WO2024037668A1

WO2024037668A1 - 2-nitrogen-substituted pyrimidine compound, preparation method therefor, and application thereof

Info

Publication number: WO2024037668A1
Application number: PCT/CN2023/124994
Authority: WO
Inventors: 张所明
Original assignee: 德明药泰生物技术（深圳）有限公司
Priority date: 2022-08-19
Filing date: 2023-10-17
Publication date: 2024-02-22
Also published as: CN117624135A

Abstract

Disclosed are a 2-nitrogen-substituted pyrimidine compound represented by formula I, a respective optical isomer, a deuterated substance, a prodrug or a pharmaceutically acceptable salt thereof, a pharmaceutical composition comprising the 2-nitrogen-substituted pyrimidine compound, and a use thereof as an AHR inhibitor. In the present invention, the 2-nitrogen-substituted pyrimidine compound represented by the formula I, the respective optical isomer, deuterated substance, prodrug or pharmaceutically acceptable salt thereof can inhibit AHR and the functions and signal pathways controlled by AHR, so that the growth and proliferation of cancer cells and the invasiveness of tumor cells can be affected. Thus, the 2-nitrogen-substituted pyrimidine compound represented by formula I of the present invention, the respective optical isomer, the deuterated substance, the prodrug or pharmaceutically acceptable salt thereof can be used for inhibiting the growth of cancer cells and inhibiting the metastasis and invasion of tumor cells.

Description

2-Nitrogen-substituted pyrimidine compounds and their preparation methods and applications

Technical field

The invention belongs to the technical field of biopharmaceuticals, and in particular relates to a 2-nitrogen-substituted pyrimidine compound and its pharmaceutically acceptable salt, as well as its preparation method and application.

Background technique

Aryl hydrocarbon receptor (AHR) is a member of the subfamily bHLH-PAS (bHLH-PER-ARNT-SIM) of the basic helix-loop-helix {basic helix-loop-helix (bHLH-PAS)} superfamily. One of them is the only receptor in the bHLH-PAS family that can be activated by ligands [Nat.Rev.Cancer, 2014, 14(12), 801; Nat.Rev.Cancer, 2013, 13(12), 827]. AHR existing in the cytoplasm can sense the stimulation of aromatic hydrocarbons (xenobiotics) in the external environment, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), and then move in The cell nucleus forms a heterodimer with the aryl hydrocarbon receptor nuclear transporter (ARNT). The AHR/ARNT complex then interacts with the XRE (xenobiotic response element) of the AHR corresponding gene to regulate their transcription; AHR can also activate non- XRE-dependent protein-protein interaction pathway.

AHR is the best understood enzyme that binds environmental toxins and induces metabolic machinery, such as cytochrome CYP450 enzymes (e.g., CYP1A1, CYP1A2, and CYP1B1), which can eliminate environmental toxins (Reyes et al., Science, 1992, 256(5060), 1193- 5; Murray et al., Nat Rev Cancer, 2015, 14(12), 801-14). Activation of AHR by environmental toxins has demonstrated the role of AHR in numerous cellular processes, such as embryogenesis, tumorigenesis, and inflammation. AHR is expressed in many cells of the immune system, including dendritic cells, macrophages, T-cells and NK cells, and plays an important role in immune regulation (Nguyen et al., Front Immunol. 2014, 5, 511). Classic exogenous AHR ligands such as TCDD induce profound immunosuppression, promote cancer and induce tumor growth (Oncogene, 2009, 28(28), 2593-2605, Oncogene, 2009, 28(41), 3642-51, Trends Immunol,2009,30,447-454).

Through XRE-dependent or -independent activities, AHR regulates many key innate and adaptive immune responses. Among these responses, AHR agonists promote the production of IL-17 from Th17 cells (T-helper cells) and Treg cells (regulatory T-cells). Activation of AHR further induces the lateral differentiation of Th17 cells and Treg cells and enhances the suppressive activity of Treg. Studies have shown that AHR activation can inhibit the innate inflammatory response regulated by macrophages (such as reducing the expression of IL-1b, IL-6, IL-12 and TNFa induced by LPS), and inhibit dendritic cells (the expression of dendritic cells Activate and promote the expression of IL-10) (Clin Exp Immunol, 2014, 177 (2), 521-30; J Immunol, 2010, 185 (^), 3190-8; Lab Invest, 2014, 94 (5), 528 -35; PNAS, 2010, 107(46), 19961-6).

In order to establish an effective anti-tumor immune response, antigen presenting cells (APCs) need to be processed, presented, and subsequently activated to helper CD4+T-cells (Th) and cytotoxic CD8+T- cells (cytotoxic CD8+T-cells, Tc), these cells work together to effectively dissolve tumor cells. Tumor cells have developed several mechanisms to escape Th and Tc cytolytic regulation of immunity. One of them is the release of high concentrations of kynurenine and other potential AHR ligands in the tumor microenvironment (TME).

High concentrations of AHR ligands in the tumor microenvironment (TME) can lead to direct inhibition of APCs, Th and Tc, as well as the recruitment, production and activation of Treg and Th17, thereby further inhibiting the activities of Tc and Th. Tumors can evade anti-tumor immune responses through these mechanisms. Therefore, AHR inhibitors can block the AHR-dependent immune escape pathways used by malignant tumor cells, thereby restoring anti-tumor immunity.

Recent studies on tumor immunobiology have shown that malignant tumor cells adopt a complex immune evasion mechanism. Preclinical and clinical studies have demonstrated that blocking or enhancing these mechanisms through a combination of therapeutic applications, such as immune checkpoint inhibition and vaccines, can provide optimal restoration of anti-tumor immune responses. While it is hoped that AHR modulators alone will restore anti-tumor immunity, it is expected that AHR inhibitors combined with checkpoint inhibitors and vaccines, or even synergistically with other treatments, will enhance immunotherapy responses.

The immune mechanisms regulated by AHR are related to autoimmune and inflammatory diseases, such as multiple sclerosis and inflammatory bowel disease. sick. Therefore, activating the AHR pathway through AHR agonists may be beneficial in the treatment of autoimmune and inflammatory diseases. Although AHR agonists have been described in the art, there remains a need for improvement in immunomodulatory components and methods for treating autoimmune and inflammatory diseases by modulating the AHR.

For example, some aromatic hydrocarbon receptor compounds have been disclosed in Chinese patent applications CN101466363A, CN108239083A, CN113480530A, TWI752155B, CN114181208, WO2022078356 and other documents. However, there is still an urgent clinical need to develop or improve AHR inhibitors for the treatment of diseases related to AHR pathway disorders.

Contents of the invention

Therefore, according to the first aspect of the present invention, an object of the present invention is to provide a class of 2-nitrogen-substituted pyrimidine compounds represented by the following formula I, each of which is an optical isomer, a deuterated product, a prodrug or a pharmaceutically acceptable compound. Salt accepted:

in,

Ring A is a C _6-10 aryl group or a 5- to 10-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O and S heteroatoms;

R ¹ and R ² are each independently hydrogen, saturated or unsaturated substituted or unsubstituted C ₁ -C ₈ alkyl, saturated or unsaturated substituted or unsubstituted C ₃ -C ₈ cycloalkyl, -OC (=O)C _1-8 alkyl, -OC(=O)C ₃ -C ₈ cycloalkyl, -C(=O)OC ₁ -C ₈ alkyl, -C(=O)C ₃ -C ₈ cycloalkyl, -S(O) _m R ^c , saturated or unsaturated substituted or unsubstituted C ₁ -C ₈ acyl, C ₆ -C ₁₄ aryl, containing 1 to 3 selected from N, O and A 4- to 14-membered heterocycloalkyl group containing a heteroatom of S or a 5- to 14-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S, containing The group is a saturated or unsaturated halogenated or unhalogenated C _1-8 alkyl group, containing The group is a saturated or unsaturated halogenated or unhalogenated C _3-8 cycloalkyl group, wherein "substituted" means optionally substituted by 1 to 10 deuterons, or optionally containing 1 to 4 Each one is selected from hydroxyl, halogen, cyano, -S(O) _m R ^c , -NR ^d ^Re , saturated or unsaturated C ₁ -C ₈ alkyl, saturated or unsaturated C ₃ -C ₈ cycloalkyl base, saturated or unsaturated C ₁ -C ₈ alkoxy group, saturated or unsaturated C ₃ -C ₈ cycloalkoxy group, -OC(=O)C ₁ -C ₈ alkyl group, -OC(=O )C ₃ -C ₈ cycloalkyl, -C(=O)OC _1-8 alkyl, -C(=O)OC ₃ -C ₈ cycloalkyl, containing The group is a saturated or unsaturated halogenated or unhalogenated C _1-8 alkyl group, containing The group is a saturated or unsaturated halogenated or unhalogenated C _3-8 cycloalkyl group, a saturated or unsaturated C ₁ -C ₈ acyl group, a saturated or unsaturated C ₁ -C ₈ alkoxycarbonyl group, C ₆ -C ₁₄ aryl, 4 to 14 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O, and S, or 5 containing 1 to 3 heteroatoms selected from N, O, and S to 14-membered heteroaryl substituents;

Or R ¹ and R ² together with the N atom connecting them form a substituted or unsubstituted 4 to 14 membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, O and S, wherein said "substituted" Refers to being substituted by 1 to 10 deuterium, or optionally containing 1 to 4 selected from hydroxyl, halogen, cyano, sulfonyl, carboxyl -S(O) _m R ^c , -NR ^d R ^e , C ₁ to C ₈ alkyl, C ₃ to C ₈ cycloalkyl, C ₁ to C 8 alkoxy, C ₃ to _{C 8} _cycloalkoxy , -OC(=O)C _1-8 alkyl, - OC(=O)C ₃ ~C ₈ cycloalkyl, -C(=O)OC _1-8 alkyl, -C(=O)OC ₃ ~C ₈ cycloalkyl, containing The group is a saturated or unsaturated halogenated or unhalogenated C _1-8 alkyl group, containing Saturated or unsaturated halogenated or unhalogenated C _3-8 cycloalkyl group, C ₁ to C ₈ alkyl group substituted by R ^f , C ₃ to C ₈ cycloalkyl group, C ₁ to C ₈ Substituents of alkoxy and C ₃ to C ₈ cycloalkoxy;

R ³ is selected from deuterium, halogen, nitro, cyano, carboxyl, hydroxyl, -NR ^d R ^e , -OR ^g , -CO ₂ R ^g , -S(O) _m R ^c , or is replaced by 1 to 3 R ^h -substituted C _1-8 alkyl, C _3-8 cycloalkyl, C _1-8 alkoxy, C _3-8 cycloalkoxy, C _1-8 alkoxycarbonyl, C _1-8 alkyl Carbonyl group, C _1-8 alkylcarboxyl group, 3-10 membered cycloalkyl group, 3-10 membered heterocycloalkyl group, 6-10 membered aryl group, 5-10 membered heteroaryl group.

R ⁴ is H or D.

L is a chemical bond or -NHR ⁱ .

R ^a and R ^b are each independently selected from saturated or unsaturated substituted or unsubstituted C ₃ -C ₈ cycloalkyl, saturated or unsaturated substituted or unsubstituted C ₁ -C ₈ alkyl, substituted or unsubstituted Substituted 6- to 10-membered aryl groups or substituted or unsubstituted 4- to 10-membered heteroaryl groups containing 1 to 3 heteroatoms selected from N, O and S, wherein the "substituted" refers to selectively substituted by 1 ^to 10 deuterium substitutions, or optionally containing 1 to 4 selected from hydroxyl, halogen, cyano, -S(O) _mRc , ^-NRdRe ^, saturated or unsaturated C1 _- _C8 Alkyl, saturated or unsaturated C ₃ -C ₈ cycloalkyl, saturated or unsaturated C ₁ -C ₈ alkoxy, saturated or unsaturated C ₃ -C ₈ cycloalkoxy, -OC(= O)C ₁ -C ₈ alkyl, -OC(=O)C ₃ -C ₈ cycloalkyl, -C(=O)OC _1-8 alkyl, -C(=O)OC ₃ -C ₈ ring Alkyl, saturated or unsaturated C ₁ -C ₈ acyl, saturated or unsaturated C ₁ -C ₈ alkoxycarbonyl, containing The group is a saturated or unsaturated halogenated or unhalogenated C _1-8 alkyl group, containing The group is saturated or unsaturated halogenated or unhalogenated C _3-8 cycloalkyl, C ₆ -C ₁₄ aryl, 4 to 14 containing 1 to 3 heteroatoms selected from N, O and S A substituent of a 5- to 14-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S;

Or R ^a and R ^b together with the N atom connecting them form a substituted or unsubstituted 4 to 14-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, O and S, a substituted or unsubstituted containing 5 to 14 membered heteroaryl groups with 1 to 3 heteroatoms selected from N, O and S, wherein "substituted" means substituted with 1 to 10 deuterons, or optionally containing 1 to 4 selected from Hydroxy, halogen, cyano, sulfonyl, carboxyl -S(O) _m R ^c , -NR ^d R ^e , C ₁ to C ₈ alkyl, C ₃ to C ₈ cycloalkyl, C ₁ to C ₈ alkoxy Base, C ₃ to C ₈ cycloalkoxy group, -OC(=O)C _1-8 alkyl group, -OC(=O)C ₃ to C ₈ cycloalkyl group, -C(=O)OC _1-8 Alkyl, -C(=O)OC ₃ ~ C ₈ cycloalkyl, containing The group is a saturated or unsaturated halogenated or unhalogenated C _1-8 alkyl group, containing Saturated or unsaturated halogenated or unhalogenated C _3-8 cycloalkyl group, C ₁ to C ₈ alkyl group substituted by R ^f , C ₃ to C ₈ cycloalkyl group, C ₁ to C ₈ Alkoxy group and substituent of C ₃ to C ₈ cycloalkoxy group.

n is an integer of 0, 1, 2, 3, 4 or 5.

n1 is an integer of 0, 1 or 2.

m is an integer of 0, 1 or 2.

R ^c , R ^g , ^Rh and R ⁱ are each independently selected from hydrogen, hydroxyl, amino, saturated or unsaturated substituted or unsubstituted C ₁ -C ₈ alkyl, saturated or unsaturated substituted or unsubstituted C ₁ -C ₈ alkyl, C ₃ -C ₈ cycloalkyl, -C(=O)C _1-8 alkyl, -C(=O)C ₃ -C ₈ cycloalkyl, -C(=O )OC ₁ -C ₈ alkyl, -C(=O)OC ₃ -C ₈ cycloalkyl, -C(=O)NC ₁ -C ₈ alkyl, -C(=O)NC ₃ -C ₈ cyclo Alkyl, saturated or unsaturated substituted or unsubstituted C ₁ -C ₈ sulfonyl, C ₆ -C ₁₄ aryl, C ₇ -C ₁₄ arylalkyl, containing 1 to 3 selected from N, O and A 4- to 14-membered heterocycloalkyl group containing a heteroatom of S or a 5- to 14-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S, wherein "substituted" means substituted by 1 to 10 deuterium substituted, or optionally containing 1 to 4 selected from hydroxyl, halogen, cyano, sulfonyl, -NR ^d ^Re , saturated or unsaturated C ₁ -C ₈ alkyl, saturated or unsaturated C ₃ -C ₈ cycloalkyl, saturated or unsaturated C ₁ -C ₈ alkoxy, saturated or unsaturated C ₃ -C ₈ cycloalkoxy, -OC(=O)C ₁ -C ₈ alkyl , -OC(=O)C ₃ -C ₈ cycloalkyl, -C(=O)OC _1-8 alkyl, -C(=O)OC ₃ -C ₈ cycloalkyl, saturated or unsaturated C ₁ -C ₈ sulfonyl group, saturated or unsaturated C ₁ -C ₈ acyl group, saturated or unsaturated C ₁ -C ₈ alkoxycarbonyl group, C ₆ -C ₁₄ aryl group, containing 1 to 3 selected from N , a 4- to 14-membered heterocycloalkyl group with heteroatoms of O and S or a 5- to 14-membered heteroaryl substituent containing 1 to 3 heteroatoms selected from N, O and S, wherein R ^c is not hydrogen ;

R ^d and R ^e are each independently selected from hydrogen, halogen, cyano, hydroxyl, saturated or unsaturated C ₁ to C ₃ alkyl, C ₃ to C ₆ cycloalkyl, saturated or unsaturated halogen or hydroxyl Substituted C ₁ to C ₃ alkyl, C ₃ to C ₆ cycloalkyl substituted by halogen or hydroxyl, saturated or unsaturated C ₁ to C ₃ alkoxy, C ₃ to C ₆ cycloalkoxy, saturated or Unsaturated C ₁ to C ₃ alkoxy group substituted by halogen or hydroxyl group, C ₃ to C ₆ cycloalkoxy group substituted by halogen or hydroxyl group.

Preferably, ring A is a C _6-10 aryl group or a 5-8 membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O and S heteroatoms.

Preferably, R ¹ and R ² are each independently hydrogen, saturated or unsaturated substituted or unsubstituted C ₁ -C ₆ alkyl, saturated or unsaturated substituted or unsubstituted C ₃ -C ₆ cycloalkyl , -OC(=O)C _1-6 alkyl, -OC(=O)C ₃ -C ₆ cycloalkyl, -C(=O)OC ₁ -C ₆ alkyl, -C(=O)C ₃ -C ₆ cycloalkyl, -S(O) _m R ^c , saturated or unsaturated substituted or unsubstituted C ₁ -C ₆ acyl, C ₆ -C ₁₀ aryl, containing 1 to 3 selected from N , a 5- to 10-membered heterocycloalkyl group containing heteroatoms of O and S or a 5- to 10-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S, containing The group is a saturated or unsaturated halogenated or unhalogenated C _1-6 alkyl group, containing The group is a saturated or unsaturated halogenated or unhalogenated C _3-6 cycloalkyl group, wherein "substituted" means substituted by 1 to 10 deuterons, or optionally contains 1 to 4 selected from Hydroxy, halogen, cyano, -S(O) _m R ^c , -NR ^d R ^e , saturated or unsaturated C ₁ -C ₆ alkyl, saturated or unsaturated C ₃ -C ₆ cycloalkyl, saturated Or unsaturated C ₁ -C ₆ alkoxy, saturated or unsaturated C ₃ -C ₆ cycloalkoxy, -OC(=O)C ₁ -C ₆ alkyl, -OC(=O)C ₃ -C ₆ cycloalkyl, -C(=O)OC _1-6 alkyl, -C(=O)OC ₃ -C ₆ cycloalkyl, containing The group is a saturated or unsaturated halogenated or unhalogenated C _1-6 alkyl group, containing The group is a saturated or unsaturated halogenated or unhalogenated C _3-6 cycloalkyl group, a saturated or unsaturated C ₁ -C ₆ acyl group, a saturated or unsaturated C ₁ -C ₆ alkoxycarbonyl group, C ₆ -C ₁₀ aryl, 5 to 10 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O, and S, or 5 to 3 heteroatoms selected from N, O, and S to 10-membered heteroaryl substituents;

Or R ¹ and R ² together with the N atom connecting them form a substituted or unsubstituted 5 to 10 membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, O and S, wherein said "substituted" means replaced by 1 to 10 deuterium, or Those optionally contain 1 to 4 selected from hydroxyl, halogen, cyano, -S(O) _m R ^c , -NR ^d R ^e , C ₁ to C ₆ alkyl, C ₃ to C ₆ cycloalkyl, C ₁ to C ₆ alkoxy group, C ₃ to C ₆ cycloalkoxy group, -OC(=O)C _1-6 alkyl group, -OC(=O)C ₃ to C ₆ cycloalkyl group, -C( =O)OC _1-6 alkyl, -C(=O)OC ₃ ~C ₆ cycloalkyl, containing The group is a saturated or unsaturated halogenated or unhalogenated C _1-6 alkyl group, containing Saturated or unsaturated halogenated or unhalogenated C _3-6 cycloalkyl group, C ₁ to C ₆ alkyl group substituted by R ^f , C ₃ to C ₆ cycloalkyl group, C ₁ to C ₆ Alkoxy group and substituent of C ₃ to C ₆ cycloalkoxy group.

More preferably, R ¹ and R ² are each independently hydrogen, saturated or unsaturated substituted or unsubstituted C ₁ -C ₄ alkyl, saturated or unsaturated substituted or unsubstituted C ₃ -C ₆ cycloalkyl base, -OC(=O)C _1-4 alkyl, -OC(=O)C ₃ -C ₆ cycloalkyl, -C(=O)OC ₁ -C ₄ alkyl, -C(=O) C ₃ -C ₆ cycloalkyl, -S(O) _m R ^c , saturated or unsaturated substituted or unsubstituted C ₁ -C ₄ acyl, C ₆ -C ₁₀ aryl, containing 1 to 3 selected from A 5- to 8-membered heterocycloalkyl group containing heteroatoms of N, O, and S or a 5- to 8-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S, containing The group is a saturated or unsaturated halogenated or unhalogenated C _1-4 alkyl group, containing The group is a saturated or unsaturated halogenated or unhalogenated C _3-6 cycloalkyl group, wherein "substituted" means substituted by 1 to 10 deuterons, or optionally contains 1 to 3 selected from Hydroxy, halogen, cyano, -S(O) _m R ^c , -NR ^d R ^e , saturated or unsaturated C ₁ -C ₄ alkyl, saturated or unsaturated C ₃ -C ₆ cycloalkyl, saturated Or unsaturated C ₁ -C ₄ alkoxy, saturated or unsaturated C ₃ -C ₆ cycloalkoxy, -OC(=O)C ₁ -C ₄ alkyl, -OC(=O)C ₃ -C ₆ cycloalkyl, -C(=O)OC _1-4 alkyl, -C(=O)OC ₃ -C ₆ cycloalkyl, containing The group is a saturated or unsaturated halogenated or unhalogenated C _1-4 alkyl group, containing The group is a saturated or unsaturated halogenated or unhalogenated C _3-6 cycloalkyl group, a saturated or unsaturated C ₁ -C ₄ acyl group, a saturated or unsaturated C ₁ -C ₄ alkoxycarbonyl group, C ₆ -C ₁₀ aryl, 5 to 8 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O, and S, or 5 to 3 heteroatoms selected from N, O, and S to 10-membered heteroaryl substituents;

Or R ¹ and R ² together with the N atom connecting them form a substituted or unsubstituted 5 to 8 membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, O and S, wherein said "substituted" Refers to being substituted by 1 to 10 deuterium, or optionally containing 1 to 3 selected from hydroxyl, halogen, cyano, -S(O) _m R ^c , -NR ^d R ^e , C ₁ ~ C ₄ alkyl , C ₃ ~ C ₆ cycloalkyl, C ₁ ~ C ₄ alkoxy, C ₃ ~ C ₆ cycloalkoxy, -OC(=O)C _1-4 alkyl, -OC(=O)C ₃ ~C ₆ cycloalkyl, -C(=O)OC _1-4 alkyl, -C(=O)OC ₃ ~C ₆ cycloalkyl, containing The group is a saturated or unsaturated halogenated or unhalogenated C _1-4 alkyl group, containing Saturated or unsaturated halogenated or unhalogenated C _3-6 cycloalkyl group, C ₁ to C ₄ alkyl group, C ₃ to C ₆ cycloalkyl group substituted by halogen, hydroxyl, amino or R ^f , C ₁ ~ C ₄ alkoxy group, Substituent of C ₃ to C ₆ cycloalkoxy group.

Preferably, R ³ is selected from deuterium, halogen, nitro, cyano, carboxyl, hydroxyl, -NR ^d R ^e , -OR ^g , -CO ₂ R ^g , -S(O) _m R ^c , or is replaced by 1 to 3 R ^h substituted C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 cycloalkoxy, C _1-6 alkoxycarbonyl, C _{1- 6-} alkylcarbonyl, C _1-6 alkylcarboxyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 6-10-membered aryl, 5-10-membered heteroaryl.

More preferably, R ³ is selected from deuterium, halogen, nitro, cyano, carboxyl, hydroxyl, -NR ^d R ^e , -OR ^g , -CO ₂ R ^g , -S(O) _m R ^c , or is replaced by 1 To 3 R ^h substituted C _1-4 alkyl, C _3-6 cycloalkyl, C _1-4 alkoxy, C _3-6 cycloalkoxy, C _1-4 alkoxycarbonyl, C _{1 -4} alkylcarbonyl, C _1-4 alkylcarboxyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl.

Preferably, R ^a and R ^b are each independently selected from saturated or unsaturated substituted or unsubstituted C ₃ -C ₆ cycloalkyl, saturated or unsaturated substituted or unsubstituted C ₁ -C ₆ alkyl, Substituted or unsubstituted 6- to 10-membered aryl groups or substituted or unsubstituted 5- to 8-membered heteroaryl groups containing 1 to 3 heteroatoms selected from N, O and S heteroatoms, wherein the "substituted" refers to 1 ^to 10 deuterium substitutions, or optionally containing 1 to 3 selected from hydroxyl, halogen, cyano, -S(O) _mRc , ^-NRdRe ^, saturated or unsaturated C1 _- _C6 Alkyl, saturated or unsaturated C ₃ -C ₆ cycloalkyl, saturated or unsaturated C ₁ -C ₆ alkoxy, saturated or unsaturated C ₃ -C ₆ cycloalkoxy, -OC(= O)C ₁ -C ₆ alkyl, -OC(=O)C ₃ -C ₆ cycloalkyl, -C(=O)OC _1-6 alkyl, -C(=O)OC ₃ -C ₆ ring Alkyl, saturated or unsaturated C ₁ -C ₆ acyl, saturated or unsaturated C ₁ -C ₆ alkoxycarbonyl, containing The group is a saturated or unsaturated halogenated or unhalogenated C _1-6 alkyl group, containing The group is saturated or unsaturated halogenated or unhalogenated C _3-6 cycloalkyl, C ₆ -C ₁₀ aryl, 5 to 10 containing 1 to 3 heteroatoms selected from N, O and S A substituent of a 5- to 10-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S;

Or R ^a and R ^b together with the N atom connecting them form a substituted or unsubstituted 4 to 10-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, O and S, a substituted or unsubstituted containing 5 to 10 membered heteroaryl groups with 1 to 3 heteroatoms selected from N, O and S, wherein "substituted" means substituted with 1 to 10 deuteriums, or optionally containing 1 to 4 selected from Hydroxy, halogen, cyano, sulfonyl, carboxyl -S(O) _m R ^c , -NR ^d R ^e , C ₁ to C ₆ alkyl, C ₃ to C ₆ cycloalkyl, C ₁ to C ₆ alkoxy Base, C ₃ to C ₆ cycloalkoxy group, -OC(=O)C _1-6 alkyl group, -OC(=O)C ₃ to C ₆ cycloalkyl group, -C(=O)OC _1-6 Alkyl, -C(=O)OC ₃ ~ C ₆ cycloalkyl, containing The group is a saturated or unsaturated halogenated or unhalogenated C _1-6 alkyl group, containing Saturated or unsaturated halogenated or unhalogenated C _3-6 cycloalkyl group, C ₁ to C ₆ alkyl group substituted by R ^f , C ₃ to C ₆ cycloalkyl group, C ₁ to C ₆ Alkoxy group and substituent of C ₃ to C ₆ cycloalkoxy group.

More preferably, R ^a and R ^b are each independently selected from saturated or unsaturated substituted or unsubstituted C ₃ -C ₆ cycloalkyl, saturated or unsaturated substituted or unsubstituted C ₁ -C ₄ alkyl. , a substituted or unsubstituted 6 to 10-membered aryl group or a substituted or unsubstituted 5 to 8-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O and S heteroatoms, wherein the "substituted" refers to Substituted with 1 ^to 10 deuterium, or optionally containing 1 to 3 selected from hydroxyl, halogen, cyano, -S(O) _mRc , ^-NRdRe ^, saturated or unsaturated C1- _C ₄ alkyl, saturated or unsaturated C ₃ -C ₆ cycloalkyl, saturated or unsaturated C ₁ -C ₄ alkyl Oxygen group, saturated or unsaturated C ₃ -C ₆ cycloalkoxy group, -OC(=O)C ₁ -C ₄ alkyl group, -OC(=O)C ₃ -C ₆ cycloalkyl group, -C( =O)OC _1-4 alkyl, -C(=O)OC ₃ -C ₆ cycloalkyl, saturated or unsaturated C ₁ -C ₄ acyl, saturated or unsaturated C ₁ -C ₄ alkoxy carbonyl, containing The group is a saturated or unsaturated halogenated or unhalogenated C _1-4 alkyl group, containing The group is saturated or unsaturated halogenated or unhalogenated C _3-6 cycloalkyl, C ₆ -C ₁₀ aryl, 5 to 10 containing 1 to 3 heteroatoms selected from N, O and S A substituent of a 5- to 10-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S;

Or R ^a and R ^b together with the N atom connecting them form a substituted or unsubstituted 5- to 8-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, O and S, a substituted or unsubstituted containing A 5- to 6-membered heteroaryl group with 1 to 3 heteroatoms selected from N, O and S, wherein "substituted" means substituted with 1 to 10 deuteriums, or optionally containing 1 to 3 selected from Hydroxy, halogen, cyano, sulfonyl, carboxyl, -S(O) _m R ^c , -NR ^d R ^e , C ₁ to C ₄ alkyl, C ₅ to C ₆ cycloalkyl, C ₁ to C ₄ alkyl Oxygen group, C ₅ to C ₆ cycloalkoxy group, -OC(=O)C _1-4 alkyl group, -OC(=O)C ₅ to C ₆ cycloalkyl group, -C(=O)OC _{1- 4} alkyl, -C(=O)OC ₅ ~ C ₆ cycloalkyl, containing The group is a saturated or unsaturated halogenated or unhalogenated C _1-4 alkyl group, containing Saturated or unsaturated halogenated or unhalogenated C _3-6 cycloalkyl group, C ₁ to C ₄ alkyl group, C ₅ to C ₆ cycloalkyl group substituted by halogen, hydroxyl, amino or R ^f , C ₁ to C ₄ alkoxy group, C ₅ to C ₆ cycloalkoxy group substituent.

Preferably, R ^c , R ^f , R ^g , ^Rh and R ⁱ are each independently selected from hydrogen, hydroxyl, amino, saturated or unsaturated substituted or unsubstituted C ₁ -C ₆ alkyl, saturated or unsaturated Substituted or unsubstituted C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, -C(=O)C _1-6 alkyl, -C(=O)C ₃ -C ₆ cycloalkyl , -C(=O)OC ₁ -C ₆ alkyl, -C(=O)OC ₃ -C ₆ cycloalkyl, -C(=O)NC ₁ -C ₆ alkyl, -C(=O) NC ₃ -C ₆ cycloalkyl, saturated or unsaturated substituted or unsubstituted C ₁ -C ₆ sulfonyl, C ₆ -C ₁₀ aryl, C ₇ -C ₁₁ arylalkyl, containing 1 to 3 A 5- to 10-membered heterocycloalkyl group containing heteroatoms selected from N, O, and S or a 5- to 10-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S, wherein the "substituted" Refers to being substituted by 1 to 10 deuterium, or optionally containing 1 to 4 selected from hydroxyl, halogen, cyano, sulfonyl, C ₁ -C ₆ sulfo, -NR ^d R ^e , saturated or unsaturated C ₁ -C ₆ alkyl, saturated or unsaturated C ₃ -C ₆ cycloalkyl, saturated or unsaturated C ₁ -C ₆ alkoxy, saturated or unsaturated C ₃ -C ₆ cycloalkoxy , -OC(=O)C ₁ -C ₆ alkyl, -OC(=O)C ₃ -C ₈ cycloalkyl, -C(=O)OC _1-6 alkyl, -C(=O)OC ₃ -C ₆ cycloalkyl, saturated or unsaturated C ₁ -C ₆ sulfonyl, saturated or unsaturated C ₁ -C ₆ acyl, saturated or unsaturated C ₁ -C ₆ alkoxycarbonyl, C ₆ -C ₁₀ aryl, 5 to 10 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O, and S, or 5 to 10 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O, and S A substituent of a heteroaryl group, wherein R ^c is not hydrogen;

More preferably, R ^c , R ^f , R ^g , ^Rh and R ⁱ are each independently selected from hydrogen, hydroxyl, amino, saturated or unsaturated substituted or unsubstituted C ₁ -C ₄ alkyl, saturated or unsaturated Saturated substituted or unsubstituted C ₁ -C ₄ alkyl, C ₄ -C ₆ cycloalkyl, -C(=O)C _1-4 alkyl, -C(=O)C ₄ -C ₆ cycloalkyl base, -C(=O)OC ₁ -C ₄ alkyl, -C(=O)OC ₄ -C ₈ cycloalkyl, -C(=O)NC ₁ -C ₄ alkyl, -C(=O )NC ₄ -C ₆ cycloalkyl, saturated or unsaturated substituted or unsubstituted C ₁ -C ₄ sulfonyl, C ₆ -C ₁₀ aryl, C ₇ -C ₁₁ arylalkyl, containing 1 to 3 A 5- to 8-membered heterocycloalkyl group containing a heteroatom selected from N, O, and S or a 5- to 10-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S, wherein the "substituted ” refers to being substituted by 1 to 10 deuterium, or optionally containing 1 to 3 selected from hydroxyl, halogen, cyano, sulfonate Acyl group, C ₁ -C ₄ sulfo group, -NR ^d R ^e , saturated or unsaturated C ₁ -C ₄ alkyl group, saturated or unsaturated C ₄ -C ₆ cycloalkyl group, saturated or unsaturated C ₁ -C ₄ alkoxy, saturated or unsaturated C ₄ -C ₆ cycloalkoxy, -OC(=O)C ₁ -C ₄ alkyl, -OC(=O)C ₄ -C ₆ cycloalkyl , -C(=O)OC _1-4 alkyl, -C(=O)OC ₄ -C ₆ cycloalkyl, saturated or unsaturated C ₁ -C ₄ sulfonyl, saturated or unsaturated C ₁ - C ₄ acyl, saturated or unsaturated C ₁ -C ₄ alkoxycarbonyl, C ₆ -C ₁₀ aryl, 5 to 8 membered heterocycloalkane containing 1 to 3 heteroatoms selected from N, O and S group or a substituent of a 5- to 10-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O and S, wherein R ^c is not hydrogen.

More preferably, R ^f is selected from deuterium, halogen, cyano, hydroxyl, amino, saturated or unsaturated C ₁ to C ₆ alkyl, saturated or unsaturated C ₃ to C ₆ cycloalkyl, -S(O) _m R ^c , NR ^d ^Re , saturated or unsaturated C ₁ to C ₆ alkyl group substituted by deuterium, halogen, hydroxyl or amino group, C ₃ to C ₆ cycloalkyl group substituted by deuterium, halogen, hydroxyl group or amino group, Saturated or unsaturated C ₁ to C ₆ alkoxy group, C ₃ to C ₆ cycloalkoxy group, saturated or unsaturated C ₁ to C ₆ alkoxy group substituted by deuterium, halogen, hydroxyl or amino group, substituted by deuterium, Halogen, hydroxyl or amino substituted C ₃ to C ₆ cycloalkoxy group.

More preferably, the structure formed by R ¹ and R ² in formula I together with the N atom connecting them is selected from the following groups:

More preferably, the structure formed by R ^a and R ^b in formula I together with the N atom connecting them is selected from the following groups:

Wherein, each occurrence of R ^j and R ^k is independently hydroxyl, halogen, cyano, sulfonyl, amino, C ₁ to C ₈ alkyl, C ₃ to C ₈ cycloalkyl, C ₁ to C ₈ alkyl Oxygen group, C ₃ to C ₈ cycloalkoxy group, -OC(=O)C _1-8 alkyl group, -OC(=O)C ₃ to C ₈ cycloalkyl group, -C(=O)OC _{1- 8} alkyl, -C(=O)OC ₃ ~ C ₈ cycloalkyl, C ₁ ~ C ₈ alkyl substituted by R ^f , C ₃ ~ C ₈ cycloalkyl, C ₁ ~ C ₈ alkoxy, Substituents of C ₃ to C ₈ cycloalkoxy groups, wherein R ^f is selected from deuterium, halogen, cyano, hydroxyl, amino, saturated or unsaturated C ₁ to C ₆ alkyl, saturated or unsaturated C ₃ ~ C ₆ cycloalkyl, saturated or unsaturated C ₁ to C ₆ alkyl substituted by deuterium, halogen, hydroxyl or amino, C ₃ to C ₆ cycloalkyl substituted by deuterium, halogen, hydroxyl or amino group, saturated or unsaturated C ₁ to C ₆ alkoxy group, C ₃ to C ₆ cycloalkoxy group, saturated or unsaturated C ₁ to C ₆ alkoxy group substituted by deuterium, halogen, hydroxyl or amino group, substituted by C ₃ to C ₆ cycloalkoxy substituted by deuterium, halogen, hydroxyl or amino; n2 is an integer of 0, 1, 2, 3, 4 or 5.

Preferably, each occurrence of R ^j and R ^k is independently hydroxyl, halogen, cyano, sulfonyl, amino C ₁ to C ₆ alkyl, C ₃ to C ₆ cycloalkyl, C ₁ to C ₆ alkyl Oxy group, C ₃ to C ₆ cycloalkoxy group, -OC(=O)C _1-6 alkyl group, -OC(=O)C ₃ to C ₆ cycloalkyl group, -C(=O)OC _{1- 6} alkyl, -C(=O)OC ₃ ~ C ₆ cycloalkyl, C ₁ ~ C ₆ alkyl substituted by R ^f , C ₃ ~ C ₆ cycloalkyl, C ₁ ~ C ₆ alkoxy, Substituents of C ₃ to C ₆ cycloalkoxy, wherein R ^f is selected from deuterium, halogen, cyano, hydroxyl, amino, saturated or unsaturated C ₁ to C ₄ alkyl, saturated or unsaturated C ₃ ~ C ₆ cycloalkyl, saturated or unsaturated C ₁ to C ₄ alkyl substituted by deuterium, halogen, hydroxyl or amino, C ₃ to C ₆ cycloalkyl substituted by deuterium, halogen, hydroxyl or amino, saturated or unsaturated Saturated C ₁ to C ₄ alkoxy group, C ₃ to C ₆ cycloalkoxy group, saturated or unsaturated C ₁ to C ₄ alkoxy group substituted by deuterium, halogen, hydroxyl or amino group, substituted by deuterium, halogen, hydroxyl group Or amino-substituted C ₃ to C ₆ cycloalkoxy group.

More preferably, each occurrence of R ^j and R ^k is independently hydroxyl, halogen, cyano, sulfonyl, amino C ₁ to C ₄ alkyl, C ₄ to C ₆ cycloalkyl, C ₁ to C ₄ Alkoxy group, C ₄ to C ₆ cycloalkoxy group, -OC(=O)C _1-4 alkyl group, -OC(=O)C ₄ to C ₆ cycloalkyl group, -C(=O)OC _{1 -4} alkyl, -C(=O)OC ₄ ~ C ₆ cycloalkyl, C ₁ ~ C ₄ alkyl substituted by R ^f , C ₄ ~ C ₆ cycloalkyl, C ₁ ~ C ₄ alkoxy , C ₄ to C ₆ cycloalkoxy substituents, wherein R ^f is selected from deuterium, halogen, cyano, hydroxyl, amino, saturated or unsaturated C ₁ to C ₃ alkyl, saturated or unsaturated C ₅ ~C ₆ cycloalkyl, saturated or unsaturated C ₁ ~ C ₃ alkyl substituted by deuterium, halogen, hydroxyl or amino. C ₅ ~ C ₆ cycloalkyl substituted by deuterium, halogen, hydroxyl or amino, saturated or Unsaturated C ₁ to C ₃ alkoxy group, C ₅ to C ₆ cycloalkoxy group, saturated or unsaturated C ₁ to C ₃ alkoxy group substituted by deuterium, halogen, hydroxyl or amino group, substituted by deuterium, halogen, Hydroxyl or amino-substituted C ₅ to C ₆ cycloalkoxy group.

More preferably, according to the 2-nitrogen-substituted pyrimidine compound represented by formula I, each of its optical isomers, deuterated products, prodrugs or pharmaceutically acceptable salts is selected from the following compounds:

According to the second aspect of the present invention, another object of the present invention is to provide a pharmaceutical composition, said pharmaceutical composition comprising a therapeutically effective amount of a 2-nitrogen-substituted pyrimidine compound represented by Formula I according to the present invention, Each of its optical isomers, deuterated products, prodrugs or pharmaceutically acceptable salts and pharmaceutically acceptable excipients or carriers.

According to the third aspect of the present invention, another object of the present invention is to provide 2-nitrogen-substituted pyrimidine compounds represented by formula I according to the present invention, each of which is an optical isomer, a deuterated product, a prodrug or a pharmaceutically acceptable compound. Use of the accepted salts in the preparation of inhibitors of AHR disorders.

According to the fourth aspect of the present invention, another object of the present invention is to provide 2-nitrogen-substituted pyrimidine compounds represented by formula I according to the present invention, each of which is an optical isomer, a deuterated product, a prodrug or a pharmaceutically acceptable compound. Use of the salts accepted for the preparation of a medicament for the treatment of tumors associated with AHR disorders.

According to the fifth aspect of the present invention, another object of the present invention is to provide a method for treating tumors associated with AHR disorders, the method comprising administering to a subject in need thereof an effective amount of a compound according to the present invention represented by the formula The 2-nitrogen-substituted pyrimidine compound represented by I, each of its optical isomers, deuterated products, prodrugs or pharmaceutically acceptable salts or the pharmaceutical composition according to the present invention.

According to the sixth aspect of the present invention, another object of the present invention is to provide 2-nitrogen-substituted pyrimidine compounds represented by formula I according to the present invention, each of which is an optical isomer, a deuterated product, a prodrug or a pharmaceutically acceptable compound. The preparation method of the accepted salt, the method is selected from the following reaction formula 1 or reaction formula 2:

Reaction 1

In reaction formula 1, the compound of formula III and the compound of formula II undergo an esterification reaction to form a compound represented by formula I, in which the substituents R ¹ , R ² , R ³ , R ⁴ , R ^a , R ^b , ring A, The definition of L is the same as in Formula I;

Reaction 2

In reaction formula 2, the compound of formula III and the hydrazine compound of formula IV undergo an esterification reaction to form an intermediate compound of formula Ia, and then the intermediate compound Ia reacts with a compound containing substituent R ² (such as an acid anhydride compound) to form formula I represents a compound in which the definitions of the substituents R ¹ , R ² , R ³ , R ⁴ , R ^a , R ^b , and rings A and L are the same as those in Formula I.

In reaction formulas 1 and 2, compound III can be prepared according to one of the following methods, and the following is only an example.

Method A

Step 1) Preparation of intermediate X-A

Concentrated hydrochloric acid was added to the ethanol solution of urea and the dicarbonyl compound V containing the A ring structure, stirred overnight, cooled to room temperature, filtered, washed with cold ethanol, and dried to obtain compound VI.

Step 2) Preparation of Intermediate VII

Compound VI was added to phosphorus oxychloride, heated and stirred under nitrogen protection, concentrated to dryness under reduced pressure, added with ethyl acetate and ice water, stirred, filtered, and dried to obtain compound VII.

Step 3) Preparation of Intermediate VIII

Dissolve compound VII and amino compound NHR ^a R ^b in dimethyl sulfoxide, add K ₂ CO ₃ , heat to 70°C, stir overnight, cool to room temperature, add ice water, filter, wash with water, and dry to obtain compound VIII;

Step 4) Preparation of Compound III

Dissolve compound VIII in the mixed solvent, add lithium hydroxide, stir at room temperature overnight, concentrate under reduced pressure, add ice water, stir, extract with ethyl acetate, adjust the pH of the aqueous phase to 6-7 with hydrochloric acid, filter and dry to obtain compound III , the mixed solvent is THF/MeOH/H ₂ O (volume ratio: 1/1/1).

Method B

Step 1) Preparation of intermediate X

2,6-Dichloropyrimidine-4-carboxylic acid ethyl ester and the boric acid compound IX containing the A ring structure are dissolved in dioxane, add saturated sodium carbonate, tetrakis (triphenylphosphorus) palladium, degassed, and protected by nitrogen Heated at room temperature, stirred overnight, cooled to room temperature, concentrated under reduced pressure, added ice water, extracted with ethyl acetate, dried, and purified to obtain compound X;

Step 2) Preparation of intermediate XI

^Compound ^_ _{_} _{_}

Step 3) Preparation of Compound III

Dissolve compound XI in the mixed solvent, add lithium hydroxide, stir at room temperature overnight, concentrate under reduced pressure, add ice water, stir, extract with ethyl acetate, adjust the pH of the aqueous phase to 6~7 with hydrochloric acid, filter and dry to obtain compound III , the mixed solvent is THF/MeOH/H ₂ O (volume ratio: 1/1/1).

Method C

Step 1) Preparation of intermediate XII

Dissolve 2,6-dichloropyrimidine-4-carboxylic acid ethyl ester and amino compound NHR ^a R ^b in dimethyl sulfoxide, add K ₂ CO ₃ , heat to 70°C, stir overnight, cool to room temperature, add Ice water, filtered, washed, and dried to obtain compound XII;

Step 2) Preparation of intermediate XIII

compound Concentrate under pressure, add ice water, extract with ethyl acetate, dry and purify to obtain compound XIII;

Step 3) Preparation of Intermediate III

Dissolve compound XIII in the mixed solvent, add lithium hydroxide, stir at room temperature overnight, concentrate under reduced pressure, add ice water, stir, extract with ethyl acetate, adjust the pH of the aqueous phase to 6~7 with hydrochloric acid, filter and dry to obtain compound III , the mixed solvent is THF/MeOH/H ₂ O (volume ratio: 1/1/1).

Detailed ways

Hereinafter, the present invention will be described in detail. Before proceeding to the description, it is to be understood that the terms used in this specification and the appended claims should not be construed to be limited to ordinary and dictionary meanings, but rather to allow the inventor to appropriately define the terms for best interpretation. On the basis of the principles, explanations are made according to the meanings and concepts corresponding to the technical aspects of the present invention. Accordingly, the descriptions set forth herein are preferred examples for illustrative purposes only and are not intended to limit the scope of the invention, so that it will be understood that others may be derived therefrom without departing from the spirit and scope of the invention. price or improvement methods.

In this article, all characteristics or conditions defined in the form of numerical ranges or percentage ranges are for brevity and convenience only. Accordingly, descriptions of numerical ranges or percentage ranges shall be deemed to cover and specifically disclose all possible subranges and individual values within the ranges, in particular integer values. For example, a range description of "1 to 8" should be deemed to have specifically disclosed all sub-ranges such as 1 to 7, 2 to 8, 2 to 6, 3 to 6, 4 to 8, 3 to 8, etc., particularly is a secondary range defined by all integer values and shall be deemed to have been specifically disclosed as individual values within the range such as 1, 2, 3, 4, 5, 6, 7, 8, etc. Unless otherwise indicated, the foregoing method of interpretation applies to all contents of the present invention, whether broad or not.

If a quantity or other numerical value or parameter is expressed as a range, a preferred range, or a series of upper and lower limits, it should be understood that any pairing of the upper limit of the range or the preferred value and the lower limit of the range has been specifically disclosed herein. or all ranges consisting of better values, whether or not these ranges are separately disclosed. In addition, when reference is made herein to a range of values, such range shall include its endpoints and all integers and fractions within the range, unless otherwise stated.

In this document, numerical values shall be understood to have an accuracy of 100 significant digits, provided that the object of the invention is achieved. For example, the number 40.0 should be understood to cover the range from 39.50 to 40.49.

In this article, when Markush groups or alternative terms are used to describe features or examples of the present invention, those skilled in the art will understand that Markush groups or subgroups of all elements in the alternative list group or any Any individual elements may also be used to describe the invention. For example, if X is described as “selected from the group consisting of X1, X2, and X3,” it also means that the claim that X is X1 and the claim that X is X1 and/or Furthermore, when Markush groups or optional terms are used to describe features or examples of the present invention, those skilled in the art should understand the sub-groups or individual elements of all elements in the Markush group or option list. Any combination of may also be used to describe the invention. Accordingly, for example, if X is described as "selected from the group consisting of X1, Indicates that the claim that X is X1 or X2 or X3 and Y is Y1 or Y2 or Y3 has been fully described.

definition

"Alkyl" refers to a straight or branched chain saturated hydrocarbon radical having 1 to 8 carbon atoms ("C _1-8 alkyl"). In some embodiments, an alkyl group has 1 to 7 carbon atoms ("C _1-7 alkyl"). In some embodiments, an alkyl group has 1 to 6 carbon atoms ("C _1-6 alkyl"). In some embodiments, an alkyl group has 1 to 5 carbon atoms ("C _1-5 alkyl"). In some embodiments, an alkyl group has 1 to 4 carbon atoms ("C _1-4 alkyl"). In some embodiments, an alkyl group has 1 to 3 carbon atoms ("C _1-3 alkyl"). In some embodiments, an alkyl group has 1 to 2 carbon atoms ("C _1-2 alkyl"). In some embodiments, an alkyl group has 1 carbon atom ("C ₁ alkyl"). In some embodiments, an alkyl group has 1 to 6 carbon atoms ("C _1-6 alkyl"). Examples of C _1-6 alkyl groups include methyl (C ₁ ), ethyl (C ₂ ), propyl (C ₃ ) (e.g., n-propyl, isopropyl), butyl (C ₄ ) (e.g., n-propyl) Butyl, tert-butyl, sec-butyl, isobutyl), pentyl (C ₅ ) (for example, n-pentyl, 3-pentyl, neopentyl, 3-methyl-2-butyl, tert-pentyl group) and hexyl (C ₆ ) (e.g., n-hexyl). Additional examples of alkyl groups include n-heptyl (C ₇ ), n-octyl (C ₈ ), and the like. Unless otherwise specified, each instance of an alkyl group is independently unsubstituted ("unsubstituted alkyl") or substituted with one or more substituents (e.g., halogen, such as F) ("substituted alkyl" ). In certain embodiments, alkyl is unsubstituted C _1-8 alkyl (eg, unsubstituted C ₁ alkyl, such as -CH ₃ ). In certain embodiments, alkyl is substituted C _1-8 alkyl (eg, substituted C ₁ alkyl, such as -CF ₃ ).

"Alkoxy" means a monovalent -O-alkyl group, wherein the alkyl moiety has the specified number of carbon atoms. In this disclosure, alkoxy groups generally contain 1-8 carbon atoms ("C1 to C8 alkoxy"), 1-6 carbon atoms ("C1 to C6 alkoxy"), or 1-4 carbon atoms ( "C1-C4 alkoxy"). For example, C1-C4 alkoxy groups include methoxy, ethoxy, isopropoxy, tert-butyloxy, etc. Unless otherwise specified, each instance of alkoxy is independently optionally substituted, i.e., unsubstituted ("unsubstituted alkoxy") or substituted with one or more substituents ("substituted alkoxy" ). In certain embodiments, alkoxy is unsubstituted C1 to C6 alkoxy. In certain embodiments, alkoxy is substituted C1 to C6 alkoxy.

"Cycloalkyl" refers to a non-aromatic cyclic hydrocarbon group having 3 to 8 ring carbon atoms ("C _3-8 cycloalkyl") and zero heteroatoms in a non-aromatic ring system. In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms ("C _3-8 cycloalkyl"). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ("C _3-6 cycloalkyl"). In some embodiments, a cycloalkyl group has 5 to 8 ring carbon atoms ("C _5-8 cycloalkyl"). Exemplary C _3-6 cycloalkyl groups include, but are not limited to, cyclopropyl (C ₃ ), cyclopropenyl (C ₃ ), cyclobutyl (C ₄ ), cyclobutenyl (C ₄ ), cyclopentyl group (C ₅ ), cyclopentenyl (C ₅ ), cyclohexyl (C ₆ ), cyclohexenyl (C ₆ ), cyclohexadienyl (C ₆ ), etc. Exemplary C _3-8 cycloalkyl groups include, but are not limited to, the C _3-6 cycloalkyl groups described above as well as cycloheptyl (C ₇ ), cycloheptenyl (C ₇ ), cycloheptadienyl (C ₇ ), cycloheptatrienyl (C ₇ ), cyclooctyl (C ₈ ), cyclooctenyl (C ₈ ), etc. Unless otherwise specified, each instance of cycloalkyl is independently optionally substituted, i.e., unsubstituted ("unsubstituted cycloalkyl") or substituted with one or more substituents ("substituted cycloalkyl" ). In certain embodiments, cycloalkyl is unsubstituted C _3-8 cycloalkyl; in certain embodiments, cycloalkyl is substituted C _3-8 cycloalkyl.

"Heterocycloalkyl" means a group of 4 to 14 membered non-aromatic ring systems having ring carbon atoms and 1 to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen and sulfur (" 4-14 membered heterocyclic group"). In heterocyclic groups containing one or more nitrogen atoms, the point of attachment may be a carbon atom or a nitrogen atom, as long as the valency permits. Heterocyclic groups may be monocyclic ("monocyclic heterocyclyl") or fused, bridged or spiro ring systems, such as bicyclic systems ("bicyclic heterocyclyl"), and may be saturated or may be partially Unsaturated. "Heterocyclic group" also includes a heterocyclic group as defined above combined with one or more cyclic A ring system in which an alkyl group is fused (wherein the point of attachment is on a cycloalkyl group or a heterocycle), or in which a heterocycle as defined above is fused with one or more aryl or heteroaryl groups (wherein the attachment point on a heterocyclic ring), and in this case, the number of ring members continues to refer to the number of ring members in the heterocyclic ring system. Unless otherwise specified, each instance of a heterocyclic group is independently optionally substituted, i.e., unsubstituted ("unsubstituted heterocycloalkyl") or substituted with one or more substituents ("substituted heterocycloalkyl"). Cycloalkyl"). In certain embodiments, heterocycloalkyl is unsubstituted 4-14 membered heterocycloalkyl. In certain embodiments, heterocycloalkyl substituted 4-14 membered heterocycloalkyl.

"Aryl" or "aromatic ring" or "aromatic ring group" refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic ring) having 6 to 14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system. Ring) A group of 4n+2 aromatic ring systems (eg, having 6, 10, or 14 π electrons shared in a cyclic array) ("C _6-14 aryl"). 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"; for example, naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms ("C ₁₄ aryl"; for example, anthracenyl). "Aryl" also includes ring systems in which an aryl ring as defined above is fused to one or more cycloalkyl or heterocyclic groups, wherein the point of attachment is on the aromatic ring, and in this case, the carbon atom The number continues to refer to the number of carbon atoms in the aromatic ring system. Unless otherwise specified, each instance of aryl is independently optionally substituted, ie, unsubstituted ("unsubstituted aryl") or substituted with one or more substituents ("substituted aryl"). In certain embodiments, aryl is unsubstituted C _6-14 aryl. In certain embodiments, aryl is substituted C _6-14 aryl.

"Heteroaryl" is a 5-10 membered aromatic ring system having ring carbon atoms provided in the aromatic ring system and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen and sulfur ("5-10 membered heteroaryl"). In some embodiments, heteroaryl is a 5-8 membered aromatic ring system having ring carbon atoms provided in the aromatic ring system and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen , oxygen and sulfur ("5-8 membered heteroaryl"). In some embodiments, heteroaryl is a 5-6 membered aromatic ring system having ring carbon atoms provided in the aromatic ring system and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen , oxygen and sulfur ("5-6 membered heteroaryl"). In some embodiments, a 5-6 membered heteroaryl group has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5-6 membered heteroaryl group has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5-6 membered heteroaryl group has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of heteroaryl is independently optionally substituted, i.e., unsubstituted ("unsubstituted heteroaryl") or substituted with one or more substituents ("substituted heteroaryl" ). In certain embodiments, heteroaryl is unsubstituted 5-10 membered heteroaryl. In certain embodiments, heteroaryl is a substituted 5-10 membered heteroaryl.

"Halogen" or "halo" refers to fluorine (fluorine, -F), chlorine (chlorine, -Cl), bromine (bromine, -Br) or iodine (iodine, -I).

"Substituted" or "optionally substituted" means that an atom, such as a hydrogen atom, in the group is substituted. In certain embodiments, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are substituted (e.g., "substituted" alkyl, "substituted" cycloalkyl, "substituted" heterocycloalkyl radical, "substituted" aryl, or "substituted" heteroaryl). Generally, the term "substituted", whether or not preceded by the term "optionally", means that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced by a permissible substituent, e.g. Substitution results in the formation of stable compounds, eg, compounds that do not undergo spontaneous transformation (eg, by rearrangement, cyclization, elimination, or other reactions). Unless otherwise specified, a "substituted" group has a substituent at one or more substitutable positions on the group, and when more than one position in any given structure is substituted, the substituent is present at each The location is the same or different. The term "substituted" is intended to include substitution with all permissible substituents of organic compounds, any substituent described herein that results in the formation of a stable compound. This disclosure contemplates any and all of these combinations to obtain stable compounds. For purposes of this disclosure, a heteroatom such as nitrogen may have a hydrogen substituent and/or any suitable substituent as described herein that satisfies the valency of the heteroatom and results in the formation of a stable moiety. In certain embodiments, the substituents are carbon atom substituents. In certain embodiments, the substituents are nitrogen atom substituents. In certain embodiments, the substituents are oxygen atom substituents. In certain embodiments, the substituent is a sulfur atom substituent.

"Unsaturated" or "partially unsaturated" refers to a group containing at least one double or triple bond. "Partially unsaturated" ring systems are also intended to encompass rings having multiple sites of unsaturation, but are not intended to include aromatic groups (eg, aryl or heteroaryl). Likewise, "saturated" refers to a group that contains no double or triple bonds, that is, all single bonds.

In this article, when there are multiple substitutions in a defined substituent, there may be repeated definitions in the text description of such multiple substitutions, but this description should be understood as at least consistent with the basic laws of general medicinal chemistry. For example, when a substituent appears When repeating a definition, those skilled in the art can determine whether such repeating is feasible or unfeasible based on common common sense in medicinal chemistry, and make a reasonable choice.

As used herein, the term "pharmaceutically acceptable" refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissue. , without undue toxicity, irritation, allergic reactions, or other problems or complications, commensurate with a reasonable benefit/risk ratio.

The term "pharmaceutically acceptable salts" refers to salts of compounds of the present invention prepared from compounds having specific substituents found in the present invention and relatively non-toxic acids or bases. When compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of base in pure solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts or similar salts. When the compounds of the present invention contain relatively basic functional groups, acid addition salts (i.e., pharmaceutical Acceptable salts above), examples include inorganic acid salts and organic acid salts, the inorganic acid includes, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid , hydrogen sulfate, hydriodic acid, phosphorous acid, etc.; the organic acids include benzoic acid, 2-hydroxyethanesulfonic acid, sulfamic acid, benzenesulfonic acid, phenylacetic acid, mandelic acid, malonic acid, propionic acid, Oxalic acid, p-aminobenzenesulfonic acid, p-toluenesulfonic acid, polygalacturonic acid, pantothenic acid, fumaric acid, glutamic acid, succinic acid, methane sulfonic acid, tartaric acid, ascorbic acid, phthalic acid, maleic acid, Citric acid, malic acid, glucoheptonic acid, gluconic acid, isethionic acid, lactic acid, lactobionic acid, dodecyl sulfonic acid, pamoic acid, salicylic acid, suberic acid, leucovorin, idetamine Acid, glycolic acid, acetic acid, ethanesulfonic acid, isobutyric acid, stearic acid and similar acids; also includes salts of amino acids (such as arginine, etc.), and salts of organic acids such as glucuronic acid (see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66:1-19 (1977)). Certain specific compounds of the present invention contain both basic and acidic functional groups and thus can be converted into either base or acid addition salts. The parent form of a compound differs from its various salt forms in certain physical properties, such as solubility in polar solvents.

As used herein, the modifier term "about" refers to numerical variations that may occur, e.g., through routine testing and handling; through inadvertent errors in such testing and handling; through variations in the manufacture, source, or purity of the ingredients used in the invention. Difference; etc. As used herein, "about" a particular value also includes that particular value, for example, "about 10%" includes 10%. Whether or not modified by the term "about," the claims include equivalents of the recited quantities. In one embodiment, the term "about" means within 20% of the reported value.

As used herein, the term "treating" means eliminating, alleviating or ameliorating a disease or condition and/or symptoms associated therewith. Although not excluded, treatment of a disease or condition does not require the complete elimination of the disease, condition or symptoms associated with it. As used herein, the term "treatment" and the like may include "preventive treatment" which refers to reducing the recurrence of a disease or condition in a subject who does not have or is at risk of developing or susceptible to the disease or condition or the recurrence of the disease or condition. The possibility of development or recurrence of a previously controlled disease or condition. The term "treatment" and synonyms contemplate the administration of a therapeutically effective amount of a compound described herein to a subject in need of such treatment.

The term "effective amount" or "therapeutically effective amount" with respect to a drug or pharmacologically active agent refers to a non-toxic amount of the drug or agent sufficient to achieve the desired effect. For the oral dosage form of the present invention, the "effective amount" of an active substance in the composition refers to the amount required to achieve the desired effect when combined with another active substance in the composition. The determination of the effective amount varies from person to person, depends on the age and general condition of the recipient, and also depends on the specific active substance. The appropriate effective amount in individual cases can be determined by those skilled in the art based on routine experiments.

The AHR pathway-related diseases according to the present invention include, but are not limited to, tumors related to the AHR pathway.

The following examples are merely examples of embodiments of the present invention and do not constitute any limitation to the present invention. Those skilled in the art can understand that modifications within the scope that do not deviate from the essence and concept of the present invention fall within the protection of the present invention. scope. Unless otherwise stated, the reagents and instruments used in the following examples are all commercially available products.

Example 1: Intermediate III-A

Method A

Step 1) Preparation of 2,4-dicarbonyl-4-(4-(trifluoromethyl)phenyl)butyric acid ethyl ester

Cool the mixed solution of diethyl oxalate (15.2g, 104mmol) in absolute ethanol (250ml) and sodium ethoxide (10.9g, 160mmol) below 10 degrees, stir for 30 minutes, and add trifluoromethylbenzophenone (18.8g) dropwise , 100mmol) absolute ethanol solution (80ml), remove the ice bath, stir at room temperature overnight, the reaction solution is almost solidified, filter, wash with a small amount of ethanol, and dry to obtain 2,4-dicarbonyl-4-(4-(trifluoromethyl Ethyl)phenyl)butyrate (28g, yield 97%). LC/MS(ESI): m/z 289[M+1] ⁺ .

Step 2) Preparation of intermediate VI-A

To an ethanol solution (4 ml) of urea (66 mg, 1.1 mmol) and ethyl 2,4-dicarbonyl-4-(4-(trifluoromethyl)phenyl)butyrate (288.2 mg, 1 mmol) was added Concentrated hydrochloric acid, stir at 80°C overnight, cool to room temperature, filter, wash with cold ethanol, and dry to obtain VI-A. LC/MS(ESI): m/z 313[M+1] ⁺ .

Step 3) Preparation of intermediate VII-A

Compound VI-A (78 mg, 0.25 mmol) was added to 2 ml of phosphorus oxychloride, heated to 85°C under nitrogen protection, stirred for 6 hours, concentrated to dryness under reduced pressure, and added ethyl acetate (EA) (50 ml) and 20 g of crushed ice. block, stir for 20 min, filter and dry to obtain compound VII-A. LC/MS(ESI): m/z 331[M+1] ⁺ .

Step 4) Preparation of intermediate III-A

Compound VII-A (56 mg, 0.16 mmol) and imidazole (55 mg, 0.8 mmol) were dissolved in dimethyl sulfoxide (DMSO) (5 ml), added K ₂ CO ₃ (150 mg, 1.09 mmol), and heated to 70°C. Stir overnight. Cool to room temperature, add 20 ml of ice water, filter, wash with water, and dry to obtain compound III-A. LC/MS(ESI): m/z 335[M+1] ⁺ , 333[M-1] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ): δ11.5(brs,1H),9.00(s,1H),8.66(d,2H),8.50(s,1H),7.96(m,3H),7.20 (s,1H).

Intermediates I-B to I-Z in Table 1 below can be prepared according to the same method as Intermediate III-A.

Table 1

Example 2: Preparation of intermediate III-AA

Method C

Step 1) Preparation of intermediate XII-AA

2,6-Dichloropyrimidine-4-carboxylic acid ethyl ester (2.21g, 10mmol) and imidazole (1.02g, 15mmol) were dissolved in DMSO (25ml), added K ₂ CO ₃ (4.14g, 30mmol), and heated to 70°C and stir overnight. Cool to room temperature, add 200 ml of ice water, filter, and purify by silica gel column chromatography to obtain compound XII-AA (533 mg, yield 21%). LC/MS(ESI): m/z 253[M+1] ⁺ .

Step 2) Preparation of intermediate XII-AA

Compound XII-AA (506 mg, 2 mmol) and 6-(trifluoromethyl)pyridin-3-ylboronic acid (480 mg, 2.5 mmol) were dissolved in dioxane (10 ml), and saturated sodium carbonate (1 ml) was added. (Triphenylphosphine)palladium (115 mg, 0.1 mmol), degassed, heated to 100°C under nitrogen protection, and stirred overnight. Cool to room temperature, concentrate under reduced pressure, add 50 ml of ice water, extract with ethyl acetate, dry, and purify the crude product by silica gel column chromatography to obtain compound XIII-AA (568 mg, yield 78%). LC/MS(ESI): m/z 364[M+1] ⁺ .

Step 3) Preparation of intermediate I-AA

Compound XIII-AA (500 mg, 1.37 mmol) was dissolved in a mixed solvent (15 ml) of THF/MeOH/H ₂ O (1/1/1), lithium hydroxide (220 mg, 9.2 mmol) was added, and the mixture was stirred at room temperature overnight. Concentrate under pressure, add 20g of ice water, stir, extract with ethyl acetate, adjust the pH of the aqueous phase to 6~7 with 6N hydrochloric acid, filter, and dry to obtain compound I-AA (380 mg, yield 83%) LC/MS (ESI): m/z 336[M+1] ⁺ , 334[M-1].

Intermediates I-BB to I-GG in Table 2 below can be prepared according to the same method as Intermediate I-AA.

Table 2

Example 3: Preparation of intermediate II-1 hydrochloride

Method D

Step 1) Preparation of intermediate XIV-1

Dissolve BocNHNH ₂ (13.2g, 100mmol) in 100ml acetone and 50ml methanol, add anhydrous magnesium sulfate (12g, 100mmol), stir at room temperature overnight, filter to remove magnesium sulfate, concentrate the filtrate to dryness under reduced pressure, add 100ml methanol to dissolve , add sodium borohydride (15.2g, 400mmol) in batches at room temperature, stir for 1 hour, concentrate to dryness under reduced pressure, add 200ml of distilled water, extract 100ml × 3 times with dichloromethane, combine the organic phases, dry over anhydrous sodium sulfate, and filter , concentrated to dryness under reduced pressure. Purification by silica gel column chromatography (20% ethyl acetate/petroleum ether) gave XIV-1 (15.1 g, yield 87%). LC/MS(ESI): m/z 175[M+1] ⁺ .

Step 2) Preparation of intermediate XV-1

Intermediate XIV-1 (1.74g, 10mmol), propylene oxide (2.9g, 50mmol), and DIEA (2.58g, 20mmol) were dissolved in 20 ml of ethanol, and stirred at 80°C overnight in a sealed reaction bottle. Concentrate to dryness under reduced pressure and purify by silica gel column chromatography (20%-50% ethyl acetate/petroleum ether) to obtain XV-1 (1.82g, yield 78%). LC/MS(ESI):m/z233[M+1] ⁺ .

Step 3) Preparation of intermediate II-1 hydrochloride

Dissolve 1.82g of compound XV-1 in 10 ml of methanol, add HCl methanol solution (excess), stir at room temperature overnight, and concentrate to dryness under reduced pressure at 40°C to obtain intermediate II-1 hydrochloride (2.3g, yield 95 %). LC/MS(ESI): m/z 133[M+1] ⁺ .

Example 4: Preparation of intermediate II-2 hydrochloride

Method E

Step 1) Preparation of intermediate XIV-2

Add BocNHNH ₂ (30g, 227mmol), 300ml methanol, 20.4g hydroxyacetone and anhydrous magnesium sulfate (68g) to a 500ml round-bottomed flask in sequence, stir at room temperature for 3.5h, filter to remove magnesium sulfate, and wash the filter cake with anhydrous methanol. , add sodium borohydride (15.2g, 400mmol) to the filtrate in batches at 0°C, complete the addition, stir at room temperature for 1 hour, concentrate to dryness under reduced pressure, add 200ml of distilled water, extract 100mlx3 times with dichloromethane, combine the organic phases, no Dry over sodium sulfate, filter, and concentrate to dryness under reduced pressure. Purification by silica gel column chromatography (20-40% ethyl acetate/petroleum ether) gave XIV-2 (36 g, yield 84%). LC/MS(ESI): m/z 191[M+1] ⁺ .

Step 2) Preparation of intermediate XV-2

Add intermediate XVI-2 (19.0g, 100mmol), acetone (17.4g, 300mmol), 300ml of methanol, and 1ml of acetic acid to a 1L round-bottomed flask. Add sodium cyanoborohydride (15.7g, 250mmol) at room temperature and react. The mixture was stirred at room temperature overnight. Concentrate to dryness under reduced pressure, add distilled water, extract with ethyl acetate, dry, filter and concentrate. Purification by silica gel column chromatography (10%-50% ethyl acetate/petroleum ether) gave white solid XV-2 (14.1g, yield 61%). LC/MS(ESI): m/z 233[M+1] ⁺ .

Step 3) Preparation of intermediate II-2 hydrochloride

Intermediate II-2 hydrochloride was prepared according to step 3) of the preparation method of intermediate II-1 hydrochloride, with a yield of 90%. LC/MS(ESI): m/z 133[M+1] ⁺ .

Example 5: Preparation of intermediate II-3

Step 1) Preparation of intermediate XV-3

To a solution of 2-hydroxyethylhydrazine (5g, 65mmol) in methanol (100ml) at 0°C, add 13ml of triethylamine and Boc ₂ O (17.2g, 78mmol), stir at room temperature for 16h under nitrogen protection, and reduce the pressure. Concentrate to dryness, add citric acid solution, extract with ethyl acetate, dry over anhydrous sodium sulfate, filter, and concentrate to dryness under reduced pressure. Purification by silica gel column chromatography (20-40% ethyl acetate/petroleum ether) gave XV-3 (6.8 g, yield 89%). LC/MS(ESI): m/z 177[M+1] ⁺ .

Step 2) Preparation of intermediate II-3

Dissolve intermediate XV-3 (2g, 11.2mmol) in 50 ml of THF, add lithium aluminum hydride (LAH) (1.7g, 44.8mmol), reflux under nitrogen protection for 5 hours, cool to 0°C, and add Na in batches ₂ SO ₄ ·10H ₂ O, filter, wash the filter cake with THF, dry the filtrate over anhydrous magnesium sulfate, and concentrate to obtain crude II-3, which can be used directly in the next step without purification. LC/MS(ESI): m/z 91[M+1] ⁺ .

Example 6: Preparation of intermediate II-4

Step 1) Preparation of intermediate XV-4

At 0°C, add 2-hydroxyethylhydrazine (7.6g, 100mmol) to a mixed solvent of methanol (100ml) and acetone (50ml), add anhydrous magnesium sulfate (12g, 100mmol), stir at room temperature overnight, and filter to remove sulfuric acid. Magnesium, the filtrate was concentrated to dryness under reduced pressure, added 100ml dichloromethane to dissolve, added triethylamine (20.2g, 200mmol), added acetic anhydride (10.7g, 105mmol) dropwise at 0°C, stirred at room temperature overnight, added 200ml distilled water, Extract with dichloromethane, combine the organic phases and concentrate to dryness under reduced pressure. Add tetrahydrofuran (50ml) and 5ml of hydrochloric acid, stir at room temperature for 12 hours, and concentrate to dryness under reduced pressure to obtain XV-4, which is used directly in the next step without purification. LC/MS(ESI): m/z 119[M+1] ⁺ .

Step 2) Preparation of intermediate II-4

Dissolve intermediate XV-4 (1.2g, 10mmol) in 50ml of THF, add lithium aluminum tetrahydride (LAH) (1.5g, 44.8mmol), reflux under nitrogen protection for 4 hours, cool to below 0°C, and add in batches Na ₂ SO ₄ ·10H ₂ O quenched the reaction, filtered, the filter cake was washed with THF, the filtrate was dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to dryness to obtain II-4. LC/MS(ESI): m/z 105[M+1] ⁺ .

Example 7: Preparation of Intermediate II-5

Step 1) Preparation of intermediate XVI-5

Intermediate XVI-1 (12.8g, 73.5mmol), ethyl bromoacetate (36.6g, 219mmol), and anhydrous potassium carbonate (30.2g, 219mmol) were dissolved in 250ml DMF and heated to 80°C under nitrogen protection. Stir overnight, cool to room temperature, add water, extract with ethyl acetate, dry over anhydrous sodium sulfate, filter, and concentrate to dryness under reduced pressure to obtain 18 g of crude XVI-5. LC/MS(ESI): m/z 261[M+1] ⁺ .

Step 2) Preparation of intermediate XV-5

Add 380 ml of ethanol, NaBH ₄ (7.2 g, 189 mmol) and LiCl (7.9 g, 188 mmol) in sequence to a 2L round-bottomed flask, then add a THF solution (380 ml) of XVI-5 (18 g, 69 mmol) dropwise at room temperature, and stir 6h, concentrate under reduced pressure to remove a large amount of dissolved matter, add water, extract with ethyl acetate, dry the combined organic phase with anhydrous Na ₂ SO ₄ , filter, and concentrate to dryness under reduced pressure to obtain XV-5 (12.9g, yield 86%) . LC/MS(ESI): m/z 219[M+1] ⁺ .

Step 3) Preparation of intermediate IV-5

Dissolve XV-5 (12.9g) in 50ml of dioxane, add HCl in dioxane (6N, 30ml), stir at room temperature overnight, and concentrate to dryness under reduced pressure to obtain intermediate II-5 (12.8g ). LC/MS(ESI): m/z 119[M+1] ⁺ .

Example 8: Preparation of intermediate IV-6

Step 1) Preparation of intermediate XVII-6

To a THF solution (15 ml) of 3-methylmorpholine (1.0 g, 10 mmol), add tert-butyl nitrite (1.1 g, 11 mmol), reflux for 12 h, and concentrate to dryness under reduced pressure to obtain XVII-6 without purification. used directly in the next step. LC/MS(ESI): m/z 131[M+1] ⁺ .

Step 2) Preparation of intermediate II-6

Dissolve the intermediate XIX-6 (80mmol) from the previous step in 200 ml of THF, add LAH (6.1g, 160mmol) in batches at 0°C, stir at room temperature overnight, cool, and add Na ₂ SO ₄ ·10H in batches ₂ O, filtered, the filter cake was washed with THF, the filtrate was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain compound II-6 (yield 72%). LC/MS(ESI): m/z 117[M+1] ⁺ .

The hydrazine in Table 3 below can be prepared according to the same method as compound II-6.

table 3

Example 9: 6-(4-trifluoromethylphenyl)-N-(1-hydroxypropyl-2-yl)-N-isopropyl-2-(1H-imidazol 1-yl)pyrimidine-4 -Preparation of hydrazide (compound 1)

IA prepared in Example 1 (36 mg, 0.1 mmol), hydrazine hydrochloride (20 mg, 0.12 mmol), 2-(7-azobenzotriazole)-N,N,N',N'- Tetramethylurea hexafluorophosphate (HATU) (57mg, 0.15mmol) was dissolved in 2ml of dimethylformamide (DMF), and N,N-diisopropylethylamine (DIPEA) (47mg, 0.36mmol) was added ), stir overnight under nitrogen, dilute with ethyl acetate, wash with water, dry the organic phase with anhydrous sodium sulfate, filter, concentrate to dryness under reduced pressure, and purify by silica gel chromatography (PE/EA, 1:1) to obtain the compound 1 (23 mg, yield 50%). LC/MS(ESI): m/z 449[M+1] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ): δ10.15(s,1H),9.00(s,1H),8.66(d,2H),8.56(s,1H),7.96(m,3H),7.19 (s,1H),4.34-4.37(m,1H),3.40-3.48(m,1H),3.28-3.35(m,1H),3.16-3.23(m,2H),1.14-1.20(m,6H) ,0.98(d,J＝6.8Hz,3H).

The compounds in Table 4 below can be prepared according to the same method as Compound 1.

Table 4

Example 10 Preparation of Compound 29

Compound 27 (39 mg, 0.1 mmol) was dissolved in 5 ml of DCM, added DIPEA (0.1 ml), cooled to 0°C, dropwise added 0.06 ml of acetic anhydride, completed the addition, stirred at room temperature overnight, washed three times with water, and anhydrous sodium sulfate Dry, filter, and concentrate to dryness under reduced pressure. Compound 29 is purified by silica gel column chromatography (PE/EA, 1:1). The yield is 77%. LC/MS(ESI): m/z 433[M+1] ⁺ . ¹ HNMR (400MHz, DMSO-d ₆ ): δ10.13(s,1H),8.98(s,1H),8.66(d,2H),8.56(s,1H),7.96(m,3H),7.19( s,1H),3.27-3.18(m,1H),2.09(s,3H),1.14(d,J＝6.8Hz,6H).

The compounds in Table 5 below can be prepared according to the same method as compound 29.

table 5

Example 11 Preparation of Compound 33

According to a preparation method similar to Example 1, compound 33 was obtained by reacting intermediate III-J and (S)-N-(2-aminopropyl)-1-methylcyclopropanyl-1-sulfonamide group. LC/MS(ESI): m/z 455[M+H] ⁺ .

Effect Example 1 Test of antagonism between research compounds and AHR in human cell lines

The test used the human liver cancer HepG2 cell line that endogenously expresses AHR protein (provided by the Stem Cell Bank of the Chinese Academy of Sciences). CYP1A1 gene expression is regulated by AHR activity. After AHR is activated, it can bind to the CYP1A1 enhancer called The sequence of the xenobiotic response element (XRE) triggers CYP1A1 gene expression. In order to quantitatively measure the effect of compounds on AHR activity, the 1200 bp (-1143 to +57) regulatory sequence upstream of the CYP1A1 gene promoter was synthesized and inserted into a plasmid vector containing firefly luciferase. The plasmid was then linearized by single enzyme digestion and transfected into HepG2 cells via lipofectamine 3000. The transfected HepG2 cells were screened with puromycin to obtain stable expression cell lines. When measuring the antagonism between compounds and AHR, use AHR agonists (such as L-Kynurenine, Kynurenic acid, indirubin, TCDD, ITE (2-(1H-Indol-3-ylcarbonyl)-4-thiazolecarboxylic acid methyl ester)), etc. Expression of firefly luciferase is elicited while cells are treated with different concentrations of compounds, and the inhibition of luciferase expression by the compounds is measured.

Stably transfected HepG2 cells were subcultured in Minimum Eagle's medium (MEM) at 37°C in a 5% carbon dioxide environment. MEM medium was supplemented with 1mM sodium pyruvate, 2mM GlutaMax, 1× non-essential amino acids, 10% Australian fetal calf serum, 100U/mL penicillin and 5ug/mL puromycin. Before testing, HepG2 cells were seeded into 96-well plates at a density of 5 to 8 × 10 ⁴ /well and grown for 24 to 48 h to reach ~90% confluence before drug treatment (the culture medium did not contain puromyces white). Before drug treatment, 2× compound solutions containing AHR agonists at different concentrations were prepared with the same culture medium, and then half of the cell culture medium in the 96-well plate was replaced with 2× compound solution. The negative control group was set to the AHR agonist solution containing only corresponding concentrations of DMSO, while the positive control group was set to the corresponding concentrations of CH223191 and BAY2416964.

Each compound (including positive control and negative control) was tested in two independent sets. HepG2 cells were lysed by Promega's Steady-Glo luciferase detection system 24 hours after compound treatment, and the luciferase signal was measured using Tecan's InfiniteM1000Pro microplate reader.

In terms of data processing, each compound was tested repeatedly for each group. The well signal with a compound concentration of 0 was taken as 100%, and the cell signal with untreated agonist was taken as 0. The AHR activity inhibition percentage at different compound concentrations was calculated in turn. The average value of 2 sets of repeated data is calculated by nonlinear fitting according to the formula Calculate the IC ₅₀ corresponding to the compound, where y is the percent inhibition and x is the concentration of the corresponding compound.

Reference: Buckley, S.M.K.et al.In vivo bioimaging with tissue-specific transcription factor activated luciferase reporters.Sci.Rep.5:11842(2015).

The IC ₅₀ of each compound is shown in Table 6, where A means IC ₅₀ ≤100nM, B means 100nM＜IC ₅₀ ≤1.0μM, C means 1μM＜IC ₅₀ ≤5.0μM, and D means IC ₅₀ >5.0μM.

Table 6 EC ₅₀ of each compound

As can be seen from Table 6, the above-mentioned compounds according to the present invention can inhibit those functions and signaling pathways controlled by AHR, thereby affecting the growth and proliferation of cancer cells and the invasiveness of tumor cells. Therefore, 2- represented by Formula I of the present invention Nitrogen-substituted pyrimidine compounds, their respective optical isomers, deuterated products, prodrugs or pharmaceutically acceptable salts can be used to inhibit the growth of cancer cells and inhibit the metastasis and invasion of tumor cells.

The above are only specific embodiments of the present invention, but the protection scope of the present invention is not limited thereto. Any person familiar with the technical field can easily think of changes or replacements within the technical scope disclosed by the present invention. are covered by the protection scope of the present invention. Therefore, the protection scope of the present invention should be determined by the protection scope of the claims.

Claims

A class of 2-nitrogen-substituted pyrimidine compounds represented by the following formula I, each of which is an optical isomer, deuterated product, prodrug or pharmaceutically acceptable salt:

in,

Ring A is a C 6-10 aryl group or a 5- to 10-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O and S heteroatoms;

R 1 and R 2 are each independently hydrogen, saturated or unsaturated substituted or unsubstituted C 1 -C 8 alkyl, saturated or unsaturated substituted or unsubstituted C 3 -C 8 cycloalkyl, -OC (=O)C 1-8 alkyl, -OC(=O)C 3 -C 8 cycloalkyl, -C(=O)OC 1 -C 8 alkyl, -C(=O)C 3 -C 8 cycloalkyl, -S(O) m R c , saturated or unsaturated substituted or unsubstituted C 1 -C 8 acyl, C 6 -C 14 aryl, containing 1 to 3 selected from N, O and A 4- to 14-membered heterocycloalkyl group containing a heteroatom of S or a 5- to 14-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S, containing The group is a saturated or unsaturated halogenated or unhalogenated C 1-8 alkyl group, containing The group is a saturated or unsaturated halogenated or unhalogenated C 3-8 cycloalkyl group, wherein "substituted" means optionally substituted by 1 to 10 deuterons, or optionally containing 1 to 4 Each one is selected from hydroxyl, halogen, cyano, amino, -S(O) m R c , -NR d R e , saturated or unsaturated C 1 -C 8 alkyl, saturated or unsaturated C 3 -C 8 Cycloalkyl, saturated or unsaturated C 1 -C 8 alkoxy, saturated or unsaturated C 3 -C 8 cycloalkoxy, -OC(=O)C 1 -C 8 alkyl, -OC( =O)C 3 -C 8 cycloalkyl, -C(=O)OC 1-8 alkyl, -C(=O)OC 3 -C 8 cycloalkyl, containing The group is a saturated or unsaturated halogenated or unhalogenated C 1-8 alkyl group, containing The group is a saturated or unsaturated halogenated or unhalogenated C 3-8 cycloalkyl group, a saturated or unsaturated C 1 -C 8 acyl group, a saturated or unsaturated C 1 -C 8 alkoxycarbonyl group, C 6 -C 14 aryl, 4 to 14 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O, and S, or 5 containing 1 to 3 heteroatoms selected from N, O, and S to 14-membered heteroaryl substituents;

Or R 1 and R 2 together with the N atom connecting them form a substituted or unsubstituted 4 to 14 membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, O and S, wherein said "substituted" Refers to being substituted by 1 to 10 deuterium, or optionally containing 1 to 4 selected from hydroxyl, halogen, cyano, -S(O) m R c , -NR d R e , C 1 to C 8 alkyl , C 3 ~ C 8 cycloalkyl, C 1 ~ C 8 alkoxy, C 3 ~ C 8 cycloalkoxy, -OC(=O)C 1-8 alkyl, -OC(=O)C 3 ~C 8 cycloalkyl, -C(=O)OC 1-8 alkyl, -C(=O)OC 3 ~C 8 cycloalkyl, containing Saturated or unsaturated halogenated or unsaturated groups Halogenated C 1-8 alkyl, containing Saturated or unsaturated halogenated or unhalogenated C 3-8 cycloalkyl group, C 1 to C 8 alkyl group substituted by R f , C 3 to C 8 cycloalkyl group, C 1 to C 8 Substituents of alkoxy and C 3 to C 8 cycloalkoxy;

R 3 is selected from deuterium, halogen, nitro, cyano, carboxyl, hydroxyl, -NR d R e , -OR g , -CO 2 R g , -S(O) m R c , or is replaced by 1 to 3 R h -substituted C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 alkoxy, C 3-8 cycloalkoxy, C 1-8 alkoxycarbonyl, C 1-8 alkyl Carbonyl group, C 1-8 alkylcarboxyl group, 3-10 membered cycloalkyl group, 3-10 membered heterocycloalkyl group, 6-10 membered aryl group, 5-10 membered heteroaryl group.

R 4 is H or D;

L is a chemical bond or -NHR i ;

R a and R b are each independently selected from saturated or unsaturated substituted or unsubstituted C 3 -C 8 cycloalkyl, saturated or unsaturated substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted Substituted 6- to 10-membered aryl groups or substituted or unsubstituted 4- to 10-membered heteroaryl groups containing 1 to 3 heteroatoms selected from N, O and S, wherein the "substituted" refers to selectively substituted by 1 to 10 deuterium substitutions, or optionally containing 1 to 4 selected from hydroxyl, halogen, cyano, -S(O) mRc , -NRdRe , saturated or unsaturated C1 - C8 Alkyl, saturated or unsaturated C 3 -C 8 cycloalkyl, saturated or unsaturated C 1 -C 8 alkoxy, saturated or unsaturated C 3 -C 8 cycloalkoxy, -OC(= O)C 1 -C 8 alkyl, -OC(=O)C 3 -C 8 cycloalkyl, -C(=O)OC 1-8 alkyl, -C(=O)OC 3 -C 8 ring Alkyl, saturated or unsaturated C 1 -C 8 acyl, saturated or unsaturated C 1 -C 8 alkoxycarbonyl, containing The group is a saturated or unsaturated halogenated or unhalogenated C 1-8 alkyl group, containing The group is saturated or unsaturated halogenated or unhalogenated C 3-8 cycloalkyl, C 6 -C 14 aryl, 4 to 14 containing 1 to 3 heteroatoms selected from N, O and S A substituent of a 5- to 14-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S;

Or R a and R b together with the N atom connecting them form a substituted or unsubstituted 4 to 14-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, O and S, a substituted or unsubstituted containing 5 to 14 membered heteroaryl groups with 1 to 3 heteroatoms selected from N, O and S, wherein "substituted" means substituted with 1 to 10 deuterons, or optionally containing 1 to 4 selected from Hydroxy, halogen, cyano, sulfonyl, carboxyl -S(O) m R c , -NR d R e , C 1 to C 8 alkyl, C 3 to C 8 cycloalkyl, C 1 to C 8 alkoxy Base, C 3 to C 8 cycloalkoxy group, -OC(=O)C 1-8 alkyl group, -OC(=O)C 3 to C 8 cycloalkyl group, -C(=O)OC 1-8 Alkyl, -C(=O)OC 3 ~ C 8 cycloalkyl, containing The group is a saturated or unsaturated halogenated or unhalogenated C 1-8 alkyl group, containing Saturated or unsaturated halogenated or unhalogenated C 3-8 cycloalkyl group, C 1 to C 8 alkyl group substituted by R f , C 3 to C 8 cycloalkyl group, C 1 to C 8 Alkoxy, C 3 to C 8 cycloalkoxy substituents, wherein R f is selected from deuterium, halogen, cyano, hydroxyl, amino, saturated or unsaturated C 1 to C 6 alkyl, saturated or unsaturated C 3 ~ C 6 cycloalkyl, -S(O) m R c , NR d R e , saturated or unsaturated substituted by deuterium, halogen, hydroxyl or amino group C 1 ~ C 6 alkyl, substituted by deuterium, halogen , C 3 ~ C 6 cycloalkyl substituted by hydroxyl or amino, saturated or unsaturated C 1 ~ C 6 alkoxy, C 3 ~ C 6 cycloalkoxy, saturated or unsaturated substituted by deuterium, halogen, hydroxyl Or C 1 to C 6 alkoxy group substituted by amino group, C 3 to C 6 cycloalkoxy group substituted by deuterium, halogen, hydroxyl group or amino group;

n is an integer of 0, 1, 2, 3, 4 or 5;

n1 is an integer of 0, 1 or 2;

m is an integer of 0, 1 or 2;

R c , R g , Rh and R i are each independently selected from hydrogen, hydroxyl, amino, saturated or unsaturated substituted or unsubstituted C 1 -C 8 alkyl, saturated or unsaturated substituted or unsubstituted C 3 -C 8 cycloalkyl, -C(=O)C 1-8 alkyl, -C(=O)C 3 -C 8 cycloalkyl, -C(=O)OC 1 -C 8 alkyl , -C(=O)OC 3 -C 8 cycloalkyl, -C(=O)NC 1 -C 8 alkyl, -C(=O)NC 3 -C 8 cycloalkyl, C 1 -C 8 Sulfo group, saturated or unsaturated substituted or unsubstituted C 1 -C 8 sulfonyl group, C 6 -C 14 aryl group, C 7 -C 14 arylalkyl group, containing 1 to 3 selected from N, O and A 4- to 14-membered heterocycloalkyl group containing a heteroatom of S or a 5- to 14-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S, wherein "substituted" means substituted by 1 to 10 Deuterium substitution, or optionally containing 1 to 4 selected from hydroxyl, halogen, cyano, sulfonyl, C 1 -C 8 sulfo, -NR d R e , saturated or unsaturated C 1 -C 8 alkane group, saturated or unsaturated C 3 -C 8 cycloalkyl group, saturated or unsaturated C 1 -C 8 alkoxy group, saturated or unsaturated C 3 -C 8 cycloalkoxy group, -OC(=O )C 1 -C 8 alkyl, -OC(=O)C 3 -C 8 cycloalkyl, -C(=O)OC 1-8 alkyl, -C(=O)OC 3 -C 8 cycloalkyl base, saturated or unsaturated C 1 -C 8 sulfonyl group, saturated or unsaturated C 1 -C 8 acyl group, saturated or unsaturated C 1 -C 8 alkoxycarbonyl group, C 6 -C 14 aryl group, Substitution of a 4- to 14-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, O, and S or a 5- to 14-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S Base, where R c is not hydrogen;

R d and R e are each independently selected from hydrogen, halogen, cyano, hydroxyl, saturated or unsaturated C 1 to C 3 alkyl, C 3 to C 6 cycloalkyl, saturated or unsaturated halogen or hydroxyl Substituted C 1 to C 3 alkyl, C 3 to C 6 cycloalkyl substituted by halogen or hydroxyl, saturated or unsaturated C 1 to C 3 alkoxy, C 3 to C 6 cycloalkoxy, saturated or Unsaturated C 1 to C 3 alkoxy group substituted by halogen or hydroxyl group, C 3 to C 6 cycloalkoxy group substituted by halogen or hydroxyl group.
The 2-nitrogen-substituted pyrimidine compound represented by formula I according to claim 1, each of which is an optical isomer, a deuterated product, a prodrug or a pharmaceutically acceptable salt, characterized in that,

Preferably, ring A is a C 6-10 aryl group or a 5-8 membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O and S heteroatoms.
The 2-nitrogen-substituted pyrimidine compound represented by formula I according to claim 1, each of which is an optical isomer, a deuterated product, a prodrug or a pharmaceutically acceptable salt, characterized in that,

Preferably, R 1 and R 2 are each independently hydrogen, saturated or unsaturated substituted or unsubstituted C 1 -C 6 alkyl, saturated or unsaturated substituted or unsubstituted C 3 -C 6 cycloalkyl , -OC(=O)C 1-6 alkyl, -OC(=O)C 3 -C 6 cycloalkyl, -C(=O)OC 1 -C 6 alkyl, -C(=O)C 3 -C 6 cycloalkyl, -S(O) m R c , saturated or unsaturated substituted or unsubstituted C 1 -C 6 sulfonyl group, saturated or unsaturated substituted or unsubstituted C 1 -C 6 Acyl group, C 6 -C 10 aryl group, 5 to 10 membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, O and S or 1 to 3 heteroatoms selected from N, O and S 5- to 10-membered heteroaryl groups containing The group is a saturated or unsaturated halogenated or unhalogenated C 1-6 alkyl group, containing The group is a saturated or unsaturated halogenated or unhalogenated C 3-6 cycloalkyl group, wherein "substituted" means substituted by 1 to 10 deuterons, or optionally contains 1 to 4 selected from Hydroxy, halogen, cyano, -S(O) m R c , -NR d R e , saturated or unsaturated C 1 -C 6 alkyl, saturated or unsaturated C 3 -C 6 cycloalkyl, saturated Or unsaturated C 1 -C 6 alkoxy, saturated or unsaturated C 3 -C 6 cycloalkoxy, -OC(=O)C 1 -C 6 alkyl, -OC(=O)C 3 -C 6 cycloalkyl, -C(=O)OC 1-6 alkyl, -C(=O)OC 3 -C 6 cycloalkyl, containing The group is a saturated or unsaturated halogenated or unhalogenated C 1-6 alkyl group, containing Saturated or unsaturated halogenated or unhalogenated C 3-6 cycloalkyl group, saturated or unsaturated C 1 -C 6 acyl, saturated or unsaturated C 1 -C 6 alkoxycarbonyl, C 6 -C 10 aryl, 5 to 10 yuan containing 1 to 3 heteroatoms selected from N, O and S Heterocycloalkyl or a 5- to 10-membered heteroaryl substituent containing 1 to 3 heteroatoms selected from N, O and S;

Or R 1 and R 2 together with the N atom connecting them form a substituted or unsubstituted 5 to 10 membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, O and S, wherein said "substituted" Refers to being substituted by 1 to 10 deuterium, or optionally containing 1 to 4 selected from hydroxyl, halogen, cyano, -S(O) m R c , -NR d R e , C 1 to C 6 alkyl , C 3 ~ C 6 cycloalkyl, C 1 ~ C 6 alkoxy, C 3 ~ C 6 cycloalkoxy, -OC(=O)C 1-6 alkyl, -OC(=O)C 3 ~C 6 cycloalkyl, -C(=O)OC 1-6 alkyl, -C(=O)OC 3 ~C 6 cycloalkyl, containing The group is a saturated or unsaturated halogenated or unhalogenated C 1-6 alkyl group, containing Saturated or unsaturated halogenated or unhalogenated C 3-6 cycloalkyl group, C 1 to C 6 alkyl group substituted by R f , C 3 to C 6 cycloalkyl group, C 1 to C 6 Substituents of alkoxy and C 3 to C 6 cycloalkoxy;

More preferably, R 1 and R 2 are each independently hydrogen, saturated or unsaturated substituted or unsubstituted C 1 -C 4 alkyl, saturated or unsaturated substituted or unsubstituted C 3 -C 6 cycloalkyl base, -OC(=O)C 1-4 alkyl, -OC(=O)C 3 -C 6 cycloalkyl, -C(=O)OC 1 -C 4 alkyl, -C(=O) C 3 -C 6 cycloalkyl, -S(O) m R c , saturated or unsaturated substituted or unsubstituted C 1 -C 4 acyl, C 6 -C 10 aryl, containing 1 to 3 selected from A 5- to 8-membered heterocycloalkyl group containing heteroatoms of N, O, and S or a 5- to 8-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S, containing The group is a saturated or unsaturated halogenated or unhalogenated C 1-4 alkyl group, containing The group is a saturated or unsaturated halogenated or unhalogenated C 3-6 cycloalkyl group, wherein "substituted" means substituted by 1 to 10 deuterons, or optionally contains 1 to 3 selected from Hydroxy, halogen, cyano, -S(O) m R c , -NR d R e , saturated or unsaturated C 1 -C 4 alkyl, saturated or unsaturated C 3 -C 6 cycloalkyl, saturated Or unsaturated C 1 -C 4 alkoxy, saturated or unsaturated C 3 -C 6 cycloalkoxy, -OC(=O)C 1 -C 4 alkyl, -OC(=O)C 3 -C 6 cycloalkyl, -C(=O)OC 1-4 alkyl, -C(=O)OC 3 -C 6 cycloalkyl, containing The group is a saturated or unsaturated halogenated or unhalogenated C 1-4 alkyl group, containing The group is a saturated or unsaturated halogenated or unhalogenated C 3-6 cycloalkyl group, a saturated or unsaturated C 1 -C 4 acyl group, a saturated or unsaturated C 1 -C 4 alkoxycarbonyl group, C 6 -C 10 aryl, 5 to 8 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O, and S, or 5 to 3 heteroatoms selected from N, O, and S to 10-membered heteroaryl substituents;

Or R 1 and R 2 together with the N atom connecting them form a substituted or unsubstituted 5 to 8 membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, O and S, wherein said "substituted" Refers to being substituted by 1 to 10 deuterium, or optionally containing 1 to 3 selected from hydroxyl, halogen, cyano, -S(O) m R c , -NR d R e , C 1 ~ C 4 alkyl , C 3 ~ C 6 cycloalkyl, C 1 ~ C 4 alkoxy, C 3 ~ C 6 cycloalkoxy, -OC(=O)C 1-4 alkyl, -OC(=O)C 3 ~C 6 ring Alkyl, -C(=O)OC 1-4 alkyl, -C(=O)OC 3 ~ C 6 cycloalkyl, containing The group is a saturated or unsaturated halogenated or unhalogenated C 1-4 alkyl group, containing Saturated or unsaturated halogenated or unhalogenated C 3-6 cycloalkyl group, C 1 to C 4 alkyl group substituted by R f , C 3 to C 6 cycloalkyl group, C 1 to C 4 Alkoxy, C 3 to C 6 cycloalkoxy substituents, where R f is selected from deuterium, halogen, cyano, hydroxyl, amino, saturated or unsaturated C 1 to C 4 alkyl, saturated or unsaturated C 3 ~ C 6 cycloalkyl, -S(O) m R c , NR d R e , saturated or unsaturated substituted by deuterium, halogen, hydroxyl or amino group C 1 ~ C 4 alkyl, substituted by deuterium, halogen , C 3 ~ C 6 cycloalkyl substituted by hydroxyl or amino, saturated or unsaturated C 1 ~ C 4 alkoxy, C 3 ~ C 6 cycloalkoxy, saturated or unsaturated substituted by deuterium, halogen, hydroxyl Or C 1 to C 4 alkoxy group substituted by amino group, C 3 to C 6 cycloalkoxy group substituted by deuterium, halogen, hydroxyl group or amino group;

Preferably, R 3 is selected from deuterium, halogen, nitro, cyano, carboxyl, hydroxyl, -NR d R e , -OR g , -CO 2 R g , -S(O) m R c , or is replaced by 1 to 3 R h substituted C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, C 1-6 alkoxycarbonyl, C 1- 6- alkylcarbonyl, C 1-6 alkylcarboxyl, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 6-10-membered aryl, 5-10-membered heteroaryl;

More preferably, R 3 is selected from deuterium, halogen, nitro, cyano, carboxyl, hydroxyl, -NR d R e , -OR g , -CO 2 R g , -S(O) m R c , or is replaced by 1 To 3 R h substituted C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, C 3-6 cycloalkoxy, C 1-4 alkoxycarbonyl, C 1 -4 alkylcarbonyl, C 1-4 alkylcarboxyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl;

Preferably, R a and R b are each independently selected from saturated or unsaturated substituted or unsubstituted C 3 -C 6 cycloalkyl, saturated or unsaturated substituted or unsubstituted C 1 -C 6 alkyl, Substituted or unsubstituted 6- to 10-membered aryl groups or substituted or unsubstituted 5- to 8-membered heteroaryl groups containing 1 to 3 heteroatoms selected from N, O and S heteroatoms, wherein the "substituted" refers to 1 to 10 deuterium substitutions, or optionally containing 1 to 3 selected from hydroxyl, halogen, cyano, -S(O) mRc , -NRdRe , saturated or unsaturated C1 - C6 Alkyl, saturated or unsaturated C 3 -C 6 cycloalkyl, saturated or unsaturated C 1 -C 6 alkoxy, saturated or unsaturated C 3 -C 6 cycloalkoxy, -OC(= O)C 1 -C 6 alkyl, -OC(=O)C 3 -C 6 cycloalkyl, -C(=O)OC 1-6 alkyl, -C(=O)OC 3 -C 6 ring Alkyl, saturated or unsaturated C 1 -C 6 acyl, saturated or unsaturated C 1 -C 6 alkoxycarbonyl, containing The group is a saturated or unsaturated halogenated or unhalogenated C 1-6 alkyl group, containing The group is saturated or unsaturated halogenated or unhalogenated C 3-6 cycloalkyl, C 6 -C 10 aryl, 5 to 10 containing 1 to 3 heteroatoms selected from N, O and S A substituent of a 5- to 10-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S;

Or R a and R b together with the N atom connecting them form a substituted or unsubstituted 4 to 10-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, O and S, a substituted or unsubstituted containing 5 to 10 membered heteroaryl groups with 1 to 3 heteroatoms selected from N, O and S, wherein "substituted" means substituted with 1 to 10 deuteriums, or optionally containing 1 to 4 selected from Hydroxy, halogen, cyano, sulfonyl, carboxyl, -S(O) m R c , -NR d R e , C 1 to C 6 alkyl, C 3 to C 6 cycloalkyl, C 1 to C 6 alkyl Oxygen group, C 3 to C 6 cycloalkoxy group, -OC(=O)C 1-6 alkyl group, -OC(=O)C 3 to C 6 Cycloalkyl, -C(=O)OC 1-6 alkyl, -C(=O)OC 3 ~ C 6 cycloalkyl, containing The group is a saturated or unsaturated halogenated or unhalogenated C 1-6 alkyl group, containing Saturated or unsaturated halogenated or unhalogenated C 3-6 cycloalkyl group, C 1 to C 6 alkyl group substituted by R f , C 3 to C 6 cycloalkyl group, C 1 to C 6 Substituents of alkoxy and C 3 to C 6 cycloalkoxy;

More preferably, R a and R b are each independently selected from saturated or unsaturated substituted or unsubstituted C 3 -C 6 cycloalkyl, saturated or unsaturated substituted or unsubstituted C 1 -C 4 alkyl. , a substituted or unsubstituted 6 to 10-membered aryl group or a substituted or unsubstituted 5 to 8-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O and S heteroatoms, wherein the "substituted" refers to Substituted with 1 to 10 deuterium, or optionally containing 1 to 3 selected from hydroxyl, halogen, cyano, -S(O) mRc , -NRdRe , saturated or unsaturated C1- C 4 alkyl, saturated or unsaturated C 3 -C 6 cycloalkyl, saturated or unsaturated C 1 -C 4 alkoxy, saturated or unsaturated C 3 -C 6 cycloalkoxy, -OC( =O)C 1 -C 4 alkyl, -OC(=O)C 3 -C 6 cycloalkyl, -C(=O)OC 1-4 alkyl, -C(=O)OC 3 -C 6 Cycloalkyl, saturated or unsaturated C 1 -C 4 acyl, saturated or unsaturated C 1 -C 4 alkoxycarbonyl, containing The group is a saturated or unsaturated halogenated or unhalogenated C 1-4 alkyl group, containing The group is saturated or unsaturated halogenated or unhalogenated C 3-6 cycloalkyl, C 6 -C 10 aryl, 5 to 10 containing 1 to 3 heteroatoms selected from N, O and S A substituent of a 5- to 10-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S;

Or R a and R b together with the N atom connecting them form a substituted or unsubstituted 5- to 8-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, O and S, a substituted or unsubstituted containing A 5- to 6-membered heteroaryl group with 1 to 3 heteroatoms selected from N, O and S, wherein "substituted" means substituted with 1 to 10 deuteriums, or optionally containing 1 to 3 selected from Hydroxy, halogen, cyano, sulfonyl, carboxyl, -S(O) m R c , -NR d R e , C 1 to C 4 alkyl, C 5 to C 6 cycloalkyl, C 1 to C 4 alkyl Oxygen group, C 5 to C 6 cycloalkoxy group, -OC(=O)C 1-4 alkyl group, -OC(=O)C 5 to C 6 cycloalkyl group, -C(=O)OC 1- 4 alkyl, -C(=O)OC 5 ~ C 6 cycloalkyl, containing The group is a saturated or unsaturated halogenated or unhalogenated C 1-4 alkyl group, containing Saturated or unsaturated halogenated or unhalogenated C 3-6 cycloalkyl group, C 1 to C 4 alkyl group substituted by R f , C 5 to C 6 cycloalkyl group, C 1 to C 4 Substituents of alkoxy and C 5 to C 6 cycloalkoxy;

Preferably, R c , R f , R g , Rh and R i are each independently selected from hydrogen, hydroxyl, amino, saturated or unsaturated substituted or unsubstituted C 1 -C 6 alkyl, saturated or unsaturated Substituted or unsubstituted C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, -C(=O)C 1-6 alkyl, -C(=O)C 3 -C 6 cycloalkyl , -C(=O)OC 1 -C 6 alkyl, -C(=O)OC 3 -C 6 cycloalkyl, -C(=O)NC 1 -C 6 alkyl, -C(=O) NC 3 -C 6 cycloalkyl, saturated or unsaturated substituted or unsubstituted C 1 -C 6 sulfonyl, C 6 -C 10 aryl, C 7 -C 11 arylalkyl, containing 1 to 3 A 5- to 10-membered heterocycloalkyl group containing heteroatoms selected from N, O, and S or a 5- to 10-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S, wherein the "substituted" Refers to being substituted by 1 to 10 deuterium, or optionally containing 1 to 4 selected from hydroxyl, halogen, cyano, sulfonate Acyl group, C 1 -C 6 sulfo group, -NR d R e , saturated or unsaturated C 1 -C 6 alkyl group, saturated or unsaturated C 3 -C 6 cycloalkyl group, saturated or unsaturated C 1 -C 6 alkoxy, saturated or unsaturated C 3 -C 6 cycloalkoxy, -OC(=O)C 1 -C 6 alkyl, -OC(=O)C 3 -C 8 cycloalkyl , -C(=O)OC 1-6 alkyl, -C(=O)OC 3 -C 6 cycloalkyl, saturated or unsaturated C 1 -C 6 sulfonyl, saturated or unsaturated C 1 - C 6 acyl, saturated or unsaturated C 1 -C 6 alkoxycarbonyl, C 6 -C 10 aryl, 5 to 10 membered heterocycloalkane containing 1 to 3 heteroatoms selected from N, O and S group or a substituent of a 5- to 10-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O and S, wherein R c is not hydrogen;

More preferably, R c , R f , R g , Rh and R i are each independently selected from hydrogen, hydroxyl, amino, saturated or unsaturated substituted or unsubstituted C 1 -C 4 alkyl, saturated or unsaturated Saturated substituted or unsubstituted C 1 -C 4 alkyl, C 4 -C 6 cycloalkyl, -C(=O)C 1-4 alkyl, -C(=O)C 4 -C 6 cycloalkyl base, -C(=O)OC 1 -C 4 alkyl, -C(=O)OC 4 -C 8 cycloalkyl, -C(=O)NC 1 -C 4 alkyl, -C(=O )NC 4 -C 6 cycloalkyl, saturated or unsaturated substituted or unsubstituted C 1 -C 4 sulfonyl, C 6 -C 10 aryl, C 7 -C 11 arylalkyl, containing 1 to 3 A 5- to 8-membered heterocycloalkyl group containing a heteroatom selected from N, O, and S or a 5- to 10-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S, wherein the "substituted ” means substituted by 1 to 10 deuterium, or optionally containing 1 to 3 selected from hydroxyl, halogen, cyano, sulfonyl, C 1 -C 4 sulfo, -NR d R e , saturated or unsaturated C 1 -C 4 alkyl, saturated or unsaturated C 4 -C 6 cycloalkyl, saturated or unsaturated C 1 -C 4 alkoxy, saturated or unsaturated C 4 -C 6 cycloalkoxy base, -OC(=O)C 1 -C 4 alkyl, -OC(=O)C 4 -C 6 cycloalkyl, -C(=O)OC 1-4 alkyl, -C(=O) OC 4 -C 6 cycloalkyl, saturated or unsaturated C 1 -C 4 sulfonyl, saturated or unsaturated C 1 -C 4 acyl, saturated or unsaturated C 1 -C 4 alkoxycarbonyl, C 6 -C 10 aryl, 5- to 8-membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O, and S, or 5- to 8-membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O, and S A substituent for a 10-membered heteroaryl group, where R c is not hydrogen;

More preferably, R f is selected from deuterium, halogen, cyano, hydroxyl, amino, saturated or unsaturated C 1 to C 6 alkyl, saturated or unsaturated C 3 to C 6 cycloalkyl, -S(O) m R c , NR d Re , saturated or unsaturated C 1 to C 6 alkyl group substituted by deuterium, halogen, hydroxyl or amino group, C 3 to C 6 cycloalkyl group substituted by deuterium, halogen, hydroxyl group or amino group, Saturated or unsaturated C 1 to C 6 alkoxy group, C 3 to C 6 cycloalkoxy group, saturated or unsaturated C 1 to C 6 alkoxy group substituted by deuterium, halogen, hydroxyl or amino group, substituted by deuterium, Halogen, hydroxyl or amino substituted C 3 to C 6 cycloalkoxy group.
The 2-nitrogen-substituted pyrimidine compound represented by formula I according to claim 1, each of which is an optical isomer, a deuterated product, a prodrug or a pharmaceutically acceptable salt, characterized in that,

More preferably, the structure formed by R 1 and R 2 in formula I together with the N atom connecting them is selected from the following groups:
The 2-nitrogen-substituted pyrimidine compound represented by formula I according to claim 1, each of which is an optical isomer, a deuterated product, a prodrug or a pharmaceutically acceptable salt, characterized in that,

More preferably, the structure formed by R a and R b in formula I together with the N atom connecting them is selected from the following groups:

Wherein, each occurrence of R j and R k is independently hydroxyl, halogen, cyano, sulfonyl, amino, C 1 to C 8 alkyl, C 3 to C 8 cycloalkyl, C 1 to C 8 alkyl Oxygen group, C 3 to C 8 cycloalkoxy group, -OC(=O)C 1-8 alkyl group, -OC(=O)C 3 to C 8 cycloalkyl group, -C(=O)OC 1- 8 alkyl, -C(=O)OC 3 ~ C 8 cycloalkyl, C 1 ~ C 8 alkyl substituted by R f , C 3 ~ C 8 cycloalkyl, C 1 ~ C 8 alkoxy, C 3 to C 8 cycloalkoxy substituents; n2 is an integer of 0, 1, 2, 3, 4 or 5;

Preferably, each occurrence of R j and R k is independently hydroxyl, halogen, cyano, sulfonyl, amino C 1 to C 6 alkyl, C 3 to C 6 cycloalkyl, C 1 to C 6 alkyl Oxy group, C 3 to C 6 cycloalkoxy group, -OC(=O)C 1-6 alkyl group, -OC(=O)C 3 to C 6 cycloalkyl group, -C(=O)OC 1- 6 alkyl, -C(=O)OC 3 ~ C 6 cycloalkyl, C 1 ~ C 6 alkyl substituted by R f , C 3 ~ C 6 cycloalkyl, C 1 ~ C 6 alkoxy, Substituents of C 3 to C 6 cycloalkoxy;

More preferably, each occurrence of R j and R k is independently hydroxyl, halogen, cyano, sulfonyl, amino C 1 to C 4 alkyl, C 4 to C 6 cycloalkyl, C 1 to C 4 Alkoxy group, C 4 to C 6 cycloalkoxy group, -OC(=O)C 1-4 alkyl group, -OC(=O)C 4 to C 6 cycloalkyl group, -C(=O)OC 1 -4 alkyl, -C(=O)OC 4 to C 6 cycloalkyl, C 1 to C 4 alkyl, C 4 to C 6 cycloalkyl, C 1 substituted by halogen, hydroxyl, amino or R f Substituents of ~C 4 alkoxy and C 4 ~C 6 cycloalkoxy.
The 2-nitrogen-substituted pyrimidine compound represented by formula I according to any one of claims 1 to 5, each of which is an optical isomer, a deuterated product, a prodrug or a pharmaceutically acceptable salt, characterized in that: The 2-nitrogen-substituted pyrimidine compounds are selected from the following compounds:
A pharmaceutical composition comprising a therapeutically effective amount of a 2-nitrogen-substituted pyrimidine compound represented by formula I according to any one of claims 1 to 6, each of its optical isomers and deuterated products , a prodrug or a pharmaceutically acceptable salt and a pharmaceutically acceptable excipient or carrier.
According to the 2-nitrogen-substituted pyrimidine compound represented by formula I according to any one of claims 1 to 6, each of its optical isomers, deuterated products, prodrugs or pharmaceutically acceptable salts is used in the preparation of AHR disorder inhibitors uses in.
According to the 2-nitrogen-substituted pyrimidine compound represented by formula I according to any one of claims 1 to 6, each of its optical isomers, deuterated products, prodrugs or pharmaceutically acceptable salts is used in the preparation and treatment of AHR disorders. Applications related to oncology drugs.
A method of treating tumors associated with AHR disorders, the method comprising administering an effective amount of a 2-nitrogen-substituted pyrimidine represented by Formula I according to any one of claims 1 to 6 to a subject in need thereof compounds, their respective optical isomers, deuterated products, prodrugs or pharmaceutically acceptable salts or a pharmaceutical composition according to claim 7.