Substituted pyrimidine hydrazide compounds, methods for producing the same, and their 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] This invention belongs to the field of biopharmaceutical technology and specifically relates to substituted pyrimidine hydrazide compounds, methods for producing the same, and their use. [Background technology]

[0002] Aromatic hydrocarbon receptors (AHRs) are members of the bHLH-PAS (bHLH-PER-ARNT-SIM) subfamily of the basic helix-loop-helix (bHLH) superfamily, and are unique receptors within the bHLH-PAS family that can be activated by ligands [Murray et al., Nat. Rev. Cancer, 2014, 14(12), 801-814; Bersten et al., Nat. Rev. Cancer, 2013, 13(12), 827-841]. AHRs present in the cytoplasm can receive stimulation from aromatic hydrocarbon xenobiotics, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), and can translocate to the cell nucleus to form a heterodimer with the Aryl Hydrocarbon Receptor Nuclear Translocator (ARNT). The AHR / ARNT complex then interacts with xenobiotic response elements (XREs) upstream of AHR regulatory genes, thereby regulating the transcription of those genes. AHRs can also activate non-XRE-dependent protein-protein interaction pathways.

[0003] The AHR pathway is one of the best-known mechanisms for binding to and inducing the metabolism of environmental toxins, such as 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 AHR by environmental toxins has already demonstrated the role of AHR in many cellular processes, such as embryonic development, tumorigenesis, and inflammation. 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 immunomodulation (Nguyen et al.). al., Front.Immunol., 2014, 5, 511). Classic exogenous AHR ligands such as TCDD induce deep immunosuppression, promote cancer development, and induce tumor growth [Gramatzki et al., Oncogene, 2009, 28(28), 2593-2605; Buietal., Oncogene, 2009, 28(41), 3642-3651; Esseretal., Trends.Immunol., 2009, 30(9), 447-454].

[0004] Through XRE-dependent or independent activity, AHRs modulate many important innate and adaptive immune responses. Studies have found that several AHR agonists can promote the differentiation of Th17 cells (T-helper cells) and the secretion of IL-17. On the other hand, several other AHR agonists can induce the lateral differentiation of Th17 cells into Treg cells and enhance the inhibitory activity of Treg cells [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 lead to the inhibition of macrophage-regulated innate inflammatory responses (e.g., decreased expression of lipopolysaccharide (LPS)-induced IL-1β, IL-6, IL-12, and TNFalpha) and dendritic cell inhibition (reduced dendritic cell activation and increased IL-10 expression) [Kimura et al., J.Exp.Med., 2009, 206(9), 2027-2035; Wang et al., Clin.Exp.Immunol., 2014, 177(2), 521-530; Weiet 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, and then activate helper CD4+ T-cells (Th) and cytotoxic CD8+ T-cells (Tc), which then work synergistically to effectively eliminate tumor cells. Tumor cells have already developed several mechanisms to evade immunity, which is controlled by Th and Tc cell lysis. 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 reinforcing Treg recruitment, production, and activation. 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 evasion pathway employed by malignant tumor cells.

[0007] Recent research in tumor immunobiology has revealed that malignant tumor cells employ various immune evasion mechanisms to escape the immune system. Preclinical and clinical studies have demonstrated that optimal restoration of the anti-tumor immune response can be achieved by blocking or attenuating these mechanisms through combinations of therapeutic use (e.g., immune checkpoint inhibitors and vaccines). Research data suggests that anti-tumor immunity can be restored with the use of AHR modulators alone. Due to the unique characteristics of the AHR signaling pathway, AHR inhibitors can be used in conjunction with other tumor immunotherapies, and are expected to enhance the immunotherapy response through synergistic effects with other treatment methods. Clinically, the response rate of single immune checkpoint inhibitors is not yet at a relatively high level, so the development of new anti-tumor immune regulatory targets is of great significance for tumor treatment. AHRs are a target full of potential, and the research and development of relevant inhibitors provides new space for novel anti-tumor therapies. [Overview of the project]

[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. JPEG0007894167000001.jpg4261

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

[0012] where the substituent R C and R DThese are, independently, hydrogen, halogen, cyano group, hydroxyl group, amino group, saturated or unsaturated C1-C6 alkyl group, C3-C6 cycloalkyl group, halogen, hydroxyl group, and -S(O). n R E or NR F R G Saturated or unsaturated C1-C6 alkyl groups, halogens, hydroxyl groups, -S(O) substituted with n R E or NR F R G Substituted C3-C6 cycloalkyl groups, saturated or unsaturated C1-C6 alkoxy groups, C3-C6 cycloalkoxy groups, halogens, hydroxyl groups, -S(O) n R E or NR F R G Saturated or unsaturated C1-C6 alkoxy groups, halogens, hydroxyl groups, -S(O) substituted with n R E or NR F R G Selected from C3-C6 cycloalkoxy groups substituted with, where R E , R F and R G Each is independently selected from hydrogen, deuterium, halogen, cyano group, hydroxyl group, amino group, saturated or unsaturated C1-C6 alkyl group, C3-C6 cycloalkyl group, saturated or unsaturated C1-C6 alkyl group substituted with halogen, hydroxyl group or amino group, C3-C6 cycloalkyl group substituted with halogen, hydroxyl group or amino group, saturated or unsaturated C1-C6 alkoxy group, C3-C6 cycloalkoxy group, saturated or unsaturated C1-C6 alkoxy group substituted with halogen, hydroxyl group or amino group, and C3-C6 cycloalkoxy group substituted with halogen, hydroxyl group or amino group.

[0013] R1 and R2 are independently hydrogen, saturated or unsaturated substituted or unsubstituted C1-C8 alkyl groups, saturated or unsaturated substituted or unsubstituted C3-C8 cycloalkyl groups, and -OC(=O)C 1-8 Alkyl alkyl groups, -OC(=O)C3~C8 cycloalkyl groups, -C(=O)OC1-8 Alkyl alkyl groups, -C(=O)OC3~C8 cycloalkyl groups, -S(O) n Rc, saturated or unsaturated substituted or unsubstituted C1-C8 sulfonyl groups, saturated or unsaturated substituted or unsubstituted C1-C8 acyl groups, C6-C 14 A 4-14 member heterocycloalkyl group or heteroaryl group containing an aryl group, 1-3 heteroatoms selected from N, O and S, where "substitution" refers to selectively a hydroxyl group, halogen, cyano group, sulfonyl group, amino group, -S(O) n Rc, NR C R D , saturated or unsaturated C1-C8 alkyl groups, saturated or unsaturated C3-C8 cycloalkyl groups, saturated or unsaturated C1-C8 alkoxy groups, saturated or unsaturated C3-C8 cycloalkoxy groups, -OC(=O)C 1-8 Alkyl alkyl groups, -OC(=O)C3~C8 cycloalkyl groups, -C(=O)OC 1-8 Alkyl groups, -C(=O)OC3~C8 cycloalkyl groups, saturated or unsaturated C1~C8 sulfonyl groups, saturated or unsaturated C1~C8 acyl groups, saturated or unsaturated C1~C8 alkoxycarbonyl groups, C6~C 14 It contains an aryl group, a 4-14 membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, O, and S, or a heteroaryl group containing 1-4 substituents selected from 1-4 heteroaryl groups.

[0014] Alternatively, R1 and R2 may form a substituted or unsubstituted 4-14 member heterocycloalkyl group containing 1-3 heteroatoms selected from N, O, and S together with the N atom that binds them, or a substituted or unsubstituted 5-14 member heteroaryl group containing 1-3 heteroatoms selected from N, O, and S, where "substituted" refers to a group that selectively contains deuterium, a hydroxyl group, a halogen, a cyano group, a sulfonyl group, an amino group, or -S(O). n Rc, NR C R D , C1-C8 alkyl groups, C3-C8 cycloalkyl groups, C1-C8 alkoxy groups, C3-C8 cycloalkoxy groups, -OC(=O)C 1-8Alkyl alkyl groups, -OC(=O)C3~C8 cycloalkyl groups, -C(=O)OC 1-8 Alkyl alkyl groups, -C(=O)OC3~C8 cycloalkyl groups, halogens, hydroxyl groups, amino groups, or R H It contains 1 to 4 substituents selected from C1-C8 alkyl groups, C3-C8 cycloalkyl groups, C1-C8 alkoxy groups, and C3-C8 cycloalkoxy groups substituted with R, where R H This includes hydrogen, deuterium, halogens, cyano groups, hydroxyl groups, amino groups, saturated or unsaturated C1-C6 alkyl groups, C3-C6 cycloalkyl groups, and -S(O). n Rc, NR C R D Selected from saturated or unsaturated C1-C6 alkyl groups substituted with deuterium, halogens, hydroxyl groups, or amino groups; C3-C6 cycloalkyl groups substituted with deuterium, halogens, hydroxyl groups, or amino groups; saturated or unsaturated C1-C6 alkoxy groups; C3-C6 cycloalkoxy groups; saturated or unsaturated C1-C6 alkoxy groups substituted with deuterium, halogens, hydroxyl groups, or amino groups; C3-C6 cycloalkoxy groups substituted with deuterium, halogens, hydroxyl groups, or amino groups.

[0015] R3 is a halogen, hydroxyl group, -S(O) n Rc, NR C R D , saturated or unsaturated C1-C8 alkyl groups, C3-C8 cycloalkyl groups, C1-C8 alkoxy groups, C3-C8 cycloalkoxy groups, halogens, hydroxyl groups, amino groups or R H A saturated or unsaturated C1-C8 alkyl group, C3-C8 cycloalkyl group, C1-C8 alkoxy group, or C3-C8 cycloalkoxy group substituted with R, where the substituent R HThis is selected from hydrogen, deuterium, halogen, cyano group, hydroxyl group, amino group, saturated or unsaturated C1-C6 alkyl group, C3-C6 cycloalkyl group, saturated or unsaturated C1-C6 alkyl group substituted with halogen, hydroxyl group or amino group, C3-C6 cycloalkyl group substituted with halogen, hydroxyl group or amino group, saturated or unsaturated C1-C6 alkoxy group, C3-C6 cycloalkoxy group, saturated or unsaturated C1-C6 alkoxy group substituted with halogen, hydroxyl group or amino group, and C3-C6 cycloalkoxy group substituted with halogen, hydroxyl group or amino group.

[0016] R4 is hydrogen or deuterium.

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

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

[0019] Furthermore, A1 and A3 are CR A A2 is N, and the substituent R A It 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 are each independently bonded to a substituent R B wherein the substituent R B is 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 substituted saturated or unsaturated C1-C3 alkyl group, halogen, hydroxy group, amino group or R C substituted C3-C6 cycloalkyl group, saturated or unsaturated C1-C3 alkoxy group, C3-C6 cycloalkoxy group, halogen, hydroxy group, amino group or R C substituted saturated or unsaturated C1-C3 alkoxy group, halogen, hydroxy group, amino group or C3-C6 cycloalkoxy group substituted with R', saturated or unsaturated substituted or unsubstituted C1-C3 acyl group, saturated or unsaturated substituted or unsubstituted C1-C3 alkoxycarbonyl group, NR C R D selected from Preferably, the substituents 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 <00%]] E or NR F R G substituted saturated or unsaturated C1-C3 alkyl group, halogen, hydroxy group, -S(O) n R E or NR F R G substituted C3-C6 cycloalkyl group, saturated or unsaturated C1-C3 alkoxy group, C3-C6 cycloalkoxy group, halogen, hydroxy group, -S(O) n RE or NR F R G and is selected from a saturated or unsaturated C1-C3 alkoxy group substituted with R, halogen, hydroxy group, -S(O) n R E or NR F R G and is selected from a C3-C6 cycloalkoxy group substituted with R

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

[0023] Preferably, A7 is C

[0024] Preferably, R1 and R2 are each independently hydrogen, a saturated or unsaturated substituted or unsubstituted C1-C6 alkyl group, a saturated or unsaturated substituted or unsubstituted C3-C6 cycloalkyl group, -OC(=O)C 1-6 alkyl group, -OC(=O)C3-C6 cycloalkyl group, -C(=O)OC 1-6 alkyl group, -C(=O)OC3-C^{6} cycloalkyl group, a saturated or unsaturated substituted or unsubstituted C1-C6 alkoxy group, a saturated or unsaturated substituted or unsubstituted C3-C6 cycloalkoxy group, -S(O) n Rc, NR C R D and, a saturated or unsaturated substituted or unsubstituted C1-C6 sulfonyl group, a saturated or unsaturated substituted or unsubstituted C1-C6 acyl group, C6-C 10A 5-10 membered heteroaryl group containing an aryl group, 1-3 heteroatoms selected from N, O, and S, where "substitution" refers to selectively a hydroxyl group, halogen, cyano group, sulfonyl group, amino group, or -S(O). n Rc, NR C R D , saturated or unsaturated C1-C6 alkyl groups, saturated or unsaturated C3-C6 cycloalkyl groups, -OC(=O)C 1-6 Alkyl alkyl groups, -OC(=O)C3~C6 cycloalkyl groups, -C(=O)OC 1-6 Alkyl groups, -C(=O)OC3~C6 cycloalkyl groups, saturated or unsaturated C1~C6 sulfonyl groups, saturated or unsaturated C1~C6 acyl groups, C6~C 10 It contains an aryl group, 1 to 3 heteroatoms selected from N, O and S, and 1 to 4 substituents selected from a 6 to 10-membered heterocycloalkyl group or a heteroaryl group,

[0025] Alternatively, R1 and R2 may form a substituted or unsubstituted 4-10 membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, O, and S together with the N atom that binds them, or a substituted or unsubstituted 5-10 membered heteroaryl group containing 1-3 heteroatoms selected from N, O, and S, where "substituted" refers to a hydroxyl group, halogen, cyano group, sulfonyl group, amino group, -S(O) n Rc, NR C R D , C1-C6 alkyl groups, C3-C6 cycloalkyl groups, C1-C6 alkoxy groups, C3-C6 cycloalkoxy groups, -OC(=O)C 1-6 Alkyl alkyl groups, -OC(=O)C3~C6 cycloalkyl groups, -C(=O)OC 1-6 Alkyl alkyl groups, -C(=O)OC3~C6 cycloalkyl groups, halogens, hydroxyl groups, amino groups, or R E It contains 1 to 4 substituents selected from C1-C6 alkyl groups, C3-C6 cycloalkyl groups, C1-C6 alkoxy groups, and C3-C6 cycloalkoxy groups substituted with R, where R EThis includes hydrogen, halogens, cyano groups, hydroxyl groups, amino groups, saturated or unsaturated C1-C6 alkyl groups, C3-C6 cycloalkyl groups, and -S(O). n Rc, NR C R D Selected from saturated or unsaturated C1-C6 alkyl groups substituted with deuterium, halogens, hydroxyl groups, or amino groups; C3-C6 cycloalkyl groups substituted with deuterium, halogens, hydroxyl groups, or amino groups; saturated or unsaturated C1-C6 alkoxy groups; C3-C6 cycloalkoxy groups; saturated or unsaturated C1-C6 alkoxy groups substituted with deuterium, halogens, hydroxyl groups, or amino groups; C3-C6 cycloalkoxy groups substituted with deuterium, halogens, hydroxyl groups, or amino groups.

[0026] Preferably, R3 is a halogen, -S(O) n Rc, NR C R D , saturated or unsaturated C1-C6 alkyl groups, C3-C6 cycloalkyl groups, C1-C6 alkoxy groups, C3-C6 cycloalkoxy groups, halogens, hydroxyl groups, amino groups or R H A saturated or unsaturated C1-C6 alkyl group, C3-C6 cycloalkyl group, C1-C6 alkoxy group, or C3-C6 cycloalkoxy group substituted with R, where the substituent R H This is selected from hydrogen, halogen, cyano group, hydroxyl group, amino group, saturated or unsaturated C1-C3 alkyl group, C3-C6 cycloalkyl group, saturated or unsaturated C1-C3 alkyl group substituted with halogen, hydroxyl group or amino group, C3-C6 cycloalkyl group substituted with halogen, hydroxyl group or amino group, saturated or unsaturated C1-C3 alkoxy group, C3-C6 cycloalkoxy group, saturated or unsaturated C1-C3 alkoxy group substituted with halogen, hydroxyl group or amino group, and C3-C6 cycloalkoxy group substituted with halogen, hydroxyl group or amino group.

[0027] More preferably, R1 and R2 are independently hydrogen, saturated or unsaturated substituted or unsubstituted C1-C3 alkyl groups, saturated or unsaturated substituted or unsubstituted C3-C6 cycloalkyl groups, and -OC(=O)C 1-3 Alkyl alkyl groups, -OC(=O)C3~C6 cycloalkyl groups, -C(=O)OC 1-3 Alkyl alkyl groups, -C(=O)OC3~C6 cycloalkyl groups, -S(O) n Rc, NR C R D , saturated or unsaturated substituted or unsubstituted C1-C3 sulfonyl groups, saturated or unsaturated substituted or unsubstituted C1-C3 acyl groups, C6-C 10 A 6-8 membered heteroaryl group containing an aryl group, 1-3 heteroatoms selected from N, O, and S, where "substitution" refers to selectively a hydroxyl group, halogen, cyano group, sulfonyl group, amino group, or -S(O). n Rc, NR C R D -OC(=O)C 1-3 Alkyl alkyl groups, -OC(=O)C3~C6 cycloalkyl groups, -C(=O)OC 1-3 Alkyl groups, -C(=O)OC3-C6 cycloalkyl groups, saturated or unsaturated C1-C3 alkyl groups, saturated or unsaturated C3-C6 cycloalkyl groups, saturated or unsaturated C1-C3 sulfonyl groups, saturated or unsaturated C1-C3 acyl groups, C6-C 10 It contains an aryl group, and 1 to 4 substituents selected from a 6-8 membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S.

[0028] Alternatively, R1 and R2 may form a substituted or unsubstituted 5-10 member heterocycloalkyl group containing 1-3 heteroatoms selected from N, O, and S together with the N atom that binds them, or a substituted or unsubstituted 5-10 member heteroaryl group containing 1-3 heteroatoms selected from N, O, and S, where "substituted" refers to selectively hydroxyl groups, halogens, cyano groups, sulfonyl groups, amino groups, -S(O) n Rc, NR C R D, C1-C3 alkyl groups, C3-C6 cycloalkyl groups, C1-C3 alkoxy groups, C3-C6 cycloalkoxy groups, -OC(=O)C 1-3 Alkyl alkyl groups, -OC(=O)C3~C6 cycloalkyl groups, -C(=O)OC 1-3 Alkyl alkyl groups, -C(=O)OC3~C6 cycloalkyl groups, halogens, hydroxyl groups, amino groups, or R H It contains 1 to 4 substituents selected from C1-C3 alkyl groups, C3-C6 cycloalkyl groups, C1-C3 alkoxy groups, and C3-C6 cycloalkoxy groups substituted with R, where R H This includes hydrogen, halogens, cyano groups, hydroxyl groups, amino groups, saturated or unsaturated C1-C3 alkyl groups, C3-C6 cycloalkyl groups, and -S(O). n Rc, NR C R D Selected from saturated or unsaturated C1-C3 alkyl groups substituted with halogens, hydroxyl groups, or amino groups; C3-C6 cycloalkyl groups substituted with halogens, hydroxyl groups, or amino groups; saturated or unsaturated C1-C3 alkoxy groups; C3-C6 cycloalkoxy groups; saturated or unsaturated C1-C3 alkoxy groups substituted with halogens, hydroxyl groups, or amino groups; C3-C6 cycloalkoxy groups substituted with halogens, hydroxyl groups, or amino groups.

[0029] More preferably, R3 is halogen, -S(O) n Rc, NR C R D , saturated or unsaturated C1-C3 alkyl groups, C3-C6 cycloalkyl groups, C1-C3 alkoxy groups, C3-C6 cycloalkoxy groups, halogens, hydroxyl groups, amino groups or R H A saturated or unsaturated C1-C3 alkyl group, C3-C6 cycloalkyl group, C1-C3 alkoxy group, or C3-C6 cycloalkoxy group substituted with R, where the substituent R HThis is selected from hydrogen, halogen, cyano group, hydroxyl group, amino group, saturated or unsaturated C1-C3 alkyl group, C3-C6 cycloalkyl group, saturated or unsaturated C1-C3 alkyl group substituted with halogen, hydroxyl group or amino group, C3-C6 cycloalkyl group substituted with halogen, hydroxyl group or amino group, saturated or unsaturated C1-C3 alkoxy group, C3-C6 cycloalkoxy group, saturated or unsaturated C1-C3 alkoxy group substituted with halogen, hydroxyl group or amino group, and C3-C6 cycloalkoxy group substituted with halogen, hydroxyl group or amino group.

[0030] More preferably, the structure formed by R1 and R2 together with the N atom that binds them is The following is selected from the base files: JPEG0007894167000002.jpg71111JPEG0007894167000003.jpg64111JPEG0007894167000004.jpg56106JPEG0007894167000005.jpg66105JPEG0007894167000006.jpg29103.

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

[0032] JPEG0007894167000007.jpg143109JPEG0007894167000008.jpg187129JPEG0007894167000009.jpg160127

[0033] According to a second aspect of the present invention, another object of the present invention is to provide a pharmaceutical composition comprising a therapeutically effective amount of a substituted pyrimidine hydrazide compound according to the present invention, an optical isomer thereof, a prodrug or pharmaceutically acceptable salt thereof, 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 applications for substituted pyrimidine hydrazide compounds according to the present invention, their respective optical isomers, prodrugs, or pharmaceutically acceptable salts in the production of AHR disorder inhibitors.

[0035] According to a fourth aspect of the present invention, another object of the present invention is to provide the use of substituted pyrimidine hydrazide compounds according to the present invention, their respective optical isomers, prodrugs, or pharmaceutically acceptable salts in the manufacture of drugs 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 disorder, the 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 the 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 producing substituted pyrimidine hydrazide compounds, their respective optical isomers, prodrugs, or pharmaceutically acceptable salts, the method being described in the following reaction formula 1: JPEG0007894167000010.jpg3676

[0038] A carboxylic acid compound represented by formula III and a hydrazine compound represented by formula IV are condensed to obtain a substituted pyrimidine hydrazide compound shown in formula I.

[0039] Here, the carboxylic acid compound represented by formula III is prepared according to one of the following methods: Method A (JPEG0007894167000011.jpg301071) A methyl carbonyl compound represented by formula V is reacted with dimethyl oxalate to obtain a compound represented by formula VI. 2) A compound represented by formula VI and a hydrazine compound represented by formula X are cyclized to obtain a pyrimidine compound represented by formula VII. 3) Hydrolyze the pyrimidine compound represented by formula VII to obtain the carboxylic acid compound represented by formula III.

[0040] Method B JPEG0007894167000012.jpg31100

[0041] 1) Methyl carbonyl compound represented by formula V and monoalkyl oxalate By reacting with JPEG0007894167000013.jpg1116, a compound represented by formula VIII is obtained, where the substituent R is a methyl group, an ethyl group, an isopropyl group, a terbutyl group, etc.

[0042] 2) A compound represented by formula VIII and a hydrazine compound represented by formula X are cyclized to obtain a pyrimidine compound represented by formula IX.

[0043] 3) Hydrolyze the pyrimidine compound represented by formula IX to remove substituent R and obtain the carboxylic acid compound represented by formula III.

[0044] Method C JPEG0007894167000014.jpg28116

[0045] 1) A methylcarbonyl compound represented by formula V is cyclized with urea to obtain a compound represented by formula XI.

[0046] 2) A compound represented by formula XI is reacted with a chlorinating agent, such as phosphorus oxychloride, phosphorus pentachloride, or thionyl chloride, to obtain a chlorinated compound represented by formula XII.

[0047] 3) Chlorinated compounds represented by formula XII and boric acid compounds JPEG0007894167000015.jpg1623, or the corresponding borate ester or trialkyltin compound, is reacted to produce a compound represented by formula XIII,

[0048] 4) Remove the ethyl group from the compound represented by formula XIII to form a carboxylic acid group, and obtain the compound represented by formula III.

[0049] Method D JPEG0007894167000016.jpg27112

[0050] 1) Carbonate compounds JPEG0007894167000017.jpg1733 is cyclized with a hydrazine compound represented by formula X to obtain a compound represented by formula XIV.

[0051] 2) A compound represented by formula XIV is reacted with a chlorinating agent, such as phosphorus oxychloride, phosphorus pentachloride, or thionyl chloride, to obtain a chlorinated compound represented by formula XV.

[0052] 3) Chlorinated compounds represented by formula XV and boric acid compounds JPEG0007894167000018.jpg1619 is reacted with a corresponding borate ester or trialkyltin compound to obtain a compound represented by formula III.

[0053] Method E JPEG0007894167000019.jpg31100

[0054] 1) JPEG0007894167000020.jpg1771 is reacted with the corresponding borate ester or trialkyltin compound, and after separation and purification, the compound is obtained. Obtain JPEG0007894167000021.jpg2220,

[0055] 2) Compound Reacting with JPEG0007894167000022.jpg25110 or a trialkyltin compound yields a compound represented by formula III.

[0056] Method F JPEG0007894167000023.jpg30107

[0057] 1) JPEG0007894167000024.jpg1572 or the corresponding borate ester, Alternatively, react it with a trialkyltin compound, separate and purify it to obtain a compound represented by formula XV.

[0058] 2) The compound represented by formula XV is further a boric acid compound JPEG0007894167000025.jpg1614 or the corresponding borate ester, Alternatively, the compound represented by formula III is obtained by reacting it with a trialkyltin compound.

[0059] The synthesis flow of the hydrazine compound represented by formula IV in the present invention is as follows. Method G JPEG0007894167000026.jpg1699

[0060] 1) Dissolve BocNHNH2 (tert-butoxycarbonylhydrazine) in an alcoholic solvent such as methanol or ethanol, then add a ketone compound (R1(C=O)R1) or an aldehyde compound (R1(C=O)H) and react, and then add sodium borohydride to reduce the hydrogenate. Purified and separated compounds Obtain JPEG0007894167000027.jpg1330,

[0061] 2) Compound Dissolve JPEG0007894167000028.jpg1230 in an amine solvent such as N,N-diisopropylethylamine (DIEA), and then react with a ketone compound (R2(C=O)R2), an aldehyde compound (R2(C=O)H), or an epoxy compound substituted with the corresponding R2. compound Obtained JPEG0007894167000029.jpg1317, 3) Compound Dissolve JPEG0007894167000030.jpg1319 in an alcoholic solvent such as methanol or ethanol, and then add a solution of excess HCl in methanol to obtain the hydrochloride salt of the compound represented by formula IV.

[0062] Method H JPEG0007894167000031.jpg1960

[0063] 1) Dissolve the substituted amino compound (HNR1R2) in a solvent, add a nitrosating reagent (selected from tert-butyl nitrite and isobutyl nitrite), heat under reflux, and concentrate under reduced pressure to obtain the intermediate nitrosoamino compound (R1N(R2)-N=O).

[0064] 2) Dissolve the nitrosoamino compound (R1N(R2)-N=O) in a solvent, add a hydrogenation reagent such as lithium aluminum hydride, and carry out a hydrogenation reaction to obtain the compound represented by formula IV. [Modes for carrying out the invention]

[0065] The present invention will now be described in detail. Before describing, it should be understood that the terms used herein and in the appended claims should not be interpreted as being limited to their general and dictionary meanings, but rather as meanings and concepts applicable to the technical aspects of the invention, based on the principle that inventors are permitted to appropriately define terms for the best possible interpretation. Therefore, the descriptions proposed herein are merely preferred examples for illustrative purposes and are not intended to limit the scope of the invention, and it should be understood that other equivalent or improved methods can be obtained without departing from the spirit and scope of the invention.

[0066] When listing a range 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 It is intended to cover [this].

[0067] definition "Alkyl group" refers to a linear or branched saturated hydrocarbon group having 1 to 8 carbon atoms ("C"). 1-8The alkyl group is an alkyl group consisting of 1 to 7 carbon atoms ("C"). In some embodiments, the alkyl group consists of 1 to 7 carbon atoms ("C"). 1-7 The alkyl group has 1 to 6 carbon atoms ("C"). In some embodiments, the alkyl group has 1 to 6 carbon atoms ("C"). 1-6 The alkyl group has 1 to 5 carbon atoms ("C"). In some embodiments, the alkyl group has 1 to 5 carbon atoms ("C"). 1-5 The alkyl group has 1 to 4 carbon atoms ("C"). In some embodiments, the alkyl group has 1 to 4 carbon atoms ("C"). 1-4 The alkyl group has 1 to 3 carbon atoms ("C"). In some embodiments, the alkyl group has 1 to 3 carbon atoms ("C"). 1-3 The alkyl group has 1 to 2 carbon atoms ("C"). In some embodiments, the alkyl group has 1 to 2 carbon atoms ("C"). 1-2 The alkyl group has an alkyl group ("C1 alkyl group"). In some embodiments, the alkyl group has an alkyl group ("C1 alkyl group"). In some embodiments, the alkyl group has an alkyl group ("C1 alkyl group"). 1-6 It has an alkyl group. 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). Other examples of alkyl groups include n-heptyl (C7), n-octyl (C8), and so on. Unless otherwise specified, each example of an alkyl group is independently unsubstituted ("unsubstituted alkyl group") or substituted with one or more substituents (e.g., halogens, e.g., F) ("substituted alkyl group"). In some embodiments, the alkyl group is unsubstituted C 1-8 The alkyl group is an alkyl group (e.g., an unsubstituted C1 alkyl group, e.g., -CH3). In some embodiments, the alkyl group is a substituted C 1-8 It is an alkyl group (for example, a substituted C1 alkyl group, e.g., -CF3).

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

[0069] A "cycloalkyl group" is a non-aromatic ring system containing 3 to 8 ring carbon atoms ("C"). 3-8 A non-aromatic ring hydrocarbon group having a cycloalkyl group ("C") and 0 heteroatoms. In some embodiments, the cycloalkyl group has 3 to 8 ring carbon atoms ("C"). 3-8 The cycloalkyl group has 3 to 6 ring carbon atoms ("C"). In some embodiments, the cycloalkyl group has 3 to 6 ring carbon atoms ("C"). 3-6 The cycloalkyl group has 5 to 8 ring carbon atoms ("C"). In some embodiments, the cycloalkyl group has 5 to 8 ring carbon atoms ("C"). 5-8 It has a cycloalkyl group. Exemplary C 3-6 Cycloalkyl groups include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), and cyclohexadienyl (C6). (Example C) 3-8 The cycloalkyl group is the above C 3-6This includes, but is not limited to, cycloalkyl groups and cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptyltriakenyl (C7), cyclooctyl (C8), and cyclooctenyl (C8). Unless otherwise specified, each example of a cycloalkyl group can be independently and optionally substituted, i.e., unsubstituted ("unsubstituted cycloalkyl group") or substituted with one or more substituents ("substituted cycloalkyl group"). In some embodiments, the cycloalkyl group is unsubstituted C 3-8 It is a cycloalkyl group. In some embodiments, the cycloalkyl group is a substituted C 3-8 It is a cycloalkyl group.

[0070] A "heterocycloalkyl group" is a 5-14 membered non-aromatic ring system having a ring carbon atom and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-14 membered heterocyclic group"). In a heterocyclic group containing one or more nitrogen atoms, the bond site may be a carbon atom or a nitrogen atom, as long as the valency allows. The heterocyclic group may be a monocyclic ("monocyclic heterocyclic group"), a fused ring, a bridging ring, or a spirocyclic system, such as a bicyclic system ("bicyclic heterocyclic group"), and may be saturated or partially unsaturated. "Heterocyclic group" further includes a ring system in which the heterocyclic group defined above is fused to one or more cycloalkyl groups (where the bond site is on the cycloalkyl group or heterocyclic group), or a ring system in which the heterocyclic group defined above is fused to one or more aryl or heteroaryl groups (where the bond site is on the heterocyclic group), and in such cases, the number of ring members continues to refer to the number of ring members in the heterocyclic system. Unless otherwise specified, each example of a heterocyclic group is independently and optionally substituted, i.e., unsubstituted ("unsubstituted heterocycloalkyl group") or substituted with one or more substituents ("substituted heterocycloalkyl group"). In some embodiments, the heterocycloalkyl group is an unsubstituted 5- to 14-membered heterocycloalkyl group. In some embodiments, the heterocycloalkyl group is a substituted 5- to 14-membered heterocycloalkyl group.

[0071] An "aryl group" or "aromatic ring" or "aromatic ring group" is a monocyclic or polycyclic (e.g., dicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic arrangement) having 6 to 14 ring carbon atoms and 0 heteroatoms provided in an aromatic ring system ("C 6-14 The aryl group is a "C6 aryl group" (e.g., a phenyl group). In some embodiments, the aryl group has six ring carbon atoms ("C6 aryl group"). In some embodiments, the aryl group has ten ring carbon atoms ("C6 aryl group"). 10 The group has an aryl group, for example, naphthyl (e.g., 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has 14 ring carbon atoms ("C"). 14 The aryl group has an "aryl group" (e.g., an anthracenyl group). The "aryl group" further includes a ring system in which the aryl ring defined above is fused to one or more cycloalkyl or heterocyclic groups (where the bond site 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 example of an aryl group is independently and optionally substituted, i.e., unsubstituted ("unsubstituted aryl group") or substituted with one or more substituents ("substituted aryl group"). In some embodiments, the aryl group is unsubstituted C 6-14 It is an aryl group. In some embodiments, the aryl group is a substituted C 6-14 It is an aryl group.

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

[0073] "Halogen" or "halogenated element" refers to fluorine (fluorine, -F), chlorine (chlorine, -Cl), bromine (bromine, -Br), or iodine (iodine, -I).

[0074] "Substituted" or "optionally substituted" means that an atom in the group, such as a hydrogen atom, has been substituted. In some embodiments, alkyl groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups are substituted (e.g., "substituted" alkyl groups, "substituted" cycloalkyl groups, "substituted" heterocycloalkyl groups, "substituted" aryl groups, or "substituted" heteroaryl groups). Generally, the term "substituted," whether preceded by the term "optionally," means that at least one hydrogen atom on the group (e.g., a carbon or nitrogen atom) has been substituted with an acceptable substituent, such as a substituent that forms a stable compound after substitution, such as a compound that does not spontaneously convert (e.g., by rearrangement, cyclization, removal, or other reaction). Unless otherwise specified, a "substituted" group has substituents at one or more substituted positions on the group, and if one or more positions in any designated structure are substituted, the substituents are either the same or different at each position. The term “substituted” is to be desired to include all acceptable substituents of an organic compound, including any substituents described herein that lead to the formation of a stable compound. In this disclosure, any and all combinations thereof are desired to yield a stable compound. For the purposes of this disclosure, for example, a nitrogen heteroatom may have a hydrogen substituent and / or any suitable substituent that satisfies the valence of the heteroatom described herein and leads to the formation of a stable moiety. In some embodiments, the substituent is a carbon atom substituent. In some embodiments, the substituent is a nitrogen atom substituent. In some embodiments, the substituent is an oxygen atom substituent. In some embodiments, the substituent is a sulfur atom substituent.

[0075] "Unsaturated" or "partially unsaturated" refers to a group containing at least one double or triple bond. A "partially unsaturated" ring system is intended to include rings with multiple unsaturated sites, but it is not intended to include aromatic groups (e.g., aryl or heteroaryl groups). Similarly, "saturated" refers to a group containing a double or triple bond, i.e., all single bonds.

[0076] In this specification, when a defined substituent has multiple substitutions, there may be repeated definitions in the literal descriptions of such multiple substitutions. However, such descriptions should be understood as conforming to at least the fundamental laws of general medicinal chemistry. For example, when a substituent has repeated definitions, a person skilled in the art can determine whether such repeated definitions are possible or not according to the common sense of general medicinal chemistry. Substituent R A To give an example of the definition, R A This refers to "saturated or unsaturated C1-C8 alkyl groups" or "halogens, hydroxyl groups, amino groups, or R C The substituent Rc may be a saturated or unsaturated C1-C8 alkyl group substituted with a hydroxyl group, and the substituent Rc may be defined as "hydrogen, halogen, hydroxyl group, amino group," etc. A person skilled in the art can determine whether such a repeating definition is possible based on common sense in general pharmacochemistry and make a reasonable choice.

[0077] As used herein, “pharmaceutically acceptable” means that, for any compound, material, composition, and / or dosage form, it is applicable to contact use with human and animal tissues within the bounds of reliable medical judgment, without excessive toxicity, irritation, allergic reactions, or other problems or complications, and is suitable in terms of a reasonable benefit / risk ratio.

[0078] The term "pharmaceutically acceptable salt" means that a salt of the compound of the present invention is prepared from a compound having a specific substituent discovered in the present invention and a relatively non-toxic acid or base. When the compound of the present invention contains a relatively acidic functional group, a base addition salt can be obtained by contacting a sufficient amount of base with the neutral form of such compound in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia, or magnesium salts or similar salts. When the compound of the present invention contains a relatively basic functional group, an acid addition salt (i.e., a pharmaceutically acceptable salt) can be obtained by contacting a sufficient amount of acid with the neutral form of such compound in a pure solution or a suitable inert solvent. Examples include inorganic acid salts and organic acid salts, where the inorganic acid includes, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, bisulfite, hydroiodic acid, and phosphorous acid, and the organic acid includes, for example, benzoic acid, 2-hydroxyethanesulfonic acid, sulfamic acid, benzenesulfonic acid, phenylacetic acid, mandelic acid, malonic acid, propionic acid, and oxalic acid. This includes 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, and further includes salts of amino acids (e.g., arginine) and salts of 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, thereby allowing them to be converted into either a base or an acid addition salt. The differences between the original compound and its various salt forms lie in several physical properties, such as differences in solubility in polar solvents.

[0079] As used herein, the modifying term "about" means any possible change in a numerical value, such as that resulting from normal testing and processing, unintentional errors in such testing and processing, or differences in the manufacture, origin, or purity of the components used in the present invention. As used herein, "about" + a specific value further includes this specific value, for example, about 10% includes 10%. Whether modified by the term "about," each claim includes an equivalent form of the enumerated number. In one embodiment, the term "about" means an error of no more than 20% of the reported numerical value.

[0080] As used herein, the term “treatment” means the elimination, reduction, or improvement of a disease or condition and / or associated symptoms. Treatment of a disease or condition does not necessarily have to be the complete elimination of the disease, condition, or symptoms. As used herein, the term “treatment,” etc., may include “preventive treatment,” which is the potential to reduce the progression of a disease or condition or the recurrence of a previously controlled disease or condition in subjects who are susceptible to or prone to a disease or condition, or who are at or not at risk of recurrence of a disease or condition. The term “treatment” and its synonyms consider the administration of a therapeutically effective amount of the compound described herein to subjects who require such treatment.

[0081] For drugs or pharmacological activators, the term "effective dose" or "therapeutic effective dose" refers to the amount of drug or agent that is non-toxic but sufficient to achieve the desired effect. For oral dosage forms in this invention, the "effective dose" of one active substance in the composition refers to the dose required to achieve the desired effect when used in combination with another active substance in the composition. Determining the effective dose varies from person to person, depends on the receptor's age and general circumstances, and also depends on the specific active substance. In individual cases, the appropriate effective dose can be determined by those skilled in the art based on standard testing.

[0082] The diseases related to the AHR disorder according to the present invention include, but are not limited to, tumors.

[0083] The following examples are merely illustrative of embodiments of the present invention and do not constitute any limitation to the invention. Any modifications that do not depart from the substance and concept of the invention, as will be understood by those skilled in the art, are within the scope of protection of the invention. Unless otherwise specified, the reagents and instruments used in the following examples are all commercially available.

[0084] Experimental section: Example 1: Production of intermediate III-A according to manufacturing method A JPEG0007894167000032.jpg26116

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

[0086] Step 2) Manufacturing 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 overnight at 70°C. LC / MS showed that 60% intermediate II-A and 40% intermediate III-A were obtained. The mixture was concentrated under reduced pressure until dry to obtain a mixture of II-A and III-A, which was used directly in the next step 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) is dissolved in a methanol / tetrahydrofuran / water (1 / 1 / 1) mixed solvent, lithium hydroxide monohydrate (4 equivalents) is added, the mixture is stirred at room temperature for 5 hours, neutralized with 1N hydrochloric acid to pH 7, concentrated under reduced pressure to a small volume, filtered, the solid is 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] + That is the case.

[0088] Example 2: Production of intermediate III-A according to manufacturing method C JPEG0007894167000033.jpg2694

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

[0090] Step 2) Preparation of Compound III-A To a solution of compound XI-A (245 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 overnight at 70°C. The mixture was concentrated under reduced pressure, water and ethyl acetate were added, and the mixture was stirred for 30 minutes. The mixture was then filtered to obtain product III-A (200 mg, yield 58%). 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] + That is the case.

[0091] Example 3: Preparation of intermediate III-B according to manufacturing method B JPEG0007894167000034.jpg2294

[0092] Step 1) Preparation of Compound XI-B To a solution of glyoxylic acid (8.83 g, 96 mmol) in acetic acid (50 ml) at room temperature, p-chloroacetophenone (9.3 g, 60 mmol) was added, stirred overnight at 120 °C, concentrated under reduced pressure until dry, water was added, stirred for 30 min, filtered, washed, and dried to obtain compound XI-B (9.4 g, yield 75%), LC / MS (ESI): m / z209 [M-1]. + That is the case.

[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 the mixture was stirred overnight at 70°C. After the reaction was complete, the mixture was concentrated under reduced pressure, water and ethyl acetate were added, and the mixture was stirred for 30 minutes. The mixture was then filtered to obtain product III-B (149 mg, 48% yield), and the results were obtained via LC / MS (ESI): m / z 312 [M+1]. + That is the case.

[0094] The following intermediates III-C to III-G can be produced using the similar method B described in Example 3.

[0095] JPEG0007894167000035.jpg106128

[0096] Example 4: Preparation of intermediate III-H according to manufacturing method C JPEG0007894167000036.jpg2886

[0097] Step 1) Preparation of intermediate VIII-H To a 4 ml ethanol solution of urea (66 mg, 1.1 mmol) and compound VII-C (305 mg, 1 mmol), 1 ml of concentrated hydrochloric acid was added, the mixture was stirred overnight at 80°C, cooled to room temperature, filtered, washed with cold ethanol, and dried to obtain 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 hours, concentrated under reduced pressure until dry, ethyl acetate (10 ml) and 20 g of crushed ice were added, stirred for 20 minutes, filtered, and dried to obtain compound IX-H. LC / MS (ESI): m / z 347 [M+1] + .

[0099] Step 3) Preparation of intermediate III-H To a mixed solution 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 sodium carbonate aqueous solution (1 ml), tetrakis(triphenylphosphine)palladium (10 mg) and PdCl2(dppf)2) (10 mg) were added under nitrogen gas protection. The mixture was heated to 100°C and stirred overnight. The organic phase was concentrated under reduced pressure until dry, 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 produced using the similar method C described in Example 4.

[0101] JPEG0007894167000037.jpg180127JPEG0007894167000038.jpg58128

[0102] Example 5: Production of intermediate III-Q according to manufacturing method D JPEG0007894167000039.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 sodium oxalacetate (6.65 g, 31.7 mmol) in water (40 ml), and the mixture was stirred until the solid was completely dissolved. 3-methylamidopyridine hydrochloride (3.85 g, 31.8 mmol) was added, the mixture was heated to 70°C, stirred overnight, cooled to room temperature, pH adjusted to 1 with concentrated hydrochloric acid, filtered, and the solid was washed with ethyl acetate to obtain intermediate XIII-Q (4.42 g, yield 83%). 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 under reduced pressure until dry, 50 ml of EA was added, stirred for 10 minutes, 1 ml of methanol was added, stirred, washed, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain intermediate XIV-Q, which was used directly in the next step without purification.

[0105] Step 3) Preparation of intermediate III-Q A mixed solution of compound XIV-Q (250 mg, 1 mmol) and 3-fluorophenylboronic acid (140 mg, 1 mmol) in dioxane (10 ml) and saturated sodium carbonate aqueous solution (1 ml) was mixed with tetrakis(triphenylphosphine)palladium (15 mg) under nitrogen gas protection. The mixture was heated to 100°C and stirred overnight. The organic phase was concentrated under reduced pressure until dry 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 produced using the similar method D described in Example 5.

[0107] JPEG0007894167000040.jpg109127

[0108] Example 6: Production of intermediates III-W and III-Y according to manufacturing methods E and F Method E JPEG0007894167000041.jpg23114

[0109] Step 1) Preparation of Intermediate XIV-W 2,6-Dichloropyrimidine-4-carboxylic acid (1.93 g, 10 mmol) and 3-trifluorophenylboronic acid (2.27 g, 11 mmol) were mixed in toluene (50 ml) and saturated sodium carbonate aqueous solution (10 ml). Tetrakis(triphenylphosphine)palladium (50 mg) and PdCl2(dppf)2) (50 mg) were added, and the mixture was heated to 110°C under nitrogen gas protection and stirred overnight. The organic phase was concentrated under reduced pressure until dry, and purified by silica gel column chromatography to obtain intermediate XIV-W (2.04 g, 376%) and by-product (XV-Y) 1.4 g. 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) Manufacturing 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 until dry, the pH was adjusted to 6-7 with 2N HCl, filtered, washed with DCM, and the crude was purified by silica gel column chromatography to obtain compound III-W. LC / MS (ESI): m / z 299 [M+1] + ,297[M-1] + .

[0111] Method F JPEG0007894167000042.jpg33106

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

[0113] Step 2) Manufacturing of III-W Compound XV-Y (504 mg, 2 mmol) and 6-(trifluoromethyl)pyridine-3-boric 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 until dry, the pH was adjusted to 6-7 with 2N HCl, filtered, washed with DCM, and purified by silica gel column chromatography to obtain compound III-Y. LC / MS(ESI): m / z 364[M+1] + ,362[M-1] + .

[0114] Example 7: Preparation of Intermediate IV-1 JPEG0007894167000043.jpg2099

[0115] Step 1) Preparation of Intermediate XVI-1 BocNHNH2 (13.2g, 100 mmol) was dissolved in 100 ml of acetone and 50 ml of methanol. Anhydrous magnesium sulfate (12g, 100 mmol) was added, the mixture was stirred overnight at room temperature, filtered to remove magnesium sulfate, and concentrated under reduced pressure until the filtrate was dry. 100 ml of methanol was added to dissolve the filtrate, and sodium borohydride (15.2g, 400 mmol) was added in several batches at room temperature. After the addition was complete, the mixture was stirred for 1 hour at room temperature, concentrated under reduced pressure until dry, 200 ml of distilled water was added, and the mixture was extracted with dichloromethane three times at 100 ml intervals. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure until dry. Purification by silica gel column chromatography (20% ethyl acetate / petroleum ether) yielded XVI-1 (15.1 g, yield 87%). 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 under reduced pressure until dry, and purified by silica gel column chromatography (20%-50% ethyl acetate / petroleum ether) to obtain XVII-1 (1.82 g, yield 78%). 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, an excess of HCl solution in methanol was added, and the mixture was stirred overnight at room temperature. The mixture was then concentrated under reduced pressure at 40°C until dry to obtain 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 JPEG0007894167000044.jpg2198

[0119] Step 1) Preparation of Intermediate XVI-2 In a 500 ml round-bottom flask, BocNHNH2 (30 g, 227 mmol), 300 ml methanol, 20.4 g hydroxyacetone, and anhydrous magnesium sulfate (68 g) were added sequentially. The mixture was stirred at room temperature for 3.5 hours, filtered to remove magnesium sulfate, and the filter cake was washed with anhydrous methanol. Sodium borohydride (15.2 g, 400 mmol) was added to the filtrate in several batches at 0°C. After the addition was complete, the mixture was stirred at room temperature for 1 hour, concentrated under reduced pressure until dry, 200 ml of distilled water was added, and 100 ml was extracted three times with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure until dry. Purification by silica gel column chromatography (20-40% ethyl acetate / petroleum ether) was obtained to obtain XVI-2 (36 g, yield 84%). LC / MS (ESI): m / z 191 [M+1] + .

[0120] Step 2) Preparation of Intermediate XVII-2 In a 1 L round-bottom flask, intermediate XVI-2 (19.0 g, 100 mmol), acetone (17.4 g, 300 mmol), 300 ml methanol, and 1 ml acetic acid were added. 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 until dry, distilled water was added, and the mixture was extracted with ethyl acetate. The mixture was dried, filtered, and concentrated. Purification by silica gel column chromatography (10%-50% ethyl acetate / petroleum ether) yielded a white solid XVII-2 (14.1 g, yield 61%). 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 JPEG0007894167000045.jpg1982

[0123] Step 1) Preparation of Intermediate XVII-3 At 0°C, 13 ml of triethylamine and 17.2 g of Boc2O (78 mmol) were added to a methanol (100 ml) solution of 2-hydroxyethylhydrazine (5 g, 65 mmol). The mixture was stirred at room temperature for 16 hours under nitrogen gas protection, concentrated under reduced pressure until dry, citric acid solution was added, and the solution was extracted with ethyl acetate. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure until dry. Purification by silica gel column chromatography (20-40% ethyl acetate / petroleum ether) yielded XVII-3 (6.8 g, yield 89%). 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, refluxed for 5 hours under nitrogen gas protection, cooled to 0°C, Na2SO4·10H2O was added in several batches, filtered, the filter cake was washed with THF, the filtrate was dried over anhydrous magnesium sulfate, concentrated to obtain crude IV-3, which was used directly in the next step without purification. LC / MS(ESI): m / z 91[M+1] + .

[0125] Example 9: Preparation of Intermediate IV-4 JPEG0007894167000046.jpg1974

[0126] Step 1) Preparation of Intermediate XVII-4 At 0°C, 7.6 g of 2-hydroxyethylhydrazine (100 mmol) was added to a mixed solvent of 100 ml of methanol and 50 ml of acetone. 12 g of anhydrous magnesium sulfate (100 mmol) was added, and the mixture was stirred overnight at room temperature. The mixture was filtered to remove the magnesium sulfate, and the filtrate was concentrated under reduced pressure until dry. 100 ml of dichloromethane was added to dissolve the filtrate, and triethylamine (20.2 g of trichloromethane) was added. At 0°C, 10.7 g of acetic anhydride (105 mmol) was added dropwise, and the mixture was stirred overnight at room temperature. 200 ml of distilled water was added, and the mixture was extracted with dichloromethane. The organic phases were combined and concentrated under reduced pressure until dry. 50 ml of tetrahydrofuran and 5 ml of hydrochloric acid were added, and the mixture was stirred at room temperature for 12 hours. The mixture was concentrated under reduced pressure until dry to obtain XVII-4, which was used directly in the next step without 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 tetrahydrogen (LAH) (1.5 g, 44.8 mmol) was added, refluxed under nitrogen gas protection for 4 hours, cooled to below 0°C, and Na2SO4·10H2O was added in several batches to quench the reaction. The mixture was filtered, the filter cake was washed with THF, the filtrate was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure until dry to obtain IV-4. LC / MS(ESI): m / z 10⁵[M+1] + .

[0128] Example 10: Preparation of Intermediate IV-5 JPEG0007894167000047.jpg2399

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

[0130] Step 2) Preparation of Intermediate XVIII-5 In a 2 L round-bottom flask, 380 ml of ethanol, NaBH4 (7.2 g, 189 mmol), and LiCl (7.9 g, 188 mmol) were added sequentially. At room temperature, 380 ml of THF solution of XVII-5 (18 g, 69 mmol) was added dropwise, the mixture was stirred for 6 hours, and the solution was concentrated under reduced pressure to remove a large amount of solvent. Water was added, and the mixture was extracted with ethyl acetate. The combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure until dry to obtain XVIII-5 (12.9 g, yield 86%). LC / MS (ESI): m / z 219 [M+1] + .

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

[0132] Example 11: Preparation of Intermediate IV-6 JPEG0007894167000048.jpg1768

[0133] Step 1) Preparation of intermediate XIX-6 To a 15 ml THF solution of 3-methylmorpholine (1.0 g, 10 mmol), tert-butyl nitrite (1.1 g, 11 mmol) was added, refluxed for 12 hours, and concentrated under reduced pressure until dry to obtain XIX-6. This solution was used directly in the next step without 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 batches at 0°C. The mixture was stirred overnight at room temperature, and under cooling, Na2SO4·10H2O was added in several batches. The mixture was filtered, the filter cake was washed with THF, the filtrate was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain compound IV-6 (72% yield). LC / MS (ESI): m / z 117 [M+1] + .

[0135] The following hydrazines can be produced using the method of Example 11.

[0136] JPEG0007894167000049.jpg158127

[0137] Example 12: Preparation of 6-(4-trifluoromethylphenyl)-N-(1-hydroxypropyl-2-yl)-N-isopropyl-2-(pyridine-3-yl)pyrimidine-4-hydrazide (Compound 1) JPEG0007894167000050.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 (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. The mixture was filtered, concentrated under reduced pressure until dry, and purified by silica gel chromatography (PE / EA, 1:1) to obtain compound 1 (23 mg, 50% yield). 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 listed in Table 1 below can be produced using a method similar to that of Example 1.

[0140] Table 1 JPEG0007894167000051.jpg175127JPEG0007894167000052.jpg186127JPEG0007894167000053.jpg181127JPEG0007894167000054.jpg177127 JPEG0007894167000055.jpg185127JPEG0007894167000056.jpg172127JPEG0007894167000057.jpg173127JPEG0007894167000058.jpg151127

[0141] Example 13: Preparation of Compound 66 JPEG0007894167000059.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. Once the addition was complete, the mixture was stirred at room temperature and allowed to react overnight. The mixture was washed three times, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure until dry, and purified by silica gel column chromatography (PE / EA, 1:1) to obtain compound 66 in 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 JPEG0007894167000060.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, with a yield of 41% and LC / MS(ESI): m / z 480[M+1]. + That is the case. 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 JPEG0007894167000061.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, with a yield of 84% and LC / MS(ESI): m / z 507[M+1]. + That is the case.

[0147] Effect Example 1: Antagonistic effect test of research compound and AHR in human-derived cell lines The test used a human liver cancer HepG2 cell line that endogenously expresses the AHR protein (provided by the Chinese Academy of Sciences Stem Cell Bank). CYP1A1 gene expression is regulated by AHR activity, and after AHR activation, it can bind to a sequence called a xenobiotic response element (XRE) on the CYP1A1 enhancer, triggering CYP1A1 gene expression. To quantitatively measure the effect of compounds on AHR activity, a regulatory sequence 1200 bp (-1143 to +57) upstream of the CYP1A1 gene promoter was synthesized and then inserted into a plasmid vector containing firefly luciferase. The plasmid was then linearized by single-enzyme cleavage and transfected into HepG2 cells via lipofectamine (Lipofectamine 3000). The transfected HepG2 cells were then screened with puromycin to obtain cell lines that stably expressed the compound. To measure the antagonistic effect of compounds on AHR, we induced firefly luciferase expression using AHR agonists (e.g., L-Kynurenine, Kynurenic acid, indirubin, TCDD, ITE (2-(1H-Indol-3-ylcarbonyl)-4-thiazolecarboxylic acid methyl ester)), treated cells with different concentrations of the compound, and measured the inhibition of luciferase expression by the compound.

[0148] Stable transfected HepG2 cells were subcultured in Minimum Eagle's medium (MEM) at 37°C under 5% carbon dioxide. The 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 U / mL puromycin. Before testing, HepG2 cells were subcultured to 5–8 × 10⁶ cells. 4Cells were seeded at a density of / well into 96-well plates and grown for 24–48 hours to reach ~90% confluence before drug treatment (the medium did not contain puromycin). Before drug treatment, 2× solutions of different concentrations of the AHR agonist were first prepared in the same medium, and half of the cell medium in the 96-well plates was replaced with the 2× compound solutions. The negative control group consisted of an AHR agonist solution containing only DMSO at the corresponding concentration, and the positive control group consisted of CH223191 (commercial product) at the corresponding concentration. Each compound (including positive and negative controls) was subjected to independent repeated testing in both groups. HepG2 cells were isolated 24 hours after compound treatment using a Promega Steady-Glo luciferase detection system, and the luciferase signal was measured using a Tecan InfiniteM1000 Pro microplate reader.

[0149] In data processing, each compound is repeatedly tested in separate groups, with the well signal at a compound concentration of 0 set to 100%, and the cell signal of the untreated agonist set to 0. The percentage of AHR activity inhibition at different compound concentrations is then calculated sequentially, and the mean of the repeated data from the two groups is nonlinearly fitted. JPEG0007894167000062.jpg1239 IC corresponding to compound 50 The following is calculated, where y is the inhibition percentage 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] Each compound IC 50 This is as shown in Table 2, where A is IC 50 This represents ≤500nM, and B is 500nM <IC 50 This represents ≤1.0mM, and C is 1mM. <IC 50This represents ≤5.0mM, and D is IC. 50 This represents >5.0 mM.

[0152] Table 2 ICs of each compound 50 JPEG0007894167000063.jpg133128

[0153] As can be seen from Table 2, each of the above compounds can bind to AHR and inhibit their functions and signaling pathways controlled by AHR, and can further affect the growth and proliferation of cancer cells and the invasiveness of tumor cells. Therefore, the compounds shown in 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, their respective optical isomers, or pharmaceutically acceptable salts, Here, A ２ CR Ａ Or N, A １ A ３ Each of them is independently CR Ａ And, The substituent R Ａ is each independently hydrogen; deuterium; halogen; cyano group; hydroxy group; amino group; saturated or unsaturated C １ to C ８ alkyl group; C ３ to C ８ cycloalkyl group; saturated or unsaturated C Ｃ substituted with halogen, hydroxy group, amino group or R １ to C s ８ alkyl group; saturated or unsaturated C Ｃ substituted with halogen, hydroxy group, amino group or R ３ to C ８ cycloalkyl group; saturated or unsaturated C １ to C ８ alkoxy group; C ３ to C ８ cycloalkoxy group; saturated or unsaturated C Ｃ substituted with halogen, hydroxy group, amino group or R １ to C ８ alkoxy group; saturated or unsaturated C Ｃ substituted with halogen, hydroxy group, amino group or R ３ to C ８ cycloalkoxy group; -S(O) ｎ Rc; saturated or unsaturated substituted or unsubstituted C １ to C ８ acyl group; NR Ｃ R Ｄ selected from Here, substituent R Ｃ and R Ｄ These are, independently, hydrogen; halogen; cyano group; hydroxyl group; amino group; and saturated or unsaturated C. １ ~C ６ Alkyl alkyl group; C ３ ~C ６ Cycloalkyl groups; halogens, hydroxyl 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 replaced by ３ ~C ６ Cycloalkyl groups; saturated or unsaturated C １ ~C ６ Alkoxy group; C ３ ~C ６ Cycloalkoxy group; halogen, hydroxyl group, -S(O) ｎ R Ｅ Or NR Ｆ R Ｇ Saturated or unsaturated C substituted with １ ~C ６ Alkoxy groups; halogens, hydroxyl groups, -S(O) ｎ R Ｅ Or NR Ｆ R Ｇ C replaced by ３ ~C ６ Selected from cycloalkoxy groups, Here, R Ｅ , R Ｆ and R Ｇ These are, independently, hydrogen; deuterium; halogen; cyano group; hydroxyl group; amino group; and saturated or unsaturated C. １ ~C ６ Alkyl alkyl group; C ３ ~C ６ Cycloalkyl groups; saturated or unsaturated C atoms substituted with halogens, hydroxyl groups, or amino groups. １ ~C ６ Alkyl alkyl groups; C substituted with halogen, hydroxyl, or amino groups ３ ~C ６ Cycloalkyl groups; saturated or unsaturated C １ ~C ６ Alkoxy group; C ３ ~C ６ Cycloalkoxy group; saturated or unsaturated carbon substituted with halogen, hydroxyl, or amino group. １ ~C ６ Alkoxy group; C substituted with halogen, hydroxyl, or amino group ３ ~C ６ Selected from cycloalkoxy groups, The group is a phenyl group, a 3-pyridyl group, a thienyl group, an isothiazolyl group, or a pyrazolyl group. R １ and R ２ each independently represents hydrogen; a saturated or unsaturated, substituted or unsubstituted C １ to C ８ alkyl group; a saturated or unsaturated, substituted or unsubstituted C ３ to C ８ cycloalkyl group; -OC(=O)C １－８ alkyl group; -OC(=O)C ３ to C ８ cycloalkyl group; -C(=O)OC １－８ alkyl group; -C(=O)OC ３ to C ８ cycloalkyl group; -S(O) ｎ Rc; a saturated or unsaturated, substituted or unsubstituted C １ to C ８ sulfonyl group; a saturated or unsaturated, substituted or unsubstituted C １ to C ８ acyl group; C ６ to C １４ aryl group; a 4- to 14-membered heterocycloalkyl group or heteroaryl group containing 1 to 3 heteroatoms selected from N, O and S, Here, "substitution" refers to selective substitution of hydroxyl groups; halogens; cyano groups; sulfonyl groups; amino groups; and -S(O). ｎ Rc; NR 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 carbon ３ ~C ８ Cycloalkoxy group; -OC(=O)C １－８ Alkyl group; -OC(=O)C ３ ~C ８ Cycloalkyl group; -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 carbon １ ~C ８ Acyl group; saturated or unsaturated carbon １ ~C ８ Alkoxycarbonyl group; C ６ ~C １４ The aryl group contains 1 to 4 substituents selected from a 4 to 14-membered heterocycloalkyl group or heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S. Or, R １ and R ２ This forms a substituted or unsubstituted 4-14 member heterocycloalkyl group containing 1-3 heteroatoms selected from N, O, and S together with the N atom that binds them, or a substituted or unsubstituted 5-14 member heteroaryl group containing 1-3 heteroatoms selected from N, O, and S. Here, "substitution" refers to the selective substitution of deuterium; hydroxyl group; halogen; cyano group; sulfonyl group; amino group; -S(O) ｎ Rc; NR Ｃ R Ｄ ; C １ ~C ８ Alkyl 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 group; -C(=O)OC １－８ Alkyl group; -C(=O)OC ３ ~C ８ Cycloalkyl groups; halogens, hydroxyl groups, amino groups or R Ｈ C replaced by １ ~C ８ Alkyl alkyl group; C ３ ~C ８ Cycloalkyl group; C １ ~C ８ Alkoxy group; C ３ ~C ８ It contains 1 to 4 substituents selected from cycloalkoxy groups, Here, R Ｈ C is a hydrogen; deuterium; halogen; cyano group; hydroxyl group; amino group; saturated or unsaturated C １ ~C ６ Alkyl alkyl group; C ３ ~C ６ Cycloalkyl group; -S(O) ｎ Rc; NR Ｃ R Ｄ ; saturated or unsaturated C substituted with deuterium, halogen, hydroxyl group or amino group １ ~C ６ Alkyl group; C substituted with 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 Cycloalkoxy group; saturated or unsaturated carbon substituted with deuterium, halogen, hydroxyl, or amino group. １ ~C ６ Alkoxy group; C substituted with deuterium, halogen, hydroxyl group or amino group ３ ~C ６ Selected from cycloalkoxy groups, R ３ is hydrogen; halogen; hydroxyl group; -S(O) ｎ Rc; NR Ｃ R Ｄ ; saturated or unsaturated C １ ~C ８ Alkyl alkyl group; C ３ ~C ８ Cycloalkyl group; C １ ~C ８ Alkoxy group; C ３ ~C ８ Cycloalkoxy group; halogen, hydroxyl group, amino group or R Ｈ Saturated or unsaturated C substituted with １ ~C ８ Alkyl alkyl group; C ３ ~C ８ Cycloalkyl group; C １ ~C ８ Alkoxy group; C ３ ~C ８ It is a cycloalkoxy group, Here, substituent R Ｈ C is a hydrogen; deuterium; halogen; cyano group; hydroxyl group; amino group; saturated or unsaturated C １ ~C ６ Alkyl alkyl group; C ３ ~C ６ Cycloalkyl groups; saturated or unsaturated C atoms substituted with halogens, hydroxyl groups, or amino groups. １ ~C ６ Alkyl alkyl groups; C substituted with halogen, hydroxyl, or amino groups ３ ~C ６ Cycloalkyl groups; saturated or unsaturated C １ ~C ６ Alkoxy group; C ３ ~C ６ Cycloalkoxy group; saturated or unsaturated carbon substituted with halogen, hydroxyl, or amino group. １ ~C ６ Alkoxy group; C substituted with halogen, hydroxyl, or amino group ３ ~C ６ Selected from cycloalkoxy groups, R ４ It is hydrogen or deuterium, n is an integer of 0, 1, or 2, and the compound is a substituted pyrimidine hydrazide represented by formula I, their respective optical isomers, or a pharmaceutically acceptable salt.

2. A １ and A ３ CR Ａ A ２ is N, and the substituent R Ａ These are, independently, hydrogen; halogen; cyano group; hydroxyl group; amino group; and saturated or unsaturated C. １ ~C ３ Alkyl alkyl group; C ３ ~C ６ Cycloalkyl groups; halogens, hydroxyl groups, amino groups or R Ｃ Saturated or unsaturated C substituted with １ ~C ３ Alkyl alkyl group; halogen, hydroxyl group, amino group or R Ｃ C replaced by ３ ~C ６ Cycloalkyl groups; saturated or unsaturated C １ ~C ３ Alkoxy group; C ３ ~C ６ Cycloalkoxy group; halogen, hydroxyl group, amino group or R Ｃ Saturated or unsaturated C substituted with １ ~C ３ Alkoxy group; halogen, hydroxyl group, amino group or R Ｃ C replaced by ３ ~C ６ Cycloalkoxy group; -S(O) ｎ Rc; saturated, unsaturated, substituted, or unsubstituted C １ ~C ３ Acyl group; NR Ｃ R Ｄ A substituted pyrimidine hydrazide compound represented by formula I as described in claim 1, an optical isomer thereof, or a pharmaceutically acceptable salt, selected from the above.

3. A １ and A ３ CR Ａ A ２ is N, and the substituent R Ａ The compound represented by formula I as described in claim 1, characterized in that is hydrogen, is an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

4. substituent R Ｃ and R Ｄ These are, independently, hydrogen; halogen; cyano group; hydroxyl group; amino group; and saturated or unsaturated C. １ ~C ３ Alkyl alkyl group; C ３ ~C ６ Cycloalkyl groups; halogens, hydroxyl 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 replaced by ３ ~C ６ Cycloalkyl groups; saturated or unsaturated C １ ~C ３ Alkoxy group; C ３ ~C ６ Cycloalkoxy group; halogen, hydroxyl group, -S(O) ｎ R Ｅ Or NR Ｆ R Ｇ Saturated or unsaturated C substituted with １ ~C ３ Alkoxy groups; halogens, hydroxyl groups, -S(O) ｎ R Ｅ Or NR Ｆ R Ｇ C replaced by ３ ~C ６ Selected from cycloalkoxy groups, R Ｅ , R Ｆ and R Ｇ These are, independently, hydrogen; deuterium; halogen; cyano group; hydroxyl group; amino group; and saturated or unsaturated C. １ ~C ３ Alkyl alkyl group; C ３ ~C ６ Cycloalkyl groups; saturated or unsaturated C atoms substituted with halogens, hydroxyl groups, or amino groups. １ ~C ３ Alkyl alkyl groups; C substituted with halogen, hydroxyl, or amino groups ３ ~C ６ Cycloalkyl groups; saturated or unsaturated C １ ~C ３ Alkoxy group; C ３ ~C ６ Cycloalkoxy group; saturated or unsaturated carbon substituted with halogen, hydroxyl, or amino group. １ ~C ３ Alkoxy group; C substituted with halogen, hydroxyl, or amino group ３ ~C ６ A substituted pyrimidine hydrazide compound represented by formula I according to claim 1, characterized by being selected from a cycloalkoxy group, their respective optical isomers, or pharmaceutically acceptable salts.

5. R １ and R ２ These are, independently, hydrogen; saturated or unsaturated substituted or unsubstituted C. １ ~C ６ Alkyl alkyl groups; saturated or unsaturated substituted or unsubstituted C ３ ~C ６ Cycloalkyl group; -OC(=O)C １－６ Alkyl group; -OC(=O)C ３ ~C ６ Cycloalkyl group; -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 group; saturated or unsaturated substituted or unsubstituted C ３ ~C ６ Cycloalkoxy group; -S(O) ｎ Rc; NR 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 Aryl group; a 5-10 membered heteroaryl group containing 1-3 heteroatoms selected from N, O and S, Here, "substitution" refers to selective substitution of hydroxyl groups; halogens; cyano groups; sulfonyl groups; amino groups; and -S(O). ｎ Rc; NR Ｃ R Ｄ ; saturated or unsaturated C １ ~C ６ Alkyl group; saturated or unsaturated C ３ ~C ６ Cycloalkyl group; -OC(=O)C １－６ Alkyl group; -OC(=O)C ３ ~C ６ Cycloalkyl group; -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 carbon １ ~C ６ Acyl group; C ６ ~C １０ An aryl group; containing 1 to 4 substituents selected from a 6-10 membered heterocycloalkyl group or heteroaryl group containing 1 to 3 heteroatoms selected from N, O and S, Or, R １ and R ２ This forms a substituted or unsubstituted 4-10 membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, O, and S together with a bonding N atom, or a substituted or unsubstituted 5-10 membered heteroaryl group containing 1-3 heteroatoms selected from N, O, and S, where "substituted" selectively refers to a hydroxyl group; halogen; cyano group; sulfonyl group; amino group; -S(O) ｎ Rc; NR Ｃ R Ｄ ; C １ ~C ６ Alkyl 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 group; -C(=O)OC １－６ Alkyl group; -C(=O)OC ３ ~C ６ Cycloalkyl groups; halogens, hydroxyl groups, amino groups or R Ｅ C replaced by １ ~C ６ Alkyl alkyl group; C ３ ~C ６ Cycloalkyl group; C １ ~C ６ Alkoxy group; C ３ ~C ６ It contains one to four substituents selected from cycloalkoxy groups; where R Ｅ C is a hydrogen; halogen; cyano group; hydroxyl group; amino group; saturated or unsaturated C １ ~C ６ Alkyl alkyl group; C ３ ~C ６ Cycloalkyl group; -S(O) ｎ Rc; NR Ｃ R Ｄ ; saturated or unsaturated C substituted with deuterium, halogen, hydroxyl group or amino group １ ~C ６ Alkyl group; C substituted with 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 Cycloalkoxy group; saturated or unsaturated carbon substituted with deuterium, halogen, hydroxyl, or amino group. １ ~C ６ Alkoxy group; C substituted with deuterium, halogen, hydroxyl group or amino group ３ ~C ６ A substituted pyrimidine hydrazide compound represented by formula I according to claim 1, characterized by being selected from a cycloalkoxy group, their respective optical isomers, or pharmaceutically acceptable salts.

6. R ３ is hydrogen; halogen; -S(O) ｎ Rc; NR Ｃ R Ｄ ; saturated or unsaturated C １ ~C ６ Alkyl alkyl group; C ３ ~C ６ Cycloalkyl group; C １ ~C ６ Alkoxy group; C ３ ~C ６ Cycloalkoxy group; halogen, hydroxyl group, amino group or R Ｈ Saturated or unsaturated C substituted with １ ~C ６ Alkyl alkyl group; C ３ ~C ６ Cycloalkyl group; C １ ~C ６ Alkoxy group; C ３ ~C ６ It is a cycloalkoxy group, where the substituent R Ｈ C is a hydrogen; halogen; cyano group; hydroxyl group; amino group; saturated or unsaturated C １ ~C ３ Alkyl alkyl group; C ３ ~C ６ Cycloalkyl groups; saturated or unsaturated C atoms substituted with halogens, hydroxyl groups, or amino groups. １ ~C ３ Alkyl alkyl groups; C substituted with halogen, hydroxyl, or amino groups ３ ~C ６ Cycloalkyl groups; saturated or unsaturated C １ ~C ３ Alkoxy group; C ３ ~C ６ Cycloalkoxy group; saturated or unsaturated carbon substituted with halogen, hydroxyl, or amino group. １ ~C ３ Alkoxy group; C substituted with halogen, hydroxyl, or amino group ３ ~C ６ A substituted pyrimidine hydrazide compound represented by formula I according to claim 1, characterized by being selected from a cycloalkoxy group, their respective optical isomers, or pharmaceutically acceptable salts.

7. R １ and R ２ These are, independently, hydrogen; saturated or unsaturated substituted or unsubstituted C. １ ~C ３ Alkyl alkyl groups; saturated or unsaturated substituted or unsubstituted C ３ ~C ６ Cycloalkyl group; -OC(=O)C １－３ Alkyl group; -OC(=O)C ３ ~C ６ Cycloalkyl group; -C(=O)OC １－３ Alkyl group; -C(=O)OC ３ ~C ６ Cycloalkyl group; -S(O) ｎ Rc; NR 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 An aryl group is a 6-8 membered heteroaryl group containing 1-3 heteroatoms selected from N, O, and S, where "substitution" selectively refers to a hydroxyl group, halogen, cyano group, sulfonyl group, amino group, or -S(O). ｎ Rc; NR Ｃ R Ｄ ; -OC(=O)C １－３ Alkyl group; -OC(=O)C ３ ~C ６ Cycloalkyl group; -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 carbon １ ~C ３ Acyl group; C ６ ~C １０ The aryl group contains 1 to 4 substituents selected from a 6 to 8-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O and S. Or, R １ and R ２ This forms a substituted or unsubstituted 5-10 membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, O, and S together with a bonding N atom, or a substituted or unsubstituted 5-10 membered heteroaryl group containing 1-3 heteroatoms selected from N, O, and S, where "substituted" selectively refers to a hydroxyl group; halogen; cyano group; sulfonyl group; amino group; -S(O) ｎ Rc; NR Ｃ R Ｄ ; C １ ~C ３ Alkyl 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 group; -C(=O)OC １－３ Alkyl group; -C(=O)OC ３ ~C ６ Cycloalkyl groups; halogens, hydroxyl groups, amino groups or R Ｈ C replaced by １ ~C ３ Alkyl alkyl group; C ３ ~C ６ Cycloalkyl group; C １ ~C ３ Alkoxy group; C ３ ~C ６ It contains one to four substituents selected from cycloalkoxy groups; where R Ｈ C is a hydrogen; halogen; cyano group; hydroxyl group; amino group; saturated or unsaturated C １ ~C ３ Alkyl alkyl group; C ３ ~C ６ Cycloalkyl group; -S(O) ｎ Rc; NR Ｃ R Ｄ ; saturated or unsaturated C substituted with halogen, hydroxyl, or amino groups １ ~C ３ Alkyl alkyl groups; C substituted with halogen, hydroxyl, or amino groups ３ ~C ６ Cycloalkyl groups; saturated or unsaturated C １ ~C ３ Alkoxy group; C ３ ~C ６ Cycloalkoxy groups; halogens; saturated or unsaturated carbons substituted with hydroxyl or amino groups. １ ~C ３ Alkoxy group; C substituted with halogen, hydroxyl, or amino group ３ ~C ６ A substituted pyrimidine hydrazide compound represented by formula I according to claim 1, characterized by being selected from a cycloalkoxy group, their respective optical isomers, or pharmaceutically acceptable salts.

8. R ３ is hydrogen; halogen; -S(O) ｎ Rc; NR Ｃ R Ｄ ; saturated or unsaturated C １ ~C ３ Alkyl alkyl group; C ３ ~C ６ Cycloalkyl group; C １ ~C ３ Alkoxy group; C ３ ~C ６ Cycloalkoxy group; halogen, hydroxyl group, amino group or R Ｈ Saturated or unsaturated C substituted with １ ~C ３ Alkyl alkyl group; C ３ ~C ６ Cycloalkyl group; C １ ~C ３ Alkoxy group; C ３ ~C ６ It is a cycloalkoxy group, where the substituent R Ｈ C is a hydrogen; halogen; cyano group; hydroxyl group; amino group; saturated or unsaturated C １ ~C ３ Alkyl alkyl group; C ３ ~C ６ Cycloalkyl groups; saturated or unsaturated C atoms substituted with halogens, hydroxyl groups, or amino groups. １ ~C ３ Alkyl alkyl groups; C substituted with halogen, hydroxyl, or amino groups ３ ~C ６ Cycloalkyl groups; saturated or unsaturated C １ ~C ３ Alkoxy group; C ３ ~C ６ Cycloalkoxy group; saturated or unsaturated carbon substituted with halogen, hydroxyl, or amino group. １ ~C ３ Alkoxy group; C substituted with halogen, hydroxyl, or amino group ３ ~C ６ A substituted pyrimidine hydrazide compound represented by formula I according to claim 1, characterized by being selected from a cycloalkoxy group, their respective optical isomers, or pharmaceutically acceptable salts.

9. R １ and R ２ The structure that these form together with the N atoms that bind them is, A substituted pyrimidine hydrazide compound represented by formula I as described in claim 1, selected from the following groups, their respective optical isomers, or pharmaceutically acceptable salts.

10. A substituted pyrimidine hydrazide compound, characterized by being selected from the following compounds, their respective optical isomers, or pharmaceutically acceptable salts.

11. A method for producing a substituted pyrimidine hydrazide compound represented by formula I according to any one of claims 1 to 9, their respective optical isomers, or pharmaceutically acceptable salts, wherein the method is as shown in the following reaction formula 1, A carboxylic acid compound represented by formula III and a hydrazine compound represented by formula IV are condensed to obtain a substituted pyrimidine hydrazide compound shown in formula I. Here, the carboxylic acid compound represented by formula III is prepared according to one of the following methods: Method A 1) A methylcarbonyl compound represented by formula V is reacted with dimethyl oxalate to obtain a compound represented by formula VI. 2) A compound represented by formula VI and a hydrazine compound represented by formula X are cyclized to obtain a pyrimidine compound represented by formula VII. 3) Hydrolyze the pyrimidine compound represented by formula VII to obtain the carboxylic acid compound represented by formula III. Method B 1) Methyl carbonyl compound represented by formula V and monoalkyl oxalate By reacting with, a compound represented by formula VIII is obtained, where the substituent R is a methyl group, an ethyl group, an isopropyl group, a terbutyl group, etc. 2) A compound represented by formula VIII and a hydrazine compound represented by formula X are cyclized to obtain a pyrimidine compound represented by formula IX. 3) Hydrolyze the pyrimidine compound represented by formula IX to remove substituent R and obtain the carboxylic acid compound represented by formula III. Method C 1) A methylcarbonyl compound represented by formula V is cyclized with urea to obtain a compound represented by formula XI. 2) A compound represented by formula XI is reacted with a chlorinating agent, such as phosphorus oxychloride, phosphorus pentachloride, or thionyl chloride, to obtain a chlorinated compound represented by formula XII. 3) Chlorinated compounds represented by formula XII and boric acid compounds or react with the applicable borate ester or trialkyltin compound to produce a compound represented by formula XIII, 4) Remove the ethyl group from the compound represented by formula XIII to form a carboxylic acid group, and obtain the compound represented by formula III. Method D 1) Carbonate compounds A hydrazine compound represented by formula X is subjected to a cyclization reaction to obtain a compound represented by formula XIV. 2) A compound represented by formula XIV is reacted with a chlorinating agent, such as phosphorus oxychloride, phosphorus pentachloride, or thionyl chloride, to obtain a chlorinated compound represented by formula XV. 3) Chlorinated compounds represented by formula XV and boric acid compounds Alternatively, by reacting with the appropriate borate ester or trialkyltin compound, a compound represented by formula III is obtained. Method E １） Alternatively, the compound is reacted with the appropriate borate ester or trialkyltin compound, and after separation and purification, the compound is obtained. Obtained, 2) Compound Alternatively, by reacting with a trialkyltin compound, a compound represented by formula III is obtained. Method F １） Alternatively, react the appropriate borate ester or trialkyltin compound, separate and purify it to obtain the compound represented by formula XV. 2) Further the compound represented by formula XV is a boric acid compound Alternatively, by reacting it with the appropriate borate ester or trialkyltin compound, a compound represented by formula III is obtained. The hydrazine compound represented by formula IV is synthesized according to one of the following synthesis methods. Method G 1) BocNHNH ２ (tert-butoxycarbonylhydrazine) is dissolved in an alcohol-based 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 and the reaction is carried out, then sodium borohydride is added and hydrogenation reduction is performed, followed by purification and separation to obtain the compound. Obtained, 2) Compound Dissolve it in an amine solvent such as N,N-diisopropylethylamine (DIEA), and then dissolve a ketone compound (R ２ (C=O)R ２ ), aldehyde compounds (R ２ (C=O)H) or the corresponding R ２ Add the epoxy compound substituted with and react to form the compound Obtained, 3) Compound Dissolve it in an alcoholic solvent such as methanol or ethanol, and then add a solution of excess HCl in methanol to obtain the hydrochloride salt of the compound represented by formula IV. Method H 1) Substituted amino compounds (HNR １ R ２ Dissolve the ) in a solvent, add a nitrosating reagent, the nitrosating reagent is selected from tert-butyl nitrite and isobutyl nitrite, heat under reflux, and concentrate under reduced pressure to obtain an intermediate nitrosamino compound (R １ N(R) ２ ) - N = O) 2) Nitrosoamino compounds (R １ N(R) ２ Dissolve )-N=O) in a solvent, add a hydrogenation reagent such as lithium aluminum hydride, and carry out the hydrogenation reaction to obtain the compound represented by formula IV. Here, substituent A １ ~A ７ , R １ ~R ４ A method wherein the definition of is the same as that described in claim 1.

12. A pharmaceutical composition comprising a therapeutically effective amount of a substituted pyrimidine hydrazide compound represented by formula I as described in any one of claims 1 to 9, each of their optical isomers, or a pharmaceutically acceptable salt, and a pharmaceutically acceptable excipient or carrier.

13. Use of a substituted pyrimidine hydrazide compound represented by formula I according to any one of claims 1 to 9, their respective optical isomers, or pharmaceutically acceptable salts in the manufacture of an AHR disorder inhibitor.

14. Use of a substituted pyrimidine hydrazide compound represented by formula I according to any one of claims 1 to 9, each of their optical isomers, or pharmaceutically acceptable salts in the manufacture of a drug for treating tumors associated with AHR disorder.

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