₂ , -OP(R ^cc ) ₃ , -B(R ^aa ) ₂ , -B(OR ^cc ) ₂ , -BR ^aa (OR ^cc ), alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl, including but not limited to, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R ^dd groups;

or two geminal hydrogens on a carbon atom are replaced by =O, =S, =NN(R ^bb ) ₂ , =NNR ^bb C(=O)R ^aa , =NNR ^bb C(=O)OR ^aa , =NNR ^bb S(=O) ₂ R ^aa , =NR ^bb or =NOR ^cc groups;

R ^aa is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl, or two R ^aa groups combine to form a heterocyclyl or heteroaryl ring, wherein alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl are each independently substituted with 0, 1, 2, 3, 4, or 5 R ^dd groups;

R ^bb is independently hydrogen, -OH, -OR ^aa , -N(R ^cc ) ₂ , -CN, -C(=O)R ^aa , -C(=O)N(R ^cc ) ₂ , -CO ₂ R ^aa , -SO ₂ R ^aa , -C(=NR ^cc )OR ^aa , -C(=NR ^cc )N(R ^cc ) ₂ , -SO ₂ N(R ^cc ) ₂ , -SO ₂ R ^cc , -SO ₂ OR ^cc , -SOR ^aa , -C(=S)N(R ^cc ) ₂ , -C(=O)SR ^cc , -C(=S)SR ^cc , -P(=O) ₂ R ^aa , -P(=O)(R ^aa ) ₂ , -P(=O) ₂ N(R ^cc ) ₂ , -P(=O)(NR ^cc ) ₂ , selected from alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl, or two R ^bb groups combine to form a heterocyclyl or heteroaryl ring, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl are each independently substituted with 0, 1, 2, 3, 4, or 5 R ^dd groups;

R ^cc is each independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl, or two R ^cc groups combine to form a heterocyclyl or heteroaryl ring, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl are each independently substituted with 0, 1, 2, 3, 4, or 5 R ^dd groups;

R ^dd are each independently halogen, -CN, -NO ₂ , -N ₃ , -SO ₂ H, -SO ₃ H, -OH, -OR ^ee , -ON(R ^ff ) ₂ , -N(R ^ff ) ₂ , -N(R ^ff ) ₃ ⁺ X ^- , -N(OR ^ee )R ^ff , -SH, -SR ^ee , -SSR ^ee , -C(=O)R ^ee , -CO ₂ H, -CO ₂ R ^ee , -OC(=O)R ^ee , -OCO ₂ R ^ee , -C(=O)N(R ^ff ) ₂ , -OC(=O)N(R ^ff ) ₂ , -NR ^ff C(=O)R ^ee , -NR ^ff CO ₂ R ^ee , -NR ^ff C(=O)N(R ^ff ) ₂ , -C(=NR ^ff )OR ^ee , -OC(=NR ^ff )R ^ee , -OC(=NR ^ff )OR ^ee , -C(=NR ^ff )N(R ^ff ) ₂ , -OC(=NR ^ff )N(R ^ff ) ₂ , -NR ^ff C(=NR ^ff )N(R ^ff ) ₂ , -NR ^ff SO ₂ R ^ee , -SO ₂ N(R ^ff) ) ₂ , -SO ₂ R ^ee , -SO ₂ OR ^ee , -OSO ₂ R ^ee , -S(=O)R ^ee , -Si(R ^ee ) ₃ , -OSi(R ^ee ) ₃ , -C(=S)N(R ^ff ) ₂ , -C(=O)SR ^ee , -C(=S)SR ^ee , -SC(=S)SR ^ee , -P(=O) ₂ R ^ee , -P(=O)(R ^ee ) ₂ , -OP(=O)(R ^ee ) ₂ , -OP(=O)(OR ^ee ) ₂ , alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl, wherein each of the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R ^gg groups, or two same-site R ^dd substituents can combine to form =O or =S;

R ^ee is each independently selected from alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, aryl, heterocyclyl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl are each independently substituted with 0, 1, 2, 3, 4, or 5 R ^gg groups;

R ^ff is each independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl, or two R ^ff groups combine to form a heterocyclyl or heteroaryl ring, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl are each independently substituted with 0, 1, 2, 3, 4, or 5 R ^gg groups;

R ^gg is independently halogen, -CN, -NO ₂ , -N ₃ , -SO ₂ H, -SO ₃ H, -OH, -OC _1-6 alkyl, -ON(C _1-6 alkyl) ₂ , -N(C _1-6 alkyl) ₂ , -N(C _1-6 alkyl) ₃ ⁺ X ^- , -NH(C _1-6 alkyl) ₂ ⁺ X ^- , -NH ₂ (C _1-6 alkyl) ⁺ X ^- , -NH ₃ ⁺ X ^- , -N(OC _1-6 alkyl)(C _1-6 alkyl), -N(OH)(C _1-6 alkyl), -NH(OH), -SH, -SC _1-6 alkyl, -SS(C _1-6 alkyl), -C(=O)(C _1-6 alkyl), -CO ₂ H, -CO ₂ (C _1-6 alkyl), -OC(=O)(C _1-6 alkyl), -OCO ₂ (C _1-6 alkyl), -C(=O)NH ₂ , -C(=O)N(C _1-6 alkyl) ₂ , -OC(=O)NH(C _1-6 alkyl), -NHC(=O)(C _1-6 alkyl), -N(C _1-6 alkyl)C(=O)(C _1-6 alkyl), -NHCO ₂ (C _1-6 alkyl), -NHC(=O)N(C _1-6 alkyl) ₂ , -NHC(=O)NH(C _1-6 alkyl), -NHC(=O)NH ₂ , -C(=NH)O(C _1-6 alkyl), -OC(=NH)(C _1-6 alkyl), -OC(=NH)OC _1-6 alkyl, -C(=NH)N(C _1-6 alkyl) ₂ , -C(=NH)NH(C _1-6 alkyl), -C(=NH)NH ₂ , -OC(=NH)N(C _1-6 alkyl) ₂ , -OC(NH)NH(C _1-6 alkyl), -OC(NH)NH ₂ , -NHC(NH)N(C _1-6 alkyl) ₂ , -NHC(=NH)NH ₂ , -NHSO ₂ (C _1-6 alkyl), -SO ₂ N(C _1-6 alkyl) ₂ , -SO ₂ NH(C _1-6 alkyl), -SO ₂ NH ₂ , -SO ₂ C _1-6 alkyl, -SO ₂ OC _1-6 alkyl, -OSO ₂ C _1-6 alkyl, -SOC _1-6 alkyl, -Si(C _1-6 alkyl) ₃ , -OSi(C _1-6 alkyl) ₃ , -C(=S)N(C _1-6 alkyl) ₂ , C(=S)NH(C _1-6 alkyl), C(=S)NH ₂ , -C(=O)S(C _1-6 alkyl), -C(=S)SC _1-6 alkyl, -SC(=S)SC _1-6 alkyl, -P(=O) ₂ (C _1-6 alkyl), -P(=O)(C _1-6 alkyl) ₂ , -OP(=O)(C _1-6 alkyl) ₂ , -OP(=O)(OC _1-6 alkyl) ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₇ carbocyclyl, C ₆ -C ₁₀ aryl, C ₃ -C ₇ heterocyclyl, C ₅ -C ₁₀ heteroaryl; or two same R ^gg substituents can combine to form =O or =S; wherein X- is a counterion.

Exemplary substituents on the nitrogen atom are hydrogen, -OH, -OR ^aa , -N(R ^cc ) ₂ , -CN, -C(=O)R ^aa , -C(=O)N(R ^cc ) ₂ , -CO ₂ R ^aa , -SO ₂ R ^aa , -C(=NR ^bb )R ^aa , -C(=NR ^cc )OR ^aa , -C(=NR ^cc )N(R ^cc ) ₂ , -SO ₂ N(R ^cc ) ₂ , -SO ₂ R ^cc , -SO ₂ OR ^cc , -SOR ^aa , -C(=S)N(R ^cc ) ₂ , -C(=O)SR ^cc , -C(=S)SR ^cc , -P(=O) ₂ R ^aa , -P(=O)(R ^aa ) ₂ , -P(=O) ₂ N(R ^cc ) ₂ , -P(=O)(NR ^cc ) ₂ , alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl, or two R ^cc groups attached to a nitrogen atom combine to form a heterocyclyl or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 R ^dd groups, wherein R ^aa , R ^bb , R ^cc and R ^dd are as described herein.

Additional definition

The present invention provides compounds that are inhibitors of ALPK1, compositions comprising the same, and methods of using the same in therapy.

The term "ALPK1" herein may be used interchangeably to refer indiscriminately to isoform 1 (Q96QP1-1) or alternative splice variant isoform 2 (Q96QP1-2) of the human sequence identified by UniProtKB-Q96QP1 (ALPK1_HUMAN).

To facilitate understanding of the disclosure herein, several additional terms are defined below. In general, the nomenclature used herein and the experimental procedures in organic chemistry, medicinal chemistry, and pharmacology described herein are well known and commonly used in the art; for example, nomenclature can be generated using software such as ChemDraw. Unless otherwise defined, all scientific and technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. All patents, applications, published applications, and other publications referred to in this specification and the appendices are incorporated herein by reference in their entirety.

Terms such as "comprising," "containing," or "having" mean not only "including but not limited to," but also "consisting of," so that a composition "comprising" X may consist only of X, or may include something additional, such as X plus Y. Additionally, it should be understood that where "comprising" or any other open-ended term is used in an embodiment, the same embodiment may also be more narrowly claimed using the intermediate term "consisting essentially of," or the closed term "consisting of." As used herein, the singular articles "a" and "an" refer to one or to more than one (i.e., at least one) of the grammatical object of the article. The term "or" is used herein to mean, and can be used interchangeably with, the term "and/or," unless the context clearly dictates otherwise.

As used herein, "immunotherapeutic" or "immunomodulator" refers to a small molecule drug, antibody, or other biologic molecule. In some embodiments, the modulator is used to suppress inhibitory immunoreceptor signals of T cells and/or other immune cells, such as dendritic cells. In some embodiments, the modulator is used to enhance and/or stimulate co-stimulatory immunoreceptor signals of T cells and/or other immune cells, such as dendritic cells. In some embodiments, biological immunomodulators include, but are not limited to, cancer vaccines, antibodies, and cytokines. In some embodiments, the antibody is a monoclonal antibody. In another aspect, the monoclonal antibody is humanized.

The terms "treat," "treating," and "treatment," in the context of treating a disease, disorder, or condition, are intended to include alleviating or eliminating the disease, disorder, or condition, or one or more symptoms associated with the disease, disorder, or condition; or slowing the progression, spread, or worsening of the disease, disorder, or condition, or one or more symptoms thereof. The beneficial effects that a subject receives from a therapeutic agent often do not result in a complete cure of the disease, disorder, or condition. In some embodiments, the terms "treat," "treating," and "treatment" include virologically curing a viral disease, disease, or condition; reducing viral shedding; reducing viral RNA load (e.g., as measured by PCR); shortening the length of a hospital stay; shortening the length of stay in an infectious disease ward and/or intensive care unit; or slowing (including stopping) the progression/onset of respiratory (or other severe) symptoms.

"Treatment of cancer" refers to one or more of the following effects: (1) some degree of inhibition, including (i) slowing and (ii) complete growth arrest, of tumor growth; (2) a reduction in the number of tumor cells; (3) maintenance of tumor size; (4) a reduction in tumor size; (5) inhibition, including (i) a reduction, (ii) a slowing, or (iii) a complete prevention, of tumor cell invasion into peripheral organs; (6) inhibition, including (i) a reduction, (ii) a slowing, or (iii) a complete prevention, of metastasis; (7) an enhancement of an anti-tumor immune response, which may lead to (i) maintenance of tumor size, (ii) a reduction in tumor size, (iii) a slowing of tumor growth, (iv) a reduction, slowing, or prevention of invasion, and/or (8) some relief of the severity or frequency of one or more symptoms associated with the disease.

The term "therapeutically effective amount" means an amount of a drug or other pharmaceutical agent (e.g., a compound disclosed herein) that will elicit a biological and/or medical response in a tissue, system, animal, or human (e.g., a subject or patient) that is sought by, for example, a researcher or clinician. The term "therapeutically effective amount" also means an amount sufficient to reduce the rate of progression of, prevent the onset of, or alleviate to some extent, one or more symptoms of the condition or disease being treated, compared to a subject (e.g., a patient) not administered such amount. The therapeutically effective amount will vary depending on the compound in question, the disease and its severity, the age, weight, etc. of the mammal to be treated, and the like. Furthermore, the therapeutically effective amount may be administered, applied, or taken once or multiple times, and is not limited to a particular formulation or route of administration.

The terms "subject or patient," as used interchangeably herein, refer to an animal, including, but not limited to, a primate (e.g., a human), a monkey, a cow, a pig, a sheep, a goat, a horse, a dog, a cat, a rabbit, a rat, or a mouse. In some embodiments, the subject to be treated by the methods and compositions of the present invention is a human. In some embodiments, the methods described herein further comprise the step of identifying (e.g., via biopsy, endoscopy, or other conventional methods known in the art) a subject (e.g., a patient) in need of such treatment. In some embodiments, the chemical entities, methods, and compositions described herein can be administered to patient populations that are resistant to certain therapeutic agents (e.g., patients resistant to checkpoint inhibitors; for example, patients with one or more immunologically refractory tumors, such as tumors with T cell deficient or exhausted T cells).

The term "vaccine" refers to a biological preparation administered to a human or animal to induce or enhance a specific immune response or protection against one or more antigens in that human or animal. In some embodiments, the vaccine is a cancer vaccine directed against one or more antigens of cancer cells.

The term "adjuvant" refers to a secondary therapeutic agent that is administered (either sequentially or simultaneously in any order) with a primary therapeutic agent to achieve some kind of complementary, synergistic, or other beneficial effect that cannot be achieved with the primary therapeutic agent alone. Adjuvants may be used in conjunction with vaccines, chemotherapy, or other therapeutic agents. Adjuvants may enhance the efficacy of the primary therapeutic agent, reduce the toxicity or side effects of the primary therapeutic agent, or provide some kind of protective function to the subject receiving the primary therapeutic agent, including, but not limited to, improving the function of the immune system.

The term "cancer," as used herein, refers to a physiological condition of a subject characterized by uncontrolled or abnormally regulated cell growth or cell death. The term "cancer" includes solid tumors and blood-borne tumors, regardless of whether they are malignant or benign.

The term "acceptable" as used herein with respect to a formulation, composition or ingredient means that it does not have a lasting detrimental effect on the overall health of the subject receiving treatment.

“API” stands for Active Pharmaceutical Ingredient.

The term "excipient" or "pharmaceutically acceptable excipient" refers to a pharmaceutically acceptable substance, composition, or vehicle, such as a liquid or solid filler, diluent, carrier, solvent, or encapsulating material. In one embodiment, each component is "pharmaceutically acceptable" in the sense that it is compatible with the other ingredients of the pharmaceutical preparation, suitable for use in contact with the tissues or organs of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problem or complication, and commensurate with a reasonable benefit/risk ratio. See, e.g., [ Remington: The Science and Practice of Pharmacy, 21st ed .; Lippincott Williams & Wilkins: Philadelphia, PA, 2005]; [ Handbook of Pharmaceutical Excipients, 6th ed.; Rowe et al. , Eds.; The Pharmaceutical Press and the American Pharmaceutical Association: 2009]; [ Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash Eds.; Gower Publishing Company: 2007]; [ Pharmaceutical Preformulation and Formulation, 2nd ed. ; Gibson Ed.; CRC Press LLC: Boca Raton, FL, 2009.

The term "pharmaceutically acceptable salt" refers to a preparation of a compound that does not cause significant irritation to the organism to which it is administered and does not impair the biological activity and properties of the compound. In some cases, the pharmaceutically acceptable salt is obtained by reacting a compound described herein with an acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. In some cases, the pharmaceutically acceptable salt is obtained by reacting a compound having an acidic group described herein with a base to form salts with organic bases such as ammonium salts, alkali metal salts such as sodium or potassium salts, alkaline earth metal salts such as calcium or magnesium salts, dicyclohexylamine, N -methyl-D-glucamine, tris(hydroxymethyl)methylamine, and salts with amino acids such as arginine, lysine, and the like, or by other methods known in the art. Pharmaceutically acceptable salts are not particularly limited as long as they can be used as medicines. Examples of salts that the compounds described herein form with bases include: salts with inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum; salts with organic bases such as methylamine, ethylamine, and ethanolamine; salts with basic amino acids such as lysine and ornithine; and ammonium salts. The salts may be acid addition salts, specifically, acid addition salts with: inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, and ethanesulfonic acid; acidic amino acids such as aspartic acid and glutamic acid.

The compounds described herein may contain one or more asymmetric centers and thus may exist in various stereoisomeric forms, such as enantiomers and/or diastereomers. For example, the compounds described herein may exist in the form of individual enantiomers, diastereomers, or geometric isomers (such as cis-isomers and trans-isomers), or in the form of mixtures of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers may be separated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or the desired isomers may be prepared by asymmetric synthesis.

Prodrugs are also encompassed within the context of the present invention. The term "prodrug," as used herein, refers to a compound that is converted in vivo into a medicinally effective active form, for example, by hydrolysis in the blood. Pharmaceutically acceptable prodrugs are described in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, A.C.S. Symposium Series, Vol. 14, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, and D. Fleisher, S. Ramon, and H. Barbra, “Improved oral drug delivery: overcoming solubility limitations by the use of prodrugs,” Advanced Drug Delivery Reviews (1996) 19(2) 115-130, each of which is incorporated herein by reference.

A prodrug is any covalently bonded carrier that releases the compound of formula (I) in vivo when administered to a patient. Prodrugs are typically prepared by modifying a functional group in such a way that the modification can be cleaved in vivo by routine manipulations to yield the parent compound. Prodrugs include, for example, compounds disclosed herein in which a hydroxy, amine, or sulfhydryl group is bonded to any group that can be cleaved to form a hydroxy, amine, or sulfhydryl group when administered to a patient. Thus, representative examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of the alcohol, mercapto, and amine functional groups of the compound of formula (I). Additionally, for carboxylic acids (-COOH), esters such as methyl esters, ethyl esters, and the like may be used. The esters themselves can be activated and/or hydrolyzed in the human body. Suitable pharmaceutically acceptable biohydrolyzable ester groups include those that readily decompose in the human body to release the parent acid or a salt thereof.

Also disclosed herein are all suitable isotopic derivatives of the compounds disclosed herein. An isotopic derivative of a compound disclosed herein is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass normally occurring in nature. Examples of isotopes that may be enumerated in the compounds disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, and chlorine, such as ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁷ O, ¹⁸ O, ¹⁸ F, ³¹ P, ³² P, ³⁵ S, and ³⁶ Cl, respectively. Certain isotopic derivatives of the compounds disclosed herein, such as radioactive isotopes of ³ H and ¹⁴ C, are also useful for tissue distribution experiments of drugs and substrates if included herein. Tritium, i.e., ³ H, and carbon-14, i.e., ¹⁴ C, are preferred isotopes due to their ease of preparation and detection. Furthermore, substitution with isotopes such as deuterium, i.e., ² H, has excellent metabolic stability, which is advantageous in some therapeutic applications, such as extending the in vivo half-life or reducing the administered dose, and may be used preferentially in some cases. Isotopic derivatives of the compounds disclosed herein can be prepared using appropriate isotopic derivatives in appropriate reagents by conventional procedures, for example, by technical methods, or by the preparation methods described in the examples below. The term "stable isotope" refers to an isotope that exists stably in nature.

The term "pharmaceutical composition" refers to a mixture of a compound described herein and other chemical components (collectively referred to herein as "excipients"), such as carriers, stabilizers, diluents, dispersants, suspending agents, and/or thickeners. The pharmaceutical composition facilitates administration of the compound to an organism. Various techniques for administering compounds exist in the art, including, but not limited to, rectal, oral, intravenous, aerosol, parenteral, ocular, pulmonary, and topical administration.

Details of one or more embodiments of the present invention are set forth in the detailed description below. Other features and advantages of the present invention will be apparent from the detailed description and the claims.

The present invention provides compounds of formula (I), and pharmaceutically acceptable salts, stereoisomers, tautomers, stable isotopic variants, prodrugs or crystalline forms thereof:

In the above chemical formula,

M ₁ is selected from CR ₁ and N;

M ₂ is selected from CR ₂ and N;

M ₃ is selected from CR ₃ and N;

M ₄ is selected from CR ₄ and N;

L is selected from chemical bonds, -O-, -S-, and -NH-;

Y is -C(O)-, -C(S)-, -C(N-OH)-, -S(O)-, -S(O) ₂ -, and is selected from;

Z is -C(R _2s )(R _3s )- or -N(R _2s )-;

Ring A is selected from C _3-6 cycloalkyl, 4-6 membered heterocyclyl, phenyl and 5-10 membered heteroaryl, preferably phenyl or 5-9 membered heteroaryl;

At this time, R _a is selected from H, D, halo, oxo, CN, NO ₂ , NH ₂ , -C _0-6 alkylene-OH, -C(O)OR _x , -C(O)NR _{y R z ,} -S ₍ O)NR _y R _z , -S(O) ₂ NR y R z , C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, C _2-6 haloalkynyl, C _3-6 cycloalkyl, 4-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl and amino protecting group, which is optionally substituted with 1, 2 or 3 halo, oxo, OR _x , NR _y R _z , C _1-6 alkyl or C _1-6 haloalkyl. m=0, 1, 2, 3, 4 or 5; or two adjacent _{R a} form phenyl or a 5- to 6-membered heteroaryl together with the atoms to which they are connected;

R ₁ is selected from H, D, halo, CN, OR _x , NR _y R _z , C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxyl, C _1-6 haloalkoxyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, C _2-6 haloalkynyl, C _3-8 cycloalkyl and 4- to 10-membered heterocyclyl;

R ₂ is selected from H, D, halo, CN, -C _0-6 alkylene-OH, -C _0-6 alkylene-NH ₂ , -C(O)C _1-6 alkyl, -C(O)C _1-6 haloalkyl, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxyl, C _1-6 haloalkoxyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, C _2-6 haloalkynyl, -TC _3-8 cycloalkyl, -T-4 to 10 membered heterocyclyl, -TC _6-10 aryl and -T-5 to 10 membered heteroaryl, which is optionally selected from 1, 2, 3, 4 or 5 CN, halo, oxo, -C _1-6 alkylene-OH, C Substituted with _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl or 5-6 membered heterocyclyl;

Here, T is a chemical bond, -O-, -S- or -NH-;

R ₃ is selected from H, D, halo, CN, -C _0-6 alkylene-OH, -C _0-6 alkylene-NH ₂ , C _1-6 alkyl and C _1-6 haloalkyl;

R ₄ is selected from H, D, halo, C _1-6 alkyl and C _1-6 haloalkyl;

Alternatively, R ₁ and R ₂ together with the carbon atom to which they are connected form C _5-6 cycloalkyl, 5-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, which optionally comprises 1, 2 or 3 halo, CN, C _1-6 alkyl, C _1-6 haloalkyl, -C(O)H, -C(O)C _1-6 alkyl, -C(O)C _1-6 haloalkyl, C _2-6 alkenyl, C 2-6 haloalkenyl, C _2-6 alkynyl, C _2-6 haloalkynyl or C _2-6 alkynyl-substituted phenyl, preferably 1, 2 or 3 halo, CN, C _1-6 alkyl, C _1-6 haloalkyl, -C(O)C _1-6 alkyl, -C(O)C _{1-6 haloalkyl} , substituted with C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, C _2-6 haloalkynyl, or C _2-6 alkynyl-substituted phenyl;

Alternatively, R ₂ and R ₃ together with the carbon atoms to which they are connected form C _5-6 cycloalkyl, 5-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, which are optionally substituted with 1, 2, 3 or 4 halo, C _1-6 alkyl, C _1-6 haloalkyl, -C _1-6 alkylene-C _1-6 alkoxyl, -C _{1-6 alkylene-C 1-6 haloalkoxyl} , -C(O)C _1-6 alkyl or -C(O)C _1-6 haloalkyl;

R _1s is selected from H, D, -C _0-6 alkylene-OR _x , -C _0-6 alkylene-NR _y R _z , C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _{2-6 alkynyl, C 2-6 haloalkynyl} , C _3-6 cycloalkyl and phenyl;

R _2s is selected from H, D, C _1-6 alkyl, C _1-6 haloalkyl and C(R _2s1 )(R _2s2 )(R _2s3 );

At this time, R _2s1 is selected from H, D, -C _0-6 alkylene-OR _x , -C _0-6 alkylene-NR _y R _z , C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, C _2-6 haloalkynyl and C _3-6 cycloalkyl;

R _2s2 is selected from H, D, -C _0-6 alkylene-OH, C _1-6 alkyl and C _1-6 haloalkyl;

R _2s3 is C _1-6 alkyl or C _1-6 haloalkyl;

Alternatively, R _2s1 and R _2s2 together with the carbon atoms to which they are connected form a C _3-6 cycloalkyl;

Alternatively, R _2s2 and R _2s3 together with the atoms to which they are connected form a C _3-6 cycloalkyl or a 4- to 6-membered heterocyclyl, which is optionally substituted with 1 or 2 halo;

Alternatively, R _2s1 , R _2s2 and R _2s3 together with the atoms to which they are connected form a C _4-8 bridged bicycloalkyl (optionally substituted with 1 or 2 halo, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl and C _2-6 haloalkynyl), or a 4- to 8-membered bridged heterocyclyl;

or R _1s and R _2s3 are linked to form C _2-6 alkylene, which is optionally substituted with 1, 2 or 3 halo, OR _x , NR _y R _z , C _1-6 alkyl or C _1-6 haloalkyl;

R _3s is selected from H, D, C _1-6 alkyl and C _1-6 haloalkyl;

Alternatively, R _2s and R _3s together with the carbon atoms to which they are connected form a C _3-6 cycloalkyl or a 4- to 6-membered heterocyclyl, which is optionally substituted with 1 or 2 halo, C _1-6 alkyl or C _1-6 haloalkyl;

Alternatively, R _1s and R _2s together with the nitrogen atom to which they are connected form a 4- to 6-membered heterocyclyl, which is optionally substituted with 1 or 2 halo, C _1-6 alkyl or C _1-6 haloalkyl;

Alternatively, R _1s , R _2s and R _3s together with the carbon atoms to which they are connected form a C _4-8 bridged bicycloalkyl (which is optionally substituted with 1 or 2 halo, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl and C _2-6 haloalkynyl), or to form;

At this time, Y ₁ is CR ₁₁ or N;

Y ₂ is CR ₁₂ or N;

R ₁₁ and R ₁₃ are independently selected from H, D, C _1-6 alkyl and C _1-6 haloalkyl;

R ₁₂ is selected from H and D;

R _x , R _y and R _z are independently selected from H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, C _2-6 haloalkynyl, C _3-8 cycloalkyl and 4- to 6-membered heterocyclyl; or R _y and R _z together with the nitrogen atom to which they are connected form a 4- to 6-membered heterocyclyl;

The above-mentioned atoms may be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated.

The present invention further provides a compound of formula (I), and pharmaceutically acceptable salts, stereoisomers, tautomers, stable isotopic variants, prodrugs or crystalline forms thereof:

In the above chemical formula,

M ₁ is selected from CR ₁ and N;

M ₂ is selected from CR ₂ and N;

M ₃ is selected from CR ₃ and N;

M ₄ is selected from CR ₄ and N;

L is selected from chemical bonds, -O-, -S-, and -NH-;

Y is -C(O)-, -C(S)-, -C(N-OH)-, -S(O)-, -S(O) ₂ -, and is selected from;

Z is -C(R _2s )(R _3s )- or -N(R _2s )-;

Ring A is selected from phenyl and 5- to 9-membered heteroaryl;

wherein R _a is selected from H, D, halo, CN, NO ₂ , NH ₂ , -C _0-6 alkylene-OH, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C 2-6 haloalkenyl, C _2-6 alkynyl, _{C 2-6 haloalkynyl} and amino protecting group, and m=0, 1, 2, 3, 4 or 5; or two adjacent R _a together with the atoms to which they are connected form phenyl or a 5- to 6-membered heteroaryl;

R ₁ is selected from H, D, halo, OR _x , NR _y R _z , C _1-6 alkyl, C _1-6 haloalkyl, C 1-6 alkoxyl, C _1-6 haloalkoxyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, C _2-6 haloalkynyl, C _3-8 cycloalkyl and 4- to 10-membered heterocyclyl _;

R ₂ is selected from H, D, halo, CN, -C _0-6 alkylene-OH, -C _0-6 alkylene-NH ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxyl, C _1-6 haloalkoxyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, C _2-6 haloalkynyl, -TC _3-8 cycloalkyl, -T-4 to 10 membered heterocyclyl, -TC _6-10 aryl and -T-5 to 10 membered heteroaryl, which is optionally selected from 1, 2, 3, 4 or 5 CN, halo, oxo, -C _1-6 alkylene-OH, C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl or 5 membered substituted with a 6-membered heterocyclyl;

Here, T is a chemical bond, -O-, -S- or -NH-;

R ₃ is selected from H, D, halo, CN, -C _0-6 alkylene-OH, -C _0-6 alkylene-NH ₂ , C _1-6 alkyl and C _1-6 haloalkyl;

R ₄ is selected from H, D, halo, C _1-6 alkyl and C _1-6 haloalkyl;

Alternatively, R ₁ and R ₂ together with the carbon atoms to which they are connected form a C _5-6 cycloalkyl, a 5-6 membered heterocyclyl, phenyl or a 5-6 membered heteroaryl, which is optionally substituted with 1, 2 or 3 halo, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _{2-6 haloalkenyl, C 2-6 alkynyl} , C _2-6 haloalkynyl, or C _2-6 alkynyl-substituted phenyl;

Alternatively, R ₂ and R ₃ together with the carbon atoms to which they are connected form a C _5-6 cycloalkyl or a 5- to 7-membered heterocyclyl, which is optionally substituted with 1, 2, 3 or 4 halo, C _1-6 alkyl, C _1-6 haloalkyl, -C _1-6 alkylene-C _1-6 alkoxyl, -C _1-6 alkylene-C _1-6 haloalkoxyl, -C(O)C _1-6 alkyl or -C(O)C _1-6 haloalkyl;

R _1s is selected from H, D, -C _0-6 alkylene-OR _x , -C _0-6 alkylene-NR _y R _z , C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _{2-6 alkynyl, C 2-6 haloalkynyl} , C _3-6 cycloalkyl and phenyl;

R _2s is selected from H, D, C _1-6 alkyl, C _1-6 haloalkyl and C(R _2s1 )(R _2s2 )(R _2s3 );

At this time, R _2s1 is selected from H, D, -C _0-6 alkylene-OR _x , -C _0-6 alkylene-NR _y R _z , C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, C _2-6 haloalkynyl and C _3-6 cycloalkyl;

R _2s2 is selected from H, D, -C _0-6 alkylene-OH, C _1-6 alkyl and C _1-6 haloalkyl;

R _2s3 is C _1-6 alkyl or C _1-6 haloalkyl;

Alternatively, R _2s2 and R _2s3 together with the atoms to which they are connected form a C _3-6 cycloalkyl or a 4- to 6-membered heterocyclyl, which is optionally substituted with 1 or 2 halo;

Alternatively, R _2s1 and R _2s3 together with the atoms to which they are connected form a C _4-8 bridged bicycloalkyl or a 4- to 8-membered bridged heterocyclyl; or

or R _1s and R _2s3 are linked to form C _2-6 alkylene, which is optionally substituted with 1, 2 or 3 halo, OR _x , NR _y R _z , C _1-6 alkyl or C _1-6 haloalkyl;

R _3s is selected from C _1-6 alkyl and C _1-6 haloalkyl;

Alternatively, R _2s and R _3s together with the carbon atoms to which they are connected form a C _3-6 cycloalkyl or a 4- to 6-membered heterocyclyl, which is optionally substituted with 1 or 2 halo, C _1-6 alkyl or C _1-6 haloalkyl;

Alternatively, R _1s and R _2s together with the nitrogen atom to which they are connected form a 4- to 6-membered heterocyclyl, which is optionally substituted with 1 or 2 halo, C _1-6 alkyl or C _1-6 haloalkyl;

Alternatively, R _1s , R _2s and R _3s together with the carbon atoms to which they are connected may be C _4-8 bridged bicycloalkyl or to form;

At this time, Y ₁ is CR ₁₁ or N;

Y ₂ is CR ₁₂ or N;

R ₁₁ and R ₁₃ are independently selected from H, D, C _1-6 alkyl and C _1-6 haloalkyl;

R ₁₂ is selected from H and D;

R _x , R _y and R _z are independently selected from H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, C _2-6 haloalkynyl, C _3-8 cycloalkyl and 4- to 6-membered heterocyclyl; or R _y and R _z together with the nitrogen atom to which they are connected form a 4- to 6-membered heterocyclyl;

The above-mentioned atoms may be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated.

M ₁ , M ₂ , M ₃ , and M ₄

In some embodiments, M ₁ is CR ₁ ; in some embodiments, M ₁ is N.

In some embodiments, M ₂ is CR ₂ ; in some embodiments, M ₂ is N.

In some embodiments, M ₃ is CR ₃ ; in some embodiments, M ₃ is N.

In some embodiments, M ₄ is CR ₄ ; in some embodiments, M ₄ is N.

L

In some embodiments, L is a chemical bond; in some embodiments, L is -O-; in some embodiments, L is -S-; in some embodiments, L is -NH-.

Y

In some embodiments, Y is -C(O)-; In some embodiments, Y is -C(S)-; In some embodiments, Y is -C(N-OH)-; In some embodiments, Y is -S(O)-; In some embodiments, Y is -S(O) ₂ -; In some embodiments, Y is am.

Z

In some embodiments, Z is -C(R _2s )(R _3s )-; in some embodiments, Z is -N(R _2s )-.

Ring A

In some embodiments, ring A is C _3-6 cycloalkyl; in some embodiments, ring A is a 4-6 membered heterocyclyl; in some embodiments, ring A is a 5-10 membered heteroaryl; in some embodiments, ring A is phenyl; in some embodiments, ring A is a 5-9 membered heteroaryl.

R _a and m

In some embodiments, R _a is H; in some embodiments, R _a is D; in some embodiments, R _a is halo; in some embodiments, R _a is oxo; in some embodiments, R _a is CN; in some embodiments, R _a is NO ₂ ; in some embodiments, R _a is OH; in some embodiments, R _a is NH ₂ ; in some embodiments, R a is —C _1-6 alkylene-OH; in some embodiments, R _a is —C(O)OR _x ; in some embodiments, R _a is —C(O)NR _y R _z ; in some embodiments, R _a is —S(O)NR _y R _z ; in some embodiments, R _a is —S(O) ₂ NR _y R _z ; in some embodiments, R _a is C _1-6 alkyl; in some embodiments, R _a is C _1-6 haloalkyl; In some embodiments, R _a is C _2-6 alkenyl; in some embodiments, R _a is C _2-6 haloalkenyl; in some embodiments, R _a is C _2-6 alkynyl; in some embodiments, R _a is C _2-6 haloalkynyl; in some embodiments, R _a is C _3-6 cycloalkyl; in some embodiments, R _a is 4-6 membered heterocyclyl; in some embodiments, R _a is phenyl; in some embodiments, R _a is 5-6 membered heteroaryl; in some embodiments, R _a is an amino protecting group; in some embodiments, the above-mentioned groups are optionally substituted with 1, 2 or 3 halo, oxo, OR _x , NR _y R _z , C _1-6 alkyl or C _1-6 haloalkyl; in some embodiments, two adjacent R _a together with the atoms to which they are connected form phenyl; In some embodiments, two adjacent R _a together with the atoms to which they are connected form a 5- or 6-membered heteroaryl.

In some embodiments, m=0; in some embodiments, m=1; in some embodiments, m=2; in some embodiments, m=3; in some embodiments, m=4; and in some embodiments, m=5.

R ₁

In some embodiments, R ₁ is H; in some embodiments, R ₁ is D; in some embodiments, R ₁ is halo; in some embodiments, R ₁ is CN; in some embodiments, R ₁ is OR _x ; in some embodiments, R ₁ is NR _y R _z ; in some embodiments, R ₁ is C _1-6 alkyl; in some embodiments, R ₁ is C _1-6 haloalkyl; in some embodiments, R ₁ is C _1-6 alkoxyl; in some embodiments, R ₁ is C _1-6 haloalkoxyl; in some embodiments, R ₁ is C _2-6 alkenyl; in some embodiments, R ₁ is C _2-6 haloalkenyl; in some embodiments, R ₁ is C _2-6 alkynyl; in some embodiments, R ₁ is C _2-6 haloalkynyl; In some embodiments, R ₁ is C _3-8 cycloalkyl; in some embodiments, R ₁ is 4-10 membered heterocyclyl.

R ₂ and T

In some embodiments, R ₂ is H; in some embodiments, R ₂ is D; in some embodiments, R ₂ is halo; in some embodiments, R ₂ is CN; in some embodiments, R ₂ is —C _0-6 alkylene-OH; in some embodiments, R ₂ is —C(O)C _1-6 alkyl; in some embodiments, R ₂ is —C(O)C _1-6 haloalkyl; in some embodiments, R ₂ is —C _0-6 alkylene-NH ₂ ; in some embodiments, R ₂ is C _1-6 alkyl; in some embodiments, R ₂ is C _1-6 haloalkyl; in some embodiments, R ₂ is C _1-6 alkoxyl; in some embodiments, R ₂ is C _1-6 haloalkoxyl; in some embodiments, R ₂ is C _2-6 alkenyl; In some embodiments, R ₂ is C _2-6 haloalkenyl; in some embodiments, R ₂ is C _2-6 alkynyl; in some embodiments, R ₂ is C _2-6 haloalkynyl; in some embodiments, R ₂ is -TC _3-8 cycloalkyl; in some embodiments, R ₂ is -T-4 to 10 membered heterocyclyl; in some embodiments, R ₂ is -TC _6-10 aryl; in some embodiments, R ₂ is -T-5 to 10 membered heteroaryl.

In some embodiments, T is a chemical bond; in some embodiments, T is -O-; in some embodiments, T is -S-; in some embodiments, T is -NH-.

R ₃

In some embodiments, R ₃ is H; in some embodiments, R ₃ is D; in some embodiments, R ₃ is halo; in some embodiments, R ₃ is CN; in some embodiments, R ₃ is —C _0-6 alkylene-OH; in some embodiments, R ₃ is —C _0-6 alkylene-NH ₂ ; in some embodiments, R ₃ is C _1-6 alkyl; R ₃ is C _1-6 haloalkyl.

R ₄

In some embodiments, R ₄ is H; in some embodiments, R ₄ is D; in some embodiments, R ₄ is halo; in some embodiments, R ₄ is C _1-6 alkyl; in some embodiments, R ₄ is C _1-6 haloalkyl.

In some embodiments, R ₁ and R ₂ together with the carbon atom to which they are connected form a C _5-6 cycloalkyl; in some embodiments, R ₁ and R ₂ together with the carbon atom to which they are connected form a 5-6 membered heterocyclyl; in some embodiments, R ₁ and R ₂ together with the carbon atom to which they are connected form a phenyl group; in some embodiments, R ₁ and R ₂ together with the carbon atom to which they are connected form a 5-6 membered heteroaryl.

In some embodiments, R ₂ and R ₃ together with the carbon atoms to which they are connected form a C _5-6 cycloalkyl; in some embodiments, R ₂ and R ₃ together with the carbon atoms to which they are connected form a 5-7 membered heterocyclyl.

R _1s

In some embodiments, R ₁ is H; in some embodiments, R _1s is D; in some embodiments, R _1s is -C _0-6 alkylene-OR _x ; in some embodiments, R _1s is -C _0-6 alkylene-NR _y R _z ; in some embodiments, R _1s is C _1-6 alkyl; in some embodiments, R _1s is C _1-6 haloalkyl; in some embodiments, R _1s is C _2-6 alkenyl; in some embodiments, R _1s is C _2-6 haloalkenyl; in some embodiments, R _1s is C _2-6 alkynyl; in some embodiments, R _1s is C _2-6 haloalkynyl; in some embodiments, R _1s is C _3-6 cycloalkyl; in some embodiments, R _1s is phenyl.

R _2s

In some embodiments, R _2s is H; in some embodiments, R _2s is D; in some embodiments, R _2s is C _1-6 alkyl; in some embodiments, R _2s is C _1-6 haloalkyl; in some embodiments, R _2s is C(R _2s1 )(R _2s2 )(R _2s3 ).

In some embodiments, R _2s1 is H; in some embodiments, R _2s1 is D; in some embodiments, R _2s1 is -C _0-6 alkylene-OR _x ; in some embodiments, R _2s1 is -C _0-6 alkylene-NR _y R _z ; in some embodiments, R _2s1 is C _1-6 alkyl; in some embodiments, R _2s1 is C _1-6 haloalkyl; in some embodiments, R _2s1 is C _2-6 alkenyl; in some embodiments, R _2s1 is C _2-6 haloalkenyl; in some embodiments, R _2s1 is C _2-6 alkynyl; in some embodiments, R _2s1 is C _2-6 haloalkynyl; in some embodiments, R _2s1 is C _3-6 cycloalkyl.

In some embodiments, R _2s2 is H; in some embodiments, R _2s2 is D; in some embodiments, R _2s2 is C _1-6 alkyl; in some embodiments, R _2s2 is C _1-6 haloalkyl.

In some embodiments, R _2s3 is C _1-6 alkyl; in some embodiments, R _2s3 is C _1-6 haloalkyl.

In some embodiments, R _2s2 and R _2s3 together with the carbon atoms to which they are connected form a C _3-6 cycloalkyl; in some embodiments, R _2s2 and R _2s3 together with the carbon atoms to which they are connected form a 4-6 membered heterocyclyl.

In some embodiments, R _2s1 and R _2s2 together with the carbon atoms to which they are connected form a C _3-6 cycloalkyl.

In some embodiments, R _2s1 , R _2s2 and R _2s3 together with the atoms to which they are connected form a C _4-8 bridged bicycloalkyl (optionally substituted with 1 or 2 halo, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl and C _2-6 haloalkynyl); in some embodiments, R _2s1 , R _2s2 and R _2s3 together with the atoms to which they are connected form a 4-8 membered bridged heterocyclyl.

In some embodiments, R _1s and R _2s3 are linked to form a C _2-6 alkylene.

R _3s

In some embodiments, R _3s is H; in some embodiments, R _3s is D; in some embodiments, R _3s is C _1-6 alkyl; in some embodiments, R _3s is C _1-6 haloalkyl.

In some embodiments, R _2s and R _3s together with the carbon atoms to which they are connected form a C _3-6 cycloalkyl; in some embodiments, R _2s and R _3s together with the carbon atoms to which they are connected form a 4-6 membered heterocyclyl.

In some embodiments, R _1s and R _2s together with the nitrogen atom to which they are connected form a 4- to 6-membered heterocyclyl.

In some embodiments, R _1s , R _2s and R _3s together with the carbon atoms to which they are connected form a C _4-8 bridged bicycloalkyl (optionally substituted with 1 or 2 halo, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _{2-6 haloalkenyl} , C _{2-6 alkynyl} and C _{2-6 haloalkynyl} ); ... It forms.

In some embodiments, Y ₁ is CR ₁₁ ; in some embodiments, Y ₁ is N.

In some embodiments, Y ₂ is CR ₁₂ ; in some embodiments, Y ₂ is N.

In some embodiments, R ₁₁ and R ₁₃ are H; in some embodiments, R ₁₁ and R ₁₃ are D; in some embodiments, R ₁₁ and R ₁₃ are C _1-6 alkyl; in some embodiments, R ₁₁ and R ₁₃ are C _1-6 haloalkyl.

In some embodiments, R ₁₂ is H; in some embodiments, R ₁₂ is D.

Preparation of compounds of formula X and exemplary compounds

As will be appreciated by those skilled in the art, methods for synthesizing compounds of the formulae described herein will be apparent to those skilled in the art. For example, the compounds described herein can be synthesized, for example, using one or more of the methods described herein. Synthetic chemical transformations and protecting group methodologies (protection and deprotection) useful in synthesizing the compounds described herein are known to those skilled in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T. W. Greene and R. G. M. Wuts, Protective Groups in Organic Synthesis, 2d. Ed., John Wiley and Sons (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), and subsequent editions thereof. The starting materials used to prepare the compounds described herein are known, prepared by known methods, or commercially available. Those skilled in the art will appreciate that the conditions and reagents described herein may be interchanged with art-recognized equivalents. For example, in many reactions, triethylamine may be interchanged with another base, such as a non-nucleophilic base (e.g., diisopropylethylamine, 1,8-diazabicycloundec-7-ene, 2,6-di-tert-butylpyridine, or tetrabutylphosphazene).

Those skilled in the art will be aware of a variety of analytical methods that can be used to characterize the compounds described herein, including, for example, ¹ H NMR, heteronuclear NMR, mass spectrometry, liquid chromatography, and infrared spectroscopy. The foregoing list is only a partial list of characterization methods available to those skilled in the art and is not intended to be limiting.

The present invention specifically relates to the following technical solutions:

1. A compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof:

In the above chemical formula,

M ₁ is selected from CR ₁ and N;

M ₂ is selected from CR ₂ and N;

M ₃ is selected from CR ₃ and N;

M ₄ is selected from CR ₄ and N;

L is selected from chemical bonds, -O-, -S-, and -NH-;

Y is -C(O)-, -C(S)-, -C(N-OH)-, -S(O)-, -S(O) ₂ -, and is selected from;

Z is -C(R _2s )(R _3s )- or -N(R _2s )-;

Ring A is selected from C _3-6 cycloalkyl, 4-6 membered heterocyclyl, phenyl and 5-10 membered heteroaryl, preferably phenyl or 5-9 membered heteroaryl;

At this time, R _a is selected from H, D, halo, oxo, CN, NO ₂ , NH ₂ , -C _0-6 alkylene-OH, -C(O)OR _x , -C(O)NR _{y R z ,} -S ₍ O)NR _y R _z , -S(O) ₂ NR y R z , C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, C _2-6 haloalkynyl, C _3-6 cycloalkyl, 4-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl and amino protecting group, which is optionally substituted with 1, 2 or 3 halo, oxo, OR _x , NR _y R _z , C _1-6 alkyl or C _1-6 haloalkyl. m=0, 1, 2, 3, 4 or 5; or two adjacent _{R a} form phenyl or a 5- to 6-membered heteroaryl together with the atoms to which they are connected;

R ₁ is selected from H, D, halo, CN, OR _x , NR _y R _z , C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxyl, C _1-6 haloalkoxyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, C _2-6 haloalkynyl, C _3-8 cycloalkyl and 4- to 10-membered heterocyclyl;

R ₂ is selected from H, D, halo, CN, -C _0-6 alkylene-OH, -C _0-6 alkylene-NH ₂ , -C(O)C _1-6 alkyl, -C(O)C _1-6 haloalkyl, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxyl, C _1-6 haloalkoxyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, C _2-6 haloalkynyl, -TC _3-8 cycloalkyl, -T-4 to 10 membered heterocyclyl, -TC _6-10 aryl and -T-5 to 10 membered heteroaryl, which is optionally selected from 1, 2, 3, 4 or 5 CN, halo, oxo, -C _1-6 alkylene-OH, C Substituted with _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl or 5-6 membered heterocyclyl;

Here, T is a chemical bond, -O-, -S- or -NH-;

R ₃ is selected from H, D, halo, CN, -C _0-6 alkylene-OH, -C _0-6 alkylene-NH ₂ , C _1-6 alkyl and C _1-6 haloalkyl;

R ₄ is selected from H, D, halo, C _1-6 alkyl and C _1-6 haloalkyl;

Alternatively, R ₁ and R ₂ together with the carbon atom to which they are connected form C _5-6 cycloalkyl, 5-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, which optionally comprises 1, 2 or 3 halo, CN, C _1-6 alkyl, C _1-6 haloalkyl, -C(O)H, -C(O)C _1-6 alkyl, -C(O)C _1-6 haloalkyl, C _2-6 alkenyl, C 2-6 haloalkenyl, C _2-6 alkynyl, C _2-6 haloalkynyl or C _2-6 alkynyl-substituted phenyl, preferably 1, 2 or 3 halo, CN, C _1-6 alkyl, C _1-6 haloalkyl, -C(O)C _1-6 alkyl, -C(O)C _{1-6 haloalkyl} , substituted with C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, C _2-6 haloalkynyl, or C _2-6 alkynyl-substituted phenyl;

Alternatively, R ₂ and R ₃ together with the carbon atoms to which they are connected form C _5-6 cycloalkyl, 5-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, which are optionally substituted with 1, 2, 3 or 4 halo, C _1-6 alkyl, C _1-6 haloalkyl, -C _1-6 alkylene-C _1-6 alkoxyl, -C _{1-6 alkylene-C 1-6 haloalkoxyl} , -C(O)C _1-6 alkyl or -C(O)C _1-6 haloalkyl;

R _1s is selected from H, D, -C _0-6 alkylene-OR _x , -C _0-6 alkylene-NR _y R _z , C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _{2-6 alkynyl, C 2-6 haloalkynyl} , C _3-6 cycloalkyl and phenyl;

R _2s is selected from H, D, C _1-6 alkyl, C _1-6 haloalkyl and C(R _2s1 )(R _2s2 )(R _2s3 );

At this time, R _2s1 is selected from H, D, -C _0-6 alkylene-OR _x , -C _0-6 alkylene-NR _y R _z , C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, C _2-6 haloalkynyl and C _3-6 cycloalkyl;

R _2s2 is selected from H, D, -C _0-6 alkylene-OH, C _1-6 alkyl and C _1-6 haloalkyl;

R _2s3 is C _1-6 alkyl or C _1-6 haloalkyl;

Alternatively, R _2s1 and R _2s2 together with the carbon atoms to which they are connected form a C _3-6 cycloalkyl;

Alternatively, R _2s2 and R _2s3 together with the atoms to which they are connected form a C _3-6 cycloalkyl or a 4- to 6-membered heterocyclyl, which is optionally substituted with 1 or 2 halo;

Alternatively, R _2s1 , R _2s2 and R _2s3 together with the atoms to which they are connected form a C _4-8 bridged bicycloalkyl (optionally substituted with 1 or 2 halo, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl and C _2-6 haloalkynyl), or a 4- to 8-membered bridged heterocyclyl;

or R _1s and R _2s3 are linked to form C _2-6 alkylene, which is optionally substituted with 1, 2 or 3 halo, OR _x , NR _y R _z , C _1-6 alkyl or C _1-6 haloalkyl;

R _3s is selected from H, D, C _1-6 alkyl and C _1-6 haloalkyl;

Alternatively, R _2s and R _3s together with the carbon atoms to which they are connected form a C _3-6 cycloalkyl or a 4- to 6-membered heterocyclyl, which is optionally substituted with 1 or 2 halo, C _1-6 alkyl or C _1-6 haloalkyl;

Alternatively, R _1s and R _2s together with the nitrogen atom to which they are connected form a 4- to 6-membered heterocyclyl, which is optionally substituted with 1 or 2 halo, C _1-6 alkyl or C _1-6 haloalkyl;

Alternatively, R _1s , R _2s and R _3s together with the carbon atoms to which they are connected form a C _4-8 bridged bicycloalkyl (which is optionally substituted with 1 or 2 halo, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl and C _2-6 haloalkynyl), or to form;

At this time, Y ₁ is CR ₁₁ or N;

Y ₂ is CR ₁₂ or N;

R ₁₁ and R ₁₃ are independently selected from H, D, C _1-6 alkyl and C _1-6 haloalkyl;

R ₁₂ is selected from H and D;

R _x , R _y and R _z are independently selected from H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, C _2-6 haloalkynyl, C _3-8 cycloalkyl and 4- to 6-membered heterocyclyl; or R _y and R _z together with the nitrogen atom to which they are connected form a 4- to 6-membered heterocyclyl;

The above-mentioned atoms may be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated.

2. A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein M ₁ is CR ₁ in the first paragraph.

3. A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein M ₂ is CR ₂ in claim 1 or 2.

4. A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein M ₃ is CR ₃ according to any one of claims 1 to 3.

5. A compound according to any one of claims 1 to 4, wherein M ₄ is CR ₄ , or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug, or crystalline form thereof.

6. A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein L is a chemical bond according to any one of claims 1 to 5.

7. A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, according to any one of claims 1 to 5, wherein L is -NH-.

8. A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein Y is selected from -C(O)-, -C(S)-, -C(N-OH)-, -S(O)- and -S(O) ₂ -; or Y is selected from -C(O)-, -C(S)- and -C(N-OH)-; or Y is selected from -C(O)- and -C(S)-; or Y is -C(O)-.

9. A compound according to any one of claims 1 to 8, wherein Z is -C(R _2s )(R _3s )-, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug, or crystalline form thereof.

10. A compound according to any one of claims 1 to 8, wherein Z is -N(R _2s )-, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug, or crystalline form thereof.

11. In any one of paragraphs 1 to 10,

Ring A is selected from phenyl and 5- to 9-membered heteroaryl; wherein R _a is selected from H, D, halo, NO ₂ , NH ₂ , -C _1-6 alkylene-OH, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, C _2-6 haloalkynyl and amino protecting group, and m=0, 1, 2, 3, 4 or 5; or two adjacent R _a together with the atoms to which they are connected form phenyl or 5- to 6-membered heteroaryl;

Alternatively, ring A is selected from phenyl and 5-6 membered heteroaryl, wherein R _a is selected from C _3-6 cycloalkyl, 4-6 membered heterocyclyl, phenyl and 5-6 membered heteroaryl, which is optionally substituted with 1, 2 or 3 halo, oxo, OR _x , NR _y R _z , C _1-6 alkyl or C _1-6 haloalkyl, and m is 1, 2 or 3;

Alternatively, ring A is

is selected from; wherein R _a is selected from H, D, halo, NO ₂ , NH ₂ , -C _1-6 alkylene-OH, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, C _2-6 haloalkynyl and amino protecting group, and m=0, 1, 2, 3, 4 or 5; or two adjacent R _a together with the atoms to which they are connected form phenyl or a 5- to 6-membered heteroaryl;

Alternatively, ring A is

is selected from; wherein R _a is selected from H, D, halo, NO ₂ , NH ₂ , -C _1-6 alkylene-OH, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, C _2-6 haloalkynyl and amino protecting group, and m=0, 1, 2, 3, 4 or 5; or two adjacent R _a together with the atoms to which they are connected form phenyl or a 5- to 6-membered heteroaryl;

Alternatively, ring A is

is selected from; wherein R _a is selected from H, D, halo, NO ₂ , NH ₂ , -C _1-6 alkylene-OH, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkynyl, C _2-6 haloalkynyl and amino protecting group, and m=0, 1, 2, 3, 4 or 5; or two adjacent R _a together with the atoms to which they are connected form phenyl or a 5- to 6-membered heteroaryl;

Alternatively, ring A is

is selected from; wherein R _a is selected from H, D, halo, NO ₂ , NH ₂ , -C _1-6 alkylene-OH, C _2-4 alkynyl, C _2-4 haloalkynyl and Boc, and m = 0, 1, 2, 3, 4 or 5;

Alternatively, ring A is is selected from; wherein R _a is selected from H, D, halo, CN, C _1-6 alkyl and C _1-6 haloalkyl, and m=0, 1, 2, 3, 4 or 5;

Alternatively, ring A is

is selected from; wherein R _a is selected from H, D, halo, NO ₂ , NH ₂ , C _1-6 alkyl, C _1-6 haloalkyl and amino protecting group, and m = 0, 1, 2, 3, 4 or 5;

Alternatively, ring A is is selected from; wherein R _a is selected from H, D, halo, NO ₂ , NH ₂ , C _1-6 alkyl, C _1-6 haloalkyl and amino protecting group, and m = 0, 1, 2, 3, 4 or 5;

Alternatively, ring A is is selected from; wherein R _a is selected from H, D, halo, NO ₂ , NH ₂ , and Boc, and m = 0, 1, 2, 3, 4, or 5;

Alternatively, ring A is is selected from; wherein R _a is selected from H, D, halo, CN, C _1-6 alkyl and C _1-6 haloalkyl, and m=0, 1, 2, 3, 4 or 5;

Alternatively, ring A is is selected from; wherein R _a is selected from H, D, F, Cl, Br, CN, and Me, and m=0, 1, 2, 3, 4, or 5;

Alternatively, ring A is is selected from; wherein R _a is selected from H, D and halo (e.g., F), and m=0, 1, 2, 3, 4 or 5;

Alternatively, ring A is is selected from; wherein R _a is selected from H, D, halo (e.g., F), C _1-6 alkyl (e.g., Me) and C _1-6 haloalkyl, and m=0, 1, 2, 3 or 4;

Alternatively, ring A is is selected from; wherein R _a is selected from H, D and halo (e.g., F), and m=0, 1, 2 or 3;

Alternatively, ring A is and; wherein R _a is selected from H and D, and m=0, 1, 2, 3, 4, or 5;

Alternatively, ring A is

or selected from;

Alternatively, ring A is

or selected from;

Alternatively, ring A is

or selected from;

Alternatively, ring A is

or selected from;

Alternatively, ring A is

or selected from;

Alternatively, ring A is

or selected from;

Alternatively, ring A is

or selected from;

Alternatively, ring A is

or selected from;

Alternatively, ring A is

or selected from;

Alternatively, ring A is

or selected from;

Alternatively, ring A is

or selected from;

Alternatively, ring A is

or selected from;

Alternatively, ring A is or selected from;

Alternatively, ring A is or selected from;

Alternatively, ring A is or selected from;

Alternatively, ring A is

or selected from;

Alternatively, ring A is

or selected from;

Alternatively, ring A is or selected from;

Alternatively, ring A is or selected from;

Alternatively, ring A is or selected from;

Alternatively, ring A is or selected from;

Alternatively, ring A is or selected from;

Alternatively, ring A is or selected from;

Alternatively, ring A is This or;

Alternatively, ring A is This or;

Alternatively, ring A is or selected from;

Alternatively, ring A is is selected from , where R _a is is selected from, and preferably, R _a is

is selected from, and m = 1, 2, or 3;

Alternatively, ring A is , and at this time R _a is

is selected from, and preferably, R _a is

is selected from, preferably , and preferably, R _a is is selected from, and preferably, R _a is is selected from, and m= is selected from 1, 2 or 3;

Alternatively, ring A is am.

12. In any one of claims 1 to 11, R ₁ is selected from H, D, halo, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxyl, C _1-6 haloalkoxyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, C _2-6 haloalkynyl, C _3-8 cycloalkyl, and 4- to 10-membered heterocyclyl; or

Alternatively, R ₁ is selected from H, D, halo, CN, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, C _2-6 haloalkynyl, C _1-6 alkoxyl, C _{1-6 haloalkoxyl, and C 3-6 cycloalkyl} ;

Alternatively, R ₁ is selected from H, D, halo, CN, C _1-4 alkyl, C _1-4 haloalkyl, C _2-4 alkenyl, C _2-4 haloalkenyl, C _2-4 alkynyl, C _2-4 haloalkynyl, C _1-4 alkoxyl, C _1-4 haloalkoxyl, and C _3-6 cycloalkyl;

Alternatively, R ₁ is selected from H, D, halo, CN, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, and C _2-6 haloalkynyl;

Alternatively, R ₁ is selected from H, D, halo, CN, C _1-4 alkyl, C _1-4 haloalkyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, and C _2-6 haloalkynyl;

Alternatively, R ₁ is selected from H, D, halo, C _1-6 alkyl and C _1-6 haloalkyl;

Alternatively, R ₁ is selected from halo, C _1-6 alkyl and C _1-6 haloalkyl;

Alternatively, R ₁ is selected from H, D, halo, C _1-4 alkyl and C _1-4 haloalkyl;

Alternatively, R ₁ is selected from H, D and halo;

Alternatively, R ₁ is halo;

Alternatively, R ₁ is selected from H, D, F, Cl, CN, Me, CH=CH ₂ , CF ₃ , and cyclopropyl;

Alternatively, R ₁ is selected from H, D, F, Cl, CN, Me, CH=CH ₂ , CF ₃ , OMe, and cyclopropyl;

Alternatively, R ₁ is selected from H, D, F, Cl, CN, Me, CH=CH ₂ , and CF ₃ ;

Alternatively, R ₁ is selected from H, D, F, Cl, Me, and CF ₃ ;

Alternatively, R ₁ is selected from H, D, F, Cl, and Me;

Alternatively, R ₁ is selected from H, D, F, Me, and OMe;

Alternatively, R ₁ is selected from H, D, F, and Me;

Alternatively, R ₁ is selected from H, D, Cl, and Me;

Alternatively, R ₁ is selected from H, D, F, and Cl;

Alternatively, R ₁ is selected from H, D and F;

Alternatively, R ₁ is selected from Cl and Me;

Alternatively, R ₁ is selected from F and Cl;

Alternatively, R ₁ is selected from H and D, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof.

13. In any one of paragraphs 1 to 12, R ₂ is selected from H, D, halo, -C _0-6 alkylene-OH, NH ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxyl, C _{1-6 haloalkoxyl, -TC 5-6 cycloalkyl} , -T-5 to 10 membered heterocyclyl, -TC _6-10 aryl and -T-5 to 10 membered heteroaryl, which is optionally substituted with 1, 2, 3, 4 or 5 CN, halo, oxo, -C _1-6 alkylene-OH, C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl or 5 to 6 membered heterocyclyl;

Alternatively, R ₂ is selected from H, D, halo, -C _0-6 alkylene-OH, NH ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxyl, C _5-6 cycloalkyl, 5-6 membered heterocyclyl, C _6-10 aryl, 5-10 membered heteroaryl, -O-5-6 membered heteroaryl, -NH-5-6 membered heteroaryl, -OC(O)-5-6 membered heteroaryl, or -NHC(O)-5-6 membered heteroaryl, which is optionally selected from 1, 2, 3, 4 or 5 CN, halo, oxo, -C _1-6 alkylene-OH, C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl or 5- substituted with a 6-membered heterocyclyl;

Alternatively, R ₂ is selected from H, D, halo, NH ₂ , -C _0-6 alkylene-OH, -OC _1-6 alkylene-OH, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxyl, C _1-6 haloalkoxyl and 5-membered heteroaryl, which is optionally substituted with 1, 2 or 3 halo;

Alternatively, R ₂ is selected from H, D, halo, NH ₂ , -C _0-4 alkylene-OH, -OC _1-4 alkylene-OH, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxyl, C _1-4 haloalkoxyl and 5-membered heteroaryl, which is optionally substituted with 1 or 2 halo;

Alternatively, R ₂ is selected from H, D, halo, NH ₂ , -C _0-6 alkylene-OH, -OC _1-6 alkylene-OH, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxyl, and C _1-6 haloalkoxyl;

Alternatively, R ₂ is selected from H, D, halo, NH ₂ , -C _0-4 alkylene-OH, -OC _1-4 alkylene-OH, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxyl, and C _1-4 haloalkoxyl;

Alternatively, R ₂ is selected from H, D, halo, -C _0-6 alkylene-OH, -OC _1-6 alkylene-OH, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxyl, and C _1-6 haloalkoxyl;

Alternatively, R ₂ is selected from H, D, halo, -C _0-4 alkylene-OH, -OC _1-4 alkylene-OH, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxyl, and C _1-4 haloalkoxyl;

Alternatively, R ₂ is selected from H, D, halo, -C _0-6 alkylene-OH, NH ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxyl, C _5-6 cycloalkyl, 5-6 membered heterocyclyl, C _6-10 aryl, 5-10 membered heteroaryl, -O-5-6 membered heteroaryl, -NH-5-6 membered heteroaryl, -OC(O)-5-6 membered heteroaryl, or -NHC(O)-5-6 membered heteroaryl; which is optionally substituted with 1, 2, 3, 4 or 5 CN, halo, oxo, -C _1-6 alkylene-OH, C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl or 5-6 membered heterocyclyl;

Alternatively, R ₂ is selected from H, D, halo, C _1-4 alkyl and C _1-4 haloalkyl;

Alternatively, R ₂ is selected from H, D, halo, -C _0-6 alkylene-OH, NH ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxyl, C _1-6 haloalkoxyl, -T C _5-6 cycloalkyl, -T-5 to 6 membered heterocyclyl, -T C _6-10 aryl and -T-5 to 6 membered heteroaryl, which is optionally substituted with 1, 2, 3, 4 or 5 halo, oxo, C _1-6 alkyl or C _1-6 haloalkyl;

Alternatively, R ₂ is selected from H, D, halo, -C _0-6 alkylene-OH, NH ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxyl, C _5-6 cycloalkyl, 5-6 membered heterocyclyl, C _6-10 aryl, 5-6 membered heteroaryl, -O-5-6 membered heteroaryl, and -NH-5-6 membered heteroaryl; which is optionally substituted with 1, 2, 3, 4 or 5 oxo, C _1-6 alkyl or C _1-6 haloalkyl;

Alternatively, R ₂ is selected from H, D, halo, NH ₂ , -C _0-6 alkylene-OH, -OC _1-6 alkylene-OH, -C(O)C _1-6 alkyl, -C(O)C _1-6 haloalkyl, C _1-6 alkyl, C _1-6 haloalkyl, C _{1-6 alkoxyl, C 1-6} haloalkoxyl and 5-membered heteroaryl, which is optionally substituted with 1, 2 or 3 halo;

Alternatively, R ₂ is selected from H, D, halo, NH ₂ , -C _0-4 alkylene-OH, -OC _1-4 alkylene-OH, -C(O)C _1-4 alkyl, -C(O)C _1-4 haloalkyl, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxyl, C _1-4 haloalkoxyl and 5-membered heteroaryl, which is optionally substituted with 1 or 2 halo;

Alternatively, R ₂ is selected from H, D, halo, NH ₂ , -C _0-6 alkylene-OH, -OC _1-6 alkylene-OH, -C(O)C _1-6 alkyl, -C(O)C _1-6 haloalkyl, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxyl, and C _1-6 haloalkoxyl;

Alternatively, R ₂ is selected from H, D, halo, NH ₂ , -C _0-4 alkylene-OH, -OC _1-4 alkylene-OH, -C(O)C _1-4 alkyl, -C(O)C _1-4 haloalkyl, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxyl, and C _1-4 haloalkoxyl;

Alternatively, R ₂ is selected from H, D, halo, OH, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxyl, C _1-6 haloalkoxyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _{2-6 alkynyl, and C 2-6 haloalkynyl} ;

Alternatively, R ₂ is selected from H, D, halo, OH, C _1-6 alkoxyl and C _1-6 haloalkoxyl;

Alternatively, R ₂ is H, D, halo, -C _0-6 alkylene-OH, NH ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxyl, C _1-6 haloalkoxyl,

or selected from;

Alternatively, R ₂ is H, D, Cl, OH, Me, CH ₂ F, CHF ₂ , CF ₃ , OMe, CH ₂ OH, NH ₂ ,

, which is optionally substituted with 1, 2, 3, 4 or 5 CN, halo, -C _1-6 alkylene-OH, C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl or 5-6 membered heterocyclyl;

Alternatively, R ₂ is H, D, halo, -C _0-6 alkylene-OH, NH ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxyl, C _1-6 haloalkoxyl,

, which is optionally substituted with 1, 2, 3, 4 or 5 CN, halo, C _1-6 alkyl, C _1-6 haloalkyl or C _3-6 cycloalkyl;

Alternatively, R ₂ is H, D, halo, -C _0-6 alkylene-OH, NH ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxyl, C _1-6 haloalkoxyl,

or selected from;

Alternatively, R ₂ is H, D, Cl, OH, NH ₂ , Me, CH ₂ F, CHF ₂ , CF ₃ , OMe, CH ₂ OH,

or selected from;

Alternatively, R ₂ is H, D, Cl, OH, Me, CH ₂ F, CHF ₂ , CF ₃ , OMe, CH ₂ OH, NH ₂ ,

, which is optionally substituted with 1, 2, 3, 4 or 5 C _1-6 alkyl or C _1-6 haloalkyl;

Alternatively, R ₂ is H, D, halo, -C _0-6 alkylene-OH, NH ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxyl, C _1-6 haloalkoxyl,

, which is optionally substituted with 1, 2, 3, 4 or 5 C _1-6 alkyl or C _1-6 haloalkyl;

Alternatively, R ₂ is H, D, halo, -C _0-6 alkylene-OH, NH ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxyl, C _1-6 haloalkoxyl,

or selected from;

Alternatively, R ₂ is H, D, Cl, OH, NH ₂ , Me, CH ₂ F, CHF ₂ , CF ₃ , OMe, CH ₂ OH,

or selected from;

Alternatively, R ₂ can be H, D, Cl, Br, OH, Me, CH ₂ F, CHF ₂ , CF ₃ , OMe, OCH ₂ CH ₂ OH, CH ₂ OH, NH ₂ , or selected from;

Alternatively, R ₂ can be H, D, Cl, Br, OH, Me, CH ₂ F, CHF ₂ , CF ₃ , OMe, OCH ₂ CH ₂ OH, CH ₂ OH, NH ₂ , and selected from;

Alternatively, R ₂ is H, D, Cl, Br, OH, Me, CH ₂ F, CHF ₂ , CF ₃ , OMe, OCH ₂ CH ₂ OH, CH ₂ OH, -C(O)Me, NH ₂ , or selected from;

Alternatively, R ₂ is selected from H, D, Cl, Br, OH, Me, CH ₂ F, CHF ₂ , CF ₃ , OMe, OCH ₂ CH ₂ OH, CH ₂ OH, -C(O)Me, and NH ₂ ;

Alternatively, R ₂ is selected from H, D, Cl, Br, OH, Me, CH ₂ F, CHF ₂ , CF ₃ , OMe, OCH ₂ CH ₂ OH, CH ₂ OH, and NH ₂ ;

Alternatively, R ₂ is selected from H, D, Cl, Br, OH, Me, CH ₂ F, CHF ₂ , CF ₃ , OMe, OCH ₂ CH ₂ OH, and CH ₂ OH;

Alternatively, R ₂ is selected from H, D, halo, CN, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxyl, C 1-6 haloalkoxyl, C _2-4 alkenyl, C _2-4 haloalkenyl, C _2-4 alkynyl, C _2-4 haloalkynyl, C _4-6 cycloalkyl and 5-6 membered heterocyclyl _;

Alternatively, R ₂ is selected from H, D, halo, CN, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxyl, C 1-6 haloalkoxyl, C _2-4 alkenyl, C _2-4 haloalkenyl, C _2-4 alkynyl, C _2-4 haloalkynyl and C _{3-8 cycloalkyl} ;

Alternatively, R ₂ is selected from H, D, halo, C _1-6 alkyl, C _1-6 haloalkyl and C _3-6 cycloalkyl;

Alternatively, R ₂ is selected from H, D, halo, OH, C _1-6 alkyl and C _1-6 haloalkyl;

Alternatively, R ₂ is selected from H, D, halo, OH, C _1-4 alkyl and C _1-4 haloalkyl;

Alternatively, R ₂ is selected from H, D, C _1-6 alkyl and C _1-6 haloalkyl;

Alternatively, R ₂ is selected from C _1-6 alkyl and C _1-6 haloalkyl;

Alternatively, R ₂ is H, D, F, Cl, CN, Me, Et, iPr, OMe, cyclopropyl, CH=CH ₂ , C≡CH, or selected from;

Alternatively, R ₂ is H, D, F, Cl, CN, Me, Et, iPr, OMe, cyclopropyl, CH=CH ₂ , C≡CH, or selected from;

Alternatively, R ₂ is selected from H, D, Cl, OH, Me, CH ₂ F, CHF ₂ and CF ₃ ;

Alternatively, R ₂ is selected from H, D, Cl, OH, OMe and OCHF ₂ ;

Alternatively, R ₂ is selected from H, D, Cl, Me and cyclopropyl;

Alternatively, R ₂ is selected from H, D, Me and CF ₃ ;

Alternatively, R ₂ is selected from H, D and Me;

Alternatively, R ₂ is selected from H and D;

Or, a compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein R ₂ is Me.

14. In any one of claims 1 to 13, R ₃ is selected from H, D, halo, OH, C _1-6 alkyl and C _1-6 haloalkyl;

Alternatively, R ₃ is selected from H, D, halo, C _1-6 alkyl and C _1-6 haloalkyl;

Alternatively, R ₃ is selected from H, D, halo and OH;

Alternatively, R ₃ is selected from H, D and halo;

Alternatively, R ₃ is selected from H, D, halo, OH, C _1-6 alkoxyl and C _1-6 haloalkoxyl;

Alternatively, R ₃ is selected from H, D, halo, OH, C _1-4 alkoxyl and C _1-4 haloalkoxyl;

Alternatively, R ₃ is selected from H, D, F, Br, OH and OMe;

Alternatively, R ₃ is selected from H, D, F, Br and OH;

Alternatively, R ₃ is selected from H, D, F and OH;

Alternatively, R ₃ is selected from H, D and OH;

Alternatively, R ₃ is selected from H, D and F;

Alternatively, R ₃ is selected from H and D, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof.

15. In any one of paragraphs 1 to 14, R ₄ is selected from H, D, halo, C _1-6 alkyl and C _1-6 haloalkyl;

Alternatively, R ₄ is selected from H, D and halo;

Alternatively, R ₄ is selected from H, D, F, and Me;

Alternatively, R ₄ is selected from H, D and F;

Alternatively, R ₄ is selected from H and D, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof.

16. In any one of paragraphs 1 to 15, R ₁ and R ₂ together with the carbon atom to which they are connected form a 5- to 6-membered heterocyclyl, phenyl or a 5- to 6-membered heteroaryl;

Alternatively, R ₁ and R ₂ together with the carbon atoms to which they are connected form phenyl or a 5- to 6-membered heteroaryl;

Alternatively, R ₁ and R ₂ together with the carbon atoms to which they are connected form C _5-6 cycloalkyl or phenyl;

Alternatively, R ₁ and R ₂ together with the carbon atoms to which they are connected , which is optionally substituted with 1, 2 or 3 halo, CN, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C 2-6 haloalkenyl, C _2-6 alkynyl, C _2-6 haloalkynyl, or _{C 2-6 alkynyl} -substituted phenyl;

Alternatively, R ₁ and R ₂ together with the carbon atoms to which they are connected , which is optionally substituted with 1, 2 or 3 halo, CN or C _2-6 alkynyl-substituted phenyl;

Alternatively, R ₁ and R ₂ together with the carbon atoms to which they are connected , which is optionally substituted with 1 or 2 Br or C _2-6 alkynyl-substituted phenyl;

Alternatively, R ₁ and R ₂ together with the carbon atoms to which they are connected , which is optionally substituted with 1, 2 or 3 halo or C _2-6 alkynyl-substituted phenyl;

Alternatively, R ₁ and R ₂ together with the carbon atoms to which they are connected , which is optionally substituted with 1 or 2 Br or C _2-6 alkynyl-substituted phenyl;

Alternatively, R ₁ and R ₂ together with the carbon atoms to which they are connected , which is optionally substituted with Br or C _2-6 alkynyl-substituted phenyl;

Alternatively, R ₁ and R ₂ together with the carbon atoms to which they are connected , which is optionally substituted with 1, 2 or 3 halo, C _1-6 alkyl or C _1-6 haloalkyl;

Alternatively, R ₁ and R ₂ together with the carbon atoms to which they are connected , which is optionally substituted with 1, 2 or 3 halo, C _1-6 alkyl or C _1-6 haloalkyl;

Alternatively, R ₁ and R ₂ together with the carbon atoms to which they are connected , which is optionally substituted with 1, 2 or 3 halo, CN, C _1-6 alkyl, C _1-6 haloalkyl, -C(O)C _1-6 alkyl, or -C(O)C _1-6 haloalkyl;

Alternatively, R ₁ and R ₂ together with the carbon atoms to which they are connected , which is optionally substituted with 1, 2 or 3 halo, CN, C _1-6 alkyl or C _1-6 haloalkyl;

Alternatively, R ₁ and R ₂ together with the carbon atoms to which they are connected to form or;

Alternatively, R ₁ and R ₂ together with the carbon atoms to which they are connected to form or;

Alternatively, R ₁ and R ₂ together with the carbon atoms to which they are connected to form or;

Alternatively, R ₁ and R ₂ together with the carbon atoms to which they are connected to form or;

Alternatively, R ₁ and R ₂ together with the carbon atoms to which they are connected to form or;

Alternatively, R ₁ and R ₂ together with the carbon atoms to which they are connected to form or;

Alternatively, R ₁ and R ₂ together with the carbon atoms to which they are connected to form or;

Alternatively, R ₁ and R ₂ together with the carbon atoms to which they are connected to form or;

Alternatively, R ₁ and R ₂ together with the carbon atoms to which they are connected to form or;

Alternatively, R ₁ and R ₂ together with the carbon atoms to which they are connected to form or;

Alternatively, R ₁ and R ₂ together with the carbon atoms to which they are connected to form or;

Alternatively, R ₁ and R ₂ together with the carbon atoms to which they are connected to form or;

Alternatively, R ₁ and R ₂ together with the carbon atoms to which they are connected to form or;

Alternatively, R ₁ and R ₂ together with the carbon atoms to which they are connected A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, which forms a compound.

17. In any one of paragraphs 1 to 16, R ₂ and R ₃ together with the carbon atoms to which they are connected form a 5- to 7-membered heterocyclyl, which is optionally substituted with 1, 2, 3 or 4 halo, C _1-6 alkyl, C _1-6 haloalkyl, -C _1-6 alkylene-C _1-6 alkoxyl or -C _1-6 alkylene-C _1-6 haloalkoxyl;

Alternatively, R ₂ and R ₃ together with the carbon atoms to which they are connected form a C _5-6 cycloalkyl or a 5- to 7-membered heterocyclyl;

Alternatively, R ₂ and R ₃ together with the carbon atoms to which they are connected form a 5- to 7-membered heterocyclyl, which is optionally substituted with 1, 2, 3 or 4 halo, C _1-6 alkyl or C _1-6 haloalkyl;

Alternatively, R ₂ and R ₃ together with the carbon atoms to which they are connected form a 5- to 6-membered heterocyclyl, which is optionally substituted with 1, 2, 3 or 4 halo, C _1-6 alkyl, C _1-6 haloalkyl, -C(O)C _1-6 alkyl, or -C(O)C _1-6 haloalkyl;

Alternatively, R ₂ and R ₃ together with the carbon atoms to which they are connected form a 5- to 6-membered heterocyclyl, which is optionally substituted with 1, 2, 3 or 4 halo;

Alternatively, R ₂ and R ₃ together with the carbon atoms to which they are connected form a C _5-6 cycloalkyl or a 5- to 6-membered heterocyclyl;

Alternatively, R ₂ and R ₃ together with the carbon atoms to which they are connected to form or;

Alternatively, R ₂ and R ₃ together with the carbon atoms to which they are connected to form or;

Alternatively, R ₂ and R ₃ together with the carbon atoms to which they are connected to form or;

Alternatively, R ₂ and R ₃ together with the carbon atoms to which they are connected to form or;

Alternatively, R ₂ and R ₃ together with the carbon atoms to which they are connected to form or;

Alternatively, R ₂ and R ₃ together with the carbon atoms to which they are connected to form or;

Alternatively, R ₂ and R ₃ together with the carbon atoms to which they are connected to form or;

Alternatively, R ₂ and R ₃ together with the carbon atoms to which they are connected to form or;

Alternatively, R ₂ and R ₃ together with the carbon atoms to which they are connected to form or;

Alternatively, R ₂ and R ₃ together with the carbon atoms to which they are connected to form or;

Alternatively, R ₂ and R ₃ together with the carbon atoms to which they are connected A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, which forms a compound.

18. In any one of claims 1 to 17, R _1s is selected from H, D, OH, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _{2-6 alkynyl, and C 2-6 haloalkynyl} ; or

Alternatively, R _1s is selected from H, D, -C _0-6 alkylene-OH, C _1-4 alkyl, C _1-4 haloalkyl, C _2-4 alkenyl, C _2-4 haloalkenyl, C _2-4 alkynyl, and C _2-4 haloalkynyl;

Alternatively, R _1s is selected from H, D, OH, C _1-4 alkyl, C _1-4 haloalkyl, C _2-4 alkenyl, C _2-4 haloalkenyl, C _2-4 alkynyl, and C _2-4 haloalkynyl;

Alternatively, R _1s is selected from C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl and phenyl;

Alternatively, R _1s is selected from C _1-6 alkyl, C _1-6 haloalkyl, and C _3-6 cycloalkyl;

Alternatively, R _1s is selected from C _1-4 alkyl, C _1-4 haloalkyl, C _2-4 alkenyl, and C _2-4 haloalkenyl;

Alternatively, R _1s is selected from C _1-4 alkyl, C _1-4 haloalkyl, and C _2-4 alkenyl;

Alternatively, R _1s is selected from C _1-6 alkyl and C _1-6 haloalkyl;

Alternatively, R _1s is selected from C _1-4 alkyl and C _1-4 haloalkyl;

Alternatively, R _1s is selected from H, D, C _1-6 alkyl and C _1-6 haloalkyl;

Alternatively, R _1s is selected from H, C _1-6 alkyl and C _1-6 haloalkyl;

Alternatively, R _1s is selected from H, D, OH, Me, Et, iPr, CH ₂ F, CHF ₂ , CF ₃ , CH ₂ OH, CH=CH ₂ , and C≡CH;

Alternatively, R _1s is selected from H, D, OH, Me, Et, iPr, CF ₃ , CH=CH ₂ , and C≡CH;

Alternatively, R _1s is selected from H, D, Me, CHF ₂ , and CF ₃ ;

Alternatively, R _1s is selected from H, D, Me and CHF ₂ ;

Alternatively, R _1s is selected from H, Me and Et;

Alternatively, R _1s is selected from H and Me;

Alternatively, R _1s is selected from Me, cyclopropyl and phenyl;

Alternatively, R _1s is selected from Me, Et, CH ₂ F, CHF ₂ , CF ₃ , and CH=CH ₂ ;

Alternatively, R _1s is selected from Me, Et, CF ₃ , and CH=CH ₂ ;

Alternatively, R _1s is selected from Me and cyclopropyl;

Alternatively, R _1s is selected from Me and CHF ₂ ;

Alternatively, R _1s is Me;

Alternatively, R _1s is H, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof.

19. In any one of paragraphs 1 to 18, R _2s is selected from H, D, C _1-6 alkyl and C _1-6 haloalkyl;

Alternatively, R _2s is selected from H, D, C _1-4 alkyl and C _1-4 haloalkyl;

Alternatively, R _2s is selected from C _1-6 alkyl and C _1-6 haloalkyl;

Alternatively, R _2s is selected from C _1-4 alkyl and C _1-4 haloalkyl;

Alternatively, R _2s is selected from H, D and Me;

Alternatively, R _2s is selected from H and D;

Alternatively, R _2s is Me, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof.

20. In any one of paragraphs 1 to 19, R _2s is C(R _2s1 )(R _2s2 )(R _2s3 ), and R _2s1 is selected from H, D, -C _0-6 alkylene-OH, C _1-6 alkyl, C _1-6 haloalkyl, C 2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, C _2-6 haloalkynyl _{, and C 3-6 cycloalkyl} ;

Alternatively, R _2s1 is selected from H, D, -C _0-6 alkylene-OR _x , -C _0-6 alkylene-NR _y R _z , C _1-6 alkyl, C _1-6 haloalkyl, and C _3-6 cycloalkyl;

Alternatively, R _2s1 is selected from H, D, -C _0-6 alkylene-OR _x , -C _0-6 alkylene-NR _y R _z , C _1-6 alkyl, and C _1-6 haloalkyl;

Alternatively, R _2s1 is selected from -C _0-6 alkylene-OR _x , C _1-6 alkyl, C _1-6 haloalkyl, and C _3-6 cycloalkyl;

Alternatively, R _2s1 is selected from -C _0-6 alkylene-OH, C _1-6 alkyl and C _1-6 haloalkyl;

Alternatively, R _2s1 is selected from H, D, -C _0-4 alkylene-OH, C _1-4 alkyl, C _1-4 haloalkyl, C _2-4 alkenyl, C _2-4 haloalkenyl, C _2-4 alkynyl, C _2-4 haloalkynyl and C _3-6 cycloalkyl;

Alternatively, R _2s1 is selected from H, D, -C _0-6 alkylene-OH, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, and C _2-4 haloalkynyl;

Alternatively, R _2s1 is selected from H, D, -C _0-4 alkylene-OH, C _1-4 alkyl, C _1-4 haloalkyl, C _2-4 alkenyl, C _2-4 haloalkenyl, C _2-4 alkynyl, and C _2-4 haloalkynyl;

Alternatively, R _2s1 is selected from H, D, C _1-6 alkyl and C _1-6 haloalkyl;

Alternatively, R _2s1 is selected from H, D, C _1-4 alkyl and C _1-4 haloalkyl;

Alternatively, R _2s1 is selected from H, D, -C _0-6 alkylene-OR _x , -C _0-6 alkylene-NR _y R _z , C _1-6 alkyl, and C _1-6 haloalkyl;

Alternatively, R _2s1 is selected from -C _0-6 alkylene-OR _x , C _1-6 alkyl and C _1-6 haloalkyl;

Alternatively, R _2s1 is selected from C _1-6 alkyl and C _1-6 haloalkyl;

Alternatively, R _2s1 is selected from H, D, OH, Me, Et, CH ₂ F, CHF ₂ , CF ₃ , CH ₂ OH, CH ₂ CH ₂ OH, C≡CH, and cyclopropyl;

Alternatively, R _2s1 is selected from H, D, OH, Me, Et, CH ₂ F, CHF ₂ , CF ₃ , CH ₂ OH, CH ₂ CH ₂ OH, and C≡CH;

Alternatively, R _2s1 is selected from H, D and Me;

Alternatively, R _2s1 is selected from Me, CH ₂ F, CH ₂ OH, CH ₂ OCH ₃ , and cyclopropyl;

Alternatively, R _2s1 is selected from Me, CH ₂ F, CH ₂ OH, and cyclopropyl;

Alternatively, R _2s1 is selected from Me, Et, iPr, CH ₂ F, CHF ₂ , and CH ₂ OH;

Alternatively, R _2s1 is selected from Me, Et, iPr, CH ₂ F, and CHF ₂ ;

Alternatively, R _2s1 is selected from Me, and CH ₂ OH;

Alternatively, R _2s1 is Me, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof.

21. In any one of paragraphs 1 to 20, R _2s is C(R _2s1 )(R _2s2 )(R _2s3 ), and R _2s2 is selected from H, D, -C _1-4 alkylene-OH, C _{1-4 alkyl, and C 1-4 haloalkyl} ;

Alternatively, R _2s2 is H, D, C _1-6 alkyl or C _1-6 haloalkyl;

Alternatively, R _2s2 is H, D, C _1-4 alkyl or C _1-4 haloalkyl;

Alternatively, R _2s2 is selected from C _1-6 alkyl and C _1-6 haloalkyl;

Alternatively, R _2s2 is selected from H, D and Me;

Alternatively, R _2s2 is Me, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof.

22. In any one of paragraphs 1 to 21, R _2s is C(R _2s1 )(R _2s2 )(R _2s3 ), and R _2s3 is C _1-6 alkyl, or C _1-6 haloalkyl;

Alternatively, R _2s3 is selected from C _1-6 alkyl and C _1-6 haloalkyl;

Alternatively, R _2s3 is C _1-4 alkyl or C _1-4 haloalkyl;

Alternatively, R _2s3 is Me, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof.

23. In any one of paragraphs 1 to 22, R _2s is C(R _2s1 )(R _2s2 )(R _2s3 ), and R _2s2 and R _2s3 together with the carbon atom to which they are connected form C _3-6 cycloalkyl; or

Alternatively, R _2s2 and R _2s3 together with the carbon atom to which they are connected form a cyclopropyl, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotopic variant, prodrug or crystalline form thereof.

24. In any one of paragraphs 1 to 23, R _2s is C(R _2s1 )(R _2s2 )(R _2s3 ), and R _2s1 and R _2s2 together with the carbon atom to which they are connected form C _3-6 cycloalkyl; or

Alternatively, R _2s1 and R _2s2 together with the carbon atoms to which they are connected form a C _3-5 cycloalkyl;

Alternatively, R _2s1 and R _2s2 together with the carbon atom to which they are connected form a cyclopropyl, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotopic variant, prodrug or crystalline form thereof.

25. In any one of paragraphs 1 to 24, R _2s is C(R _2s1 )(R _2s2 )(R _2s3 ), and R _1s and R _2s3 together with the carbon atom to which they are connected form a 4- to 7-membered heterocyclyl, which is optionally substituted with 1 or 2 halo;

Alternatively, R _1s and R _2s3 together with the atoms to which they are connected form a 5- to 7-membered heterocyclyl, which is optionally substituted with 1 or 2 halo;

Alternatively, R _1s and R _2s3 together with the atoms to which they are connected form a 5-membered heterocyclyl, which is optionally substituted with 1 or 2 halo;

Alternatively, R _1s and R _2s3 together with the atoms to which they are connected form a 4- to 6-membered heterocyclyl; or

Alternatively, R _1s and R _2s3 together with the atoms to which they are connected form a 4- to 5-membered heterocyclyl, which is optionally substituted with OH;

Alternatively, R _1s and R _2s3 together with the atoms to which they are connected form a 4- to 5-membered heterocyclyl, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotopic variant, prodrug or crystalline form thereof.

26. In any one of claims 1 to 25, R _3s is selected from H, D, C _1-6 alkyl and C _1-6 haloalkyl;

Alternatively, R _3s is selected from C _1-4 alkyl and C _1-4 haloalkyl;

Alternatively, R _3s is selected from H and D;

Alternatively, R _3s is Me, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof.

27. In any one of paragraphs 1 to 26, R _2s and R _3s together with the carbon atom to which they are connected form C _3-6 cycloalkyl, which is optionally substituted with 1 or 2 halo, C _1-6 alkyl or C _1-6 haloalkyl;

Alternatively, R _2s and R _3s together with the carbon atoms to which they are connected form a C _3-5 cycloalkyl, which is optionally substituted with 1 or 2 halo;

Alternatively, R _2s and R _3s together with the carbon atoms to which they are connected form a C _3-4 cycloalkyl, which is optionally substituted with 1 or 2 halo;

Alternatively, R _2s and R _3s together with the carbon atoms to which they are connected form a C _3-4 cycloalkyl;

Alternatively, R _2s and R _3s together with the carbon atoms to which they are connected form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, which is optionally substituted with 1 or 2 F or Me;

Alternatively, R _2s and R _3s together with the carbon atoms to which they are connected form cyclopropyl, cyclobutyl or cyclopentyl, which is optionally substituted with 1 or 2 F;

Alternatively, R _2s and R _3s together with the carbon atoms to which they are connected form cyclopropyl or cyclobutyl, which is optionally substituted with 1 or 2 F;

Alternatively, R _2s and R _3s together with the carbon atom to which they are connected form a cyclopropyl, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotopic variant, prodrug or crystalline form thereof.

28. In any one of paragraphs 1 to 27, R _2s1 , R _2s2 and R _2s3 together with the carbon atoms to which they are connected form a C _4-8 bridged bicycloalkyl, which is optionally substituted with 1 or 2 halo, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _{2-6 alkynyl and C 2-6 haloalkynyl} ;

Alternatively, R _2s1 , R _2s2 and R _2s3 together with the carbon atoms to which they are connected form a C4-8 bridged bicycloalkyl, which is optionally substituted with 1, 2 or 3 halo, C _1-6 alkyl or C _1-6 haloalkyl;

Alternatively, R _2s1 , R _2s2 and R _2s3 together with the carbon atoms to which they are connected form a C _4-8 bridged bicycloalkyl; or

Alternatively, R _2s1 , R _2s2 and R _2s3 together with the carbon atoms to which they are connected to form or;

Alternatively, R _2s1 , R _2s2 and R _2s3 together with the carbon atoms to which they are connected to form or;

Alternatively, R _2s1 , R _2s2 and R _2s3 together with the carbon atoms to which they are connected A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, which forms a compound.

29. In any one of paragraphs 1 to 28, R _1s , R _2s and R _3s together with the carbon atoms to which they are connected form a C _4-8 bridged bicycloalkyl; or

Alternatively, R _1s , R _2s and R _3s together with the carbon atoms to which they are connected to form or;

Alternatively, R _1s , R _2s and R _3s together with the carbon atoms to which they are connected and forms; wherein Y ₁ is CR ₁₁ or N; Y ₂ is CR ₁₂ or N; R ₁₁ and R ₁₃ are independently selected from H, D, C _1-6 alkyl and C _1-6 haloalkyl; R ₁₂ is selected from H and D;

Alternatively, R _1s , R _2s and R _3s together with the carbon atoms to which they are connected and forms; wherein Y ₁ is CR ₁₁ ; Y ₂ is CR ₁₂ ; R ₁₁ and R ₁₃ are independently selected from H, D, C _1-6 alkyl and C _1-6 haloalkyl; R ₁₂ is selected from H and D; or

Alternatively, R _1s , R _2s and R _3s together with the carbon atoms to which they are connected and forms; wherein Y ₁ is CR ₁₁ ; Y ₂ is CR ₁₂ ; R ₁₁ is selected from H, D, C _1-6 alkyl and C _1-6 haloalkyl; R ₁₂ and R ₁₃ are independently selected from H and D; or

Alternatively, R _1s , R _2s and R _3s together with the carbon atoms to which they are connected A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein Y ₁ is CR ₁₁ ; Y ₂ is CR ₁₂ ; and R ₁₁ , R ₁₂ and R ₁₃ are independently selected from H and D.

30. A compound according to any one of claims 1 to 29, wherein the compound has a chemical formula selected from the following, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug, or crystalline form thereof:

and

In the above equations, the variables are as defined in any one of the first to 29th clauses.

31. In claim 30, a compound of formula (II), or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof:

In the above chemical formula,

M ₁ is selected from CR ₁ and N, preferably CR ₁ ;

M ₂ is selected from CR ₂ and N, preferably CR ₂ ;

M ₃ is selected from CR ₃ and N, preferably CR ₃ ;

M ₄ is selected from CR ₄ and N, preferably CR ₄ ;

Y is selected from -C(O)-, -C(S)-, -C(N-OH)-, -S(O)-, and -S(O) ₂ -;

Ring A is selected from phenyl and 5- to 9-membered heteroaryl;

wherein R _a is selected from H, D, halo, NO ₂ , NH ₂ , -C _1-6 alkylene-OH, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, C _2-6 haloalkynyl and amino protecting group, and m=0, 1, 2, 3, 4 or 5; or two adjacent R _a together with the atoms to which they are connected form phenyl or a 5- to 6-membered heteroaryl;

R ₁ and R ₄ are independently selected from H, D and halo;

R ₂ is selected from H, D, halo, -C _0-6 alkylene-OH, NH ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxyl, C _1-6 haloalkoxyl, -T C _5-6 cycloalkyl, -T-5 to 10 membered heterocyclyl, -T C _6-10 aryl and -T-5 to 10 membered heteroaryl, which is optionally substituted with 1, 2, 3, 4 or 5 CN, halo, oxo, -C _1-6 alkylene-OH, C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl or 5 to 6 membered heterocyclyl;

Here, T is a chemical bond, -O-, -S- or -NH-;

R ₃ is selected from H, D, halo, CN, -C _0-6 alkylene-OH, -C _0-6 alkylene-NH ₂ , C _1-6 alkyl and C _1-6 haloalkyl;

Alternatively, R ₁ and R ₂ together with the carbon atoms to which they are connected form a 5- to 6-membered heterocyclyl, phenyl or a 5- to 6-membered heteroaryl;

Alternatively, R ₂ and R ₃ together with the carbon atoms to which they are connected form a 5-6 membered heterocyclyl, which is optionally substituted with 1, 2, 3 or 4 halo, C _1-6 alkyl, C _1-6 haloalkyl, -C(O)C _1-6 alkyl, or -C(O)C _1-6 haloalkyl;

Alternatively, R _1s is selected from H, D, -C _0-6 alkylene-OH, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, and C _2-6 haloalkynyl;

R _2s is selected from H, D, C _1-6 alkyl and C _1-6 haloalkyl;

R _3s is selected from C _1-6 alkyl and C _1-6 haloalkyl;

Alternatively, R _2s and R _3s together with the carbon atoms to which they are connected form a C _3-6 cycloalkyl, which is optionally substituted with 1 or 2 halo, C _1-6 alkyl or C _1-6 haloalkyl;

Alternatively, R _1s , R _2s and R _3s together with the carbon atoms to which they are connected form a C _4-8 bridged bicycloalkyl;

The above-mentioned atoms may be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated.

32. In paragraph 31,

M ₁ is selected from CR ₁ and N, preferably CR ₁ ;

M ₂ is selected from CR ₂ and N, preferably CR ₂ ;

M ₃ is selected from CR ₃ and N, preferably CR ₃ ;

M ₄ is selected from CR ₄ and N, preferably CR ₄ ;

Y is selected from -C(O)-, -C(S)-, -C(N-OH)-, -S(O)-, and -S(O) ₂ -;

Ring A is

and is selected from;

wherein R _a is selected from H, D, halo, NO ₂ , NH ₂ , -C _1-6 alkylene-OH, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, C _2-6 haloalkynyl and amino protecting group, and m=0, 1, 2, 3, 4 or 5; or two adjacent R _a together with the atoms to which they are connected form phenyl or a 5- to 6-membered heteroaryl;

R ₁ and R ₄ are independently selected from H, D and halo;

R ₂ is selected from H, D, halo, -C _0-6 alkylene-OH, NH ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxyl, C _5-6 cycloalkyl, 5-6 membered heterocyclyl, C _6-10 aryl, 5-10 membered heteroaryl, -O-5-6 membered heteroaryl, -NH-5-6 membered heteroaryl, -OC(O)-5-6 membered heteroaryl, or -NHC(O)-5-6 membered heteroaryl; which is optionally substituted with 1, 2, 3, 4 or 5 CN, halo, oxo, -C _1-6 alkylene-OH, C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl or 5-6 membered heterocyclyl;

R ₃ is selected from H, D, halo, OH, C _1-6 alkyl and C _1-6 haloalkyl;

Alternatively, R ₁ and R ₂ together with the carbon atoms to which they are connected form a 5- to 6-membered heterocyclyl, phenyl or a 5- to 6-membered heteroaryl;

Alternatively, R ₂ and R ₃ together with the carbon atoms to which they are connected form a 5-6 membered heterocyclyl, which is optionally substituted with 1, 2, 3 or 4 halo, C _1-6 alkyl, C _1-6 haloalkyl, -C(O)C _1-6 alkyl, or -C(O)C _1-6 haloalkyl;

R _1s is selected from H, D, -C _0-6 alkylene-OH, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, and C _2-6 haloalkynyl;

R _2s is selected from H, D, C _1-6 alkyl and C _1-6 haloalkyl;

R _3s is selected from C _1-6 alkyl and C _1-6 haloalkyl;

Alternatively, R _2s and R _3s together with the carbon atoms to which they are connected form a C _3-6 cycloalkyl, which is optionally substituted with 1 or 2 halo, C _1-6 alkyl or C _1-6 haloalkyl;

Alternatively, R _1s , R _2s and R _3s together with the carbon atoms to which they are connected form a C _4-8 bridged bicycloalkyl;

A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated.

33. In paragraph 30, a compound of chemical formula (II-1), or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof:

In the above chemical formula,

M ₁ is selected from CR ₁ and N, preferably CR ₁ ;

M ₂ is selected from CR ₂ and N, preferably CR ₂ ;

M ₃ is selected from CR ₃ and N, preferably CR ₃ ;

M ₄ is selected from CR ₄ and N, preferably CR ₄ ;

X is selected from O, S and N-OH;

Ring A is

is selected from;

At this time, R _a is selected from H and D, and m=0, 1, 2, 3, 4 or 5;

R ₁ is selected from H, D, F, and Cl;

Alternatively, R ₂ is H, D, Cl, OH, Me, CH ₂ F, CHF ₂ , CF ₃ , OMe, CH ₂ OH, NH ₂ ,

, which is optionally substituted with 1, 2, 3, 4 or 5 CN, halo, -C _1-6 alkylene-OH, C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl or 5-6 membered heterocyclyl;

R ₃ is selected from H, D, F, Br and OH;

R ₄ is selected from H, D and F;

Alternatively, R ₁ and R ₂ together with the carbon atoms to which they are connected to form or;

Alternatively, R ₂ and R ₃ together with the carbon atoms to which they are connected , forming;

R _1s is selected from H, D, OH, Me, Et, iPr, CH ₂ F, CHF ₂ , CF ₃ , CH ₂ OH, CH=CH ₂ , and C≡CH;

R _2s is selected from H, D and Me;

R _3s is Me;

Alternatively, R _2s and R _3s together with the carbon atoms to which they are connected form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, which is optionally substituted with 1 or 2 F or Me;

Alternatively, R _1s , R _2s and R _3s together with the carbon atoms to which they are connected to form;

The above-mentioned atoms may be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated.

34. In paragraph 33,

M ₁ is selected from CR ₁ and N, preferably CR ₁ ;

M ₂ is selected from CR ₂ and N, preferably CR ₂ ;

M ₃ is selected from CR ₃ and N, preferably CR ₃ ;

M ₄ is selected from CR ₄ and N, preferably CR ₄ ;

X is selected from O, S and N-OH;

Ring A is

is selected from;

wherein R _a is selected from H, D, halo, NO ₂ , NH ₂ , -C _1-6 alkylene-OH, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkynyl, C _2-6 haloalkynyl and amino protecting group, and m=0, 1, 2, 3, 4 or 5; or two adjacent R _a form phenyl or 5-6 membered heteroaryl together with the atoms to which they are connected;

R ₁ and R ₄ are independently selected from H, D and halo;

R ₂ is H, D, halo, -C _0-6 alkylene-OH, NH ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxyl, C _1-6 haloalkoxyl,

, which is optionally substituted with 1, 2, 3, 4 or 5 CN, halo, C _1-6 alkyl, C _1-6 haloalkyl or C _3-6 cycloalkyl;

R ₃ is selected from H, D, halo, OH, C _1-6 alkyl and C _1-6 haloalkyl;

Alternatively, R ₁ and R ₂ together with the carbon atoms to which they are connected form phenyl or a 5- to 6-membered heteroaryl;

Alternatively, R ₂ and R ₃ together with the carbon atoms to which they are connected form a 5-6 membered heterocyclyl, which is optionally substituted with 1, 2, 3 or 4 halo, C _1-6 alkyl, C _1-6 haloalkyl, -C(O)C _1-6 alkyl, or -C(O)C _1-6 haloalkyl;

R _1s is selected from H, D, -C _0-6 alkylene-OH, C _1-4 alkyl, C _1-4 haloalkyl, C _2-4 alkenyl, C _2-4 haloalkenyl, C _2-4 alkynyl, and C _2-4 haloalkynyl;

R _2s is selected from H, D, C _1-4 alkyl and C _1-4 haloalkyl;

R _3s is selected from C _1-4 alkyl and C _1-4 haloalkyl;

Alternatively, R ₂ and R ₃ together with the carbon atoms to which they are connected form a C _3-5 cycloalkyl, which is optionally substituted with 1 or 2 halo;

Alternatively, R _1s , R _2s and R _3s together with the carbon atoms to which they are connected form a C _4-8 bridged bicycloalkyl;

A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated.

35. In paragraph 30, a compound of chemical formula (II-2), or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof:

In the above chemical formula,

M ₁ is selected from CR ₁ and N, preferably CR ₁ ;

M ₂ is selected from CR ₂ and N, preferably CR ₂ ;

M ₃ is selected from CR ₃ and N, preferably CR ₃ ;

M ₄ is selected from CR ₄ and N, preferably CR ₄ ;

Ring A is selected from phenyl and 5- to 6-membered heteroaryl;

wherein R _a is selected from C _3-6 cycloalkyl, 4-6 membered heterocyclyl, phenyl and 5-6 membered heteroaryl, which is optionally substituted with 1, 2 or 3 halo, oxo, OR _x , NR _y R _z , C _1-6 alkyl or C _1-6 haloalkyl, and m is 1, 2 or 3;

R ₁ is selected from H, D, halo, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxyl, C _1-6 haloalkoxyl, C 2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, C _2-6 haloalkynyl _{, C 3-8 cycloalkyl} and 4- to 10-membered heterocyclyl;

R ₂ is selected from H, D, halo, OH, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxyl, C _1-6 haloalkoxyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, and C _2-6 haloalkynyl;

R ₃ and R ₄ are independently selected from H, D, halo, C _1-6 alkyl and C _1-6 haloalkyl;

Alternatively, R ₁ and R ₂ together with the carbon atoms to which they are connected , which is optionally substituted with 1, 2 or 3 halo, C _1-6 alkyl or C _1-6 haloalkyl;

R _1s , R _2s and R _3s are independently selected from H, D, C _1-6 alkyl and C _1-6 haloalkyl;

Alternatively, R _2s and R _3s together with the carbon atoms to which they are connected form a C _3-6 cycloalkyl;

Alternatively, R _2s1 , R _2s2 and R _2s3 together with the carbon atoms to which they are connected form a C _4-8 bridged bicycloalkyl, which is optionally substituted with 1 or 2 halo, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl and C _2-6 haloalkynyl;

The above-mentioned atoms may be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated.

36. In paragraph 35,

M ₁ is selected from CR ₁ and N, preferably CR ₁ ;

M ₂ is selected from CR ₂ and N, preferably CR ₂ ;

M ₃ is selected from CR ₃ and N, preferably CR ₃ ;

M ₄ is selected from CR ₄ and N, preferably CR ₄ ;

Ring A is and;

At this time, R _a is is selected from, m = 1, 2 or 3;

R ₁ is selected from H, D, halo, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxyl, C _1-6 haloalkoxyl, C 2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, C _2-6 haloalkynyl _{, C 3-8 cycloalkyl} and 4- to 10-membered heterocyclyl;

R ₂ is selected from H, D, halo, OH, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxyl, C _1-6 haloalkoxyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, and C _2-6 haloalkynyl;

R ₃ and R ₄ are independently selected from H, D, halo, C _1-6 alkyl and C _1-6 haloalkyl;

Alternatively, R ₁ and R ₂ together with the carbon atoms to which they are connected to form;

R _1s , R _2s and R _3s are independently selected from H, D, C _1-6 alkyl and C _1-6 haloalkyl;

Alternatively, R _2s and R _3s together with the carbon atoms to which they are connected form a C _3-5 cycloalkyl;

Alternatively, R _2s1 , R _2s2 and R _2s3 together with the carbon atoms to which they are connected form a C _4-8 bridged bicycloalkyl;

A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated.

37. In paragraph 36,

M ₁ is selected from CR ₁ and N, preferably CR ₁ ;

M ₂ is selected from CR ₂ and N, preferably CR ₂ ;

M ₃ is selected from CR ₃ and N, preferably CR ₃ ;

M ₄ is selected from CR ₄ and N, preferably CR ₄ ;

Ring A is and;

At this time, R _a is is selected from, m = 1, 2 or 3;

R ₁ , R ₂ , R ₃ and R ₄ are independently selected from H, D and halo;

Alternatively, R ₁ and R ₂ together with the carbon atoms to which they are connected to form;

R _1s is selected from H, D, C _1-6 alkyl and C _1-6 haloalkyl;

R _2s and R _3s are independently selected from H and D;

Alternatively, R _2s and R _3s together with the carbon atoms to which they are connected form a C _3-5 cycloalkyl;

A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated.

38. In paragraph 37,

M ₁ is selected from CR ₁ and N, preferably CR ₁ ;

M ₂ is selected from CR ₂ and N, preferably CR ₂ ;

M ₃ is selected from CR ₃ and N, preferably CR ₃ ;

M ₄ is selected from CR ₄ and N, preferably CR ₄ ;

Ring A is and;

At this time, R _a is is selected from, m = 1, 2 or 3;

R ₁ , R ₂ , R ₃ and R ₄ are independently selected from H, D and halo;

Alternatively, R ₁ and R ₂ together with the carbon atoms to which they are connected to form;

R _1s is selected from H, D, Me and CHF ₂ ;

R _2s and R _3s are independently selected from H and D;

Alternatively, R _2s and R _3s together with the carbon atoms to which they are connected form cyclopropyl;

A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated.

39. In paragraph 30, a compound of chemical formula (II-2), or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof:

In the above chemical formula,

M ₁ is selected from CR ₁ and N, preferably CR ₁ ;

M ₂ is selected from CR ₂ and N, preferably CR ₂ ;

M ₃ is selected from CR ₃ and N, preferably CR ₃ ;

M ₄ is selected from CR ₄ and N, preferably CR ₄ ;

Ring A is is selected from;

At this time, R _a is selected from H and D, and m=0, 1, 2, 3, 4 or 5;

R ₁ and R ₂ together with the carbon atoms to which they are connected , which is optionally substituted with 1, 2 or 3 halo, C _1-6 alkyl or C _1-6 haloalkyl;

R ₃ and R ₄ are independently selected from H, D, halo, C _1-6 alkyl and C _1-6 haloalkyl;

R _1s is selected from H, D, C _1-6 alkyl and C _1-6 haloalkyl;

R _2s and R _3s together with the carbon atoms to which they are connected form C _3-6 cycloalkyl;

The above-mentioned atoms may be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated.

40. In paragraph 39,

M ₁ is selected from CR ₁ and N, preferably CR ₁ ;

M ₂ is selected from CR ₂ and N, preferably CR ₂ ;

M ₃ is selected from CR ₃ and N, preferably CR ₃ ;

M ₄ is selected from CR ₄ and N, preferably CR ₄ ;

Ring A is is selected from;

At this time, R _a is selected from H and D, and m=0, 1, 2, 3, 4 or 5;

R ₁ and R ₂ together with the carbon atoms to which they are connected to form;

R ₃ is selected from H and D;

R ₄ is selected from H, D and halo;

R _1s is selected from H, D, C _1-6 alkyl and C _1-6 haloalkyl;

R _2s and R _3s together with the carbon atoms to which they are connected form a C _3-5 cycloalkyl;

A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated.

41. In paragraph 40,

M ₁ is selected from CR ₁ and N, preferably CR ₁ ;

M ₂ is selected from CR ₂ and N, preferably CR ₂ ;

M ₃ is selected from CR ₃ and N, preferably CR ₃ ;

M ₄ is selected from CR ₄ and N, preferably CR ₄ ;

Ring A is is selected from;

At this time, R _a is selected from H and D, and m=0, 1, 2, 3, 4 or 5;

R ₁ and R ₂ together with the carbon atoms to which they are connected to form;

R ₃ is selected from H and D;

R ₄ is selected from H, D and F;

R _1s is selected from H, D, Me, CHF ₂ , and CF ₃ ;

R _2s and R _3s together with the carbon atoms to which they are connected form cyclopropyl;

A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated.

42. In paragraph 40,

M ₁ is selected from CR ₁ and N, preferably CR ₁ ;

M ₂ is selected from CR ₂ and N, preferably CR ₂ ;

M ₃ is selected from CR ₃ and N, preferably CR ₃ ;

M ₄ is selected from CR ₄ and N, preferably CR ₄ ;

Ring A is and;

At this time, R _a is selected from H and D, and m=0, 1, 2, 3, 4 or 5;

R ₁ and R ₂ together with the carbon atoms to which they are connected , which is optionally substituted with 1, 2 or 3 halo, C _1-6 alkyl or C _1-6 haloalkyl;

R ₃ and R ₄ are independently selected from H, D, halo, C _1-6 alkyl and C _1-6 haloalkyl;

R _1s is selected from H, D, C _1-6 alkyl and C _1-6 haloalkyl;

R _2s and R _3s together with the carbon atoms to which they are connected form C _3-6 cycloalkyl;

A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated.

43. In paragraph 42,

M ₁ is selected from CR ₁ and N, preferably CR ₁ ;

M ₂ is selected from CR ₂ and N, preferably CR ₂ ;

M ₃ is selected from CR ₃ and N, preferably CR ₃ ;

M ₄ is selected from CR ₄ and N, preferably CR ₄ ;

Ring A is and;

At this time, R _a is selected from H and D, and m=0, 1, 2, 3, 4 or 5;

R ₁ and R ₂ together with the carbon atoms to which they are connected to form;

R ₃ is selected from H and D;

R ₄ is selected from H, D and halo;

R _1s is selected from H, D, C _1-6 alkyl and C _1-6 haloalkyl;

R _2s and R _3s together with the carbon atoms to which they are connected form a C _3-5 cycloalkyl;

A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated.

44. In paragraph 43,

M ₁ is selected from CR ₁ and N, preferably CR ₁ ;

M ₂ is selected from CR ₂ and N, preferably CR ₂ ;

M ₃ is selected from CR ₃ and N, preferably CR ₃ ;

M ₄ is selected from CR ₄ and N, preferably CR ₄ ;

Ring A is and;

At this time, R _a is selected from H and D, and m=0, 1, 2, 3, 4 or 5;

R ₁ and R ₂ together with the carbon atoms to which they are connected to form;

R ₃ is selected from H and D;

R ₄ is selected from H, D and F;

R _1s is selected from H, D, Me, CHF ₂ , and CF ₃ ;

R _2s and R _3s together with the carbon atoms to which they are connected form cyclopropyl;

A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated.

45. In paragraph 30, a compound of chemical formula (II-2), or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof:

In the above chemical formula,

M ₁ is selected from CR ₁ and N, preferably CR ₁ ;

M ₂ is selected from CR ₂ and N, preferably CR ₂ ;

M ₃ is selected from CR ₃ and N, preferably CR ₃ ;

M ₄ is selected from CR ₄ and N, preferably CR ₄ ;

Ring A is

is selected from;

At this time, R _a is selected from H and D, and m = 1, 2, or 3;

R ₁ and R ₄ are independently selected from H, D and halo;

R ₂ and R ₃ together with the carbon atoms to which they are connected to form;

R _1s is selected from C _1-6 alkyl and C _1-6 haloalkyl;

R _2s and R _3s together with the carbon atoms to which they are connected form C _3-6 cycloalkyl;

The above-mentioned atoms may be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated.

46. In paragraph 45,

M ₁ is selected from CR ₁ and N, preferably CR ₁ ;

M ₂ is selected from CR ₂ and N, preferably CR ₂ ;

M ₃ is selected from CR ₃ and N, preferably CR ₃ ;

M ₄ is selected from CR ₄ and N, preferably CR ₄ ;

Ring A is

is selected from;

At this time, R _a is selected from H and D, and m = 1, 2, or 3;

R ₁ is halo;

R ₂ and R ₃ together with the carbon atoms to which they are connected to form;

R ₄ is selected from H and D;

R _1s is selected from C _1-6 alkyl and C _1-6 haloalkyl;

R _2s and R _3s together with the carbon atoms to which they are connected form a C _3-5 cycloalkyl;

A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated.

47. In paragraph 46,

M ₁ is selected from CR ₁ and N, preferably CR ₁ ;

M ₂ is selected from CR ₂ and N, preferably CR ₂ ;

M ₃ is selected from CR ₃ and N, preferably CR ₃ ;

M ₄ is selected from CR ₄ and N, preferably CR ₄ ;

Ring A is

is selected from;

At this time, R _a is selected from H and D, and m = 1, 2, or 3;

R ₁ is selected from F, and Cl;

R ₂ and R ₃ together with the carbon atoms to which they are connected to form;

R ₄ is selected from H and D;

R _1s is selected from Me and CHF ₂ ;

R _2s and R _3s together with the carbon atoms to which they are connected form cyclopropyl;

A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated.

48. In paragraph 46,

M ₁ is selected from CR ₁ and N, preferably CR ₁ ;

M ₂ is selected from CR ₂ and N, preferably CR ₂ ;

M ₃ is selected from CR ₃ and N, preferably CR ₃ ;

M ₄ is selected from CR ₄ and N, preferably CR ₄ ;

Ring A is is selected from;

At this time, R _a is selected from H and D, and m = 1, 2, or 3;

R ₁ and R ₄ are independently selected from H, D and halo;

R ₂ and R ₃ together with the carbon atoms to which they are connected to form;

R _1s is selected from C _1-6 alkyl and C _1-6 haloalkyl;

R _2s and R _3s together with the carbon atoms to which they are connected form C _3-6 cycloalkyl;

A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated.

49. In paragraph 48,

M ₁ is selected from CR ₁ and N, preferably CR ₁ ;

M ₂ is selected from CR ₂ and N, preferably CR ₂ ;

M ₃ is selected from CR ₃ and N, preferably CR ₃ ;

M ₄ is selected from CR ₄ and N, preferably CR ₄ ;

Ring A is is selected from;

At this time, R _a is selected from H and D, and m = 1, 2, or 3;

R ₁ is halo;

R ₂ and R ₃ together with the carbon atoms to which they are connected to form;

R ₄ is selected from H and D;

R _1s is selected from C _1-6 alkyl and C _1-6 haloalkyl;

R _2s and R _3s together with the carbon atoms to which they are connected form a C _3-5 cycloalkyl;

A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated.

50. In paragraph 49,

M ₁ is selected from CR ₁ and N, preferably CR ₁ ;

M ₂ is selected from CR ₂ and N, preferably CR ₂ ;

M ₃ is selected from CR ₃ and N, preferably CR ₃ ;

M ₄ is selected from CR ₄ and N, preferably CR ₄ ;

Ring A is is selected from;

At this time, R _a is selected from H and D, and m = 1, 2, or 3;

R ₁ is selected from F, and Cl;

R ₂ and R ₃ together with the carbon atoms to which they are connected to form;

R ₄ is selected from H and D;

R _1s is selected from Me and CHF ₂ ;

R _2s and R _3s together with the carbon atoms to which they are connected form cyclopropyl;

A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated.

51. In paragraph 30, a compound of chemical formula (II-2), or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof:

In the above chemical formula,

M ₁ is selected from CR ₁ and N, preferably CR ₁ ;

M ₂ is selected from CR ₂ and N, preferably CR ₂ ;

M ₃ is selected from CR ₃ and N, preferably CR ₃ ;

M ₄ is selected from CR ₄ and N, preferably CR ₄ ;

Ring A is is selected from;

wherein R _a is selected from H, D, halo, NO ₂ , NH ₂ , -C _1-6 alkylene-OH, C _2-4 alkynyl, C _2-4 haloalkynyl and Boc, and m = 0, 1, 2, 3, 4 or 5;

R ₁ and R ₄ are independently selected from H, D and halo;

R ₂ is H, D, halo, -C _0-6 alkylene-OH, NH ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxyl, C _1-6 haloalkoxyl,

is selected from;

R ₃ is selected from H, D, halo, OH, C _1-6 alkyl and C _1-6 haloalkyl;

Alternatively, R ₁ and R ₂ together with the carbon atoms to which they are connected form phenyl or a 5- to 6-membered heteroaryl;

Alternatively, R ₂ and R ₃ together with the carbon atoms to which they are connected form a 5-6 membered heterocyclyl, which is optionally substituted with 1, 2, 3 or 4 halo, C _1-6 alkyl, C _1-6 haloalkyl, -C(O)C _1-6 alkyl, or -C(O)C _1-6 haloalkyl;

R _1s is selected from H, D, OH, C _1-4 alkyl, C _1-4 haloalkyl, C _2-4 alkenyl, C _2-4 haloalkenyl, C _2-4 alkynyl, and C _2-4 haloalkynyl;

R _2s is selected from H, D, C _1-4 alkyl and C _1-4 haloalkyl;

R _3s is selected from C _1-4 alkyl and C _1-4 haloalkyl;

Alternatively, R ₂ and R ₃ together with the carbon atoms to which they are connected form a C _3-5 cycloalkyl, which is optionally substituted with 1 or 2 halo;

Alternatively, R _1s , R _2s and R _3s together with the carbon atoms to which they are connected form a C _4-8 bridged bicycloalkyl;

The above-mentioned atoms may be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated.

52. In paragraph 51,

M ₁ is selected from CR ₁ and N, preferably CR ₁ ;

M ₂ is selected from CR ₂ and N, preferably CR ₂ ;

M ₃ is selected from CR ₃ and N, preferably CR ₃ ;

M ₄ is selected from CR ₄ and N, preferably CR ₄ ;

Ring A is

is selected from;

At this time, R _a is selected from H and D, and m=0, 1, 2, 3, 4 or 5;

R ₁ is selected from H, D, F, and Cl;

Alternatively, R ₂ is H, D, Cl, OH, NH ₂ , Me, CH ₂ F, CHF ₂ , CF ₃ , OMe, CH ₂ OH, is selected from;

R ₃ is selected from H, D, F, Br and OH;

R ₄ is selected from H, D and F;

Alternatively, R ₁ and R ₂ are linked together with the carbon atoms to which they are attached. form or;

Alternatively, R ₂ and R ₃ together with the carbon atoms to which they are connected , forming;

R _1s is selected from H, D, OH, Me, Et, iPr, CH ₂ F, CHF ₂ , CF ₃ , CH ₂ OH, CH=CH ₂ , and C≡CH;

R _2s is selected from H, D and Me;

R _3s is Me;

Alternatively, R _2s and R _3s together with the carbon atoms to which they are connected form cyclopropyl, cyclobutyl or cyclopentyl, which is optionally substituted with 1 or 2 F;

Alternatively, R _1s , R _2s and R _3s together with the carbon atoms to which they are connected to form;

A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated.

53. In paragraph 51,

M ₁ is selected from CR ₁ and N, preferably CR ₁ ;

M ₂ is selected from CR ₂ and N, preferably CR ₂ ;

M ₃ is selected from CR ₃ and N, preferably CR ₃ ;

M ₄ is selected from CR ₄ and N, preferably CR ₄ ;

Ring A is is selected from;

wherein R _a is selected from H, D, halo, C _1-6 alkyl, and C _1-6 haloalkyl, and m=0, 1, 2, or 3;

R ₁ and R ₄ are independently selected from H, D and halo;

R ₂ and R ₃ are independently selected from H, D, halo, OH, C _1-6 alkyl and C _1-6 haloalkyl;

Alternatively, R ₂ and R ₃ together with the carbon atoms to which they are connected form a 5- to 6-membered heterocyclyl, which is optionally substituted with 1, 2, 3 or 4 halo;

R _1s is selected from C _1-4 alkyl, C _1-4 haloalkyl, C _2-4 alkenyl, and C _2-4 haloalkenyl;

R _2s and R _3s together with the carbon atoms to which they are connected form a C _3-4 cycloalkyl, which is optionally substituted with 1 or 2 halo;

A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated.

54. In paragraph 51,

M ₁ is selected from CR ₁ and N, preferably CR ₁ ;

M ₂ is selected from CR ₂ and N, preferably CR ₂ ;

M ₃ is selected from CR ₃ and N, preferably CR ₃ ;

M ₄ is selected from CR ₄ and N, preferably CR ₄ ;

Ring A is is selected from;

Here, R _a is selected from H, D and halo, and m = 0, 1, 2 or 3;

R ₁ and R ₄ are independently selected from H, D and halo;

R ₂ is selected from H, D, halo, C _1-4 alkyl and C _1-4 haloalkyl;

R ₃ is selected from H, D, halo and OH;

Alternatively, R ₂ and R ₃ are linked together with the carbon atoms to which they are attached. to form;

R _1s is selected from C _1-4 alkyl, C _1-4 haloalkyl, and C _2-4 alkenyl;

R _2s and R _3s together with the carbon atoms to which they are connected form a C _3-4 cycloalkyl, which is optionally substituted with 1 or 2 halo;

A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated.

55. In paragraph 51,

M ₁ is selected from CR ₁ and N, preferably CR ₁ ;

M ₂ is selected from CR ₂ and N, preferably CR ₂ ;

M ₃ is selected from CR ₃ and N, preferably CR ₃ ;

M ₄ is selected from CR ₄ and N, preferably CR ₄ ;

Ring A is is selected from;

At this time, R _a is selected from H and D, and m=0, 1, 2, or 3;

R ₁ is selected from H, D, F, and Cl;

R ₂ is selected from H, D, Cl, OH, Me, CH ₂ F, CHF ₂ and CF ₃ ;

R ₃ is selected from H, D, F and OH;

R ₄ is selected from H, D and F;

Alternatively, R ₂ and R ₃ together with the carbon atoms to which they are connected to form;

R _1s is selected from Me, Et, CH ₂ F, CHF ₂ , CF ₃ , and CH=CH ₂ ;

R _2s and R _3s together with the carbon atoms to which they are connected form cyclopropyl or cyclobutyl, which is optionally substituted with 1 or 2 F;

A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated.

56. In paragraph 30, a compound of chemical formula (III-1), or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof:

In the above chemical formula,

M ₁ is selected from CR ₁ and N, preferably CR ₁ ;

M ₂ is selected from CR ₂ and N, preferably CR ₂ ;

M ₃ is selected from CR ₃ and N, preferably CR ₃ ;

M ₄ is selected from CR ₄ and N, preferably CR ₄ ;

Ring A is

is selected from;

wherein R _a is selected from H, D, halo, CN, C _1-6 alkyl, and C _1-6 haloalkyl, and m=0, 1, 2, 3, 4, or 5;

R ₁ is selected from H, D, halo, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxyl and C _1-6 haloalkoxyl;

R ₂ is selected from H, D, halo, CN, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxyl, C _1-6 haloalkoxyl, C _{2-4 alkenyl, C 2-4 haloalkenyl, C 2-4 alkynyl ,} C _2-4 haloalkynyl, C _4-6 cycloalkyl and 5-6 membered heterocyclyl;

R ₃ is selected from H, D, halo, C _1-6 alkyl and C _1-6 haloalkyl;

R ₄ is selected from H, D, halo, C _1-6 alkyl and C _1-6 haloalkyl;

Alternatively, R ₁ and R ₂ together with the carbon atoms to which they are connected form C _5-6 cycloalkyl, 5-6 membered heterocyclyl, phenyl and 5-6 membered heteroaryl;

Y ₁ is CR ₁₁ or N;

Y ₂ is CR ₁₂ or N;

R ₁₁ and R ₁₃ are independently selected from H, D, C _1-6 alkyl and C _1-6 haloalkyl;

R ₁₂ is selected from H and D;

A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated.

57. In paragraph 30, a compound of chemical formula (III-2), or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof:

In the above chemical formula,

M ₁ is selected from CR ₁ and N, preferably CR ₁ ;

M ₂ is selected from CR ₂ and N, preferably CR ₂ ;

M ₃ is selected from CR ₃ and N, preferably CR ₃ ;

M ₄ is selected from CR ₄ and N, preferably CR ₄ ;

Ring A is is selected from;

wherein R _a is selected from H, D, halo, C _1-6 alkyl, and C _1-6 haloalkyl, and m=0, 1, 2, 3, or 4;

R ₁ is selected from H, D, halo, C _1-6 alkyl and C _1-6 haloalkyl;

R ₂ is selected from H, D, C _1-6 alkyl and C _1-6 haloalkyl;

R ₃ is selected from H and D;

R ₄ is selected from H, D and halo;

Alternatively, R ₁ and R ₂ together with the carbon atoms to which they are connected to form;

R ₁₁ , R ₁₂ and R ₁₃ are independently selected from H and D;

The above-mentioned atoms may be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated.

58. In paragraph 57, ring A A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof selected from.

59. In paragraph 57,

M ₁ is selected from CR ₁ and N, preferably CR ₁ ;

M ₂ is selected from CR ₂ and N, preferably CR ₂ ;

M ₃ is selected from CR ₃ and N, preferably CR ₃ ;

M ₄ is selected from CR ₄ and N, preferably CR ₄ ;

Ring A is is selected from;

At this time, R _a is selected from H, D, F, and Me, and m = 0, 1, 2, 3, or 4;

R ₁ is selected from H, D, F, and Me;

R ₂ is selected from H, D, Me and CF ₃ ;

R ₃ is selected from H and D;

R ₄ is selected from H, D and F;

Alternatively, R ₁ and R ₂ together with the carbon atoms to which they are connected to form;

R ₁₁ , R ₁₂ and R ₁₃ are independently selected from H and D;

A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups may be substituted with 1, 2, 3 or 4 deuterium atoms.

60. In paragraph 57,

M ₁ is selected from CR ₁ and N, preferably CR ₁ ;

M ₂ is selected from CR ₂ and N, preferably CR ₂ ;

M ₃ is selected from CR ₃ and N, preferably CR ₃ ;

M ₄ is selected from CR ₄ and N, preferably CR ₄ ;

Ring A is is selected from;

Here, R _a is selected from H, D and halo, and m = 0, 1, 2 or 3;

R ₁ is selected from H, D and halo;

R ₂ is Me;

R ₃ is selected from H and D;

R ₄ is selected from H, D and halo;

R ₁₁ , R ₁₂ and R ₁₃ are independently selected from H and D;

A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups may be substituted with 1, 2 or 3 deuterium atoms.

61. In paragraph 57,

M ₁ is selected from CR ₁ and N, preferably CR ₁ ;

M ₂ is selected from CR ₂ and N, preferably CR ₂ ;

M ₃ is selected from CR ₃ and N, preferably CR ₃ ;

M ₄ is selected from CR ₄ and N, preferably CR ₄ ;

Ring A is is selected from;

At this time, R _a is selected from H, D and F, and m = 0, 1, 2 or 3;

R ₁ is selected from H, D and F;

R ₂ is Me;

R ₃ is selected from H and D;

R ₄ is selected from H, D and F;

R ₁₁ , R ₁₂ and R ₁₃ are independently selected from H and D;

A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups may be substituted with 1, 2 or 3 deuterium atoms.

62. In paragraph 57,

M ₁ is selected from CR ₁ and N, preferably CR ₁ ;

M ₂ is selected from CR ₂ and N, preferably CR ₂ ;

M ₃ is selected from CR ₃ and N, preferably CR ₃ ;

M ₄ is selected from CR ₄ and N, preferably CR ₄ ;

Ring A is is selected from;

wherein R _a is selected from H, D, halo, CN, C _1-6 alkyl, and C _1-6 haloalkyl, and m=0, 1, 2, 3, 4, or 5;

R ₁ is selected from H, D, halo, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxyl and C _1-6 haloalkoxyl;

R ₂ is selected from H, D, halo, CN, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxyl, C _1-6 haloalkoxyl, C _{2-4 alkenyl, C 2-4 haloalkenyl, C 2-4 alkynyl ,} C _2-4 haloalkynyl, C _4-6 cycloalkyl and 5-6 membered heterocyclyl;

R ₃ is selected from H, D and halo;

R ₄ is selected from H, D, halo, C _1-6 alkyl and C _1-6 haloalkyl;

Alternatively, R ₁ and R ₂ together with the carbon atoms to which they are connected form C _5-6 cycloalkyl, 5-6 membered heterocyclyl, phenyl and 5-6 membered heteroaryl;

R ₁₁ and R ₁₃ are independently selected from H, D, C _1-6 alkyl and C _1-6 haloalkyl;

R ₁₂ is selected from H and D;

A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated.

63. In paragraph 57,

M ₁ is selected from CR ₁ and N, preferably CR ₁ ;

M ₂ is selected from CR ₂ and N, preferably CR ₂ ;

M ₃ is selected from CR ₃ and N, preferably CR ₃ ;

M ₄ is selected from CR ₄ and N, preferably CR ₄ ;

Ring A is is selected from;

At this time, R _a is selected from H, D, F, Cl, Br, CN and Me, and m = 0, 1, 2, 3, 4 or 5;

R ₁ is selected from H, D, F, Me, and OMe;

R ₂ is H, D, F, Cl, CN, Me, Et, iPr, OMe, cyclopropyl, CH=CH ₂ , C≡CH, is selected from;

R ₃ is selected from H, D and F;

R ₄ is selected from H, D, F, and Me;

Alternatively, R ₁ and R ₂ together with the carbon atoms to which they are connected to form;

R ₁₁ and R ₁₃ are independently selected from H, D and Me;

R ₁₂ is selected from H and D;

A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated.

64. In paragraph 57,

M ₁ is selected from CR ₁ and N, preferably CR ₁ ;

M ₂ is selected from CR ₂ and N, preferably CR ₂ ;

M ₃ is selected from CR ₃ and N, preferably CR ₃ ;

M ₄ is selected from CR ₄ and N, preferably CR ₄ ;

Ring A is is selected from;

wherein R _a is selected from H, D, halo, CN, C _1-6 alkyl, and C _1-6 haloalkyl, and m=0, 1, 2, 3, 4, or 5;

R ₁ is selected from H, D, halo, C _1-6 alkyl and C _1-6 haloalkyl;

R ₂ is selected from H, D, halo, CN, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxyl, C _1-6 haloalkoxyl, C _2-4 alkenyl, C _2-4 haloalkenyl, C _2-4 alkynyl, C 2-4 haloalkynyl and C _3-8 cycloalkyl _;

R ₃ is selected from H, D and halo;

R ₄ is selected from H, D, halo, C _1-6 alkyl and C _1-6 haloalkyl;

Alternatively, R ₁ and R ₂ together with the carbon atoms to which they are connected form C _5-6 cycloalkyl or phenyl;

R ₁₁ is selected from H, D, C _1-6 alkyl and C _1-6 haloalkyl;

R ₁₂ and R ₁₃ are independently selected from H and D;

A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated.

65. In paragraph 57,

M ₁ is selected from CR ₁ and N, preferably CR ₁ ;

M ₂ is selected from CR ₂ and N, preferably CR ₂ ;

M ₃ is selected from CR ₃ and N, preferably CR ₃ ;

M ₄ is selected from CR ₄ and N, preferably CR ₄ ;

Ring A is is selected from;

At this time, R _a is selected from H, D, F, Cl, Br, CN and Me, and m = 0, 1, 2, 3, 4 or 5;

R ₁ is selected from H, D, F, and Me;

R ₂ is H, D, F, Cl, CN, Me, Et, iPr, OMe, cyclopropyl, CH=CH ₂ , C≡CH, is selected from;

R ₃ is selected from H, D and F;

R ₄ is selected from H, D, F, and Me;

Alternatively, R ₁ and R ₂ together with the carbon atoms to which they are connected to form;

R ₁₁ is selected from H, D, and Me;

R ₁₂ and R ₁₃ are independently selected from H and D;

A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated.

66. In paragraph 57,

M ₁ is selected from CR ₁ and N, preferably CR ₁ ;

M ₂ is selected from CR ₂ and N, preferably CR ₂ ;

M ₃ is selected from CR ₃ and N, preferably CR ₃ ;

M ₄ is selected from CR ₄ and N, preferably CR ₄ ;

Ring A is and;

At this time, R _a is selected from H and D, and m=0, 1, 2, 3, 4 or 5;

R ₁ , R ₃ and R ₄ are independently selected from H, D and halo;

R ₂ is selected from H, D, halo, C _1-6 alkyl, C _1-6 haloalkyl and C _3-6 cycloalkyl;

R ₁₁ is selected from H, D, C _1-6 alkyl and C _1-6 haloalkyl;

R ₁₂ and R ₁₃ are independently selected from H and D;

A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated.

67. In paragraph 57,

M ₁ is selected from CR ₁ and N, preferably CR ₁ ;

M ₂ is selected from CR ₂ and N, preferably CR ₂ ;

M ₃ is selected from CR ₃ and N, preferably CR ₃ ;

M ₄ is selected from CR ₄ and N, preferably CR ₄ ;

Ring A is and;

At this time, R _a is selected from H and D, and m=0, 1, 2, 3, 4 or 5;

R ₁ , R ₃ and R ₄ are independently selected from H, D and F;

R ₂ is selected from H, D, Cl, Me and cyclopropyl;

R ₁₁ is selected from H, D, and Me;

R ₁₂ and R ₁₃ are independently selected from H and D;

A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated.

68. In claim 30, a compound of formula (IV), or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof:

In the above chemical formula,

M ₁ is selected from CR ₁ and N, preferably CR ₁ ;

M ₂ is selected from CR ₂ and N, preferably CR ₂ ;

M ₃ is selected from CR ₃ and N, preferably CR ₃ ;

M ₄ is selected from CR ₄ and N, preferably CR ₄ ;

Ring A is selected from phenyl and 5- to 6-membered heteroaryl;

wherein R _a is selected from C _3-6 cycloalkyl, 4-6 membered heterocyclyl, phenyl and 5-6 membered heteroaryl, which is optionally substituted with 1, 2 or 3 halo, oxo, OR _x , NR _y R _z , C _1-6 alkyl or C _1-6 haloalkyl, and m is 1, 2 or 3;

R ₁ is selected from H, D, halo, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxyl, C _1-6 haloalkoxyl, C 2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, C _2-6 haloalkynyl _{, C 3-8 cycloalkyl} and 4- to 10-membered heterocyclyl;

R ₂ is selected from H, D, halo, OH, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxyl, C _1-6 haloalkoxyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, and C _2-6 haloalkynyl;

R ₃ and R ₄ are independently selected from H, D, halo, C _1-6 alkyl and C _1-6 haloalkyl;

Alternatively, R ₁ and R ₂ together with the carbon atoms to which they are connected , which is optionally substituted with 1, 2 or 3 halo, C _1-6 alkyl or C _1-6 haloalkyl;

Alternatively, R ₂ and R ₃ together with the carbon atoms to which they are connected form a C _5-6 cycloalkyl or a 5- to 7-membered heterocyclyl;

R _1s is H;

R _2s1 is selected from -C _0-6 alkylene-OR _x , -C _0-6 alkylene-NR _y R _z , C _1-6 alkyl, and C _1-6 haloalkyl;

R _2s2 and R _2s3 are independently selected from C _1-6 alkyl and C _1-6 haloalkyl;

Alternatively, R _2s2 and R _2s3 together with the carbon atoms to which they are connected form a C _3-6 cycloalkyl;

Alternatively, R _2s1 , R _2s2 and R _2s3 together with the carbon atoms to which they are connected form a C _4-8 bridged bicycloalkyl, which is optionally substituted with 1 or 2 halo, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl and C _2-6 haloalkynyl;

R _x , R _y and R _z are independently selected from H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, C _2-6 haloalkynyl, C _3-8 cycloalkyl and 4- to 6-membered heterocyclyl; or R _y and R _z together with the nitrogen atom to which they are connected form a 4- to 6-membered heterocyclyl;

The above-mentioned atoms may be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated.

69. In paragraph 68,

M ₁ is selected from CR ₁ and N, preferably CR ₁ ;

M ₂ is selected from CR ₂ and N, preferably CR ₂ ;

M ₃ is selected from CR ₃ and N, preferably CR ₃ ;

M ₄ is selected from CR ₄ and N, preferably CR ₄ ;

Ring A is is selected from;

At this time, R _a is is selected from, m = 1, 2 or 3;

R ₁ is selected from H, D, halo, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxyl, C _1-6 haloalkoxyl, C 2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, C _2-6 haloalkynyl _{, C 3-8 cycloalkyl} and 4- to 10-membered heterocyclyl;

R ₂ is selected from H, D, halo, OH, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxyl, C _1-6 haloalkoxyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, and C _2-6 haloalkynyl;

R ₃ and R ₄ are independently selected from H, D, halo, C _1-6 alkyl and C _1-6 haloalkyl;

Alternatively, R ₁ and R ₂ together with the carbon atoms to which they are connected , which is optionally substituted with 1, 2 or 3 halo, C _1-6 alkyl or C _1-6 haloalkyl;

Alternatively, R ₂ and R ₃ together with the carbon atoms to which they are connected form a C _5-6 cycloalkyl or a 5- to 7-membered heterocyclyl;

R _1s is H;

R _2s1 is selected from -C _0-6 alkylene-OR _x , -C _0-6 alkylene-NR _y R _z , C _1-6 alkyl, and C _1-6 haloalkyl;

R _2s2 and R _2s3 are independently selected from C _1-6 alkyl and C _1-6 haloalkyl;

Alternatively, R _2s2 and R _2s3 together with the carbon atoms to which they are connected form a C _3-6 cycloalkyl;

Alternatively, R _2s1 , R _2s2 and R _2s3 together with the carbon atoms to which they are connected form a C _4-8 bridged bicycloalkyl;

R _x , R _y and R _z are independently selected from H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, C _2-6 haloalkynyl, C _3-8 cycloalkyl and 4- to 6-membered heterocyclyl; or R _y and R _z together with the nitrogen atom to which they are connected form a 4- to 6-membered heterocyclyl;

A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated.

70. In paragraph 69,

M ₁ is selected from CR ₁ and N, preferably CR ₁ ;

M ₂ is selected from CR ₂ and N, preferably CR ₂ ;

M ₃ is selected from CR ₃ and N, preferably CR ₃ ;

M ₄ is selected from CR ₄ and N, preferably CR ₄ ;

Ring A is is selected from;

At this time, R _a is R _a is is selected from, m = 1, 2 or 3;

R ₁ is selected from H, D, halo, C _1-6 alkyl and C _1-6 haloalkyl;

R ₂ is selected from H, D, halo, OH, C _1-6 alkoxyl and C _1-6 haloalkoxyl;

R ₃ and R ₄ are independently selected from H and D;

Alternatively, R ₁ and R ₂ together with the carbon atoms to which they are connected to form or;

Alternatively, R ₂ and R ₃ together with the carbon atoms to which they are connected to form;

R _1s is H;

R _2s1 is selected from -C _1-6 alkylene-OR _x , C _1-6 alkyl and C _1-6 haloalkyl;

R _2s2 and R _2s3 are independently selected from C _1-6 alkyl and C _1-6 haloalkyl;

Alternatively, R _2s2 and R _2s3 together with the carbon atoms to which they are connected form a C _3-5 cycloalkyl;

Alternatively, R _2s1 , R _2s2 and R _2s3 together with the carbon atoms to which they are connected to form;

R _x is selected from H, C _1-6 alkyl and C _1-6 haloalkyl;

A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated.

71. In paragraph 70,

M ₁ is selected from CR ₁ and N, preferably CR ₁ ;

M ₂ is selected from CR ₂ and N, preferably CR ₂ ;

M ₃ is selected from CR ₃ and N, preferably CR ₃ ;

M ₄ is selected from CR ₄ and N, preferably CR ₄ ;

Ring A is is selected from;

At this time, R _a is is selected from, m = 1, 2 or 3;

R ₁ is selected from H, D, Cl, and Me;

R ₂ is selected from H, D, Cl, OH, OMe and OCHF ₂ ;

R ₃ and R ₄ are independently selected from H and D;

Alternatively, R ₁ and R ₂ together with the carbon atoms to which they are connected to form or;

Alternatively, R ₂ and R ₃ together with the carbon atoms to which they are connected to form;

R _1s is H;

R _2s1 is selected from Me, Et, iPr, CH ₂ F, CHF ₂ , and CH ₂ OH;

R _2s2 and R _2s3 are independently selected from Me and Et;

Alternatively, R _2s2 and R _2s3 together with the carbon atoms to which they are connected form cyclopropyl;

Alternatively, R _2s1 , R _2s2 and R _2s3 together with the carbon atoms to which they are connected to form;

A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated.

72. In paragraph 68,

M ₁ is selected from CR ₁ and N, preferably CR ₁ ;

M ₂ is selected from CR ₂ and N, preferably CR ₂ ;

M ₃ is selected from CR ₃ and N, preferably CR ₃ ;

M ₄ is selected from CR ₄ and N, preferably CR ₄ ;

Ring A is and;

At this time, R _a is is selected from, m = 1, 2 or 3;

R ₁ is selected from H, D, halo, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxyl, C _1-6 haloalkoxyl, C 2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, C _2-6 haloalkynyl _{, C 3-8 cycloalkyl} and 4- to 10-membered heterocyclyl;

R ₂ is selected from H, D, halo, OH, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxyl, C _1-6 haloalkoxyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, and C _2-6 haloalkynyl;

R ₃ and R ₄ are independently selected from H, D, halo, C _1-6 alkyl and C _1-6 haloalkyl;

Alternatively, R ₁ and R ₂ together with the carbon atoms to which they are connected to form or;

Alternatively, R ₂ and R ₃ together with the carbon atoms to which they are connected , forming;

R _1s is H;

R _2s1 , R _2s2 and R _2s3 are independently selected from C _1-6 alkyl and C _1-6 haloalkyl;

Alternatively, R _2s2 and R _2s3 together with the carbon atoms to which they are connected form a C _3-5 cycloalkyl;

Alternatively, R _2s1 , R _2s2 and R _2s3 together with the carbon atoms to which they are connected form a C _4-8 bridged bicycloalkyl;

A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated.

73. In paragraph 72,

M ₁ is selected from CR ₁ and N, preferably CR ₁ ;

M ₂ is selected from CR ₂ and N, preferably CR ₂ ;

M ₃ is selected from CR ₃ and N, preferably CR ₃ ;

M ₄ is selected from CR ₄ and N, preferably CR ₄ ;

Ring A is and;

At this time, R _a is Selected from among, preferably , and m = 1, 2, or 3;

R ₁ is selected from H, D, halo, C _1-6 alkyl and C _1-6 haloalkyl;

R ₂ is selected from H, D, halo, OH, C _1-6 alkoxyl and C _1-6 haloalkoxyl;

R ₃ and R ₄ are independently selected from H and D;

Alternatively, R ₁ and R ₂ together with the carbon atoms to which they are connected to form or;

Alternatively, R ₂ and R ₃ together with the carbon atoms to which they are connected to form;

R _1s is H;

R _2s1 , R _2s2 and R _2s3 are independently selected from C _1-6 alkyl and C _1-6 haloalkyl;

Alternatively, R _2s2 and R _2s3 together with the carbon atoms to which they are connected form cyclopropyl;

Alternatively, R _2s1 , R _2s2 and R _2s3 together with the carbon atoms to which they are connected to form;

A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated.

74. In paragraph 73,

M ₁ is selected from CR ₁ and N, preferably CR ₁ ;

M ₂ is selected from CR ₂ and N, preferably CR ₂ ;

M ₃ is selected from CR ₃ and N, preferably CR ₃ ;

M ₄ is selected from CR ₄ and N, preferably CR ₄ ;

Ring A is and;

At this time, R _a is Selected from among, preferably , and m = 1, 2, or 3;

R ₁ is selected from H, D, Cl, and Me;

R ₂ is selected from H, D, Cl, OH, OMe and OCHF ₂ ;

R ₃ and R ₄ are independently selected from H and D;

Alternatively, R ₁ and R ₂ together with the carbon atoms to which they are connected to form or;

Alternatively, R ₂ and R ₃ together with the carbon atoms to which they are connected to form;

R _1s is H;

R _2s1 is selected from Me, Et, iPr, CH ₂ F, and CHF ₂ ;

R _2s2 and R _2s3 are independently selected from Me and Et;

Alternatively, R _2s2 and R _2s3 together with the carbon atoms to which they are connected form cyclopropyl;

Alternatively, R _2s1 , R _2s2 and R _2s3 together with the carbon atoms to which they are connected to form;

A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated.

75. In claim 30, a compound of formula (IV), or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof:

In the above chemical formula,

M ₁ is selected from CR ₁ and N, preferably CR ₁ ;

M ₂ is selected from CR ₂ and N, preferably CR ₂ ;

M ₃ is selected from CR ₃ and N, preferably CR ₃ ;

M ₄ is selected from CR ₄ and N, preferably CR ₄ ;

Ring A is is selected from;

At this time, R _a is selected from H and D, and m=0, 1, 2, 3, 4 or 5;

R ₁ and R ₂ together with the carbon atoms to which they are connected , which is optionally substituted with 1, 2 or 3 halo, CN, C _1-6 alkyl, C _1-6 haloalkyl, -C(O)C _1-6 alkyl, or -C(O)C _1-6 haloalkyl;

R ₃ and R ₄ are independently selected from H, D, halo, C _1-6 alkyl and C _1-6 haloalkyl;

R _1s is H;

R _2s1 is selected from H, D, -C _0-6 alkylene-OR _x , -C _0-6 alkylene-NR _y R _z , C _1-6 alkyl, C _1-6 haloalkyl, and C _3-6 cycloalkyl;

R _2s2 and R _2s3 are independently selected from C _1-6 alkyl and C _1-6 haloalkyl;

Alternatively, R _2s2 and R _2s3 together with the carbon atoms to which they are connected form a C _3-6 cycloalkyl;

Alternatively, R _1s and R _2s3 together with the atoms to which they are connected form a 4- to 6-membered heterocyclyl; or

Alternatively, R _2s1 , R _2s2 and R _2s3 together with the carbon atoms to which they are connected form a C _4-8 bridged bicycloalkyl, which is optionally substituted with 1, 2 or 3 halo, C _1-6 alkyl or C _1-6 haloalkyl;

R _x , R _y and R _z are independently selected from H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, C _2-6 haloalkynyl, C _3-8 cycloalkyl and 4- to 6-membered heterocyclyl; or R _y and R _z together with the nitrogen atom to which they are connected form a 4- to 6-membered heterocyclyl;

The above-mentioned atoms may be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated.

76. In paragraph 75,

M ₁ is selected from CR ₁ and N, preferably CR ₁ ;

M ₂ is selected from CR ₂ and N, preferably CR ₂ ;

M ₃ is selected from CR ₃ and N, preferably CR ₃ ;

M ₄ is selected from CR ₄ and N, preferably CR ₄ ;

Ring A is is selected from;

At this time, R _a is selected from H and D, and m=0, 1, 2, 3, 4 or 5;

R ₁ and R ₂ together with the carbon atoms to which they are connected to form;

R ₃ and R ₄ are independently selected from H and D;

R _1s is H;

R _2s1 is selected from Me, CH ₂ F, CH ₂ OH, CH ₂ OCH ₃ , and cyclopropyl;

R _2s2 and R _2s3 are Me;

Alternatively, R _2s2 and R _2s3 together with the carbon atoms to which they are connected form cyclopropyl;

Alternatively, R _1s and R _2s3 together with the atoms to which they are connected form a 4- to 5-membered heterocyclyl;

Alternatively, R _2s1 , R _2s2 and R _2s3 together with the carbon atoms to which they are connected to form;

A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated.

77. In paragraph 75,

M ₁ is selected from CR ₁ and N, preferably CR ₁ ;

M ₂ is selected from CR ₂ and N, preferably CR ₂ ;

M ₃ is selected from CR ₃ and N, preferably CR ₃ ;

M ₄ is selected from CR ₄ and N, preferably CR ₄ ;

Ring A is is selected from;

At this time, R _a is selected from H and D, and m=0, 1, 2, 3, 4 or 5;

R ₁ and R ₂ together with the carbon atoms to which they are connected , which is optionally substituted with 1, 2 or 3 halo, CN, C _1-6 alkyl, C _1-6 haloalkyl, -C(O)C _1-6 alkyl, or -C(O)C _1-6 haloalkyl;

R ₃ and R ₄ are independently selected from H, D, halo, C _1-6 alkyl and C _1-6 haloalkyl;

R _1s is H;

R _2s1 is selected from H, D, -C _0-6 alkylene-OR _x , -C _0-6 alkylene-NR _y R _z , C _1-6 alkyl, C _1-6 haloalkyl, and C _3-6 cycloalkyl;

R _2s2 and R _2s3 are independently selected from C _1-6 alkyl and C _1-6 haloalkyl;

Alternatively, R _2s2 and R _2s3 together with the carbon atoms to which they are connected form a C _3-6 cycloalkyl;

Alternatively, R _1s and R _2s3 together with the atoms to which they are connected form a 4- to 6-membered heterocyclyl; or

Alternatively, R _2s1 , R _2s2 and R _2s3 together with the carbon atoms to which they are connected form a C _4-8 bridged bicycloalkyl, which is optionally substituted with 1, 2 or 3 halo, C _1-6 alkyl or C _1-6 haloalkyl;

R _x , R _y and R _z are independently selected from H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, C _2-6 haloalkynyl, C _3-8 cycloalkyl and 4- to 6-membered heterocyclyl; or R _y and R _z together with the nitrogen atom to which they are connected form a 4- to 6-membered heterocyclyl;

A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated.

78. In paragraph 77,

M ₁ is selected from CR ₁ and N, preferably CR ₁ ;

M ₂ is selected from CR ₂ and N, preferably CR ₂ ;

M ₃ is selected from CR ₃ and N, preferably CR ₃ ;

M ₄ is selected from CR ₄ and N, preferably CR ₄ ;

Ring A is is selected from;

At this time, R _a is selected from H and D, and m=0, 1, 2, 3, 4 or 5;

R ₁ and R ₂ together with the carbon atoms to which they are connected to form;

R ₃ and R ₄ are independently selected from H and D;

R _1s is H;

R _2s1 is selected from -C _0-6 alkylene-OR _x , C _1-6 alkyl, C _1-6 haloalkyl and C _3-6 cycloalkyl;

R _2s2 and R _2s3 are independently selected from C _1-6 alkyl and C _1-6 haloalkyl;

Alternatively, R _2s2 and R _2s3 together with the carbon atoms to which they are connected form a C _3-6 cycloalkyl;

Alternatively, R _1s and R _2s3 together with the atoms to which they are connected form a 4- to 6-membered heterocyclyl; or

Alternatively, R _2s1 , R _2s2 and R _2s3 together with the carbon atoms to which they are connected to form;

R _x is selected from H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, C _2-6 haloalkynyl, C _3-8 cycloalkyl and 4- to 6-membered heterocyclyl;

A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated.

79. In paragraph 78,

M ₁ is selected from CR ₁ and N, preferably CR ₁ ;

M ₂ is selected from CR ₂ and N, preferably CR ₂ ;

M ₃ is selected from CR ₃ and N, preferably CR ₃ ;

M ₄ is selected from CR ₄ and N, preferably CR ₄ ;

Ring A is is selected from;

At this time, R _a is selected from H and D, and m=0, 1, 2, 3, 4 or 5;

R ₁ and R ₂ together with the carbon atoms to which they are connected to form;

R ₃ and R ₄ are independently selected from H and D;

R _1s is H;

R _2s1 is selected from Me, CH ₂ F, CH ₂ OH, CH ₂ OCH ₃ , and cyclopropyl;

R _2s2 and R _2s3 are Me;

Alternatively, R _2s2 and R _2s3 together with the carbon atoms to which they are connected form cyclopropyl;

Alternatively, R _1s and R _2s3 together with the atoms to which they are connected form a 4- to 5-membered heterocyclyl;

Alternatively, R _2s1 , R _2s2 and R _2s3 together with the carbon atoms to which they are connected to form;

A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated.

80. In paragraph 75,

M ₁ is selected from CR ₁ and N, preferably CR ₁ ;

M ₂ is selected from CR ₂ and N, preferably CR ₂ ;

M ₃ is selected from CR ₃ and N, preferably CR ₃ ;

M ₄ is selected from CR ₄ and N, preferably CR ₄ ;

Ring A is is selected from;

At this time, R _a is selected from H and D, and m=0, 1, 2, 3, 4 or 5;

R ₁ and R ₂ together with the carbon atoms to which they are connected , which is optionally substituted with 1, 2 or 3 halo, CN, C _1-6 alkyl or C _1-6 haloalkyl;

R ₃ and R ₄ are independently selected from H, D, halo, C _1-6 alkyl and C _1-6 haloalkyl;

R _1s is H;

R _2s1 is selected from H, D, -C _0-6 alkylene-OR _x , -C _0-6 alkylene-NR _y R _z , C _1-6 alkyl, C _1-6 haloalkyl, and C _3-6 cycloalkyl;

R _2s2 and R _2s3 are independently selected from C _1-6 alkyl and C _1-6 haloalkyl;

Alternatively, R _2s2 and R _2s3 together with the carbon atoms to which they are connected form a C _3-6 cycloalkyl;

Alternatively, R _2s1 , R _2s2 and R _2s3 together with the carbon atoms to which they are connected form a C _4-8 bridged bicycloalkyl, which is optionally substituted with 1, 2 or 3 halo, C _1-6 alkyl or C _1-6 haloalkyl;

R _x , R _y and R _z are independently selected from H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, C _2-6 haloalkynyl, C _3-8 cycloalkyl and 4- to 6-membered heterocyclyl; or R _y and R _z together with the nitrogen atom to which they are connected form a 4- to 6-membered heterocyclyl;

A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated.

81. In paragraph 80,

M ₁ is selected from CR ₁ and N, preferably CR ₁ ;

M ₂ is selected from CR ₂ and N, preferably CR ₂ ;

M ₃ is selected from CR ₃ and N, preferably CR ₃ ;

M ₄ is selected from CR ₄ and N, preferably CR ₄ ;

Ring A is is selected from;

At this time, R _a is selected from H and D, and m=0, 1, 2, 3, 4 or 5;

R ₁ and R ₂ together with the carbon atoms to which they are connected

to form;

R ₃ and R ₄ are independently selected from H and D;

R _1s is H;

R _2s1 is selected from -C _0-6 alkylene-OH, C _1-6 alkyl, C _1-6 haloalkyl and C _3-6 cycloalkyl;

R _2s2 and R _2s3 are independently selected from C _1-6 alkyl and C _1-6 haloalkyl;

Alternatively, R _2s2 and R _2s3 together with the carbon atoms to which they are connected form a C _3-6 cycloalkyl;

Alternatively, R _2s1 , R _2s2 and R _2s3 together with the carbon atoms to which they are connected to form;

A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated.

82. In paragraph 81,

M ₁ is selected from CR ₁ and N, preferably CR ₁ ;

M ₂ is selected from CR ₂ and N, preferably CR ₂ ;

M ₃ is selected from CR ₃ and N, preferably CR ₃ ;

M ₄ is selected from CR ₄ and N, preferably CR ₄ ;

Ring A is is selected from;

At this time, R _a is selected from H and D, and m=0, 1, 2, 3, 4 or 5;

R ₁ and R ₂ together with the carbon atoms to which they are connected to form;

R ₃ and R ₄ are independently selected from H and D;

R _1s is H;

R _2s1 is selected from Me, CH ₂ F, CH ₂ OH, and cyclopropyl;

R _2s2 and R _2s3 are Me;

Alternatively, R _2s2 and R _2s3 together with the carbon atoms to which they are connected form cyclopropyl;

Alternatively, R _2s1 , R _2s2 and R _2s3 together with the carbon atoms to which they are connected to form;

A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated.

83. In claim 30, a compound of formula (IV), or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof:

In the above chemical formula,

M ₁ is selected from CR ₁ and N, preferably CR ₁ ;

M ₂ is selected from CR ₂ and N, preferably CR ₂ ;

M ₃ is selected from CR ₃ and N, preferably CR ₃ ;

M ₄ is selected from CR ₄ and N, preferably CR ₄ ;

Ring A is is selected from;

At this time, R _a is selected from H and D, and m = 1, 2, or 3;

R ₁ and R ₄ are independently selected from H, D, halo, C _1-6 alkyl and C _1-6 haloalkyl;

R ₂ and R ₃ together with the carbon atoms to which they are connected to form;

R _1s is selected from H, C _1-6 alkyl and C _1-6 haloalkyl;

R _2s1 is selected from H, D, -C _0-6 alkylene-OR _x , -C _0-6 alkylene-NR _y R _z , C _1-6 alkyl, and C _1-6 haloalkyl;

R _2s2 and R _2s3 are independently selected from C _1-6 alkyl and C _1-6 haloalkyl;

R _1s and R _2s3 together with the atoms to which they are connected form a 4- to 6-membered heterocyclyl, which is optionally substituted with OH;

R _2s1 and R _2s2 together with the carbon atoms to which they are connected form C _3-6 cycloalkyl;

R _x , R _y and R _z are independently selected from H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, C _2-6 haloalkynyl, C _3-8 cycloalkyl and 4- to 6-membered heterocyclyl; or R _y and R _z together with the nitrogen atom to which they are connected form a 4- to 6-membered heterocyclyl;

The above-mentioned atoms may be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated.

84. In paragraph 83,

M ₁ is selected from CR ₁ and N, preferably CR ₁ ;

M ₂ is selected from CR ₂ and N, preferably CR ₂ ;

M ₃ is selected from CR ₃ and N, preferably CR ₃ ;

M ₄ is selected from CR ₄ and N, preferably CR ₄ ;

Ring A is is selected from;

At this time, R _a is selected from H and D, and m = 1, 2, or 3;

R ₁ is selected from halo, C _1-6 alkyl and C _1-6 haloalkyl;

R ₂ and R ₃ together with the carbon atoms to which they are connected to form;

R ₄ is selected from H and D;

R _1s is selected from H, C _1-6 alkyl and C _1-6 haloalkyl;

R _2s1 is selected from -C _0-6 alkylene-OH, C _1-6 alkyl and C _1-6 haloalkyl;

R _2s2 and R _2s3 are independently selected from C _1-6 alkyl and C _1-6 haloalkyl;

R _1s and R _2s3 together with the atoms to which they are connected form a 4- to 5-membered heterocyclyl, which is optionally substituted with OH;

R _2s1 and R _2s2 together with the carbon atoms to which they are connected form C _3-5 cycloalkyl;

A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated.

85. In paragraph 84,

M ₁ is selected from CR ₁ and N, preferably CR ₁ ;

M ₂ is selected from CR ₂ and N, preferably CR ₂ ;

M ₃ is selected from CR ₃ and N, preferably CR ₃ ;

M ₄ is selected from CR ₄ and N, preferably CR ₄ ;

Ring A is is selected from;

At this time, R _a is selected from H and D, and m = 1, 2, or 3;

R ₁ is selected from Cl, and Me;

R ₂ and R ₃ together with the carbon atoms to which they are connected to form;

R ₄ is selected from H and D;

R _1s is selected from H, Me and Et;

R _2s1 is selected from Me and CH ₂ OH;

R _2s2 is Me;

R _2s3 is Me;

R _1s and R _2s3 together with the atoms to which they are connected form a 4- to 5-membered heterocyclyl, which is optionally substituted with OH;

R _2s1 and R _2s2 together with the carbon atoms to which they are connected form cyclopropyl;

A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated.

86. In paragraph 83,

M ₁ is selected from CR ₁ and N, preferably CR ₁ ;

M ₂ is selected from CR ₂ and N, preferably CR ₂ ;

M ₃ is selected from CR ₃ and N, preferably CR ₃ ;

M ₄ is selected from CR ₄ and N, preferably CR ₄ ;

Ring A is and;

At this time, R _a is selected from H and D, and m = 1, 2, or 3;

R ₁ and R ₄ are independently selected from H, D, halo, C _1-6 alkyl and C _1-6 haloalkyl;

R ₂ and R ₃ together with the carbon atoms to which they are connected to form;

R _1s is selected from H, C _1-6 alkyl and C _1-6 haloalkyl;

R _2s1 is selected from -C _0-6 alkylene-OH, C _1-6 alkyl and C _1-6 haloalkyl;

R _2s2 and R _2s3 are independently selected from C _1-6 alkyl and C _1-6 haloalkyl;

R _1s and R _2s3 together with the atoms to which they are connected form a 4- to 6-membered heterocyclyl;

A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated.

87. In paragraph 86,

M ₁ is selected from CR ₁ and N, preferably CR ₁ ;

M ₂ is selected from CR ₂ and N, preferably CR ₂ ;

M ₃ is selected from CR ₃ and N, preferably CR ₃ ;

M ₄ is selected from CR ₄ and N, preferably CR ₄ ;

Ring A is and;

At this time, R _a is selected from H and D, and m = 1, 2, or 3;

R ₁ is halo;

R ₂ and R ₃ together with the carbon atoms to which they are connected to form;

R ₄ is selected from H and D;

R _1s is selected from H, C _1-6 alkyl and C _1-6 haloalkyl;

R _2s1 is selected from -C _0-6 alkylene-OH, C _1-6 alkyl and C _1-6 haloalkyl;

R _2s2 and R _2s3 are independently selected from C _1-6 alkyl and C _1-6 haloalkyl;

R _1s and R _2s3 together with the atoms to which they are connected form a 4- to 5-membered heterocyclyl;

A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated.

88. In paragraph 87,

M ₁ is selected from CR ₁ and N, preferably CR ₁ ;

M ₂ is selected from CR ₂ and N, preferably CR ₂ ;

M ₃ is selected from CR ₃ and N, preferably CR ₃ ;

M ₄ is selected from CR ₄ and N, preferably CR ₄ ;

Ring A is and;

At this time, R _a is selected from H and D, and m = 1, 2, or 3;

R ₁ is Cl;

R ₂ and R ₃ together with the carbon atoms to which they are connected to form;

R ₄ is selected from H and D;

R _1s is selected from H and Me;

R _2s1 is selected from Me and CH ₂ OH;

R _2s2 is Me;

R _2s3 is Me;

R _1s and R _2s3 together with the atoms to which they are connected form a 4- to 5-membered heterocyclyl;

A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated.

89. In paragraph 30, a compound of formula (IV), or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof:

In the above chemical formula,

M ₁ is selected from CR ₁ and N, preferably CR ₁ ;

M ₂ is selected from CR ₂ and N, preferably CR ₂ ;

M ₃ is selected from CR ₃ and N, preferably CR ₃ ;

M ₄ is selected from CR ₄ and N, preferably CR ₄ ;

Ring A is Selected from among;

wherein R _a is selected from H, D, halo, C _1-6 alkyl, and C _1-6 haloalkyl, and m=0, 1, 2, 3, 4, or 5;

R ₁ is selected from H, D, halo, CN, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, C _2-6 haloalkynyl, C _1-6 alkoxyl, C _{1-6 haloalkoxyl, and C 3-6 cycloalkyl} ;

R ₂ is selected from H, D, halo, NH ₂ , -C _0-6 alkylene-OH, -OC _1-6 alkylene-OH, -C(O)C _1-6 alkyl, -C(O)C _1-6 haloalkyl, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxyl, C _1-6 haloalkoxyl and 5-membered heteroaryl, which is optionally substituted with 1, 2 or 3 halo;

R ₃ is selected from H, D, halo, OH, C _1-6 alkoxyl and C _1-6 haloalkoxyl;

R ₄ is selected from H, D and halo;

Alternatively, R ₁ and R ₂ together with the carbon atoms to which they are connected , which is optionally substituted with 1, 2 or 3 halo, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, C _2-6 haloalkynyl, or C _2-6 alkynyl-substituted phenyl;

Alternatively, R ₂ and R ₃ together with the carbon atoms to which they are connected form a 5- to 7-membered heterocyclyl, which is optionally substituted with 1, 2, 3 or 4 halo, C _1-6 alkyl, C _1-6 haloalkyl, -C _1-6 alkylene-C _1-6 alkoxyl or -C _1-6 alkylene-C _1-6 haloalkoxyl;

R _1s is H, C _1-6 alkyl or C _1-6 haloalkyl;

R _2s1 is selected from H, D, -C _0-6 alkylene-OH, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, C _2-6 haloalkynyl and C _3-6 cycloalkyl;

R _2s2 is H, D, C _1-6 alkyl or C _1-6 haloalkyl;

R _2s3 is C _1-6 alkyl or C _1-6 haloalkyl;

Alternatively, R _1s and R _2s3 together with the atoms to which they are connected form a 4- to 7-membered heterocyclyl, which is optionally substituted with 1 or 2 halo;

Alternatively, R _2s2 and R _2s3 together with the carbon atoms to which they are connected form a C _3-6 cycloalkyl, which is optionally substituted with 1 or 2 halo;

Alternatively, R _2s1 , R _2s2 and R _2s3 together with the carbon atoms to which they are connected form a C _4-8 bridged bicycloalkyl, which is optionally substituted with 1 or 2 halo, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl and C _2-6 haloalkynyl;

A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated.

90. In paragraph 89,

M ₁ is selected from CR ₁ and N, preferably CR ₁ ;

M ₂ is selected from CR ₂ and N, preferably CR ₂ ;

M ₃ is selected from CR ₃ and N, preferably CR ₃ ;

M ₄ is selected from CR ₄ and N, preferably CR ₄ ;

Ring A is Selected from among;

At this time, R _a is selected from H, D and halo, and m = 0, 1, 2, 3, 4 or 5;

R ₁ is selected from H, D, halo, CN, C _1-4 alkyl, C _1-4 haloalkyl, C _2-4 alkenyl, C _2-4 haloalkenyl, C _2-4 alkynyl, C _2-4 haloalkynyl, C _1-4 alkoxyl, C 1-4 haloalkoxyl, and C _3-6 cycloalkyl _;

R ₂ is selected from H, D, halo, NH ₂ , -C _0-4 alkylene-OH, -OC _1-4 alkylene-OH, -C(O)C _1-4 alkyl, -C(O)C _1-4 haloalkyl, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxyl, C _1-4 haloalkoxyl and 5-membered heteroaryl, which is optionally substituted with 1 or 2 halo;

R ₃ is selected from H, D, halo, OH, C _1-4 alkoxyl and C _1-4 haloalkoxyl;

R ₄ is selected from H, D and halo;

Alternatively, R ₁ and R ₂ together with the carbon atoms to which they are connected , which is optionally substituted with 1 or 2 Br or C _2-6 alkynyl-substituted phenyl;

Alternatively, R ₂ and R ₃ together with the carbon atoms to which they are connected form a 5- to 7-membered heterocyclyl, which is optionally substituted with 1, 2, 3 or 4 halo, C _1-6 alkyl, C _1-6 haloalkyl, -C _1-4 alkylene-OH, -C _1-4 alkylene-C _1-4 alkoxyl or -C _1-4 alkylene-C _1-4 haloalkoxyl;

R _1s is H, C _1-6 alkyl or C _1-6 haloalkyl;

R _2s1 is selected from H, D, -C _0-4 alkylene-OH, C _1-4 alkyl, C _1-4 haloalkyl, C _2-4 alkenyl, C _2-4 haloalkenyl, C _2-4 alkynyl, C _2-4 haloalkynyl and C _3-6 cycloalkyl;

R _2s2 is H, D, C _1-4 alkyl or C _1-4 haloalkyl;

R _2s3 is C _1-4 alkyl or C _1-4 haloalkyl;

Alternatively, R _1s and R _2s3 together with the atoms to which they are connected form a 5- to 7-membered heterocyclyl, which is optionally substituted with 1 or 2 halo;

Alternatively, R _2s2 and R _2s3 together with the carbon atoms to which they are connected form a C _3-6 cycloalkyl, which is optionally substituted with 1 or 2 halo;

Alternatively, R _2s1 , R _2s2 and R _2s3 together with the carbon atoms to which they are connected form a C _4-8 bridged bicycloalkyl, which is optionally substituted with 1 or 2 halo, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl and C _2-6 haloalkynyl;

A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated.

91. In paragraph 89,

M ₁ is selected from CR ₁ and N, preferably CR ₁ ;

M ₂ is selected from CR ₂ and N, preferably CR ₂ ;

M ₃ is selected from CR ₃ and N, preferably CR ₃ ;

M ₄ is selected from CR ₄ and N, preferably CR ₄ ;

Ring A is Selected from among;

At this time, R _a is selected from H and D, and m=0, 1, 2, 3, 4 or 5;

R ₁ is selected from H, D, F, Cl, CN, Me, CH=CH ₂ , CF ₃ , and cyclopropyl;

R ₂ is H, D, Cl, Br, OH, Me, CH ₂ F, CHF ₂ , CF ₃ , OMe, OCH ₂ CH ₂ OH, CH ₂ OH, -C(O)Me, NH ₂ , is selected from;

R ₃ is selected from H, D, F, Br, OH and OMe;

R ₄ is selected from H, D and F;

Alternatively, R ₁ and R ₂ together with the carbon atoms to which they are connected , which is optionally substituted with Br or C _2-6 alkynyl-substituted phenyl;

Alternatively, R ₂ and R ₃ together with the carbon atoms to which they are connected , forming;

R _1s is H, C _1-6 alkyl or C _1-6 haloalkyl;

R _2s1 is selected from H, D, OH, Me, Et, CH ₂ F, CHF ₂ , CF ₃ , CH ₂ OH, CH ₂ CH ₂ OH, C≡CH, and cyclopropyl;

R _2s2 is selected from H, D and Me;

R _2s3 is Me, or

Alternatively, R _1s and R _2s3 together with the atoms to which they are connected form a 5-membered heterocyclyl, which is optionally substituted with 1 or 2 halo;

Alternatively, R _2s2 and R _2s3 together with the carbon atoms to which they are connected form cyclopropyl, cyclobutyl or cyclopentyl;

Alternatively, R _2s1 , R _2s2 and R _2s3 together with the carbon atoms to which they are connected to form;

A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated.

92. In paragraph 89,

M ₁ is selected from CR ₁ and N, preferably CR ₁ ;

M ₂ is selected from CR ₂ and N, preferably CR ₂ ;

M ₃ is selected from CR ₃ and N, preferably CR ₃ ;

M ₄ is selected from CR ₄ and N, preferably CR ₄ ;

Ring A is

Selected from among;

wherein R _a is selected from H, D, halo, C _1-6 alkyl, and C _1-6 haloalkyl, and m=0, 1, 2, 3, 4, or 5;

R ₁ is selected from H, D, halo, CN, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, C _2-6 haloalkynyl, C _1-6 alkoxyl, C _{1-6 haloalkoxyl, and C 3-6 cycloalkyl} ;

R ₂ is selected from H, D, halo, NH ₂ , -C _0-6 alkylene-OH, -OC _1-6 alkylene-OH, -C(O)C _1-6 alkyl, -C(O)C _1-6 haloalkyl, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxyl, and C _1-6 haloalkoxyl;

R ₃ is selected from H, D, halo, OH, C _1-6 alkoxyl and C _1-6 haloalkoxyl;

R ₄ is selected from H, D and halo;

Alternatively, R ₁ and R ₂ together with the carbon atoms to which they are connected , which is optionally substituted with 1, 2 or 3 halo or C _2-6 alkynyl-substituted phenyl;

Alternatively, R ₂ and R ₃ together with the carbon atoms to which they are connected form a 5- to 7-membered heterocyclyl, which is optionally substituted with 1, 2, 3 or 4 halo, C _1-6 alkyl or C _1-6 haloalkyl;

R _1s is H, C _1-6 alkyl or C _1-6 haloalkyl;

R _2s1 is selected from H, D, -C _0-6 alkylene-OH, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, and C _2-6 haloalkynyl;

R _2s2 is C _1-6 alkyl or C _1-6 haloalkyl;

R _2s3 is C _1-6 alkyl or C _1-6 haloalkyl;

Alternatively, R _1s and R _2s3 together with the atoms to which they are connected form a 4- to 7-membered heterocyclyl, which is optionally substituted with 1 or 2 halo;

Alternatively, R _2s2 and R _2s3 together with the carbon atoms to which they are connected form a C _3-6 cycloalkyl, which is optionally substituted with 1 or 2 halo;

A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated.

93. In paragraph 89,

M ₁ is selected from CR ₁ and N, preferably CR ₁ ;

M ₂ is selected from CR ₂ and N, preferably CR ₂ ;

M ₃ is selected from CR ₃ and N, preferably CR ₃ ;

M ₄ is selected from CR ₄ and N, preferably CR ₄ ;

Ring A is

Selected from among;

At this time, R _a is selected from H, D and halo, and m = 0, 1, 2, 3, 4 or 5;

R ₁ is selected from H, D, halo, CN, C _1-4 alkyl, C _1-4 haloalkyl, C _2-4 alkenyl, C _2-4 haloalkenyl, C _2-4 alkynyl, C _2-4 haloalkynyl, C _1-4 alkoxyl, C 1-4 haloalkoxyl, and C _3-6 cycloalkyl _;

R ₂ is selected from H, D, halo, NH ₂ , -C _0-4 alkylene-OH, -OC _1-4 alkylene-OH, -C(O)C _1-4 alkyl, -C(O)C _1-4 haloalkyl, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxyl, and C _1-4 haloalkoxyl;

R ₃ is selected from H, D, halo, OH, C _1-4 alkoxyl and C _1-4 haloalkoxyl;

R ₄ is selected from H, D and halo;

Alternatively, R ₁ and R ₂ together with the carbon atoms to which they are connected , which is optionally substituted with 1 or 2 Br or C _2-6 alkynyl-substituted phenyl;

Alternatively, R ₂ and R ₃ together with the carbon atoms to which they are connected form a 5- to 7-membered heterocyclyl, which is optionally substituted with 1, 2, 3 or 4 halo, C _1-6 alkyl or C _1-6 haloalkyl;

R _1s is H, C _1-6 alkyl or C _1-6 haloalkyl;

R _2s1 is selected from H, D, -C _0-4 alkylene-OH, C _1-4 alkyl, C _1-4 haloalkyl, C _2-4 alkenyl, C _2-4 haloalkenyl, C _2-4 alkynyl, and C _2-4 haloalkynyl;

R _2s2 is C _1-4 alkyl or C _1-4 haloalkyl;

R _2s3 is C _1-4 alkyl or C _1-4 haloalkyl;

Alternatively, R _1s and R _2s3 together with the atoms to which they are connected form a 5- to 7-membered heterocyclyl, which is optionally substituted with 1 or 2 halo;

Alternatively, R _2s2 and R _2s3 together with the carbon atoms to which they are connected form a C _3-6 cycloalkyl, which is optionally substituted with 1 or 2 halo;

A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated.

94. In paragraph 89,

M ₁ is selected from CR ₁ and N, preferably CR ₁ ;

M ₂ is selected from CR ₂ and N, preferably CR ₂ ;

M ₃ is selected from CR ₃ and N, preferably CR ₃ ;

M ₄ is selected from CR ₄ and N, preferably CR ₄ ;

Ring A is

Selected from among;

At this time, R _a is selected from H and D, and m=0, 1, 2, 3, 4 or 5;

R ₁ is selected from H, D, F, Cl, CN, Me, CH=CH ₂ , CF ₃ , OMe, and cyclopropyl;

R ₂ is selected from H, D, Cl, Br, OH, Me, CH ₂ F, CHF ₂ , CF ₃ , OMe, OCH ₂ CH ₂ OH, CH ₂ OH, -C(O)Me, and NH ₂ ;

R ₃ is selected from H, D, F, Br, OH and OMe;

R ₄ is selected from H, D and F;

Alternatively, R ₁ and R ₂ together with the carbon atoms to which they are connected , which is optionally substituted with 1 or 2 Br or C _2-6 alkynyl-substituted phenyl;

Alternatively, R ₂ and R ₃ together with the carbon atoms to which they are connected to form or;

R _1s is H or Me;

R _2s1 is selected from H, D, OH, Me, Et, CH ₂ F, CHF ₂ , CF ₃ , CH ₂ OH, CH ₂ CH ₂ OH, and C≡CH;

R _2s2 is Me;

R _2s3 is Me;

Alternatively, R _1s and R _2s3 together with the atoms to which they are connected form a 5-membered heterocyclyl, which is optionally substituted with 1 or 2 halo;

Alternatively, R _2s2 and R _2s3 together with the carbon atoms to which they are connected form cyclopropyl, cyclobutyl and cyclopentyl;

A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated.

95. In paragraph 89,

M ₁ is selected from CR ₁ and N, preferably CR ₁ ;

M ₂ is selected from CR ₂ and N, preferably CR ₂ ;

M ₃ is selected from CR ₃ and N, preferably CR ₃ ;

M ₄ is selected from CR ₄ and N, preferably CR ₄ ;

Ring A is is selected from;

wherein R _a is selected from H, D, halo, C _1-6 alkyl, and C _1-6 haloalkyl, and m=0, 1, 2, 3, 4, or 5;

R ₁ is selected from H, D, halo, CN, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, and C _2-6 haloalkynyl;

R ₂ is selected from H, D, halo, -C _0-6 alkylene-OH, -OC _1-6 alkylene-OH, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxyl, and C _1-6 haloalkoxyl;

R ₃ is selected from H, D, halo and OH;

R ₄ is selected from H and D;

Alternatively, R ₁ and R ₂ are linked together with the carbon atoms to which they are attached. to form or;

Alternatively, R ₂ and R ₃ together with the carbon atoms to which they are connected , forming;

R _1s is H, C _1-6 alkyl or C _1-6 haloalkyl;

R _2s1 is selected from H, D, -C _0-6 alkylene-OH, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, and C _2-6 haloalkynyl;

R _2s2 is C _1-6 alkyl or C _1-6 haloalkyl;

R _2s3 is C _1-6 alkyl or C _1-6 haloalkyl;

Alternatively, R _1s and R _2s3 together with the atoms to which they are connected form a 5- to 7-membered heterocyclyl, which is optionally substituted with 1 or 2 halo;

Alternatively, R _2s2 and R _2s3 together with the carbon atoms to which they are connected form a C _3-5 cycloalkyl, which is optionally substituted with 1 or 2 halo;

A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated.

96. In paragraph 89,

M ₁ is selected from CR ₁ and N, preferably CR ₁ ;

M ₂ is selected from CR ₂ and N, preferably CR ₂ ;

M ₃ is selected from CR ₃ and N, preferably CR ₃ ;

M ₄ is selected from CR ₄ and N, preferably CR ₄ ;

Ring A is is selected from;

At this time, R _a is selected from H, D and halo, and m = 0, 1, 2, 3, 4 or 5;

R ₁ is selected from H, D, halo, CN, C _1-4 alkyl, C _1-4 haloalkyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, and C _2-6 haloalkynyl;

R ₂ is selected from H, D, halo, -C _0-4 alkylene-OH, -OC _1-4 alkylene-OH, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxyl, and C _1-4 haloalkoxyl;

R ₃ is selected from H, D, halo and OH;

R ₄ is selected from H and D;

Alternatively, R ₁ and R ₂ together with the carbon atoms to which they are connected to form or;

Alternatively, R ₂ and R ₃ together with the carbon atoms to which they are connected , forming;

R _1s is H, C _1-6 alkyl or C _1-6 haloalkyl;

R _2s1 is selected from H, D, -C _0-4 alkylene-OH, C _1-4 alkyl, C _1-4 haloalkyl, C _2-4 alkenyl, C _2-4 haloalkenyl, C _2-4 alkynyl, and C _2-4 haloalkynyl;

R _2s2 is C _1-4 alkyl or C _1-4 haloalkyl;

R _2s3 is C _1-4 alkyl or C _1-4 haloalkyl;

Alternatively, R _1s and R _2s3 together with the atoms to which they are connected form a 5- to 7-membered heterocyclyl, which is optionally substituted with 1 or 2 halo;

Alternatively, R _2s2 and R _2s3 together with the carbon atoms to which they are connected form a C _3-5 cycloalkyl, which is optionally substituted with 1 or 2 halo;

A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated.

97. In paragraph 89,

M ₁ is selected from CR ₁ and N, preferably CR ₁ ;

M ₂ is selected from CR ₂ and N, preferably CR ₂ ;

M ₃ is selected from CR ₃ and N, preferably CR ₃ ;

M ₄ is selected from CR ₄ and N, preferably CR ₄ ;

Ring A is is selected from;

At this time, R _a is selected from H and D, and m=0, 1, 2, 3, 4 or 5;

R ₁ is selected from H, D, F, Cl, CN, Me, CH=CH ₂ , and CF ₃ ;

R ₂ is selected from H, D, Cl, Br, OH, Me, CH ₂ F, CHF ₂ , CF ₃ , OMe, OCH ₂ CH ₂ OH, and CH ₂ OH;

R ₃ is selected from H, D, F, Br and OH;

R ₄ is selected from H and D;

Alternatively, R ₁ and R ₂ are linked together with the carbon atoms to which they are attached. to form or;

Alternatively, R ₂ and R ₃ together with the carbon atoms to which they are connected , forming;

R _1s is H or Me;

R _2s1 is selected from H, D, OH, Me, Et, CH ₂ F, CHF ₂ , CF ₃ , CH ₂ OH, CH ₂ CH ₂ OH, and C≡CH;

R _2s2 is Me;

R _2s3 is Me;

Alternatively, R _1s and R _2s3 together with the atoms to which they are connected form a 5-membered heterocyclyl, which is optionally substituted with 1 or 2 halo;

Alternatively, R _2s2 and R _2s3 together with the carbon atoms to which they are connected form cyclopropyl, cyclobutyl and cyclopentyl;

A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated.

98. In paragraph 89,

R _1s and R _2s3 are linked to form C _2-6 alkylene, which is optionally substituted with 1, 2 or 3 halo, OH, C _1-6 alkyl or C _1-6 haloalkyl;

The above-mentioned groups may be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated;

Other variables are as defined in any one of claims 1 to 29, the compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof.

99. In paragraph 98,

M ₁ is selected from CR ₁ and N, preferably CR ₁ ;

M ₂ is selected from CR ₂ and N, preferably CR ₂ ;

M ₃ is selected from CR ₃ and N, preferably CR ₃ ;

M ₄ is selected from CR ₄ and N, preferably CR ₄ ;

Ring A is is selected from;

wherein R _a is selected from H, D, halo, NO ₂ , NH ₂ , -C _1-6 alkylene-OH, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, C _2-6 haloalkynyl and amino protecting group, and m=0, 1, 2, 3, 4 or 5; or two adjacent R _a together with the atoms to which they are connected form phenyl or a 5- to 6-membered heteroaryl;

R ₁ and R ₄ are independently selected from H, D and halo;

R ₂ is selected from H, D, halo, -C _0-6 alkylene-OH, NH ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxyl, C _5-6 cycloalkyl, 5-6 membered heterocyclyl, C _6-10 aryl, 5-10 membered heteroaryl, -O-5-6 membered heteroaryl, -NH-5-6 membered heteroaryl, -OC(O)-5-6 membered heteroaryl, or -NHC(O)-5-6 membered heteroaryl; which is optionally substituted with 1, 2, 3, 4 or 5 CN, halo, oxo, -C _1-6 alkylene-OH, C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl or 5-6 membered heterocyclyl;

R ₃ is selected from H, D, halo, OH, C _1-6 alkyl and C _1-6 haloalkyl;

Alternatively, R ₂ and R ₃ together with the carbon atoms to which they are connected form a 5-6 membered heterocyclyl, which is optionally substituted with 1, 2, 3 or 4 halo, C _1-6 alkyl, C _1-6 haloalkyl, -C(O)C _1-6 alkyl, or -C(O)C _1-6 haloalkyl;

R _1s and R _2s3 are linked to form C _2-6 alkylene, which is optionally substituted with 1, 2 or 3 halo, OH, C _1-6 alkyl or C _1-6 haloalkyl;

R _2s1 is selected from H, D, C _1-6 alkyl and C _1-6 haloalkyl;

R _2s2 is selected from H, D, -C _0-6 alkylene-OH, C _1-6 alkyl and C _1-6 haloalkyl;

Alternatively, R _2s1 and R _2s2 together with the carbon atoms to which they are connected form a C _3-6 cycloalkyl;

A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated.

100. In paragraph 98,

M ₁ is selected from CR ₁ and N, preferably CR ₁ ;

M ₂ is selected from CR ₂ and N, preferably CR ₂ ;

M ₃ is selected from CR ₃ and N, preferably CR ₃ ;

M ₄ is selected from CR ₄ and N, preferably CR ₄ ;

Ring A is is selected from;

Here, R _a is selected from H, D and halo, and m = 0, 1, 2 or 3;

R ₁ is selected from H, D and halo;

R ₂ is selected from H, D, halo, C _1-4 alkyl and C _1-4 haloalkyl;

R ₃ is selected from H, D and halo;

R ₄ is selected from H and D;

Alternatively, R ₂ and R ₃ together with the carbon atoms to which they are connected , forming;

R _1s and R _2s3 are linked to form C _2-4 alkylene, which is optionally substituted with 1, 2 or 3 halo, OH, C _1-4 alkyl or C _1-4 haloalkyl;

R _2s1 is selected from H, D, C _1-4 alkyl and C _1-4 haloalkyl;

R _2s2 is selected from H, D, -C _1-4 alkylene-OH, C _1-4 alkyl and C _1-4 haloalkyl;

Alternatively, R _2s1 and R _2s2 together with the carbon atoms to which they are connected form a C _3-5 cycloalkyl;

A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated.

101. In paragraph 98,

M ₁ is selected from CR ₁ and N, preferably CR ₁ ;

M ₂ is selected from CR ₂ and N, preferably CR ₂ ;

M ₃ is selected from CR ₃ and N, preferably CR ₃ ;

M ₄ is selected from CR ₄ and N, preferably CR ₄ ;

Ring A is

is selected from;

At this time, R _a is selected from H and D, and m=0, 1, 2, 3, 4 or 5;

R ₁ is Cl;

R ₂ is Cl;

R ₃ is selected from H and D;

R ₄ is selected from H and D;

Alternatively, R ₂ and R ₃ together with the carbon atoms to which they are connected to form;

R _1s and R _2s3 are linked to form C _2-3 alkylene, which is optionally substituted with 1 or 2 OH;

R _2s1 is selected from H, D and Me;

R _2s2 is selected from H, D, Me and CH ₂ OH;

Alternatively, R _2s1 and R _2s2 together with the carbon atoms to which they are connected form cyclopropyl;

A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated.

102. A compound selected from the group consisting of compounds described in Tables 1 to 13 , or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof.

103. As a pharmaceutical composition,

A compound as described in any one of claims 1 to 102, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof;

Pharmaceutically acceptable excipient(s); and

Optionally, one or more other treatments

A pharmaceutical composition comprising:

104. As a kit,

A first container containing a compound as described in any one of claims 1 to 102, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof; and

Optionally, a second container containing one or more other therapeutic agents; and

Optionally, a kit comprising a third container containing pharmaceutically acceptable excipient(s) for diluting or suspending the compound and/or other therapeutic agent(s).

105. Use of a compound according to any one of claims 1 to 102, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, in the manufacture of a medicament for treating an immune and/or inflammatory disease, disorder or condition associated with excessive or inappropriate ALPK1-dependent proinflammatory signaling.

106. A compound according to any one of claims 1 to 102, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, for use in treating an immune and/or inflammatory disease, disorder or condition associated with excessive or inappropriate ALPK1-dependent proinflammatory signaling.

107. A method for treating an immune and/or inflammatory disease, disorder or condition associated with excessive or inappropriate ALPK1-dependent inflammatory signaling in a subject, the method comprising administering to a subject in need thereof a compound according to any one of claims 1 to 102, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof.

108. A use, compound or method according to any one of claims 105 to 107, wherein the disease, disorder or condition is selected from sepsis, cancer, systemic lupus erythematosus, hidradenoma, hidradenoma, Kawasaki disease, ROSAH (retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis and migraine) syndrome, PFAPA (periodic fevers, aphthous stomatitis, pharyngitis and adenitis) syndrome, inflammatory bowel disease (IBD), NASH, gout, diabetes, chronic kidney disease, pancreatitis, Kawasaki disease, inflammatory skin diseases, and neurodegenerative diseases including Alzheimer's disease.

109. A use, compound or method according to claim 108, wherein the cancer is selected from lung cancer, colon cancer and oral squamous cell carcinoma.

110. A use, compound or method according to claim 108, wherein the disease or disorder is ROSAH.

111. A use, compound or method according to claim 108, wherein the disease or disorder is PFAPA.

112. A use, compound or method according to claim 108, wherein the disease or disorder is a sweat gland tumor or sweat gland carcinoma.

113. A use, compound or method according to claim 108, wherein the disease or disorder is sepsis.

114. A use, compound or method according to claim 108, wherein the disease or disorder is systemic lupus erythematosus.

115. A use, compound or method according to claim 108, wherein the disease or disorder is Kawasaki disease.

116. A use, compound or method according to claim 108, wherein the subject has one or more ALPK1 gene mutations.

Reverse amide (Example A)

General Method 1

Compound 1-1 is halogenated in the presence or absence of a Pd catalyst to form compound 1-2, which is further coupled with an amine in the presence of a coupling reagent such as HATU, HOBt, etc. Compound 1-4 is synthesized from compound 1-3 and key intermediates such as boric acid/ester, tin, etc. in the presence of Pd or Cu and other heavy metals as a catalyst.

Example 1:

N -( Grade 3- Butyl)-2,3-dichloro-4-hydroxy-6-(1 H Preparation of -pyrazol-1-yl)benzamide (compound A10)

Step 1: Synthesis of 2,3-dichloro-6-iodo-4-methoxy-benzoic acid

A mixture of 2,3-dichloro-4-methoxy-benzoic acid (300 mg, 1.36 mmol), NIS (610.71 mg, 2.71 mmol), and Pd(OAc) ₂ (30.47 mg, 135.72 μmol) in DMF (3 mL) was stirred at 60°C for 12 h. The resulting mixture was diluted with water (10 mL), extracted with EA (10 mL × 3), and concentrated in vacuo. The residue was purified by silica gel (EA/PE, 0–100%) column chromatography to give the title compound as a yellow solid (300 mg, 63.71%).

Step 2: N - Grade 3- Synthesis of butyl-2,3-dichloro-6-iodo-4-methoxy-benzamide

A mixture of 2,3-dichloro-6-iodo-4-methoxy-benzoic acid (300 mg, 864.72 μmol), DIPEA (223.52 mg, 1.73 mmol), HATU (493.19 mg, 1.30 mmol), and 2-methylpropan-2-amine (63.24 mg, 864.72 μmol) in DMF (3 mL) was stirred at 50°C for 2 h, diluted with water (10 mL), extracted with EA (10 mL × 3), and concentrated in vacuo. The residue was purified by silica gel (EA/PE, 0-50%) column chromatography to give the title compound as a white solid (270 mg, yield 77.66%).

Step 3: N - (3rd grade- Synthesis of butyl)-2,3-dichloro-4-methoxy-6-(pyrazol-1-yl)-benzamide

A mixture of N - tert- butyl-2,3-dichloro-6-iodo-4-methoxy-benzamide ( ₁₀₀ mg, 248.72 μmol), _Cs2CO3 (162.08 mg, 497.44 μmol), CuI (4.74 mg, 24.87 μmol), and 1 H -pyrazole (16.93 mg, 248.72 μmol) in DMF (2 mL) was stirred at 110°C for 2 h. The resulting mixture was diluted with water (10 mL), extracted with EA (10 mL × 3), and concentrated in vacuo. The residue was purified by silica gel (EA/PE, 0-30%) column chromatography to give the title compound as a yellow solid (60 mg, 70.49%).

Step 4: N - (3rd grade- Synthesis of butyl)-2,3-dichloro-4-hydroxy-6-(pyrazol-1-yl)-benzamide

To a solution of N-tert- butyl-2,3-dichloro-4-methoxy-6-pyrazol-1-yl-benzamide (60 mg, 175.33 μmol) in DCM (2 mL) was added Bbr ₃ (87.85 mg, 350.65 μmol) at 0°C. The mixture was stirred at 0°C for 2 h, diluted with MeOH (10 mL), and concentrated in vacuo to obtain a residue, which was purified by prep-HPLC (0-90% water in acetonitrile) to give the title compound as a white solid (4 mg, yield 6.95%).

Example 2:

N -( Grade 3- Preparation of butyl)-4-chloro-6-(thiazol-4-yl)-2,3-dihydrobenzofuran-5-carboxamide (Compound A6)

Step 1: Synthesis of 2-(3-bromo-2-chloro-6-fluorophenyl)ethan-1-ol

To a solution of 1-bromo-2-chloro-4-fluorobenzene (75.0 g, 358 mmol) in DMF (750 mL) was added LDA (2 M in THF, 215 mL) dropwise at -78°C. The mixture was stirred at -78°C for 3 h, then oxirane (31.5 g, 716 mmol) was added at -78°C, warmed to 25°C, and stirred for 9 h. The reaction was stopped by adding saturated NH ₄ Cl aqueous solution (1 L) to the mixture at 0°C, and extracted with EtOAc (600 mL × 3). The combined organic layers were concentrated under reduced pressure to obtain a residue, which was purified by column chromatography eluting with EA in PE 25-100% to obtain the title compound as a yellow solid (41.0 g, yield 45%). ^1H NMR (400 MHz, DMSO _-d6 ) δ 7.81 - 7.59 (m, 1H), 7.31 - 7.09 (m, 1H), 5.02 - 4.81 (m, 1H), 3.77 - 3.48 (m, 2H), 3.15 - 2.86 (m, 2H).

Step 2: Synthesis of 5-bromo-4-chloro-2,3-dihydrobenzofuran

2-(3-Bromo-2-chloro-6-fluorophenyl)ethan-1-ol (40.0 g, 158 mmol) was dissolved in THF (300 mL) to a solution of NaH (14.2 g, 355 mmol, purity 60%) was added dropwise at 0°C. The mixture was stirred at 75°C for 12 h, saturated NH ₄ Cl aqueous solution (500 mL) was added at 0°C to quench the reaction, and the mixture was extracted with EtOAc (300 mL × 3). The combined organic layers were concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography, eluting with EA in PE 25-100%, to obtain the title compound as a yellow solid (22.0 g, yield 63%). ^1H NMR (400 MHz, DMSO _-d6 ) δ 7.45 (d, J = 8.4 Hz, 1H), 6.72 (d, J = 8.4 Hz, 1H), 4.63 (t, J = 8.4 Hz, 2H), 3.27 (t, J = 8.4 Hz, 2H).

Step 3: Synthesis of methyl 4-chloro-2,3-dihydrobenzofuran-5-carboxylate

To a solution of 5-bromo-4-chloro-2.3-dihydrobenzofuran (22.0 g, 93.9 mmol) in THF (220 mL) was added dropwise n -BuLi (2.5 M in hexane, 41.4 mL) at -78°C. The mixture was stirred at -78°C for 1 h, and then methyl carbonochloridate (13.3 g, 142 mmol, 10.9 mL) was added at -78°C. The reaction mixture was warmed to 25°C and stirred for 15 h, and then saturated _NH4Cl aqueous solution (500 mL) was added at 0°C to quench the reaction and extract with EtOAc (300 mL × 3). The above mixed organic layer was concentrated under reduced pressure to obtain a residue, which was purified by column chromatography eluting with 25-100% EA in PE to obtain the title compound as a yellow solid (10.0 g, yield 50%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.73 (d, J = 8.4 Hz, 1H), 6.82 (d, J = 8.4 Hz, 1H), 4.69 (t, J = 8.8 Hz, 2H), 3.80 (s, 3H), 3.25 (t, J = 8.7 Hz, 2H). MS (ESI) m/z [M+H] ⁺ 213.1, 215.1 (Cl).

Step 4: Synthesis of 4-chloro-2,3-dihydrobenzofuran-5-carboxylic acid

A solution of methyl 4-chloro-2,3-dihydrobenzofuran-5-carboxylate (10.0 g, 47.2 mmol) and LiOH (3.38 g, 141 mmol) in MeOH (100 mL) and water (20 mL) was stirred at 25°C for 12 h. The reaction mixture was concentrated under reduced pressure to remove MeOH, and the residue was diluted with water (80 mL) and extracted with DCM (60 mL x 3). The aqueous phase was adjusted to pH 4–5 with dilute hydrochloric acid and extracted with EtOAc (60 mL x 3). The combined organic layers were washed with saturated brine (150 mL), dried over Na₂SO₄, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound as a pale yellow color (5.00 g, yield 54%). ^1H NMR (400 MHz, DMSO- d ₆ ) δ 13.43 - 12.26 (m, 1H), 7.73 (d, J = 8.3 Hz, 1H), 6.80 (d, J = 8.5 Hz, 1H), 4.68 (t, J = 8.8 Hz, 2H), 3.24 (t, J) = 8.8 Hz, 2H). MS (ESI) m/z [MH] ^- 197.0, 199.0 (Cl).

Step 5: Synthesis of 4-chloro-6-iodo-2,3-dihydrobenzofuran-5-carboxylic acid

A solution of 4-chloro-2,3-dihydrobenzofuran-5-carboxylic acid (600 mg, 2.09 mmol), iodobenzene diacetate (1.62 g, 5.04 mol), I ₂ (1.28 g, 5.04 mol), and Pd(OAc) ₂ (113 mg, 505 μmol) in DMF (12 mL) was stirred at 40 °C for 12 h. The solvent was removed in vacuo, and the residue was purified by prep-HPLC (column: Phenomenex Luna 80*30mm*3um; mobile phase: [water (HCl)-ACN]; B%: 20%-55%, 8 min) to give the title compound as a pale yellow solid (300 mg, yield 31%). ^1H NMR (400 MHz, DMSO -d6 ) δ 7.24 (s, 1H), 4.63 (t, J ₌ 8.8 Hz, 2H), 3.19 (t, J = 8.7 Hz, 2H). MS (ESI) m/z [MH] ^- 322.9, 324.8 (Cl).

Step 6: N - (3rd grade- Synthesis of butyl)-4-chloro-6-iodo-2,3-dihydrobenzofuran-5-carboxamide

A solution of 4-chloro-6-iodo-2,3-dihydrobenzofuran-5-carboxylic acid (300 mg, 925 μmol), HATU (527 mg, 139 μmol), and DIPEA (239 mg, 185 μmol, 322 μL) in DCM (3 mL) was stirred at 25 °C for 0.5 h, and then 2-methylpropan-2-amine (81.2 mg, 1.11 mmol, 117 μL) was added. The reaction mixture was stirred at 25 °C for 15.5 h, then the reaction was quenched by the addition of water (10 mL) at 25 °C, and extracted with DCM (6 mL × 3). The above mixed organic layers were concentrated under reduced pressure to obtain a residue, which was purified by prep-HPLC (column: Waters Xbridge BEH C18 100*30mm*10um; mobile phase: [water (NH ₄ HCO ₃ )-ACN]; B%: 30%-70%, 8 min) to obtain the title compound as a white solid (148.5 mg, yield 42%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 18.01 (s, 1H), 7.18 (s, 1H), 4.61 (t, J = 8.7 Hz, 2H), 3.16 (t, J = 8.8 Hz, 2H), 1.34 (s, 9H). MS (ESI) m/z [MH] ^- 377.9, 379.9 (Cl).

Step 7: Synthesis of N- ( tert- butyl)-4-chloro-6-(thiazol-4-yl)-2,3-dihydrobenzofuran-5- carboxamide

A solution of N-(tert- butyl)-4-chloro-6-iodo-2,3-dihydrobenzofuran-5-carboxamide (25 mg, 65.9 μmol), 4-(tributylstannyl)thiazole (29.6 mg, 79.0 μmol), and Pd(PPh ₃ ) ₄ (7.61 mg, 6.59 μmol) in dioxane (0.2 mL) was stirred at 110°C for 16 h. The reaction mixture was cooled to room temperature and filtered, and the filtrate was concentrated under reduced pressure to obtain a residue, which was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10um; mobile phase: [water (NH ₄ HCO ₃ )-ACN]; B%: 25%-65%, 8 min) to obtain the title compound as a pale yellow solid (2.0 mg, yield 9%). ¹ H NMR (400 MHz, MeOD) δ 9.13 - 8.96 (m, 1H), 7.77 (s, 1H), 7.06 (s, 1H), 4.67 (t, J = 8.8 Hz, 2H), 3.30 - 3.27 (m, 2H), 1.31 (s, 9H). MS (ESI) m/z [M+H] ⁺ 337.0, 339.0 (Cl).

Example 3:

5-bromo- N -( Grade 3- Preparation of butyl)-2-(2-ethynylphenyl)-1-naphthamide (Compound A47)

Step 1: Synthesis of 5-bromo-2-iodo-1-naphthoic acid

To a solution of 5-bromonaphthalene-1-carboxylic acid (1 g, 3.98 mmol) in DMF (30 mL) were added NIS (1.08 g, 4.78 mmol) and Pd(OAc) ₂ (89.42 mg, 398.29 μmol) at room temperature. The mixture was stirred at 65°C for 4 h. The crude mixture was concentrated and purified by column (PE/EA=1/1) to obtain the title compound (550 mg, yield 36.63%) as an off-white solid. MS (ESI) m/z [M+H] ⁺ 376.9, 378.9 (Br).

Step 2: 5-Bromo- N -( Grade 3- Synthesis of butyl)-2-iodo-1-naphthamide

To a solution of 5-bromo-2-iodo-naphthalene-1-carboxylic acid (200 mg, 530.54 μmol) and 2-methylpropan-2-amine (388.02 mg, 5.31 mmol) in DMF (5 mL) were added N -ethyl- N -isopropyl-propan-2-amine (274.28 mg, 2.12 mmol, 369.64 μL) and HATU (403.46 mg, 1.06 mmol) at room temperature. The mixture was stirred at 70 °C for 4 h, concentrated, and purified by Prep-HPLC (0.5% FA in MeCN + water = 95% to 10%) to give the title compound as a white solid (200 mg, yield 87.24%). MS (ESI) m/z [M+H] ⁺ 431.9, 433.9 (Br).

Step 3. 5-Bromo- N -( Grade 3- Synthesis of butyl)-2-(-2-((trimethylsilyl)))-naphthamide

To a solution of trimethyl-[2-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-ethynyl]silane (120 mg, 399.63 μmol) and 5-bromo-N-tert-butyl-2-iodo-naphthalene-1-carboxamide (220 mg, 509.15 μmol) in dioxane (5 mL) and water (1 mL) were added Pd(dppf)Cl ₂ (29.24 mg, 39.96 μmol) and Na ₂ CO ₃ (84.71 mg, 799.27 μmol). The mixture was stirred at 80°C for 2 h. The above mixture was purified by a silica gel column (PE/EA=1/1) to obtain the title compound (70 mg, yield 36.61%) as a white solid.

Step 4: 5-Bromo- N -( Grade 3- Synthesis of butyl)-2-(2-ethynylphenyl)-1-naphthamide

To a solution of 5-bromo- N -tert - butyl-2-[2-(2-trimethylsilylethynyl)phenyl]naphthalene-1-carboxamide (35 mg, 73.15 μmol) in THF (2 mL) was added N,N-diethylethanamine trihydrofluoride (990 mg, 6.14 mmol) at room temperature. The mixture was stirred overnight at 50°C, concentrated, and purified by Prep-HPLC to give the title compound as a white solid (8 mg, yield 26.92%). ^1H NMR (400 MHz, DMSO- d ₆ ) δ 8.19 (d, J = 8.8 Hz, 1H), 7.95 (dd, J = 14.6, 7.9 Hz, 2H), 7.88 (s, 1H), 7.65 (d, J = 8.7 Hz, 1H), 7.62 - 7.58 (m, 1H), 7.55 (dd, J = 10.6, 5.2 Hz, 2H), 7.44 (dd, J = 7.4, 1.6 Hz, 2H), 4.00 (s, 1H), 1.16 (s, 9H). MS (ESI) m/z [M+H] ⁺ 406.0, 408.0 (Br).

The following compounds ( A1 to A159 ) in Table 1 were synthesized using appropriate starting materials and corresponding intermediates in a manner similar to that described in Examples 1, 2 , and 3 .

General Method 2

Compound 2-1 was iodinated with NIS or I ₂ in the presence of a catalyst Pd to produce compound 2, which was then further coupled with an amine intermediate in the presence of a coupling reagent such as HATU or HOBt to produce intermediate 2-3. The methoxy group was removed with BBr3 or another acid to produce diphenol intermediate 2-4, which was then alkylated with a halide under basic conditions to produce intermediate 2-5. The final product 2-6 was formed through a heavy metal-catalyzed reaction between intermediate 2-5 and another boric acid or activated intermediate.

Example 4:

N -( 3rd class -butyl)-5-chloro-7-(1 H -pyrazol-1-yl)-2,3-dihydrobenzo[ b ] Preparation of [1,4]dioxin-6-carboxamide (compound A180)

Step 1: Synthesis of 2-chloro-6-iodo-3,4-dimethoxybenzoic acid

To a solution of 2-chloro-3,4-dimethoxy-benzoic acid (3 g, 13.85 mmol) and Pd(OAc) ₂ (621.85 mg, 2.77 mmol) in DMF (40 mL) was added NIS (4.05 g, 18.00 mmol) at room temperature, and the mixture was stirred at 60°C for 28 h. The mixture was concentrated and purified by C18-flash chromatography (0-30% ACN in water) to give the title compound as a yellow solid (3 g, yield 63.24%).

Step 2: N - (3rd grade- Synthesis of butyl)-2-chloro-6-iodo-3,4-dimethoxybenzamide

HATU (1.33 g, 3.50 mmol) was added to a solution of 2-chloro-6-iodo-3,4-dimethoxy-benzoic acid (1 g, 2.92 mmol), 2-methylpropan-2-amine (427.06 mg, 5.84 mmol), and DIPEA (1.13 g, 8.76 mmol) in DMF (10 mL) at room temperature, and the mixture was stirred for 2 hours. The reaction mixture was diluted with water (50 mL) and extracted with EA (60 mL×2). The combined organic layers were concentrated, and purified by silica gel column chromatography (EA in PE 0-40%) to give the title compound as a yellow solid (830 mg, yield 71.49%).

Step 3: N - (3rd grade- Synthesis of butyl)-2-chloro-3,4-dihydroxy-6-iodobenzamide

To a solution of N-tert-butyl-2 -chloro-6-iodo-3,4-dimethoxy-benzamide (830 mg, 2.09 mmol) in DCM (5 mL) was added BBr ₃ (2.09 g, 8.35 mmol) at room temperature, and the mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with water (50 mL) and extracted with EA (60 mL×2). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated to obtain a residue, which was purified by silica gel column chromatography (EA in PE 0-100%) to obtain the title compound as a yellow solid (700 mg, yield 90.74%).

Step 4: N - (3rd grade- Butyl)-5-chloro-7-iodo-2,3-dihydrobenzo[ b ][1,4] Synthesis of dioxin-6-carboxamide

To a solution of N-tert-butyl-2 -chloro-3,4-dihydroxy-6-iodo-benzamide (350 mg, 947.02 μmol) in DMF (5 mL) was added 1,2-dibromoethane (355.81 mg, 1.89 mmol) at room temperature, and the mixture was stirred at 80°C for 2 hours. The reaction mixture was diluted with water (40 mL) and extracted with EA (40 mL × 2). The combined organic layers were concentrated, and purified by silica gel column chromatography (EA in PE 0-100%) to obtain the title compound as a yellow solid (280 mg, yield 74.73%).

Step 5: N -( 3rd class -butyl)-5-chloro-7-(1 H -pyrazol-1-yl)-2,3-dihydrobenzo-[ b ][1,4] Preparation of dioxin-6-carboxamide (compound A180)

To a solution of N- ( tert -butyl)-5-chloro-7-iodo-2,3-dihydrobenzo[ b ][1,4]dioxine-6-carboxamide (62 mg, 157.24 μmol) and 1 H -pyrazole (21.41 mg, 314.47 μmol) in DMF (3 mL) were added CuI (5.99 mg, 31.45 μmol) and Cs ₂ CO ₃ (102.46 mg, 314.47 μmol) under a nitrogen atmosphere at room temperature, and the mixture was stirred at 90 °C for 3 h. The crude product was purified by C18-flash chromatography (ACN in water 0-70%) to give the title compound as a white solid (15.94 mg, yield 30.18%). ^1H NMR (400 MHz, DMSO _-d6 ) δ 8.09 (s, 1H), 7.94 (d, J = 2.4 Hz, 1H), 7.65 (d, J = 1.6 Hz, 1H), 7.05 (s, 1H), 6.42 (t, J = 2.4 Hz, 1H), 4.43 - 4.38 (m, 2H), 4.36 - 4.32 (dd, J = 5.2, 2.2 Hz, 2H), 1.20 (s, 9H). MS (ESI) m/z [M+H] ⁺ 336.1, 338.1 (Cl).

Example 5:

N -( 3rd class -butyl)-5-chloro-7-(1 H -imidazol-2-yl)-2,3-dihydrobenzo-[ b ][1,4] Preparation of dioxin-6-carboxamide (compound A200)

Step 1: 2-(tributylstannyl)-1 H -Synthesis of imidazole

2-Bromo-1 H -imidazole (300 mg, 2.04 mmol) was dissolved in THF (4 mL) at -78 °C under N ₂ atmosphere. n -BuLi (2.5 M in hexane, 0.9 mL) was added dropwise, and the mixture was stirred at -78 °C for 1 h. Subsequently, Bu ₃ SnCl (797.30 mg, 2.45 mmol) was added dropwise, and the mixture was stirred at -78 °C for an additional 30 min and then at room temperature for 3 h. The reaction was quenched with water (10 mL) and extracted with EA (15 mL × 2). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , and concentrated in vacuo to give the title crude compound (700 mg, yield 96.03%), which was used without further purification.

Step 2: N -( 3rd class -butyl)-5-chloro-7-(1 H -imidazol-2-yl)-2,3-dihydro-benzo-[ b ][1,4] Preparation of dioxin-6-carboxamide (compound A200)

A mixture of Pd(PPh) ₄ (26.28 mg, 22.75 μmol), N - tert -butyl-5-chloro-7-iodo-2,3-dihydro-1,4-benzodioxin-6-carboxamide (90 mg, 227.49 μmol), tributyl(1 H -imidazol-2-yl)stannane (162.48 mg, 454.98 μmol), LiCl (28.93 mg, 682.47 μmol), and CuI (8.67 mg, 45.50 μmol) in dioxane (4 mL) was stirred at 100 °C for 8 h under a nitrogen atmosphere. The resulting mixture was concentrated and purified by C18-flash chromatography (0-30% ACN in water) to obtain the title compound as a white solid (20 mg, yield 26.18%). ^1H NMR (400 MHz, DMSO _-d6 ) δ 11.53 (s, 1H), 7.94 (s, 1H), 7.20 (s, 1H), 7.15 (s, 1H), 6.95 (s, 1H), 4.39 (d, J = 2.8 Hz, 2H), 4.32 (d, J = 2.7 Hz, 2H), 1.28 (s, 9H). MS (ESI) m/z [M+H] ⁺ 336.1, 338.1 (Cl).

The following compounds ( A160 to A250 ) in Table 2 were synthesized using appropriate starting materials and corresponding intermediates in a manner similar to that described in Examples 4 and 5 .

General Method 3

Compound 3-1 was iodinated with NIS or I ₂ in the presence of a catalyst Pd to form compound 3-2, which was then further coupled with an amine intermediate in the presence of a coupling reagent such as HATU or HOBt to form intermediate 3-3. Intermediate 3-3 was further activated with a borate/OTf intermediate under heavy metal catalysis or basic conditions, which was further coupled with another boric acid/halide intermediate to form the final product 3-4.

Example 6:

N -( Grade 3- Butyl)-2-methyl-6-(1 H -pyrazol-1-yl)-3-(1 H Preparation of -pyrazol-3-yl)benzamide (compound A263)

Step 1: Synthesis of 3-bromo-6-iodo-2-methylbenzoic acid

To a solution of 3-bromo-2-methylbenzoic acid (5 g, 23.26 mmol) and Pd(OAc) ₂ (387.21 mg, 2.33 mmol) in DMF (45 mL) was added NIS (8.53 g, 27.91 mmol) at room temperature. The mixture was stirred at 60°C for 10 h, concentrated in vacuo, and the residue was purified by flash column chromatography (EA/PE = 20–80%) to give the title compound as a yellow solid (6.7 g, yield 84.47%). MS (ESI) m/z [M+H] ⁺ 341.1, 343.1 (Br).

Step 2: 3-Bromo- N -( Grade 3- Synthesis of butyl)-6-iodo-2-methylbenzamide

HATU (11.21 g, 29.48 mmol) and DIPEA (3.81 g, 29.48 mmol) were added to a solution of 3-bromo-6-iodo-2-methylbenzoic acid (6.7 g, 19.65 mmol) in DMF (30 mL) at room temperature. After stirring at room temperature for 40 minutes, 2-methylpropan-2-amine (1.72 g, 23.58 mmol) was added and stirred until benzoic acid was consumed. The reaction mixture was concentrated in vacuo and purified by flash column chromatography (EA/PE = 10-60%) to give the title compound (4.37 g, 11.04 mmol, yield 56.18%) as a white solid. MS (ESI) m/z [M+H] ⁺ 396.2, 398.2 (Br).

Step 3: 3-Bromo- N - (3rd grade- Butyl)-2-methyl-6-(1 H Synthesis of -pyrazol-1-yl)-benzamide

To a solution of 3-bromo- N -( tert -butyl)-6-iodo-2-methylbenzamide (3 g, 7.58 mmol) in DMF (30 mL) were added 1 H -pyrazole (0.62 g, 9.09 mmol), Cs ₂ CO ₃ (4.94 g, 15.16 mmol), CuI (144.74 mg, 0.76 mmol), and L-proline (174.54 mg, 1.52 mmol) at room temperature. The reaction mixture was stirred at 80 °C for 6 h, concentrated in vacuo, and purified by flash column chromatography (EA/PE = 10-50%) to give the title compound (1.7 g, yield 66.75%) as a white solid. MS (ESI) m/z [M+H] ⁺ 336.0, 338.1 (Br).

Step 4: N -( Grade 3- Butyl)-2-methyl-6-(1 H Synthesis of -pyrazol-1-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide

To a solution of 3-bromo- N -( tert -butyl)-2-methyl-6-(1 H -pyrazol-1-yl)benzamide (1.7 g, 5.06 mmol) in dioxane (20 mL) were added (Bpin) ₂ (1.54 g, 6.07 mmol), KOAc (993.18 mg, 10.12 mmol), and Pd(dppf)Cl ₂ (184.94 mg, 0.25 mmol) at room temperature. The reaction mixture was stirred at 100 °C under N ₂ atmosphere for 4 h, concentrated in vacuo, and purified by flash column chromatography (EA/PE = 10-50%) to give the title compound (1.3 g, yield 67.08%) as a white solid. MS (ESI) m/z [M+H] ⁺ 384.2.

Step 5: N -( Grade 3- Butyl)-2-methyl-6-(1 H -pyrazol-1-yl)-3-(1 H Preparation of -pyrazol-3-yl)benzamide (compound A263)

To a solution of N- ( tert -butyl)-2-methyl-6-(1 H -pyrazol-1-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (60 mg, 0.16 mmol) in dioxane (5 mL) and water (0.5 mL) were added 3-bromo-1 H -pyrazole (28.22 mg, 0.19 mmol), K ₃ PO ₄ (101.88 mg, 0.48 mmol), and Pd(dppf)Cl ₂ (5.85 mg, 8 μmol) at room temperature. The reaction mixture was stirred at 100°C under N ₂ for 1 hour, concentrated in vacuo, and purified by flash column chromatography (EA/PE = 10-80%) to obtain the title compound (26.03 mg, yield 50.31%) as a white solid. ^1H NMR (400 MHz, DMSO _-d6 ) δ 13.00 (s, 1H), 8.09 (s, 1H), 8.02 (d, J = 2.4 Hz, 1H), 7.80 (s, 1H), 7.69 (d, J = 2.0 Hz, 1H), 7.58 (s, 1H), 7.42 (d, J = 8.4 Hz, 1H), 6.51 (s, 1H), 6.45 (t, J = 2.0 Hz, 1H), 2.40 (s, 3H), 1.22 (s, 9H). MS (ESI) m/z [M+H] ⁺ 324.0.

Example 7:

N -( 3rd class -butyl)-2'-ethynyl-5-hydroxy-4-(1 H Preparation of -pyrazol-3-yl)-[1,1'-biphenyl]-2-carboxamide (Compound A278)

Step 1: Synthesis of 5-bromo-2-iodo-4-methoxybenzoic acid

To a solution of 3-bromo-4-methoxy-benzoic acid (4.6 g, 19.91 mmol) in DMF (50 mL) were added NIS (4.48 g, 19.91 mmol) and Pd(OAc) ₂ (446.99 mg, 1.99 mmol). The mixture was stirred at 80°C for 16 h, diluted with 50 mL of EA, washed with water, dried, and concentrated. The crude product was purified by silica gel chromatography (PE/EA=1/1) to obtain the title compound (1.1 g, yield 14.07%).

Step 2: 5-Bromo- N -( Grade 3- Synthesis of butyl)-2-iodo-4-methoxybenzamide

To a solution of 5-bromo-2-iodo-4-methoxy-benzoic acid (0.5 g, 1.40 mmol) in DMF (1.26 mL) were added DIPEA (543.12 mg, 4.20 mmol), HATU (639.15 mg, 1.68 mmol), and tert -butylamine (204.91 mg, 2.80 mmol). The mixture was stirred at 60°C for 2 h, diluted with 15 mL of EA, washed with water, dried, and concentrated. The residue was purified by silica gel column chromatography (EA/PE = 0–25%) to give the title compound (0.3 g, yield 51.97%).

Step 3: 4-Bromo- N -( Grade 3- Synthesis of butyl)-5-methoxy-2'-((trimethylsilyl)ethynyl)-[1,1'-biphenyl]-2-carboxamide

To a solution of 5-bromo- N-tert -butyl-2-iodo-4-methoxy-benzamide (0.1 g, 242.68 μmol) and trimethyl-[2-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-ethynyl]silane (72.87 mg, 242.68 μmol) in water (0.5 mL) and dioxane (4 mL) were added Pd(dppf)Cl ₂ (35.50 mg, 48.54 μmol) and K ₃ PO ₄ (154.54 mg, 728.05 μmol). The mixture was stirred at 90 °C under N ₂ for 1 h, diluted with 15 mL of EA, washed with water, dried, and concentrated. The residue was purified by column chromatography (EA/PE = 0-20%) to obtain the title compound (0.08 g, yield 71.9%).

Step 4: N -( Grade 3- Butyl)-5-methoxy-4-(1 H Synthesis of -pyrazol-3-yl)-2'-((trimethylsilyl)ethynyl)-[1,1'-biphenyl]-2-carboxamide

To a solution of 5-bromo- N-tert -butyl-4-methoxy-2-[2-(2-trimethylsilylethynyl)-phenyl]benzamide (0.08 g, 174.50 μmol) and 1 H -pyrazol-3-ylboronic acid (19.53 mg, 174.50 μmol) in dioxane (4 mL) and water (0.5 mL) were added Pd(dppf)Cl ₂ (28.50 mg, 34.90 μmol) and K ₃ PO ₄ (111.12 mg, 523.49 μmol). The mixture was stirred at 100 °C under N ₂ for 3 h, diluted with 15 mL of EA, washed with water, dried, and concentrated. The residue was purified by column chromatography (EA/PE = 0-10%) to obtain the title compound as a white solid (0.04 g, yield 51.44%).

Step 5: N-(3rd grade -butyl)-2'-ethynyl-5-hydroxy-4-(1 H Synthesis of -pyrazol-3-yl)-[1,1'-biphenyl]-2-carboxamide (Compound A278)

To a solution of N-tert -butyl-4-methoxy-5-(1 H -pyrazol-3-yl)-2-[2-(2-trimethylsilyl-ethynyl)phenyl]benzamide (0.04 g, 89.76 μmol) dissolved in DCM (2 mL) was added BBr ₃ . The mixture was stirred at room temperature for 2 h and then at 50 °C for 24 h. After the reaction was quenched with MeOH, the mixture was purified by column chromatography on silica gel (EA/PE = 0-20%) to obtain the title compound (2 mg, yield 6.2%). ^1H NMR (400 MHz, DMSO -d6 ) δ 13.25 (s, 1H), 11.16 ( _s , 1H), 7.93 (s, 1H), 7.89 (s, 1H), 7.55 (dd, J = 7.6, 1.6 Hz, 1H), 7.44 - 7.36 (m, 2H), 7.35 -7.29 (m, 1H), 6.96 (s, 1H), 6.83 (s, 1H), 6.72 (s, 1H), 4.03 (s, 1H), 1.12 (s, 9H). MS (ESI) m/z [M+H] ⁺ 359.9.

The following compounds ( A251 to A285 ) in Table 3 were synthesized using appropriate starting materials and corresponding intermediates in a similar manner as described in Examples 6 and 7 .

General Method 4

Compound 4-2 was synthesized from 4-1 and CO ₂ under basic conditions such as LDA, NaHMDS, etc. Then, compound 4-3 was prepared in a similar manner to general method 1.

Example 8:

6-(2-Aminobenzo[d]thiazol-4-yl)- N -( 3rd class Preparation of -butyl)-2,3-dichloro-benzamide (Compound A292)

Step 1: Synthesis of 2,3-dichloro-6-iodobenzoic acid

To a solution of 1,2-dichloro-4-iodo-benzene (5 g, 18.32 mmol) in THF (50 mL) at -78°C was added LDA (2 M in THF, 18.32 mmol, 10 mL) under nitrogen. After stirring for 20 minutes, dry ice was added, and the reaction mixture was warmed to room temperature for 3 hours. The mixture was diluted with water and extracted with EA. The aqueous layer was acidified with diluted aqueous HCl (200 mL) and extracted twice with EA. The organic layer was concentrated, and it was purified by column chromatography (0-25% EA in PE) to give the title compound as a yellow solid (4.2 g, yield 72.33%).

Step 2: N - (3rd grade- Synthesis of butyl)-2,3-dichloro-6-iodobenzamide

A mixture of HATU (1.56 g, 4.10 mmol), 2,3-dichloro-6-iodo-benzoic acid (1 g, 3.16 mmol), 2-methylpropan-2-amine (461.56 mg, 6.31 mmol), and DIPEA (1.22 g, 9.47 mmol, 1.65 mL) in DMF (10 mL) was stirred at room temperature for 2 h. The reaction mixture was diluted with water (100 mL) and extracted with EA (100 mL × 2). The combined organic layers were washed with brine, dried, and concentrated. The residue was purified by silica gel column chromatography (EA in PE 0-30%) to give the title compound as a white solid (1 g, yield 85.18%).

Step 3: 3rd class -Butyl N Synthesis of -(4-bromo-1,3-benzothiazol-2-yl)carbamate

To a solution of Boc ₂ O (3.81 g, 17.46 mmol), DMAP (106.65 mg, 872.99 μmol), and Et ₃ N (1.77 g, 17.46 mmol, 2.43 mL) in DCM (20 mL) was added 4-bromo-1,3-benzothiazol-2-amine (2 g, 8.73 mmol), and the mixture was stirred at room temperature for 2 h. The resulting mixture was diluted with water (20 mL), extracted with EA (20 mL × 3), and the combined organic layers were concentrated in vacuo. The residue was purified by column chromatography on silica gel (EA in PE, 0-30%) to give the title compound as a white solid (2 g, yield 69.59%).

Step 4: [2-( 3rd class Synthesis of -butoxycarbonylamino)-1,3-benzothiazol-4-yl]boronic acid

A mixture of Pd(dppf)Cl ₂ (444.52 mg, 607.51 μmol), (Bpin) ₂ (3.09 g, 12.15 mmol), KOAc (1.19 g, 12.15 mmol), and tert -butyl N- (4-bromo-1,3-benzothiazol-2-yl)carbamate (2 g, 6.08 mmol) in dioxane (20 mL) was stirred at 80 °C for 4 h, diluted with water (20 mL), and extracted with EA (20 mL × 3). The combined organic layers were dried and concentrated in vacuo to obtain a residue, which was purified by silica gel column chromatography (EA in PE 0-40%) to give the title compound as a white solid (1.6 g, yield 89.54%).

Step 5: 3rd class -Butyl N -[4-[2-( 3rd class Synthesis of [-butylcarbamoyl]-3,4-dichloro-phenyl]-1,3-benzothiazol-2-yl]carbamate

To a solution of N-tert -butyl-2,3-dichloro-6-iodo-benzamide (100 mg, 268.80 μmol) and [2-( tert -butoxycarbonylamino)-1,3-benzothiazol-4-yl]boronic acid (79.06 mg, 268.80 μmol) in dioxane (4 mL) and water (1 mL) were added Pd(dppf)Cl ₂ (19.67 mg, 26.88 μmol) and K ₃ PO ₄ (114.11 mg, 537.59 μmol). The mixture was stirred at 80 °C for 4 h, diluted with water (5 mL), and extracted with EA (5 mL × 3). After mixing and concentrating the organic layers, the residue was purified by silica gel column chromatography (EA in PE 0-40%) to obtain the title compound as a white solid (60 mg, yield 45.15%).

Step 6: 6-(2-Amino-1,3-benzothiazol-4-yl)- N - 3rd class Synthesis of -butyl-2,3-dichloro-benzamide (Compound A292)

To a solution of tert -butyl N- [4-[2-( tert -butylcarbamoyl)-3,4-dichloro-phenyl]-1,3-benzothiazol-2-yl]carbamate (60 mg, 121.35 μmol) dissolved in DCM (3 mL) was added TFA (1 mL), the reaction mixture was stirred at room temperature for 4 h, concentrated, and the residue was purified by silica gel column chromatography (EA in PE 0-40%) to give the title compound (10.59 mg, yield 22.13%) as a white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.70 - 7.57 (m, 5H), 7.33 (d, J = 8.3 Hz, 1H), 7.23 (dd, J = 7.5, 1.3 Hz, 1H), 7.02 (t, J = 7.7 Hz, 1H), 1.04 (s, 9H). MS (ESI) m/z [M+H] ⁺ 394.1, 396.1, 398.1 (2Cl).

The following compounds ( A286 to A325 ) in Table 4 were synthesized using appropriate starting materials and corresponding intermediates in a similar manner to that described in Example 8 .

General Method 5

Compound 5-1 is brominated in the presence of NBS or other brominating reagent to give intermediate 5-2, which is cyclized with NaNO ₂ under acidic conditions to form compound 5-3. Compound 5-3 is alkylated under basic conditions to give two isomers 5-4a and 5-4b. The final products 5-5a or 5-5b can be synthesized from 5-4a or 5-4b using a method similar to General Method 1.

Example 9:

N -( Grade 3- Butyl)-1-methyl-5-(1 H -pyrazol-1-yl)-1 H - Preparation of indazole-4-carboxamide (Compound A327)

Step 1: Synthesis of methyl 3-amino-6-bromo-2-methylbenzoate

To a solution of methyl 3-amino-2-methyl-benzoate (2 g, 12.11 mmol) in ACN (24.25 mL) was added NBS (2.15 g, 12.11 mmol, 1.03 mL). The resulting solution was stirred at 25°C for 1 h, concentrated under reduced pressure, and purified by flash column chromatography on silica gel (EA/PE = 0–30%) to obtain the title compound as a yellow solid (1.5 g, yield 48.73%). MS (ESI) m/z [M+H] ⁺ 244.1, 246.1 (Br).

Step 2: Methyl 5-bromo-1 H -Synthesis of indazole-4-carboxylate

To a solution of methyl 3-amino-6-bromo-2-methyl-benzoate (1.2 g, 4.92 mmol) in water (2 mL) and acetic acid (10 mL) was added NaNO ₂ (440.99 mg, 6.39 mmol) in portions. The resulting solution was stirred at 60°C for 1 h, concentrated under reduced pressure, and the residue was purified by C18-prep-HPLC (ACN/water = 0-40%) to give the title compound as a yellow solid (690 mg, yield 49.52%). MS (ESI) m/z [M+H] ⁺ 255.1, 257.1 (Br).

Step 3: Methyl 5-bromo-1-methyl-1 H -Synthesis of indazole-4-carboxylate

To a mixture of K ₂ CO ₃ (980.92 mg, 7.06 mmol) and methyl 5-bromo-1 H -indazole-4-carboxylate (600 mg, 2.35 mmol) in ACN (1.30 mL) was added iodomethane (500.83 mg, 3.53 mmol, 219.66 μL). The resulting solution was stirred at 50 °C for 1 h, concentrated under reduced pressure, and the residue was purified by C18-prep-HPLC (ACN/water = 0-60%) to give the title compound as a yellow solid (300 mg, yield 42.65%). MS (ESI) m/z [M+H] ⁺ 269.2, 271.2 (Br).

Step 4: 5-Bromo-1-methyl-1 H -Synthesis of indazole-4-carboxylic acid

To a solution of 5-bromo-1-methyl-indazole-4-carboxylate (300 mg, 1.11 mmol) in methanol (5 mL) was added a solution of NaOH (445.91 mg, 11.15 mmol) in water (5 mL). The resulting solution was stirred at 50°C for 1 h, concentrated under reduced pressure, and the residue was purified by C18-prep-HPLC (ACN/water = 0-60%) to give the title compound as a yellow solid (260 mg, yield 87.78%). MS (ESI) m/z [M+H] ⁺ 255.0, 257.0 (Br).

Step 5: 5-Bromo- N - (3rd grade- Butyl)-1-methyl-1 H -Synthesis of indazole-4-carboxamide

A solution of 5-bromo-1-methyl-indazole-4-carboxylic acid (300 mg, 1.18 mmol), 2-methylpropan-2-amine (86.02 mg, 1.18 mmol), HATU (447.21 mg, 1.18 mmol), and DIPEA (455.17 mg, 3.53 mmol) in DMF (5 mL) was stirred at 80°C for 3 h. The resulting solution was concentrated under reduced pressure, and the residue was purified by C18-prep-HPLC (ACN/water = 0-60%) to give the title compound as a yellow solid (150 mg, yield 39.47%). MS (ESI) m/z [M+H] ⁺ 310.0, 312.0 (Br).

Step 6: N -( Grade 3- Butyl)-1-methyl-5-(1 H -pyrazol-1-yl)-1 H -Synthesis of indazole-4-carboxamide (Compound A327)

A mixture of 5-bromo- N -tert-butyl-1 -methyl-indazole-4-carboxamide (50 mg, 161.19 μmol), 1 H -pyrazole (109.73 mg, 1.61 mmol), CuI (30.70 mg, 161.19 μmol), Cs ₂ CO ₃ (157.65 mg, 483.58 μmol), and (1R,2R)-(-)-1,2-diaminocyclohexane (36.81 mg, 322.38 μmol) in DMF (1.2 mL) was stirred at 110°C for 1 h. The resulting solution was concentrated under reduced pressure and purified by C18-prep-HPLC (ACN/water = 0-60%) to give the title compound as a red solid (2.9 mg, yield 5.75%). ^1H NMR (400 MHz, DMSO- d ₆ ) δ 7.99 (t, J = 1.8 Hz, 2H), 7.91 (s, 1H), 7.80 (dd, J = 8.9, 1.0 Hz, 1H), 7.70 (d, J = 1.8 Hz, 1H), 7.60 (d, J = 8.9 Hz, 1H), 6.48 (t, J = 2.1 Hz, 1H), 4.11 (s, 3H), 1.28 (s, 9H). MS (ESI) m/z [M+H] ⁺ 297.9.

The following compounds ( A326 to A344 and A438 to A439 ) in Table 5 were synthesized in a similar manner to that described in Example 9 using appropriate starting materials and corresponding intermediates.

General Method 5-1

Intermediate 5-1-2 was synthesized using CDI and 5-1-1, which was nitrated in the presence of KNO ₃ /H ₂ SO ₄ to form intermediate 5-1-3. Ring opening under basic conditions gave 5-1-4, which was brominated to give compound 5-1-5. An indole intermediate was prepared from 5-1-5 using DMF-DMA, which was then reduced with Fe powder. Intermediate 5-1-6b was formed by alkylation of 5-1-6a under basic conditions. The ester was hydrolyzed under basic conditions to give acidic compound 5-1-7, which could then be used to prepare the final compound 5-1 using a method similar to General Method 1.

Example 10:

5-(2-Aminobenzo[ d ]thiazol-4-yl)- N -( 3rd class -butyl)-1 H - Preparation of indole-4-carboxamide (compound A346)

Step 1: 5-Methyl-2 H -Benzo[ d ][1,3]Oxazine-2,4(1 H )-Dion's synthesis

A mixture of CDI (6.97 g, 43.00 mmol) and 2-amino-6-methyl-benzoic acid (5 g, 33.08 mmol) in dioxane (50 mL) was stirred at room temperature for 5 h. The resulting mixture was concentrated and filtered, and the precipitate was dried to obtain the title compound as a white solid (5 g, yield 85.33%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.65 (s, 1H), 7.57 (t, J = 7.8 Hz, 1H), 7.06 (d, J = 7.5 Hz, 1H), 7.00 (d, J = 8.2 Hz, 1H), 2.60 (s, 3H). MS (ESI) m/z [M+H] ⁺ 178.1.

Step 2: 5-Methyl-6-nitro-2 H -Benzo[ d ][1,3]Oxazine-2,4(1 H )-Dion's synthesis

5-Methyl-1 H -3,1-benzoxazine-2,4-dione (5 g, 28.22 mmol) was dissolved in H ₂ SO ₄ (30 mL) at 0 °C, to which was added KNO ₃ (2.85 g, 28.22 mmol), and the mixture was stirred at 0 °C for 2 h. The reaction was quenched with ice water. The crude product was filtered, and the precipitate was dried to obtain the title compound as a yellow solid (4 g, yield 63.80%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.09 (s, 1H), 8.17 (d, J = 8.9 Hz, 1H), 7.14 (d, J = 9.0 Hz, 1H), 2.69 (s, 3H). MS (ESI) m/z [M+H] ⁺ 223.0.

Step 3: Synthesis of methyl 6-amino-2-methyl-3-nitrobenzoate

A mixture of 5-methyl-6-nitro-1 H -3,1-benzoxazine-2,4-dione (4 g, 18.01 mmol) and Na ₂ CO ₃ (1.91 g, 18.01 mmol) dissolved in methanol (40 mL) was stirred at 0°C for 0.5 h and then at room temperature for 3 h. The resulting mixture was concentrated, and purified by flash chromatography on silica gel (EA in PE 0-40%) to give the title compound as a yellow solid (3.5 g, yield 92.48%). ^1H NMR (400 MHz, DMSO _-d6 ) δ 7.89 (d, J = 9.2 Hz, 1H), 6.67 (d, J = 9.2 Hz, 1H), 6.58 (s, 2H), 3.87 (s, 3H), 2.38 (s, 3H). MS (ESI) m/z [M+H] ⁺ 211.1.

Step 4: Synthesis of methyl 6-bromo-2-methyl-3-nitrobenzoate

To an ice-cold solution of HBr (30% in acetic acid, 20 mL) and water (40 mL) was added methyl 6-amino-2-methyl-3-nitro-benzoate (3.5 g, 16.65 mmol), followed by dropwise addition of a solution of NaNO ₂ (1.34 g, 19.48 mmol) in water (5 mL). The mixture was stirred at 0°C for 0.5 h, after which methyl CuBr (0.6 g, 4.18 mmol) was added. The resulting mixture was stirred at room temperature for further 1.5 h, diluted with water (60 mL), and extracted with EA (100 mL×2). The combined organic layers were concentrated in vacuo, and the residue was purified by chromatography on silica gel (EA in PE 0-30%) to give the title compound as a white solid (4 g, yield 87.65%). ^1H NMR (400 MHz, DMSO _- d6 ) δ 7.99 (d, J = 8.8 Hz, 1H), 7.88 - 7.83 (m, 1H), 3.94 (s, 3H), 2.39 (s, 3H). MS (ESI) m/z [M+H] ⁺ 274.0, 276.0 (Br).

Step 5: Methyl 5-bromo-1 H -Synthesis of indole-4-carboxylate

To a solution of methyl 6-bromo-2-methyl-3-nitro-benzoate (1 g, 3.65 mmol) in DMF (10 mL) was added DMF-DMA (1.30 g, 10.95 mmol, 1.47 mL) at room temperature. The mixture was stirred at 130°C for 5 h and then concentrated in vacuo. The residue was dissolved in AcOH (10 mL), and Fe powder (3.39 g, 60.76 mmol) was added. The resulting mixture was stirred at 100°C for 7 h, diluted with water (60 mL), and extracted with EA (100 mL×2). The combined organic layers were concentrated, and purified by silica gel chromatography (EA in PE 0-30%) to obtain the title compound as a white solid (600 mg, yield 77.73%). ^1H NMR (400 MHz, DMSO _-d6 ) δ 11.57 (s, 1H), 7.52 (t, J = 2.8 Hz, 1H), 7.49 (dd, J = 8.6, 0.7 Hz, 1H), 7.36 - 7.31 (m, 1H), 6.49 (t, J = 2.1) Hz, 1H), 3.93 (s, 3H). MS (ESI) m/z [M+H] ⁺ 254.0, 256.0 (Br).

Step 6: 5-Bromo-1 H -Synthesis of indole-4-carboxylic acid

To a solution of methyl 5-bromo-1 H -indole-4-carboxylate (200 mg, 787.15 μmol) in water (2 mL) was added NaOH (62.97 mg, 1.57 mmol). The mixture was stirred at 80°C for 12 h, acidified with diluted aqueous HCl, and extracted twice with EA. The combined organic layers were concentrated in vacuo, and the residue was purified by column chromatography (0-60% EA in PE) to give the title compound as a white solid (160 mg, yield 84.67%). MS (ESI) m/z [M+H] ⁺ 240.0, 242.0 (Br).

Step 7: 5-Bromo- N - (3rd grade- Butyl)-1 H -Synthesis of indole-4-carboxamide

A mixture of HATU (304.12 mg, 799.82 μmol), 5-bromo-1 H -indole-4-carboxylic acid (160 mg, 666.52 μmol), 2-methylpropan-2-amine (97.49 mg, 1.33 mmol, 140.08 μL), and DIPEA (258.43 mg, 2.00 mmol, 348.29 μL) in DMF (4 mL) was stirred at room temperature for 2 h, diluted with water (20 mL), and extracted with EA (40 mL × 2). The combined organic layers were concentrated in vacuo, and the residue was purified by flash chromatography on silica gel (EA in PE 0-30%) to give the title compound as a white solid (170 mg, yield 86.41%). MS (ESI) m/z [M+H] ⁺ 295.1, 297.1 (Br).

Step 8: 3rd class -Butyl (4-(4-( 3rd class -Butylcarbamoyl]-1 H -Indole-5-yl)benzo[ d Synthesis of thiazol-2-yl)carbamate

A mixture of Pd(dppf)Cl ₂ (123.83 mg, 169.39 μmol), 5-bromo- N -tert -butyl-1 H -indole-4-carboxamide (50 mg, 169.39 μmol), [2-( tert -butoxycarbonylamino)-1,3-benzothiazol-4-yl]boronic acid (64.77 mg, 220.21 μmol) and K ₃ PO ₄ (35.96 mg, 169.39 μmol) in water (0.5 mL) and dioxane (4 mL) was stirred at 90 °C for 2 h. The resulting mixture was concentrated in vacuo, and the residue was purified by chromatography on silica gel (EA in PE 0-40%) to give the title compound as a white solid (50 mg, yield 63.54%). MS (ESI) m/z [M+H] ⁺ 465.2.

Step 9: 5-(2-Aminobenzo[ d ]thiazol-4-yl)- N -( 3rd class -butyl)-1 H -Synthesis of indole-4-carboxamide (compound A346)

To a solution of tert -butyl N- [4-[4-( tert -butylcarbamoyl)-1 H -indol-5-yl]-1,3-benzothiazol-2-yl]carbamate (50 mg, 107.62 μmol) in DCM (4 mL) was added TFA (1.48 g, 12.98 mmol, 1 mL). The mixture was stirred at room temperature for 8 h, concentrated, and the residue was purified by C18-prep-HPLC (0-70% ACN in water) to give the title compound as a white solid (8 mg, yield 20.40%). ^1H NMR (400 MHz, DMSO _-d6 ) δ 11.18 (s, 1H), 7.65 (d, J = 7.7 Hz, 1H), 7.53 (s, 2H), 7.39 (dd, J = 8.2, 5.5 Hz, 2H), 7.10 (d, J = 6.4 Hz, 1H), 7.02 (t, J = 7.6 Hz, 1H), 6.97 (d, J = 8.3 Hz, 1H), 6.91 (s, 1H), 6.41 (s, 1H), 0.99 (s, 9H). MS (ESI) m/z [M+H] ⁺ 365.1.

Example 11:

N -(bicyclo[1.1.1]pentan-1-yl)-1-methyl-5-(pyrazolo[1,5- a ]pyridin-7-yl)-1 H - Preparation of indole-4-carboxamide (compound A347)

Step 1: Methyl 5-bromo-1-methyl-1 H -Synthesis of indole-4-carboxylate

To a mixture of methyl 5-bromo-1 H -indole-4-carboxylate (200 mg, 787.15 μmol) and Cs ₂ CO ₃ (512.94 mg, 1.57 mmol) in DMF (5 mL) was added CH ₃ I (335.18 mg, 2.36 mmol, 147.01 μL). The mixture was stirred at room temperature for 2 h, diluted with water (20 mL), and extracted with EA (40 mL × 2). The combined organic layers were concentrated in vacuo, and the residue was purified by silica gel chromatography (EA in PE 0-40%) to give the title compound as a white solid (200 mg, yield 94.77%). MS (ESI) m/z [M+H] ⁺ 268.0, 270.0 (Br).

Step 2: 5-Bromo-1-methyl-1 H -Synthesis of indole-4-carboxylic acid

To a mixture of methyl 5-bromo-1-methyl-indole-4-carboxylate (200 mg, 745.97 μmol) dissolved in water (2 mL) was added NaOH (59.67 mg, 1.49 mmol). The mixture was stirred at 80°C for 12 h, acidified with diluted aqueous HCl, and extracted twice with EA. The combined organic layers were concentrated in vacuo, and the residue was purified by column chromatography (0-60% EA in PE) to give the title compound as a white solid (170 mg, yield 89.69%). MS (ESI) m/z [M+H] ⁺ 254.0, 256.0 (Br).

Step 3: N -(bicyclo[1.1.1]pentan-1-yl)-5-bromo-1-methyl-1 H -Synthesis of indole-4-carboxamide

A mixture of HATU (179.58 mg, 472.29 μmol), 5-bromo-1-methyl-indole-4-carboxylic acid (100 mg, 393.58 μmol), bicyclo[1.1.1]pentan-1-yl-amine (65.44 mg, 787.15 μL), and DIPEA (152.60 mg, 1.18 mmol, 205.66 μL) in DMF (2 mL) was stirred at room temperature for 2 h, diluted with water (20 mL), and extracted with EA (40 mL × 2). The combined organic layers were concentrated in vacuo, and the residue was purified by chromatography on silica gel (EA in PE 0-30%) to give the title compound as a white solid (100 mg, yield 79.60%). MS (ESI) m/z [M+H] ⁺ 319.0, 321.0 (Br).

Step 4: N -(bicyclo[1.1.1]pentan-1-yl)-1-methyl-5-(pyrazolo[1,5- a ]pyridin-7-yl)-1 H -Synthesis of indole-4-carboxamide (Compound A347)

A mixture of Pd(dppf)Cl ₂ (18.32 mg, 25.06 μmol), N-(1-bicyclo[1.1.1]pentanyl)-5-bromo-1-methyl-indole-4-carboxamide (80 mg, 250.63 μmol), pyrazolo[1,5- a ]pyridin-7-ylboronic acid (52.77 mg, 325.82 μmol), and K ₃ PO ₄ (159.60 mg, 751.89 μmol) in water (0.5 mL) and dioxane (4 mL) was stirred at 90 °C for 2 h. The resulting mixture was concentrated in vacuo, and the residue was purified by C18-prep-HPL (0-70% ACN in water) to give the title compound as a white solid (31 mg, yield 34.70%). ^1H NMR (400 MHz, DMSO _-d6 ) δ 8.36 (s, 1H), 7.89 (d, J = 2.2 Hz, 1H), 7.73 - 7.65 (m, 1H), 7.60 (d, J = 8.5 Hz, 1H), 7.47 (d, J = 3.1 Hz, 1H), 7.37 (d, J = 8.5 Hz, 1H), 7.25 (dd, J = 8.8, 6.9 Hz, 1H), 6.85 - 6.76 (m, 1H), 6.67 (d, J = 2.2 Hz, 1H), 6.47 (d, J = 3.0 Hz, 1H), 3.87 (s, 3H), 2.30 (s, 1H), 1.78 (s, 6H). MS (ESI) m/z [M+H] ⁺ 357.2.

The following compounds ( A345-A387 ) in Table 6 were synthesized in a similar manner to that described in Examples 10 and 11 using appropriate starting materials and corresponding intermediates.

General Method 5-2

Using a method similar to General Method 1, compound 5-2-2 can be synthesized from 5-2-1 via Sonogashira coupling with N -protected but-3-yn-1-amine, which gives 5-2-3, which is cyclized under basic conditions to give 5-2-4. Compound 5-2-5, which is formed by oxidation of compound 5-2-4, undergoes C-C or C-N coupling in the presence of Pd or Cu and other heavy metal catalysts of the reagent, to finally give the target product 5-2-6.

Example 12:

5-(3-(1 H) -pyrazol-3-yl)-1 H -pyrrole-2-yl)- N -( 3rd class -butyl)-1 H - Preparation of indole-4-carboxamide (compound A388)

Step 1: 3rd class -Butyl 5-bromo-4-( 3rd class -Butylcarbamoyl)-1 H -Synthesis of indole-1-carboxylate

To a solution of 5-bromo- N-tert -butyl-1 H -indole-4-carboxamide (2.5 g, 8.47 mmol), TEA (2.57 g, 25.41 mmol, 3.54 mL), and DMAP (103.47 mg, 8.47 mmol) in DCM (15 mL) was added Boc ₂ O (3.70 g, 16.94 mmol, 3.89 mL) at room temperature. The mixture was stirred at room temperature for 3 h, concentrated, and the residue was purified by silica gel chromatography (EA in PE 0-10%) to give the title compound as a white solid (2.3 g, yield 68.7%). ^1H NMR (400 MHz, DMSO _-d6 ) δ 8.16 (s, 1H), 7.96 (dd, J = 8.8, 0.8 Hz, 1H), 7.73 (d, J = 3.7 Hz, 1H), 7.50 (d, J = 8.8 Hz, 1H), 6.50 (dd, J = 8.8 Hz, 1H ) 3.7, 0.8 Hz, 1H), 1.63 (s, 9H), 1.40 (s, 9H). MS (ESI) m/z [M+H] ⁺ 395.1, 397.1 (Br).

Step 2: 3rd class -Butyl 4-(tert-butylcarbamoyl)-5-(4-((4-methylphenyl)-sulfonamido)but-1-yn-1-yl)-1 H -Synthesis of indole-1-carboxylate

To a solution of tert -butyl 5-bromo-4-( tert -butylcarbamoyl)indole-1-carboxylate (1 g, 2.53 mmol), N -but-3-ynyl-4-methyl-benzenesulfonamide (1.13 g, 5.06 mmol), CuI (96.36 mg, 0.51 mmol), LiCl (536 mg, 12.65 mmol), and Pd(PPh ₃ ) ₂ Cl ₂ (184.93 mg, 252.98 μmol) in DMF (10 mL) was added TEA (1.28 g, 12.65 mmol, 1.76 mL) at room temperature under a nitrogen atmosphere. The mixture was stirred at 80 °C for 5 h, cooled, and diluted with water (20 mL). The aqueous layer was extracted twice with EA (40 mL), the combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated to obtain a residue, which was purified by silica gel column chromatography (EA in PE 0-30%) to obtain the title compound as a yellow solid (730 mg, yield 53.67%). MS (ESI) m/z [M+H] ⁺ 538.2.

Step 3: 3rd class -Butyl 4-( 3rd class -Butylcarbamoyl)-5-(3-iodo-1-tosyl-1 H -pyrrole-2-yl)-1 H -Synthesis of indole-1-carboxylate

To a solution of tert -butyl 4-( tert -butylcarbamoyl)-5-[4-(p-tolylsulfonylamino)but-1-ynyl]indole-1-carboxylate (730 mg, 1.36 mmol) and K ₂ CO ₃ (562.93 mg, 4.07 mmol) in acetonitrile (60.00 mL) at room temperature under a nitrogen atmosphere was added I ₂ (262.57 mg, 2.05 mmol). The mixture was stirred at room temperature for 5 h and then concentrated to obtain a crude intermediate, which was dissolved in DMF (12.00 mL) and then DBU (6.19 g, 40.69 mmol) was added at 0 °C. The resulting mixture was stirred at room temperature for 16 h and then diluted with water (20 mL). The aqueous phase was extracted twice with EA (40 mL), the combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to obtain a residue, which was purified by silica gel column chromatography (EA in PE 0-15%) to obtain the title compound as a yellow solid (470 mg, yield 52.38%). ^1H NMR (400 MHz, DMSO _-d6 ) δ 7.98 (d, J = 8.5 Hz, 1H), 7.79 (d, J = 3.7 Hz, 1H), 7.65 (d, J = 3.5 Hz, 1H), 7.49 (d, J = 8.5 Hz, 2H), 7.43 (d, J = 8.4 Hz, 2H), 6.75 (d, J = 3.7 Hz, 1H), 6.64 (d, J = 3.4 Hz, 1H), 6.42 - 6.32 (m, 2H), 2.42 (s, 3H), 1.66 (s, 9H), 1.21 (s, 9H). MS (ESI) m/z [M+H] ⁺ 662.1.

Step 4: 3rd class -Butyl 4-( 3rd class -Butylcarbamoyl)-5-(3-iodo-1 H -pyrrole-2-yl)-1 H -Synthesis of indole-1-carboxylate

To a solution of tert -butyl 4-( tert -butylcarbamoyl)-5-[3-iodo-1-(p-tolylsulfonyl)pyrrol-2-yl]indole-1-carboxylate (470 mg, 710.45 μmol) in THF (5 mL) was added TBAF (2 mL, 1N in THF) at room temperature. The mixture was stirred at room temperature for 2 h, concentrated, and the residue was purified by silica gel chromatography (EA in PE 0-30%) to give the title compound as a white solid (350 mg, yield 97.10%). ^1H NMR (400 MHz, DMSO _-d6 ) δ 11.10 (s, 1H), 8.12 (d, J = 8.5 Hz, 1H), 7.76 (d, J = 3.7 Hz, 1H), 7.29 (d, J = 8.6 Hz, 1H), 6.89 (t, J = 2.8) Hz, 1H), 6.74 (d, J = 3.7 Hz, 1H), 6.55 (s, 1H), 6.26 (t, J = 2.6 Hz, 1H), 1.65 (s, 9H), 1.19 (s, 9H). MS (ESI) m/z [M+Na] ⁺ 530.0.

Step 5: 3rd class -Butyl 5-(3-(1 H -pyrazol-3-yl)-1 H -pyrrole-2-yl)-4-( 3rd class -Butylcarbamoyl)-1 H -Synthesis of indole-1-carboxylate

tert -Butyl 4-( tert -butylcarbamoyl)-5-(3-iodo-1 H -pyrrol-2-yl)indole-1-carboxylate (0.124 g, 244.40 μmol), (1- tert -butoxycarbonylpyrazol-3-yl)boronic acid (77.72 mg, 366.60 μmol), Pd(PPh ₃ ) ₄ (28.24 mg, 24.44 μmol) and Na ₂ CO ₃ (129.52 mg, 1.22 mmol) were dissolved in a mixed solution of water/ethanol/toluene (1/2/2, 8 mL). The mixture was heated at 120 °C for 2 h under a nitrogen atmosphere, cooled, and extracted with EA. The above mixed organic layer was concentrated and purified by silica gel column chromatography (EA in PE 0-50%) to obtain the title compound as a white solid (50 mg, yield 37.4%). MS (ESI) m/z [M+H] ⁺ 548.2.

Step 6: 5-(3-(1 H) -pyrazol-3-yl)-1 H -pyrrole-2-yl)- N -( 3rd class -butyl)-1 H -Synthesis of indole-4-carboxamide (compound A388)

To a solution of tert -butyl 5-(3-(1-( tert -butoxycarbonyl)-1 H -pyrazol-3-yl)-1 H -pyrrol-2-yl)-4-( tert -butylcarbamoyl)-1 H -indole-1-carboxylate (42 mg, 76.7 μmol) in THF (3 mL) was added MeONa (41.8 mg, 231.57 μmol, 30% w/w in methanol) at room temperature. The mixture was stirred at room temperature for 1 h, diluted with water, and extracted with EA. The combined organic layers were concentrated, and the residue was purified by silica gel column chromatography (EA in PE 0-70%) to give the title compound as a gray solid (10 mg, yield 30.67%). ^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.43 (s, 1H), 11.27 (s, 1H), 10.79 (t, J = 2.7 Hz, 1H), 7.48 - 7.37 (m, 2H), 7.30 (s, 1H), 6.91 (d, J = 8.3 Hz, 1H), 6.78 (t, J = 2.7 Hz, 1H), 6.50 (t, J = 2.6 Hz, 1H), 6.44 (s, 1H), 5.67 (s, 1H), 1.05 (s, 9H). MS (ESI) m/z [M+H] ⁺ 348.2.

Example 13:

5-(3-(1 H -pyrazol-3-yl)-1 H -pyrrole-2-yl)- N -(bicyclo[1.1.1]pentan-1-yl)-1 H - Preparation of indole-4-carboxamide (Compound A397)

Step 1: N -(bicyclo[1.1.1]pentan-1-yl)-5-bromo-1 H -Synthesis of indole-4-carboxamide

HATU (1.9 g, 5.0 mmol) was added to a solution of 5-bromo-1 H -indole-4-carboxylic acid (1.0 g, 4.2 mmol), bicyclo[1.1.1]pentan-1-amine (0.52 g, 6.2 mmol), and DIPEA (1.6 g, 12.5 mmol) in DMF (10 mL) at room temperature, and the mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with H ₂ O (30 mL), and the aqueous phase was extracted with EA (40 mL × 2). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting crude product was purified by silica gel chromatography (EA in DCM 0-10%) to give the title compound as a white solid (1.2 g, yield 93.6%). ^1H NMR (400 MHz, DMSO _-d6 ) δ 11.38 (s, 1H), 8.86 (s, 1H), 7.42 (q, J = 3.7 Hz, 1H), 7.35 (dd, J = 8.6, 0.9 Hz, 1H), 7.22 (d, J = 8.6 Hz, 1H), 6.28 (t, J = 2.4 Hz, 1H), 2.46 (s, 1H), 2.10 (s, 6H). MS (ESI) m/z [M+H] ⁺ 305.1, 307.1 (Br).

Step 2: 3rd class -Butyl 4-(bicyclo[1.1.1]pentan-1-ylcarbamoyl)-5-bromo-1 H -Synthesis of indole-1-carboxylate

To a solution of N- (1-bicyclo[1.1.1]pentanyl)-5-bromo-1 H -indole-4-carboxamide (1.2 g, 4.0 mmol) and DMAP (98.4 mg, 0.8 mmol) in DCM (15 mL) was added di-tert -butyl dicarbonate (0.88 g, 4.0 mmol) at room temperature, and the mixture was stirred at room temperature for 2 h. H ₂ O (30 mL) was added to the reaction mixture, and the aqueous phase was extracted with DCM (30 mL × 2). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting crude product was purified by silica gel chromatography (EA in PE 0-30%) to give the title compound as a white solid (1.4 g, yield 86.4%). ^1H NMR (400 MHz, DMSO _-d6 ) δ 9.02 (s, 1H), 7.98 (d, J = 8.9 Hz, 1H), 7.74 (d, J = 3.7 Hz, 1H), 7.52 (d, J = 8.8 Hz, 1H), 6.52 - 6.47 (m, 1H), 2.48 (s, 1H), 2.11 (s, 6H), 1.63 (s, 9H). MS (ESI) m/z [M+H] ⁺ 405.1, 407.1 (Br).

Step 3: 3rd class -Butyl 4-(bicyclo[1.1.1]pentan-1-ylcarbamoyl)-5-(4-(( 3rd class -butoxycarbonyl)amino)but-1-yn-1-yl)-1 H -Synthesis of indole-1-carboxylate

A mixture of TEA (1.7 g, 16.8 mmol), tert -butyl 4-(1-bicyclo[1.1.1]pentanylcarbamoyl)-5-bromo-indole-1-carboxylate (1.4 g, 3.4 mmol), tert -butyl N -but-3-ynylcarbamate (1.42 g, 8.4 mmol), CuI (0.26 g, 1.3 mmol), LiCl (0.7 g, 16.8 mmol), and Pd(PPh ₃ ) ₂ Cl ₂ (0.25 g, 0.34 mmol) in DMF (8 mL) was stirred at 80 °C under a nitrogen atmosphere for 2 h. The reaction mixture was cooled and diluted with H ₂ O (20 mL), the aqueous phase was extracted with EA (30 mL × 2), and the combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting crude product was purified by silica gel chromatography (EA in PE 0-30%) to obtain the title compound as a gray solid (1.48 g, yield 89.4%). ^1H NMR (400 MHz, DMSO _-d6 ) δ 8.84 (s, 1H), 8.04 (d, J = 8.6 Hz, 1H), 7.72 (d, J = 3.8 Hz, 1H), 7.36 (d, J = 8.6 Hz, 1H), 6.97 (q, J = 5.7 Hz, 1H), 6.59 (d, J = 3.8 Hz, 1H), 3.18 (q, J = 6.8 Hz, 2H), 2.53 (d, J = 7.1 Hz, 2H), 2.47 (s, 1H), 2.11 (s, 6H), 1.63 (s, 9H), 1.38 (s, 9H). MS (ESI) m/z [M+H] ⁺ 494.3.

Step 4: 3rd class -Butyl 4-(bicyclo[1.1.1]pentan-1-ylcarbamoyl)-5-(1-( 3rd class -butoxycarbonyl)-3-iodo-1 H -pyrrole-2-yl)-1 H -Synthesis of indole-1-carboxylate

A mixture of bis(pyridine)iodine(I) hexafluorophosphate (2.6 g, 6.0 mmol), tert -butyl 4-(1-bicyclo[1.1.1]pentanylcarbamoyl)-5-[4-(tert-butoxycarbonylamino)but-1-ynyl]indole-1-carboxylate (1.48 g, 3.0 mmol), and dipotassium carbonate (1.24 g, 9.0 mmol) in acetonitrile (100 mL) was stirred at room temperature for 5 h. The solvent was removed under reduced pressure, dissolved in DMF (10 mL), and DBU (3.66 g, 24.0 mmol) was added. The mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with H ₂ O (40 mL), and the aqueous phase was extracted with EA (40 mL×2). The above mixed organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting crude product was purified by silica gel chromatography (0-10% EA in PE) to obtain the title compound as a gray solid (0.9 g, yield 48.6%). ^1H NMR (400 MHz, DMSO _- d6 ) δ 8.14 (d, J = 8.5 Hz, 1H), 7.77 (d, J = 3.8 Hz, 1H), 7.59 (s, 1H), 7.39 (d, J = 3.4 Hz, 1H), 7.17 (d, J = 8.5 Hz, 1H), 6.73 (d, J = 3.8 Hz, 1H), 6.45 (d, J = 3.4 Hz, 1H), 2.38 (s, 1H), 1.92 (s, 6H), 1.65 (s, 9H), 1.10 (s, 9H). MS (ESI) m/z [M+H] ⁺ 618.1.

Step 5: 3rd class -Butyl 4-(bicyclo[1.1.1]pentan-1-ylcarbamoyl)-5-(1-( 3rd class -butoxycarbonyl)-3-(1-( 3rd class -butoxycarbonyl)-1 H -pyrazol-3-yl)-1 H -pyrrole-2-yl)-1 H -Synthesis of indole-1-carboxylate

A mixture of Pd(PPh ₃ ) ₄ (75 mg, 65 μmol), tert -butyl 4-(1-bicyclo[1.1.1]pentanylcarbamoyl)-5-(1- tert -butoxycarbonyl-3-iodo-pyrrol-2-yl)indole-1-carboxylate (0.2 g, 324 μmol), (1- tert -butoxycarbonylpyrazol-3-yl)boronic acid (137 mg, 648 μmol), and dipotassium carbonate (172 mg, 1.62 mmol) was dissolved in a mixed solution of water/ethanol/toluene (1/2/2, 15 mL). The mixture was stirred at 100°C under a nitrogen atmosphere for 8 h. The reaction mixture was cooled and diluted with H ₂ O (20 mL), and then extracted with EA (40 mL×2). The above mixed organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (EA in PE 0-80%) to obtain the title compound as a light brown solid (40 mg, yield 18.8%). ^1H NMR (400 MHz, DMSO _-d6 ) δ 8.01 (d, J = 8.5 Hz, 1H), 7.71 (d, J = 3.7 Hz, 1H), 7.62 (d, J = 1.6 Hz, 1H), 7.48 (d, J = 3.6 Hz, 1H), 7.38 (s, 1H), 7.20 (d, J = 8.5 Hz, 1H), 6.78 (d, J = 3.7 Hz, 1H), 6.49 (d, J = 1.6 Hz, 1H), 6.40 (d, J = 3.4 Hz, 1H), 2.42 (s, 1H), 1.98 (s, 6H), 1.62 (s, 9H), 1.43 (s, 9H), 1.14 (s, 9H). MS (ESI) m/z [M-Boc+H] ⁺ 558.3.

Step 6: 5-(3-(1 H -pyrazol-3-yl)-1 H -pyrrole-2-yl)- N -(bicyclo[1.1.1]pentan-1-yl)-1 H -Synthesis of indole-4-carboxamide (Compound A397)

To a solution of tert -butyl 4-(1-bicyclo[1.1.1]pentanylcarbamoyl)-5-[1- tert -butoxycarbonyl-3-(1- tert -butoxycarbonylpyrazol-3-yl)pyrrol-2-yl]indole-1-carboxylate (40 mg, 61 μmol) in THF (3 mL) was added sodium methoxide solution (approximately 30% w/w in methanol, 32.9 mg, 183 μmol), and the reaction mixture was stirred at room temperature for 1 h. The mixture was diluted with H ₂ O (10 mL), and the aqueous phase was extracted with EA (12 mL×2). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (EA in PE 0-70%) to obtain the title compound as an off-white solid (10 mg, yield 46.0%). ^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.45 (s, 1H), 11.30 (s, 1H), 10.66 (s, 1H), 7.74 (s, 1H), 7.49 - 7.37 (m, 2H), 7.29 (s, 1H), 6.93 (d, J = 8.3 Hz, 1H), 6.79 (t, J = 2.7 Hz, 1H), 6.48 (t, J = 2.7 Hz, 1H), 6.42 (t, J = 2.7 Hz, 1H), 5.66 (s, 1H), 2.34 (s, 1H), 1.84 (s, 6H). MS (ESI) m/z [M+H] ⁺ 358.2.

Example 14:

N -( Grade 3- Butyl)-5-(3-(thiazol-4-yl)-1 H -pyrrole-2-yl)-1 H - Preparation of indole-4-carboxamide (Compound A396)

Step 1: 3rd class -Butyl 4-( 3rd class -Butylcarbamoyl)-5-(3-thiazol-4-yl-1 H Synthesis of -pyrrole-2-yl)indole-1-carboxylate

A mixture of Pd(PPh ₃ ) ₄ (9.1 mg, 7.9 μmol), tert -butyl 4-( tert -butylcarbamoyl)-5-(3-iodo-1 H -pyrrol-2-yl)indole-1-carboxylate (40 mg, 79 μmol), tributyl(thiazol-4-yl)stannane (59 mg, 158 μmol), CuI (3.0 mg, 15.8 μmol), and LiCl (10 mg, 237 μmol) in dioxane (2 mL) was stirred at 100 °C for 8 h. The reaction mixture was diluted with H ₂ O (20 mL), and the aqueous phase was extracted with EA (40 mL × 2). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (EA in PE 0-30%) to give the title compound as a gray solid (15 mg, yield 40.9%). MS (ESI) m/z [M+H] ⁺ 465.2.

Step 2: N -( Grade 3- Butyl)-5-(3-(thiazol-4-yl)-1 H -pyrrole-2-yl)-1 H -Synthesis of indole-4-carboxamide (compound A396)

To a solution of tert -butyl 4-( tert -butoxycarbamoyl)-5-(3-thiazol-4-yl)-1H-pyrrol-2-yl)indole-1-carboxylate (15 mg, 32.3 μmol) in THF (2 mL) was added MeONa (11.6 mg, 64.6 μmol, 30% w/w in methanol) at room temperature. The mixture was stirred at room temperature for 1 h and concentrated to obtain a residue, which was purified by prep-HPLC (Daisogel-C18-5-100, 0-60% acetonitrile in water) to give the title compound as a white solid (2 mg, yield 17%). ^1H NMR (400 MHz, DMSO- d ₆ ) δ 11.27 (s, 1H), 10.87 (s, 1H), 8.90 (d, J = 1.9 Hz, 1H), 7.44 - 7.37 (m, 2H), 6.96 (d, J = 1.9 Hz, 1H), 6.93 - 6.86 (m, 2H), 6.78 (t, J = 2.7 Hz, 1H), 6.53 - 6.48 (m, 2H), 1.02 (s, 9H). MS (ESI) m/z [M+H] ⁺ 365.0.

Example 15:

5-(3-(2 H -1,2,3-triazol-4-yl)-1 H -pyrrole-2-yl)- N -( 3rd class -butyl)-1 H - Preparation of indole-4-carboxamide (compound A405)

Step 1: 3rd class -Butyl 5-(1-( 3rd class -butoxycarbonyl)-3-(2-(tetrahydro-2 H -Evacuation-2-days)-2 H -1,2,3-triazol-4-yl)-1 H -pyrrole-2-yl)-4-( 3rd class -Butylcarbamoyl)-1 H -Synthesis of indole-1-carboxylate

A mixture of Pd(PPh ₃ ) ₄ (33.3 mg, 21.4 μmol), tert -butyl 5-(1- tert -butoxycarbonyl-3-iodo-pyrrol-2-yl)-4-( tert -butylcarbamoyl)indole-1-carboxylate (130 mg, 214 μmol), 2-tetrahydropyran-2-yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)triazole (179 mg, 642 μmol), and KF (37.3 mg, 642 μmol) in dioxane (2 mL) and water (0.2 mL) was stirred at 80 °C for 5 h. The reaction mixture was diluted with H ₂ O (20 mL), and the aqueous phase was extracted with EA (40 mL×2). The above mixed organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (0-20% EA in PE) to give the title compound as a gray solid (29 mg, yield 21.4%). MS (ESI) m/z [M+H] ⁺ 633.2.

Step 2: 5-(3-(2 H -1,2,3-triazol-4-yl)-1 H -pyrrole-2-yl)- N -( 3rd class -butyl)-1 H -Synthesis of indole-4-carboxamide (Compound A405)

3 -Butyl 5-[ 1-tert -butoxycarbonyl-3-(2-tetrahydropyran-2-yltriazol-4-yl)pyrrol-2-yl]-4-( 3- butylcarbamoyl)indole-1-carboxylate (29 mg, 45.8 μmol) was dissolved in methanol (1 mL) at room temperature. 6N HCl dissolved in H ₂ O (0.25 mL, 1.5 mmol) was added thereto. The mixture was stirred at 65°C for 8 h and then concentrated to obtain a residue. This was purified by prep-HPLC (Daisogel-C18-5-100, 0-30% acetonitrile in water) to give the title compound as a white solid (5.8 mg, yield 36.3%). ^1H NMR (400 MHz, DMSO- d ₆ ) δ 14.39 (s, 1H), 11.31 (s, 1H), 10.87 (s, 1H), 7.46 - 7.39 (m, 2H), 7.11 (s, 1H), 6.93 (d, J = 8.3 Hz, 1H), 6.84 (t, J = 2.7 Hz, 1H), 6.71 (s, 1H), 6.51 (t, J = 2.5 Hz, 1H), 6.45 (t, J = 2.7 Hz, 1H), 1.08 (s, 9H). MS (ESI) m/z [M+H] ⁺ 349.2.

Example 16:

N -( Grade 3- Butyl)-5-(3-(4-fluoro-1 H -pyrazol-3-yl)-1 H -pyrrole-2-yl)-1 H - Preparation of indole-4-carboxamide (compound A407)

Step 1: 3rd class -Butyl 5-(1-( 3rd class -butoxycarbonyl)-3-(1-( 3rd class -butoxycarbonyl)-4-fluoro-1 H -pyrazol-3-yl)-1 H -pyrrole-2-yl)-4-( 3rd class -Butylcarbamoyl)-1 H -Synthesis of indole-1-carboxylate

A mixture of Pd(PPh ₃ ) ₄ (26.6 mg, 23.1 μmol), tert -butyl 5-(1- tert -butoxycarbonyl-3-iodo-pyrrol-2-yl)-4-( tert -butylcarbamoyl)indole-1-carboxylate (140 mg, 230.5 μmol), tert -butyl 4-fluoro-3-trimethylstannyl-pyrazole-1-carboxylate (161 mg, 462 μmol), CuI (8.8 mg, 46.1 μmol), and LiCl (29.3 mg, 693 μmol) in dioxane (3 mL) was stirred at 100 °C for 8 h. The reaction mixture was cooled and diluted with H ₂ O (20 mL), and the aqueous phase was extracted with EA (30 mL×2). The above mixed organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (EA in PE 0-40%) to give the title compound as a gray solid (50 mg, yield 38.4%). MS (ESI) m/z [M+H] ⁺ 666.2.

Step 2: N -( Grade 3- Butyl)-5-(3-(4-fluoro-1 H -pyrazol-3-yl)-1 H -pyrrole-2-yl)-1 H -Synthesis of indole-4-carboxamide (Compound A407)

To a solution of tert -butyl 5-(1-( tert -butoxycarbonyl)-3-(1-( tert -butoxycarbonyl)-4-fluoro-1 H -pyrazol-3-yl)-1 H -pyrrol-2-yl)-4-( tert -butoxycarbamoyl)-1 H -indole-1-carboxylate (50 mg, 88.4 μmol) in THF (2 mL) was added a solution of sodium methanolate (approximately 30% w/w in methanol, 14.3 mg, 265 μmol), and the mixture was stirred at room temperature for 1 h. The resulting mixture was partitioned between EA (10 mL) and water (5 mL). The aqueous layer was extracted with EA (10 mL × 2), and the organic layers were combined, washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated in vacuo. The residue was purified by prep-HPLC (Daisogel-C18-5-100, 30% acetonitrile in water) to give the title compound as a white solid (10 mg, yield 31.0%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.42 - 12.04 (m, 1H), 11.37 - 11.11 (m, 1H), 11.09 - 10.60 (m, 1H), 7.81 - 6.67 (m, 6H), 6.47 (t, J = 2.6 Hz, 1H), 6.38 - 6.16 (m, 1H), 1.33 - 0.87 (m, 9H). MS (ESI) m/z [M+H] ⁺ 366.1.

General Method 6

Example 17:

6-(3-(1 H) -pyrazol-3-yl)-1 H -pyrrole-2-yl)- N -( 3rd class Preparation of -butyl)-2-chloro-3-methoxybenzamide (Compound A416)

Step 1: 1-(3-bromo-1 H Synthesis of -pyrrol-1-yl)-2,2-dimethylpropan-1-one

2,2-Dimethylpropanoyl chloride (2.25 g, 18.7 mmol, 2.29 mL) was added dropwise to a solution of 3-bromo-1 H -pyrrole (2.1 g, 14.4 mmol), DMAP (175.7 mg, 1.44 mmol), and TEA (2.18 g, 21.6 mmol, 3.01 mL) in DCM (20 mL) at 0°C. The solution was stirred at room temperature for 16 h. The reaction mixture was then evaporated to dryness under reduced pressure, and the crude product was partitioned between ethyl acetate (50 mL) and saturated NH ₄ Cl aqueous solution (50 mL). After separating the two layers, the aqueous layer was extracted with EtOAc (50 mL). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , and evaporated to dryness. The resulting crude product was purified by silica gel chromatography (EA in PE 0-5%) to obtain the title compound as an oil (2.7 g, yield 81.6%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.43 (dd, J = 2.4, 1.6 Hz, 1H), 7.36 (dd, J = 3.5, 2.4 Hz, 1H), 6.26 (dd, J = 3.5, 1.6 Hz, 1H), 1.44 (s, 9H).

Step 2: 3-Bromo-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1 H -Synthesis of pyrrole

BBr ₃ (2N in DCM, 1.23 g, 1.7 mL) was added to 1-(3-bromopyrrol-1-yl)-2,2-dimethyl-propan-1-one (700 mg, 3.04 mmol) dissolved in DCM (15 mL) at room temperature under a nitrogen atmosphere, and the mixture was stirred at room temperature for 4 h. The reaction was then quenched with a solution of pinacol (539.2 mg, 4.56 mmol) and TEA (3.08 g, 30.4 mmol, 4.24 mL) at 0 °C, and the resulting mixture was warmed to room temperature and stirred for an additional 1 h. The reaction was partitioned between EtOAc (50 mL) and water (50 mL), the two layers were separated, and the organic layer was washed with water and brine, dried over anhydrous Na ₂ SO ₄ , and evaporated to dryness to give the title compound (800 mg, yield 96.7%) as an oil, which was used directly in the next step without further purification. MS (ESI) m/z [M+H] ⁺ 271.8.

Step 3: 6-(3-bromo-1 H) -pyrrole-2-yl)-N-( 3rd class Synthesis of -butyl)-2-chloro-3-methoxybenzamide (Compound A135)

A mixture of Pd(dppf)Cl ₂ (99.4 mg, 136 μmol), N- tert -butyl-2-chloro-6-iodo-3-methoxy-benzamide (500 mg, 1.36 mmol), 3-bromo-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1 H -pyrrole (740 mg, 2.72 mmol) and K ₃ PO ₄ (866 mg, 4.08 mmol) in dioxane (8 mL) and water (1 mL) was stirred at 100 °C for 2 h under a nitrogen atmosphere. The reaction mixture was cooled and filtered, and the filtrate was evaporated under reduced pressure. The resulting crude product was purified by silica gel chromatography (EA in PE 0-50%) to obtain the title compound as a white solid (270 mg, yield 51.5%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.58 (s, 1H), 7.67 (s, 1H), 7.32 (d, J = 8.5 Hz, 1H), 7.20 (d, J = 8.6 Hz, 1H), 6.80 (t, J = 3.0 Hz, 1H), 6.13 (t, J = 2.7 Hz, 1H), 3.90 (s, 3H), 1.18 (s, 9H). MS (ESI) m/z [M+H] ⁺ 384.7, 386.8 (Br).

Step 4: 6-(3-(1 H) -pyrazol-3-yl)-1 H -pyrrole-2-yl)- N -( 3rd class Synthesis of -butyl)-2-chloro-3-methoxybenzamide (Compound A416)

A mixture of Pd(dppf)Cl ₂ (9.5 mg, 13 μmol), 6-(3-bromo-1 H -pyrrol- 2 -yl)- N - tert -butyl-2-chloro-3-methoxy-benzamide (50 mg, 130 μmol), ( 2- tert -butoxycarbonylpyrazol-3-yl)boronic acid (55 mg, 260 μmol), and K ₃ PO ₄ (83 mg, 389 μmol) in dioxane (4 mL) and water (0.5 mL) was stirred at 100 °C for 2 h. The reaction mixture was cooled to room temperature and filtered, the filtrate was evaporated under reduced pressure, and the resulting crude product was purified by prep-HPLC (Daisogel-C18-5-100, 0-70% acetonitrile in water) to obtain the title compound as a white solid (15.6 mg, yield 32.2%). ^1H NMR (400 MHz, DMSO _-d6 ) δ 12.32 (s, 1H), 10.63 (s, 1H), 7.60 (s, 1H), 7.42 (s, 1H), 7.10 (q, J = 8.5 Hz, 2H), 6.75 (t, J = 2.6 Hz, 1H), 6.35 (t, J = 2.6 Hz, 1H), 5.96 (s, 1H), 3.89 (s, 3H), 1.00 (s, 9H). MS (ESI) m/z [M+H] ⁺ 373.1.

The following compounds ( A135, A144, A388~A437, A440~A449 ) in Table 7 were synthesized using appropriate starting materials and corresponding intermediates in a similar manner to that described in Examples 12~17 .

Amide (Example B)

General Method 7

Example 18:

1-methyl- N -(5-methyl-2-(1 H Preparation of -pyrazol-1-yl)phenyl)cyclopropane-1-carboxamide (Compound B2)

Step 1: Synthesis of 1-(4-methyl-2-nitro-phenyl)pyrazole

A mixture of 1-fluoro-4-methyl-2-nitro-benzene (2 g, 12.89 mmol, 1.58 mL), K ₂ CO ₃ (3.56 g, 25.79 mmol), and 1H-pyrazole (1.76 g, 25.79 mmol) dissolved in DMF (30 mL) was stirred at 80°C for 4 h, diluted with water (50 mL), and extracted with EA (50 mL × 3). The organic layer was concentrated, and purified by silica gel column chromatography (PE/EA 20/80) to obtain the title compound as a white solid (2 g, yield 76.34%). MS (ESI) m/z [M+H] ⁺ 204.0.

Step 2: Synthesis of 5-methyl-2-pyrazol-1-yl-aniline

A mixture of 1-(4-methyl-2-nitro-phenyl)pyrazole (2 g, 9.84 mmol) and Pd-C (5 wt%, 200 mg, 1.88 mmol) in methanol (50 mL) was stirred at room temperature under a hydrogen atmosphere for 1 h. The solid was filtered to obtain a filtrate, which was concentrated in vacuo and purified by silica gel column chromatography (PE/EA 50/50) to give the title compound as a white solid (1.6 g, yield 93.85%). MS (ESI) m/z [M+H] ⁺ 174.1.

Step 3: 1-Methyl- N -(5-methyl-2-(1 H Synthesis of -pyrazol-1-yl)phenyl)cyclopropane-1-carboxamide (Compound B2)

A solution of 5-methyl-2-pyrazol-1-yl-aniline (52 mg, 0.3 mmol), 1-methylcyclopropane-1-carboxylic acid (45 mg, 0.45 mmol), HATU (171 mg, 0.45 mmol), and N,N-diisopropylethylamine (91 mg, 0.9 mmol, 125 μL) in acetonitrile (2 mL) was stirred at 30°C for 5 h. The solvent was removed in vacuo, and the residue was purified by silica gel column chromatography (EA in PE 0-50%) to give the title compound as a white solid (58.9 mg, yield 77%). ^1H NMR (400 MHz, DMSO _-d6 ) δ 10.59 (s, 1H), 8.29 (d, J = 2.4 Hz, 1H), 8.11 (d, J = 1.6 Hz, 1H), 7.90 (d, J = 2.0 Hz, 1H), 7.48 (d, J = 8.4) Hz, 1H), 7.05 (dd, J = 8.0, 1.6 Hz, 1H), 6.60 (t, J = 2.4 Hz, 1H), 2.33 (s, 3H), 1.34 (s, 3H), 1.04 (q, J = 3.6 Hz, 2H), 0.67 (q, J = 3.6 Hz, 2H). MS (ESI) m/z [M+H] ⁺ 256.1.

Example 19:

N -(2-(1 H -Imidazo[1,2- a Preparation of ]imidazol-1-yl)-5-methylphenyl)-1-methylcyclopropane-1-carboxamide (Compound B42)

Step 1: N Synthesis of -(2-bromo-5-methylphenyl)-1-methylcyclopropane-1-carboxamide

A solution of 1-methylcyclopropanecarboxylic acid (215.25 mg, 2.15 mmol), HATU (1.23 g, 3.22 mmol), DIPEA (555.74 mg, 4.30 mmol, 748.97 μL), and 2-bromo-5-methyl-aniline (400 mg, 2.15 mmol) in DMF (2 mL) was stirred at 80°C overnight. The reaction mixture was cooled and diluted with water (10 mL), then extracted with EA (10 mL × 3). The organic layer was washed with brine and concentrated in vacuo to obtain a residue, which was purified by silica gel column chromatography (EA in PE 0-30%) to give the title compound as a yellow solid (400 mg, yield 69%). MS (ESI) m/z [M+H] ⁺ 268.1.

Step 2: 1-(2,2-diethoxyethyl)-1 H -Synthesis of imidazol-2-amine

1 H -Imidazol-2-amine (500 mg, 6.02 mmol) and 2-bromo-1,1-diethoxy-ethane (1.42 g, 7.22 mmol) were dissolved in DMF (5 mL) to which sodium amide (234.76 mg, 6.02 mmol) was added. The resulting solution was stirred at room temperature for 1 h, diluted with saturated NH ₄ Cl aqueous solution (30 mL), and extracted with EA (20 mL × 3). The combined organic layers were concentrated in vacuo to obtain a residue, which was purified by silica gel column chromatography (EA in PE 0-10%) to give the title compound as a yellow solid (400 mg, yield 33%). MS (ESI) m/z [M+H] ⁺ 200.0.

Step 3: 1 H -Imidazo[1,2- a ]Synthesis of imidazole

A mixture of 1-(2,2-diethoxyethyl)imidazol-2-amine (300 mg, 1.51 mmol) and 6N HCl (3 mL) was stirred at room temperature for 1 h and then concentrated in vacuo. The residue was purified by silica gel column chromatography (EA in PE, 0–80%) to give the title compound as a yellow solid (130 mg, yield 81%). MS (ESI) m/z [M+H] ⁺ 108.2.

Step 4: N -(2-(1 H -Imidazo[1,2- a Synthesis of ]imidazol-1-yl)-5-methylphenyl)-cyclopropanecarboxamide (Compound B42)

To a solution of 1 H -imidazo[1,2- a ]imidazole (19.97 mg, 186.46 μmol) and Cs ₂ CO ₃ (121.51 mg, 372.93 μmol) in DMF (2 mL) were added CuI (3.55 mg, 18.65 μmol) and (2 S )-pyrrolidine-2-carboxylic acid (4.29 mg, 37.29 μmol) at room temperature, followed by the addition of N -(2-bromo-5-methyl-phenyl)-1-methyl-cyclopropanecarboxamide (50 mg, 186.46 μmol) at room temperature. The resulting mixture was stirred at 110°C overnight, cooled with water (3 mL) to quench the reaction, and extracted with EA (5 mL × 3). The above mixed organic layers were concentrated under vacuum to obtain a residue, which was purified by silica gel column chromatography (EA in PE 0-40%) to obtain the title compound as a white solid (3.8 mg, yield 6.92%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.70 (s, 1H), 7.61 (s, 1H), 7.22 - 7.16 (m, 4H), 7.10 (d, J = 8.3 Hz, 1H), 7.06 (s, 1H), 2.42 (s, 3H), 1.31 (s, 3H), 1.10 (s, 2H), 0.54 (d, J = 2.9 Hz, 2H). MS (ESI) m/z [M+H] ⁺ 259.2.1.

The following compounds ( B1 to B260 ) in Table 8 were synthesized using appropriate starting materials and corresponding intermediates in a manner similar to that described in Examples 18 and 19 .

General Method 8

Example 20:

N Preparation of -(7-chloro-5-(2-ethynylphenyl)benzo[d]thiazol-6-yl)-1-methylcyclopropane-1-carboxamide (Compound B290)

Step 1: 7-chlorobenzo[ d ]Synthesis of thiazol-6-amine

To a solution of 1,3-benzothiazol-5-amine (3 g, 19.97 mmol) in DMF (1.35 mL) cooled to 0°C was added NCS (3.20 g, 23.97 mmol, 1.94 mL), stirred for 3 h, diluted with EA (15 mL), and the mixture washed with water, dried, and concentrated. The residue was purified by silica gel column chromatography (EA/PE, 0-20%) to give the title compound as a yellow solid (2 g, yield 54.23%).

Step 2: 5-Bromo-7-chlorobenzo[ d ]Synthesis of thiazol-6-amine

To a solution of 4-chloro-1,3-benzothiazol-5-amine (1 g, 5.42 mmol) in DMF (2.66 mL) was added NBS (1.25 g, 7.04 mmol). The mixture was stirred at 60°C for 2 h, diluted with EA (15 mL), washed with water, dried and concentrated to obtain a residue, which was purified by silica gel column chromatography (EA/PE, 0-30%) to obtain the title compound as a yellow solid (0.6 g, yield 42.04%).

Step 3: N -(5-Bromo-7-chlorobenzo[ d Synthesis of thiazol-6-yl)-1-methylcyclopropane-1-carboxamide

To a solution of 1-methylcyclopropanecarboxylic acid (379.88 mg, 3.79 mmol) in DCM (10 mL) was added oxalyl chloride (529.78 mg, 4.17 mmol, 364.11 μL), followed by DMF (1 drop). The mixture was stirred at room temperature for 2 h and then added to a solution of 5-bromo-7-chloro-1,3-benzothiazol-6-amine (0.5 g, 1.90 mmol) in DCM (5 mL) and pyridine (5 mL). The resulting mixture was stirred at 40°C for 16 h, concentrated, and purified by silica gel column chromatography (EA/PE, 0-20%) to obtain the title compound as a yellow solid (0.5 g, yield 76.25%).

Step 4: N -(7-chloro-5-(2-((trimethylsilyl)ethynyl)phenyl)benzo[ d Synthesis of thiazol-6-yl)-1-methylcyclopropane-1-carboxamide

To a solution of N- (5-bromo-7-chloro-1,3-benzothiazol-6-yl)-1-methyl-cyclopropanecarboxamide (0.1 g, 289.32 μmol) and trimethyl-[2-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-ethynyl]silane (104.25 mg, 347.18 μmol) in dioxane (4 mL) and water (0.5 mL) were added Pd(dppf)Cl ₂ (42.34 mg, 57.86 μmol) and K ₃ PO ₄ (184.24 mg, 867.95 μmol). The mixture was stirred at 95°C for 2 hours, diluted with EA (15 mL), washed with water, dried and concentrated to obtain a residue, which was purified by silica gel column chromatography (EA/PE, 0-10%) to obtain the title compound as a white solid (0.11 g, yield 86.60%).

Step 5: N -(7-chloro-5-(2-ethynylphenyl)benzo[ d Synthesis of thiazol-6-yl)-1-methylcyclopropane-1-carboxamide (Compound B290)

To a solution of N- [7-chloro-5-[2-(2-trimethylsilylethynyl)phenyl]-1,3-benzothiazol-6-yl]-1-methyl-cyclopropanecarboxamide (0.11 g, 250.54 μmol) in THF (4.95 mL) was added TBAF (1 M in THF, 501.09 μL). The mixture was stirred at room temperature for 0.5 h, concentrated, and purified by silica gel column chromatography (EA/PE, 0-15%) to give the title compound as a white solid (0.08 g, yield: 87.04%). ^1H NMR (400 MHz, DMSO- d ₆ ) δ 9.51 (s, 1H), 9.10 (s, 1H), 8.07 (s, 1H), 7.62 (dd, J = 6.8, 2.0 Hz, 1H), 7.47 -7.38 (m, 2H), 7.34 - 7.28 (m, 1H), 4.04 (s, 1H), 1.19 (s, 3H), 0.80 (s, 2H), 0.46 (d, J = 2.8 Hz, 2H). MS (ESI) m/z [M+H] ⁺ 367.0, 369.0 (Cl).

Example 21:

N -(5-(1 H -pyrazol-1-yl)-1 H Preparation of -indol-4-yl)-1-methylcyclopropane-1-carboxamide (Compound B296)

Step 1: 5-Bromo-1-tosyl-1 H -Synthesis of indole-4-amine

To a solution of 1-( p -tolylsulfonyl)indol-4-amine (7.5 g, 26.19 mmol) in DMF (100 mL) cooled to -20°C was added NBS (4.66 g, 26.19 mmol), the reaction was stirred at -20°C for 5 minutes, quenched with saturated NaHCO ₃ aqueous solution, and extracted with EA. The organic layer was concentrated, and the residue was purified by flash chromatography (EA in PE 0-100%) to give the title compound as a solid (8 g, yield 83.63%). ^1H NMR (400 MHz, DMSO _-d6 ) δ 7.79 (d, J = 8.4 Hz, 2H), 7.60 (d, J = 3.7 Hz, 1H), 7.37 (d, J = 8.1 Hz, 2H), 7.26 (d, J = 8.7 Hz, 1H), 7.07 (t, J = 6.0 Hz, 2H), 5.77 (d, J = 3.7 Hz, 2H). MS (ESI) m/z [M+H] ⁺ 365.0, 367.0 (Br).

Step 2: 5-Bromo-1 H -Synthesis of indole-4-amine

To a solution of 5-bromo-1-( p -tolylsulfonyl)indol-4-amine (800 mg, 2.19 mmol) in water (2 mL), methanol (2 mL) and dioxane (6 mL) was added NaOH (262.82 mg, 6.57 mmol), and the resulting mixture was stirred at 70°C for 3 h and then concentrated to obtain a residue, which was purified by column chromatography (EA in PE 0-80%) to obtain the title compound as a white solid (400 mg, yield 86.53%). ^1H NMR (400 MHz, DMSO- d ₆ ) δ 10.95 (s, 1H), 7.12 (t, J = 2.8 Hz, 1H), 6.99 (d, J = 8.5 Hz, 1H), 6.65 - 6.62 (m, 1H), 6.60 (d, J = 8.7 Hz, 1H), 5.32 (s, 2H). MS (ESI) m/z [M+H] ⁺ 211.0, 213.0 (Br).

Step 3: N -(5-bromo-1 H Synthesis of -indol-4-yl)-1-methylcyclopropane-1-carboxamide

A mixture of HATU (1.44 g, 3.79 mmol), 5-bromo-1 H -indol-4-amine (400 mg, 1.90 mmol), 1-methylcyclopropanecarboxylic acid (379.48 mg, 3.79 mmol), and DIPEA (734.83 mg, 5.69 mmol, 990.33 μL) in DMF (5 mL) was stirred at 85 °C for 4 h, concentrated to obtain a residue, which was purified by column chromatography (EA in PE 0-70%) to give the title compound (130 mg, yield 23.40%) as a yellow solid. MS (ESI) m/z [M+H] ⁺ 293.1, 295.1 (Br).

Step 4: N -(5-(1 H -pyrazol-1-yl)-1 H Synthesis of -indol-4-yl)-1-methylcyclopropane-1-carboxamide (Compound B296)

A mixture of (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (12.62 mg, 88.69 μmol), N -(5-bromo-1 H -indol-4-yl)-1-methyl-cyclopropanecarboxamide (130 mg, 443.45 μmol), 1 H -pyrazole (60.38 mg, 886.89 μmol) and CuI (16.89 mg, 88.69 μmol, 3.01 μL) in DMF (5 mL) was stirred at 90°C for 3 h and then concentrated to obtain a residue, which was purified by prep-HPLC (0-50% ACN in water containing 0.5% FA) to give the title compound (28.3 mg, yield 22.77%) as a white solid. ^1H NMR (400 MHz, DMSO _-d6 ) δ 11.30 (s, 1H), 9.47 (s, 1H), 7.97 (d, J = 2.4 Hz, 1H), 7.73 (d, J = 2.4 Hz, 1H), 7.40 (d, J = 4.0 Hz, 1H), 7.39 (d, J = 0.8 Hz, 1H), 7.23 (d, J = 8.4 Hz, 1H), 6.48 (t, J = 2.0 Hz, 1H), , 6.29 (t, J = 2.0 Hz, 1H), 1.35 (s, 3H), 0.99 (q, J = 3.6) Hz, 2H), 0.60 (q, J = 3.6 Hz, 2H). MS (ESI) m/z [M+H] ⁺ 281.2.

Example 22:

1-methyl- N -[6-(pyrazol-1-yl)-3 H Preparation of -1,3-benzodiazol-5-yl]cyclopropane-1-carboxamide (Compound B300)

Step 1: 5-Bromo-6-nitro-1 H -Synthesis of benzo[di]imidazole

To a solution of 5-bromo-1 H -1,3-benzodiazole (1.5 g, 7.6 mmol) in H ₂ SO ₄ (20 mL) was added HNO ₃ (2 mL) at 0°C. After stirring for 2 h, the mixture was poured into ice water (20 mL) and extracted with EA (20 mL × 2). The combined organic layers were dried and concentrated to obtain the title compound (1.6 g, yield 78%), which was used without purification. MS (ESI) m/z [M+H] ⁺ 241.9, 243.9 (Br).

Step 2: N -(5-(1 H -pyrazol-1-yl)-1 H -Benzo[ d Synthesis of ]imidazol-6-yl)-1-methylcyclopropane-1-carboxamide

To a mixture of 5-bromo-6-nitro-1 H -1,3-benzodiazole (500 mg, 2.06 mmol), 1 H -pyrazole (211 mg, 3.1 mmol), and Cs ₂ CO ₃ (1346 mg, 4.13 mmol) in DMF (5 mL) were added CuI (197 mg, 1.03 mmol) and N,N'-dimethyl-1,2-cyclohexanediamine (147 mg, 1.03 mmol). The mixture was stirred at 100 °C under N ₂ atmosphere for 1 h, then the reaction was quenched with water (5 mL) and extracted with EA (10 mL × 2). The combined organic layers were dried, concentrated, and purified by flash chromatography (EA/PE 0-50%) to give the title compound as a brown solid (500 mg, yield 95%). MS (ESI) m/z [M+H] ⁺ 230.1.

Step 3: 3rd class -Butyl 6-nitro-5-(1 H -pyrazol-1-yl)-1 H -Benzo[ d ]Synthesis of imidazole-1-carboxylate

To a mixture of 5-nitro-6-(pyrazol-1-yl)-3 H -1,3-benzodiazole (500 mg, 2.18 mmol) and TEA (440 mg, 4.36 mmol) in DCM (5 mL) were added Boc ₂ O (476 mg, 2.18 mmol) and DMAP (26.6 mg, 0.22 mmol). The mixture was stirred at 25 °C for 2 h, quenched with water (10 mL), and extracted with DCM (10 mL × 2). The organic layer was dried, concentrated, and purified by flash chromatography (EA/PE 0-30%) to give the title compound as a yellow solid (600 mg, yield 75%). MS (ESI) m/z [M+H] ⁺ 330.2.

Step 4: 3rd class -Butyl 6-amino-5-(1 H -pyrazol-1-yl)-1 H -Benzo[ d ]Synthesis of imidazole-1-carboxylate

To a solution of tert -butyl 6-nitro-5-(1 H -pyrazol-1-yl)-1 H -benzo[ d ]imidazole-1-carboxylate (600 mg, 1.81 mmol) in EtOH (10 mL) was added Pd/C (5% wt, 600 mg). The mixture was stirred at 25°C for 5 h and filtered. The filtrate was concentrated, and it was purified by flash chromatography (EA/PE 0-30%) to give the title compound as a yellow solid (250 mg, yield 41%). MS (ESI) m/z [M+H] ⁺ 300.2.

Step 5: 3rd class -Butyl 6-(1-methylcyclopropane-1-carboxamido-5-(1 H -pyrazol-1-yl)-1 H -Benzo[ d ]Synthesis of imidazole-1-carboxylate

To a solution of tert-butyl 6-amino-5-(1 H -pyrazol-1-yl)-1 H -benzo[ d ]imidazole-1-carboxylate (200 mg, 0.66 mmol) in DCM (4 mL) were added 1-methylcyclopropane-1-carbonyl chloride (79 mg, 0.66 mmol) and TEA (202 mg, 1.99 mmol) sequentially. The mixture was stirred at room temperature for 2 h, concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (EA/PE 0-30%) to give the title compound as a yellow oil (150 mg, yield 53%). MS (ESI) m/z [M+H] ⁺ 382.1.

Step 6: N -(5-(1 H -pyrazol-1-yl)-1 H -Benzo[ d Synthesis of ]imidazol-6-yl)-1-methylcyclopropane-1-carboxamide) (Compound B300)

To a solution of tert-butyl 6-(1-methylcyclopropane-1-carboxamido-5-(1 H -pyrazol-1-yl)-1 H -benzo[ d ]imidazole-1-carboxylate (150 mg, 0.39 mmol) in DCM (3 mL) was added TFA (1 mL). The mixture was stirred at room temperature for 2 h and then concentrated under reduced pressure. The residue was purified by flash chromatography (EA/PE 0-50%) to give the title compound as a white solid (80 mg, yield 71%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.48 (s, 1H), 9.26 - 8.99 (m, 1H), 8.68 - 8.54 (m, 1H), 8.36 (d, J = 1.8 Hz, 1H), 8.04 - 7.79 (m, 2H), 6.71 - 6.54 (m, 1H), 1.30 (s, 3H), 1.09 - 0.90 (m, 2H), 0.72 - 0.53 (m, 2H). MS (ESI) m/z [M+H] ⁺ 282.0.

Example 23:

N -(5-(1 H -pyrrole-2-yl)-1 H Preparation of -indol-4-yl)-1-(difluoromethyl)cyclopropane-1-carboxamide (Compound B322)

Step 1: N -(5-bromo-1 H Synthesis of -indol-4-yl)-1-(difluoromethyl)cyclopropane-1-carboxamide

To a solution of 1-(difluoromethyl)cyclopropanecarboxylic acid (0.53 g, 3.9 mmol) in DCM (5 mL) was added oxalyl chloride (0.54 g, 4.2 mmol), followed by one drop of DMF, and the mixture was stirred at room temperature for 2 h. Then, a solution of 5-bromo-1 H -indol-4-amine (0.82 g, 3.9 mmol) and DIPEA (1.0 g, 7.7 mmol) in DCM (10 mL) was added dropwise, cooled with ice water. The mixture was stirred at 10°C for 1 h, and DCM (20 mL) was added. The solution was washed successively with water and brine, dried, and concentrated. The residue was purified by column chromatography (EA in PE 0-70%) to give the title compound as a brown solid (530 mg, yield 41.7%). ^1H NMR (400 MHz, DMSO- d ₆ ) δ 11.34 (s, 1H), 9.38 (s, 1H), 7.36 (t, J = 2.8 Hz, 1H), 7.31- 7.26 (m, 2H), 6.64 (t, J = 57.2 Hz, 1H), 6.21 (dd, J = 3.2, 2.0 Hz, 1H), 1.44 - 1.37 (m, 2H), 1.21 - 1.13 (m, 2H). MS (ESI) m/z [M+H] ⁺ 329.1, 331.0 (Br).

Step 2: 3rd class -Butyl 2-(4-(1-(difluoromethyl)cyclopropane-1-carboxamido)-1 H -Indol-5-day)-1 H -Synthesis of pyrrole-1-carboxylate

To a solution of N- (5-bromo-1 H -indol-4-yl)-1-(difluoromethyl)cyclopropanecarboxamide (0.2 g, 0.61 mmol) and (1- tert -butoxycarbonylpyrrol-2-yl)boronic acid (0.19 g, 0.91 mmol) in a water (0.5 mL)/ n -BuOH (5 mL) mixture, tripotassium phosphate (0.26 g, 1.2 mmol) and diacetoxypalladium (13.6 mg, 60.8 μmol) were added. The mixture was stirred at 85°C under N ₂ for 2 h. The mixture was diluted with EA (15 mL), washed with water and brine, and concentrated to obtain a residue, which was purified by prep-HPLC (0-50% ACN in water containing 0.5% FA) to give the title compound as an off-white solid (168 mg, yield 66.6%). ^1H NMR (400 MHz, DMSO -d6 ) δ 11.14 (s, 1H), 8.61 (s, 1H), 7.35 - 7.24 (m, 3H), 6.95 (dd, J = 8.0, 1.6 Hz, 1H), 6.28 ₍ t, J = 56.4 Hz, 1H), 6.26 - 6.22 (m, 1H), 6.22 - 6.19 (m, 1H), 6.07 - 6.04 (m, 1H), 1.21 (s, 9H), 1.12 - 1.08 (m, 2H), 1.03 - 0.99 (m, 2H). MS (ESI) m/z [M+Na] ⁺ 438.2.

Step 3: N -(5-(1 H -pyrrole-2-yl)-1 H Synthesis of -indol-4-yl)-1-(difluoromethyl)cyclopropane-1-carboxamide

To a solution of tert -butyl 2-[4-[[1-(difluoromethyl)cyclopropanecarbonyl]amino]-1 H -indol-5-yl]pyrrole-1-carboxylate (0.15 g, 0.36 mmol) in THF (5 mL) was added sodium methoxide (65 mg, 0.36 mmol). The mixture was stirred at room temperature for 1 h. The mixture was diluted with EA (20 mL), washed with water and brine, dried, and concentrated. The crude product was purified by prep-HPLC (0-50% ACN in water containing 0.5% FA) to give the title compound as a white solid (38.2 mg, yield 33.7%). ^1H NMR (400 MHz, DMSO _-d6 ) δ 11.11 (s, 1H), 10.81 (s, 1H), 9.19 (s, 1H), 7.35 (d, J = 8.4 Hz, 1H), 7.29 (t, J = 2.8 Hz, 1H), 7.25 (d, J = 8.4 Hz, 1H), 6.79 - 6.76 (m, 1H), 6.61 (t, J = 57.2 Hz, 1H), 6.22 - 6.18 (m, 1H), 6.17 - 6.14 (m, 1H), 6.10 - 6.06 (m, 1H), 1.34 - 1.28 (m, 2H), 1.14 - 1.08 (m, 2H). MS (ESI) m/z [M+H] ⁺ 316.1.

The following compounds ( B261 to B340 ) in Table 9 were synthesized using appropriate starting materials and corresponding intermediates in a manner similar to that described in Examples 20 to 23 .

General Method 9

Example 24:

N -(5-(1 H -imidazol-2-yl)-2-(1 H Preparation of -pyrazol-1-yl)phenyl)-1-methylcyclopropane-1-carboxamide (Compound B350)

Step 1: 1-(4-bromo-2-nitrophenyl)-1 H -Synthesis of pyrazole

A mixture of 1 H -pyrazole (835.51 mg, 12.27 mmol), 4-bromo-1-fluoro-2-nitro-benzene (3 g, 13.64 mmol), and K ₂ CO ₃ (5.65 g, 40.91 mmol) in DMF (16 mL) was stirred at 85°C for 3 h, cooled, and filtered to remove the solid. The filtrate was concentrated, and the residue was purified by flash chromatography (EA in PE 0-10%) to give the title compound as a pale yellow solid (3 g, yield 82.07%). ^1H NMR (400 MHz, DMSO -d6 ) δ 7.86 (s, 1H), 7.58 (dd, J = 8.6, 5.9 Hz, 1H), 7.29 (dd, J = 9.9, 2.7 Hz, 1H), 7.24 - 7.17 ₍ m, 1H), 6.86 (s, 1H), 4.40 (dd, J = 5.0, 2.4 Hz, 2H), 4.35 - 4.26 (m, 2H), 4.07 (s, 1H), 1.12 (s, 9H). MS (ESI) m/z [M+H] ⁺ 268.0, 270.0 (Br).

Step 2: 5-Bromo-2-(1 H - Synthesis of pyrazol-1-yl)aniline

To a mixture of 1-(4-bromo-2-nitro-phenyl)pyrazole (3 g, 11.19 mmol) and NH ₄ Cl (2.99 g, 55.96 mmol) in water (3 mL) and EtOH (30 mL) was added Fe powder (6.25 g, 111.91 mmol) at room temperature. The mixture was stirred at 90°C for 3 h, cooled, and filtered to remove the solid. The filtrate was concentrated, and the residue was purified by flash chromatography (EA in PE 0-10%) to give the title compound as a pale yellow solid (2.4 g, yield 90.1%). ^1H NMR (400 MHz, DMSO- d ₆ ) δ 8.10 (dd, J = 2.4, 0.5 Hz, 1H), 7.76 (d, J = 1.5 Hz, 1H), 7.19 (d, J = 8.4 Hz, 1H), 7.08 (d, J = 2.2 Hz, 1H), 6.78 (dd, J = 8.4, 2.2 Hz, 1H), 6.53 - 6.48 (m, 1H), 5.86 (s, 2H). MS (ESI) m/z [M+H] ⁺ 238.0, 240.0 (Br).

Step 3: N -(5-bromo-2-(1 H Synthesis of -pyrazol-1-yl)phenyl)-1-methylcyclopropane-1-carboxamide

A mixture of HATU (7.35 g, 19.32 mmol), 5-bromo-2-pyrazol-1-yl-1-aniline (2.3 g, 9.66 mmol), 1-methylcyclopropanecarboxylic acid (1.93 g, 19.32 mmol) and DIPEA (3.75 g, 28.98 mmol, 5.05 mL) in DMF (20 mL) was stirred at 85°C overnight, concentrated to obtain a residue, which was purified by column chromatography (EA in PE 0-5%) to give the title compound (2.4 g, yield 77.59%) as a pale yellow solid. ^1H NMR (400 MHz, DMSO- d ₆ ) δ 10.97 (s, 1H), 8.58 (d, J = 2.3 Hz, 1H), 8.44 - 8.38 (m, 1H), 7.97 (d, J = 1.6 Hz, 1H), 7.62 (d, J = 8.6 Hz, 1H), 7.43 (dd, J = 8.6, 2.3 Hz, 1H), 6.66 (dd, J = 2.4, 2.0 Hz, 1H), 1.37 (s, 3H), 1.08 (q, J = 3.6 Hz, 2H), 0.71 (q, J = 3.7 Hz, 2H). MS (ESI) m/z [M+H] ⁺ 320.0, 322.0 (Br).

Step 4: N -(2-(1 H Synthesis of -pyrazol-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-methylcyclopropane-1-carboxamide

A mixture of Pd(dppf)Cl ₂ (228.31 mg, 312.32 μmol), N -(5-bromo-2-pyrazol-1-yl-phenyl)-1-methyl-cyclopropanecarboxamide (500 mg, 1.56 mmol), (Bpin) ₂ (475.86 mg, 1.87 mmol) and KOAc (1.32 g, 4.68 mmol) in dioxane (8 mL) was stirred at 90 °C under N ₂ atmosphere for 3 h, concentrated and the residue was purified by silica gel column chromatography (EA in PE 0-10%) to give the title compound (530 mg, yield 92.4%) as a pale yellow solid. ^1H NMR (400 MHz, MeOD) δ 8.03 (d, J = 8.1 Hz, 1H), 6.00 (s, 1H), 5.69 (d, J = 8.1 Hz, 1H), 4.11 (d, J = 8.9 Hz, 1H), 3.98 - 3.84 (m, 2H), 3.75 (dd, J = 12.5, 2.9 Hz, 1H), 1.75 (s, 3H). MS (ESI) m/z [M+H] ⁺ 283.0.

Step 5: 3rd class -Butyl 2-(3-(1-methylcyclopropane-1-carboxamido)-4-(1 H -pyrazol-1-yl)phenyl)-1 H -Synthesis of imidazole-1-carboxylate

A mixture of Pd(dppf)Cl ₂ (59.71 mg, 81.69 μmol), 1-methyl-N-[2-pyrazol-1-yl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclopropanecarboxamide (150 mg, 408.44 μmol), tert -butyl 2-bromoimidazole-1-carboxylate (201.84 mg, 816.89 μmol) and K ₃ PO ₄ (260.10 mg, 1.23 mmol) in water (0.5 mL) and dioxane (4 mL) was stirred at 90°C for 3 h, concentrated, and purified by silica gel column chromatography (EA in PE 0-50%) to give the title compound as a white solid (140 mg, yield 84.1%) was obtained.

Step 6: N -(5-(1 H -imidazol-2-yl)-2-(1 H Synthesis of -pyrazol-1-yl)phenyl)-1-methylcyclopropane-1-carboxamide (Compound B350)

To a mixture of tert -butyl 2-[3-[(1-methylcyclopropanecarbonyl)amino]-4-pyrazol-1-yl-phenyl]imidazole-1-carboxylate (140 mg, 343.59 μmol) dissolved in DCM (4 mL) was added TFA (1.48 g, 12.98 mmol). The mixture was stirred at room temperature for 1 h, concentrated, and purified by C18-prep-HPLC (0-50% ACN in water) to give the title compound (90 mg, yield 85.23%) as a white solid. ^1H NMR (400 MHz, DMSO _-d6 ) δ 14.66 (s, 1H), 11.15 (s, 1H), 8.95 (d, J = 2.0 Hz, 1H), 8.53 (d, J = 2.8 Hz, 1H), 8.03 (d, J = 2.0 Hz, 1H), 7.96 (d, J = 8.4 Hz, 1H), 7.85 (dd, J = 8.4, 2.0 Hz, 1H), 7.80 (s, 2H), 6.72 (t, J = 2.4 Hz,, 1H), 1.43 (s, 3H), 1.11 (q, J = 3.6 Hz, 2H), 0.76 (q, J = 3.8 Hz, 2H). MS (ESI) m/z [M+H] ⁺ 308.1.

Example 25:

N Preparation of -(2'-fluoro-4-morpholino-[1,1'-biphenyl]-2-yl)furan-3-carboxamide (Compound B419)

Step 1: Synthesis of 4-bromo-1-(2-fluorophenyl)-2-nitrobenzene

A solution of 4-bromo-1-iodo-2-nitro-benzene (2.20 g, 6.71 mmol), Pd(dppf)Cl ₂ (491.21 mg, 671.32 μmol), (2-fluorophenyl)boronic acid (939.32 mg, 6.71 mmol), and K ₃ PO ₄ (2.85 g, 13.43 mmol) in dioxane (20 mL) and water (5 mL) was stirred at 50°C under N ₂ for 1 h. The mixture was cooled and diluted with water (30 mL), extracted with EA (20 mL), and the combined organic layers were concentrated to obtain a residue, which was purified by silica gel column chromatography (EA/PE, 30-70%) to obtain the title compound as a white solid (1.2 g, yield 60.37%).

Step 2: Synthesis of 5-bromo-2-(2-fluorophenyl)aniline

To a solution of 4-bromo-1-(2-fluorophenyl)-2-nitrobenzene (1.2 g, 4.05 mmol) in ethanol (20 mL) and water (5 mL) were added NH ₄ Cl (1.08 g, 20.26 mmol) and Fe powder (1.13 g, 20.26 mmol). The resulting mixture was stirred at 90°C overnight. The mixture was cooled and filtered to remove the solid, and the filtrate was concentrated to obtain a residue, which was purified by silica gel column chromatography (EA in PE 50-90%) to obtain the title compound as a white solid (1 g, yield 92.72%).

Step 3: N - Synthesis of [5-bromo-2-(2-fluorophenyl)phenyl]furan-3-carboxamide

To a solution of furan-3-carboxylic acid (842.39 mg, 7.52 mmol) in DMF (20 mL) were added HATU (2.14 g, 5.64 mmol), DIPEA (971.36 mg, 7.52 mmol, 1.31 mL), followed by 5-bromo-2-(2-fluorophenyl)aniline (1 g, 3.76 mmol). After stirring at room temperature for 1 h, the resulting mixture was stirred at room temperature overnight, diluted with water (20 mL), and extracted with EA (20 mL × 3). The organic layer was concentrated to obtain a residue, which was purified by silica gel column chromatography (EA in PE 0-40%) to obtain the title compound as a white solid (900 mg, yield 66.49%).

Step 4: N Synthesis of -[2-(2-fluorophenyl)-5-morpholinophenyl]furan-3-carboxamide (compound B419)

A mixture of N- [5-bromo-2-(2-fluorophenyl)phenyl]furan-3-carboxamide (100 mg, 277.64 μmol), morpholine (48.38 mg, 555.28 μmol, 48.57 μL), Pd ₂ (dba) ₃ (15.96 mg, 27.76 μmol), and t -BuONa (53.36 mg, 555.28 μmol) in toluene (1.95 mL) was stirred at 110°C overnight, diluted with water (2 mL), and extracted with EA (2 mL × 3). The organic layer was concentrated to obtain a residue, which was purified by silica gel column chromatography (EA in PE 0-50%) to give the title compound as a white solid (12.9 mg, yield 12.68%). ^1H NMR (400 MHz, DMSO -d6 ) δ 9.35 (s, 1H), 8.04 (s, 1H), 7.62 (t, J = 1.6 Hz, 1H), 7.28 - 7.18 (m, 2H), 7.18 - 7.04 ₍ m, 3H), 6.96 (d, J = 2.4 Hz, 1H), 6.88 (dd, J = 8.4, 2.4 Hz, 1H), 6.68 (s, 1H), 3.76 - 3.60 (m, 4H), 3.18 - 3.03 (m, 4H). MS (ESI) m/z [M+H] ⁺ 367.1.

Example 26:

N -(2-(1 H Preparation of -pyrazol-1-yl)-5-(thiazol-2-ylamino)phenyl)-1-methylcyclopropane-1-carboxamide (Compound B423)

Step 1: N Synthesis of -(2-bromo-5-nitrophenyl)-1-methylcyclopropane-1-carboxamide

1-Methylcyclopropanecarbonyl chloride (122.92 mg, 1.04 mmol) was added to a mixture of 2-bromo-5-nitro-aniline (150 mg, 691.18 μmol) and pyridine (0.5 mL) in DCM (1.5 mL). The resulting solution was stirred at 40°C for 3 h, then concentrated to obtain a residue, which was purified by flash column chromatography on silica gel (EA/PE 0-50%) to give the title compound as a yellow solid (160 mg, yield 75.8%). MS (ESI) m/z [M+H] ⁺ 299.0, 301.0 (Br).

Step 2: 1-Methyl- N -(5-nitro-2-(1 H Synthesis of -pyrazol-1-yl)phenyl)cyclopropane-1-carboxamide

A mixture of N- (2-bromo-5-nitro-phenyl)-1-methyl-cyclopropanecarboxamide (600 mg, 2.01 mmol), 1 H -pyrazole (1.37 g, 20.06 mmol), CuI (38.20 mg, 200.59 μmol), and (1R,2R)-cyclohexane-1,2-diamine (22.90 mg, 200.59 μmol) in DMF (1 mL) was stirred at 100°C for 2 h. The resulting solution was concentrated to obtain a residue, which was purified by flash chromatography on silica gel (EA/PE 0-50%) to give the title compound as a yellow solid (700 mg, yield 109.71%). MS (ESI) m/z [M+H] ⁺ 287.0.

Step 3: N -(5-amino-2-(1 H Synthesis of -pyrazol-1-yl)phenyl)-1-methylcyclopropane-1-carboxamide

A mixture of 1-methyl- N -(5-nitro-2-pyrazol-1-yl-phenyl)cyclopropanecarboxamide (600 mg, 2.10 mmol) and Pd/C (5% wt, 763.61 mg, 6.29 mmol) in methanol (5 mL) was stirred at 25°C under an H ₂ atmosphere for 1 h, and then the solid was filtered off. The filtrate was concentrated, and the residue was purified by silica gel flash chromatography (EA/PE 0-50%) to give the title compound as a white solid (550 mg, yield 92.15%). MS (ESI) m/z [M+H] ⁺ 257.1.

Step 4: N -(2-(1 H Synthesis of -pyrazol-1-yl)-5-(thiazol-2-ylamino)phenyl)-1-methylcyclopropane-1-carboxamide (Compound B423)

A mixture of N- (5-amino-2-pyrazol-1-yl-phenyl)-1-methyl-cyclopropanecarbox-amide (25 mg, 97.54 μmol), 2-bromothiazole (54.40 mg, 331.64 μmol, 29.89 μL), Pd ₂ (dba) ₃ (26.80 mg, 29.26 μmol), BINAP (60.74 mg, 97.54 μmol), and t -BuONa (112.37 mg, 1.17 mmol) in toluene (482.07 μL) was stirred at 100°C for 0.5 h. The resulting solution was concentrated to obtain a residue, which was purified by C18-prep-HPLC (ACN/water = 0-80%) to obtain the title compound as a white solid (1.7 mg, yield 4.88%). ^1H NMR (400 MHz, DMSO _-d6 ) δ 10.53 (s, 1H), 10.41 (s, 1H), 8.47 (d, J = 2.5 Hz, 1H), 8.24 (d, J = 2.4 Hz, 1H), 7.89 (d, J = 1.9 Hz, 1H), 7.67 (dd, J = 8.8, 2.5 Hz, 1H), 7.51 (d, J = 8.8 Hz, 1H), 7.28 (d, J = 3.6 Hz, 1H), 6.95 (d, J = 3.6 Hz, 1H), 6.59 (t, J = 2.2 Hz, 1H), 1.34 (s, 3H), 1.05 (q, J = 3.6 Hz, 2H), 0.68 (q, J = 3.7 Hz, 2H). MS (ESI) m/z [M+H] ⁺ 340.1.

The following compounds ( B325 , B341~B437 ) in Table 10 were synthesized using appropriate starting materials and corresponding intermediates in a similar manner to that described in Examples 24~26 .

General Method 10

Example 27:

N -(2,5 - Difluoro-3-methyl-6-(1 H Preparation of -pyrazol-1-yl)phenyl)-1-methyl-cyclopropane-1-carboxamide (Compound B439)

Step 1: Synthesis of 2,5-difluoro-3-methylaniline

A mixture of 2,5 - difluoro-1-methyl-3-nitrobenzene (1 g, 5.78 mmol) and Pd/C (5% wt, 92.48 mg, 6.29 mmol) in methanol (6 mL) was stirred at 25°C for 3 h, and then the solid was filtered off. The filtrate was concentrated in vacuo, and the residue was purified by silica gel flash chromatography (EA/PE 0-15%) to give the title compound as a white solid (940 mg, yield 113.62%). MS (ESI) m/z [M+H] ⁺ 144.1.

Step 2: Synthesis of 4-bromo-2.5-difluoro-6-iodo-3-methylaniline

To a solution of 2,5-difluoro-3-methyl-aniline (700 mg, 4.89 mmol) in DMF (7 mL) was added NBS (870.44 mg, 4.89 mmol) at 0°C. The resulting solution was stirred at 0°C for 2 hours, then NIS (3.30 g, 14.67 mmol) was added, stirred for another 2 hours, and concentrated to obtain a residue, which was purified by flash chromatography on silica gel (EA/PE 0-25%) to obtain the title compound as a brown solid (1 g, yield 52.89%). MS (ESI) m/z [M+H] ⁺ 348.1, 350.1 (Br).

Step 3: N Synthesis of -(4-bromo-2,5-difluoro-6-iodo-3-methylphenyl)-1-methylcyclopropane-1-carboxamide

To a solution of 4-bromo-2,5-difluoro-6-iodo-3-methyl-aniline (700 mg, 2.01 mmol) and pyridine (1 mL) in DCM (1 mL) was added 1-methylcyclopropane-1-carbonyl chloride (477.07 mg, 4.02 mmol). The resulting solution was stirred at 0°C for 3 h, concentrated, and the residue was purified by flash C18-prep-HPLC (ACN/water 0-60%) to give the title compound as a white solid (850 mg, yield 93.33%). MS (ESI) m/z [M+H] ⁺ 430.1, 432.1 (Br).

Step 4: N -(4-Bromo-2,5-difluoro-3-methyl-6-(1 H Synthesis of -pyrazol-1-yl)phenyl)-1-methylcyclopropane-1-carboxamide

A mixture of N- (4-bromo-2,5-difluoro-6-iodo-3-methyl-phenyl)-1-methyl-cyclopropanecarboxamide (50 mg, 116.27 μmol), 1 H -pyrazole (11.87 mg, 174.41 μmol), CuI (4.43 mg, 23.25 μmol), (1R,2R)-(-)-1,2-diaminocyclohexane (2.66 mg, 23.25 μmol) and Cs ₂ CO ₃ (75.81 mg, 232.54 μmol) in DMF (1 mL) was stirred at 100°C for 0.2 h, concentrated to obtain a residue, which was purified by flash chromatography on silica gel (EA/PE 0-25%) to give the title compound (25 mg, yield 58.08%) as a yellow solid. Obtained. MS (ESI) m/z [M+H] ⁺ 370.0, 372.0 (Br).

Step 5: N -(2,5 - Difluoro-3-methyl-6-(1 H Synthesis of -pyrazol-1-yl)phenyl)-1-methylcyclopropane-1-carboxamide (Compound B439)

A mixture of N- (4-bromo-2,5-difluoro-3-methyl-6-pyrazol-1-yl-phenyl)-1-methylcyclopropanecarboxamide (25 mg, 67.53 μmol) and Pd/C (5% wt, 8.20 mg, 67.53 μmol) in methanol (3 mL) was stirred at 25°C under H ₂ atmosphere for 2 h, and then the solid was filtered off. The filtrate was concentrated under reduced pressure to obtain a residue, which was purified by silica gel flash chromatography (EA/PE 0-15%) to give the title compound as a white solid (3.5 mg, yield 17.79%). ^1H NMR (400 MHz, DMSO _-d6 ) δ 8.97 (s, 1H), 7.81 (t, J = 2.0 Hz, 1H), 7.77 (d, J = 1.8 Hz, 1H), 7.41 (dd, J = 10.4, 6.4 Hz, 1H), 6.50 (dd, J = 2.5, 1.9 Hz, 1H), 2.32 (d, J = 2.2 Hz, 3H), 1.21 (s, 3H), 0.88 (q, J = 3.7 Hz, 2H), 0.55 (q, J = 3.8 Hz, 2H). MS (ESI) m/z [M+H] ⁺ 292.2.

Example 28:

N -(2',3-Difluoro-4-methyl-5-(1 H Preparation of -pyrazol-4-yl)-[1,1'-biphenyl]-2-yl)-1-methylcyclopropane-1-carboxamide (Compound B451)

Step 1: Synthesis of 4-bromo-2-fluoro-6-iodo-3-methylaniline

To a solution of 2-fluoro-3-methylaniline (4.6 g, 36.76 mmol) in DMF (90 mL) was added NBS (6.6 g, 36.76 mmol) at 0°C and stirred at room temperature for 4 h. Then, NIS (10 g, 44.1 mmol) was added at 0°C and stirred at room temperature overnight. The mixture was diluted with water (200 mL) and extracted with EA (100 mL×2). The combined organic layers were concentrated in vacuo, and the residue was purified by flash chromatography on silica gel (EA/PE 0-5%) to give the title compound as a white solid (5 g, yield 37%). MS (ESI) m/z [M+H] ⁺ 330.0, 331.9 (Br).

Step 2: Synthesis of 5-bromo-2',3-difluoro-4-methyl-[1,1'-biphenyl]-2-amine

To a solution of 4-bromo-2-fluoro-6-iodo-3-methylaniline (3.7 g, 11.21 mmol) and (2-fluorophenyl)borandiol (1.6 g, 11.21 mmol) in dioxane/water = 4:1 (110 mL) was added K ₃ PO ₄ (4.76 g, 22.43 mmol), followed by Pd(dppf)Cl ₂ (821 mg, 1.12 mmol) under a N ₂ atmosphere. The mixture was stirred at 50 °C for 8 h, cooled, and filtered to remove the solid. The filtrate was concentrated under reduced pressure, and it was purified by flash chromatography (EA/PE 0-10%) to obtain the title compound as an off-white solid (2.5 g, yield 71%). MS (ESI) m/z [M+H] ⁺ 297.8, 299.9 (Br).

Step 3: N Synthesis of -(5-bromo-2',3-difluoro-4-methyl-[1,1'-biphenyl]-2-yl)-1-methylcyclopropane-1-carboxamide

To a solution of 4-bromo-2-fluoro-6-(2-fluorophenyl)-3-methylaniline (1.5 g, 5.03 mmol) in DCM (30 mL) was added DIPEA (1.3 g, 10.06 mmol), followed by 1-methylcyclopropane-1-carbonyl chloride (597 mg, 5.03 mmol) at 0°C. The mixture was stirred at room temperature for 3 h, concentrated, and purified by flash chromatography (EA/PE 0-30%) to give the title compound as a white solid (1.2 g, yield 59%). MS (ESI) m/z [M+H] ⁺ 379.7, 381.8 (Br).

Step 4: N -(2',3-Difluoro-4-methyl-5-(1 H Synthesis of -pyrazol-4-yl)-[1,1'-biphenyl]-2-yl)-1-methylcyclopropane-1-carboxamide (Compound B451)

To a solution of N- [4-bromo-2-fluoro-6-(2-fluorophenyl)-3-methylphenyl]-1-methylcyclopropane-1-carboxamide (100 mg, 0.26 mmol) and 1 H -pyrazol-4-ylboranediol (58.8 mg, 0.53 mmol) in THF/water = 5:1 (3 mL) was added K₃PO₄ (111.6 mg, 0.53 mmol), followed by Xphos-Pd-G3 (6.7 mg, 0.008 mmol) under N ₂ atmosphere. The mixture was stirred at 80 °C for 2 h, diluted with water, and extracted with EA (10 mL×3). The above mixed organic layer was concentrated and purified by silica gel column chromatography (PE/EA 0-60%) to obtain the title compound as a white solid (26 mg, yield 24%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.63 - 7.50 (m, 2H), 7.42 - 7.33 (m, 1H), 7.30 - 7.26 (m, 1H), 7.25 - 7.19 (m, 2H), 7.19 - 7.13 (m, 1H), 7.08 (s, 1H), 2.27 (d, J = 2.3 Hz, 3H), 1.11 (q, J = 3.8 Hz, 2H), 0.56 (q, J = 4.1 Hz, 2H). MS (ESI) m/z [M+H] ⁺ 367.8.

The following compounds ( B438 to B463 ) in Table 11 were synthesized in a similar manner to that described in Examples 27 and 28 using appropriate starting materials and corresponding intermediates.

General Method 11

Example 29:

N -5-(3-(1 H -pyrazol-3-yl)-1 H -pyrrole-2-yl)-1 H Preparation of -indol-4-yl)-1-(difluoromethyl)cyclopropane-1-carboxamide (Compound B465)

Step 1: 3rd class -Butyl 5-bromo-4-(1-(difluoromethyl)cyclopropane-1-carboxamido)-1 H -Synthesis of indole-1-carboxylate

To a solution of N- (5-bromo-1 H- indole-4-dlf)-1-(difluoromethyl)cyclopropanecarboxamide (6 g, 8.47 mmol), TEA (5.53 g, 54.69 mmol, 7.62 mL), and DMAP (222.71 mg, 8.47 mmol) in DCM (60 mL) was added Boc ₂ O (3.98 g, 18.23 mmol, 4.18 mL) at room temperature. The mixture was stirred at room temperature for 3 h, concentrated, and the residue was purified by silica gel chromatography (EA in PE 0-30%) to give the title compound as a white solid (6.8 g, yield 86.90%). ^1H NMR (400 MHz, DMSO _- d6 ) δ 9.54 (s, 1H), 7.92 (d, J = 8.8 Hz, 1H), 7.70 (d, J = 3.8 Hz, 1H), 7.58 (d, J = 8.8 Hz, 1H), 6.79 - 6.47 (m, 1H), 6.46 (dd, J = 3.8, 0.8 Hz, 1H), 1.63 (s, 9H), 1.42 (dd, J = 4.9, 2.0 Hz, 2H), 1.22 - 1.16 (m, 2H). MS (ESI) m/z [M+H] ⁺ 429.1.

Step 2: 3rd class -Butyl 5-(4-(( 3rd class -butoxycarbonyl)amino)but-1-yn-1-yl)-4-(1-(difluoromethyl)cyclopropane-1-carboxamido)-1 H -Synthesis of indole-1-carboxylate

To a mixture of tert- butyl 5-bromo-4-[[1-(difluoromethyl)cyclopropanecarbonyl]amino]indole-1-carboxylate (6.8 g, 15.84 mmol), tert -butyl N -but-3-ynylcarbamate (8.04 g, 47.52 mmol), CuI (603.40 mg, 3.17 mmol), LiCl (3.36 g, 79.2 mmol), and Pd(PPh ₃ ) ₂ Cl ₂ (1.11 g, 1.58 μmol) in DMF (40 mL) was added TEA (8.01 g, 79.21 mmol, 11.04 mL) at room temperature under a nitrogen atmosphere. The mixture was stirred at 80 °C for 4 h, cooled, and diluted with water (40 mL). The aqueous phase was extracted twice with EA (80 mL). The mixed organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated to obtain a residue, which was purified by silica gel column chromatography (EA in PE 0-20%) to obtain the title compound as a solid (7.4 g, yield 90.26%). ^1H NMR (400 MHz, DMSO _-d6 ) δ 9.39 (s, 1H), 7.93 (d, J = 8.6 Hz, 1H), 7.66 (d, J = 3.8 Hz, 1H), 7.37 (d, J = 8.6 Hz, 1H), 6.98 (dt, J = 15.6, 6.0 Hz, 1H), 6.78 - 6.46 (m, 1H), 6.43 (d, J = 3.7 Hz, 1H), 3.18 (q, J = 6.8 Hz, 2H), 2.53 (t, J = 7.0 Hz, 2H), 1.63 (s, 9H), 1.38 (s, 11H), 1.18 (dq, J = 5.0, 2.5 Hz, 2H). MS (ESI) m/z [M+H] ⁺ 518.2.

Step 3: 3rd class -Butyl 5-(1-( 3rd class -butoxycarbonyl)-3-iodo-4,5-dihydro-1 H -pyrrol-2-yl)-4-(1-(difluoromethyl)cyclopropane-1-carboxamido)-1 H -Synthesis of indole-1-carboxylate

To a mixture of tert-butyl 5- [4-( tert -butoxycarbonylamino)but-1-ynyl]-4-[[1-(difluoromethyl)cyclopropanecarbonyl]amino]indole-1-carboxylate (2.5 g, 4.83 mmol) and K ₂ CO ₃ (2.00 g, 14.49 mmol) in acetonitrile (250 mL) was added iodine (1.85 g, 14.49 mmol) under a nitrogen atmosphere at room temperature. The mixture was stirred at room temperature for 2 h and then filtered to remove the solid. The filtrate was concentrated and purified by silica gel chromatography (EA in PE 0-30%) to give the title compound as a solid (1.5 g, yield 48.26%). ^1H NMR (400 MHz, DMSO _-d6 ) δ 8.56 (d, J = 2.6 Hz, 1H), 7.95 (dd, J = 8.6, 3.4 Hz, 1H), 7.64 (d, J = 3.7 Hz, 1H), 7.12 (dd, J = 8.4, 3.4 Hz, 1H), 6.45 (d, J = 3.8 Hz, 1H), 6.40 - 6.07 (m, 1H), 4.01 - 3.77 (m, 2H), 2.88 (m, 7.3 Hz, 2H), 1.64 (d, J = 3.3 Hz, 10H), 1.37 (d, J = 3.6 Hz, 2H), 1.28 (q, J = 3.5 Hz, 2H), 0.99 (s, 9H). MS (ESI) m/z [M+H] ⁺ 644.1.

Step 5: 3rd class -Butyl 5-(1-( 3rd class -butoxycarbonyl)-3-iodo-1 H -pyrrol-2-yl)-4-(1-(difluoromethyl)cyclopropane-1-carboxamido)-1 H -Synthesis of indole-1-carboxylate

To a solution of tert -butyl 5-(1 -tert -butoxycarbonyl-4-iodo-2,3-dihydropyrrol-5-yl)-4-[[1-(difluoromethyl)cyclopropanecarbonyl]amino]indole-1-carboxylate (1.5 g, 2.33 mmol) in DCM (30 mL) was added MnO ₂ (6.08 g, 69.93 mmol) at room temperature, and the mixture was stirred at 50°C for 16 h, filtered through a celite bed, and concentrated to obtain the title compound (1.4 g, yield 93.63%) as a solid. ^1H NMR (400 MHz, DMSO _-d6 ) δ 8.61 (d, J = 2.2 Hz, 1H), 7.99 (d, J = 8.5 Hz, 1H), 7.67 (d, J = 3.7 Hz, 1H), 7.41 (d, J = 3.4 Hz, 1H), 7.15 (dd, J = 8.5, 1.9 Hz, 1H), 6.48 (dd, J = 6.2, 3.6 Hz, 2H), 6.38 - 6.03 (m, 1H), 1.65 (d, J = 1.9 Hz, 9H), 1.36 (d, J = 2.0 Hz, 1H), 1.15 (d, J = 2.0 Hz, 9H), 1.13 - 0.92 (m, 4H). MS (ESI) m/z [M+Na] ⁺ 664.1.

Step 6: 3rd class -Butyl 5-(1-( 3rd class -butoxycarbonyl)-3-(1 H -pyrazol-3-yl)-1 H -pyrrol-2-yl)-4-(1-(difluoromethyl)cyclopropane-1-carboxamido)-1 H -Synthesis of indole-1-carboxylate

To a mixture of tert -butyl 5-(1 -tert -butoxycarbonyl-3-iodo-pyrrol-2-yl)-4-[[1-(difluoromethyl)cyclopropanecarbonyl]amino]indole-1-carboxylate (100 mg, 0.16 mmol), (1 -tert -butoxycarbonylpyrazol-3-yl)boronic acid (102 mg, 0.48 mmol), and Na ₂ CO ₃ (84.8 mg, 0.8 mmol) in a mixed solution of water/ethanol/toluene (1/2/2, 15 mL) was added Pd(PPh ₃ ) ₄ (50 mg, 32 μmol) at room temperature under a nitrogen atmosphere. The mixture was stirred at 100 °C for 8 h, cooled, and diluted with water (20 mL). The aqueous phase was extracted twice with EA (40 mL), the combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to obtain a residue, which was purified by silica gel column chromatography (EA in PE 0-80%) to obtain the title compound as a gray solid (60 mg, yield 55.0%). ^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.96 - 12.56 (m, 1H), 8.97 - 8.47 (m, 1H), 7.96 (d, J = 8.5 Hz, 1H), 7.74 - 7.33 (m, 3H), 7.13 (d, J = 8.5) Hz, 1H), 6.68 (s, 1H), 6.46 (d, J = 3.6 Hz, 1H), 6.32 - 6.03 (m, 1H), 5.63 - 5.06 (m, 1H), 1.64 (s, 9H), 1.17 (s, 9H), 1.08 - 0.91 (m, 4H). MS (ESI) m/z [M+H] ⁺ 582.2.

Step 7: N -5-(3-(1 H -pyrazol-3-yl)-1 H -pyrrole-2-yl)-1 H Synthesis of -indol-4-yl)-1-(difluoromethyl)cyclopropane-1-carboxamide (Compound B465)

To a solution of tert- butyl 5-[1 -tert -butoxycarbonyl-3-(1 H -pyrazol-3-yl)pyrrol-2-yl]-4-[[1-(difluoromethyl)cyclopropanecarbonyl]amino]indole-1-carboxylate (60 mg, 0.088 mmol) in THF (8 mL) was added MeONa (47.5 mg, 0.264 mmol, 30% w/w in methanol) at room temperature. The mixture was stirred at room temperature for 1 h, diluted with water, and extracted with EA. The combined organic layers were concentrated to obtain a residue, which was purified by C18 flash chromatography (0-30% acetonitrile in water) to give the title compound as a white solid (26 mg, yield 77.5%). ^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.89 - 12.25 (m, 1H), 11.16 (s, 1H), 10.78 (s, 1H), 10.20 (s, 1H), 7.81 - 7.09 (m, 3H), 7.00 (d, J = 8.3 Hz, 1H), 6.81 (t, J = 2.8 Hz, 1H), 6.62 - 5.30 (m, 4H), 0.96 (d, J = 2.5 Hz, 4H). MS (ESI) m/z [M+H] ⁺ 382.2

The following compounds ( B464 to B484 ) in Table 12 were synthesized in a similar manner to that described in Example 29 using appropriate starting materials and corresponding intermediates.

Example C

General Method 12

Example 30:

N Preparation of -(2'-fluoro-4-methyl-[1,1'-biphenyl]-2-yl)pyridin-3-amine (Compound C4)

Step 1: Synthesis of 2-(2-fluorophenyl)-5-methyl-aniline

A mixture of 2-bromo-5-methyl-aniline (2 g, 10.75 mmol), Pd(dppf)Cl ₂ (786.57 mg, 1.07 mmol), (2-fluorophenyl)boronic acid (1.50 g, 10.75 mmol), and K ₃ PO ₄ (4.56 g, 21.50 mmol) in dioxane (4 mL) and water (1 mL) was stirred at 80°C for 2 h. The resulting mixture was diluted with water (50 mL) and extracted with EA (50 mL×3). The organic layer was concentrated in vacuo, and the residue was purified by column chromatography on silica gel (EA/PE 0-30%) to give the title compound as a white solid (2 g, yield 92.45%).

Step 2: N - Synthesis of [2-(2-fluorophenyl)-5-methyl-phenyl] pyridin-3-amine (C4 compound)

A mixture of 2-(2-fluorophenyl)-5-methyl-aniline (50 mg, 248.46 μmol), 3-bromopyridine (39.26 mg, 248.46 μmol), BINAP (30.94 mg, 49.69 μmol), t -BuONa (47.76 mg, 496.92 μmol), and Pd ₂ (dba) ₃ (22.75 mg, 24.85 μmol) in toluene was stirred at 100°C for 2 h. The resulting mixture was diluted with water (50 mL) and extracted with EA (50 mL×3). The combined organic layers were concentrated in vacuo, and the residue was purified with C18-prep-HPL (0-90% ACN in water) to obtain the title compound as a white solid (4 mg, yield 5.78%). ^1H NMR (400 MHz, DMSO _-d6 ) δ 8.09 (d, J = 2.4 Hz, 1H), 7.85 (dd, J = 4.4, 1.6 Hz, 1H), 7.50 (s, 1H), 7.35 - 7.28 (m, 2H), 7.22 - 7.01 (m, 6H), 6.97 (d, J = 7.6 Hz, 1H), 2.31 (s, 3H). MS (ESI) m/z [M+H] ⁺ 279.1.

Example 31:

N Preparation of -(2'-fluoro-4-methyl-[1,1'-biphenyl]-2-yl)pyridin-3-amine (Compound C11)

Step 1: Synthesis of 2'-fluoro-4-methyl-[1,1'-biphenyl]-2-carbohydrazide

A solution of methyl 2-(2-fluorophenyl)-5-methylbenzoate (500 mg, 2.04 mmol) in hydrazine hydrate (10 mL) was stirred at 120°C for 1 h, then cooled and diluted with water (20 mL). Extracted with DCM (20 mL × 2), the combined organic layers were concentrated in vacuo, and the residue was purified by flash chromatography on silica gel (EA/PE 0-50%) to give the title compound as a white solid (130 mg, yield 24.7%). MS (ESI) m/z [M+H] ⁺ 244.9.

Step 2: Synthesis of 2-(2'-fluoro-4-methyl-[1,1'-biphenyl]-2-yl)-5-(furan-3-yl)-1,3,4-oxadiazole (Compound C11)

To a mixture of 2-(2-fluorophenyl)-5-methylbenzohydrazide (100 mg, 0.41 mmol) and furan-3-carboxylic acid (46 mg, 0.41 mmol) in MeCN (2 mL) were added DIPEA (159 mg, 1.23 mmol) and TBTU (145 mg, 0.45 mmol). The mixture was stirred at room temperature overnight, then DIPEA (106 mg, 0.82 mmol) and TsCl (234 mg, 1.23 mmol) were added, and the reaction was stirred at room temperature for an additional 4 h. The resulting mixture was concentrated and purified by Prep-TLC (PE/EA = 3/1) to give the title compound (24 mg, yield 17%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.10 (s, 1H), 7.61 (s, 1H), 7.46 (t, J = 1.7 Hz, 1H), 7.45 - 7.37 (m, 2H), 7.34 (d, J = 7.8 Hz, 1H), 7.32 - 7.27 (m, 1H), 7.25 - 7.19 (m, 1H), 7.11 (t, J = 9.1 Hz, 1H), 6.67 (d, J = 1.4 Hz, 1H), 2.50 (s, 3H). MS (ESI) m/z [M+H] ⁺ 320.8.

Example 32:

4-( 3rd class -Butyl)-1-(2'-fluoro-4-methyl-[1,1'-biphenyl]-2-yl)-1 H Preparation of -1,2,3-triazole (compound C20)

Step 1: Synthesis of 2-azido-1-iodo-4-methylbenzene

2-Iodo-5-methylaniline (500 mg, 2.15 mmol) was dissolved in THF (10 mL) to a solution of tert-butyl nitrite (332 mg, 3.22 mmol) at 0°C. After stirring for 30 minutes, TMSN ₃ (371 mg, 3.22 mmol) was added and the mixture was stirred at room temperature for another 1.5 hours. The reaction was quenched with water (20 mL) and extracted with EA (20 mL × 2). The combined organic layers were concentrated in vacuo, and the residue was purified by flash chromatography (EA/PE 0-3%) to give the title compound as a yellow solid (500 mg, yield 85%).

Step 2: 4-( 3rd class -butyl)-1-(2-iodo-5-methylphenyl)-1 H -Synthesis of 1,2,3-triazole

To a mixture of 2-azido-1-iodo-4-methylbenzene (900 mg, 3.47 mmol) and 3,3-dimethylbut-1-yne (285 mg, 3.47 mmol) in t-BuOH/water = 1:1 (10 mL) were added CuSO ₄ -5H ₂ O (17 mg, 0.069 mmol) and L-ascorbic acid sodium salt (132 mg, 0.869 mmol). The mixture was stirred overnight at 65 °C in a sealed tube, cooled, and diluted with water (10 mL). After extraction with EA (10 mL × 2), the combined organic layers were concentrated and purified by prep-TLC (PE/EA = 9/1) to obtain the title compound as a brown solid (500 mg, yield 40%). MS (ESI) m/z [M+H] ⁺ 342.0.

Step 3: 4-( 3rd class -Butyl)-1-(2'-fluoro-4-methyl-[1,1'-biphenyl]-2-yl)-1 H -Synthesis of 1,2,3-triazole (compound C20)

4- Tert -butyl-1-(2-iodo-5-methylphenyl)-1,2,3-triazole (100 mg, 0.29 mmol) and (2-fluorophenyl)borandiol (49 mg, 0.35 mmol) were dissolved in dioxane/water=4:1 (5 mL). Cs ₂ CO ₃ (191 mg, 0.586 mmol) and Pd(dppf)Cl ₂ (21 mg, 0.029 mmol) were added under N ₂ atmosphere, and the mixture was stirred at 90°C for 8 hours. The resulting mixture was concentrated and purified by flash chromatography (EA/PE 0-10%) to obtain the title compound as a yellow oil (23 mg, yield 25%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.55 - 7.50 (m, 1H), 7.42 - 7.34 (m, 2H), 7.30 - 7.26 (m, 1H), 7.08 - 6.97 (m, 3H), 6.93 (s, 1H), 2.47 (s, 3H), 1.22 (s, 9H). MS (ESI) m/z [M+H] ⁺ 309.9.

Example 33:

Preparation of 4-(3,4-dimethyl-2-(4-methyl-1H-imidazol-2-yl)phenyl)thiazole (Compound C25)

Step 1: Synthesis of 6-bromo-2,3-dimethylbenzaldehyde

To a solution of 2,3-dimethylbenzaldehyde (54 mg, 0.40 mmol) in DCE/TFA=5:1 (3 mL) were added NBS (86 mg, 0.48 mmol), 2-amino-5-chlorobenzotrifluoride (16 mg, 0.08 mmol), and Pd(OAc) ₂ (9 mg, 0.04 mmol) under a N ₂ atmosphere. The mixture was stirred at 60°C for 24 h, diluted with water (20 mL), and extracted with EA (20 mL × 3). The combined organic layers were concentrated under reduced pressure, and the residue was purified by flash chromatography (EA/PE 0-25%) to obtain the title compound as a brown solid (50 mg, yield 55.38%). ^1H NMR (400 MHz, CDCl ₃ ) δ 10.49 (s, 1H), 7.39 (d, J = 8.1 Hz, 1H), 7.16 (d, J = 8.1 Hz, 1H), 2.46 (s, 3H), 2.28 (s, 3H).

Step 2: 2-(6-bromo-2,3-dimethylphenyl)-4-methyl-1 H -Synthesis of imidazole

To a solution of 6-bromo-2,3-dimethylbenzaldehyde (70 mg, 0.33 mmol) in methanol (1 mL) were added (NH ₄ ) ₂ CO ₃ (32 mg, 0.33 mmol) and methylglyoxal (95 mg, 1.31 mmol) under an N ₂ atmosphere. The mixture was stirred at 35°C for 16 h, diluted with water (20 mL), and extracted with EA (20 mL × 3). The combined organic layers were concentrated under reduced pressure, and the residue was purified by flash chromatography (EA/PE 0-25%) to obtain the title compound as a white solid (10 mg, yield 10.9%). MS (ESI) m/z [M+H] ⁺ 264.8, 266.8 (Br).

Step 3: Synthesis of 4-[3,4-dimethyl-2-(4-methyl-1H-imidazol-2-yl)phenyl]-1,3-thiazole (Compound C25)

To a solution of 2-(6-bromo-2,3-dimethylphenyl)-4-methyl-1H-imidazole (20 mg, 0.08 mmol) in toluene (1 mL) was added 4-(tributylstannyl)thiazole (56 mg, 0.15 mmol), LiCl (5 mg, 0.11 mmol), and Pd(PPh ₃ ) ₄ (9 mg, 0.01 mmol) under _a N 2 atmosphere. The mixture was stirred at 110 °C for 16 h, cooled, and diluted with water (20 mL). After extraction with EA (20 mL × 3), the combined organic layers were concentrated and purified by flash chromatography (EA/PE 0-25%) to obtain the title compound as a brown oil (5 mg, yield 23.3%). ^1H NMR (400 MHz, CDCl ₃ ) δ 8.67 (s, 1H), 7.37 - 7.27 (m, 3H), 6.88 (s, 1H), 2.32 (s, 3H), 2.26 (s, 3H), 2.04 (s, 3H). MS (ESI) m/z [M+H] ⁺ 269.9.

The following compounds ( C1~C30 ) in Table 13 were synthesized using appropriate starting materials and corresponding intermediates in a similar manner to that described in Examples 30~33 .

Biological analysis

Biological Example 1. The compounds disclosed herein are potent inhibitors of ALPK1 in cellular assays.

The compounds disclosed herein inhibit ALPK1 kinase activity in 293T cells, as confirmed by an NF-κB luciferase reporter assay. For this NF-κB luciferase assay, 293T cells were transfected with the plasmid (pNL2.2-BII-5RE-Luc) and the control vector (pRL-TK) using Jetprime reagent (Polyplus). NF-κB luciferase activity was measured using a dual luciferase assay kit (Promega) according to the manufacturer's instructions.

The IC ₅₀ values of the compounds disclosed herein were measured using the 293T cells described above using an NF-κB luciferase reporter assay. Briefly, 16 hours after transfection of 293T cells with the NF-κB luciferase plasmid (pNL2.2-BII-5RE-Luc) and the control vector (pRL-TK), the indicated compounds were serially diluted and added to the culture medium of 293T cells together with an ALPK1 activator, an analog of ADP-heptose. After 8 hours, the cells were lysed, and NF-κB luciferase activity was measured using a dual luciferase assay kit (Promega) according to the manufacturer's instructions. As a result, the compounds provided herein exhibited activity for the inhibition of ALPK1. Therefore, in consideration of the foregoing, the chemical entities of the present disclosure exhibit antagonistic activity against ALPK1. These chemicals exhibit potent inhibitory activity against the immune regulator NF-κB, which is activated by the ALPK1-TIFA axis.

Biological Example 2. The compounds disclosed herein are potent inhibitors of ALPK1 in an in vitro kinase cell assay.

The compounds disclosed herein inhibit ALPK1 kinase activity in vitro, as confirmed using an ADP-Glo kinase assay kit (Promega). Purified full-length (FL) or ALPK1-(N K) (a complex of the ALPK1 N-terminal domain and the ALPK1 kinase domain) proteins were activated by ADP-heptose. In this kinase reaction system, TIFA was used as a phosphorylation substrate. The compounds disclosed herein were added to this kinase reaction system, and inhibitory activity was measured using an ADP-Glo kinase assay kit (Promega) according to the manufacturer's instructions.

To determine the IC ₅₀ of the compounds disclosed herein, an in vitro ALPK1 kinase assay was developed. Briefly, serially diluted compounds were dispensed into 384-well assay plates. FL or ALPK1-(NK) was then added and incubated with the compounds. ATP, ADP-heptose, and TIFA were added to the plates to initiate the kinase reaction. After 1 hour, the reaction was terminated, and the consumed ATP was measured using an ADP-Glo kinase assay kit (Promega) according to the manufacturer's instructions. As a result, the compounds provided herein exhibited activity for the inhibition of ALPK1. Therefore, considering the foregoing, the chemical entities of the present disclosure exhibit antagonistic activity against ALPK1.

Claims (116)

A compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof:

In the above chemical formula,
M ₁ is selected from CR ₁ and N;
M ₂ is selected from CR ₂ and N;
M ₃ is selected from CR ₃ and N;
M ₄ is selected from CR ₄ and N;
L is selected from chemical bonds, -O-, -S-, and -NH-;
Y is -C(O)-, -C(S)-, -C(N-OH)-, -S(O)-, -S(O) ₂ - and is selected from;
Z is -C(R _2s )(R _3s )- or -N(R _2s )-;
Ring A is selected from C _3-6 cycloalkyl, 4-6 membered heterocyclyl, phenyl and 5-10 membered heteroaryl, preferably phenyl or 5-9 membered heteroaryl;
At this time, R _a is selected from H, D, halo, oxo, CN, NO ₂ , NH ₂ , -C _0-6 alkylene-OH, -C(O)OR _x , -C(O)NR _{y R z ,} -S ₍ O)NR _y R _z , -S(O) ₂ NR y R z , C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, C _2-6 haloalkynyl, C _3-6 cycloalkyl, 4-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl and amino protecting group, which is optionally substituted with 1, 2 or 3 halo, oxo, OR _x , NR _y R _z , C _1-6 alkyl or C _1-6 haloalkyl. m=0, 1, 2, 3, 4 or 5; or two adjacent _{R a} form phenyl or a 5- to 6-membered heteroaryl together with the atoms to which they are connected;
R ₁ is selected from H, D, halo, CN, OR _x , NR _y R _z , C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxyl, C _1-6 haloalkoxyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, C _2-6 haloalkynyl, C _3-8 cycloalkyl and 4- to 10-membered heterocyclyl;
R ₂ is selected from H, D, halo, CN, -C _0-6 alkylene-OH, -C _0-6 alkylene-NH ₂ , -C(O)C _1-6 alkyl, -C(O)C _1-6 haloalkyl, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxyl, C _1-6 haloalkoxyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, C _2-6 haloalkynyl, -TC _3-8 cycloalkyl, -T-4 to 10 membered heterocyclyl, -TC _6-10 aryl and -T-5 to 10 membered heteroaryl, which is optionally selected from 1, 2, 3, 4 or 5 CN, halo, oxo, -C _1-6 alkylene-OH, C Substituted with _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl or 5-6 membered heterocyclyl;
Here, T is a chemical bond, -O-, -S- or -NH-;
R ₃ is selected from H, D, halo, CN, -C _0-6 alkylene-OH, -C _0-6 alkylene-NH ₂ , C _1-6 alkyl and C _1-6 haloalkyl;
R ₄ is selected from H, D, halo, C _1-6 alkyl and C _1-6 haloalkyl;
Alternatively, R ₁ and R ₂ together with the carbon atoms to which they are connected form C _5-6 cycloalkyl, 5-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, which is optionally substituted with 1, 2 or 3 halo, CN, C _1-6 alkyl, C _1-6 haloalkyl, -C(O)H, -C(O)C _1-6 alkyl, -C(O)C _1-6 haloalkyl, C 2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, C _2-6 haloalkynyl or C _2-6 alkynyl-substituted phenyl _;
Alternatively, R ₂ and R ₃ together with the carbon atoms to which they are connected form C _5-6 cycloalkyl, 5-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, which are optionally substituted with 1, 2, 3 or 4 halo, C _1-6 alkyl, C _1-6 haloalkyl, -C _1-6 alkylene-C _1-6 alkoxyl, -C _{1-6 alkylene-C 1-6 haloalkoxyl} , -C(O)C _1-6 alkyl or -C(O)C _1-6 haloalkyl;
R _1s is selected from H, D, -C _0-6 alkylene-OR _x , -C _0-6 alkylene-NR _y R _z , C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _{2-6 alkynyl, C 2-6 haloalkynyl} , C _3-6 cycloalkyl and phenyl;
R _2s is selected from H, D, C _1-6 alkyl, C _1-6 haloalkyl and C(R _2s1 )(R _2s2 )(R _2s3 );
At this time, R _2s1 is selected from H, D, -C _0-6 alkylene-OR _x , -C _0-6 alkylene-NR _y R _z , C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, C _2-6 haloalkynyl and C _3-6 cycloalkyl;
R _2s2 is selected from H, D, -C _0-6 alkylene-OH, C _1-6 alkyl and C _1-6 haloalkyl;
R _2s3 is C _1-6 alkyl or C _1-6 haloalkyl;
Alternatively, R _2s1 and R _2s2 together with the carbon atoms to which they are connected form a C _3-6 cycloalkyl;
Alternatively, R _2s2 and R _2s3 together with the atoms to which they are connected form a C _3-6 cycloalkyl or a 4- to 6-membered heterocyclyl, which is optionally substituted with 1 or 2 halo;
Alternatively, R _2s1 , R _2s2 and R _2s3 together with the atoms to which they are connected form a C _4-8 bridged bicycloalkyl (optionally substituted with 1 or 2 halo, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl and C _2-6 haloalkynyl), or a 4- to 8-membered bridged heterocyclyl;
or R _1s and R _2s3 are linked to form C _2-6 alkylene, which is optionally substituted with 1, 2 or 3 halo, OR _x , NR _y R _z , C _1-6 alkyl or C _1-6 haloalkyl;
R _3s is selected from H, D, C _1-6 alkyl and C _1-6 haloalkyl;
Alternatively, R _2s and R _3s together with the carbon atoms to which they are connected form a C _3-6 cycloalkyl or a 4- to 6-membered heterocyclyl, which is optionally substituted with 1 or 2 halo, C _1-6 alkyl or C _1-6 haloalkyl;
Alternatively, R _1s and R _2s together with the nitrogen atom to which they are connected form a 4- to 6-membered heterocyclyl, which is optionally substituted with 1 or 2 halo, C _1-6 alkyl or C _1-6 haloalkyl;
Alternatively, R _1s , R _2s and R _3s together with the carbon atoms to which they are connected form a C _4-8 bridged bicycloalkyl (which is optionally substituted with 1 or 2 halo, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl and C _2-6 haloalkynyl), or to form;
At this time, Y ₁ is CR ₁₁ or N;
Y ₂ is CR ₁₂ or N;
R ₁₁ and R ₁₃ are independently selected from H, D, C _1-6 alkyl and C _1-6 haloalkyl;
R ₁₂ is selected from H and D;
R _x , R _y and R _z are independently selected from H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, C _2-6 haloalkynyl, C _3-8 cycloalkyl and 4- to 6-membered heterocyclyl; or R _y and R _z together with the nitrogen atom to which they are connected form a 4- to 6-membered heterocyclyl;
The above-mentioned atoms may be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated. A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein M ₁ is CR ₁ in claim 1. A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein M ₂ is CR ₂ in claim 1 or 2. A compound according to any one of claims 1 to 3, wherein M ₃ is CR ₃ , or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof. A compound according to any one of claims 1 to 4, wherein M ₄ is CR ₄ , or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof. A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein L is a chemical bond according to any one of claims 1 to 5. A compound according to any one of claims 1 to 5, wherein L is -NH-, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof. A compound according to any one of claims 1 to 7, wherein Y is -C(O)-, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof. A compound according to any one of claims 1 to 8, wherein Z is -C(R _2s )(R _3s )-, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof. A compound according to any one of claims 1 to 8, wherein Z is -N(R _2s )-, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof. A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotopic variant, prodrug or crystalline form thereof, wherein ring A is selected from phenyl and 5- to 9 _- membered heteroaryl; wherein R _a is selected from H, D, halo, NO ₂ , NH ₂ , -C _1-6 alkylene-OH, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C 2-6 alkynyl, C _2-6 haloalkynyl and an amino protecting group, and m=0, 1, 2, 3, 4 or 5; or two adjacent R _a form phenyl or 5- to 6-membered heteroaryl together with the atoms to which they are connected. A compound or a pharmaceutically _{acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, according to any one of claims 1 to 11, wherein R 1 is selected from H, D, halo, C 1-6 alkyl , C 1-6} haloalkyl, C _1-6 alkoxyl, C _1-6 haloalkoxyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, C 2-6 haloalkynyl, C 3-8 cycloalkyl and 4- to 10-membered heterocyclyl. A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, or stable compound thereof, wherein R ₂ is selected from H, D, halo, -C _0-6 alkylene-OH, NH ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxyl, C _1-6 haloalkoxyl, -TC _5-6 cycloalkyl, -T-5 to 10 membered heterocyclyl, -TC _6-10 aryl, and -T-5 to 10 membered heteroaryl, which is optionally substituted with 1, 2, 3, 4, or 5 of CN, halo, oxo, -C _1-6 alkylene-OH, C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl, or 5 to 6 membered heterocyclyl. Isotope variants, prodrugs or crystalline forms. A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, according to any one of claims 1 to 13, wherein R ₃ is selected from H, D, halo, OH, C _1-6 alkyl and C _1-6 haloalkyl. A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, according to any one of claims 1 to 14, wherein R ₄ is selected from H, D, halo, C _1-6 alkyl and C _1-6 haloalkyl. A compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotopic variant, prodrug or crystalline form thereof, wherein R ₁ and R ₂ together with the carbon atoms to which they are connected form a 5- to 6-membered heterocyclyl, phenyl or 5- to 6-membered heteroaryl. A compound according to any one of claims 1 to 16, wherein R ₂ and R ₃ together with the carbon atoms to which they are connected form a 5- to 7-membered heterocyclyl, which is optionally substituted with 1, 2, 3 or 4 halo, C _1-6 alkyl, C _1-6 haloalkyl, -C _1-6 alkylene-C _1-6 alkoxyl or -C _1-6 alkylene-C _1-6 haloalkoxyl, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotopic variant, prodrug or crystalline form thereof. A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, _stable isotope variant, prodrug or crystalline form thereof, according to any one of claims 1 to 17, wherein R _1s is selected from H, D, OH, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C 2-6 alkynyl, and C _2-6 haloalkynyl. A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, according to any one of claims 1 to 18, wherein R _2s is selected from H, D, C _1-6 alkyl and C _1-6 haloalkyl. A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein R _2s is C(R _2s1 )(R _2s2 )(R _2s3 ), and R _2s1 is selected from H, D, -C _0-6 alkylene _- OH, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, C 2-6 haloalkynyl and C _3-6 cycloalkyl. A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein R _2s is C(R _2s1 )(R _2s2 )(R _2s3 ), and R _2s2 is selected from H, D, -C _1-4 alkylene-OH, C _1-4 alkyl, and C _1-4 haloalkyl. A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein R _2s is C(R _2s1 )(R _2s2 )(R _2s3 ), and R _2s3 is C _1-6 alkyl, or C _1-6 haloalkyl, according to any one of claims 1 to 21. A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, according to any one of claims 1 to 22, wherein R _2s is C(R _2s1 )(R _2s2 )(R _2s3 ), and R _2s2 and R _2s3 together with the carbon atom to which they are connected form C _3-6 cycloalkyl. A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, according to any one of claims 1 to 23, wherein R _2s is C(R _2s1 )(R _2s2 )(R _2s3 ), and R _2s1 and R _2s2 together with the carbon atom to which they are connected form C _3-6 cycloalkyl. A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein in any one of claims 1 to 24, R _2s is C(R _2s1 )(R _2s2 )(R _2s3 ), and R _1s and R _2s3 together with the carbon atom to which they are connected form a 4- to 7-membered heterocyclyl, which is optionally substituted with 1 or 2 halo. A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, according to any one of claims 1 to 25, wherein R _3s is selected from H, D, C _1-6 alkyl and C _1-6 haloalkyl. A compound according to any one of claims 1 to 26, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein R _2s and R _3s together with the carbon atoms to which they are connected form a C _3-6 cycloalkyl, which is optionally substituted with one or two halo, C _1-6 alkyl or C _1-6 haloalkyl. A compound according to any one of claims 1 to 27, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotopic variant, prodrug or crystalline form thereof, wherein R _2s1 , R _2s2 and R _2s3 together with the carbon atoms to which they are connected form _a C _4-8 bridged bicycloalkyl, which is optionally substituted with one or two halo, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C 2-6 alkynyl and C _2-6 haloalkynyl. A compound according to any one of claims 1 to 28, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein R _1s , R _2s and R _3s together with the carbon atoms to which they are connected form a C _4-8 bridged bicycloalkyl. A compound according to any one of claims 1 to 29, wherein the compound has a chemical formula selected from the following, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug, or crystalline form thereof:

and
In the above equations, the variables are as defined in any one of the first to 29th clauses. In claim 30, a compound of formula (II), or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof:

In the above chemical formula,
M ₁ is selected from CR ₁ and N, preferably CR ₁ ;
M ₂ is selected from CR ₂ and N, preferably CR ₂ ;
M ₃ is selected from CR ₃ and N, preferably CR ₃ ;
M ₄ is selected from CR ₄ and N, preferably CR ₄ ;
Y is selected from -C(O)-, -C(S)-, -C(N-OH)-, -S(O)-, and -S(O) ₂ -;
Ring A is selected from phenyl and 5- to 9-membered heteroaryl;
wherein R _a is selected from H, D, halo, NO ₂ , NH ₂ , -C _1-6 alkylene-OH, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, C _2-6 haloalkynyl and amino protecting group, and m=0, 1, 2, 3, 4 or 5; or two adjacent R _a together with the atoms to which they are connected form phenyl or a 5- to 6-membered heteroaryl;
R ₁ and R ₄ are independently selected from H, D and halo;
R ₂ is selected from H, D, halo, -C _0-6 alkylene-OH, NH ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxyl, C _1-6 haloalkoxyl, -T C _5-6 cycloalkyl, -T-5 to 10 membered heterocyclyl, -T C _6-10 aryl and -T-5 to 10 membered heteroaryl, which is optionally substituted with 1, 2, 3, 4 or 5 CN, halo, oxo, -C _1-6 alkylene-OH, C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl or 5 to 6 membered heterocyclyl;
Here, T is a chemical bond, -O-, -S- or -NH-;
R ₃ is selected from H, D, halo, CN, -C _0-6 alkylene-OH, -C _0-6 alkylene-NH ₂ , C _1-6 alkyl and C _1-6 haloalkyl;
Alternatively, R ₁ and R ₂ together with the carbon atoms to which they are connected form a 5- to 6-membered heterocyclyl, phenyl or a 5- to 6-membered heteroaryl;
Alternatively, R ₂ and R ₃ together with the carbon atoms to which they are connected form a 5-6 membered heterocyclyl, which is optionally substituted with 1, 2, 3 or 4 halo, C _1-6 alkyl, C _1-6 haloalkyl, -C(O)C _1-6 alkyl, or -C(O)C _1-6 haloalkyl;
R _1s is selected from H, D, -C _0-6 alkylene-OH, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, and C _2-6 haloalkynyl;
R _2s is selected from H, D, C _1-6 alkyl and C _1-6 haloalkyl;
R _3s is selected from C _1-6 alkyl and C _1-6 haloalkyl;
Alternatively, R _2s and R _3s together with the carbon atoms to which they are connected form a C _3-6 cycloalkyl, which is optionally substituted with 1 or 2 halo, C _1-6 alkyl or C _1-6 haloalkyl;
Alternatively, R _1s , R _2s and R _3s together with the carbon atoms to which they are connected form a C _4-8 bridged bicycloalkyl;
The above-mentioned atoms may be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated. In Article 31,
M ₁ is selected from CR ₁ and N, preferably CR ₁ ;
M ₂ is selected from CR ₂ and N, preferably CR ₂ ;
M ₃ is selected from CR ₃ and N, preferably CR ₃ ;
M ₄ is selected from CR ₄ and N, preferably CR ₄ ;
Y is selected from -C(O)-, -C(S)-, -C(N-OH)-, -S(O)-, and -S(O) ₂ -;
Ring A is
and is selected from;
wherein R _a is selected from H, D, halo, NO ₂ , NH ₂ , -C _1-6 alkylene-OH, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, C _2-6 haloalkynyl and amino protecting group, and m=0, 1, 2, 3, 4 or 5; or two adjacent R _a together with the atoms to which they are connected form phenyl or a 5- to 6-membered heteroaryl;
R ₁ and R ₄ are independently selected from H, D and halo;
R ₂ is selected from H, D, halo, -C _0-6 alkylene-OH, NH ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxyl, C _5-6 cycloalkyl, 5-6 membered heterocyclyl, C _6-10 aryl, 5-10 membered heteroaryl, -O-5-6 membered heteroaryl, -NH-5-6 membered heteroaryl, -OC(O)-5-6 membered heteroaryl, or -NHC(O)-5-6 membered heteroaryl; which is optionally substituted with 1, 2, 3, 4 or 5 CN, halo, oxo, -C _1-6 alkylene-OH, C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl or 5-6 membered heterocyclyl;
R ₃ is selected from H, D, halo, OH, C _1-6 alkyl and C _1-6 haloalkyl;
Alternatively, R ₁ and R ₂ together with the carbon atoms to which they are connected form a 5- to 6-membered heterocyclyl, phenyl or a 5- to 6-membered heteroaryl;
Alternatively, R ₂ and R ₃ together with the carbon atoms to which they are connected form a 5-6 membered heterocyclyl, which is optionally substituted with 1, 2, 3 or 4 halo, C _1-6 alkyl, C _1-6 haloalkyl, -C(O)C _1-6 alkyl, or -C(O)C _1-6 haloalkyl;
R _1s is selected from H, D, -C _0-6 alkylene-OH, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, and C _2-6 haloalkynyl;
R _2s is selected from H, D, C _1-6 alkyl and C _1-6 haloalkyl;
R _3s is selected from C _1-6 alkyl and C _1-6 haloalkyl;
Alternatively, R _2s and R _3s together with the carbon atoms to which they are connected form a C _3-6 cycloalkyl, which is optionally substituted with 1 or 2 halo, C _1-6 alkyl or C _1-6 haloalkyl;
Alternatively, R _1s , R _2s and R _3s together with the carbon atoms to which they are connected form a C _4-8 bridged bicycloalkyl;
A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated. In claim 30, a compound of chemical formula (II-1), or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof:

In the above chemical formula,
M ₁ is selected from CR ₁ and N, preferably CR ₁ ;
M ₂ is selected from CR ₂ and N, preferably CR ₂ ;
M ₃ is selected from CR ₃ and N, preferably CR ₃ ;
M ₄ is selected from CR ₄ and N, preferably CR ₄ ;
X is selected from O, S and N-OH;
Ring A is

is selected from;
At this time, R _a is selected from H and D, and m=0, 1, 2, 3, 4 or 5;
R ₁ is selected from H, D, F, and Cl;
R ₂ is H, D, Cl, OH, Me, CH ₂ F, CHF ₂ , CF ₃ , OMe, CH ₂ OH, NH ₂ , , which is optionally substituted with 1, 2, 3, 4 or 5 CN, halo, -C _1-6 alkylene-OH, C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl or 5-6 membered heterocyclyl;
R ₃ is selected from H, D, F, Br and OH;
R ₄ is selected from H, D and F;
Alternatively, R ₁ and R ₂ together with the carbon atoms to which they are connected to form or;
Alternatively, R ₂ and R ₃ together with the carbon atoms to which they are connected , forming;
R _1s is selected from H, D, OH, Me, Et, iPr, CH ₂ F, CHF ₂ , CF ₃ , CH ₂ OH, CH=CH ₂ , and C≡CH;
R _2s is selected from H, D and Me;
R _3s is Me;
Alternatively, R _2s and R _3s together with the carbon atoms to which they are connected form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, which is optionally substituted with 1 or 2 F or Me;
Alternatively, R _1s , R _2s and R _3s together with the carbon atoms to which they are connected to form;
The above-mentioned atoms may be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated. In Article 33,
M ₁ is selected from CR ₁ and N, preferably CR ₁ ;
M ₂ is selected from CR ₂ and N, preferably CR ₂ ;
M ₃ is selected from CR ₃ and N, preferably CR ₃ ;
M ₄ is selected from CR ₄ and N, preferably CR ₄ ;
X is selected from O, S and N-OH;
Ring A is
is selected from;
wherein R _a is selected from H, D, halo, NO ₂ , NH ₂ , -C _1-6 alkylene-OH, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkynyl, C _2-6 haloalkynyl and amino protecting group, and m=0, 1, 2, 3, 4 or 5; or two adjacent R _a form phenyl or 5-6 membered heteroaryl together with the atoms to which they are connected;
R ₁ and R ₄ are independently selected from H, D and halo;
R ₂ is H, D, halo, -C _0-6 alkylene-OH, NH ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxyl, C _1-6 haloalkoxyl,

, which is optionally substituted with 1, 2, 3, 4 or 5 CN, halo, C _1-6 alkyl, C _1-6 haloalkyl or C _3-6 cycloalkyl;
R ₃ is selected from H, D, halo, OH, C _1-6 alkyl and C _1-6 haloalkyl;
Alternatively, R ₁ and R ₂ together with the carbon atoms to which they are connected form phenyl or a 5- to 6-membered heteroaryl;
Alternatively, R ₂ and R ₃ together with the carbon atoms to which they are connected form a 5-6 membered heterocyclyl, which is optionally substituted with 1, 2, 3 or 4 halo, C _1-6 alkyl, C _1-6 haloalkyl, -C(O)C _1-6 alkyl, or -C(O)C _1-6 haloalkyl;
R _1s is selected from H, D, -C _0-6 alkylene-OH, C _1-4 alkyl, C _1-4 haloalkyl, C _2-4 alkenyl, C _2-4 haloalkenyl, C _2-4 alkynyl, and C _2-4 haloalkynyl;
R _2s is selected from H, D, C _1-4 alkyl and C _1-4 haloalkyl;
R _3s is selected from C _1-4 alkyl and C _1-4 haloalkyl;
Alternatively, R ₂ and R ₃ together with the carbon atoms to which they are connected form a C _3-5 cycloalkyl, which is optionally substituted with 1 or 2 halo;
Alternatively, R _1s , R _2s and R _3s together with the carbon atoms to which they are connected form a C _4-8 bridged bicycloalkyl;
A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated. In claim 30, a compound of chemical formula (II-2), or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof:

In the above chemical formula,
M ₁ is selected from CR ₁ and N, preferably CR ₁ ;
M ₂ is selected from CR ₂ and N, preferably CR ₂ ;
M ₃ is selected from CR ₃ and N, preferably CR ₃ ;
M ₄ is selected from CR ₄ and N, preferably CR ₄ ;
Ring A is selected from phenyl and 5- to 6-membered heteroaryl;
wherein R _a is selected from C _3-6 cycloalkyl, 4-6 membered heterocyclyl, phenyl and 5-6 membered heteroaryl, which is optionally substituted with 1, 2 or 3 halo, oxo, OR _x , NR _y R _z , C _1-6 alkyl or C _1-6 haloalkyl, and m is 1, 2 or 3;
R ₁ is selected from H, D, halo, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxyl, C _1-6 haloalkoxyl, C 2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, C _2-6 haloalkynyl _{, C 3-8 cycloalkyl} and 4- to 10-membered heterocyclyl;
R ₂ is selected from H, D, halo, OH, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxyl, C _1-6 haloalkoxyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, and C _2-6 haloalkynyl;
R ₃ and R ₄ are independently selected from H, D, halo, C _1-6 alkyl and C _1-6 haloalkyl;
Alternatively, R ₁ and R ₂ together with the carbon atoms to which they are connected , which is optionally substituted with 1, 2 or 3 halo, C _1-6 alkyl or C _1-6 haloalkyl;
R _1s , R _2s and R _3s are independently selected from H, D, C _1-6 alkyl and C _1-6 haloalkyl;
Alternatively, R _2s and R _3s together with the carbon atoms to which they are connected form a C _3-6 cycloalkyl;
Alternatively, R _2s1 , R _2s2 and R _2s3 together with the carbon atoms to which they are connected form a C _4-8 bridged bicycloalkyl, which is optionally substituted with 1 or 2 halo, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl and C _2-6 haloalkynyl;
The above-mentioned atoms may be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated. In Article 35,
M ₁ is selected from CR ₁ and N, preferably CR ₁ ;
M ₂ is selected from CR ₂ and N, preferably CR ₂ ;
M ₃ is selected from CR ₃ and N, preferably CR ₃ ;
M ₄ is selected from CR ₄ and N, preferably CR ₄ ;
Ring A is and;
At this time, R _a is is selected from, m = 1, 2 or 3;
R ₁ is selected from H, D, halo, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxyl, C _1-6 haloalkoxyl, C 2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, C _2-6 haloalkynyl _{, C 3-8 cycloalkyl} and 4- to 10-membered heterocyclyl;
R ₂ is selected from H, D, halo, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxyl, C _1-6 haloalkoxyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, and C _2-6 haloalkynyl;
R ₃ and R ₄ are independently selected from H, D, halo, C _1-6 alkyl and C _1-6 haloalkyl;
Alternatively, R ₁ and R ₂ together with the carbon atoms to which they are connected to form;
R _1s , R _2s and R _3s are independently selected from H, D, C _1-6 alkyl and C _1-6 haloalkyl;
Alternatively, R _2s and R _3s together with the carbon atoms to which they are connected form a C _3-5 cycloalkyl;
Alternatively, R _2s1 , R _2s2 and R _2s3 together with the carbon atoms to which they are connected form a C _4-8 bridged bicycloalkyl;
A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated. In Article 36,
M ₁ is selected from CR ₁ and N, preferably CR ₁ ;
M ₂ is selected from CR ₂ and N, preferably CR ₂ ;
M ₃ is selected from CR ₃ and N, preferably CR ₃ ;
M ₄ is selected from CR ₄ and N, preferably CR ₄ ;
Ring A is and;
At this time, R _a is is selected from, m = 1, 2 or 3;
R ₁ , R ₂ , R ₃ and R ₄ are independently selected from H, D and halo;
Alternatively, R ₁ and R ₂ together with the carbon atoms to which they are connected to form;
R _1s is selected from H, D, C _1-6 alkyl and C _1-6 haloalkyl;
R _2s and R _3s are independently selected from H and D;
Alternatively, R _2s and R _3s together with the carbon atoms to which they are connected form a C _3-5 cycloalkyl;
A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated. In Article 37,
M ₁ is selected from CR ₁ and N, preferably CR ₁ ;
M ₂ is selected from CR ₂ and N, preferably CR ₂ ;
M ₃ is selected from CR ₃ and N, preferably CR ₃ ;
M ₄ is selected from CR ₄ and N, preferably CR ₄ ;
Ring A is and;
At this time, R _a is is selected from, m = 1, 2 or 3;
R ₁ , R ₂ , R ₃ and R ₄ are independently selected from H, D and halo;
Alternatively, R ₁ and R ₂ together with the carbon atoms to which they are connected to form;
R _1s is selected from H, D, Me and CHF ₂ ;
R _2s and R _3s are independently selected from H and D;
Alternatively, R _2s and R _3s together with the carbon atoms to which they are connected form cyclopropyl;
A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated. In claim 30, a compound of chemical formula (II-2), or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof:

In the above chemical formula,
M ₁ is selected from CR ₁ and N, preferably CR ₁ ;
M ₂ is selected from CR ₂ and N, preferably CR ₂ ;
M ₃ is selected from CR ₃ and N, preferably CR ₃ ;
M ₄ is selected from CR ₄ and N, preferably CR ₄ ;
Ring A is is selected from;
At this time, R _a is selected from H and D, and m=0, 1, 2, 3, 4 or 5;
R ₁ and R ₂ together with the carbon atoms to which they are connected , which is optionally substituted with 1, 2 or 3 halo, C _1-6 alkyl or C _1-6 haloalkyl;
R ₃ and R ₄ are independently selected from H, D, halo, C _1-6 alkyl and C _1-6 haloalkyl;
R _1s is selected from H, D, C _1-6 alkyl and C _1-6 haloalkyl;
R _2s and R _3s together with the carbon atoms to which they are connected form C _3-6 cycloalkyl;
The above-mentioned atoms may be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated. In Article 39,
M ₁ is selected from CR ₁ and N, preferably CR ₁ ;
M ₂ is selected from CR ₂ and N, preferably CR ₂ ;
M ₃ is selected from CR ₃ and N, preferably CR ₃ ;
M ₄ is selected from CR ₄ and N, preferably CR ₄ ;
Ring A is is selected from;
At this time, R _a is selected from H and D, and m=0, 1, 2, 3, 4 or 5;
R ₁ and R ₂ together with the carbon atoms to which they are connected to form;
R ₃ is selected from H and D;
R ₄ is selected from H, D and halo;
R _1s is selected from H, D, C _1-6 alkyl and C _1-6 haloalkyl;
R _2s and R _3s together with the carbon atoms to which they are connected form a C _3-5 cycloalkyl;
A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated. In Article 40,
M ₁ is selected from CR ₁ and N, preferably CR ₁ ;
M ₂ is selected from CR ₂ and N, preferably CR ₂ ;
M ₃ is selected from CR ₃ and N, preferably CR ₃ ;
M ₄ is selected from CR ₄ and N, preferably CR ₄ ;
Ring A is is selected from;
At this time, R _a is selected from H and D, and m=0, 1, 2, 3, 4 or 5;
R ₁ and R ₂ together with the carbon atoms to which they are connected to form;
R ₃ is selected from H and D;
R ₄ is selected from H, D and F;
R _1s is selected from H, D, Me, CHF ₂ , and CF ₃ ;
R _2s and R _3s together with the carbon atoms to which they are connected form cyclopropyl;
A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated. In Article 40,
M ₁ is selected from CR ₁ and N, preferably CR ₁ ;
M ₂ is selected from CR ₂ and N, preferably CR ₂ ;
M ₃ is selected from CR ₃ and N, preferably CR ₃ ;
M ₄ is selected from CR ₄ and N, preferably CR ₄ ;
Ring A is and;
At this time, R _a is selected from H and D, and m=0, 1, 2, 3, 4 or 5;
R ₁ and R ₂ together with the carbon atoms to which they are connected , which is optionally substituted with 1, 2 or 3 halo, C _1-6 alkyl or C _1-6 haloalkyl;
R ₃ and R ₄ are independently selected from H, D, halo, C _1-6 alkyl and C _1-6 haloalkyl;
R _1s is selected from H, D, C _1-6 alkyl and C _1-6 haloalkyl;
R _2s and R _3s together with the carbon atoms to which they are connected form C _3-6 cycloalkyl;
A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated. In Article 42,
M ₁ is selected from CR ₁ and N, preferably CR ₁ ;
M ₂ is selected from CR ₂ and N, preferably CR ₂ ;
M ₃ is selected from CR ₃ and N, preferably CR ₃ ;
M ₄ is selected from CR ₄ and N, preferably CR ₄ ;
Ring A is and;
At this time, R _a is selected from H and D, and m=0, 1, 2, 3, 4 or 5;
R ₁ and R ₂ together with the carbon atoms to which they are connected to form;
R ₃ is selected from H and D;
R ₄ is selected from H, D and halo;
R _1s is selected from H, D, C _1-6 alkyl and C _1-6 haloalkyl;
R _2s and R _3s together with the carbon atoms to which they are connected form a C _3-5 cycloalkyl;
A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated. In Article 43,
M ₁ is selected from CR ₁ and N, preferably CR ₁ ;
M ₂ is selected from CR ₂ and N, preferably CR ₂ ;
M ₃ is selected from CR ₃ and N, preferably CR ₃ ;
M ₄ is selected from CR ₄ and N, preferably CR ₄ ;
Ring A is and;
At this time, R _a is selected from H and D, and m=0, 1, 2, 3, 4 or 5;
R ₁ and R ₂ together with the carbon atoms to which they are connected to form;
R ₃ is selected from H and D;
R ₄ is selected from H, D and F;
R _1s is selected from H, D, Me, CHF ₂ , and CF ₃ ;
R _2s and R _3s together with the carbon atoms to which they are connected form cyclopropyl;
A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated. In claim 30, a compound of chemical formula (II-2), or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof:

In the above chemical formula,
M ₁ is selected from CR ₁ and N, preferably CR ₁ ;
M ₂ is selected from CR ₂ and N, preferably CR ₂ ;
M ₃ is selected from CR ₃ and N, preferably CR ₃ ;
M ₄ is selected from CR ₄ and N, preferably CR ₄ ;
Ring A is
is selected from;
At this time, R _a is selected from H and D, and m = 1, 2, or 3;
R ₁ and R ₄ are independently selected from H, D and halo;
R ₂ and R ₃ together with the carbon atoms to which they are connected to form;
R _1s is selected from C _1-6 alkyl and C _1-6 haloalkyl;
R _2s and R _3s together with the carbon atoms to which they are connected form C _3-6 cycloalkyl;
A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated. In Article 45,
M ₁ is selected from CR ₁ and N, preferably CR ₁ ;
M ₂ is selected from CR ₂ and N, preferably CR ₂ ;
M ₃ is selected from CR ₃ and N, preferably CR ₃ ;
M ₄ is selected from CR ₄ and N, preferably CR ₄ ;
Ring A is
is selected from;
At this time, R _a is selected from H and D, and m = 1, 2, or 3;
R ₁ is halo;
R ₂ and R ₃ together with the carbon atoms to which they are connected to form;
R ₄ is selected from H and D;
R _1s is selected from C _1-6 alkyl and C _1-6 haloalkyl;
R _2s and R _3s together with the carbon atoms to which they are connected form a C _3-5 cycloalkyl;
A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated. In Article 46,
M ₁ is selected from CR ₁ and N, preferably CR ₁ ;
M ₂ is selected from CR ₂ and N, preferably CR ₂ ;
M ₃ is selected from CR ₃ and N, preferably CR ₃ ;
M ₄ is selected from CR ₄ and N, preferably CR ₄ ;
Ring A is
is selected from;
At this time, R _a is selected from H and D, and m = 1, 2, or 3;
R ₁ is selected from F, and Cl;
R ₂ and R ₃ together with the carbon atoms to which they are connected to form;
R ₄ is selected from H and D;
R _1s is selected from Me and CHF ₂ ;
R _2s and R _3s together with the carbon atoms to which they are connected form cyclopropyl;
A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated. In Article 46,
M ₁ is selected from CR ₁ and N, preferably CR ₁ ;
M ₂ is selected from CR ₂ and N, preferably CR ₂ ;
M ₃ is selected from CR ₃ and N, preferably CR ₃ ;
M ₄ is selected from CR ₄ and N, preferably CR ₄ ;
Ring A is is selected from;
At this time, R _a is selected from H and D, and m = 1, 2, or 3;
R ₁ and R ₄ are independently selected from H, D and halo;
R ₂ and R ₃ together with the carbon atoms to which they are connected to form;
R _1s is selected from C _1-6 alkyl and C _1-6 haloalkyl;
R _2s and R _3s together with the carbon atoms to which they are connected form C _3-6 cycloalkyl;
A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated. In Article 48,
M ₁ is selected from CR ₁ and N, preferably CR ₁ ;
M ₂ is selected from CR ₂ and N, preferably CR ₂ ;
M ₃ is selected from CR ₃ and N, preferably CR ₃ ;
M ₄ is selected from CR ₄ and N, preferably CR ₄ ;
Ring A is is selected from;
At this time, R _a is selected from H and D, and m = 1, 2, or 3;
R ₁ is halo;
R ₂ and R ₃ together with the carbon atoms to which they are connected to form;
R ₄ is selected from H and D;
R _1s is selected from C _1-6 alkyl and C _1-6 haloalkyl;
R _2s and R _3s together with the carbon atoms to which they are connected form a C _3-5 cycloalkyl;
A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated. In Article 49,
M ₁ is selected from CR ₁ and N, preferably CR ₁ ;
M ₂ is selected from CR ₂ and N, preferably CR ₂ ;
M ₃ is selected from CR ₃ and N, preferably CR ₃ ;
M ₄ is selected from CR ₄ and N, preferably CR ₄ ;
Ring A is is selected from;
At this time, R _a is selected from H and D, and m = 1, 2, or 3;
R ₁ is selected from F, and Cl;
R ₂ and R ₃ together with the carbon atoms to which they are connected to form;
R ₄ is selected from H and D;
R _1s is selected from Me and CHF ₂ ;
R _2s and R _3s together with the carbon atoms to which they are connected form cyclopropyl;
A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated. In claim 30, a compound of chemical formula (II-2), or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof:

In the above chemical formula,
M ₁ is selected from CR ₁ and N, preferably CR ₁ ;
M ₂ is selected from CR ₂ and N, preferably CR ₂ ;
M ₃ is selected from CR ₃ and N, preferably CR ₃ ;
M ₄ is selected from CR ₄ and N, preferably CR ₄ ;
Ring A is is selected from;
wherein R _a is selected from H, D, halo, NO ₂ , NH ₂ , -C _1-6 alkylene-OH, C _2-4 alkynyl, C _2-4 haloalkynyl and Boc, and m = 0, 1, 2, 3, 4 or 5;
R ₁ and R ₄ are independently selected from H, D and halo;
R ₂ is H, D, halo, -C _0-6 alkylene-OH, NH ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxyl, C _1-6 haloalkoxyl,




is selected from;
R ₃ is selected from H, D, halo, OH, C _1-6 alkyl and C _1-6 haloalkyl;
Alternatively, R ₁ and R ₂ together with the carbon atoms to which they are connected form phenyl or a 5- to 6-membered heteroaryl;
Alternatively, R ₂ and R ₃ together with the carbon atoms to which they are connected form a 5-6 membered heterocyclyl, which is optionally substituted with 1, 2, 3 or 4 halo, C _1-6 alkyl, C _1-6 haloalkyl, -C(O)C _1-6 alkyl, or -C(O)C _1-6 haloalkyl;
R _1s is selected from H, D, OH, C _1-4 alkyl, C _1-4 haloalkyl, C _2-4 alkenyl, C _2-4 haloalkenyl, C _2-4 alkynyl, and C _2-4 haloalkynyl;
R _2s is selected from H, D, C _1-4 alkyl and C _1-4 haloalkyl;
R _3s is selected from C _1-4 alkyl and C _1-4 haloalkyl;
Alternatively, R _2s and R _3s together with the carbon atoms to which they are connected form a C _3-5 cycloalkyl, which is optionally substituted with 1 or 2 halo;
Alternatively, R _1s , R _2s and R _3s together with the carbon atoms to which they are connected form a C _4-8 bridged bicycloalkyl;
A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated. In Article 51,
M ₁ is selected from CR ₁ and N, preferably CR ₁ ;
M ₂ is selected from CR ₂ and N, preferably CR ₂ ;
M ₃ is selected from CR ₃ and N, preferably CR ₃ ;
M ₄ is selected from CR ₄ and N, preferably CR ₄ ;
Ring A is

is selected from;
At this time, R _a is selected from H and D, and m=0, 1, 2, 3, 4 or 5;
R ₁ is selected from H, D, F, and Cl;
R ₂ is H, D, Cl, OH, NH ₂ , Me, CH ₂ F, CHF ₂ , CF ₃ , OMe, CH ₂ OH,


is selected from;
R ₃ is selected from H, D, F, Br and OH;
R ₄ is selected from H, D and F;
Alternatively, R ₁ and R ₂ together with the carbon atoms to which they are connected to form or;
Alternatively, R ₂ and R ₃ together with the carbon atoms to which they are connected , forming;
R _1s is selected from H, D, OH, Me, Et, iPr, CH ₂ F, CHF ₂ , CF ₃ , CH ₂ OH, CH=CH ₂ , and C≡CH;
R _2s is selected from H, D and Me;
R _3s is Me;
Alternatively, R _2s and R _3s together with the carbon atoms to which they are connected form cyclopropyl, cyclobutyl or cyclopentyl, which is optionally substituted with 1 or 2 F;
Alternatively, R _1s , R _2s and R _3s together with the carbon atoms to which they are connected to form;
A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated. In Article 51,
M ₁ is selected from CR ₁ and N, preferably CR ₁ ;
M ₂ is selected from CR ₂ and N, preferably CR ₂ ;
M ₃ is selected from CR ₃ and N, preferably CR ₃ ;
M ₄ is selected from CR ₄ and N, preferably CR ₄ ;
Ring A is is selected from;
wherein R _a is selected from H, D, halo, C _1-6 alkyl, and C _1-6 haloalkyl, and m=0, 1, 2, or 3;
R ₁ and R ₄ are independently selected from H, D and halo;
R ₂ and R ₃ are independently selected from H, D, halo, OH, C _1-6 alkyl and C _1-6 haloalkyl;
Alternatively, R ₂ and R ₃ together with the carbon atoms to which they are connected form a 5- to 6-membered heterocyclyl, which is optionally substituted with 1, 2, 3 or 4 halo;
R _1s is selected from C _1-4 alkyl, C _1-4 haloalkyl, C _2-4 alkenyl, and C _2-4 haloalkenyl;
R _2s and R _3s together with the carbon atoms to which they are connected form a C _3-4 cycloalkyl, which is optionally substituted with 1 or 2 halo;
A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated. In Article 51,
M ₁ is selected from CR ₁ and N, preferably CR ₁ ;
M ₂ is selected from CR ₂ and N, preferably CR ₂ ;
M ₃ is selected from CR ₃ and N, preferably CR ₃ ;
M ₄ is selected from CR ₄ and N, preferably CR ₄ ;
Ring A is is selected from;
Here, R _a is selected from H, D and halo, and m = 0, 1, 2 or 3;
R ₁ and R ₄ are independently selected from H, D and halo;
R ₂ is selected from H, D, halo, OH, C _1-4 alkyl and C _1-4 haloalkyl;
R ₃ is selected from H, D, halo and OH;
Alternatively, R ₂ and R ₃ are linked together with the carbon atoms to which they are attached. to form or;
R _1s is selected from C _1-4 alkyl, C _1-4 haloalkyl, and C _2-4 alkenyl;
R _2s and R _3s together with the carbon atoms to which they are connected form a C _3-4 cycloalkyl, which is optionally substituted with 1 or 2 halo;
A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated. In Article 51,
M ₁ is selected from CR ₁ and N, preferably CR ₁ ;
M ₂ is selected from CR ₂ and N, preferably CR ₂ ;
M ₃ is selected from CR ₃ and N, preferably CR ₃ ;
M ₄ is selected from CR ₄ and N, preferably CR ₄ ;
Ring A is is selected from;
At this time, R _a is selected from H and D, and m=0, 1, 2, or 3;
R ₁ is selected from H, D, F, and Cl;
R ₂ is selected from H, D, Cl, OH, Me, CH ₂ F, CHF ₂ and CF ₃ ;
R ₃ is selected from H, D, F and OH;
R ₄ is selected from H, D and F;
Alternatively, R ₂ and R ₃ are linked together with the carbon atoms to which they are attached. to form or;
R _1s is selected from Me, Et, CH ₂ F, CHF ₂ , CF ₃ , and CH=CH ₂ ;
R _2s and R _3s together with the carbon atoms to which they are connected form cyclopropyl or cyclobutyl, which is optionally substituted with 1 or 2 F;
A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated. In claim 30, a compound of chemical formula (III-1), or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof:

In the above chemical formula,
M ₁ is selected from CR ₁ and N, preferably CR ₁ ;
M ₂ is selected from CR ₂ and N, preferably CR ₂ ;
M ₃ is selected from CR ₃ and N, preferably CR ₃ ;
M ₄ is selected from CR ₄ and N, preferably CR ₄ ;
Ring A is
is selected from;
wherein R _a is selected from H, D, halo, CN, C _1-6 alkyl, and C _1-6 haloalkyl, and m=0, 1, 2, 3, 4, or 5;
R ₁ is selected from H, D, halo, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxyl and C _1-6 haloalkoxyl;
R ₂ is selected from H, D, halo, CN, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxyl, C _1-6 haloalkoxyl, C _{2-4 alkenyl, C 2-4 haloalkenyl, C 2-4 alkynyl ,} C _2-4 haloalkynyl, C _4-6 cycloalkyl and 5-6 membered heterocyclyl;
R ₃ is selected from H, D, halo, C _1-6 alkyl and C _1-6 haloalkyl;
R ₄ is selected from H, D, halo, C _1-6 alkyl and C _1-6 haloalkyl;
Alternatively, R ₁ and R ₂ together with the carbon atoms to which they are connected form C _5-6 cycloalkyl, 5-6 membered heterocyclyl, phenyl and 5-6 membered heteroaryl;
Y ₁ is CR ₁₁ or N;
Y ₂ is CR ₁₂ or N;
R ₁₁ and R ₁₃ are independently selected from H, D, C _1-6 alkyl and C _1-6 haloalkyl;
R ₁₂ is selected from H and D;
The above-mentioned atoms may be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated. In claim 30, a compound of chemical formula (III-2), or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof:

In the above chemical formula,
M ₁ is selected from CR ₁ and N, preferably CR ₁ ;
M ₂ is selected from CR ₂ and N, preferably CR ₂ ;
M ₃ is selected from CR ₃ and N, preferably CR ₃ ;
M ₄ is selected from CR ₄ and N, preferably CR ₄ ;
Ring A is is selected from;
wherein R _a is selected from H, D, halo, C _1-6 alkyl, and C _1-6 haloalkyl, and m=0, 1, 2, 3, or 4;
R ₁ is selected from H, D, halo, C _1-6 alkyl and C _1-6 haloalkyl;
R ₂ is selected from H, D, C _1-6 alkyl and C _1-6 haloalkyl;
R ₃ is selected from H and D;
R ₄ is selected from H, D and halo;
Alternatively, R ₁ and R ₂ together with the carbon atoms to which they are connected to form;
R ₁₁ , R ₁₂ and R ₁₃ are independently selected from H and D;
The above-mentioned atoms may be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated. In paragraph 57, ring A A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof selected from. In Article 57,
M ₁ is selected from CR ₁ and N, preferably CR ₁ ;
M ₂ is selected from CR ₂ and N, preferably CR ₂ ;
M ₃ is selected from CR ₃ and N, preferably CR ₃ ;
M ₄ is selected from CR ₄ and N, preferably CR ₄ ;
Ring A is is selected from;
At this time, R _a is selected from H, D, F, and Me, and m = 0, 1, 2, 3, or 4;
R ₁ is selected from H, D, F, and Me;
R ₂ is selected from H, D, Me and CF ₃ ;
R ₃ is selected from H and D;
R ₄ is selected from H, D and F;
Alternatively, R ₁ and R ₂ together with the carbon atoms to which they are connected to form;
R ₁₁ , R ₁₂ and R ₁₃ are independently selected from H and D;
A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups may be substituted with 1, 2, 3 or 4 deuterium atoms. In Article 57,
M ₁ is selected from CR ₁ and N, preferably CR ₁ ;
M ₂ is selected from CR ₂ and N, preferably CR ₂ ;
M ₃ is selected from CR ₃ and N, preferably CR ₃ ;
M ₄ is selected from CR ₄ and N, preferably CR ₄ ;
Ring A is is selected from;
Here, R _a is selected from H, D and halo, and m = 0, 1, 2 or 3;
R ₁ is selected from H, D and halo;
R ₂ is Me;
R ₃ is selected from H and D;
R ₄ is selected from H, D and halo;
R ₁₁ , R ₁₂ and R ₁₃ are independently selected from H and D;
A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups may be substituted with 1, 2 or 3 deuterium atoms. In Article 57,
M ₁ is selected from CR ₁ and N, preferably CR ₁ ;
M ₂ is selected from CR ₂ and N, preferably CR ₂ ;
M ₃ is selected from CR ₃ and N, preferably CR ₃ ;
M ₄ is selected from CR ₄ and N, preferably CR ₄ ;
Ring A is is selected from;
At this time, R _a is selected from H, D and F, and m = 0, 1, 2 or 3;
R ₁ is selected from H, D and F;
R ₂ is Me;
R ₃ is selected from H and D;
R ₄ is selected from H, D and F;
R ₁₁ , R ₁₂ and R ₁₃ are independently selected from H and D;
A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups may be substituted with 1, 2 or 3 deuterium atoms. In Article 57,
M ₁ is selected from CR ₁ and N, preferably CR ₁ ;
M ₂ is selected from CR ₂ and N, preferably CR ₂ ;
M ₃ is selected from CR ₃ and N, preferably CR ₃ ;
M ₄ is selected from CR ₄ and N, preferably CR ₄ ;
Ring A is is selected from;
wherein R _a is selected from H, D, halo, CN, C _1-6 alkyl, and C _1-6 haloalkyl, and m=0, 1, 2, 3, 4, or 5;
R ₁ is selected from H, D, halo, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxyl and C _1-6 haloalkoxyl;
R ₂ is selected from H, D, halo, CN, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxyl, C _1-6 haloalkoxyl, C _{2-4 alkenyl, C 2-4 haloalkenyl, C 2-4 alkynyl ,} C _2-4 haloalkynyl, C _4-6 cycloalkyl and 5-6 membered heterocyclyl;
R ₃ is selected from H, D and halo;
R ₄ is selected from H, D, halo, C _1-6 alkyl and C _1-6 haloalkyl;
Alternatively, R ₁ and R ₂ together with the carbon atoms to which they are connected form C _5-6 cycloalkyl, 5-6 membered heterocyclyl, phenyl and 5-6 membered heteroaryl;
R ₁₁ and R ₁₃ are independently selected from H, D, C _1-6 alkyl and C _1-6 haloalkyl;
R ₁₂ is selected from H and D;
A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated. In Article 57,
M ₁ is selected from CR ₁ and N, preferably CR ₁ ;
M ₂ is selected from CR ₂ and N, preferably CR ₂ ;
M ₃ is selected from CR ₃ and N, preferably CR ₃ ;
M ₄ is selected from CR ₄ and N, preferably CR ₄ ;
Ring A is is selected from;
At this time, R _a is selected from H, D, F, Cl, Br, CN and Me, and m = 0, 1, 2, 3, 4 or 5;
R ₁ is selected from H, D, F, Me, and OMe;
R ₂ is H, D, F, Cl, CN, Me, Et, iPr, OMe, cyclopropyl, CH=CH ₂ , C≡CH, is selected from;
R ₃ is selected from H, D and F;
R ₄ is selected from H, D, F, and Me;
Alternatively, R ₁ and R ₂ together with the carbon atoms to which they are connected to form;
R ₁₁ and R ₁₃ are independently selected from H, D and Me;
R ₁₂ is selected from H and D;
A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated. In Article 57,
M ₁ is selected from CR ₁ and N, preferably CR ₁ ;
M ₂ is selected from CR ₂ and N, preferably CR ₂ ;
M ₃ is selected from CR ₃ and N, preferably CR ₃ ;
M ₄ is selected from CR ₄ and N, preferably CR ₄ ;
Ring A is is selected from;
wherein R _a is selected from H, D, halo, CN, C _1-6 alkyl, and C _1-6 haloalkyl, and m=0, 1, 2, 3, 4, or 5;
R ₁ is selected from H, D, halo, C _1-6 alkyl and C _1-6 haloalkyl;
R ₂ is selected from H, D, halo, CN, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxyl, C _1-6 haloalkoxyl, C _2-4 alkenyl, C _2-4 haloalkenyl, C _2-4 alkynyl, C 2-4 haloalkynyl and C _3-8 cycloalkyl _;
R ₃ is selected from H, D and halo;
R ₄ is selected from H, D, halo, C _1-6 alkyl and C _1-6 haloalkyl;
Alternatively, R ₁ and R ₂ together with the carbon atoms to which they are connected form C _5-6 cycloalkyl or phenyl;
R ₁₁ is selected from H, D, C _1-6 alkyl and C _1-6 haloalkyl;
R ₁₂ and R ₁₃ are independently selected from H and D;
A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated. In Article 57,
M ₁ is selected from CR ₁ and N, preferably CR ₁ ;
M ₂ is selected from CR ₂ and N, preferably CR ₂ ;
M ₃ is selected from CR ₃ and N, preferably CR ₃ ;
M ₄ is selected from CR ₄ and N, preferably CR ₄ ;
Ring A is is selected from;
At this time, R _a is selected from H, D, F, Cl, Br, CN and Me, and m = 0, 1, 2, 3, 4 or 5;
R ₁ is selected from H, D, F, and Me;
R ₂ is H, D, F, Cl, CN, Me, Et, iPr, OMe, cyclopropyl, CH=CH ₂ , C≡CH, is selected from;
R ₃ is selected from H, D and F;
R ₄ is selected from H, D, F, and Me;
Alternatively, R ₁ and R ₂ together with the carbon atoms to which they are connected to form;
R ₁₁ is selected from H, D, and Me;
R ₁₂ and R ₁₃ are independently selected from H and D;
A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated. In Article 57,
M ₁ is selected from CR ₁ and N, preferably CR ₁ ;
M ₂ is selected from CR ₂ and N, preferably CR ₂ ;
M ₃ is selected from CR ₃ and N, preferably CR ₃ ;
M ₄ is selected from CR ₄ and N, preferably CR ₄ ;
Ring A is and;
At this time, R _a is selected from H and D, and m=0, 1, 2, 3, 4 or 5;
R ₁ , R ₃ and R ₄ are independently selected from H, D and halo;
R ₂ is selected from H, D, halo, C _1-6 alkyl, C _1-6 haloalkyl and C _3-6 cycloalkyl;
R ₁₁ is selected from H, D, C _1-6 alkyl and C _1-6 haloalkyl;
R ₁₂ and R ₁₃ are independently selected from H and D;
A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated. In Article 57,
M ₁ is selected from CR ₁ and N, preferably CR ₁ ;
M ₂ is selected from CR ₂ and N, preferably CR ₂ ;
M ₃ is selected from CR ₃ and N, preferably CR ₃ ;
M ₄ is selected from CR ₄ and N, preferably CR ₄ ;
Ring A is and;
At this time, R _a is selected from H and D, and m=0, 1, 2, 3, 4 or 5;
R ₁ , R ₃ and R ₄ are independently selected from H, D and F;
R ₂ is selected from H, D, Cl, Me and cyclopropyl;
R ₁₁ is selected from H, D, and Me;
R ₁₂ and R ₁₃ are independently selected from H and D;
A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated. In claim 30, a compound of formula (IV), or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof:

In the above chemical formula,
M ₁ is selected from CR ₁ and N, preferably CR ₁ ;
M ₂ is selected from CR ₂ and N, preferably CR ₂ ;
M ₃ is selected from CR ₃ and N, preferably CR ₃ ;
M ₄ is selected from CR ₄ and N, preferably CR ₄ ;
Ring A is selected from phenyl and 5- to 6-membered heteroaryl;
wherein R _a is selected from C _3-6 cycloalkyl, 4-6 membered heterocyclyl, phenyl and 5-6 membered heteroaryl, which is optionally substituted with 1, 2 or 3 halo, oxo, OR _x , NR _y R _z , C _1-6 alkyl or C _1-6 haloalkyl, and m is 1, 2 or 3;
R ₁ is selected from H, D, halo, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxyl, C _1-6 haloalkoxyl, C 2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, C _2-6 haloalkynyl _{, C 3-8 cycloalkyl} and 4- to 10-membered heterocyclyl;
R ₂ is selected from H, D, halo, OH, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxyl, C _1-6 haloalkoxyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, and C _2-6 haloalkynyl;
R ₃ and R ₄ are independently selected from H, D, halo, C _1-6 alkyl and C _1-6 haloalkyl;
Alternatively, R ₁ and R ₂ together with the carbon atoms to which they are connected , which is optionally substituted with 1, 2 or 3 halo, C _1-6 alkyl or C _1-6 haloalkyl;
Alternatively, R ₂ and R ₃ together with the carbon atoms to which they are connected form a C _5-6 cycloalkyl or a 5- to 7-membered heterocyclyl;
R _1s is H;
R _2s1 is selected from H, D, -C _0-6 alkylene-OR _x , -C _0-6 alkylene-NR _y R _z , C _1-6 alkyl, and C _1-6 haloalkyl;
R _2s2 and R _2s3 are independently selected from C _1-6 alkyl and C _1-6 haloalkyl;
Alternatively, R _2s2 and R _2s3 together with the carbon atoms to which they are connected form a C _3-6 cycloalkyl;
Alternatively, R _2s1 , R _2s2 and R _2s3 together with the carbon atoms to which they are connected form a C _4-8 bridged bicycloalkyl, which is optionally substituted with 1 or 2 halo, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl and C _2-6 haloalkynyl;
R _x , R _y and R _z are independently selected from H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, C _2-6 haloalkynyl, C _3-8 cycloalkyl and 4- to 6-membered heterocyclyl; or R _y and R _z together with the nitrogen atom to which they are connected form a 4- to 6-membered heterocyclyl;
The above-mentioned atoms may be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated. In Article 68,
M ₁ is selected from CR ₁ and N, preferably CR ₁ ;
M ₂ is selected from CR ₂ and N, preferably CR ₂ ;
M ₃ is selected from CR ₃ and N, preferably CR ₃ ;
M ₄ is selected from CR ₄ and N, preferably CR ₄ ;
Ring A is is selected from;
At this time, R _a is is selected from, m = 1, 2 or 3;
R ₁ is selected from H, D, halo, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxyl, C _1-6 haloalkoxyl, C 2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, C _2-6 haloalkynyl _{, C 3-8 cycloalkyl} and 4- to 10-membered heterocyclyl;
R ₂ is selected from H, D, halo, OH, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxyl, C _1-6 haloalkoxyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, and C _2-6 haloalkynyl;
R ₃ and R ₄ are independently selected from H, D, halo, C _1-6 alkyl and C _1-6 haloalkyl;
Alternatively, R ₁ and R ₂ together with the carbon atoms to which they are connected , which is optionally substituted with 1, 2 or 3 halo, C _1-6 alkyl or C _1-6 haloalkyl;
Alternatively, R ₂ and R ₃ together with the carbon atoms to which they are connected form a C _5-6 cycloalkyl or a 5- to 7-membered heterocyclyl;
R _1s is H;
R _2s1 is selected from H, D, -C _0-6 alkylene-OR _x , -C _0-6 alkylene-NR _y R _z , C _1-6 alkyl, and C _1-6 haloalkyl;
R _2s2 and R _2s3 are independently selected from C _1-6 alkyl and C _1-6 haloalkyl;
Alternatively, R _2s2 and R _2s3 together with the carbon atoms to which they are connected form a C _3-6 cycloalkyl;
Alternatively, R _2s1 , R _2s2 and R _2s3 together with the carbon atoms to which they are connected form a C _4-8 bridged bicycloalkyl;
R _x , R _y and R _z are independently selected from H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, C _2-6 haloalkynyl, C _3-8 cycloalkyl and 4- to 6-membered heterocyclyl; or R _y and R _z together with the nitrogen atom to which they are connected form a 4- to 6-membered heterocyclyl;
A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated. In Article 69,
M ₁ is selected from CR ₁ and N, preferably CR ₁ ;
M ₂ is selected from CR ₂ and N, preferably CR ₂ ;
M ₃ is selected from CR ₃ and N, preferably CR ₃ ;
M ₄ is selected from CR ₄ and N, preferably CR ₄ ;
Ring A is is selected from;
At this time, R _a is is selected from, m = 1, 2 or 3;
R ₁ is selected from H, D, halo, C _1-6 alkyl and C _1-6 haloalkyl;
R ₂ is selected from H, D, halo, OH, C _1-6 alkoxyl and C _1-6 haloalkoxyl;
R ₃ and R ₄ are independently selected from H and D;
Alternatively, R ₁ and R ₂ together with the carbon atoms to which they are connected to form or;
Alternatively, R ₂ and R ₃ together with the carbon atoms to which they are connected to form;
R _1s is H;
R _2s1 is selected from -C _1-6 alkylene-OR _x , C _1-6 alkyl and C _1-6 haloalkyl;
R _2s2 and R _2s3 are independently selected from C _1-6 alkyl and C _1-6 haloalkyl;
Alternatively, R _2s2 and R _2s3 together with the carbon atoms to which they are connected form a C _3-5 cycloalkyl; or
Alternatively, R _2s1 , R _2s2 and R _2s3 together with the carbon atoms to which they are connected to form;
R _x is selected from H, C _1-6 alkyl and C _1-6 haloalkyl;
A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated. In Article 70,
M ₁ is selected from CR ₁ and N, preferably CR ₁ ;
M ₂ is selected from CR ₂ and N, preferably CR ₂ ;
M ₃ is selected from CR ₃ and N, preferably CR ₃ ;
M ₄ is selected from CR ₄ and N, preferably CR ₄ ;
Ring A is is selected from;
At this time, R _a is is selected from, m = 1, 2 or 3;
R ₁ is selected from H, D, Cl, and Me;
R ₂ is selected from H, D, Cl, OH, OMe and OCHF ₂ ;
R ₃ and R ₄ are independently selected from H and D;
Alternatively, R ₁ and R ₂ together with the carbon atoms to which they are connected to form or;
Alternatively, R ₂ and R ₃ together with the carbon atoms to which they are connected to form;
R _1s is H;
R _2s1 is selected from Me, Et, iPr, CH ₂ F, CHF ₂ , and CH ₂ OH;
R _2s2 and R _2s3 are independently selected from Me and Et;
Alternatively, R _2s2 and R _2s3 together with the carbon atoms to which they are connected form cyclopropyl;
Alternatively, R _2s1 , R _2s2 and R _2s3 together with the carbon atoms to which they are connected to form;
A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated. In Article 68,
M ₁ is selected from CR ₁ and N, preferably CR ₁ ;
M ₂ is selected from CR ₂ and N, preferably CR ₂ ;
M ₃ is selected from CR ₃ and N, preferably CR ₃ ;
M ₄ is selected from CR ₄ and N, preferably CR ₄ ;
Ring A is and;
At this time, R _a is is selected from, m = 1, 2 or 3;
R ₁ is selected from H, D, halo, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxyl, C _1-6 haloalkoxyl, C 2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, C _2-6 haloalkynyl _{, C 3-8 cycloalkyl} and 4- to 10-membered heterocyclyl;
R ₂ is selected from H, D, halo, OH, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxyl, C _1-6 haloalkoxyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, and C _2-6 haloalkynyl;
R ₃ and R ₄ are independently selected from H, D, halo, C _1-6 alkyl and C _1-6 haloalkyl;
Alternatively, R ₁ and R ₂ together with the carbon atoms to which they are connected to form or;
Alternatively, R ₂ and R ₃ together with the carbon atoms to which they are connected , forming;
R _1s is H;
R _2s1 , R _2s2 and R _2s3 are independently selected from C _1-6 alkyl and C _1-6 haloalkyl;
Alternatively, R _2s2 and R _2s3 together with the carbon atoms to which they are connected form a C _3-5 cycloalkyl; or
Alternatively, R _2s1 , R _2s2 and R _2s3 together with the carbon atoms to which they are connected form a C _4-8 bridged bicycloalkyl;
A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated. In paragraph 72,
M ₁ is selected from CR ₁ and N, preferably CR ₁ ;
M ₂ is selected from CR ₂ and N, preferably CR ₂ ;
M ₃ is selected from CR ₃ and N, preferably CR ₃ ;
M ₄ is selected from CR ₄ and N, preferably CR ₄ ;
Ring A is and;
At this time, R _a is Selected from among, preferably , and m = 1, 2, or 3;
R ₁ is selected from H, D, halo, C _1-6 alkyl and C _1-6 haloalkyl;
R ₂ is selected from H, D, halo, OH, C _1-6 alkoxyl and C _1-6 haloalkoxyl;
R ₃ and R ₄ are independently selected from H and D;
Alternatively, R ₁ and R ₂ together with the carbon atoms to which they are connected to form or;
Alternatively, R ₂ and R ₃ together with the carbon atoms to which they are connected to form;
R _1s is H;
R _2s1 , R _2s2 and R _2s3 are independently selected from C _1-6 alkyl and C _1-6 haloalkyl;
Alternatively, R _2s2 and R _2s3 together with the carbon atoms to which they are connected form cyclopropyl;
Alternatively, R _2s1 , R _2s2 and R _2s3 together with the carbon atoms to which they are connected to form;
A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated. In Article 73,
M ₁ is selected from CR ₁ and N, preferably CR ₁ ;
M ₂ is selected from CR ₂ and N, preferably CR ₂ ;
M ₃ is selected from CR ₃ and N, preferably CR ₃ ;
M ₄ is selected from CR ₄ and N, preferably CR ₄ ;
Ring A is and;
At this time, R _a is Selected from among, preferably , and m = 1, 2, or 3;
R ₁ is selected from H, D, Cl, and Me;
R ₂ is selected from H, D, Cl, OH, OMe and OCHF ₂ ;
R ₃ and R ₄ are independently selected from H and D;
Alternatively, R ₁ and R ₂ together with the carbon atoms to which they are connected to form or;
Alternatively, R ₂ and R ₃ together with the carbon atoms to which they are connected to form;
R _1s is H;
R _2s1 is selected from Me, Et, iPr, CH ₂ F, and CHF ₂ ;
R _2s2 and R _2s3 are independently selected from Me and Et;
Alternatively, R _2s2 and R _2s3 together with the carbon atoms to which they are connected form cyclopropyl;
Alternatively, R _2s1 , R _2s2 and R _2s3 together with the carbon atoms to which they are connected to form;
A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated. In claim 30, a compound of formula (IV), or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof:

In the above chemical formula,
M ₁ is selected from CR ₁ and N, preferably CR ₁ ;
M ₂ is selected from CR ₂ and N, preferably CR ₂ ;
M ₃ is selected from CR ₃ and N, preferably CR ₃ ;
M ₄ is selected from CR ₄ and N, preferably CR ₄ ;
Ring A is is selected from;
At this time, R _a is selected from H and D, and m=0, 1, 2, 3, 4 or 5;
R ₁ and R ₂ together with the carbon atoms to which they are connected , which is optionally substituted with 1, 2 or 3 halo, CN, C _1-6 alkyl, C _1-6 haloalkyl, -C(O)C _1-6 alkyl, or -C(O)C _1-6 haloalkyl;
R ₃ and R ₄ are independently selected from H, D, halo, C _1-6 alkyl and C _1-6 haloalkyl;
R _1s is H;
R _2s1 is selected from H, D, -C _0-6 alkylene-OR _x , -C _0-6 alkylene-NR _y R _z , C _1-6 alkyl, C _1-6 haloalkyl, and C _3-6 cycloalkyl;
R _2s2 and R _2s3 are independently selected from C _1-6 alkyl and C _1-6 haloalkyl;
Alternatively, R _2s2 and R _2s3 together with the carbon atoms to which they are connected form a C _3-6 cycloalkyl;
Alternatively, R _1s and R _2s3 together with the atoms to which they are connected form a 4- to 6-membered heterocyclyl; or
Alternatively, R _2s1 , R _2s2 and R _2s3 together with the carbon atoms to which they are connected form a C _4-8 bridged bicycloalkyl, which is optionally substituted with 1, 2 or 3 halo, C _1-6 alkyl or C _1-6 haloalkyl;
R _x , R _y and R _z are independently selected from H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, C _2-6 haloalkynyl, C _3-8 cycloalkyl and 4- to 6-membered heterocyclyl; or R _y and R _z together with the nitrogen atom to which they are connected form a 4- to 6-membered heterocyclyl;
The above-mentioned atoms may be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated. In Article 75,
M ₁ is selected from CR ₁ and N, preferably CR ₁ ;
M ₂ is selected from CR ₂ and N, preferably CR ₂ ;
M ₃ is selected from CR ₃ and N, preferably CR ₃ ;
M ₄ is selected from CR ₄ and N, preferably CR ₄ ;
Ring A is is selected from;
At this time, R _a is selected from H and D, and m=0, 1, 2, 3, 4 or 5;
R ₁ and R ₂ together with the carbon atoms to which they are connected to form;
R ₃ and R ₄ are independently selected from H and D;
R _1s is H;
R _2s1 is selected from Me, CH ₂ F, CH ₂ OH, CH ₂ OCH ₃ , and cyclopropyl;
R _2s2 and R _2s3 are Me;
Alternatively, R _2s2 and R _2s3 together with the carbon atoms to which they are connected form cyclopropyl;
Alternatively, R _1s and R _2s3 together with the atoms to which they are connected form a 4- to 5-membered heterocyclyl;
Alternatively, R _2s1 , R _2s2 and R _2s3 together with the carbon atoms to which they are connected to form;
A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated. In Article 75,
M ₁ is selected from CR ₁ and N, preferably CR ₁ ;
M ₂ is selected from CR ₂ and N, preferably CR ₂ ;
M ₃ is selected from CR ₃ and N, preferably CR ₃ ;
M ₄ is selected from CR ₄ and N, preferably CR ₄ ;
Ring A is is selected from;
At this time, R _a is selected from H and D, and m=0, 1, 2, 3, 4 or 5;
R ₁ and R ₂ together with the carbon atoms to which they are connected , which is optionally substituted with 1, 2 or 3 halo, CN, C _1-6 alkyl, C _1-6 haloalkyl, -C(O)C _1-6 alkyl, or -C(O)C _1-6 haloalkyl;
R ₃ and R ₄ are independently selected from H, D, halo, C _1-6 alkyl and C _1-6 haloalkyl;
R _1s is H;
R _2s1 is selected from H, D, -C _0-6 alkylene-OR _x , -C _0-6 alkylene-NR _y R _z , C _1-6 alkyl, C _1-6 haloalkyl, and C _3-6 cycloalkyl;
R _2s2 and R _2s3 are independently selected from C _1-6 alkyl and C _1-6 haloalkyl;
Alternatively, R _2s2 and R _2s3 together with the carbon atoms to which they are connected form a C _3-6 cycloalkyl;
Alternatively, R _1s and R _2s3 together with the atoms to which they are connected form a 4- to 6-membered heterocyclyl; or
Alternatively, R _2s1 , R _2s2 and R _2s3 together with the carbon atoms to which they are connected form a C _4-8 bridged bicycloalkyl, which is optionally substituted with 1, 2 or 3 halo, C _1-6 alkyl or C _1-6 haloalkyl;
R _x , R _y and R _z are independently selected from H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, C _2-6 haloalkynyl, C _3-8 cycloalkyl and 4- to 6-membered heterocyclyl; or R _y and R _z together with the nitrogen atom to which they are connected form a 4- to 6-membered heterocyclyl;
A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated. In Article 77,
M ₁ is selected from CR ₁ and N, preferably CR ₁ ;
M ₂ is selected from CR ₂ and N, preferably CR ₂ ;
M ₃ is selected from CR ₃ and N, preferably CR ₃ ;
M ₄ is selected from CR ₄ and N, preferably CR ₄ ;
Ring A is is selected from;
At this time, R _a is selected from H and D, and m=0, 1, 2, 3, 4 or 5;
R ₁ and R ₂ together with the carbon atoms to which they are connected to form;
R ₃ and R ₄ are independently selected from H and D;
R _1s is H;
R _2s1 is selected from -C _0-6 alkylene-OR _x , C _1-6 alkyl, C _1-6 haloalkyl and C _3-6 cycloalkyl;
R _2s2 and R _2s3 are independently selected from C _1-6 alkyl and C _1-6 haloalkyl;
Alternatively, R _2s2 and R _2s3 together with the carbon atoms to which they are connected form a C _3-6 cycloalkyl;
Alternatively, R _1s and R _2s3 together with the atoms to which they are connected form a 4- to 6-membered heterocyclyl; or
Alternatively, R _2s1 , R _2s2 and R _2s3 together with the carbon atoms to which they are connected to form;
R _x is selected from H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, C _2-6 haloalkynyl, C _3-8 cycloalkyl and 4- to 6-membered heterocyclyl;
A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated. In Article 78,
M ₁ is selected from CR ₁ and N, preferably CR ₁ ;
M ₂ is selected from CR ₂ and N, preferably CR ₂ ;
M ₃ is selected from CR ₃ and N, preferably CR ₃ ;
M ₄ is selected from CR ₄ and N, preferably CR ₄ ;
Ring A is is selected from;
At this time, R _a is selected from H and D, and m=0, 1, 2, 3, 4 or 5;
R ₁ and R ₂ together with the carbon atoms to which they are connected to form;
R ₃ and R ₄ are independently selected from H and D;
R _1s is H;
R _2s1 is selected from Me, CH ₂ F, CH ₂ OH, CH ₂ OCH ₃ , and cyclopropyl;
R _2s2 and R _2s3 are Me;
Alternatively, R _2s2 and R _2s3 together with the carbon atoms to which they are connected form cyclopropyl;
Alternatively, R _1s and R _2s3 together with the atoms to which they are connected form a 4- to 5-membered heterocyclyl;
Alternatively, R _2s1 , R _2s2 and R _2s3 together with the carbon atoms to which they are connected to form;
A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated. In Article 75,
M ₁ is selected from CR ₁ and N, preferably CR ₁ ;
M ₂ is selected from CR ₂ and N, preferably CR ₂ ;
M ₃ is selected from CR ₃ and N, preferably CR ₃ ;
M ₄ is selected from CR ₄ and N, preferably CR ₄ ;
Ring A is is selected from;
At this time, R _a is selected from H and D, and m=0, 1, 2, 3, 4 or 5;
R ₁ and R ₂ together with the carbon atoms to which they are connected , which is optionally substituted with 1, 2 or 3 halo, CN, C _1-6 alkyl or C _1-6 haloalkyl;
R ₃ and R ₄ are independently selected from H, D, halo, C _1-6 alkyl and C _1-6 haloalkyl;
R _1s is H;
R _2s1 is selected from H, D, -C _0-6 alkylene-OR _x , -C _0-6 alkylene-NR _y R _z , C _1-6 alkyl, C _1-6 haloalkyl, and C _3-6 cycloalkyl;
R _2s2 and R _2s3 are independently selected from C _1-6 alkyl and C _1-6 haloalkyl;
Alternatively, R _2s2 and R _2s3 together with the carbon atoms to which they are connected form a C _3-6 cycloalkyl;
Alternatively, R _2s1 , R _2s2 and R _2s3 together with the carbon atoms to which they are connected form a C _4-8 bridged bicycloalkyl, which is optionally substituted with 1, 2 or 3 halo, C _1-6 alkyl or C _1-6 haloalkyl;
R _x , R _y and R _z are independently selected from H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, C _2-6 haloalkynyl, C _3-8 cycloalkyl and 4- to 6-membered heterocyclyl; or R _y and R _z together with the nitrogen atom to which they are connected form a 4- to 6-membered heterocyclyl;
A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated. In Article 80,
M ₁ is selected from CR ₁ and N, preferably CR ₁ ;
M ₂ is selected from CR ₂ and N, preferably CR ₂ ;
M ₃ is selected from CR ₃ and N, preferably CR ₃ ;
M ₄ is selected from CR ₄ and N, preferably CR ₄ ;
Ring A is is selected from;
At this time, R _a is selected from H and D, and m=0, 1, 2, 3, 4 or 5;
R ₁ and R ₂ together with the carbon atoms to which they are connected to form;
R ₃ and R ₄ are independently selected from H and D;
R _1s is H;
R _2s1 is selected from -C _0-6 alkylene-OH, C _1-6 alkyl, C _1-6 haloalkyl and C _3-6 cycloalkyl;
R _2s2 and R _2s3 are independently selected from C _1-6 alkyl and C _1-6 haloalkyl;
Alternatively, R _2s2 and R _2s3 together with the carbon atoms to which they are connected form a C _3-6 cycloalkyl;
Alternatively, R _2s1 , R _2s2 and R _2s3 together with the carbon atoms to which they are connected to form;
A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated. In Article 81,
M ₁ is selected from CR ₁ and N, preferably CR ₁ ;
M ₂ is selected from CR ₂ and N, preferably CR ₂ ;
M ₃ is selected from CR ₃ and N, preferably CR ₃ ;
M ₄ is selected from CR ₄ and N, preferably CR ₄ ;
Ring A is is selected from;
At this time, R _a is selected from H and D, and m=0, 1, 2, 3, 4 or 5;
R ₁ and R ₂ together with the carbon atoms to which they are connected to form;
R ₃ and R ₄ are independently selected from H and D;
R _1s is H;
R _2s1 is selected from Me, CH ₂ F, CH ₂ OH, and cyclopropyl;
R _2s2 and R _2s3 are Me;
Alternatively, R _2s2 and R _2s3 together with the carbon atoms to which they are connected form cyclopropyl;
Alternatively, R _2s1 , R _2s2 and R _2s3 together with the carbon atoms to which they are connected to form;
A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated. In claim 30, a compound of formula (IV), or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof:

In the above chemical formula,
M ₁ is selected from CR ₁ and N, preferably CR ₁ ;
M ₂ is selected from CR ₂ and N, preferably CR ₂ ;
M ₃ is selected from CR ₃ and N, preferably CR ₃ ;
M ₄ is selected from CR ₄ and N, preferably CR ₄ ;
Ring A is is selected from;
At this time, R _a is selected from H and D, and m = 1, 2, or 3;
R ₁ and R ₄ are independently selected from H, D, halo, C _1-6 alkyl and C _1-6 haloalkyl;
R ₂ and R ₃ together with the carbon atoms to which they are connected to form;
R _1s is selected from H, C _1-6 alkyl and C _1-6 haloalkyl;
R _2s1 is selected from H, D, -C _0-6 alkylene-OR _x , -C _0-6 alkylene-NR _y R _z , C _1-6 alkyl, and C _1-6 haloalkyl;
R _2s2 and R _2s3 are independently selected from C _1-6 alkyl and C _1-6 haloalkyl;
R _1s and R _2s3 together with the atoms to which they are connected form a 4- to 6-membered heterocyclyl, which is optionally substituted with OH;
R _2s1 and R _2s2 together with the carbon atoms to which they are connected form C _3-6 cycloalkyl;
R _x , R _y and R _z are independently selected from H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, C _2-6 haloalkynyl, C _3-8 cycloalkyl and 4- to 6-membered heterocyclyl; or R _y and R _z together with the nitrogen atom to which they are connected form a 4- to 6-membered heterocyclyl;
The above-mentioned atoms may be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated. In Article 83,
M ₁ is selected from CR ₁ and N, preferably CR ₁ ;
M ₂ is selected from CR ₂ and N, preferably CR ₂ ;
M ₃ is selected from CR ₃ and N, preferably CR ₃ ;
M ₄ is selected from CR ₄ and N, preferably CR ₄ ;
Ring A is is selected from;
At this time, R _a is selected from H and D, and m = 1, 2, or 3;
R ₁ is selected from halo, C _1-6 alkyl and C _1-6 haloalkyl;
R ₂ and R ₃ together with the carbon atoms to which they are connected to form;
R ₄ is selected from H and D;
R _1s is selected from H, C _1-6 alkyl and C _1-6 haloalkyl;
R _2s1 is selected from -C _0-6 alkylene-OH, C _1-6 alkyl and C _1-6 haloalkyl;
R _2s2 and R _2s3 are independently selected from C _1-6 alkyl and C _1-6 haloalkyl;
R _1s and R _2s3 together with the atoms to which they are connected form a 4- to 5-membered heterocyclyl, which is optionally substituted with OH;
R _2s1 and R _2s2 together with the carbon atoms to which they are connected form C _3-5 cycloalkyl;
A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated. In Article 84,
M ₁ is selected from CR ₁ and N, preferably CR ₁ ;
M ₂ is selected from CR ₂ and N, preferably CR ₂ ;
M ₃ is selected from CR ₃ and N, preferably CR ₃ ;
M ₄ is selected from CR ₄ and N, preferably CR ₄ ;
Ring A is is selected from;
At this time, R _a is selected from H and D, and m = 1, 2, or 3;
R ₁ is selected from Cl, and Me;
R ₂ and R ₃ together with the carbon atoms to which they are connected to form;
R ₄ is selected from H and D;
R _1s is selected from H, Me and Et;
R _2s1 is selected from Me and CH ₂ OH;
R _2s2 is Me;
R _2s3 is Me;
R _1s and R _2s3 together with the atoms to which they are connected form a 4- to 5-membered heterocyclyl, which is optionally substituted with OH;
R _2s1 and R _2s2 together with the carbon atoms to which they are connected form cyclopropyl;
A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated. In Article 83,
M ₁ is selected from CR ₁ and N, preferably CR ₁ ;
M ₂ is selected from CR ₂ and N, preferably CR ₂ ;
M ₃ is selected from CR ₃ and N, preferably CR ₃ ;
M ₄ is selected from CR ₄ and N, preferably CR ₄ ;
Ring A is and;
At this time, R _a is selected from H and D, and m = 1, 2, or 3;
R ₁ and R ₄ are independently selected from H, D, halo, C _1-6 alkyl and C _1-6 haloalkyl;
R ₂ and R ₃ together with the carbon atoms to which they are connected to form;
R _1s is selected from H, C _1-6 alkyl and C _1-6 haloalkyl;
R _2s1 is selected from -C _0-6 alkylene-OH, C _1-6 alkyl and C _1-6 haloalkyl;
R _2s2 and R _2s3 are independently selected from C _1-6 alkyl and C _1-6 haloalkyl;
R _1s and R _2s3 together with the atoms to which they are connected form a 4- to 6-membered heterocyclyl;
A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated. In Article 86,
M ₁ is selected from CR ₁ and N, preferably CR ₁ ;
M ₂ is selected from CR ₂ and N, preferably CR ₂ ;
M ₃ is selected from CR ₃ and N, preferably CR ₃ ;
M ₄ is selected from CR ₄ and N, preferably CR ₄ ;
Ring A is and;
At this time, R _a is selected from H and D, and m = 1, 2, or 3;
R ₁ is halo;
R ₂ and R ₃ together with the carbon atoms to which they are connected to form;
R ₄ is selected from H and D;
R _1s is selected from H, C _1-6 alkyl and C _1-6 haloalkyl;
R _2s1 is selected from -C _0-6 alkylene-OH, C _1-6 alkyl and C _1-6 haloalkyl;
R _2s2 and R _2s3 are independently selected from C _1-6 alkyl and C _1-6 haloalkyl;
R _1s and R _2s3 together with the atoms to which they are connected form a 4- to 5-membered heterocyclyl;
A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated. In Article 87,
M ₁ is selected from CR ₁ and N, preferably CR ₁ ;
M ₂ is selected from CR ₂ and N, preferably CR ₂ ;
M ₃ is selected from CR ₃ and N, preferably CR ₃ ;
M ₄ is selected from CR ₄ and N, preferably CR ₄ ;
Ring A is and;
At this time, R _a is selected from H and D, and m = 1, 2, or 3;
R ₁ is Cl;
R ₂ and R ₃ together with the carbon atoms to which they are connected to form;
R ₄ is selected from H and D;
R _1s is selected from H and Me;
R _2s1 is selected from Me and CH ₂ OH;
R _2s2 is Me;
R _2s3 is Me;
R _1s and R _2s3 together with the atoms to which they are connected form a 4- to 5-membered heterocyclyl;
A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated. In claim 30, a compound of formula (IV), or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof:

In the above chemical formula,
M ₁ is selected from CR ₁ and N, preferably CR ₁ ;
M ₂ is selected from CR ₂ and N, preferably CR ₂ ;
M ₃ is selected from CR ₃ and N, preferably CR ₃ ;
M ₄ is selected from CR ₄ and N, preferably CR ₄ ;
Ring A is is selected from;
wherein R _a is selected from H, D, halo, C _1-6 alkyl, and C _1-6 haloalkyl, and m=0, 1, 2, 3, 4, or 5;
R ₁ is selected from H, D, halo, CN, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, C _2-6 haloalkynyl, C _1-6 alkoxyl, C _{1-6 haloalkoxyl, and C 3-6 cycloalkyl} ;
R ₂ is selected from H, D, halo, NH ₂ , -C _0-6 alkylene-OH, -OC _1-6 alkylene-OH, -C(O)C _1-6 alkyl, -C(O)C _1-6 haloalkyl, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxyl, C _1-6 haloalkoxyl and 5-membered heteroaryl, which is optionally substituted with 1, 2 or 3 halo;
R ₃ is selected from H, D, halo, OH, C _1-6 alkoxyl and C _1-6 haloalkoxyl;
R ₄ is selected from H, D and halo;
Alternatively, R ₁ and R ₂ together with the carbon atoms to which they are connected , which is optionally substituted with 1, 2 or 3 halo, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, C _2-6 haloalkynyl, or C _2-6 alkynyl-substituted phenyl;
Alternatively, R ₂ and R ₃ together with the carbon atoms to which they are connected form a 5- to 7-membered heterocyclyl, which is optionally substituted with 1, 2, 3 or 4 halo, C _1-6 alkyl, C _1-6 haloalkyl, -C _1-6 alkylene-C _1-6 alkoxyl or -C _1-6 alkylene-C _1-6 haloalkoxyl;
R _1s is H, C _1-6 alkyl or C _1-6 haloalkyl;
R _2s1 is selected from H, D, -C _0-6 alkylene-OH, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, C _2-6 haloalkynyl and C _3-6 cycloalkyl;
R _2s2 is H, D, C _1-6 alkyl or C _1-6 haloalkyl;
R _2s3 is C _1-6 alkyl or C _1-6 haloalkyl;
Alternatively, R _1s and R _2s3 together with the atoms to which they are connected form a 4- to 7-membered heterocyclyl, which is optionally substituted with 1 or 2 halo;
Alternatively, R _2s2 and R _2s3 together with the carbon atoms to which they are connected form a C _3-6 cycloalkyl, which is optionally substituted with 1 or 2 halo;
Alternatively, R _2s1 , R _2s2 and R _2s3 together with the carbon atoms to which they are connected form a C _4-8 bridged bicycloalkyl, which is optionally substituted with 1 or 2 halo, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl and C _2-6 haloalkynyl;
The above-mentioned atoms may be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated. In Article 89,
M ₁ is selected from CR ₁ and N, preferably CR ₁ ;
M ₂ is selected from CR ₂ and N, preferably CR ₂ ;
M ₃ is selected from CR ₃ and N, preferably CR ₃ ;
M ₄ is selected from CR ₄ and N, preferably CR ₄ ;
Ring A is Selected from among;
At this time, R _a is selected from H, D and halo, and m = 0, 1, 2, 3, 4 or 5;
R ₁ is selected from H, D, halo, CN, C _1-4 alkyl, C _1-4 haloalkyl, C _2-4 alkenyl, C _2-4 haloalkenyl, C _2-4 alkynyl, C _2-4 haloalkynyl, C _1-4 alkoxyl, C 1-4 haloalkoxyl, and C _3-6 cycloalkyl _;
R ₂ is selected from H, D, halo, NH ₂ , -C _0-4 alkylene-OH, -OC _1-4 alkylene-OH, -C(O)C _1-4 alkyl, -C(O)C _1-4 haloalkyl, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxyl, C _1-4 haloalkoxyl and 5-membered heteroaryl, which is optionally substituted with 1 or 2 halo;
R ₃ is selected from H, D, halo, OH, C _1-4 alkoxyl and C _1-4 haloalkoxyl;
R ₄ is selected from H, D and halo;
Alternatively, R ₁ and R ₂ together with the carbon atoms to which they are connected , which is optionally substituted with 1 or 2 Br or C _2-6 alkynyl-substituted phenyl;
Alternatively, R ₂ and R ₃ together with the carbon atoms to which they are connected form a 5- to 7-membered heterocyclyl, which is optionally substituted with 1, 2, 3 or 4 halo, C _1-6 alkyl, C _1-6 haloalkyl, -C _1-4 alkylene-OH, -C _1-4 alkylene-C _1-4 alkoxyl or -C _1-4 alkylene-C _1-4 haloalkoxyl;
R _1s is H, C _1-6 alkyl or C _1-6 haloalkyl;
R _2s1 is selected from H, D, -C _0-4 alkylene-OH, C _1-4 alkyl, C _1-4 haloalkyl, C _2-4 alkenyl, C _2-4 haloalkenyl, C _2-4 alkynyl, C _2-4 haloalkynyl and C _3-6 cycloalkyl;
R _2s2 is H, D, C _1-4 alkyl or C _1-4 haloalkyl;
R _2s3 is C _1-4 alkyl or C _1-4 haloalkyl;
Alternatively, R _1s and R _2s3 together with the atoms to which they are connected form a 5- to 7-membered heterocyclyl, which is optionally substituted with 1 or 2 halo;
Alternatively, R _2s2 and R _2s3 together with the carbon atoms to which they are connected form a C _3-6 cycloalkyl, which is optionally substituted with 1 or 2 halo;
Alternatively, R _2s1 , R _2s2 and R _2s3 together with the carbon atoms to which they are connected form a C _4-8 bridged bicycloalkyl, which is optionally substituted with 1 or 2 halo, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl and C _2-6 haloalkynyl;
A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated. In Article 89,
M ₁ is selected from CR ₁ and N, preferably CR ₁ ;
M ₂ is selected from CR ₂ and N, preferably CR ₂ ;
M ₃ is selected from CR ₃ and N, preferably CR ₃ ;
M ₄ is selected from CR ₄ and N, preferably CR ₄ ;
Ring A is Selected from among;
At this time, R _a is selected from H and D, and m=0, 1, 2, 3, 4 or 5;
R ₁ is selected from H, D, F, Cl, CN, Me, CH=CH ₂ , CF ₃ , and cyclopropyl;
R ₂ is H, D, Cl, Br, OH, Me, CH ₂ F, CHF ₂ , CF ₃ , OMe, OCH ₂ CH ₂ OH, CH ₂ OH, -C(O)Me, NH ₂ , is selected from;
R ₃ is selected from H, D, F, Br, OH and OMe;
R ₄ is selected from H, D and F;
Alternatively, R ₁ and R ₂ together with the carbon atoms to which they are connected , which is optionally substituted with Br or C _2-6 alkynyl-substituted phenyl;
Alternatively, R ₂ and R ₃ together with the carbon atoms to which they are connected , forming;
R _1s is H, C _1-6 alkyl or C _1-6 haloalkyl;
R _2s1 is selected from H, D, OH, Me, Et, CH ₂ F, CHF ₂ , CF ₃ , CH ₂ OH, CH ₂ CH ₂ OH, C≡CH, and cyclopropyl;
R _2s2 is selected from H, D and Me;
R _2s3 is Me, or
Alternatively, R _1s and R _2s3 together with the atoms to which they are connected form a 5-membered heterocyclyl, which is optionally substituted with 1 or 2 halo;
Alternatively, R _2s2 and R _2s3 together with the carbon atoms to which they are connected form cyclopropyl, cyclobutyl or cyclopentyl;
Alternatively, R _2s1 , R _2s2 and R _2s3 together with the carbon atoms to which they are connected to form;
A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated. In Article 89,
M ₁ is selected from CR ₁ and N, preferably CR ₁ ;
M ₂ is selected from CR ₂ and N, preferably CR ₂ ;
M ₃ is selected from CR ₃ and N, preferably CR ₃ ;
M ₄ is selected from CR ₄ and N, preferably CR ₄ ;
Ring A is Selected from among;
wherein R _a is selected from H, D, halo, C _1-6 alkyl, and C _1-6 haloalkyl, and m=0, 1, 2, 3, 4, or 5;
R ₁ is selected from H, D, halo, CN, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, C _2-6 haloalkynyl, C _1-6 alkoxyl, C _{1-6 haloalkoxyl, and C 3-6 cycloalkyl} ;
R ₂ is selected from H, D, halo, NH ₂ , -C _0-6 alkylene-OH, -OC _1-6 alkylene-OH, -C(O)C _1-6 alkyl, -C(O)C _1-6 haloalkyl, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxyl, and C _1-6 haloalkoxyl;
R ₃ is selected from H, D, halo, OH, C _1-6 alkoxyl and C _1-6 haloalkoxyl;
R ₄ is selected from H, D and halo;
Alternatively, R ₁ and R ₂ together with the carbon atoms to which they are connected , which is optionally substituted with 1, 2 or 3 halo or C _2-6 alkynyl-substituted phenyl;
Alternatively, R ₂ and R ₃ together with the carbon atoms to which they are connected form a 5- to 7-membered heterocyclyl, which is optionally substituted with 1, 2, 3 or 4 halo, C _1-6 alkyl or C _1-6 haloalkyl;
R _1s is H, C _1-6 alkyl or C _1-6 haloalkyl;
R _2s1 is selected from H, D, -C _0-6 alkylene-OH, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, and C _2-6 haloalkynyl;
R _2s2 is C _1-6 alkyl or C _1-6 haloalkyl;
R _2s3 is C _1-6 alkyl or C _1-6 haloalkyl;
Alternatively, R _1s and R _2s3 together with the atoms to which they are connected form a 4- to 7-membered heterocyclyl, which is optionally substituted with 1 or 2 halo;
Alternatively, R _2s2 and R _2s3 together with the carbon atoms to which they are connected form a C _3-6 cycloalkyl, which is optionally substituted with 1 or 2 halo;
A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated. In Article 89,
M ₁ is selected from CR ₁ and N, preferably CR ₁ ;
M ₂ is selected from CR ₂ and N, preferably CR ₂ ;
M ₃ is selected from CR ₃ and N, preferably CR ₃ ;
M ₄ is selected from CR ₄ and N, preferably CR ₄ ;
Ring A is Selected from among;
At this time, R _a is selected from H, D and halo, and m = 0, 1, 2, 3, 4 or 5;
R ₁ is selected from H, D, halo, CN, C _1-4 alkyl, C _1-4 haloalkyl, C _2-4 alkenyl, C _2-4 haloalkenyl, C _2-4 alkynyl, C _2-4 haloalkynyl, C _1-4 alkoxyl, C 1-4 haloalkoxyl, and C _3-6 cycloalkyl _;
R ₂ is selected from H, D, halo, NH ₂ , -C _0-4 alkylene-OH, -OC _1-4 alkylene-OH, -C(O)C _1-4 alkyl, -C(O)C _1-4 haloalkyl, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxyl, and C _1-4 haloalkoxyl;
R ₃ is selected from H, D, halo, OH, C _1-4 alkoxyl and C _1-4 haloalkoxyl;
R ₄ is selected from H, D and halo;
Alternatively, R ₁ and R ₂ together with the carbon atoms to which they are connected , which is optionally substituted with 1 or 2 Br or C _2-6 alkynyl-substituted phenyl;
Alternatively, R ₂ and R ₃ together with the carbon atoms to which they are connected form a 5- to 7-membered heterocyclyl, which is optionally substituted with 1, 2, 3 or 4 halo, C _1-6 alkyl or C _1-6 haloalkyl;
R _1s is H, C _1-6 alkyl or C _1-6 haloalkyl;
R _2s1 is selected from H, D, -C _0-4 alkylene-OH, C _1-4 alkyl, C _1-4 haloalkyl, C _2-4 alkenyl, C _2-4 haloalkenyl, C _2-4 alkynyl, and C _2-4 haloalkynyl;
R _2s2 is C _1-4 alkyl or C _1-4 haloalkyl;
R _2s3 is C _1-4 alkyl or C _1-4 haloalkyl;
Alternatively, R _1s and R _2s3 together with the atoms to which they are connected form a 5- to 7-membered heterocyclyl, which is optionally substituted with 1 or 2 halo;
Alternatively, R _2s2 and R _2s3 together with the carbon atoms to which they are connected form a C _3-6 cycloalkyl, which is optionally substituted with 1 or 2 halo;
A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated. In Article 89,
M ₁ is selected from CR ₁ and N, preferably CR ₁ ;
M ₂ is selected from CR ₂ and N, preferably CR ₂ ;
M ₃ is selected from CR ₃ and N, preferably CR ₃ ;
M ₄ is selected from CR ₄ and N, preferably CR ₄ ;
Ring A is Selected from among;
At this time, R _a is selected from H and D, and m=0, 1, 2, 3, 4 or 5;
R ₁ is selected from H, D, F, Cl, CN, Me, CH=CH ₂ , CF ₃ , OMe, and cyclopropyl;
R ₂ is selected from H, D, Cl, Br, OH, Me, CH ₂ F, CHF ₂ , CF ₃ , OMe, OCH ₂ CH ₂ OH, CH ₂ OH, -C(O)Me, and NH ₂ ;
R ₃ is selected from H, D, F, Br, OH and OMe;
R ₄ is selected from H, D and F;
Alternatively, R ₁ and R ₂ together with the carbon atoms to which they are connected , which is optionally substituted with 1 or 2 Br or C _2-6 alkynyl-substituted phenyl;
Alternatively, R ₂ and R ₃ together with the carbon atoms to which they are connected to form;
R _1s is H or Me;
R _2s1 is selected from H, D, OH, Me, Et, CH ₂ F, CHF ₂ , CF ₃ , CH ₂ OH, CH ₂ CH ₂ OH, and C≡CH;
R _2s2 is Me;
R _2s3 is Me;
Alternatively, R _1s and R _2s3 together with the atoms to which they are connected form a 5-membered heterocyclyl, which is optionally substituted with 1 or 2 halo;
Alternatively, R _2s2 and R _2s3 together with the carbon atoms to which they are connected form cyclopropyl, cyclobutyl and cyclopentyl;
A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated. In Article 89,
M ₁ is selected from CR ₁ and N, preferably CR ₁ ;
M ₂ is selected from CR ₂ and N, preferably CR ₂ ;
M ₃ is selected from CR ₃ and N, preferably CR ₃ ;
M ₄ is selected from CR ₄ and N, preferably CR ₄ ;
Ring A is is selected from;
wherein R _a is selected from H, D, halo, C _1-6 alkyl, and C _1-6 haloalkyl, and m=0, 1, 2, 3, 4, or 5;
R ₁ is selected from H, D, halo, CN, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, and C _2-6 haloalkynyl;
R ₂ is selected from H, D, halo, -C _0-6 alkylene-OH, -OC _1-6 alkylene-OH, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxyl, and C _1-6 haloalkoxyl;
R ₃ is selected from H, D, halo and OH;
R ₄ is selected from H and D;
Alternatively, R ₁ and R ₂ are linked together with the carbon atoms to which they are attached. to form or;
Alternatively, R ₂ and R ₃ together with the carbon atoms to which they are connected to form or;
R _1s is H, C _1-6 alkyl or C _1-6 haloalkyl;
R _2s1 is selected from H, D, -C _0-6 alkylene-OH, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, and C _2-6 haloalkynyl;
R _2s2 is C _1-6 alkyl or C _1-6 haloalkyl;
R _2s3 is C _1-6 alkyl or C _1-6 haloalkyl;
Alternatively, R _1s and R _2s3 together with the atoms to which they are connected form a 5- to 7-membered heterocyclyl, which is optionally substituted with 1 or 2 halo;
Alternatively, R _2s2 and R _2s3 together with the carbon atoms to which they are connected form a C _3-5 cycloalkyl, which is optionally substituted with 1 or 2 halo;
A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated. In Article 89,
M ₁ is selected from CR ₁ and N, preferably CR ₁ ;
M ₂ is selected from CR ₂ and N, preferably CR ₂ ;
M ₃ is selected from CR ₃ and N, preferably CR ₃ ;
M ₄ is selected from CR ₄ and N, preferably CR ₄ ;
Ring A is is selected from;
At this time, R _a is selected from H, D and halo, and m = 0, 1, 2, 3, 4 or 5;
R ₁ is selected from H, D, halo, CN, C _1-4 alkyl, C _1-4 haloalkyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, and C _2-6 haloalkynyl;
R ₂ is selected from H, D, halo, -C _0-4 alkylene-OH, -OC _1-4 alkylene-OH, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxyl, and C _1-4 haloalkoxyl;
R ₃ is selected from H, D, halo and OH;
R ₄ is selected from H and D;
Alternatively, R ₁ and R ₂ are linked together with the carbon atoms to which they are attached. to form or;
Alternatively, R ₂ and R ₃ together with the carbon atoms to which they are connected to form or;
R _1s is H, C _1-6 alkyl or C _1-6 haloalkyl;
R _2s1 is selected from H, D, -C _0-4 alkylene-OH, C _1-4 alkyl, C _1-4 haloalkyl, C _2-4 alkenyl, C _2-4 haloalkenyl, C _2-4 alkynyl, and C _2-4 haloalkynyl;
R _2s2 is C _1-4 alkyl or C _1-4 haloalkyl;
R _2s3 is C _1-4 alkyl or C _1-4 haloalkyl;
Alternatively, R _1s and R _2s3 together with the atoms to which they are connected form a 5- to 7-membered heterocyclyl, which is optionally substituted with 1 or 2 halo;
Alternatively, R _2s2 and R _2s3 together with the carbon atoms to which they are connected form a C _3-5 cycloalkyl, which is optionally substituted with 1 or 2 halo;
A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated. In Article 89,
M ₁ is selected from CR ₁ and N, preferably CR ₁ ;
M ₂ is selected from CR ₂ and N, preferably CR ₂ ;
M ₃ is selected from CR ₃ and N, preferably CR ₃ ;
M ₄ is selected from CR ₄ and N, preferably CR ₄ ;
Ring A is is selected from;
At this time, R _a is selected from H and D, and m=0, 1, 2, 3, 4 or 5;
R ₁ is selected from H, D, F, Cl, CN, Me, CH=CH ₂ , and CF ₃ ;
R ₂ is selected from H, D, Cl, Br, OH, Me, CH ₂ F, CHF ₂ , CF ₃ , OMe, OCH ₂ CH ₂ OH, and CH ₂ OH;
R ₃ is selected from H, D, F, Br and OH;
R ₄ is selected from H and D;
Alternatively, R ₁ and R ₂ together with the carbon atoms to which they are connected to form or;
Alternatively, R ₂ and R ₃ together with the carbon atoms to which they are connected to form;
R _1s is H or Me;
R _2s1 is selected from H, D, OH, Me, Et, CH ₂ F, CHF ₂ , CF ₃ , CH ₂ OH, CH ₂ CH ₂ OH, and C≡CH;
R _2s2 is Me;
R _2s3 is Me;
Alternatively, R _1s and R _2s3 together with the atoms to which they are connected form a 5-membered heterocyclyl, which is optionally substituted with 1 or 2 halo;
Alternatively, R _2s2 and R _2s3 together with the carbon atoms to which they are connected form cyclopropyl, cyclobutyl and cyclopentyl;
A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated. In Article 89,
R _1s and R _2s3 are linked to form C _2-6 alkylene, which is optionally substituted with 1, 2 or 3 halo, OH, C _1-6 alkyl or C _1-6 haloalkyl;
The above-mentioned groups may be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated;
Other variables are as defined in any one of claims 1 to 29, the compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof. In Article 98,
M ₁ is selected from CR ₁ and N, preferably CR ₁ ;
M ₂ is selected from CR ₂ and N, preferably CR ₂ ;
M ₃ is selected from CR ₃ and N, preferably CR ₃ ;
M ₄ is selected from CR ₄ and N, preferably CR ₄ ;
Ring A is is selected from;
wherein R _a is selected from H, D, halo, NO ₂ , NH ₂ , -C _1-6 alkylene-OH, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, C _2-6 haloalkynyl and amino protecting group, and m=0, 1, 2, 3, 4 or 5; or two adjacent R _a together with the atoms to which they are connected form phenyl or a 5- to 6-membered heteroaryl;
R ₁ and R ₄ are independently selected from H, D and halo;
R ₂ is selected from H, D, halo, -C _0-6 alkylene-OH, NH ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxyl, C _5-6 cycloalkyl, 5-6 membered heterocyclyl, C _6-10 aryl, 5-10 membered heteroaryl, -O-5-6 membered heteroaryl, -NH-5-6 membered heteroaryl, -OC(O)-5-6 membered heteroaryl, or -NHC(O)-5-6 membered heteroaryl; which is optionally substituted with 1, 2, 3, 4 or 5 CN, halo, oxo, -C _1-6 alkylene-OH, C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl or 5-6 membered heterocyclyl;
R ₃ is selected from H, D, halo, OH, C _1-6 alkyl and C _1-6 haloalkyl;
Alternatively, R ₂ and R ₃ together with the carbon atoms to which they are connected form a 5-6 membered heterocyclyl, which is optionally substituted with 1, 2, 3 or 4 halo, C _1-6 alkyl, C _1-6 haloalkyl, -C(O)C _1-6 alkyl, or -C(O)C _1-6 haloalkyl;
R _1s and R _2s3 are linked to form C _2-6 alkylene, which is optionally substituted with 1, 2 or 3 halo, OH, C _1-6 alkyl or C _1-6 haloalkyl;
R _2s1 is selected from H, D, C _1-6 alkyl and C _1-6 haloalkyl;
R _2s2 is selected from H, D, -C _0-6 alkylene-OH, C _1-6 alkyl and C _1-6 haloalkyl;
Alternatively, R _2s1 and R _2s2 together with the carbon atoms to which they are connected form a C _3-6 cycloalkyl;
A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated. In Article 98,
M ₁ is selected from CR ₁ and N, preferably CR ₁ ;
M ₂ is selected from CR ₂ and N, preferably CR ₂ ;
M ₃ is selected from CR ₃ and N, preferably CR ₃ ;
M ₄ is selected from CR ₄ and N, preferably CR ₄ ;
Ring A is is selected from;
Here, R _a is selected from H, D and halo, and m = 0, 1, 2 or 3;
R ₁ is selected from H, D and halo;
R ₂ is selected from H, D, halo, C _1-4 alkyl and C _1-4 haloalkyl;
R ₃ is selected from H, D and halo;
R ₄ is selected from H and D;
Alternatively, R ₂ and R ₃ together with the carbon atoms to which they are connected to form;
R _1s and R _2s3 are linked to form C _2-4 alkylene, which is optionally substituted with 1, 2 or 3 halo, OH, C _1-4 alkyl or C _1-4 haloalkyl;
R _2s1 is selected from H, D, C _1-4 alkyl and C _1-4 haloalkyl;
R _2s2 is selected from H, D, -C _1-4 alkylene-OH, C _1-4 alkyl and C _1-4 haloalkyl;
Alternatively, R _2s1 and R _2s2 together with the carbon atoms to which they are connected form a C _3-5 cycloalkyl;
A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated. In Article 98,
M ₁ is selected from CR ₁ and N, preferably CR ₁ ;
M ₂ is selected from CR ₂ and N, preferably CR ₂ ;
M ₃ is selected from CR ₃ and N, preferably CR ₃ ;
M ₄ is selected from CR ₄ and N, preferably CR ₄ ;
Ring A is
is selected from;
At this time, R _a is selected from H and D, and m=0, 1, 2, 3, 4 or 5;
R ₁ is Cl;
R ₂ is Cl;
R ₃ is selected from H and D;
R ₄ is selected from H and D;
Alternatively, R ₂ and R ₃ together with the carbon atoms to which they are connected to form;
R _1s and R _2s3 are linked to form C _2-6 alkylene, which is optionally substituted with 1 or 2 OH;
R _2s1 is selected from H, D and Me;
R _2s2 is selected from H, D, Me and CH ₂ OH;
Alternatively, R _2s1 and R _2s2 together with the carbon atoms to which they are connected form cyclopropyl;
A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, wherein the above-mentioned groups can be substituted with 1, 2, 3, 4, 5 or more deuterium atoms until fully deuterated. A compound selected from the group consisting of compounds described in Tables 1 to 13 , or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof. As a pharmaceutical composition,
A compound as described in any one of claims 1 to 102, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof;
Pharmaceutically acceptable excipient(s); and
Optionally, one or more other treatments
A pharmaceutical composition comprising: As a kit,
A first container containing a compound as described in any one of claims 1 to 102, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof; and
Optionally, a second container containing one or more other therapeutic agents; and
Optionally, a kit comprising a third container containing pharmaceutically acceptable excipient(s) for diluting or suspending the compound and/or other therapeutic agent(s). Use of a compound according to any one of claims 1 to 102, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, in the manufacture of a medicament for treating an immune and/or inflammatory disease, disorder or condition associated with excessive or inappropriate ALPK1-dependent proinflammatory signaling. A compound according to any one of claims 1 to 102, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, for use in treating an immune and/or inflammatory disease, disorder or condition associated with excessive or inappropriate ALPK1-dependent proinflammatory signaling. A method for treating an immune and/or inflammatory disease, disorder or condition associated with excessive or inappropriate ALPK1-dependent inflammatory signaling in a subject, the method comprising administering to a subject in need thereof a compound according to any one of claims 1 to 102, or a pharmaceutically acceptable salt, stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof. A use, compound or method according to any one of claims 105 to 107, wherein the disease, disorder or condition is selected from sepsis, cancer, systemic lupus erythematosus, hidradenoma, hidradenoma, Kawasaki disease, ROSAH (retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis and migraine) syndrome, PFAPA (periodic fevers, aphthous stomatitis, pharyngitis and adenitis) syndrome, inflammatory bowel disease (IBD), NASH, gout, diabetes, chronic kidney disease, pancreatitis, Kawasaki disease, inflammatory skin diseases, and neurodegenerative diseases including Alzheimer's disease. A use, compound or method according to claim 108, wherein the cancer is selected from lung cancer, colon cancer and oral squamous cell carcinoma. A use, compound or method according to claim 108, wherein the disease or disorder is ROSAH. A use, compound or method according to claim 108, wherein the disease or disorder is PFAPA. A use, compound or method according to claim 108, wherein the disease or disorder is a sweat gland tumor or sweat gland carcinoma. A use, compound or method according to claim 108, wherein the disease or disorder is sepsis. A use, compound or method according to claim 108, wherein the disease or disorder is systemic lupus erythematosus. A use, compound or method according to claim 108, wherein the disease or disorder is Kawasaki disease. A use, compound or method according to claim 108, wherein the subject has one or more ALPK1 gene mutations.