Substituted pyrimidine hydrazide compounds and their preparation and use

Abstract

The present invention discloses a substituted pyrimidine hydrazide compound represented by the following formula I, their respective optical isomers, prodrugs or pharma- ceutically acceptable salts, a pharmaceutical composition comprising the substituted pyrimidine hydrazide compound, and its use in the manufacture of an AHR impairment inhibitor. The substituted pyrimidine hydrazide compound according to the present invention can bind to AHR and inhibit the functions and signal pathways controlled by AHR, and can also affect the growth and proliferation of cancer cells and the invasiveness of tumor cells, so that the substituted pyrimidine hydrazide compound of the present invention can be used to inhibit the growth of cancer cells and the metastasis and invasion of tumor cells. JPEG2025513904000096.jpg4261

Description

[Technical Field]

[0001] The present invention belongs to the field of biopharmaceutical technology, and specifically relates to substituted pyrimidine hydrazide compounds and their preparation and use. [Background technology]

[0002] The aryl hydrocarbon receptor (AHR) is a member of the bHLH-PAS (bHLH-PER-ARNT-SIM) subfamily of the basic helix-loop-helix (bHLH) superfamily and is a unique ligand-activated receptor in the bHLH-PAS family [Murray et al., Nat. Rev. Cancer, 2014, 14(12), 801-814; Berstene et al., Nat. Rev. Cancer, 2013, 13(12), 827-841]. The cytoplasmic AHR is stimulated by aromatic hydrocarbon xenobiotics, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), and can translocate to the nucleus to form a heterodimer with the arylhydrocarbon receptor nuclear translocator (ARNT). The AHR / ARNT complex then interacts with xenobiotic response elements (XREs) upstream of AHR-regulated genes, thereby regulating the transcription of the corresponding genes. The AHR can also activate non-XRE-dependent protein-protein interaction pathways.

[0003] The AHR pathway is one of the best-known mechanisms for binding and directing the metabolism of environmental toxins, including regulated cytochrome CYP450 enzymes (e.g., CYP1A1, CYP1A2, and CYP1B1), which can metabolize environmental toxins [(Reyes et al., Science, 1992, 256(5060), 1193-1195; Murray et al., Nat. Rev. Cancer, 2014, 14(12), 801-814)]. Activation of the AHR by environmental toxins has already demonstrated its role in many cellular processes, such as embryonic development, tumorigenesis, and inflammation. The AHR is also expressed in many cells of the immune system, including dendritic cells, macrophages, T-cells, and NK cells, and plays an important role in immunoregulation (Nguyen et al., 2014). (e.g., Front. Immunol., 2014, 5, 511). Classic exogenous AHR ligands such as TCDD induce profound immune inhibition, promote cancer development, and induce tumor growth [Gramatzki et al., Oncogene, 2009, 28(28), 2593-2605; Buiet al., Oncogene, 2009, 28(41), 3642-3651; Esser et al., Trends. Immunol., 2009, 30(9), 447-454].

[0004] Through XRE-dependent and -independent activities, the AHR regulates many important innate and adaptive immune responses. Studies have shown that some AHR agonists can promote the differentiation of Th17 (T-helper cells) and the secretion of IL-17. On the other hand, some AHR agonists can induce the lateral differentiation of Th17 cells into Treg cells and reinforce the inhibitory activity of Tregs [Quintana et al., Nature, 2008, 453(7191), 65-71; Mezrich et al., J. Immunol., 2010, 185(6), 3190-3198;]. Studies have demonstrated that AHR activation can result in the inhibition of macrophage-mediated innate inflammatory responses (e.g., reduced expression of IL-1b, IL-6, IL-12, and TNFalpha induced by lipopolysaccharide (LPS)) and the inhibition of dendritic cells (reduced activation of dendritic cells and enhanced expression of IL-10) [Kimura et al., J. Exp. Med., 2009, 206(9), 2027-2035; Wang et al., Clin. Exp. Immunol., 2014, 177(2), 521-530; Wei et al., Lab. Invest., 2014, 94(5), 528-535; Nguyen et al., Proc. Natl. Acad. Sci. USA, 2010, 107(46), 19961-19966].

[0005] To establish an effective antitumor immune response, antigen-presenting cells (APCs) must process and present tumor antigens, subsequently activating helper CD4+ T-cells (Th) and cytotoxic CD8+ T-cells (Tc), which act cooperatively to effectively kill tumor cells. Tumor cells have evolved multiple mechanisms to evade immune cytolysis regulated by Th and Tc. One such mechanism is the release of high concentrations of kynurenine and other potential AHR ligands into the tumor microenvironment (TME).

[0006] High concentrations of AHR ligands in the tumor microenvironment (TME) can directly inhibit APCs, Th, and Tc, and further inhibit Tc and Th activity by enhancing the recruitment, generation, and activation of Tregs. Tumors can evade antitumor immune responses through these mechanisms [Opitz et al., Nature, 2011, 478(7368), 197-203]. Therefore, AHR inhibitors can restore antitumor immunity by blocking the AHR-dependent immune escape pathway employed by malignant tumor cells.

[0007] Recent research into tumor immunobiology has revealed that malignant tumor cells employ various immune evasion mechanisms to evade the immune system. Preclinical and clinical studies have demonstrated that blocking or attenuating these mechanisms through therapeutic combinations (e.g., immune checkpoint inhibitors and vaccines) can optimally restore anti-tumor immune responses. Research data suggests that the use of AHR modulators alone can restore anti-tumor immunity. Due to the unique characteristics of the AHR signaling pathway, AHR inhibitors can be used in conjunction with other tumor immunotherapies, potentially enhancing immunotherapy responses through synergy with other treatment modalities. Clinically, the response rates of individual immune checkpoint inhibitors remain relatively low. Therefore, the development of new anti-tumor immune regulatory targets is of great significance for tumor treatment. AHR is a potentially promising target, and the development of relevant inhibitors offers new avenues for novel anti-tumor therapies. Summary of the Invention

[0008] Therefore, according to a first aspect of the present invention, one object of the present invention is to provide substituted pyrimidine hydrazide compounds represented by the following formula I, their respective optical isomers, prodrugs or pharmaceutically acceptable salts: JPEG2025513904000002.jpg4261

[0009] where: A1, A2 and A3 are each independently CR A or N, and the substituent R A are each independently hydrogen, deuterium, halogen, cyano group, hydroxy group, amino group, saturated or unsaturated C1 to C8 alkyl group, C3 to C8 cycloalkyl group, halogen, hydroxy group, amino group or R C a saturated or unsaturated C1-C8 alkyl group, a halogen, a hydroxy group, an amino group, or R Ca C3-C8 cycloalkyl group, a saturated or unsaturated C1-C8 alkoxy group, a C3-C8 cycloalkoxy group, a halogen, a hydroxy group, an amino group or R C a saturated or unsaturated C1-C8 alkoxy group, a halogen, a hydroxy group, an amino group or R C C3-C8 cycloalkoxy group substituted with -S(O) n Rc, saturated or unsaturated, substituted or unsubstituted C1-C8 acyl group, NR C R D is selected from

[0010] A4 is O, S, N, C or a bond, A5, A6 and A7 are each independently O, S, N or C, and

[0011] When A4, A5, A6 and A7 are N or C, each independently represents R B and R B are independently hydrogen, deuterium, halogen, cyano group, hydroxy group, -S(O) n Rc, saturated or unsaturated C1 to C8 alkyl group, C3 to C8 cycloalkyl group, halogen, hydroxy group, amino group or R C a saturated or unsaturated C1-C8 alkyl group, a halogen, a hydroxy group, an amino group, or R C a C3-C8 cycloalkyl group, a saturated or unsaturated C1-C8 alkoxy group, a C3-C8 cycloalkoxy group, a halogen, a hydroxy group, an amino group or R C a saturated or unsaturated C1-C8 alkoxy group, a halogen, a hydroxy group, an amino group or R C a C3-C8 cycloalkoxy group substituted with , a saturated or unsaturated substituted or unsubstituted C1-C8 acyl group, a saturated or unsaturated substituted or unsubstituted C1-C8 alkoxycarbonyl group, a saturated or unsaturated substituted or unsubstituted C1-C8 alkylaminocarbonyl group, NR C R D is selected from

[0012] where the substituent R C and R Dare each independently hydrogen, halogen, cyano group, hydroxy group, amino group, saturated or unsaturated C1 to C6 alkyl group, C3 to C6 cycloalkyl group, halogen, hydroxy group, -S(O) n R E or NR F R G Saturated or unsaturated C1-C6 alkyl groups substituted with halogen, hydroxyl groups, -S(O) n R E or NR F R G C3-C6 cycloalkyl group substituted with, saturated or unsaturated C1-C6 alkoxy group, C3-C6 cycloalkoxy group, halogen, hydroxy group, -S(O) n R E or NR F R G Saturated or unsaturated C1-C6 alkoxy groups substituted with halogen, hydroxyl groups, -S(O) n R E or NR F R G C3-C6 cycloalkoxy groups substituted with R E , R F and R G are each independently selected from hydrogen, deuterium, a halogen, a cyano group, a hydroxy group, an amino group, a saturated or unsaturated C1-C6 alkyl group, a C3-C6 cycloalkyl group, a saturated or unsaturated C1-C6 alkyl group substituted with a halogen, a hydroxy group or an amino group, a C3-C6 cycloalkyl group substituted with a halogen, a hydroxy group or an amino group, a saturated or unsaturated C1-C6 alkoxy group, a C3-C6 cycloalkoxy group, a saturated or unsaturated C1-C6 alkoxy group substituted with a halogen, a hydroxy group or an amino group, and a C3-C6 cycloalkoxy group substituted with a halogen, a hydroxy group or an amino group;

[0013] R1 and R2 are each independently hydrogen, a saturated or unsaturated, substituted or unsubstituted C1 to C8 alkyl group, a saturated or unsaturated, substituted or unsubstituted C3 to C8 cycloalkyl group, -OC(=O)C 1-8 Alkyl groups, -OC(=O)C3-C8 cycloalkyl groups, -C(=O)OC1-8 Alkyl groups, -C(=O)OC3-C8 cycloalkyl groups, -S(O) n Rc, a saturated or unsaturated, substituted or unsubstituted C1 to C8 sulfonyl group, a saturated or unsaturated, substituted or unsubstituted C1 to C8 acyl group, a C6 to C 14 an aryl group, a 4- to 14-membered heterocycloalkyl group or a heteroaryl group containing 1 to 3 heteroatoms selected from N, O and S, wherein the "substituted" group is optionally substituted with a hydroxy group, a halogen atom, a cyano group, a sulfonyl group, an amino group, -S(O) n Rc, NR C R D , saturated or unsaturated C1 to C8 alkyl group, saturated or unsaturated C3 to C8 cycloalkyl group, saturated or unsaturated C1 to C8 alkoxy group, saturated or unsaturated C3 to C8 cycloalkoxy group, -OC(=O)C 1-8 Alkyl groups, -OC(=O)C3-C8 cycloalkyl groups, -C(=O)OC 1-8 Alkyl group, -C(=O)OC3 to C8 cycloalkyl group, saturated or unsaturated C1 to C8 sulfonyl group, saturated or unsaturated C1 to C8 acyl group, saturated or unsaturated C1 to C8 alkoxycarbonyl group, C6 to C 14 containing 1 to 4 substituents selected from an aryl group, a 4 to 14 membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, O and S, or a heteroaryl group;

[0014] Alternatively, R1 and R2, 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, or a substituted or unsubstituted 5- to 14-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S, wherein the "substituted" group may selectively include deuterium, a hydroxyl group, a halogen atom, a cyano group, a sulfonyl group, an amino group, -S(O) n Rc, NR C R D , C1-C8 alkyl group, C3-C8 cycloalkyl group, C1-C8 alkoxy group, C3-C8 cycloalkoxy group, -OC(=O)C 1-8Alkyl groups, -OC(=O)C3-C8 cycloalkyl groups, -C(=O)OC 1-8 Alkyl group, -C(=O)OC3-C8 cycloalkyl group, halogen, hydroxy group, amino group or R H and R substituted with 1 to 4 substituents selected from a C1 to C8 alkyl group, a C3 to C8 cycloalkyl group, a C1 to C8 alkoxy group, and a C3 to C8 cycloalkoxy group, H represents hydrogen, deuterium, halogen, cyano group, hydroxy group, amino group, saturated or unsaturated C1-C6 alkyl group, C3-C6 cycloalkyl group, -S(O) n Rc, NR C R D a saturated or unsaturated C1-C6 alkyl group substituted with deuterium, a halogen, a hydroxy group or an amino group, a C3-C6 cycloalkyl group substituted with deuterium, a halogen, a hydroxy group or an amino group, a saturated or unsaturated C1-C6 alkoxy group, a C3-C6 cycloalkoxy group, a saturated or unsaturated C1-C6 alkoxy group substituted with deuterium, a halogen, a hydroxy group or an amino group, a C3-C6 cycloalkoxy group substituted with deuterium, a halogen, a hydroxy group or an amino group,

[0015] R3 is a halogen, a hydroxyl group, or -S(O) n Rc, NR C R D , saturated or unsaturated C1 to C8 alkyl group, C3 to C8 cycloalkyl group, C1 to C8 alkoxy group, C3 to C8 cycloalkoxy group, halogen, hydroxy group, amino group or R H a saturated or unsaturated C1-C8 alkyl group, a C3-C8 cycloalkyl group, a C1-C8 alkoxy group, or a C3-C8 cycloalkoxy group substituted with His selected from hydrogen, deuterium, a halogen, a cyano group, a hydroxy group, an amino group, a saturated or unsaturated C1 to C6 alkyl group, a C3 to C6 cycloalkyl group, a saturated or unsaturated C1 to C6 alkyl group substituted with a halogen, a hydroxy group or an amino group, a C3 to C6 cycloalkyl group substituted with a halogen, a hydroxy group or an amino group, a saturated or unsaturated C1 to C6 alkoxy group, a C3 to C6 cycloalkoxy group, a saturated or unsaturated C1 to C6 alkoxy group substituted with a halogen, a hydroxy group or an amino group, and a C3 to C6 cycloalkoxy group substituted with a halogen, a hydroxy group or an amino group.

[0016] R4 is hydrogen or deuterium.

[0017] n is an integer of 0, 1 or 2.

[0018] Preferably, A1 and A3 are CR A A2 is N, and the substituent R A are each independently hydrogen, halogen, cyano group, hydroxy group, amino group, saturated or unsaturated C1 to C3 alkyl group, C3 to C6 cycloalkyl group, halogen, hydroxy group, amino group or R C a saturated or unsaturated C1-C3 alkyl group, a halogen, a hydroxy group, an amino group or R C a C3-C6 cycloalkyl group, a saturated or unsaturated C1-C3 alkoxy group, a C3-C6 cycloalkoxy group, a halogen, a hydroxy group, an amino group or R C a saturated or unsaturated C1-C3 alkoxy group, a halogen, a hydroxy group, an amino group or R C C3-C6 cycloalkoxy group substituted with -S(O) n Rc, saturated or unsaturated, substituted or unsubstituted C1-C3 acyl group, NR C R D is selected from

[0019] More preferably, A1 and A3 are CR A A2 is N, and the substituent R A is hydrogen.

[0020] Preferably, A4 is N, C or a bond, A5, A6 and A7 are each independently N or C, and

[0021] A4, A5, A6 and A7 each independently represent a substituent R B and the substituent R B are each independently hydrogen, halogen, cyano group, hydroxy group, amino group, -S(O) n Rc, saturated or unsaturated C1-C3 alkyl group, C3-C6 cycloalkyl group, halogen, hydroxy group, amino group or R C a saturated or unsaturated C1-C3 alkyl group, a halogen, a hydroxy group, an amino group or R C a C3-C6 cycloalkyl group, a saturated or unsaturated C1-C3 alkoxy group, a C3-C6 cycloalkoxy group, a halogen, a hydroxy group, an amino group or R C a saturated or unsaturated C1-C3 alkoxy group substituted with a halogen atom, a hydroxy group, an amino group, or a C3-C6 cycloalkoxy group substituted with R'; a saturated or unsaturated substituted or unsubstituted C1-C3 acyl group; a saturated or unsaturated substituted or unsubstituted C1-C3 alkoxycarbonyl group; NR C R D is selected from Preferably, the substituent R C and R D are each independently hydrogen, halogen, cyano group, hydroxy group, amino group, saturated or unsaturated C1-C3 alkyl group, C3-C6 cycloalkyl group, halogen, hydroxy group, -S(O) n R E or NR F R G Saturated or unsaturated C1-C3 alkyl groups substituted with halogen, hydroxyl groups, -S(O) n R E or NR F R G C3-C6 cycloalkyl group substituted with, saturated or unsaturated C1-C3 alkoxy group, C3-C6 cycloalkoxy group, halogen, hydroxy group, -S(O) n RE or NR F R G Saturated or unsaturated C1-C3 alkoxy groups substituted with halogen, hydroxyl groups, -S(O) n R E or NR F R G and a C3-C6 cycloalkoxy group substituted with

[0022] Preferably, R E , R F and R G are each independently selected from hydrogen, deuterium, a halogen, a cyano group, a hydroxy group, an amino group, a saturated or unsaturated C1 to C3 alkyl group, a C3 to C6 cycloalkyl group, a saturated or unsaturated C1 to C3 alkyl group substituted with a halogen, a hydroxy group or an amino group, a C3 to C6 cycloalkyl group substituted with a halogen, a hydroxy group or an amino group, a saturated or unsaturated C1 to C3 alkoxy group, a C3 to C6 cycloalkoxy group, a saturated or unsaturated C1 to C3 alkoxy group substituted with a halogen, a hydroxy group or an amino group, and a C3 to C6 cycloalkoxy group substituted with a halogen, a hydroxy group or an amino group.

[0023] Preferably, A7 is C.

[0024] Preferably, R1 and R2 are each independently hydrogen, a saturated or unsaturated, substituted or unsubstituted C1 to C6 alkyl group, a saturated or unsaturated, substituted or unsubstituted C3 to C6 cycloalkyl group, or -OC(=O)C 1-6 Alkyl groups, -OC(=O)C3-C6 cycloalkyl groups, -C(=O)OC 1-6 Alkyl groups, -C(=O)OC3-C6 cycloalkyl groups, saturated or unsaturated substituted or unsubstituted C1-C6 alkoxy groups, saturated or unsaturated substituted or unsubstituted C3-C6 cycloalkoxy groups, -S(O) n Rc, NR C R D , a saturated or unsaturated, substituted or unsubstituted C1 to C6 sulfonyl group, a saturated or unsaturated, substituted or unsubstituted C1 to C6 acyl group, a C6 to C 10an aryl group, a 5- to 10-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S, wherein the "substituted" group is optionally substituted with a hydroxy group, a halogen atom, a cyano group, a sulfonyl group, an amino group, -S(O) n Rc, NR C R D , saturated or unsaturated C1 to C6 alkyl groups, saturated or unsaturated C3 to C6 cycloalkyl groups, -OC(=O)C 1-6 Alkyl groups, -OC(=O)C3-C6 cycloalkyl groups, -C(=O)OC 1-6 Alkyl group, -C(=O)OC3-C6 cycloalkyl group, saturated or unsaturated C1-C6 sulfonyl group, saturated or unsaturated C1-C6 acyl group, C6-C 10 containing 1 to 4 substituents selected from an aryl group, a 6- to 10-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, O and S, or a heteroaryl group;

[0025] Alternatively, R1 and R2, 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, or a substituted or unsubstituted 5- to 10-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S, wherein the "substituted" group selectively includes a hydroxy group, a halogen atom, a cyano group, a sulfonyl group, an amino group, -S(O) n Rc, NR C R D , C1-C6 alkyl group, C3-C6 cycloalkyl group, C1-C6 alkoxy group, C3-C6 cycloalkoxy group, -OC(=O)C 1-6 Alkyl groups, -OC(=O)C3-C6 cycloalkyl groups, -C(=O)OC 1-6 Alkyl group, -C(=O)OC3-C6 cycloalkyl group, halogen, hydroxy group, amino group or R E and R Eis hydrogen, halogen, cyano group, hydroxy group, amino group, saturated or unsaturated C1-C6 alkyl group, C3-C6 cycloalkyl group, -S(O) n Rc, NR C R D a saturated or unsaturated C1-C6 alkyl group substituted with deuterium, a halogen, a hydroxy group or an amino group, a C3-C6 cycloalkyl group substituted with deuterium, a halogen, a hydroxy group or an amino group, a saturated or unsaturated C1-C6 alkoxy group, a C3-C6 cycloalkoxy group, a saturated or unsaturated C1-C6 alkoxy group substituted with deuterium, a halogen, a hydroxy group or an amino group, a C3-C6 cycloalkoxy group substituted with deuterium, a halogen, a hydroxy group or an amino group,

[0026] Preferably, R3 is halogen, -S(O) n Rc, NR C R D , saturated or unsaturated C1 to C6 alkyl group, C3 to C6 cycloalkyl group, C1 to C6 alkoxy group, C3 to C6 cycloalkoxy group, halogen, hydroxy group, amino group or R H a saturated or unsaturated C1-C6 alkyl group, a C3-C6 cycloalkyl group, a C1-C6 alkoxy group, or a C3-C6 cycloalkoxy group substituted with H is selected from hydrogen, halogen, cyano group, hydroxy group, amino group, saturated or unsaturated C1 to C3 alkyl group, C3 to C6 cycloalkyl group, saturated or unsaturated C1 to C3 alkyl group substituted with halogen, hydroxy group or amino group, C3 to C6 cycloalkyl group substituted with halogen, hydroxy group or amino group, saturated or unsaturated C1 to C3 alkoxy group, C3 to C6 cycloalkoxy group, saturated or unsaturated C1 to C3 alkoxy group substituted with halogen, hydroxy group or amino group, C3 to C6 cycloalkoxy group substituted with halogen, hydroxy group or amino group.

[0027] More preferably, R1 and R2 are each independently hydrogen, a saturated or unsaturated, substituted or unsubstituted C1 to C3 alkyl group, a saturated or unsaturated, substituted or unsubstituted C3 to C6 cycloalkyl group, or —OC(═O)C 1-3 Alkyl groups, -OC(=O)C3-C6 cycloalkyl groups, -C(=O)OC 1-3 Alkyl groups, -C(=O)OC3-C6 cycloalkyl groups, -S(O) n Rc, NR C R D , saturated or unsaturated, substituted or unsubstituted C1 to C3 sulfonyl group, saturated or unsaturated, substituted or unsubstituted C1 to C3 acyl group, C6 to C 10 an aryl group, a 6- to 8-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S, wherein the "substituted" group is optionally substituted with a hydroxy group, a halogen atom, a cyano group, a sulfonyl group, an amino group, -S(O) n Rc, NR C R D , -OC(=O)C 1-3 Alkyl groups, -OC(=O)C3-C6 cycloalkyl groups, -C(=O)OC 1-3 Alkyl group, -C(=O)OC3-C6 cycloalkyl group, saturated or unsaturated C1-C3 alkyl group, saturated or unsaturated C3-C6 cycloalkyl group, saturated or unsaturated C1-C3 sulfonyl group, saturated or unsaturated C1-C3 acyl group, C6-C 10 containing 1 to 4 substituents selected from an aryl group, a 6- to 8-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O and S;

[0028] Alternatively, R1 and R2, 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, or a substituted or unsubstituted 5- to 10-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S, wherein the "substituted" group selectively includes a hydroxy group, a halogen atom, a cyano group, a sulfonyl group, an amino group, -S(O) n Rc, NR C R D, C1-C3 alkyl group, C3-C6 cycloalkyl group, C1-C3 alkoxy group, C3-C6 cycloalkoxy group, -OC(=O)C 1-3 Alkyl groups, -OC(=O)C3-C6 cycloalkyl groups, -C(=O)OC 1-3 Alkyl group, -C(=O)OC3-C6 cycloalkyl group, halogen, hydroxy group, amino group or R H and R substituted with 1 to 4 substituents selected from a C1 to C3 alkyl group, a C3 to C6 cycloalkyl group, a C1 to C3 alkoxy group, and a C3 to C6 cycloalkoxy group, H is hydrogen, halogen, cyano group, hydroxy group, amino group, saturated or unsaturated C1-C3 alkyl group, C3-C6 cycloalkyl group, -S(O) n Rc, NR C R D , a saturated or unsaturated C1-C3 alkyl group substituted with a halogen, a hydroxy group or an amino group, a C3-C6 cycloalkyl group substituted with a halogen, a hydroxy group or an amino group, a saturated or unsaturated C1-C3 alkoxy group, a C3-C6 cycloalkoxy group, a saturated or unsaturated C1-C3 alkoxy group substituted with a halogen, a hydroxy group or an amino group, a C3-C6 cycloalkoxy group substituted with a halogen, a hydroxy group or an amino group,

[0029] More preferably, R3 is halogen, -S(O) n Rc, NR C R D , saturated or unsaturated C1 to C3 alkyl group, C3 to C6 cycloalkyl group, C1 to C3 alkoxy group, C3 to C6 cycloalkoxy group, halogen, hydroxy group, amino group or R H a saturated or unsaturated C1-C3 alkyl group, a C3-C6 cycloalkyl group, a C1-C3 alkoxy group, or a C3-C6 cycloalkoxy group substituted with His selected from hydrogen, halogen, cyano group, hydroxy group, amino group, saturated or unsaturated C1 to C3 alkyl group, C3 to C6 cycloalkyl group, saturated or unsaturated C1 to C3 alkyl group substituted with halogen, hydroxy group or amino group, C3 to C6 cycloalkyl group substituted with halogen, hydroxy group or amino group, saturated or unsaturated C1 to C3 alkoxy group, C3 to C6 cycloalkoxy group, saturated or unsaturated C1 to C3 alkoxy group substituted with halogen, hydroxy group or amino group, C3 to C6 cycloalkoxy group substituted with halogen, hydroxy group or amino group.

[0030] More preferably, the structure formed by R1 and R2 together with the N atom to which they are attached is: JPEG2025513904000003.jpg71111JPEG2025513904000004.jpg64111JPEG2025513904000005.jpg56106JPEG2025513904000006.jpg66105JPEG2025513904000007.jpg29103.

[0031] More preferably, the substituted pyrimidine hydrazide compounds, their respective optical isomers, prodrugs or pharmaceutically acceptable salts according to the present invention are selected from the following compounds:

[0032] JPEG2025513904000008.jpg143109JPEG2025513904000009.jpg187129JPEG2025513904000010.jpg160127

[0033] According to a 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 substituted pyrimidine hydrazide compound according to the present invention, their respective optical isomers, prodrugs or pharmaceutically acceptable salts, and a pharmaceutically acceptable excipient or carrier.

[0034] According to a third aspect of the present invention, another object of the present invention is to provide use of the substituted pyrimidine hydrazide compounds according to the present invention, their respective optical isomers, prodrugs or pharmaceutically acceptable salts in the production of an inhibitor of AHR impairment.

[0035] According to a fourth aspect of the present invention, another object of the present invention is to provide the use of the substituted pyrimidine hydrazide compounds according to the present invention, their respective optical isomers, prodrugs or pharmaceutically acceptable salts in the manufacture of a medicament for treating tumors associated with AHR disorders.

[0036] According to a fifth aspect of the present invention, another object of the present invention is to provide a method for treating tumors associated with AHR disorders, said method comprising administering to a subject in need thereof an effective amount of a substituted pyrimidine hydrazide compound according to the present invention, their respective optical isomers, prodrugs or pharmaceutically acceptable salts, or said pharmaceutical composition according to the present invention.

[0037] According to a sixth aspect of the present invention, another object of the present invention is to provide a method for preparing the substituted pyrimidine hydrazide compounds according to the present invention, their respective optical isomers, prodrugs or pharmaceutically acceptable salts, said method being as shown in the following Reaction Scheme 1: JPEG2025513904000011.jpg3676

[0038] A condensation reaction of a carboxylic acid compound represented by formula III with a hydrazine compound represented by formula IV to obtain a substituted pyrimidine hydrazide compound represented by formula I;

[0039] wherein the carboxylic acid compound of formula III is prepared according to one of the following methods: Method A JPEG2025513904000012.jpg301071) reacting a methyl carbonyl compound represented by formula V with dimethyl oxalate to obtain a compound represented by formula VI; 2) subjecting a compound represented by formula VI to a cyclization reaction with a hydrazine compound represented by formula X to obtain a pyrimidine compound represented by formula VII; 3) hydrolyzing the pyrimidine compound represented by formula VII to obtain a carboxylic acid compound represented by formula III;

[0040] Method B JPEG2025513904000013.jpg31100

[0041] 1) Methyl carbonyl compound represented by formula V and monoalkyl oxalate ester JPEG2025513904000014.jpg1116 to obtain a compound represented by formula VIII, wherein the substituent R is a methyl group, an ethyl group, an isopropyl group, a tertbutyl group, or the like;

[0042] 2) subjecting a compound represented by formula VIII to a cyclization reaction with a hydrazine compound represented by formula X to obtain a pyrimidine compound represented by formula IX;

[0043] 3) hydrolyzing the pyrimidine compound of formula IX to remove the substituent R, thereby obtaining a carboxylic acid compound of formula III;

[0044] Method C JPEG2025513904000015.jpg28116

[0045] 1) cyclizing a methyl carbonyl compound of formula V with urea to obtain a compound of formula XI;

[0046] 2) reacting a compound of formula XI with a chlorinating reagent, such as phosphorus oxychloride, phosphorus pentachloride, thionyl chloride, etc., to obtain a chlorinated compound of formula XII;

[0047] 3) Chlorinated compounds and boric acid compounds represented by formula XII JPEG2025513904000016.jpg1623, or a corresponding borate ester, or a trialkyltin compound to produce a compound of formula XIII;

[0048] 4) removing the ethyl group from the compound of formula XIII to form a carboxylic acid group, thereby obtaining a compound of formula III;

[0049] Method D JPEG2025513904000017.jpg27112

[0050] 1) Carbonate compounds JPEG2025513904000018.jpg1733 and a hydrazine compound represented by formula X are subjected to a cyclization reaction to obtain a compound represented by formula XIV,

[0051] 2) reacting a compound of formula XIV with a chlorinating reagent, such as phosphorus oxychloride, phosphorus pentachloride, thionyl chloride, etc., to obtain a chlorinated compound of formula XV;

[0052] 3) Chlorinated compounds and boric acid compounds represented by formula XV JPEG2025513904000019.jpg1619 or a corresponding boric acid ester, or a trialkyltin compound to obtain a compound of formula III,

[0053] Method E JPEG2025513904000020.jpg31100

[0054] 1) JPEG2025513904000021.jpg1771 or the corresponding boric acid ester or trialkyltin compound, and then the compound is separated and purified. JPEG2025513904000022.jpg2220 is obtained.

[0055] 2) Compound or a trialkyltin compound to obtain a compound of formula III,

[0056] Method F JPEG2025513904000024.jpg30107

[0057] 1) JPEG2025513904000025.jpg1572 or corresponding borate ester, or a trialkyltin compound, followed by separation and purification to obtain a compound represented by formula XV,

[0058] 2) The compound represented by formula XV is further treated with a boric acid compound JPEG2025513904000026.jpg1614 or corresponding borate ester, or by reacting with a trialkyltin compound to give a compound of formula III.

[0059] The synthesis flow of the hydrazine compound represented by formula IV in the present invention is as follows. Method G JPEG2025513904000027.jpg1699

[0060] 1) BocNHNH2 (tert-butoxycarbonylhydrazine) is dissolved in an alcoholic solvent such as methanol or ethanol, and a ketone compound (R1(C=O)R1) or an aldehyde compound (R1(C=O)H) is added to react with the compound, and sodium borohydride is added to reduce the reaction. Purify and separate the compound JPEG2025513904000028.jpg1330 is obtained.

[0061] 2) Compound JPEG2025513904000029.jpg1230 is dissolved in an amine solvent such as N,N-diisopropylethylamine (DIEA), and a ketone compound (R2(C=O)R2), an aldehyde compound (R2(C=O)H), or an epoxy compound substituted with the corresponding R2 is added to react with the compound. compound JPEG2025513904000030.jpg1317 is obtained. 3) Compound JPEG2025513904000031.jpg1319 is dissolved in an alcoholic solvent such as methanol or ethanol, and a solution of excess HCl in methanol is added to obtain the hydrochloride salt of the compound represented by formula IV;

[0062] Method H JPEG2025513904000032.jpg1960

[0063] 1) Dissolving the substituted amino compound (HNR1R2) in a solvent, adding a nitrosating reagent, the nitrosating reagent being selected from tert-butyl nitrite and isobutyl nitrite, heating under reflux, and concentrating under reduced pressure to obtain the intermediate nitrosoamino compound (R1N(R2)-N=O);

[0064] 2) The nitrosoamino compound (R1N(R2)-N=O) is dissolved in a solvent, and a hydrogenation reagent such as lithium aluminum hydride is added to carry out a hydrogenation reaction to obtain a compound represented by formula IV. DETAILED DESCRIPTION OF THE INVENTION

[0065] The present invention will be described in detail below. Before describing, it should be understood that the terms used in this specification and the appended claims should not be interpreted as being limited to their general meanings and dictionary meanings, but should be interpreted according to the meanings and concepts applicable to the technical aspects of the present invention, based on the principle that the inventor should appropriately define terms for the best interpretation. Therefore, the descriptions proposed here are merely preferred examples for the purpose of illustrating and explaining, and are not intended to limit the scope of the present invention. It should be understood that other equivalent or improved methods can be obtained without departing from the spirit and scope of the present invention.

[0066] When listing a series of values, it is intended to cover each value and subrange within this range. For example, "C1-C8" means C1, C2, C3, C4, C5, C6, C7, C8, C 1-8 , C 1-7 , C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-8 , C 2-7 , C 2-6 , C 2-5 , C 2-4 , C 2-3 , C 3-8 , C 3-7 , C 3-6 , C 3-5 , C 3-4 , C 4-8 , C 4-7 , C 4-6 , C 4-5 , C 5-8 , C 5-7 , C 5-6 , C 6-8 , C 6-7 and C 7-8 is intended to cover.

[0067] definition "Alkyl group" means a linear or branched saturated hydrocarbon group having 1 to 8 carbon atoms ("C 1-8In some embodiments, the alkyl group is a group having 1 to 7 carbon atoms ("C 1-7 In some embodiments, the alkyl group has 1 to 6 carbon atoms ("C 1-6 In some embodiments, the alkyl group has 1 to 5 carbon atoms ("C 1-5 In some embodiments, the alkyl group has 1 to 4 carbon atoms ("C 1-4 In some embodiments, the alkyl group has 1 to 3 carbon atoms ("C 1-3 In some embodiments, the alkyl group has 1 to 2 carbon atoms ("C 1-2 In some embodiments, the alkyl group has 1 carbon atom (a "C alkyl group"). In some embodiments, the alkyl group has 1 to 6 carbon atoms (a "C 1-6 C 1-6 Examples of alkyl groups include methyl (C1), ethyl (C2), propyl (C3) (e.g., n-propyl, isopropyl), butyl (C4) (e.g., n-butyl, tert-butyl, sec-butyl, isobutyl), pentyl (C5) (e.g., n-pentyl, 3-pentyl, neopentyl, 3-methyl-2-butyl, tert-pentyl), and hexyl (C6) (e.g., n-hexyl). Further examples of alkyl groups include n-heptyl (C7), n-octyl (C8), etc. Unless otherwise specified, each example of an alkyl group is independently unsubstituted (an "unsubstituted alkyl group") or substituted with one or more substituents (e.g., halogen, e.g., F) (a "substituted alkyl group"). In some embodiments, an alkyl group is an unsubstituted C 1-8 In some embodiments, the alkyl group is a substituted C alkyl group (e.g., an unsubstituted C alkyl group, e.g., —CH). 1-8 An alkyl group (eg, a substituted C1 alkyl group, such as -CF3).

[0068] An "alkoxy group" refers to a monovalent -O-alkyl group, where the alkyl group portion has the specified number of carbon atoms. Alkoxy groups in this disclosure typically contain 1 to 6 carbon atoms ("C1-C6 alkoxy group") or 1 to 4 carbon atoms ("C1-C4 alkoxy group"). For example, C1-C4 alkoxy groups include methoxy, ethoxy, isopropoxy, tert-butyloxy, and the like. Unless otherwise specified, each instance of an alkoxy group is independently optionally substituted, i.e., unsubstituted (an "unsubstituted alkoxy group") or substituted with one or more substituents (a "substituted alkoxy group"). In some embodiments, an alkoxy group is an unsubstituted C1-C6 alkoxy group. In some embodiments, an alkoxy group is a substituted C1-C6 alkoxy group.

[0069] A "cycloalkyl group" means a group having a non-aromatic ring system containing 3 to 8 ring carbon atoms ("C 3-8 In some embodiments, a cycloalkyl group is a non-aromatic cyclic hydrocarbon group having 3 to 8 ring carbon atoms ("C 3-8 In some embodiments, the cycloalkyl group has 3 to 6 ring carbon atoms ("C 3-6 In some embodiments, the cycloalkyl group has 5 to 8 ring carbon atoms ("C 5-8 cycloalkyl group). 3-6 Cycloalkyl groups include, but are not limited to, cyclopropyl (C), cyclopropenyl (C), cyclobutyl (C), cyclobutenyl (C), cyclopentyl (C), cyclopentenyl (C), cyclohexyl (C), cyclohexenyl (C), cyclohexadienyl (C), and the like. 3-8 The cycloalkyl group is the same as the above C 3-6Cycloalkyl groups include, but are not limited to, cycloalkyl groups such as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptyltrialkenyl (C7), cyclooctyl (C8), cyclooctenyl (C8), and the like. Unless otherwise specified, each instance of a cycloalkyl group is independently optionally substituted, i.e., unsubstituted (an "unsubstituted cycloalkyl group") or substituted with one or more substituents (a "substituted cycloalkyl group"). In some embodiments, a cycloalkyl group is an unsubstituted C 3-8 In some embodiments, the cycloalkyl group is a substituted C 3-8 It is a cycloalkyl group.

[0070] A "heterocycloalkyl group" is a radical of a 5- to 14-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur (a "5- to 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, if the valence allows. Heterocyclic groups may be monocyclic (a "monocyclic heterocyclic group") or fused, bridged, or spirocyclic systems, e.g., bicyclic systems (a "bicyclic heterocyclic group"), and may be saturated or partially unsaturated. "Heterocyclic group" further includes ring systems in which a heterocycle, as defined above, is fused to one or more cycloalkyl groups (where the point of attachment is on the cycloalkyl group or the heterocycle), or in which a heterocycle, as defined above, is fused to one or more aryl or heteroaryl groups (where the point of attachment is on the heterocycle), and in such cases, 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 (an "unsubstituted heterocycloalkyl group") or substituted with one or more substituents (a "substituted heterocycloalkyl group"). In some embodiments, a heterocycloalkyl group is an unsubstituted 5- to 14-membered heterocycloalkyl group. In some embodiments, a heterocycloalkyl group is a substituted 5- to 14-membered heterocycloalkyl group.

[0071] An "aryl group" or "aromatic ring" or "aromatic ring group" refers to a group of monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring systems (e.g., having 6, 10, or 14 pi electrons shared in a cyclic arrangement) having 6 to 14 ring carbon atoms and 0 heteroatoms provided in the aromatic ring system ("C 6-14 In some embodiments, the aryl group has 6 ring carbon atoms (a "C aryl group", e.g., a phenyl group). In some embodiments, the aryl group has 10 ring carbon atoms (a "C 10 In some embodiments, the aryl group has 14 ring carbon atoms ("C 14 "Aryl groups" include, for example, anthracenyl groups. "Aryl groups" further include ring systems in which the aryl ring, as defined above, is fused to one or more cycloalkyl or heterocyclic groups (where the point of attachment is on the aromatic ring), and in such cases, the number of carbon atoms continues to refer to the number of carbon atoms in the aromatic ring system. Unless otherwise specified, each instance of an aryl group is independently optionally substituted, i.e., unsubstituted (an "unsubstituted aryl group") or substituted with one or more substituents (a "substituted aryl group"). In some embodiments, an aryl group is an unsubstituted C 6-14 In some embodiments, the aryl group is a substituted C 6-14 It is an aryl group.

[0072] A "heteroaryl group" is a 5- to 14-membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur (a "5- to 14-membered heteroaryl group"). In some embodiments, a heteroaryl group is a 5- to 8-membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur (a "5- to 8-membered heteroaryl group"). In some embodiments, a heteroaryl group is a 5- to 6-membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur (a "5- to 6-membered heteroaryl group"). In some embodiments, a 5- to 6-membered heteroaryl group has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5- to 6-membered heteroaryl group has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5- to 6-membered heteroaryl group has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group is independently optionally substituted, i.e., unsubstituted (an "unsubstituted heteroaryl group") or substituted with one or more substituents (a "substituted heteroaryl group"). In some embodiments, a heteroaryl group is an unsubstituted 5- to 14-membered heteroaryl group. In some embodiments, a heteroaryl group is a substituted 5- to 14-membered heteroaryl group.

[0073] A "halogen" or "elemental halogen" is fluorine (-F), chlorine (-Cl), bromine (-Br), or iodine (-I).

[0074] "Substituted" or "optionally substituted" means that an atom in a group, such as a hydrogen atom, has been replaced. In some embodiments, alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are substituted (e.g., a "substituted" alkyl group, a "substituted" cycloalkyl group, a "substituted" heterocycloalkyl group, a "substituted" aryl group, or a "substituted" heteroaryl group). In general, the term "substituted," whether preceded by the term "optionally," means that at least one hydrogen atom present on the group (e.g., a carbon or nitrogen atom) has been replaced with a permissible substituent; e.g., the substituent forms a stable compound upon substitution, e.g., a compound that does not spontaneously undergo conversion (e.g., by rearrangement, cyclization, elimination, or other reaction). Unless otherwise specified, a "substituted" group has a substituent at one or more substitutable positions of the group, and when more than one position in any specified structure is substituted, the substituents may be the same or different at each position. The term "substituted" is intended to include all permissible substituents of organic compounds, any substituent described herein that result in the formation of stable compounds. It is intended that any and all combinations thereof result in stable compounds. For purposes of this disclosure, heteroatoms, such as nitrogen, may have hydrogen substituents and / or any suitable substituents that satisfy the valence of the heteroatoms, as described herein, and result in the formation of a stable moiety. In some embodiments, the substituents are carbon atom substituents. In some embodiments, the substituents are nitrogen atom substituents. In some embodiments, the substituents are oxygen atom substituents. In some embodiments, the substituents are sulfur atom substituents.

[0075] "Unsaturated" or "partially unsaturated" refers to a group that contains at least one double or triple bond. "Partially unsaturated" ring systems are also intended to encompass rings with multiple sites of unsaturation, but are not intended to include aromatic groups (e.g., aryl or heteroaryl groups). Similarly, "saturated" refers to a group that contains double or triple bonds, i.e., all single bonds.

[0076] In this specification, when a defined substituent has multiple substitutions, the character descriptions of such multiple substitutions may have repeated definitions, but such descriptions should be understood as complying with at least the basic rules of general medicinal chemistry. For example, when a substituent has a repeated definition, a person skilled in the art can determine whether or not such a repeated definition is possible according to common sense in general medicinal chemistry. Substituent R A For example, the definition of R A is "a saturated or unsaturated C1 to C8 alkyl group" or "a halogen, a hydroxy group, an amino group or R C and the definition of the substituent Rc may be "hydrogen, halogen, a hydroxy group, an amino group" or the like. Those skilled in the art can determine whether such repeated definitions are possible based on common knowledge in medicinal chemistry and make a reasonable selection.

[0077] As used herein, the term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic response, or other problem or complication, and are suitable for use at a reasonable benefit / risk ratio.

[0078] The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention prepared from a compound having certain substituents found in this invention and a relatively non-toxic acid or base. When a compound of the present invention contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of base in a 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., pharmaceutically acceptable salts) can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in a neat solution or in a suitable inert solvent. Examples include inorganic acid salts and organic acid salts, such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfite, hydroiodic acid, phosphorous acid, etc., and such organic acids include benzoic acid, 2-hydroxyethanesulfonic acid, sulfamic acid, benzenesulfonic acid, phenylacetic acid, mandelic acid, malonic acid, propionic acid, oxalic acid, etc. The salts of certain compounds of the present invention include salts of similar acids such as p-aminobenzenesulfonic acid, p-toluenesulfonic acid, polygalacturonic acid, pantothenic acid, fumaric acid, glutamic acid, succinic acid, methanesulfonic acid, tartaric acid, ascorbic acid, phthalic acid, maleic acid, citric acid, malic acid, glucoheptonic acid, gluconic acid, isethionic acid, lactic acid, lactobionic acid, dodecylsulfonic acid, pamoic acid, salicylic acid, suberic acid, folinic acid, edetic acid, glycolic acid, acetic acid, ethanesulfonic acid, isobutyric acid, and stearic acid, as well as salts of amino acids (e.g., arginine) and organic acids such as glucuronic acid (see Berge et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science 66:1-19 (1977)). Some specific compounds of the present invention contain basic and acidic functional groups and can be converted into either base or acid addition salts. The parent compound and its various salt forms differ in some physical properties, such as solubility in polar solvents.

[0079] As used herein, the modifier "about" accounts for possible variation in a numerical value, for example, through routine testing and processing, unintentional error in such testing and processing, and variations in the manufacture, source, or purity of the components used in the invention. As used herein, "about" plus a particular value further includes the particular value, for example, about 10% includes 10%. Whether modified by the term "about," any claim includes the equivalent form of the recited number. In one embodiment, the term "about" refers to a 20% error from the reported numerical value.

[0080] As used herein, the term "treatment" refers to the elimination, reduction, or amelioration of a disease or condition and / or its associated symptoms. Although not excluded, treatment of a disease or condition need not completely eliminate the disease, condition, or condition. As used herein, the term "treatment" and the like may also include "prophylactic treatment," which may reduce the recurrence of a disease or condition or a previously controlled disease or condition in a subject who has or is susceptible to the disease or condition, or who is or is not at risk of developing a recurrence of the disease or condition. Synonyms of the term "treatment" contemplate administering a therapeutically effective amount of a compound described herein to a subject in need of such treatment.

[0081] For a drug or pharmacologically active agent, the term "effective amount" or "therapeutically effective amount" refers to a non-toxic but sufficient amount of drug or agent to achieve the desired effect. For oral dosage forms of the present invention, an "effective amount" of one active substance in a composition is the dose required to achieve the desired effect when used in combination with another active substance in the composition. Determining an effective amount varies from person to person, depends on the age and general condition of the recipient, and also on the specific active substance; the appropriate effective amount in each individual case can be determined by one skilled in the art based on routine testing.

[0082] The diseases associated with impaired AHR according to the present invention include, but are not limited to, tumors.

[0083] The following examples are merely examples of embodiments of the present invention and do not constitute any limitations on the present invention. As can be understood by those skilled in the art, any modifications that do not deviate from the essence and concept of the present invention are within the scope of protection of the present invention. Unless otherwise specified, all reagents and instruments used in the following examples are commercially available products.

[0084] Experimental section: Example 1: Preparation of intermediate III-A according to preparation method A JPEG2025513904000033.jpg26116

[0085] Step 1) Preparation of Compound VII-A A mixture of (oxalato)diethyl ether (15.2 g, 104 mmol) and sodium ethoxide (10.9 g, 160 mmol) in absolute ethanol (250 mL) was cooled to below 10°C and stirred for 30 min. A solution of trifluoromethylbenzophenone (18.8 g, 100 mmol) in absolute ethanol (80 mL) was added dropwise. The ice bath was removed, and the mixture was stirred at room temperature overnight. The mixture was filtered, washed with a small amount of ethanol, and dried to give compound VII-A (28 g, 97% yield). LC / MS (ESI): m / z 289 [M+1] + .

[0086] Step 2) Fabrication of II-A Intermediate VII-A (288 mg, 1 mmol) and 3-pyridinecarboxamidine hydrochloride (157 mg, 1 mmol) were dissolved in 30 mL of ethanol, sodium ethoxide (312 mg, 4.59 mmol) was added, and the reaction suspension was stirred at 70 °C overnight. LCMS showed that 60% of intermediate II-A and 40% of intermediate III-A were obtained. Concentration to dryness under reduced pressure gave a mixture of II-A and III-A, which was used directly in the next step reaction without purification. II-A: LC / MS (ESI): m / z 374 [M+1] + ,III-A:346[M+1] + ,344[M-1] + .

[0087] Step 3) Preparation of Compound III-A The mixture of II-A and III-A obtained in step 2) was dissolved in a mixed solvent of methanol / tetrahydrofuran / water (1 / 1 / 1), lithium hydroxide monohydrate (4 equivalents) was added, and the mixture was stirred at room temperature for 5 h. The mixture was neutralized to pH 7 with 1N hydrochloric acid, concentrated under reduced pressure to a small volume, filtered, and the solid was washed with ethanol-water (1:1) and dried to obtain intermediate III-A (205 mg, 79%). LC / MS (ESI): m / z 346 [M+1] + ,344[M-1] + is.

[0088] Example 2: Preparation of intermediate III-A according to preparation method C JPEG2025513904000034.jpg2694

[0089] Step 1) Preparation of compound XI-A p-Trifluoromethylacetophenone (11.3 g, 60 mmol) was added to a solution of glyoxylic acid (8.83 g, 96 mmol) in acetic acid (50 ml) at room temperature, stirred overnight at 120 °C, concentrated under reduced pressure to dryness, added water, stirred for 30 min, filtered, washed, and dried to obtain compound XI-A (12.3 g, 84% yield), LC / MS (ESI): m / z 243 [M-1] + is.

[0090] Step 2) Preparation of Compound III-A Sodium ethoxide (310 mg, 4.6 mmol) was added to a solution of compound XI-A (245 mg, 1 mmol) and 3-pyridinecarboxamidine hydrochloride (157.6 mg, 1 mmol) in ethanol (30 mL), and the mixture was stirred at 70°C overnight. The mixture was concentrated under reduced pressure, and water and ethyl acetate were added. The mixture was stirred for 30 minutes and filtered to give product III-A (200 mg, 58% yield). 1H NMR(400 MHz,DMSO-d6):δ9.10(d,J=1.6Hz,1H),8.60-9.00(m,1H),8.80-8.81(dd,J=4.8,1.6Hz,1H), 8.66(d,J=8.0Hz,2H),8.57(s,1H),7.98(d,J=8.0Hz,2H),7.64-7.67(m,1H).LC / MS(ESI):m / z 346[M+1] + is.

[0091] Example 3: Preparation of intermediate III-B according to preparation method B JPEG2025513904000035.jpg2294

[0092] Step 1) Preparation of compound XI-B p-Chloroacetophenone (9.3 g, 60 mmol) was added to a solution of glyoxylic acid (8.83 g, 96 mmol) in acetic acid (50 ml) at room temperature, stirred overnight at 120 °C, concentrated to dryness under reduced pressure, added water, stirred for 30 min, filtered, washed, and dried to obtain compound XI-B (9.4 g, 75% yield), which was analyzed by LC / MS (ESI): m / z 209 [M-1]. + is.

[0093] Step 2) Preparation of Compound III-B To a solution of compound XI-B (210 mg, 1 mmol) and 3-pyridinecarboxamidine hydrochloride (157.6 mg, 1 mmol) in ethanol (30 ml), sodium ethoxide (310 mg, 4.6 mmol) was added and stirred at 70 °C overnight. After the reaction was completed, the mixture was concentrated under reduced pressure, water and ethyl acetate were added, and the mixture was stirred for 30 min. The mixture was filtered to obtain product III-B (149 mg, 48% yield). LC / MS (ESI): m / z 312 [M+1] + is.

[0094] The following intermediates III-C to III-G can be prepared using Method B analogous to Example 3.

[0095] JPEG2025513904000036.jpg106128

[0096] Example 4: Preparation of Intermediate III-H according to Preparation Method C JPEG2025513904000037.jpg2886

[0097] Step 1) Preparation of Intermediate VIII-H A solution of urea (66 mg, 1.1 mmol) and compound VII-C (305 mg, 1 mmol) in ethanol (4 mL) was added with 1 mL of concentrated hydrochloric acid, stirred at 80 °C overnight, cooled to room temperature, filtered, washed with cold ethanol, and dried to give compound VIII-H. LC / MS (ESI): m / z 329 [M+1] + .

[0098] Step 2) Preparation of Intermediate IX-H Compound VIII-H (81 mg, 0.25 mmol) was added to 2 mL of phosphorus oxychloride, heated to 85 °C under nitrogen gas protection, stirred for 6 h, concentrated to dryness under reduced pressure, added ethyl acetate (10 mL) and 20 g of crushed ice, stirred for 20 min, filtered, and dried to give compound IX-H. LC / MS (ESI): m / z 347 [M+1] + .

[0099] Step 3) Preparation of Intermediate III-H To a mixture of compound IX-H (348 mg, 1 mmol) and 1-methylpyrazole-4-boronic acid pinacol ester (208 mg, 1 mmol) in dioxane (5 mL) and saturated aqueous sodium carbonate (1 mL), tetrakis(triphenylphosphine)palladium (10 mg) and PdCl2(dppf)2 (10 mg) were added under nitrogen gas protection, heated to 100 °C, and stirred overnight. The organic phase was concentrated under reduced pressure to dryness and purified by silica gel column chromatography to obtain compound III-H. LC / MS (ESI): m / z 365 [M+1] + ,363[M-1] + .

[0100] The following intermediates III-I to III-P can be prepared using analogous Method C in Example 4.

[0101] JPEG2025513904000038.jpg180127JPEG2025513904000039.jpg58128

[0102] Example 5: Preparation of Intermediate III-Q according to Preparation Method D JPEG2025513904000040.jpg26105

[0103] Step 1) Preparation of Intermediate XIII-Q A NaOH solution (2.17 g, 54 mmol, 4.5 ml water) was added dropwise to a suspension of diethyl oxalacetate sodium salt (6.65 g, 31.7 mmol) in water (40 ml) and stirred until the solid was completely dissolved. 3-Methylamidopyridine hydrochloride (3.85 g, 31.8 mmol) was added, and the mixture was heated to 70° C. and stirred overnight. The mixture was cooled to room temperature, adjusted to pH 1 with concentrated hydrochloric acid, filtered, and the solid was washed with ethyl acetate to give intermediate XIII-Q (4.42 g, 83% yield). 1 H NMR (DMSO-d6): δ 9.30(d,J=2.0Hz,1H),8.76(dd,J=1.2,4.8Hz,1H),8.50(dt,J=7.6,1.2Hz,1H),7.60(dd,J=4.8,7.6Hz,1H),6.96(s,1H). LC / MS(ESI):m / z 218[M+1] + ,216[M-1] + .

[0104] Step 2) Preparation of Intermediate XIV-Q A suspension of compound XIII-Q (218 mg, 1 mmol) in POCl3 (5 ml) was stirred overnight at 85 °C under nitrogen gas protection, concentrated to dryness under reduced pressure, added with 50 ml of EA, stirred for 10 min, added with 1 ml of methanol, stirred, washed, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give intermediate XIV-Q, which was used directly in the next step without purification.

[0105] Step 3) Preparation of Intermediate III-Q To a mixture of compound XIV-Q (250 mg, 1 mmol) and 3-fluorophenylboronic acid (140 mg, 1 mmol) in dioxane (10 mL) and saturated aqueous sodium carbonate (1 mL), tetrakis(triphenylphosphine)palladium (15 mg) was added under nitrogen gas protection, heated to 100 °C, and stirred overnight. The organic phase was concentrated under reduced pressure to dryness and purified by silica gel column chromatography to obtain intermediate III-Q. LC / MS (ESI): m / z 296 [M+1] + ,294[M-1] + .

[0106] The following intermediates III-R to III-V can be prepared using Method D analogous to Example 5.

[0107] JPEG2025513904000041.jpg109127

[0108] Example 6: Preparation of Intermediates III-W and III-Y according to Preparation Methods E and F Method E JPEG2025513904000042.jpg23114

[0109] Step 1) Preparation of intermediate XIV-W A solution of 2,6-dichloropyrimidine-4-carboxylic acid (1.93 g, 10 mmol) and 3-trifluorophenylboronic acid (2.27 g, 11 mmol) in toluene (50 mL) and saturated aqueous sodium carbonate (10 mL) was added with tetrakis(triphenylphosphine)palladium (50 mg) and PdCl2(dppf)2 (50 mg). The mixture was heated to 110 °C under nitrogen gas protection and stirred overnight. The organic phase was concentrated under reduced pressure to dryness and purified by silica gel column chromatography to give intermediate XIV-W (2.04 g, 376%) and 1.4 g of by-product (XV-Y). XIV-W: 1 HNMR: (400 MHz, DMSO-d6) δ8.34 (s, 1H), 7.20-7.44 (m, 3H), 6.97 (m, 1H). LC / MS(ESI):m / z 251[M-1] + .

[0110] Step 2) Fabrication of III-W Compound XIV-W (504 mg, 2 mmol) and 1-methylpyrazole-4-boronic acid pinacol ester (624 mg, 3 mmol) were dissolved in 20 mL of dioxane, saturated sodium carbonate solution (1 mL) and tetrakis(triphenylphosphine)palladium (231 mg, 0.2 mmol) were added, and the mixture was stirred overnight at 100 °C under nitrogen gas protection. The mixture was concentrated under reduced pressure to dryness, the pH was adjusted to 6-7 with 2N HCl, filtered, washed with DCM, and the crude product was purified by silica gel column chromatography to give compound III-W. LC / MS (ESI): m / z 299 [M+1] + ,297[M-1] + .

[0111] Method F JPEG2025513904000043.jpg33106

[0112] Step 1) Preparation of intermediate XV-Y: Prepared according to Method E (see Method E Step 1). XV-Y: LC / MS (ESI): m / z 253 [M+1] + .

[0113] Step 2) Fabrication of III-W Compound XV-Y (504 mg, 2 mmol) and 6-(trifluoromethyl)pyridine-3-boronic acid (573 mg, 3 mmol) were dissolved in 20 mL of dioxane, saturated sodium carbonate solution (1 mL) and tetrakis(triphenylphosphine)palladium (231 mg, 0.2 mmol) were added, and the mixture was stirred overnight at 100 °C under nitrogen gas protection. The mixture was concentrated under reduced pressure to dryness, the pH was adjusted to 6-7 with 2N HCl, filtered, washed with DCM, and purified by silica gel column chromatography to give compound III-Y. LC / MS (ESI): m / z 364 [M+1] + ,362[M-1] + .

[0114] Example 7: Preparation of intermediate IV-1 JPEG2025513904000044.jpg2099

[0115] Step 1) Preparation of Intermediate XVI-1 BocNHNH2 (13.2 g, 100 mmol) was dissolved in 100 mL of acetone and 50 mL of methanol, anhydrous magnesium sulfate (12 g, 100 mmol) was added, and the mixture was stirred overnight at room temperature. The magnesium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure to dryness. 100 mL of methanol was added to dissolve the mixture, and sodium borohydride (15.2 g, 400 mmol) was added in several portions at room temperature. After the addition was complete, the mixture was stirred at room temperature for 1 h and concentrated under reduced pressure to dryness. 200 mL of distilled water was added, and the mixture was extracted three times with 100 mL of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness. Purification by silica gel column chromatography (20% ethyl acetate / petroleum ether) gave XVI-1 (15.1 g, 87% yield). LC / MS (ESI): m / z 175 [M+1] + .

[0116] Step 2) Preparation of Intermediate XVII-1 Intermediate XVI-1 (1.74 g, 10 mmol), propylene oxide (2.9 g, 50 mmol), and N,N-diisopropylethylamine (DIPEA) (2.58 g, 20 mmol) were dissolved in 20 mL of ethanol and stirred overnight at 80 °C in a sealed reaction flask. The mixture was concentrated to dryness under reduced pressure and purified by silica gel column chromatography (20% to 50% ethyl acetate / petroleum ether) to give XVII-1 (1.82 g, 78% yield). LC / MS (ESI): m / z 233 [M+1] + .

[0117] Step 3) Preparation of Intermediate IV-1 1.82 g of compound XVII-1 was dissolved in 10 ml of methanol, and an excess of a solution of HCl in methanol was added. The mixture was stirred overnight at room temperature and concentrated under reduced pressure at 40°C to dryness to give intermediate IV-1 hydrochloride (2.3 g, 95% yield). LC / MS (ESI): m / z 133 [M+1] + .

[0118] Example 8: Preparation of intermediate IV-2 JPEG2025513904000045.jpg2198

[0119] Step 1) Preparation of Intermediate XVI-2 A 500 mL round-bottom flask was charged with BocNHNH2 (30 g, 227 mmol), 300 mL of methanol, 20.4 g of hydroxyacetone, and anhydrous magnesium sulfate (68 g) in this order, stirred at room temperature for 3.5 h, filtered to remove the magnesium sulfate, washed the filter cake with anhydrous methanol, added sodium borohydride (15.2 g, 400 mmol) in several portions to the filtrate at 0 °C, stirred at room temperature for 1 h, concentrated to dryness under reduced pressure, added 200 mL of distilled water, extracted three times with 100 mL of dichloromethane, the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. Purification by silica gel column chromatography (20-40% ethyl acetate / petroleum ether) gave XVI-2 (36 g, 84% yield). LC / MS (ESI): m / z 191 [M+1] + .

[0120] Step 2) Preparation of Intermediate XVII-2 A 1 L round-bottom flask was charged with intermediate XVI-2 (19.0 g, 100 mmol), acetone (17.4 g, 300 mmol), 300 mL of methanol, and 1 mL of acetic acid. Sodium cyanoborohydride (15.7 g, 250 mmol) was added at room temperature, and the reaction mixture was stirred overnight at room temperature. The mixture was concentrated under reduced pressure to dryness, distilled water was added, extracted with ethyl acetate, dried, filtered, and concentrated. The residue was purified by silica gel column chromatography (10% to 50% ethyl acetate / petroleum ether) to give a white solid, XVII-2 (14.1 g, 61% yield). LC / MS (ESI): m / z 233 [M+1] + .

[0121] Step 3) Preparation of intermediate IV-2: Intermediate IV-2 is prepared according to the same steps as compound IV-1 in step 3) of Example 7, with a yield of 90%. LC / MS (ESI): m / z 133 [M+1] + .

[0122] Example 9: Preparation of intermediate IV-3 JPEG2025513904000046.jpg1982

[0123] Step 1) Preparation of Intermediate XVII-3 To a solution of 2-hydroxyethylhydrazine (5 g, 65 mmol) in methanol (100 mL) at 0 °C, 13 mL of triethylamine and 17.2 g of BocO (78 mmol) were added. The mixture was stirred at room temperature under nitrogen gas protection for 16 h, concentrated to dryness under reduced pressure, added with citric acid solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. Purification by silica gel column chromatography (20-40% ethyl acetate / petroleum ether) gave XVII-3 (6.8 g, 89% yield). LC / MS (ESI): m / z 177 [M+1] + .

[0124] Step 2) Preparation of Intermediate IV-3 Intermediate XVII-3 (2 g, 11.2 mmol) was dissolved in 50 mL of THF, lithium aluminum hydride (LAH) (1.7 g, 44.8 mmol) was added, and the mixture was refluxed under nitrogen gas protection for 5 h. The mixture was cooled to 0 °C, and NaSO 10H O was added in several portions. The mixture was filtered, the filter cake was washed with THF, and the filtrate was dried over anhydrous magnesium sulfate and concentrated to give crude IV-3, which was used directly in the next step without further purification. LC / MS (ESI): m / z 91 [M+1] + .

[0125] Example 9: Preparation of intermediate IV-4 JPEG2025513904000047.jpg1974

[0126] Step 1) Preparation of Intermediate XVII-4 At 0 °C, 2-hydroxyethylhydrazine (7.6 g, 100 mmol) was added to a mixture of methanol (100 mL) and acetone (50 mL). Anhydrous magnesium sulfate (12 g, 100 mmol) was added, and the mixture was stirred overnight at room temperature. The magnesium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure to dryness. 100 mL of dichloromethane was added to dissolve the filtrate, and triethylamine (20.2 g, 200 mmol) was added. Acetic anhydride (10.7 g, 105 mmol) was added dropwise at 0 °C, and the mixture was stirred overnight at room temperature. 200 mL of distilled water was added, and the mixture was extracted with dichloromethane. The combined organic phases were concentrated under reduced pressure to dryness. Tetrahydrofuran (50 mL) and 5 mL of hydrochloric acid were added, and the mixture was stirred at room temperature for 12 h. The mixture was concentrated under reduced pressure to dryness to give XVII-4, which was used directly in the next step without further purification. LC / MS (ESI): m / z 119 [M+1] + .

[0127] Step 2) Preparation of Intermediate IV-4 Intermediate XVII-4 (1.2 g, 10 mmol) was dissolved in 50 mL of THF, lithium aluminum tetrahydride (LAH) (1.5 g, 44.8 mmol) was added, and the mixture was refluxed under nitrogen gas for 4 h. The mixture was cooled to below 0 °C and quenched by the addition of NaSO 10H O in several portions. The mixture was filtered, the filter cake was washed with THF, and the filtrate was dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure to give IV-4. LC / MS (ESI): m / z 105 [M+1] + .

[0128] Example 10: Preparation of intermediate IV-5 JPEG2025513904000048.jpg2399

[0129] Step 1) Preparation of Intermediate XVII-5 Intermediate XVI-1 (12.8 g, 73.5 mmol), ethyl bromoacetate (36.6 g, 219 mmol), and anhydrous potassium carbonate (30.2 g, 219 mmol) were dissolved in 250 ml of DMF, heated to 80 °C under nitrogen gas protection, stirred overnight, cooled to room temperature, added with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give 18 g of crude XVII-5. LC / MS (ESI): m / z 261 [M+1] + .

[0130] Step 2) Preparation of Intermediate XVIII-5 A 2 L round-bottom flask was charged with 380 ml of ethanol, NaBH (7.2 g, 189 mmol), and LiCl (7.9 g, 188 mmol) in that order, and then a THF solution (380 ml) of XVII-5 (18 g, 69 mmol) was added dropwise at room temperature. The mixture was stirred for 6 h, concentrated under reduced pressure to remove most of the solvent, added with water, extracted with ethyl acetate, and the combined organic phases were dried over anhydrous NaSO, filtered, and concentrated to dryness under reduced pressure to give XVIII-5 (12.9 g, 86% yield). LC / MS (ESI): m / z 219 [M+1] + .

[0131] Step 3) Preparation of Intermediate IV-5 XVIII-5 (12.9 g) was dissolved in 50 ml of dioxane, and a solution of HCl in dioxane (6N, 30 ml) was added. The mixture was stirred at room temperature overnight and concentrated under reduced pressure to dryness to give intermediate IV-5 (12.8 g). LC / MS (ESI): m / z 119 [M+1] + .

[0132] Example 11: Preparation of intermediate IV-6 JPEG2025513904000049.jpg1768

[0133] Step 1) Preparation of Intermediate XIX-6 To a solution of 3-methylmorpholine (1.0 g, 10 mmol) in THF (15 mL), tert-butyl nitrite (1.1 g, 11 mmol) was added, refluxed for 12 h, and concentrated to dryness under reduced pressure to give XIX-6, which was used directly in the next step without further purification. LC / MS (ESI): m / z 131 [M+1] + .

[0134] Step 2) Preparation of Intermediate IV-6 The intermediate XIX-6 (80 mmol) from the previous step was dissolved in 200 ml of THF, and LAH (6.1 g, 160 mmol) was added in several portions at 0 °C. The mixture was stirred overnight at room temperature. Under cooling, NaSO 10H O was added in several portions, filtered, and the filter cake was washed with THF. The filtrate was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give compound IV-6 (72% yield). LC / MS (ESI): m / z 117 [M+1] + .

[0135] The method of Example 11 can be used to prepare the following hydrazines:

[0136] JPEG2025513904000050.jpg158127

[0137] Example 12: Preparation of 6-(4-trifluoromethylphenyl)-N-(1-hydroxypropyl-2-yl)-N-isopropyl-2-(pyridin-3-yl)pyrimidine-4-hydrazide (Compound 1) JPEG2025513904000051.jpg2460

[0138] Intermediate III-A (36 mg, 0.1 mmol), hydrazine hydrochloride (IV-2) (20 mg, 0.12 mmol), and 2-(7-oxybenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate ester (HATU) (57 mg, 0.15 mmol) were dissolved in 2 mL of N,N-dimethylformamide (DMF), DIPEA (47 mg, 0.36 mmol) was added, and the mixture was stirred overnight under nitrogen gas. The mixture was diluted with ethyl acetate, washed, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness. Compound 1 (23 mg, 50% yield) was purified by silica gel chromatography (PE / EA, 1:1). LC / MS (ESI): m / z 459 [M+1] + . 1 H NMR(400 MHz,DMSO-d6):δ10.22(s,1H),9.88(d,1H),9.03(t,1H),9.00(dt,1H),8.82(dd,1H),8.66(d,2H),8.56(s,1H),7.96(d,2) H),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).

[0139] The compounds in Table 1 below can be prepared using methods analogous to Example 1.

[0140] Table 1 JPEG2025513904000052.jpg175127JPEG2025513904000053.jpg186127JPEG2025513904000054.jpg181127JPEG2025513904000055.jpg177127 JPEG2025513904000056.jpg185127JPEG2025513904000057.jpg172127JPEG2025513904000058.jpg173127JPEG2025513904000059.jpg151127

[0141] Example 13: Preparation of Compound 66 JPEG2025513904000060.jpg1944

[0142] Compound 10 (40.2 mg, 0.1 mmol) was dissolved in 5 ml of dichloromethane (DCM), 0.1 ml of DIPEA was added, the mixture was cooled to 0°C, and 0.06 ml of acetic anhydride was added dropwise. After the addition was complete, the mixture was stirred at room temperature and allowed to react overnight. The mixture was then washed three times, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness. The mixture was purified by silica gel column chromatography (PE / EA, 1:1) to give compound 66 in a 64% yield. LC / MS (ESI): m / z 444 [M+1] + . 1 H NMR(400 MHz,DMSO-d6):δ10.08(s,1H),9.95(d,J=1.6Hz,1H),9.07(ddd,J=1.6,2.0,7.6Hz,1H),8.82(dd,J=1.2,4.8Hz,1H),8.65(d,J=8 .0Hz,2H),8.53(s,1H),7.97(d,J=8.0Hz,2H),7.66(dd,J=7.6,4.8Hz,1H),3.18-3.27(m,1H),2.08(s,3H),1.18(d,J=6.4Hz,6H).

[0143] Example 14: Preparation of Compound 67 JPEG2025513904000061.jpg2053

[0144] Compound 67 was prepared according to a method similar to that of Example 13, by reacting compound 10 with methanesulfonyl chloride to obtain compound 67, the yield was 41%, and LC / MS (ESI): m / z 480 [M+1] + is. 1H NMR(400 MHz,DMSO-d6):δ10.20(s,1H),9.96(d,J=1.6Hz,1H),9.067(ddd,J=1.6,2.0,7.6Hz,1H),8.82(dd,J=1.2,4.8Hz,1H),8.65(d,J=8 .0Hz,2H),8.53(s,1H),7.97(d,J=8.0Hz,2H),7.66(dd,J=7.6,4.8Hz,1H),3.18-3.27(m,1H),2.92(s,3H),1.18(d,J=6.4Hz,6H).

[0145] Example 15: Preparation of Compound 68 JPEG2025513904000062.jpg2051

[0146] Compound 68 was prepared according to a method similar to that of Example 13, by reacting compound 10 with nicotine chloride hydrochloride to obtain compound 68, the yield was 84%, and LC / MS (ESI): m / z 507 [M+1] + is.

[0147] Efficacy Example 1: Antagonistic effect test of research compounds and AHR in human-derived cell lines The test was performed using the human liver cancer HepG2 cell line, which endogenously expresses the AHR protein (provided by the Stem Cell Bank of the Chinese Academy of Sciences). CYP1A1 gene expression is regulated by AHR activity, and after AHR activation, it binds to a sequence called the xenobiotic response element (XRE) on the CYP1A1 enhancer, triggering CYP1A1 gene expression. To quantitatively measure the effects of compounds on AHR activity, a regulatory sequence 1200 bp (-1143 to +57) 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 using Lipofectamine 3000. Transfected HepG2 cells were screened with puromycin to obtain stable cell lines. To measure the antagonistic effects of compounds on AHR, firefly luciferase expression was induced using AHR agonists (e.g., L-kynurenine, kynurenic acid, indirubin, TCDD, ITE (2-(1H-Indol-3-ylcarbonyl)-4-thiazolecarboxylic acid methyl ester)), and the cells were treated with different concentrations of the compounds to measure the inhibition of luciferase expression by the compounds.

[0148] Stably transfected HepG2 cells were subcultured in Eagle's minimum essential medium (MEM) at 37°C under 5% carbon dioxide. MEM medium was supplemented with 1 mM sodium pyruvate, 2 mM GlutaMax, 1× non-essential amino acids, 10% Australian fetal bovine serum, 100 U / mL penicillin, and 5 μg / mL puromycin. Before testing, HepG2 cells were subcultured to 5–8 × 10 4Cells were seeded at a density of 1000 / well into 96-well plates and grown for 24–48 h to reach ~90% confluency before drug treatment (the medium did not contain puromycin). Before drug treatment, 2x compound solutions containing different concentrations of AHR agonists were prepared in the same medium, and half of the cell culture medium in the 96-well plate was replaced with the 2x compound solution. The negative control group contained the AHR agonist solution containing only DMSO at the corresponding concentration, and the positive control group contained CH223191 (commercially available) at the corresponding concentration. Each compound (including the positive and negative controls) was tested in two independent replicates. HepG2 cells were lysed using a Promega Steady-Glo Luciferase Detection System 24 h after compound treatment, and luciferase signals were measured using a Tecan Infinite M1000 Pro microplate reader.

[0149] In data processing, each compound was tested in duplicate in each group. The well signal at compound concentration 0 was set to 100%, and the cell signal of untreated agonist was set to 0. The percentage of AHR activity inhibition at different compound concentrations was calculated in turn, and the average values ​​of the repeated data of the two groups were subjected to nonlinear fitting. JPEG2025513904000063.jpg1239 ICs corresponding to compounds 50 where y is the percentage inhibition and x is the concentration of the corresponding compound.

[0150] Reference: Buckley, SMKet al.In vivo bioimaging with tissue-specific transcription factor activated luciferase production.Sci.Rep.5:11842(2015).

[0151] IC of each compound 50 is as shown in Table 2, where A is the IC 50 ≦500nM, B represents 500nM <IC 50 ≦1.0 mM, and C is 1 mM <IC 50≦5.0 mM, and D represents IC 50 >5.0mM.

[0152] Table 2 IC of each compound 50 JPEG2025513904000064.jpg133128

[0153] As can be seen from Table 2, each of the above compounds can bind to AHR and inhibit the functions and signal pathways regulated by AHR, and can also affect the growth and proliferation of cancer cells and the invasiveness of tumor cells. Therefore, the compound of formula I of the present invention can be used to inhibit the growth of cancer cells and inhibit the metastasis and invasion of tumor cells.

Claims

1. A substituted pyrimidine hydrazide compound represented by the following formula I, its respective optical isomers, prodrugs or pharma- ceutically acceptable salts: Where: A １ , A ２ and A ３ are each independently CR Ａ or N, and the substituent R Ａ are each independently hydrogen, deuterium, a halogen, a cyano group, a hydroxyl group, an amino group, a saturated or unsaturated C １ ~C ８ Alkyl group, C ３ ~C ８ Cycloalkyl group, halogen, hydroxyl group, amino group or R Ｃ Saturated or unsaturated C substituted with １ ~C ８ Alkyl group, halogen, hydroxyl group, amino group or R Ｃ C substituted with ３ ~C ８ Cycloalkyl groups, saturated or unsaturated C １ ~C ８ Alkoxy group, C ３ ~C ８ Cycloalkoxy group, halogen, hydroxy group, amino group or R Ｃ Saturated or unsaturated C substituted with １ ~C ８ Alkoxy group, halogen, hydroxy group, amino group or R Ｃ C substituted with ３ ~C ８ Cycloalkoxy group, -S(O) ｎ Rc, saturated or unsaturated, substituted or unsubstituted C １ ~C ８ Acyl group, NR Ｃ R Ｄ is selected from A ４ is O, S, N, C or a bond, and A ５ , A ６ and A ７ are each independently O, S, N or C, and A ４ , A ５ , A ６ and A ７ is N or C, then each independently R Ｂ and R Ｂ are each independently hydrogen, deuterium, a halogen, a cyano group, a hydroxyl group, -S(O) ｎ Rc, saturated or unsaturated C １ ~C ８ Alkyl group, C ３ ~C ８ Cycloalkyl group, halogen, hydroxyl group, amino group or R Ｃ Saturated or unsaturated C substituted with １ ~C ８ Alkyl group, halogen, hydroxyl group, amino group or R Ｃ C substituted with ３ ~C ８ Cycloalkyl groups, saturated or unsaturated C １ ~C ８ Alkoxy group, C ３ ~C ８ Cycloalkoxy group, halogen, hydroxy group, amino group or R Ｃ Saturated or unsaturated C substituted with １ ~C ８ Alkoxy group, halogen, hydroxy group, amino group or R Ｃ C substituted with ３ ~C ８ Cycloalkoxy groups, saturated or unsaturated, substituted or unsubstituted C １ ~C ８ Acyl groups, saturated or unsaturated, substituted or unsubstituted C １ ~C ８ Alkoxycarbonyl group, saturated or unsaturated substituted or unsubstituted C １ ~C ８ Alkylaminocarbonyl group, NR Ｃ R Ｄ is selected from Here, the substituent R Ｃ and R Ｄ each independently represents a hydrogen atom, a halogen atom, a cyano group, a hydroxyl group, an amino group, a saturated or unsaturated C １ ~C ６ Alkyl group, C ３ ~C ６ Cycloalkyl groups, halogens, hydroxy groups, -S(O) ｎ R Ｅ Or NR Ｆ R Ｇ Saturated or unsaturated C substituted with １ ~C ６ Alkyl group, halogen, hydroxyl group, -S(O) ｎ R Ｅ Or NR Ｆ R Ｇ C substituted with ３ ~C ６ Cycloalkyl groups, saturated or unsaturated C １ ~C ６ Alkoxy group, C ３ ~C ６ Cycloalkoxy group, halogen, hydroxy group, -S(O) ｎ R Ｅ Or NR Ｆ R Ｇ Saturated or unsaturated C substituted with １ ~C ６ Alkoxy group, halogen, hydroxy group, -S(O) ｎ R Ｅ Or NR Ｆ R Ｇ C substituted with ３ ~C ６ cycloalkoxy groups, where R Ｅ , R Ｆ and R Ｇ are each independently hydrogen, deuterium, a halogen, a cyano group, a hydroxyl group, an amino group, a saturated or unsaturated C １ ~C ６ Alkyl group, C ３ ~C ６ Saturated or unsaturated C substituted with a cycloalkyl group, a halogen, a hydroxyl group or an amino group １ ~C ６ C substituted with an alkyl group, a halogen, a hydroxyl group or an amino group ３ ~C ６ Cycloalkyl groups, saturated or unsaturated C １ ~C ６ Alkoxy group, C ３ ~C ６ Saturated or unsaturated C substituted with a cycloalkoxy group, a halogen, a hydroxy group or an amino group １ ~C ６ C substituted with an alkoxy group, a halogen, a hydroxy group or an amino group ３ ~C ６ cycloalkoxy groups; R １ and R ２ are each independently hydrogen, a saturated or unsaturated substituted or unsubstituted C １ ~C ８ Alkyl groups, saturated or unsaturated, substituted or unsubstituted C ３ ~C ８ Cycloalkyl groups, -OC(=O)C １－８ Alkyl group, -OC(=O)C ３ ~C ８ Cycloalkyl groups, -C(=O)OC １－８ Alkyl group, -C(=O)OC ３ ~C ８ Cycloalkyl group, -S(O) ｎ Rc, saturated or unsaturated, substituted or unsubstituted C １ ~C ８ Sulfonyl group, saturated or unsaturated substituted or unsubstituted C １ ~C ８ Acyl group, C ６ ~C １４ A 4- to 14-membered heterocycloalkyl or heteroaryl group containing 1 to 3 heteroatoms selected from an aryl group, N, O, and S, wherein the "substitution" is optionally substituted with a hydroxyl group, a halogen, a cyano group, a sulfonyl group, an amino group, -S(O) ｎ Rc, N.R. Ｃ R Ｄ , saturated or unsaturated C １ ~C ８ Alkyl group, saturated or unsaturated C ３ ~C ８ Cycloalkyl groups, saturated or unsaturated C １ ~C ８ Alkoxy group, saturated or unsaturated C ３ ~C ８ Cycloalkoxy group, -OC(=O)C １－８ Alkyl group, -OC(=O)C ３ ~C ８ Cycloalkyl groups, -C(=O)OC １－８ Alkyl group, -C(=O)OC ３ ~C ８ Cycloalkyl groups, 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 containing 1 to 4 substituents selected from an aryl group, a 4-14 membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, O and S, or a heteroaryl group; Or, R １ and R ２ form, together with the N atom bonding them, a substituted or unsubstituted 4- to 14-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, O, and S, or a substituted or unsubstituted 5- to 14-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S, wherein the "substitution" refers to selectively deuterium, a hydroxyl group, a halogen, a cyano group, a sulfonyl group, an amino group, -S(O) ｎ Rc, N.R. Ｃ R Ｄ , C １ ~C ８ Alkyl group, C ３ ~C ８ Cycloalkyl group, C １ ~C ８ Alkoxy group, C ３ ~C ８ Cycloalkoxy group, -OC(=O)C １－８ Alkyl group, -OC(=O)C ３ ~C ８ Cycloalkyl groups, -C(=O)OC １－８ Alkyl group, -C(=O)OC ３ ~C ８ Cycloalkyl group, halogen, hydroxyl group, amino group or R Ｈ C substituted with １ ~C ８ Alkyl group, C ３ ~C ８ Cycloalkyl group, C １ ~C ８ Alkoxy group, C ３ ~C ８ cycloalkoxy groups, where R Ｈ is hydrogen, deuterium, halogen, cyano group, hydroxyl group, amino group, saturated or unsaturated C １ ~C ６ Alkyl group, C ３ ~C ６ Cycloalkyl group, -S(O) ｎ Rc, N.R. Ｃ R Ｄ , saturated or unsaturated C substituted with deuterium, halogen, hydroxyl group or amino group １ ~C ６ C substituted with an alkyl group, deuterium, halogen, hydroxyl group or amino group ３ ~C ６ Cycloalkyl groups, saturated or unsaturated C １ ~C ６ Alkoxy group, C ３ ~C ６ Saturated or unsaturated C substituted with a cycloalkoxy group, deuterium, halogen, hydroxyl group or amino group １ ~C ６ C substituted with an alkoxy group, deuterium, halogen, hydroxyl group or amino group ３ ~C ６ cycloalkoxy groups; R ３ is a halogen, a hydroxyl group, -S(O) ｎ Rc, N.R. Ｃ R Ｄ , saturated or unsaturated C １ ~C ８ Alkyl group, C ３ ~C ８ Cycloalkyl group, C １ ~C ８ Alkoxy group, C ３ ~C ８ Cycloalkoxy group, halogen, hydroxy group, amino group or R Ｈ Saturated or unsaturated C substituted with １ ~C ８ Alkyl group, C ３ ~C ８ Cycloalkyl group, C １ ~C ８ Alkoxy group, C ３ ~C ８ A cycloalkoxy group, where the substituent R Ｈ is hydrogen, deuterium, halogen, cyano group, hydroxyl group, amino group, saturated or unsaturated C １ ~C ６ Alkyl group, C ３ ~C ６ Saturated or unsaturated C substituted with a cycloalkyl group, a halogen, a hydroxyl group or an amino group １ ~C ６ C substituted with an alkyl group, a halogen, a hydroxyl group or an amino group ３ ~C ６ Cycloalkyl groups, saturated or unsaturated C １ ~C ６ Alkoxy group, C ３ ~C ６ Saturated or unsaturated C substituted with a cycloalkoxy group, a halogen, a hydroxy group or an amino group １ ~C ６ C substituted with an alkoxy group, a halogen, a hydroxy group or an amino group ３ ~C ６ cycloalkoxy groups; R ４ is hydrogen or deuterium, Substituted pyrimidine hydrazide compounds of formula I, wherein n is an integer of 0, 1 or 2, their respective optical isomers, prodrugs or pharma- ceutically acceptable salts.

2. A １ and A ３ is CR Ａ And A ２ is N, and the substituent R Ａ each independently represents a hydrogen atom, a halogen atom, a cyano group, a hydroxyl group, an amino group, a saturated or unsaturated C １ ~C ３ Alkyl group, C ３ ~C ６ Cycloalkyl group, halogen, hydroxyl group, amino group or R Ｃ Saturated or unsaturated C substituted with １ ~C ３ Alkyl group, halogen, hydroxyl group, amino group or R Ｃ C substituted with ３ ~C ６ Cycloalkyl groups, saturated or unsaturated C １ ~C ３ Alkoxy group, C ３ ~C ６ Cycloalkoxy group, halogen, hydroxy group, amino group or R Ｃ Saturated or unsaturated C substituted with １ ~C ３ Alkoxy group, halogen, hydroxy group, amino group or R Ｃ C substituted with ３ ~C ６ Cycloalkoxy group, -S(O) ｎ Rc, saturated or unsaturated, substituted or unsubstituted C １ ~C ３ Acyl group, NR Ｃ R Ｄ The substituted pyrimidine hydrazide compound of formula I according to claim 1, characterized in that it is selected from the following:

3. A １ and A ３ is CR Ａ And A ２ is N, and the substituent R Ａ The substituted pyrimidine hydrazide compounds of formula I according to claim 1, characterized in that: is hydrogen, their respective optical isomers, prodrugs or pharma- ceutically acceptable salts.

4. A ４ is N, C or a bond, and A ５ , A ６ and A ７ are each independently N or C, and A ４ , A ５ , A ６ and A ７ each independently represents a substituent R Ｂ and the substituent R Ｂ are each independently a hydrogen atom, a halogen atom, a cyano group, a hydroxyl group, an amino group, -S(O) ｎ Rc, saturated or unsaturated C １ ~C ３ Alkyl group, C ３ ~C ６ Cycloalkyl group, halogen, hydroxyl group, amino group or R Ｃ Saturated or unsaturated C substituted with １ ~C ３ Alkyl group, halogen, hydroxyl group, amino group or R Ｃ C substituted with ３ ~C ６ Cycloalkyl groups, saturated or unsaturated C １ ~C ３ Alkoxy group, C ３ ~C ６ Cycloalkoxy group, halogen, hydroxy group, amino group or R Ｃ Saturated or unsaturated C substituted with １ ~C ３ C substituted with an alkoxy group, a halogen, a hydroxy group, an amino group or R′ ３ ~C ６ Cycloalkoxy groups, saturated or unsaturated, substituted or unsubstituted C １ ~C ３ Acyl groups, saturated or unsaturated, substituted or unsubstituted C １ ~C ３ Alkoxycarbonyl group, NR Ｃ R Ｄ The substituted pyrimidine hydrazide compound of formula I according to claim 1, characterized in that it is selected from the following:

5. substituent R Ｃ and R Ｄ each independently represents a hydrogen atom, a halogen atom, a cyano group, a hydroxyl group, an amino group, a saturated or unsaturated C １ ~C ３ Alkyl group, C ３ ~C ６ Cycloalkyl groups, halogens, hydroxy groups, -S(O) ｎ R Ｅ Or NR Ｆ R Ｇ Saturated or unsaturated C substituted with １ ~C ３ Alkyl group, halogen, hydroxyl group, -S(O) ｎ R Ｅ Or NR Ｆ R Ｇ C substituted with ３ ~C ６ Cycloalkyl groups, saturated or unsaturated C １ ~C ３ Alkoxy group, C ３ ~C ６ Cycloalkoxy group, halogen, hydroxy group, -S(O) ｎ R Ｅ Or NR Ｆ R Ｇ Saturated or unsaturated C substituted with １ ~C ３ Alkoxy group, halogen, hydroxy group, -S(O) ｎ R Ｅ Or NR Ｆ R Ｇ C substituted with ３ ~C ６ cycloalkoxy groups; R Ｅ , R Ｆ and R Ｇ are each independently hydrogen, deuterium, a halogen, a cyano group, a hydroxyl group, an amino group, a saturated or unsaturated C １ ~C ３ Alkyl group, C ３ ~C ６ Saturated or unsaturated C substituted with a cycloalkyl group, a halogen, a hydroxyl group or an amino group １ ~C ３ C substituted with an alkyl group, a halogen, a hydroxyl group or an amino group ３ ~C ６ Cycloalkyl groups, saturated or unsaturated C １ ~C ３ Alkoxy group, C ３ ~C ６ Saturated or unsaturated C substituted with a cycloalkoxy group, a halogen, a hydroxy group or an amino group １ ~C ３ C substituted with an alkoxy group, a halogen, a hydroxy group or an amino group ３ ~C ６ 2. The substituted pyrimidine hydrazide compound of formula I according to claim 1, characterized in that the substituted pyrimidine hydrazide group is selected from the group consisting of cycloalkoxy groups, their respective optical isomers, prodrugs and pharma- ceutically acceptable salts.

6. A ７ The substituted pyrimidine hydrazide compound of formula I according to claim 1, characterized in that: is C, their respective optical isomers, prodrugs or pharma- ceutically acceptable salts.

7. R １ and R ２ are each independently hydrogen, a saturated or unsaturated substituted or unsubstituted C １ ~C ６ Alkyl groups, saturated or unsaturated, substituted or unsubstituted C ３ ~C ６ Cycloalkyl groups, -OC(=O)C １－６ Alkyl group, -OC(=O)C ３ ~C ６ Cycloalkyl groups, -C(=O)OC １－６ Alkyl group, -C(=O)OC ３ ~C ６ Cycloalkyl groups, saturated or unsaturated, substituted or unsubstituted C １ ~C ６ Alkoxy groups, saturated or unsaturated substituted or unsubstituted C ３ ~C ６ Cycloalkoxy group, -S(O) ｎ Rc, N.R. Ｃ R Ｄ , 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 A 5- to 10-membered heteroaryl group containing 1 to 3 heteroatoms selected from an aryl group, N, O, and S, wherein the "substituted" group is optionally substituted with a hydroxy group, a halogen, a cyano group, a sulfonyl group, an amino group, -S(O) ｎ Rc, N.R. Ｃ R Ｄ , saturated or unsaturated C １ ~C ６ Alkyl group, saturated or unsaturated C ３ ~C ６ Cycloalkyl groups, -OC(=O)C １－６ Alkyl group, -OC(=O)C ３ ~C ６ Cycloalkyl groups, -C(=O)OC １－６ Alkyl group, -C(=O)OC ３ ~C ６ Cycloalkyl groups, saturated or unsaturated C １ ~C ６ Sulfonyl group, saturated or unsaturated C １ ~C ６ Acyl group, C ６ ~C １０ containing 1 to 4 substituents selected from an aryl group, a 6- to 10-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, O and S, or a heteroaryl group; Or, R １ and R ２ form, together with the N atom bonding them, a substituted or unsubstituted 4- to 10-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, O, and S, or a substituted or unsubstituted 5- to 10-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S, wherein the "substitution" refers to selectively a hydroxy group, a halogen, a cyano group, a sulfonyl group, an amino group, -S(O) ｎ Rc, N.R. Ｃ R Ｄ , C １ ~C ６ Alkyl group, C ３ ~C ６ Cycloalkyl group, C １ ~C ６ Alkoxy group, C ３ ~C ６ Cycloalkoxy group, -OC(=O)C １－６ Alkyl group, -OC(=O)C ３ ~C ６ Cycloalkyl groups, -C(=O)OC １－６ Alkyl group, -C(=O)OC ３ ~C ６ Cycloalkyl group, halogen, hydroxyl group, amino group or R Ｅ C substituted with １ ~C ６ Alkyl group, C ３ ~C ６ Cycloalkyl group, C １ ~C ６ Alkoxy group, C ３ ~C ６ cycloalkoxy groups, where R Ｅ is a hydrogen atom, a halogen atom, a cyano group, a hydroxyl group, an amino group, a saturated or unsaturated C １ ~C ６ Alkyl group, C ３ ~C ６ Cycloalkyl group, -S(O) ｎ Rc, N.R. Ｃ R Ｄ , saturated or unsaturated C substituted with deuterium, halogen, hydroxyl group or amino group １ ~C ６ C substituted with an alkyl group, deuterium, halogen, hydroxyl group or amino group ３ ~C ６ Cycloalkyl groups, saturated or unsaturated C １ ~C ６ Alkoxy group, C ３ ~C ６ Saturated or unsaturated C substituted with a cycloalkoxy group, deuterium, halogen, hydroxyl group or amino group １ ~C ６ C substituted with an alkoxy group, deuterium, halogen, hydroxyl group or amino group ３ ~C ６ 2. The substituted pyrimidine hydrazide compound of formula I according to claim 1, characterized in that the substituted pyrimidine hydrazide group is selected from the group consisting of cycloalkoxy groups, their respective optical isomers, prodrugs and pharma- ceutically acceptable salts.

8. R ３ is halogen, -S(O) ｎ Rc, N.R. Ｃ R Ｄ , saturated or unsaturated C １ ~C ６ Alkyl group, C ３ ~C ６ Cycloalkyl group, C １ ~C ６ Alkoxy group, C ３ ~C ６ Cycloalkoxy group, halogen, hydroxy group, amino group or R Ｈ Saturated or unsaturated C substituted with １ ~C ６ Alkyl group, C ３ ~C ６ Cycloalkyl group, C １ ~C ６ Alkoxy group, C ３ ~C ６ A cycloalkoxy group, where the substituent R Ｈ is a hydrogen atom, a halogen atom, a cyano group, a hydroxyl group, an amino group, a saturated or unsaturated C １ ~C ３ Alkyl group, C ３ ~C ６ Saturated or unsaturated C substituted with a cycloalkyl group, a halogen, a hydroxyl group or an amino group １ ~C ３ C substituted with an alkyl group, a halogen, a hydroxyl group or an amino group ３ ~C ６ Cycloalkyl groups, saturated or unsaturated C １ ~C ３ Alkoxy group, C ３ ~C ６ Saturated or unsaturated C substituted with a cycloalkoxy group, a halogen, a hydroxy group or an amino group １ ~C ３ C substituted with an alkoxy group, a halogen, a hydroxy group or an amino group ３ ~C ６ 2. The substituted pyrimidine hydrazide compound of formula I according to claim 1, characterized in that the substituted pyrimidine hydrazide group is selected from the group consisting of cycloalkoxy groups, their respective optical isomers, prodrugs and pharma- ceutically acceptable salts.

9. R １ and R ２ are each independently hydrogen, a saturated or unsaturated substituted or unsubstituted C １ ~C ３ Alkyl groups, saturated or unsaturated, substituted or unsubstituted C ３ ~C ６ Cycloalkyl groups, -OC(=O)C １－３ Alkyl group, -OC(=O)C ３ ~C ６ Cycloalkyl groups, -C(=O)OC １－３ Alkyl group, -C(=O)OC ３ ~C ６ Cycloalkyl group, -S(O) ｎ Rc, N.R. Ｃ R Ｄ , saturated or unsaturated, substituted or unsubstituted C １ ~C ３ Sulfonyl group, saturated or unsaturated substituted or unsubstituted C １ ~C ３ Acyl group, C ６ ~C １０ A 6- to 8-membered heteroaryl group containing 1 to 3 heteroatoms selected from an aryl group, N, O, and S, wherein the "substituted" group is optionally substituted with a hydroxy group, a halogen, a cyano group, a sulfonyl group, an amino group, -S(O) ｎ Rc, N.R. Ｃ R Ｄ , -OC(=O)C １－３ Alkyl group, -OC(=O)C ３ ~C ６ Cycloalkyl groups, -C(=O)OC １－３ Alkyl group, -C(=O)OC ３ ~C ６ Cycloalkyl groups, saturated or unsaturated C １ ~C ３ Alkyl group, saturated or unsaturated C ３ ~C ６ Cycloalkyl groups, saturated or unsaturated C １ ~C ３ Sulfonyl group, saturated or unsaturated C １ ~C ３ Acyl group, C ６ ~C １０ containing 1 to 4 substituents selected from an aryl group, a 6-8 membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O and S; Or, R １ and R ２ form, together with the N atom bonding them, a substituted or unsubstituted 5- to 10-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, O, and S, or a substituted or unsubstituted 5- to 10-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S, wherein the "substitution" refers to selectively a hydroxy group, a halogen, a cyano group, a sulfonyl group, an amino group, -S(O) ｎ Rc, N.R. Ｃ R Ｄ , C １ ~C ３ Alkyl group, C ３ ~C ６ Cycloalkyl Group C １ ~C ３ Alkoxy group, C ３ ~C ６ Cycloalkoxy group, -OC(=O)C １－３ Alkyl group, -OC(=O)C ３ ~C ６ Cycloalkyl groups, -C(=O)OC １－３ Alkyl group, -C(=O)OC ３ ~C ６ Cycloalkyl group, halogen, hydroxyl group, amino group or R Ｈ C substituted with １ ~C ３ Alkyl group, C ３ ~C ６ Cycloalkyl group, C １ ~C ３ Alkoxy group, C ３ ~C ６ cycloalkoxy groups, where R Ｈ is a hydrogen atom, a halogen atom, a cyano group, a hydroxyl group, an amino group, a saturated or unsaturated C １ ~C ３ Alkyl group, C ３ ~C ６ Cycloalkyl group, -S(O) ｎ Rc, N.R. Ｃ R Ｄ , a saturated or unsaturated C substituted with a halogen, a hydroxyl group or an amino group １ ~C ３ C substituted with an alkyl group, a halogen, a hydroxyl group or an amino group ３ ~C ６ Cycloalkyl groups, saturated or unsaturated C １ ~C ３ Alkoxy group, C ３ ~C ６ Saturated or unsaturated C substituted with a cycloalkoxy group, a halogen, a hydroxy group or an amino group １ ~C ３ C substituted with an alkoxy group, a halogen, a hydroxy group or an amino group ３ ~C ６ 2. The substituted pyrimidine hydrazide compound of formula I according to claim 1, characterized in that the substituted pyrimidine hydrazide group is selected from the group consisting of cycloalkoxy groups, their respective optical isomers, prodrugs and pharma- ceutically acceptable salts.

10. R ３ is halogen, -S(O) ｎ Rc, N.R. Ｃ R Ｄ , saturated or unsaturated C １ ~C ３ Alkyl group, C ３ ~C ６ Cycloalkyl group, C １ ~C ３ Alkoxy group, C ３ ~C ６ Cycloalkoxy group, halogen, hydroxy group, amino group or R Ｈ Saturated or unsaturated C substituted with １ ~C ３ Alkyl group, C ３ ~C ６ Cycloalkyl group, C １ ~C ３ Alkoxy group, C ３ ~C ６ A cycloalkoxy group, where the substituent R Ｈ is a hydrogen atom, a halogen atom, a cyano group, a hydroxyl group, an amino group, a saturated or unsaturated C １ ~C ３ Alkyl group, C ３ ~C ６ Saturated or unsaturated C substituted with a cycloalkyl group, a halogen, a hydroxyl group or an amino group １ ~C ３ C substituted with an alkyl group, a halogen, a hydroxyl group or an amino group ３ ~C ６ Cycloalkyl groups, saturated or unsaturated C １ ~C ３ Alkoxy group, C ３ ~C ６ Saturated or unsaturated C substituted with a cycloalkoxy group, a halogen, a hydroxy group or an amino group １ ~C ３ C substituted with an alkoxy group, a halogen, a hydroxy group or an amino group ３ ~C ６ 2. The substituted pyrimidine hydrazide compound of formula I according to claim 1, characterized in that the substituted pyrimidine hydrazide group is selected from the group consisting of cycloalkoxy groups, their respective optical isomers, prodrugs and pharma- ceutically acceptable salts.

11. R １ and R ２ The structure that they form with the N atom that connects them is 2. The substituted pyrimidine hydrazide compound of formula I according to claim 1, wherein the substituted pyrimidine hydrazide compound is selected from the group consisting of:

12. The substituted pyrimidine hydrazide compound of formula I according to claim 1, characterized in that the substituted pyrimidine hydrazide compound, its respective optical isomer, prodrug or pharma- ceutically acceptable salt thereof is selected from the following compounds:

13. A method for preparing a substituted pyrimidine hydrazide compound according to any one of claims 1 to 12, their respective optical isomers, prodrugs or pharma- ceutically acceptable salts, said method being as shown in reaction scheme 1 below: A condensation reaction between a carboxylic acid compound represented by formula III and a hydrazine compound represented by formula IV to obtain a substituted pyrimidine hydrazide compound represented by formula I; wherein the carboxylic acid compound of formula III is prepared according to one of the following methods: Method A 1) reacting a methyl carbonyl compound of formula V with dimethyl oxalate to obtain a compound of formula VI; 2) cyclizing a compound of formula VI with a hydrazine compound of formula X to obtain a pyrimidine compound of formula VII; 3) hydrolyzing the pyrimidine compound represented by formula VII to obtain a carboxylic acid compound represented by formula III; Method B 1) A methyl carbonyl compound represented by formula V and a monoalkyl oxalate ester to obtain a compound represented by formula VIII, where R is a methyl group, an ethyl group, an isopropyl group, a tert-butyl group, etc. 2) cyclizing a compound represented by formula VIII with a hydrazine compound represented by formula X to obtain a pyrimidine compound represented by formula IX; 3) subjecting a pyrimidine compound represented by formula IX to a hydrolysis reaction to remove the substituent R to obtain a carboxylic acid compound represented by formula III; Method C 1) Cyclization of a methyl carbonyl compound of formula V with urea to obtain a compound of formula XI; 2) reacting a compound of formula XI with a chlorinating agent, such as phosphorus oxychloride, phosphorus pentachloride, thionyl chloride, etc., to obtain a chlorinated compound of formula XII; 3) Chlorinated compounds and boric acid compounds represented by formula XII or the corresponding borate ester, or a trialkyltin compound to produce a compound of formula XIII; 4) removing the ethyl group from the compound of formula XIII to form a carboxylic acid group to obtain a compound of formula III; Method D 1) Carbonate compounds with a hydrazine compound of formula X to obtain a compound of formula XIV; 2) reacting a compound of formula XIV with a chlorinating agent such as phosphorus oxychloride, phosphorus pentachloride, thionyl chloride, etc. to obtain a chlorinated compound of formula XV; 3) Chlorinated compounds and boric acid compounds represented by formula XV or a corresponding boric acid ester, or a trialkyltin compound to give a compound of formula III, Method E １） Or react with the corresponding boric acid ester or trialkyltin compound, separate and purify it, and then obtain the compound Obtained, 2) Compound or a trialkyltin compound to give a compound of formula III, Method F １） or reacting with a corresponding boric acid ester or trialkyltin compound, and obtaining a compound represented by formula XV after separation and purification; 2) The compound represented by formula XV is further treated with a boric acid compound or with the corresponding boric acid ester, or trialkyltin compound to give a compound of formula III, The hydrazine compound of formula IV is prepared according to one of the following synthetic methods: Method G 1) BocNHNH ２ (tert-butoxycarbonylhydrazine) is dissolved in an alcohol solvent such as methanol or ethanol, and a ketone compound (R １ (C=O)R １ ) or aldehyde compounds (R １ (C=O)H) is added to react, and sodium borohydride is added to reduce hydrogenation, and the compound is purified and separated. Obtained, 2) Compound is dissolved in an amine solvent such as N,N-diisopropylethylamine (DIEA) and a ketone compound (R ２ (C=O)R ２ ), aldehyde compounds (R ２ (C=O)H) or the corresponding R ２ Add an epoxy compound substituted with Obtained, 3) Compound is dissolved in an alcoholic solvent such as methanol or ethanol, and a solution of excess HCl in methanol is added to obtain the hydrochloride salt of the compound of formula IV; Method H 1) Substituted amino compounds (HNR １ R ２ ) is dissolved in a solvent, a nitrosating agent is added, the nitrosating agent is selected from tert-butyl nitrite and isobutyl nitrite, heated under reflux, and concentrated under reduced pressure to obtain an intermediate nitrosoamino compound (R １ N (R ２ )-N=O), 2) Nitrosoamino compounds (R １ N (R ２ )-N=O) is dissolved in a solvent and a hydrogenation reagent such as lithium aluminum hydride is added to carry out a hydrogenation reaction to obtain a compound represented by formula IV; Here, the substituent A １ ~A ７ , R １ ~R ４ The definition of is the same as in claim 1.

14. A pharmaceutical composition comprising a therapeutically effective amount of a substituted pyrimidine hydrazide compound of formula I according to any one of claims 1 to 12, their respective optical isomers, prodrugs or pharma- ceutically acceptable salts, and a pharma-ceutically acceptable excipient or carrier.

15. Use of a substituted pyrimidine hydrazide compound of formula I according to any one of claims 1 to 12, their respective optical isomers, prodrugs or pharma- ceutically acceptable salts in the manufacture of an inhibitor of AHR disorder.

16. Use of a substituted pyrimidine hydrazide compound of formula I according to any one of claims 1 to 12, their respective optical isomers, prodrugs or pharma- ceutically acceptable salts in the manufacture of a medicament for treating a tumor associated with AHR disorder.

17. A method for treating a tumor associated with AHR disorder, comprising administering to a subject in need thereof an effective amount of a substituted pyrimidine hydrazide compound of formula I as defined in any one of claims 1 to 12, their respective optical isomers, prodrugs or pharma- ceutically acceptable salts, or a pharmaceutical composition as defined in claim 13.

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