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CN117624135A - 2-nitrogen substituted pyrimidine compound, and preparation method and application thereof - Google Patents

2-nitrogen substituted pyrimidine compound, and preparation method and application thereof Download PDF

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Publication number
CN117624135A
CN117624135A CN202211003425.9A CN202211003425A CN117624135A CN 117624135 A CN117624135 A CN 117624135A CN 202211003425 A CN202211003425 A CN 202211003425A CN 117624135 A CN117624135 A CN 117624135A
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saturated
unsaturated
cycloalkyl
alkyl
substituted
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张所明
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Deming Yaotai Biotechnology Shenzhen Co ltd
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Deming Yaotai Biotechnology Shenzhen Co ltd
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Priority to CN202211003425.9A priority Critical patent/CN117624135A/en
Priority to PCT/CN2023/124994 priority patent/WO2024037668A1/en
Publication of CN117624135A publication Critical patent/CN117624135A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/04—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

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Abstract

The invention discloses a 2-nitrogen substituted pyrimidine compound represented by a formula I, optical isomer, deuteride, prodrug or pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the 2-nitrogen substituted pyrimidine compound and application thereof as a pharmaceutical compositionUse of an AHR inhibitor. According to the invention, the 2-nitrogen substituted pyrimidine compound represented by the formula I can inhibit AHR and functions and signal paths controlled by AHR, and further can influence the growth and proliferation of cancer cells and the invasiveness of tumor cells, so that the 2-nitrogen substituted pyrimidine compound represented by the formula I can be used for inhibiting the growth of cancer cells and inhibiting the metastasis and invasion of tumor cells.

Description

2-nitrogen substituted pyrimidine compound, and preparation method and application thereof
Technical Field
The invention belongs to the technical field of biological pharmacy, and particularly relates to a 2-nitrogen substituted pyrimidine compound and pharmaceutically acceptable salt thereof, and a preparation method and application thereof.
Background
The aromatic hydrocarbon receptor (AHR, aryl hydrocarbon receptor) is one of the subfamily bHLH-PAS (bHLH-PER-ARNT-SIM) members of the basic helix-loop-helix { basic helix-loop-helix (bHLH-PAS) } superfamily, which is the only receptor in the bHLH-PAS family that can be activated by a ligand [ nat. Rev. Cancer,2014,14 (12), 801; nat.Rev.cancer,2013,13 (12), 827]. AHR present in the cytoplasm is able to sense the stimulation of dioxins (TCDD) by aromatic heterogenies (xenobiotics) in the external environment, such as 2,3,7, 8-tetrachlorodibenzo, and then migrate into the nucleus to form a heterodimer with the aromatic acceptor nuclear transporter (ARNT), which in turn interacts with XRE (xenobiotic response element) of the AHR corresponding gene, thereby regulating their transcription; AHR can also activate XRE-independent protein-protein interaction pathways.
AHR is the most well known enzyme that binds environmental toxins and induces metabolic machinery, such as cytochrome CYP450 enzymes (e.g., CYP1A1, CYP1A2, and CYP1B 1), which eliminate environmental toxins (Reyes et al, science,1992,256 (5060), 1193-5; murray et al, nat Rev Cancer,2015,14 (12), 801-14). Activation of AHR by environmental toxins has demonstrated a role for AHR in numerous cellular processes, such as embryogenesis, tumorigenesis, and inflammation. AHR is expressed in many cells of the immune system, including dendritic cells, macrophages, T-cells and NK cells, and plays an important role in immunomodulation (Nguyen et al, front immunol.2014,5,511). Classical exogenous AHR ligand TCDD, etc. induces deep immunosuppression, promotes carcinogenesis and induces tumor growth (Oncogene, 2009,28 (28), 2593-2605, oncogene,2009,28 (41), 3642-51,Trends Immunol,2009,30,447-454).
AHR regulates many key innate and adaptive immune responses through XRE-dependent or independent activities. In these reactions, AHR agonists promote the production of IL-17 by Th17 cells (T-helper cells) and Treg cells (regulatory T-cells). Activation of AHR further induces lateral differentiation of Th17 cells into Treg cells, enhancing the suppressive activity of Treg. Studies have demonstrated that AHR activation can produce inhibition of macrophage-mediated innate inflammatory responses (e.g., reduced LPS-induced IL-1b, IL-6, IL-12 and TNFa expression), and inhibition of dendritic cells (activation of dendritic cells and promotion of IL-10 expression) (Clin Exp Immunol,2014,177 (2), 521-30;J Immunol,2010,185 (), 3190-8;Lab Invest,2014,94 (5), 528-35; PNAS,2010,107 (46), 19961-6).
In order to establish an effective anti-tumor immune response, antigen presenting cells (antigen presenting cells, APCs) need to be processed, presented, followed by activation of helper cd4+ T-cells (Th) and cytotoxic cd8+ T-cells (Tc) which act synergistically to lyse tumor cells. Tumor cells develop immunity that several mechanisms escape Th and Tc cytolytic regulation. One of these is the release of high concentrations of kynurenine (kynurenine) and other potential AHR ligands in the tumor microenvironment (tumor microenvironment, TME).
High concentrations of AHR ligands in the Tumor Microenvironment (TME) can lead to direct inhibition of APCs, th and Tc, and recruitment, production and activation of tregs and Th17, further inhibiting Tc and Th activity. Tumors are able to evade anti-tumor immune responses through these mechanisms. Therefore, AHR inhibitors can block the AHR-dependent immune escape pathway employed by malignant cells, thereby restoring anti-tumor immunity.
Recent studies on tumor immunobiology have shown that malignant tumor cells employ a complex immune escape mechanism. Preclinical and clinical studies have demonstrated that optimal recovery of anti-tumor immune responses can be provided by blocking or boosting these mechanisms through a combination of therapeutic applications (e.g., immune checkpoint inhibition and vaccine). While it is desirable that AHR modulators alone restore anti-tumor immunity, it is contemplated that AHR inhibitors in combination with checkpoint inhibitors and vaccines, even in synergy with other therapeutic approaches, will boost the immunotherapeutic response.
AHR-regulated immune mechanisms are associated with autoimmune and inflammatory diseases, such as multiple sclerosis and inflammatory bowel disease. Thus activation of the AHR pathway by an AHR agonist may be beneficial in the treatment of autoimmune and inflammatory diseases. Although AHR agonists have been described in the art, there is a need for improvements in the compositions and methods of immunomodulation for the treatment of autoimmune and inflammatory diseases by modulating AHR.
Partial aromatic hydrocarbon receptors are disclosed in, for example, chinese patent applications CN101466363A, CN108239083A, CN113480530A, TWI752155B, CN114181208, WO2022078356, etc. There remains an urgent clinical need to develop or improve inhibitors of AHR for the treatment of diseases associated with disorders of the AHR pathway.
Disclosure of Invention
Thus, according to a first aspect of the present invention, it is an object of the present invention to provide a class of 2-nitrogen substituted pyrimidines represented by the following formula i, each of which is an optical isomer, deuterate, prodrug or pharmaceutically acceptable salt thereof:
wherein,
ring A is C 6-10 Aryl or a 5-to 10-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S;
R 1 and R is 2 Each independently is hydrogen, saturated or unsaturated substituted or unsubstituted C 1 -C 8 Alkyl, saturated or unsaturated substituted or unsubstituted C 3 -C 8 Cycloalkyl, -OC (=o) C 1-8 Alkyl, -OC (=o) C 3 -C 8 Cycloalkyl, -C (=o) OC 1 -C 8 Alkyl, -C (=o) C 3 -C 8 Cycloalkyl, -S (O) m R c Saturated or unsaturated substituted or unsubstituted C 1 -C 8 Acyl, C 6 -C 14 Aryl, 4 to 14 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S or 5 to 14 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S, containing Saturated or unsaturated, halogenated or unhalogenated C of radicals 1-8 Alkyl group containingSaturated or unsaturated, halogenated or unhalogenated C of radicals 3-8 Cycloalkyl, wherein said "substituted" means optionally substituted with 1 to 10 deuterium, or optionally containing 1 to 4 groups selected from hydroxy, halogen, cyano, -S (O) m R c 、-NR d R e Saturated or unsaturated C 1 -C 8 Alkyl, saturated or unsaturated C 3 -C 8 Cycloalkyl, saturated or unsaturated C 1 -C 8 Alkoxy, saturated or unsaturated C 3 -C 8 Cycloalkoxy, -OC (=O) C 1 -C 8 Alkyl, -OC (=o) C 3 -C 8 Cycloalkyl, -C (=o) OC 1-8 Alkyl, -C (=o) OC 3 -C 8 Cycloalkyl, containing->Saturated or unsaturated, halogenated or unhalogenated C of radicals 1-8 Alkyl group containingSaturated or unsaturated, halogenated or unhalogenated C of radicals 3-8 Cycloalkyl, saturated or unsaturated C 1 -C 8 Acyl, saturated or unsaturated C 1 -C 8 Alkoxycarbonyl group, C 6 -C 14 Aryl, a 4 to 14 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, or a 5 to 14 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S;
or R is 1 And R is 2 Form, together with the N atom to which they are attached, a substituted or unsubstituted 4 to 14 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, wherein "substituted" means substituted with 1 to 10 deuterium, or optionally containing 1 to 4 heteroatoms selected from hydroxy, halogen, cyano, sulfonyl, carboxy-S (O) m R c 、-NR d R e ，C 1 ～C 8 Alkyl, C 3 ～C 8 Cycloalkyl, C 1 ～C 8 Alkoxy, C 3 ～C 8 Cycloalkoxy, -OC (=o) C 1-8 Alkyl, -OC (=o) C 3 ～C 8 Cycloalkyl, -C (=o) OC 1-8 Alkyl, -C (=O) OC 3 ～C 8 Cycloalkyl group containingSaturated or unsaturated, halogenated or unhalogenated C of radicals 1-8 Alkyl group containingSaturated or unsaturated, halogenated or unhalogenated C of radicals 3-8 Cycloalkyl, R f Substituted C 1 ～C 8 Alkyl, C 3 ～C 8 Cycloalkyl, C 1 ～C 8 Alkoxy, C 3 ～C 8 Substituents for cycloalkoxy;
R 3 selected from deuterium, halogen, nitro, cyano, carboxyl, hydroxyl, -NR d R e 、-OR g 、-CO 2 R g 、-S(O) m R c Or by 1 to 3R h Substituted C 1-8 Alkyl, C 3-8 Cycloalkyl, C 1-8 Alkoxy, C 3-8 Cycloalkoxy radicals C 1-8 Alkoxycarbonyl group, C 1-8 Alkylcarbonyl, C 1-8 Alkylcarboxy, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl.
R 4 H or D.
L is a bond or-NHR i 。
R a 、R b Each independently selected from saturated or unsaturated substituted or unsubstituted C 3 -C 8 Cycloalkyl, saturated or unsaturated substituted or unsubstituted C 1 -C 8 Alkyl, substituted or unsubstituted 6-10 membered aryl or substituted or unsubstituted 4-10 membered heteroaryl containing from 1 to 3 heteroatoms selected from N, O and S, wherein "substituted" means optionally substituted with 1 to 10 deuterium, or optionally containing 1 to 4 heteroatoms selected from hydroxy, halogen, cyano, -S (O) ) m R c 、-NR d R e Saturated or unsaturated C 1 -C 8 Alkyl, saturated or unsaturated C 3 -C 8 Cycloalkyl, saturated or unsaturated C 1 -C 8 Alkoxy, saturated or unsaturated C 3 -C 8 Cycloalkoxy, -OC (=O) C 1 -C 8 Alkyl, -OC (=o) C 3 -C 8 Cycloalkyl, -C (=o) OC 1-8 Alkyl, -C (=o) OC 3 -C 8 Cycloalkyl, saturated or unsaturated C 1 -C 8 Acyl, saturated or unsaturated C 1 -C 8 Alkoxycarbonyl group containingSaturated or unsaturated, halogenated or unhalogenated C of radicals 1-8 Alkyl group containing->Saturated or unsaturated, halogenated or unhalogenated C of radicals 3-8 Cycloalkyl, C 6 -C 14 Aryl, a 4 to 14 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, or a 5 to 14 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S;
or R is a And R is b Form, together with the N atom to which they are attached, a substituted or unsubstituted 4 to 14 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, a substituted or unsubstituted 5 to 14 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S, wherein "substituted" means substituted with 1 to 10 deuterium, or optionally containing 1 to 4 heteroatoms selected from hydroxy, halogen, cyano, sulfonyl, carboxy-S (O) m R c 、-NR d R e ，C 1 ～C 8 Alkyl, C 3 ～C 8 Cycloalkyl, C 1 ～C 8 Alkoxy, C 3 ～C 8 Cycloalkoxy, -OC (=o) C 1-8 Alkyl, -OC (=o) C 3 ～C 8 Cycloalkyl, -C (=o) OC 1-8 Alkyl, -C (=O) OC 3 ～C 8 Cycloalkyl group containingSaturated or unsaturated, halogenated or unhalogenated C of radicals 1-8 Alkyl group containing->Saturated or unsaturated, halogenated or unhalogenated C of radicals 3-8 Cycloalkyl, R f Substituted C 1 ～C 8 Alkyl, C 3 ～C 8 Cycloalkyl, C 1 ～C 8 Alkoxy, C 3 ～C 8 Substituents for cycloalkoxy groups.
n is an integer of 0, 1, 2, 3, 4 or 5.
n1 is an integer of 0, 1 or 2.
m is an integer of 0, 1 or 2.
R c 、R g 、R h And R is i Each independently selected from hydrogen, hydroxy, amino, saturated or unsaturated substituted or unsubstituted C 1 -C 8 Alkyl, saturated or unsaturated substituted or unsubstituted C 1 -C 8 Alkyl, C 3 -C 8 Cycloalkyl, -C (=o) C 1-8 Alkyl, -C (=o) C 3 -C 8 Cycloalkyl, -C (=o) OC 1 -C 8 Alkyl, -C (=o) OC 3 -C 8 Cycloalkyl, -C (=o) NC 1 -C 8 Alkyl, -C (=o) NC 3 -C 8 Cycloalkyl, saturated or unsaturated substituted or unsubstituted C 1 -C 8 Sulfonyl, C 6 -C 14 Aryl, C 7 -C 14 Arylalkyl, 4 to 14 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, or 5 to 14 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S, wherein said "substituted" means substituted with 1 to 10 deuterium, or optionally containing 1 to 4 heteroatoms selected from hydroxy, halogen, cyano, sulfonyl, -NR d R e Saturated or unsaturated C 1 -C 8 Alkyl, saturated or unsaturated C 3 -C 8 Cycloalkyl, saturated or unsaturated C 1 -C 8 Alkoxy, saturated or unsaturated C 3 -C 8 Cycloalkoxy, -OC (=O) C 1 -C 8 Alkyl, -OC (=o) C 3 -C 8 Cycloalkyl, -C (=o) OC 1-8 Alkyl, -C (=o) O C 3 -C 8 Cycloalkyl, saturated or unsaturated C 1 -C 8 Sulfonyl, saturated or unsaturated C 1 -C 8 Acyl, saturated or unsaturated C 1 -C 8 Alkoxycarbonyl group, C 6 -C 14 Aryl, a 4 to 14 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, or a 5 to 14 membered heteroaryl substituent containing 1 to 3 heteroatoms selected from N, O and S, wherein R c Is not hydrogen;
R d and R is e Each independently selected from hydrogen, halogen, cyano, hydroxy, saturated or unsaturated C 1 ～C 3 Alkyl, C 3 ～C 6 Cycloalkyl, saturated or unsaturated C substituted by halogen or hydroxy 1 ～C 3 Alkyl, C substituted by halogen or hydroxy 3 ～C 6 Cycloalkyl, saturated or unsaturated C 1 ～C 3 Alkoxy, C 3 ～C 6 Cyclic alkoxy, saturated or unsaturated, substituted C by halogen or hydroxy 1 ～C 3 Alkoxy, C substituted by halogen or hydroxy 3 ～C 6 A cycloalkoxy group.
Preferably, ring A is C 6～10 Aryl or a 5-to 8-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O and S.
Preferably, R 1 And R is 2 Each independently is hydrogen, saturated or unsaturated substituted or unsubstituted C 1 -C 6 Alkyl, saturated or unsaturated substituted or unsubstituted C 3 -C 6 Cycloalkyl, -OC (=o) C 1-6 Alkyl, -OC (=o) C 3 -C 6 Cycloalkyl, -C (=o) OC 1 -C 6 Alkyl, -C (=o) C 3 -C 6 Cycloalkyl, -S (O) m R c Saturated or unsaturated substituted or unsubstituted C 1 -C 6 Acyl, C 6 -C 10 Aryl, containing 1 to 3 heteroatoms selected from N, O and SA 5 to 10 membered heterocycloalkyl of atoms or a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S, containingSaturated or unsaturated, halogenated or unhalogenated C of radicals 1-6 Alkyl group containing->Saturated or unsaturated, halogenated or unhalogenated C of radicals 3-6 Cycloalkyl, wherein said "substituted" means substituted with 1 to 10 deuterium groups or optionally containing 1 to 4 groups selected from hydroxy, halogen, cyano, -S (O) m R c 、-NR d R e Saturated or unsaturated C 1 -C 6 Alkyl, saturated or unsaturated C 3 -C 6 Cycloalkyl, saturated or unsaturated C 1 -C 6 Alkoxy, saturated or unsaturated C 3 -C 6 Cycloalkoxy, -OC (=O) C 1 -C 6 Alkyl, -OC (=o) C 3 -C 6 Cycloalkyl, -C (=o) OC 1-6 Alkyl, -C (=o) OC 3 -C 6 Cycloalkyl, containing->Saturated or unsaturated, halogenated or unhalogenated C of radicals 1-6 Alkyl group containingSaturated or unsaturated, halogenated or unhalogenated C of radicals 3-6 Cycloalkyl, saturated or unsaturated C 1 -C 6 Acyl, saturated or unsaturated C 1 -C 6 Alkoxycarbonyl group, C 6 -C 10 Aryl, a 5 to 10 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, or a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S;
or R is 1 And R is 2 Forms, together with the N atom to which they are attached, a substituted or unsubstituted hetero-containing 1 to 3 members selected from N, O and SA 5-to 10-membered heterocycloalkyl group of atoms, wherein said "substituted" means substituted with 1 to 10 deuterium groups or optionally containing 1 to 4 groups selected from hydroxy, halogen, cyano, -S (O) m R c 、-NR d R e ，C 1 ～C 6 Alkyl, C 3 ～C 6 Cycloalkyl, C 1 ～C 6 Alkoxy, C 3 ～C 6 Cycloalkoxy, -OC (=o) C 1-6 Alkyl, -OC (=o) C 3 ～C 6 Cycloalkyl, -C (=o) OC 1-6 Alkyl, -C (=O) OC 3 ～C 6 Cycloalkyl group containingSaturated or unsaturated, halogenated or unhalogenated C of radicals 1-6 Alkyl group containing->Saturated or unsaturated, halogenated or unhalogenated C of radicals 3-6 Cycloalkyl, R f Substituted C 1 ～C 6 Alkyl, C 3 ～C 6 Cycloalkyl, C 1 ～C 6 Alkoxy, C 3 ～C 6 Substituents for cycloalkoxy groups.
More preferably, R 1 And R is 2 Each independently is hydrogen, saturated or unsaturated substituted or unsubstituted C 1 -C 4 Alkyl, saturated or unsaturated substituted or unsubstituted C 3 -C 6 Cycloalkyl, -OC (=o) C 1-4 Alkyl, -OC (=o) C 3 -C 6 Cycloalkyl, -C (=o) OC 1 -C 4 Alkyl, -C (=o) C 3 -C 6 Cycloalkyl, -S (O) m R c Saturated or unsaturated substituted or unsubstituted C 1 -C 4 Acyl, C 6 -C 10 Aryl, 5-to 8-membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S or 5-to 8-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S, containingRadicals (C)Saturated or unsaturated, halogenated or unhalogenated C 1-4 Alkyl group containing->Saturated or unsaturated, halogenated or unhalogenated C of radicals 3-6 Cycloalkyl, wherein said "substituted" means substituted with 1 to 10 deuterium groups or optionally containing 1 to 3 groups selected from hydroxy, halogen, cyano, -S (O) m R c 、-NR d R e Saturated or unsaturated C 1 -C 4 Alkyl, saturated or unsaturated C 3 -C 6 Cycloalkyl, saturated or unsaturated C 1 -C 4 Alkoxy, saturated or unsaturated C 3 -C 6 Cycloalkoxy, -OC (=O) C 1 -C 4 Alkyl, -OC (=o) C 3 -C 6 Cycloalkyl, -C (=o) OC 1-4 Alkyl, -C (=o) OC 3 -C 6 Cycloalkyl, containing->Saturated or unsaturated, halogenated or unhalogenated C of radicals 1-4 Alkyl group containingSaturated or unsaturated, halogenated or unhalogenated C of radicals 3-6 Cycloalkyl, saturated or unsaturated C 1 -C 4 Acyl, saturated or unsaturated C 1 -C 4 Alkoxycarbonyl group, C 6 -C 10 Aryl, a 5 to 8 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, or a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S;
Or R is 1 And R is 2 Form, together with the N atom to which they are attached, a substituted or unsubstituted 5-to 8-membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, wherein said "substituted" means substituted with 1 to 10 deuterium, or optionally containing 1 to 3 heteroatoms selected from hydroxy, halogen, cyano, -S (O) m R c 、-NR d R e ，C 1 ～C 4 Alkyl, C 3 ～C 6 Cycloalkyl, C 1 ～C 4 Alkoxy, C 3 ～C 6 Cycloalkoxy, -OC (=o) C 1-4 Alkyl, -OC (=o) C 3 ～C 6 Cycloalkyl, -C (=o) OC 1-4 Alkyl, -C (=O) OC 3 ～C 6 Cycloalkyl group containingSaturated or unsaturated, halogenated or unhalogenated C of radicals 1-4 Alkyl group containing->Saturated or unsaturated, halogenated or unhalogenated C of radicals 3-6 Cycloalkyl, substituted by halogen, hydroxy, amino or R f Substituted C 1 ～C 4 Alkyl, C 3 ～C 6 Cycloalkyl, C 1 ～C 4 Alkoxy, C 3 ～C 6 Substituents for cycloalkoxy groups.
Preferably, R 3 Selected from deuterium, halogen, nitro, cyano, carboxyl, hydroxyl, -NR d R e 、-OR g 、-CO 2 R g 、-S(O) m R c Or by 1 to 3R h Substituted C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy radicals C 1-6 Alkoxycarbonyl group, C 1-6 Alkylcarbonyl, C 1-6 Alkylcarboxy, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl.
More preferably, R 3 Selected from deuterium, halogen, nitro, cyano, carboxyl, hydroxyl, -NR d R e 、-OR g 、-CO 2 R g 、-S(O) m R c Or by 1 to 3R h Substituted C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 3-6 Cycloalkoxy radicals C 1-4 Alkoxycarbonyl group, C 1-4 Alkylcarbonyl, C 1-4 Alkylcarboxy, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroarylAryl groups.
Preferably, R a 、R b Each independently selected from saturated or unsaturated substituted or unsubstituted C 3 -C 6 Cycloalkyl, saturated or unsaturated substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted 6-10 membered aryl or substituted or unsubstituted 5-8 membered heteroaryl containing from 1 to 3 heteroatoms selected from N, O and S, wherein "substituted" means substituted with 1 to 10 deuterium, or optionally containing 1 to 3 heteroatoms selected from hydroxy, halogen, cyano, -S (O) m R c 、-NR d R e Saturated or unsaturated C 1 -C 6 Alkyl, saturated or unsaturated C 3 -C 6 Cycloalkyl, saturated or unsaturated C 1 -C 6 Alkoxy, saturated or unsaturated C 3 -C 6 Cycloalkoxy, -OC (=O) C 1 -C 6 Alkyl, -OC (=o) C 3 -C 6 Cycloalkyl, -C (=o) OC 1-6 Alkyl, -C (=o) OC 3 -C 6 Cycloalkyl, saturated or unsaturated C 1 -C 6 Acyl, saturated or unsaturated C 1 -C 6 Alkoxycarbonyl group containingSaturated or unsaturated, halogenated or unhalogenated C of radicals 1-6 Alkyl group containing->Saturated or unsaturated, halogenated or unhalogenated C of radicals 3-6 Cycloalkyl, C 6 -C 10 Aryl, a 5 to 10 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, or a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S;
or R is a And R is b Form, together with the N atom to which they are attached, a substituted or unsubstituted 4 to 10 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, a substituted or unsubstituted 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S, wherein said "substituted" meansSubstituted with 1 to 10 deuterium, or optionally containing 1 to 4 groups selected from hydroxy, halogen, cyano, sulfonyl, carboxy-S (O) m R c 、-NR d R e ，C 1 ～C 6 Alkyl, C 3 ～C 6 Cycloalkyl, C 1 ～C 6 Alkoxy, C 3 ～C 6 Cycloalkoxy, -OC (=o) C 1-6 Alkyl, -OC (=o) C 3 ～C 6 Cycloalkyl, -C (=o) OC 1-6 Alkyl, -C (=O) OC 3 ～C 6 Cycloalkyl group containingSaturated or unsaturated, halogenated or unhalogenated C of radicals 1-6 Alkyl group containing->Saturated or unsaturated, halogenated or unhalogenated C of radicals 3-6 Cycloalkyl, R f Substituted C 1 ～C 6 Alkyl, C 3 ～C 6 Cycloalkyl, C 1 ～C 6 Alkoxy, C 3 ～C 6 Substituents for cycloalkoxy groups.
More preferably, R a 、R b Each independently selected from saturated or unsaturated substituted or unsubstituted C 3 -C 6 Cycloalkyl, saturated or unsaturated substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted 6-10 membered aryl or substituted or unsubstituted 5-8 membered heteroaryl containing from 1 to 3 heteroatoms selected from N, O and S, wherein "substituted" means substituted with 1 to 10 deuterium, or optionally containing 1 to 3 heteroatoms selected from hydroxy, halogen, cyano, -S (O) m R c 、-NR d R e Saturated or unsaturated C 1 -C 4 Alkyl, saturated or unsaturated C 3 -C 6 Cycloalkyl, saturated or unsaturated C 1 -C 4 Alkoxy, saturated or unsaturated C 3 -C 6 Cycloalkoxy, -OC (=O) C 1 -C 4 Alkyl, -OC (=o) C 3 -C 6 Cycloalkyl radicalsC(＝O)OC 1-4 Alkyl, -C (=o) OC 3 -C 6 Cycloalkyl, saturated or unsaturated C 1 -C 4 Acyl, saturated or unsaturated C 1 -C 4 Alkoxycarbonyl group containingSaturated or unsaturated, halogenated or unhalogenated C of radicals 1-4 Alkyl group containing->Saturated or unsaturated, halogenated or unhalogenated C of radicals 3-6 Cycloalkyl, C 6 -C 10 Aryl, a 5 to 10 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, or a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S;
or R is a And R is b And form together with the N atom to which they are attached a substituted or unsubstituted 5-to 8-membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, a substituted or unsubstituted 5-to 6-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S, wherein said "substituted" means substituted with 1 to 10 deuterium, or optionally containing 1 to 3 heteroatoms selected from hydroxy, halogen, cyano, sulfonyl, carboxy, -S (O) m R c 、-NR d R e ，C 1 ～C 4 Alkyl, C 5 ～C 6 Cycloalkyl, C 1 ～C 4 Alkoxy, C 5 ～C 6 Cycloalkoxy, -OC (=o) C 1-4 Alkyl, -OC (=o) C 5 ～C 6 Cycloalkyl, -C (=o) OC 1-4 Alkyl, -C (=O) OC 5 ～C 6 Cycloalkyl group containingSaturated or unsaturated, halogenated or unhalogenated C of radicals 1-4 Alkyl group containing->Of saturated or unsaturated halogenated or unsaturated radicalsHalogenated C 3-6 Cycloalkyl, substituted by halogen, hydroxy, amino or R f Substituted C 1 ～C 4 Alkyl, C 5 ～C 6 Cycloalkyl, C 1 ～C 4 Alkoxy, C 5 ～C 6 Substituents for cycloalkoxy groups.
Preferably, R c 、R f 、R g 、R h And R is i Each independently selected from hydrogen, hydroxy, amino, saturated or unsaturated substituted or unsubstituted C 1 -C 6 Alkyl, saturated or unsaturated substituted or unsubstituted C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, -C (=o) C 1-6 Alkyl, -C (=o) C 3 -C 6 Cycloalkyl, -C (=o) OC 1 -C 6 Alkyl, -C (=o) OC 3 -C 6 Cycloalkyl, -C (=o) NC 1 -C 6 Alkyl, -C (=o) NC 3 -C 6 Cycloalkyl, saturated or unsaturated substituted or unsubstituted C 1 -C 6 Sulfonyl, C 6 -C 10 Aryl, C 7 -C 11 Arylalkyl, a 5-to 10-membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, or a 5-to 10-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S, wherein said "substituted" means substituted with 1 to 10 deuterium, or optionally containing 1 to 4 heteroatoms selected from hydroxy, halogen, cyano, sulfonyl, C 1 -C 6 Sulfo group, -NR d R e Saturated or unsaturated C 1 -C 6 Alkyl, saturated or unsaturated C 3 -C 6 Cycloalkyl, saturated or unsaturated C 1 -C 6 Alkoxy, saturated or unsaturated C 3 -C 6 Cycloalkoxy, -OC (=O) C 1 -C 6 Alkyl, -OC (=o) C 3 -C 8 Cycloalkyl, -C (=o) OC 1-6 Alkyl, -C (=o) OC 3 -C 6 Cycloalkyl, saturated or unsaturated C 1 -C 6 Sulfonyl, saturated or unsaturated C 1 -C 6 Acyl, saturated or unsaturated C 1 -C 6 Alkoxycarbonyl group, C 6 -C 10 Aryl groups containing 1 to 3 members selected from N, O anda 5 to 10 membered heterocycloalkyl of a heteroatom of S or a substituent of a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S, wherein R c Is not hydrogen;
more preferably, R c 、R f 、R g 、R h And R is i Each independently selected from hydrogen, hydroxy, amino, saturated or unsaturated substituted or unsubstituted C 1 -C 4 Alkyl, saturated or unsaturated substituted or unsubstituted C 1 -C 4 Alkyl, C 4 -C 6 Cycloalkyl, -C (=o) C 1-4 Alkyl, -C (=o) C 4 -C 6 Cycloalkyl, -C (=o) OC 1 -C 4 Alkyl, -C (=o) OC 4 -C 8 Cycloalkyl, -C (=o) NC 1 -C 4 Alkyl, -C (=o) NC 4 -C 6 Cycloalkyl, saturated or unsaturated substituted or unsubstituted C 1 -C 4 Sulfonyl, C 6 -C 10 Aryl, C 7 -C 11 Arylalkyl, a 5-to 8-membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, or a 5-to 10-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S, wherein said "substituted" means substituted with 1 to 10 deuterium, or optionally containing 1 to 3 heteroatoms selected from hydroxy, halogen, cyano, sulfonyl, C 1 -C 4 Sulfo group, -NR d R e Saturated or unsaturated C 1 -C 4 Alkyl, saturated or unsaturated C 4 -C 6 Cycloalkyl, saturated or unsaturated C 1 -C 4 Alkoxy, saturated or unsaturated C 4 -C 6 Cycloalkoxy, -OC (=O) C 1 -C 4 Alkyl, -OC (=o) C 4 -C 6 Cycloalkyl, -C (=o) OC 1-4 Alkyl, -C (=o) OC 4 -C 6 Cycloalkyl, saturated or unsaturated C 1 -C 4 Sulfonyl, saturated or unsaturated C 1 -C 4 Acyl, saturated or unsaturated C 1 -C 4 Alkoxycarbonyl group, C 6 -C 10 Aryl, a 5-to 8-membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, or a 5-to 10-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S,wherein R is c Is not hydrogen.
More preferably, R f Selected from deuterium, halogen, cyano, hydroxy, amino, saturated or unsaturated C 1 ～C 6 Alkyl, saturated or unsaturated C 3 ～C 6 Cycloalkyl, -S (O) m R c 、NR d R e Saturated or unsaturated C substituted by deuterium, halogen, hydroxy or amino 1 ～C 6 Alkyl, C substituted by deuterium, halogen, hydroxy or amino 3 ～C 6 Cycloalkyl, saturated or unsaturated C 1 ～C 6 Alkoxy, C 3 ～C 6 Cyclic alkoxy, saturated or unsaturated, substituted C by deuterium, halogen, hydroxy or amino 1 ～C 6 Alkoxy, C substituted by deuterium, halogen, hydroxy or amino 3 ～C 6 A cycloalkoxy group.
More preferably, R in formula I 1 And R is 2 The structure formed with the N atom to which they are attached is selected from the group consisting of:
More preferably, R in formula I a And R is b The structure formed with the N atom to which they are attached is selected from the group consisting of:
wherein R is j And R is k Each occurrence is independently hydroxy, halogen, cyano, sulfonyl, amino, C 1 ～C 8 Alkyl, C 3 ～C 8 Cycloalkyl, C 1 ～C 8 Alkoxy, C 3 ～C 8 Cycloalkoxy, -OC (=o) C 1-8 Alkyl, -OC (=o) C 3 ～C 8 Cycloalkyl, -C (=o) OC 1-8 Alkyl, -C (=O) OC 3 ～C 8 Cycloalkyl, R f Substituted C 1 ～C 8 Alkyl, C 3 ～C 8 Cycloalkyl, C 1 ～C 8 Alkoxy, C 3 ～C 8 Substituents for cycloalkoxy groups, wherein R f Selected from deuterium, halogen, cyano, hydroxy, amino, saturated or unsaturated C 1 ～C 6 Alkyl, saturated or unsaturated C 3 ～C 6 Cycloalkyl, saturated or unsaturated, substituted C by deuterium, halogen, hydroxy or amino 1 ～C 6 Alkyl, C substituted by deuterium, halogen, hydroxy or amino 3 ～C 6 Cycloalkyl, saturated or unsaturated C 1 ～C 6 Alkoxy, C 3 ～C 6 Cyclic alkoxy, saturated or unsaturated, substituted C by deuterium, halogen, hydroxy or amino 1 ～C 6 Alkoxy, C substituted by deuterium, halogen, hydroxy or amino 3 ～C 6 A cycloalkoxy group; n2 is an integer of 0, 1, 2, 3, 4 or 5.
Preferably, R j And R is k Each occurrence is independently hydroxy, halogen, cyano, sulfonyl, amino C 1 ～C 6 Alkyl, C 3 ～C 6 Cycloalkyl, C 1 ～C 6 Alkoxy, C 3 ～C 6 Cycloalkoxy, -OC (=o) C 1-6 Alkyl, -OC (=o) C 3 ～C 6 Cycloalkyl, -C (=o) OC 1-6 Alkyl, -C (=O) OC 3 ～C 6 Cycloalkyl, R f Substituted C 1 ～C 6 Alkyl, C 3 ～C 6 Cycloalkyl, C 1 ～C 6 Alkoxy, C 3 ～C 6 Substituents for cycloalkoxy groups, wherein R f Selected from deuterium, halogen, cyano, hydroxy, amino, saturated or unsaturated C 1 ～C 4 Alkyl, saturated or unsaturatedC of (2) 3 ～C 6 Cycloalkyl, saturated or unsaturated, substituted C by deuterium, halogen, hydroxy or amino 1 ～C 4 Alkyl, C substituted by deuterium, halogen, hydroxy or amino 3 ～C 6 Cycloalkyl, saturated or unsaturated C 1 ～C 4 Alkoxy, C 3 ～C 6 Cyclic alkoxy, saturated or unsaturated, substituted C by deuterium, halogen, hydroxy or amino 1 ～C 4 Alkoxy, C substituted by deuterium, halogen, hydroxy or amino 3 ～C 6 A cycloalkoxy group.
More preferably, R j And R is k Each occurrence is independently hydroxy, halogen, cyano, sulfonyl, amino C 1 ～C 4 Alkyl, C 4 ～C 6 Cycloalkyl, C 1 ～C 4 Alkoxy, C 4 ～C 6 Cycloalkoxy, -OC (=o) C 1-4 Alkyl, -OC (=o) C 4 ～C 6 Cycloalkyl, -C (=o) OC 1-4 Alkyl, -C (=O) OC 4 ～C 6 Cycloalkyl, R f Substituted C 1 ～C 4 Alkyl, C 4 ～C 6 Cycloalkyl, C 1 ～C 4 Alkoxy, C 4 ～C 6 Substituents for cycloalkoxy groups, wherein R f Selected from deuterium, halogen, cyano, hydroxy, amino, saturated or unsaturated C 1 ～C 3 Alkyl, saturated or unsaturated C 5 ～C 6 Cycloalkyl, saturated or unsaturated, substituted C by deuterium, halogen, hydroxy or amino 1 ～C 3 Alkyl, C substituted by deuterium, halogen, hydroxy or amino 5 ～C 6 Cycloalkyl, saturated or unsaturated C 1 ～C 3 Alkoxy, C 5 ～C 6 Cyclic alkoxy, saturated or unsaturated, substituted C by deuterium, halogen, hydroxy or amino 1 ～C 3 Alkoxy, C substituted by deuterium, halogen, hydroxy or amino 5 ～C 6 A cycloalkoxy group.
More preferably, the 2-nitrogen substituted pyrimidines according to formula i, their respective optical isomers, deuterates, prodrugs or pharmaceutically acceptable salts are selected from the following compounds:
according to a second aspect of the present invention, it is a further object of the present invention to provide a pharmaceutical composition comprising a therapeutically effective amount of a 2-nitrogen substituted pyrimidine compound represented by formula i according to the present invention, each of its optical isomer, deuteride, prodrug or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.
According to a third aspect of the present invention, it is a further object of the present invention to provide the use of a 2-nitrogen substituted pyrimidine compound represented by formula i, each of which is an optical isomer, a deuteride, a prodrug or a pharmaceutically acceptable salt thereof in the preparation of an AHR disorder inhibitor according to the present invention.
According to a fourth aspect of the present invention, it is a further object of the present invention to provide the use of a 2-nitrogen substituted pyrimidine compound of formula i, each of which is an optical isomer, a deuterate, a prodrug or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment of a tumor associated with an AHR disorder.
According to a fifth aspect of the present invention, it is a further object of the present invention to provide a method for treating a tumor associated with AHR disorder, which comprises administering to a subject in need thereof an effective amount of a 2-nitrogen substituted pyrimidine compound of formula i according to the present invention, each of which is an optical isomer, a deuteride, a prodrug or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to the present invention.
According to a sixth aspect of the present invention, it is another object of the present invention to provide a process for preparing 2-nitrogen substituted pyrimidines represented by formula i according to the present invention, their respective optical isomers, deuterides, prodrugs or pharmaceutically acceptable salts thereof, which is selected from the group consisting of those represented by the following reaction formula 1 or reaction formula 2:
in the reaction formula 1, the compound of the formula III and the compound of the formula II undergo esterification reaction to form a compound represented by the formula I, wherein the substituent R 1 、R 2 、R 3 、R 4 、R a 、R b Ring A, L is as defined for formula I;
in reaction formula 2, the compound of formula III and the hydrazine compound of formula IV undergo esterification reaction to form an intermediate compound of formula I-a, and then the intermediate compound of formula I-a and the substituent R 2 Is reacted with a compound (e.g., an anhydride compound) to form a compound of formula I, wherein the substituent R 1 、R 2 、R 3 、R 4 、R a 、R b Ring A, L is as defined for formula I.
In equations 1 and 2, compound III can be prepared according to one of the following methods, which is only exemplified below.
Method A
Preparation of intermediate X-A in step 1)
Adding concentrated hydrochloric acid into the ethanol solution of urea and dicarbonyl compound V containing the A ring structure, stirring overnight, cooling to room temperature, filtering, washing with cold ethanol, and drying to obtain the compound VI.
Step 2) preparation of intermediate VII
And adding the compound VI into phosphorus oxychloride, heating and stirring under the protection of nitrogen, concentrating under reduced pressure until the mixture is dry, adding ethyl acetate and ice water, stirring, filtering, and drying to obtain the compound VII.
Step 3) preparation of intermediate VIII
Compound VII and amino Compound NHR a R b Dissolving in dimethyl sulfoxide, adding K 2 CO 3 Heating to 70 ℃, stirring overnight, cooling to room temperature, adding ice water, filtering, washing with water, and drying to obtain a compound VIII;
Step 4) preparation of Compound III
Dissolving a compound VIII in a mixed solvent, adding lithium hydroxide, stirring at room temperature overnight, concentrating under reduced pressure, adding ice water, stirring, extracting with ethyl acetate, adjusting the pH of a water phase to 6-7 with hydrochloric acid, filtering, and drying to obtain the compound III, wherein the mixed solvent is THF/MeOH/H 2 O (volume ratio: 1/1/1).
Method B
Step 1) preparation of intermediate X
Dissolving 2, 6-dichloropyrimidine-4-carboxylic acid ethyl ester and boric acid compound IX containing an A ring structure in dioxane, adding saturated sodium carbonate and tetra (triphenylphosphine) palladium, degassing, heating under the protection of nitrogen, stirring overnight, cooling to room temperature, concentrating under reduced pressure, adding ice water, extracting with ethyl acetate, drying, and purifying to obtain a compound X;
step 2) preparation of intermediate XI
Compound X and amino compound NHR a R b Dissolving in dimethyl sulfoxide, adding K 2 CO 3 Heating to 70deg.C, stirring overnight, cooling to room temperature, adding ice water, filtering, washing with water, and drying to obtain compound XI;
step 3) preparation of Compound III
Dissolving compound XI in mixed solvent, adding lithium hydroxide, stirring at room temperature overnight, concentrating under reduced pressure, and adding iceWater, stirring, extracting with ethyl acetate, regulating pH of water phase to 6-7 with hydrochloric acid, filtering, and drying to obtain compound III, wherein the mixed solvent is THF/MeOH/H 2 O (volume ratio: 1/1/1).
Method C
Step 1) preparation of intermediate XII
2, 6-dichloropyrimidine-4-carboxylic acid ethyl ester and amino compound NHR a R b Dissolving in dimethyl sulfoxide, adding K 2 CO 3 Heating to 70deg.C, stirring overnight, cooling to room temperature, adding ice water, filtering, washing with water, and drying to obtain compound XII;
step 2) preparation of intermediate XIII
Dissolving a compound XII and a boric acid compound IX containing an A ring structure in dioxane, adding saturated sodium carbonate and tetra (triphenylphosphine) palladium, degassing, heating under the protection of nitrogen, stirring overnight, cooling to room temperature, concentrating under reduced pressure, adding ice water, extracting with ethyl acetate, drying, and purifying to obtain a compound XIII;
step 3) preparation of intermediate III
Dissolving compound XIII in a mixed solvent, adding lithium hydroxide, stirring at room temperature overnight, concentrating under reduced pressure, adding ice water, stirring, extracting with ethyl acetate, adjusting pH of water phase to 6-7 with hydrochloric acid, filtering, and drying to obtain compound III, wherein the mixed solvent is THF/MeOH/H 2 O (volume ratio: 1/1/1).
Detailed Description
Hereinafter, the present invention will be described in detail. Before the description, it is to be understood that the terms used in this specification and the appended claims should not be construed as limited to general and dictionary meanings, but interpreted based on the meanings and concepts corresponding to technical aspects of the present invention on the basis of the principle that the inventor is allowed to define terms appropriately for the best explanation. Accordingly, the description set forth herein is merely a preferred example for the purpose of illustration and is not intended to limit the scope of the invention, so that it should be understood that other equivalents or modifications may be made thereto without departing from the spirit and scope of the invention.
All features or conditions defined herein in terms of numerical ranges or percentage ranges are for brevity and convenience only. Accordingly, the description of a numerical range or percentage range should be considered to cover and specifically disclose all possible sub-ranges and individual values within the range, particularly integer values. For example, a range description of "1 to 8" should be taken as having specifically disclosed all sub-ranges such as 1 to 7, 2 to 8, 2 to 6, 3 to 6, 4 to 8, 3 to 8, etc., particularly sub-ranges defined by all integer values, and should be taken as having specifically disclosed individual values such as 1, 2, 3, 4, 5, 6, 7, 8, etc. within the range. The foregoing explanation applies to all matters of the invention throughout its entirety unless indicated otherwise, whether or not the scope is broad.
If an amount or other numerical value or parameter is expressed as a range, preferred range, or a series of upper and lower limits, then it is understood that any range, whether or not separately disclosed, from any pair of the upper or preferred value for that range and the lower or preferred value for that range is specifically disclosed herein. Furthermore, where a range of numerical values is recited herein, unless otherwise stated, the range is intended to include the endpoints thereof, and all integers and fractions within the range.
In this context, numerical values should be understood to have the accuracy of the numerical significance of the numerical values provided that the objectives of the present invention are achieved. For example, the number 40.0 is understood to cover a range from 39.50 to 40.49.
In this document, where Markush group (Markush group) or option-type language is used to describe features or examples of the present invention, those skilled in the art will appreciate that a sub-group of all elements within a Markush group or option list or any individual element may also be used to describe the present invention. For example, if X is described as "selected from the group consisting of X1, X2, and X3," it is also meant that the claim of X as X1 and/or X2 have been fully described. Furthermore, where markush groups or option expressions are used to describe features or examples of the present invention, those skilled in the art will appreciate that any combination of sub-groups or individual elements of all elements within a markush group or option list may also be used to describe the present invention. Accordingly, for example, if X is described as "selected from the group consisting of X1, X2, and X3" and Y is described as "selected from the group consisting of Y1, Y2, and Y3," then the claim that X is X1 or X2 or X3 and Y is Y1 or Y2 or Y3 has been fully described.
Definition of the definition
"alkyl" refers to a group ("C") that is a straight or branched saturated hydrocarbon group having 1 to 8 carbon atoms 1–8 Alkyl "). In some embodiments, the alkyl group has 1 to 7 carbon atoms ("C 1-7 Alkyl "). In some embodiments, the alkyl group has 1 to 6 carbon atoms ("C 1-6 Alkyl "). In some embodiments, the alkyl group has 1 to 5 carbon atoms ("C 1-5 Alkyl "). In some embodiments, the alkyl group has 1 to 4 carbon atoms ("C 1-4 Alkyl "). In some embodiments, the alkyl group has 1 to 3 carbon atoms ("C 1-3 Alkyl "). In some embodiments, the alkyl group has 1 to 2 carbon atoms ("C 1-2 Alkyl "). In some embodiments, the alkyl group has 1 carbon atom ("C 1 Alkyl "). In some embodiments, the alkyl group has 1 to 6 carbon atoms ("C 1-6 Alkyl "). C (C) 1–6 Examples of alkyl groups include methyl (C) 1 ) Ethyl (C) 2 ) Propyl (C) 3 ) (e.g., n-propyl, isopropyl), butyl (C) 4 ) (e.g., n-butyl, t-butyl, sec-butyl, isobutyl), pentyl (C) 5 ) (e.g., n-pentyl, 3-pentyl, neopentyl, 3-methyl-2-butyl, t-pentyl) and hexyl (C) 6 ) (e.g., n-hexyl). Further examples of alkyl groups include n-heptyl (C 7 ) N-octyl (C) 8 ) Etc. Unless otherwise indicated, each instance of an alkyl group is independently unsubstituted ("unsubstituted alkyl") or substituted ("substituted alkyl") with one or more substituents (e.g., halogen, such as F). In certain embodiments, the alkyl is unsubstituted C 1-8 Alkyl group(e.g. unsubstituted C 1 Alkyl radicals, e.g. -CH 3 ). In certain embodiments, the alkyl is substituted C 1-8 Alkyl (e.g. substituted C 1 Alkyl radicals, e.g. -CF 3 )。
"alkoxy" means a monovalent-O-alkyl group in which the alkyl moiety has the indicated number of carbon atoms. Alkoxy groups in this disclosure typically contain 1-8 carbon atoms ("C1-C8 alkoxy"), 1-6 carbon atoms ("C1-C6 alkoxy"), or 1-4 carbon atoms ("C1-C4 alkoxy"). For example, C1-C4 alkoxy includes methoxy, ethoxy, isopropoxy, tert-butyloxy, and the like. Unless otherwise indicated, each instance of an alkoxy group is independently optionally substituted, i.e., unsubstituted (an "unsubstituted alkoxy") or substituted (a "substituted alkoxy") with one or more substituents. In certain embodiments, the alkoxy is unsubstituted C1 to C6 alkoxy. In certain embodiments, the alkoxy is a substituted C1 to C6 alkoxy.
"cycloalkyl" means a non-aromatic ring system having 3 to 8 ring carbon atoms ("C 3-8 Cycloalkyl ") and zero heteroatoms. In some embodiments, the cycloalkyl group has 3 to 8 ring carbon atoms ("C 3-8 Cycloalkyl "). In some embodiments, the cycloalkyl group has 3 to 6 ring carbon atoms ("C 3-6 Cycloalkyl "). In some embodiments, cycloalkyl groups have 5 to 8 ring carbon atoms ("C 5-8 Cycloalkyl "). Exemplary C 3-6 Cycloalkyl groups include, but are not limited to, cyclopropyl (C) 3 ) Cyclopropenyl (C) 3 ) Cyclobutyl (C) 4 ) Cyclobutenyl (C) 4 ) Cyclopentyl (C) 5 ) Cyclopentenyl (C) 5 ) Cyclohexyl (C) 6 ) Cyclohexenyl (C) 6 ) Cyclohexadienyl (C) 6 ) Etc. Exemplary C 3-8 Cycloalkyl groups include, but are not limited to, C described above 3-6 Cycloalkyl group and cycloheptyl (C) 7 ) Cycloheptenyl (C) 7 ) Cycloheptadienyl (C) 7 ) Cycloheptatrienyl (C) 7 ) Cyclooctyl (C) 8 ) Cyclooctenyl (C) 8 ) Etc. Unless otherwise indicated, each instance of cycloalkyl is independently optionally substituted, i.e., notSubstituted ("unsubstituted cycloalkyl") or substituted by one or more substituents ("substituted cycloalkyl"). In certain embodiments, cycloalkyl is unsubstituted C 3-8 Cycloalkyl; in certain embodiments, cycloalkyl is substituted C 3-8 Cycloalkyl groups.
"heterocycloalkyl" refers to a group of a 4 to 14 membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur ("4-14 membered heterocyclic group"). In a heterocyclic group containing one or more nitrogen atoms, the point of attachment may be a carbon atom or a nitrogen atom as the valence permits. The heterocyclic group may be a single ring ("monocyclic heterocyclic group") or a fused, bridged or spiro ring system, for example a bicyclic ring system ("bicyclic heterocyclic group"), and may be saturated or may be partially unsaturated. "heterocyclic group" also includes ring systems in which a heterocycle as defined above is fused to one or more cycloalkyl groups (where the point of attachment is on the cycloalkyl group or heterocycle), or ring systems in which a heterocycle as defined above is fused to one or more aryl or heteroaryl groups (where the point of attachment is on the heterocycle), and in such cases the number of ring members continues to refer to the number of ring members in the heterocyclic system. Each instance of a heterocyclic group is independently optionally substituted, i.e., unsubstituted ("unsubstituted heterocycloalkyl") or substituted by one or more substituents ("substituted heterocycloalkyl"), unless otherwise specified. In certain embodiments, the heterocycloalkyl is an unsubstituted 4-14 membered heterocycloalkyl. In certain embodiments, heterocycloalkyl substituted 4-14 membered heterocycloalkyl.
"aryl" or "aromatic ring group" refers to a group ("C") of a single or multiple ring (e.g., bi-or tri-cyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared in a cyclic array) having 6 to 14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system 6-14 Aryl "). In some embodiments, aryl groups have 6 ring carbon atoms ("C 6 Aryl "; for example, phenyl). In some embodiments, aryl groups have 10 ring carbon atoms ("C 10 Aryl "; for example, naphthyl groups such as 1-naphthyl and 2-naphthyl).In some embodiments, the aryl group has 14 ring carbon atoms ("C 14 Aryl "; for example, anthracyl). "aryl" also includes ring systems in which an aryl ring as defined above is fused to one or more cycloalkyl or heterocyclic groups, where the point of attachment is on the aromatic ring, and in such cases the number of carbon atoms continues to refer to the number of carbon atoms in the aromatic ring system. Each instance of an aryl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted aryl") or substituted ("substituted aryl") with one or more substituents, unless otherwise indicated. In certain embodiments, aryl is unsubstituted C 6-14 Aryl groups. In certain embodiments, aryl is substituted C 6-14 Aryl groups.
"heteroaryl" is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur ("5-10 membered heteroaryl"). In some embodiments, heteroaryl groups are 5-8 membered aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heteroaryl"). In some embodiments, heteroaryl groups are 5-6 membered aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heteroaryl"). In some embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise indicated, each instance of heteroaryl is independently optionally substituted, i.e., unsubstituted ("unsubstituted heteroaryl") or substituted by one or more substituents ("substituted heteroaryl"). In certain embodiments, the heteroaryl is an unsubstituted 5-10 membered heteroaryl. In certain embodiments, the heteroaryl is a substituted 5-10 membered heteroaryl.
"halogen" or "halo" means fluorine (fluorine, -F), chlorine (chlorine, -Cl), bromine (bromine, -Br) or iodine (iodine, -I).
"substituted" or "optionally substituted" means that an atom in the group, such as a hydrogen atom, is substituted. In certain embodiments, alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are substituted (e.g., "substituted" alkyl, "substituted" cycloalkyl, "substituted" heterocycloalkyl, "substituted" aryl, or "substituted" heteroaryl). Generally, the term "substituted", whether preceded by the term "optionally", means that at least one hydrogen present on a group (e.g., carbon or nitrogen atom) is substituted with an allowable substituent, e.g., a substituent that upon substitution forms a stable compound, e.g., a compound that does not spontaneously undergo conversion (e.g., by rearrangement, cyclization, elimination, or other reaction). Unless otherwise indicated, a "substituted" group has substituents at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituents are the same or different at each position. The term "substituted" is intended to include substitution with all permissible substituents of organic compounds, any substituents described herein which result in the formation of stable compounds. The present disclosure contemplates any and all of these combinations to obtain stable compounds. For purposes of this disclosure, heteroatoms such as nitrogen may have hydrogen substituents and/or any suitable substituent as described herein that satisfies the valences of the heteroatoms and results in the formation of a stable moiety. In certain embodiments, the substituent is a carbon atom substituent. In certain embodiments, the substituent is a nitrogen atom substituent. In certain embodiments, the substituent is an oxygen atom substituent. In certain embodiments, the substituent is a sulfur atom substituent.
"unsaturated" or "partially unsaturated" refers to a group that contains at least one double or triple bond. "partially unsaturated" ring systems are also intended to encompass rings having multiple sites of unsaturation, but are not intended to include aromatic groups (e.g., aryl or heteroaryl). Likewise, "saturated" refers to groups that do not contain double or triple bonds, i.e., all contain single bonds.
In this context, when multiple substitutions are present in defined substituents, there may be instances of repeated definitions in the literal description of such multiple substitutions, but such description should be understood to at least follow the basic rules of general pharmaceutical chemistry, such as when repeated definitions of substituents occur, those skilled in the art may determine whether such repetition is feasible or infeasible in accordance with common general pharmaceutical chemistry knowledge, and make a reasonable choice.
The term "pharmaceutically acceptable" as used herein is intended to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention prepared from the compounds of the present invention which have the specified substituents found herein with relatively non-toxic acids or bases. When the compounds of the present invention contain relatively acidic functional groups, base addition salts may be obtained by contacting neutral forms of such compounds with a sufficient amount of a base in pure solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts or similar salts. When the compounds of the present invention contain relatively basic functional groups, acid addition salts (i.e., pharmaceutically acceptable salts) may be obtained by contacting neutral forms of such compounds with sufficient amounts of an acid in pure solution or in a suitable inert solvent, examples include inorganic acid salts and organic acid salts, such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, and the like; the organic acids include acids such as benzoic acid, 2-hydroxyethanesulfonic acid, sulfamic acid, benzenesulfonic acid, phenylacetic acid, mandelic acid, malonic acid, propionic acid, oxalic acid, sulfanilic 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, stearic acid, and the like; also included are salts of amino acids such as arginine and the like, and salts of organic acids such as glucuronic acid (see Berge et al, "Pharmaceutical Salts", journal of Pharmaceutical Science 66:1-19 (1977)). Certain specific compounds of the invention contain basic and acidic functionalities that can be converted to either base or acid addition salts. The parent form of a compound differs from its various salt forms in certain physical properties, such as solubility in polar solvents.
As used herein, the modifier term "about" refers to a change in value that may occur, for example, by routine testing and processing; unintentional errors in passing such tests and processing; differences in source or purity by the manufacture of the components used in the present invention; etc. As used herein, "about" a particular value also includes the particular value, e.g., "about 10%" includes 10%. Whether or not modified by the term "about", the claims include equivalents to the listed amounts. In one embodiment, the term "about" means within 20% of the reported numerical value.
As used herein, the term "treating" refers to eliminating, alleviating or ameliorating a disease or disorder and/or symptoms associated therewith. Although not excluded, treating a disease or condition does not require complete elimination of the disease, condition, or symptom associated therewith. As used herein, the term "treatment" or the like may include "prophylactic treatment" referring to reducing the likelihood of recurrence of a disease or disorder or a previously controlled disease or disorder in a subject that is free of, or at risk of, suffering from, or susceptible to recurrence of the disease or disorder. The term "treatment" and synonyms contemplate administering a therapeutically effective amount of a compound described herein to a subject in need of such treatment.
For a drug or pharmacologically active agent, the term "effective amount" or "therapeutically effective amount" refers to a sufficient amount of the drug or agent that is non-toxic but achieves the desired effect. For the purposes of the present oral dosage form, an "effective amount" of one active agent in a composition refers to that amount which is required to achieve the desired effect when used in combination with another active agent in the composition. Determination of an effective amount varies from person to person, depending on the age and general condition of the recipient, and also on the particular active substance, a suitable effective amount in an individual case can be determined by one skilled in the art according to routine experimentation.
Diseases associated with the AHR pathway according to the invention include, but are not limited to, tumors associated with the AHR pathway.
The following examples are merely illustrative of embodiments of the present invention and are not intended to limit the invention in any way, and those skilled in the art will appreciate that modifications may be made without departing from the spirit and scope of the invention. Unless otherwise specified, reagents and equipment used in the following examples are commercially available products.
Example 1: intermediate III-A
Method A
Step 1) preparation of ethyl 2, 4-dicarbonyl-4- (4- (trifluoromethyl) phenyl) butyrate
A mixed solution of diethyl oxalate (15.2 g,104 mmol) and sodium ethoxide (10.9 g,160 mmol) was cooled to below 10℃and stirred for 30min, a solution of trifluoromethyl benzophenone (18.8 g,100 mmol) in absolute ethanol (80 ml) was added dropwise, the ice bath was removed, stirred at room temperature overnight, the reaction solution was almost solidified, filtered, washed with a small amount of ethanol and dried to give ethyl 2, 4-dicarbonyl-4- (4- (trifluoromethyl) phenyl) butyrate (28 g, yield 97%). LC/MS (ESI) m/z 289[ M+1 ]] + 。
Preparation of intermediate VI-A in step 2)
To an ethanol solution (4 ml) of urea (66 mg,1.1 mmol) and ethyl 2, 4-dicarbonyl-4- (4- (trifluoromethyl) phenyl) butyrate (288.2 mg,1 mmol) was added 1ml of concentrated hydrochloric acid, and the mixture was stirred at 80℃overnight, cooled to room temperature, filtered, washed with cold ethanol and dried to give VI-A. LC/MS (ESI) m/z 313[M+1] + 。
Preparation of intermediate VII-A in step 3)
Compound VI-A (78 mg,0.25 mmol) was added to 2ml phosphorus oxychloride, heated to 85℃under nitrogen, stirred for 6h, concentrated to dryness under reduced pressure, ethyl Acetate (EA) (50 ml) and 20g of crushed ice were added, stirred for 20min, filtered and dried to give compound VII-A. LC/MS (ESI) m/z 331[ M+1 ]] + 。
Preparation of intermediate III-A in step 4)
Compound VII-A (56 mg,0.16 mmol) and imidazole (55 mg,0.8 mmol) were dissolved in dimethyl sulfoxide (DMSO) (5 ml), and K was added 2 CO 3 (150 mg,1.09 mmol) was heated to 70℃and stirred overnight. Cooling to room temperature, adding 20ml of ice water, filtering, washing with water, and drying to obtain the compound III-A. LC/MS (ESI) m/z 335[ M+1 ]] + ，333[M-1] + 。 1 H NMR(400MHz,DMSO-d 6 ):δ11.5(brs,1H),9.00(s,1H),8.66(d,2H),8.50(s,1H),7.96(m,3H),7.20(s,1H)。
Intermediates I-B to I-Z in Table 1 below can be prepared in the same manner as intermediate III-A
TABLE 1
Example 2:preparation of intermediate III-AA
Method C
Preparation of intermediate XII-AA in step 1)
Ethyl 2, 6-dichloropyrimidine-4-carboxylate (2.21 g,10 mmol) and imidazole (1.02 g,15 mmol) were dissolved in DMSO (25 ml), K was added 2 CO 3 (4.14 g,30 mmol) was heated to 70℃and stirred overnight. Cooled to room temperature, 200ml of ice water was added, filtered, and purified by silica gel column chromatography to give compound XII-AA (533 mg, yield 21%). LC/MS (ESI) m/z 253[ M+1 ]] + 。
Preparation of intermediate XII-AA in step 2)
Compound XII-AA (506 mg,2 mmol) and 6- (trifluoromethyl) pyridin-3-ylboronic acid (480 mg,2.5 mmol) were dissolved in dioxane (10 ml), saturated sodium carbonate (1 ml) was added, tetrakis (triphenylphosphine) palladium (115 mg,0.1 mmol) was degassed, heated to 100℃under nitrogen protection and stirred overnight. Cooled to room temperature, concentrated under reduced pressure, added with 50ml of ice water, extracted with ethyl acetate, dried, and purified by silica gel column chromatography to give compound XIII-AA (568 mg, yield 78%). LC/MS (ESI) m/z 364[ M+1 ] ] + 。
Preparation of intermediate I-AA in step 3)
Compound XIII-AA (500 mg,1.37 mmol) was dissolved in THF/MeOH/H 2 Adding lithium hydroxide (220 mg,9.2 mmol) into mixed solvent (15 ml) of O (1/1/1), stirring at room temperature overnight, concentrating under reduced pressure, adding ice water 20g, stirring, extracting with ethyl acetate, adjusting pH of aqueous phase to 6-7 with 6N hydrochloric acid, filtering, and drying to obtain compound I-AA (380 mg, yield 83%) LC/MS (ESI) m/z 336[ M+1 ]] + ，334[M-1]。
Intermediates I-BB to I-GG shown in Table 2 below can be prepared in the same manner as intermediate I-AA
TABLE 2
Example 3:preparation of intermediate II-1 hydrochloride
Method D
Preparation of intermediate XIV-1 in step 1)
BocNHNH 2 (13.2 g,100 mmol) was dissolved in 100ml acetone and 50ml methanol, anhydrous magnesium sulfate (12 g,100 mmol) was added, stirred overnight at room temperature, magnesium sulfate was removed by filtration, the filtrate was concentrated to dryness under reduced pressure, 100ml methanol was added for dissolution, sodium borohydride (15.2 g,400 mmol) was added in portions at room temperature, stirred for 1h, concentrated to dryness under reduced pressure, 200ml distilled water was added, 100ml×3 times extracted with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. Purification by silica gel column chromatography (20% ethyl acetate/petroleum ether) gave XIV-1 (15.1 g, yield 87%). LC/MS (ESI) m/z 175[ M+1 ] ] + 。
Preparation of intermediate XV-1 in step 2)
Intermediate XIV-1 (1.74 g,10 mmol), propylene oxide (2.9 g,50 mmol), DIEA (2.58 g,20 mmol) were dissolved in 20ml ethanol and stirred overnight at 80℃in a sealed reaction flask. Concentrating under reduced pressure to dryness, and purifying by silica gel column chromatography (20% -50% ethyl acetate/petroleum ether) to obtain XV-1 (1.82 g, yield 78%). LC/MS (ESI) M/z233[ M+1 ]] + 。
Preparation of intermediate II-1 hydrochloride in step 3)
1.82g of Compound XV-1 was dissolved in 10ml of methanol, a methanol solution of HCl (excess) was added, stirred overnight at room temperature, and concentrated to dryness under reduced pressure at 40℃to give intermediate II-1 hydrochloride (2.3 g, yield 95%). LC/MS (ESI) m/z 133[ M+1 ]] + 。
Example 4:preparation of intermediate II-2 hydrochloride
Method E
Preparation of intermediate XIV-2 in step 1)
BocNHNH was added sequentially to a 500ml round bottom flask 2 (30g，227mmol), 300ml of methanol, 20.4g of hydroxyacetone and anhydrous magnesium sulfate (68 g), stirring at room temperature for 3.5h, filtering to remove the magnesium sulfate, washing a filter cake with anhydrous methanol, adding sodium borohydride (15.2 g,400 mmol) to the filtrate in portions at 0 ℃ after the addition, stirring at room temperature for 1h, concentrating under reduced pressure to dryness, adding 200ml of distilled water, extracting 100ml x3 times with methylene chloride, merging organic phases, drying over anhydrous sodium sulfate, filtering, concentrating under reduced pressure to dryness. Purification by silica gel column chromatography (20-40% ethyl acetate/petroleum ether) gave XIV-2 (36 g, 84% yield). LC/MS (ESI) m/z 191[ M+1 ] ] + 。
Preparation of intermediate XV-2 in step 2)
To a 1L round bottom flask was added intermediate XVI-2 (19.0 g,100 mmol), acetone (17.4 g,300 mmol), methanol 300ml,1ml acetic acid, sodium cyanoborohydride (15.7 g,250 mmol) at room temperature and the reaction mixture was stirred overnight at room temperature. Concentrating under reduced pressure to dryness, adding distilled water, extracting with ethyl acetate, drying, filtering, and concentrating. Purification by silica gel column chromatography (10% -50% ethyl acetate/petroleum ether) afforded XV-2 (14.1 g, 61% yield) as a white solid. LC/MS (ESI) m/z 233[ M+1 ]] + 。
Preparation of intermediate II-2 hydrochloride in step 3)
The intermediate II-2 hydrochloride is prepared according to the step 3) of the preparation method of the intermediate II-1 hydrochloride, and the yield is 90%. LC/MS (ESI) m/z 133[ M+1 ]] + 。
Example 5:preparation of intermediate II-3
Preparation of intermediate XV-3 in step 1)
To a solution of 2-hydroxyethylhydrazine (5 g,65 mmol) in methanol (100 ml) at 0deg.C was added 13ml of triethylamine, boc 2 O (17.2 g,78 mmol), stirring at room temperature under nitrogen protection for 16h, concentrating under reduced pressure to dryness, adding citric acid solution, extracting with ethyl acetate, drying over anhydrous sodium sulfate, filtering, concentrating under reduced pressure to dryness. Purification by silica gel column chromatography (20-40% ethyl acetate/petroleum ether) gave XV-3 (6.8 g, 89% yield). LC/MS (ESI) m/z 177[ M+1 ] ] + 。
Preparation of intermediate II-3 in step 2)
Intermediate XV-3 (2 g,11.2 mmol) was dissolved in 50ml THF, lithium Aluminum Hydride (LAH) (1.7 g,44.8 mmol) was added, refluxed under nitrogen for 5h, cooled to 0deg.C, and Na was added in portions 2 SO 4 ·10H 2 O, filtering, washing a filter cake with THF, drying filtrate with anhydrous magnesium sulfate, and concentrating to obtain a crude II-3 product, wherein the crude II-3 product is directly used in the next step without purification. LC/MS (ESI) m/z 91[ M+1 ]] + 。
Example 6:preparation of intermediate II-4
Preparation of intermediate XV-4 in step 1)
2-hydroxyethylhydrazine (7.6 g,100 mmol) was added to a mixed solvent of methanol (100 ml) and acetone (50 ml) at 0℃and anhydrous magnesium sulfate (12 g,100 mmol) was added, stirred overnight at room temperature, the magnesium sulfate was removed by filtration, the filtrate was concentrated to dryness under reduced pressure, 100ml of methylene chloride was added for dissolution, triethylamine (20.2 g,200 mmol) was added, acetic anhydride (10.7 g,105 mmol) was added dropwise at 0℃and stirred overnight at room temperature, 200ml of distilled water was added, extraction with methylene chloride was performed, the organic phases were combined and concentrated to dryness under reduced pressure, tetrahydrofuran (50 ml) and 5ml of hydrochloric acid were added, stirred at room temperature for 12 hours, and concentrated to dryness under reduced pressure to obtain XV-4 which was used directly in the next step without purification. LC/MS (ESI) m/z 119[ M+1 ]] + 。
Preparation of intermediate II-4 in step 2)
Intermediate XV-4 (1.2 g,10 mmol) was dissolved in 50ml THF, lithium Aluminum Hydride (LAH) (1.5 g,44.8 mmol) was added, refluxed under nitrogen for 4h, cooled to below 0deg.C, and Na was added in portions 2 SO 4 ·10H 2 The reaction was quenched with O, filtered, the filter cake was washed with THF, the filtrate was dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure to give II-4.LC/MS (ESI) m/z 105[ M+1 ]] + 。
Example 7:preparation of intermediate II-5
Preparation of intermediate XVI-5 in step 1)
Intermediate XVI-1 (12.8 g,73.5 mmol), ethyl bromoacetate (36.6 g,219 mmol), anhydrous potassium carbonate (30.2 g,219 mmol) dissolved in 250ml DMF, heated to 80℃under nitrogen protection, stirred overnight, cooled to room temperature, extracted with water, ethyl acetate, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to dryness to give 18g of crude XVI-5. LC/MS (ESI) m/z 261[ M+1 ]] + 。
Preparation of intermediate XV-5 in step 2)
380ml of ethanol and NaBH were added sequentially to a 2L round bottom flask 4 (7.2 g,189 mmol) and LiCl (7.9 g,188 mmol), then a solution of XVI-5 (18 g,69 mmol) in THF (380 ml) was added dropwise at RT, stirred for 6h, concentrated under reduced pressure to remove the bulk of the solvent, extracted with water, ethyl acetate and the combined organic phases were taken up in anhydrous Na 2 SO 4 Drying, filtration, and concentration under reduced pressure gave XV-5 (12.9 g, 86% yield). LC/MS (ESI) m/z 219[ M+1 ]] + 。
Preparation of intermediate IV-5 in step 3)
XV-5 (12.9 g) was dissolved in 50ml dioxane, HCl dioxane solution (6N, 30 ml) was added, stirred overnight at room temperature, and concentrated to dryness under reduced pressure to give intermediate II-5 (12.8 g). LC/MS (ESI) m/z 119[ M+1 ] ] + 。
Example 8:preparation of intermediate IV-6
Preparation of intermediate XVII-6 in step 1)
To a solution of 3-methylmorpholine (1.0 g,10 mmol) in THF (15 ml) was added tert-butyl nitrite (1.1 g,11 mmol), refluxed for 12h, and concentrated to dryness under reduced pressure to give XVII-6 which was used directly in the next step without purification. LC/MS (ESI) m/z 131[ M+1 ]] + 。
Preparation of intermediate II-6 in step 2)
The intermediate XIX-6 (80 mmol) of the previous step was dissolved in 200ml of THF, LAH (6.1 g,160 mmol) was added in portions at 0℃and stirred overnight at room temperature, and Na was added in portions under cooling 2 SO 4 ·10H 2 O, filtration, washing of the cake with THF, drying of the filtrate over anhydrous magnesium sulfate, filtration and concentration under reduced pressure gave II-6 (yield 72%) of the compound. LC/MS (ESI) m/z 117[ M+1 ]] + 。
The hydrazine in Table 3 below can be prepared in the same manner as in the compound II-6.
TABLE 3 Table 3
Example 9:preparation of 6- (4-trifluoromethylphenyl) -N- (1-hydroxypropyl-2-yl) -N-isopropyl-2- (1H-imidazol-1-yl) pyrimidine-4-hydrazide (Compound 1)
I-A (36 mg,0.1 mmol), hydrazine hydrochloride (20 mg,0.12 mmol), 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU) (57 mg,0.15 mmol) prepared in example 1 was dissolved in 2ml Dimethylformamide (DMF), N, N-Diisopropylethylamine (DIPEA) (47 mg,0.36 mmol) was added, stirred overnight under nitrogen, diluted with ethyl acetate, washed with water, the organic phase dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure to afford Compound 1 (23 mg, yield 50%) which was purified by silica gel chromatography (PE/EA, 1:1). LC/MS (ESI) m/z 449[ M+1 ] ] + 。 1 H NMR(400MHz,DMSO-d 6 ):δ10.15(s,1H),9.00(s,1H),8.66(d,2H),8.56(s,1H),7.96(m,3H),7.19(s,1H),4.34-4.37(m,1H),3.40-3.48(m,1H),3.28-3.35(m,1H),3.16-3.23(m,2H),1.14-1.20(m,6H),0.98(d,J＝6.8Hz,3H)。
The compounds in table 4 below can be prepared in the same manner as in compound 1.
TABLE 4 Table 4
EXAMPLE 10 preparation of Compound 29
Compound 27 (39 mg,0.1 mmol) was dissolved in 5ml of DCM, DIPEA (0.1 ml) was added, cooled to 0deg.C, 0.06ml of acetic anhydride was added dropwise, the reaction was stirred overnight at room temperature, washed three times with water, dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and purified (PE/EA, 1:1) compound 29 by silica gel column chromatography. The yield thereof was found to be 77%. LC/MS (ESI) m/z 433[ M+1 ]] + 。 1 HNMR(400MHz,DMSO-d 6 ):δ10.13(s,1H),8.98(s,1H),8.66(d,2H),8.56(s,1H),7.96(m,3H),7.19(s,1H),3.27-3.18(m,1H),2.09(s,3H),1.14(d,J＝6.8Hz,6H)。
The compounds in table 5 below can be prepared according to the same method as compound 29.
TABLE 5
EXAMPLE 11 preparation of Compound 33
Following a similar procedure as in example 1, intermediate III-J and (S) -N- (2-aminopropyl) -1-methylcyclopropane-1-sulfonylamino were reacted to give compound 33.LC/MS (ESI) m/z 455[ M+H ]] + 。
Effect example 1 test of Compounds studied for AHR antagonism in human cell lines
Human liver cancer HepG2 cell lines (supplied by the chinese academy of sciences stem cell bank) endogenously expressing AHR proteins were used for the test. CYP1A1 gene expression is regulated by AHR activity, which upon activation binds to a sequence called an exogenous response element (xenobiotic response element, XRE) on the CYP1A1 enhancer and initiates CYP1A1 gene expression. To quantitatively measure the effect of compounds on AHR activity, a regulatory sequence 1200bp (-1143 to +57) upstream of the CYP1A1 gene promoter was inserted into a plasmid vector containing firefly luciferase after gene synthesis. The plasmid was then linearized by single cleavage and then transferred into HepG2 cells by Lipofectamine3000, and the transfected HepG2 cells were screened for stable expression by puromycin. In measuring antagonism of compounds and AHR, expression of firefly luciferase is triggered with AHR agonists (e.g., L-Kynurenine, kynurenic acid, indirubibin, TCDD, ITE (2- (1H-Indol-3-ylcarbonyl) -4-thiazolecarboxylic acid methyl ester)) and the like, while cells are treated with different concentrations of compounds, and inhibition of luciferase expression by the compounds is measured.
Stably transfected HepG2 cells were subcultured in Minimum Eagle's Medium (MEM) at 37℃in 5% carbon dioxide. MEM medium was supplemented with 1mM sodium pyruvate, 2mM GlutaMax,1 Xnonessential amino acids, 10% Australian fetal bovine serum, 100U/mL of green streptomycin, and 5ug/mL of puromycin. HepG2 cells were passaged 5-8X 10 before testing 4 Density of wells/wells were grown in 96-well plates and grown for 24-48 h to achieve-90% confluency (medium without puromycin) prior to drug treatment. Compound solutions containing AHR agonist at 2 x different concentrations were prepared with the same medium prior to drug treatment, and half of the cell culture medium in 96-well plates was replaced with 2 x compound solutionAnd (3) liquid. The negative control group was set to contain only AHR agonist solutions at the corresponding concentrations of DMSO, while the positive control group was set to CH223191, BAY2416964 at the corresponding concentrations.
Each compound (including positive control and negative control) was tested in 2 independent replicates. HepG2 cells were lysed by a Steady-Glo luciferase assay system from Promega after 24h of compound treatment and luciferase signal was measured using an InfiniteM1000 Pro microplate reader from Tecan.
For each group of compounds, the percentage of inhibition of AHR activity at the different compound concentrations was calculated in sequence using the well signal at compound concentration 0 as 100% and the cell signal of the untreated agonist as 0, and the average of the 2 groups of replicates was fitted by non-linearity according to the formulaCalculation of IC for Compound 50 Where y is the percent inhibition and x is the concentration of the corresponding compound.
Reference is made to: buckey, S.M.K.et al In vivo bioimaging with tissue-specific transcription factor activated luciferase reports. Sci.Rep.5:11842 (2015).
IC of each Compound 50 As shown in Table 6, wherein A represents IC 50 Less than or equal to 100nM, B represents 100nM < IC 50 Less than or equal to 1.0 mu MC represents 1 mu M < IC 50 Less than or equal to 5.0 mu M, D represents IC 50 >5.0μM
TABLE 6 EC of compounds 50
As can be seen from table 6, each of the above-mentioned compounds according to the present invention can inhibit those functions and signaling pathways controlled by AHR, and thus can affect the growth and proliferation of cancer cells and the invasiveness of tumor cells, and thus the 2-nitrogen substituted pyrimidine compounds represented by formula i of the present invention, each of optical isomers, deuterides, prodrugs or pharmaceutically acceptable salts thereof can be used to inhibit the growth of cancer cells, and inhibit the metastasis and invasion of tumor cells.
The foregoing is merely illustrative of the present invention, and the present invention is not limited thereto, and any person skilled in the art will readily appreciate variations or alternatives within the scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the protection scope of the claims.

Claims (10)

1. A class of 2-nitrogen substituted pyrimidines represented by the following formula i, each of which is an optical isomer, deuterate, prodrug or pharmaceutically acceptable salt thereof:
wherein,
ring A is C 6-10 Aryl or a 5-to 10-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S;
R 1 and R is 2 Each independently is hydrogen, saturated or unsaturated substituted or unsubstituted C 1 -C 8 Alkyl, saturated or unsaturated substituted or unsubstituted C 3 -C 8 Cycloalkyl, -OC (=o) C 1-8 Alkyl, -OC (=o) C 3 -C 8 Cycloalkyl, -C (=o) OC 1 -C 8 Alkyl, -C (=o) C 3 -C 8 Cycloalkyl, -S (O) m R c Saturated or unsaturated substituted or unsubstituted C 1 -C 8 Acyl, C 6 -C 14 Aryl, 4 to 14 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S or 5 to 14 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S, containingSaturated or unsaturated, halogenated or unhalogenated C of radicals 1-8 Alkyl group containing->Saturated or unsaturated, halogenated or unhalogenated C of radicals 3-8 Cycloalkyl, wherein said "substituted" means optionally substituted with 1 to 10 deuterium, or optionally containing 1 to 4 groups selected from hydroxy, halogen, cyano, amino, -S (O) m R c 、-NR d R e Saturated or unsaturated C 1 -C 8 Alkyl, saturated or unsaturated C 3 -C 8 Cycloalkyl, saturated or unsaturated C 1 -C 8 Alkoxy, saturated or unsaturated C 3 -C 8 Cycloalkoxy, -OC (=O) C 1 -C 8 Alkyl, -OC (=o) C 3 -C 8 Cycloalkyl, -C (=o) OC 1-8 Alkyl, -C (=o) OC 3 -C 8 Cycloalkyl, containing->Saturated or unsaturated, halogenated or unhalogenated C of radicals 1-8 Alkyl group containingSaturated or unsaturated, halogenated or unhalogenated C of radicals 3-8 Cycloalkyl, saturated or unsaturated C 1 -C 8 Acyl, saturated or unsaturated C 1 -C 8 Alkoxycarbonyl group, C 6 -C 14 Aryl, a 4 to 14 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, or a 5 to 14 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S;
or R is 1 And R is 2 Form, together with the N atom to which they are attached, a substituted or unsubstituted 4 to 14 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, wherein "substituted" means substituted with 1 to 10 deuterium, or optionally containing 1 to 4 heteroatoms selected from hydroxy, halogen, Cyano, -S (O) m R c 、-NR d R e ，C 1 ～C 8 Alkyl, C 3 ～C 8 Cycloalkyl, C 1 ～C 8 Alkoxy, C 3 ～C 8 Cycloalkoxy, -OC (=o) C 1-8 Alkyl, -OC (=o) C 3 ～C 8 Cycloalkyl, -C (=o) OC 1-8 Alkyl, -C (=O) OC 3 ～C 8 Cycloalkyl group containingSaturated or unsaturated, halogenated or unhalogenated C of radicals 1-8 Alkyl group containing->Saturated or unsaturated, halogenated or unhalogenated C of radicals 3-8 Cycloalkyl, R f Substituted C 1 ～C 8 Alkyl, C 3 ～C 8 Cycloalkyl, C 1 ～C 8 Alkoxy, C 3 ～C 8 Substituents for cycloalkoxy;
R 3 selected from deuterium, halogen, nitro, cyano, carboxyl, hydroxyl, -NR d R e 、-OR g 、-CO 2 R g 、-S(O) m R c Or by 1 to 3R h Substituted C 1-8 Alkyl, C 3-8 Cycloalkyl, C 1-8 Alkoxy, C 3-8 Cycloalkoxy radicals C 1-8 Alkoxycarbonyl group, C 1-8 Alkylcarbonyl, C 1-8 Alkylcarboxy, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl.
R 4 Is H or D;
l is a bond or-NHR i ；
R a 、R b Each independently selected from saturated or unsaturated substituted or unsubstituted C 3 -C 8 Cycloalkyl, saturated or unsaturated substituted or unsubstituted C 1 -C 8 Alkyl, substituted or unsubstituted 6-10 membered aryl or substituted or unsubstituted hetero 1-containing-3 4-to 10-membered heteroaryl groups selected from N, O and S heteroatoms, wherein said "substituted" means optionally substituted with 1 to 10 deuterium, or optionally containing 1 to 4 groups selected from hydroxy, halogen, cyano, -S (O) m R c 、-NR d R e Saturated or unsaturated C 1 -C 8 Alkyl, saturated or unsaturated C 3 -C 8 Cycloalkyl, saturated or unsaturated C 1 -C 8 Alkoxy, saturated or unsaturated C 3 -C 8 Cycloalkoxy, -OC (=O) C 1 -C 8 Alkyl, -OC (=o) C 3 -C 8 Cycloalkyl, -C (=o) OC 1-8 Alkyl, -C (=o) OC 3 -C 8 Cycloalkyl, saturated or unsaturated C 1 -C 8 Acyl, saturated or unsaturated C 1 -C 8 Alkoxycarbonyl group containingSaturated or unsaturated, halogenated or unhalogenated C of radicals 1-8 Alkyl group containing->Saturated or unsaturated, halogenated or unhalogenated C of radicals 3-8 Cycloalkyl, C 6 -C 14 Aryl, a 4 to 14 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, or a 5 to 14 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S;
or R is a And R is b Form, together with the N atom to which they are attached, a substituted or unsubstituted 4 to 14 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, a substituted or unsubstituted 5 to 14 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S, wherein "substituted" means substituted with 1 to 10 deuterium, or optionally containing 1 to 4 heteroatoms selected from hydroxy, halogen, cyano, sulfonyl, carboxy-S (O) m R c 、-NR d R e ，C 1 ～C 8 Alkyl, C 3 ～C 8 Cycloalkyl, C 1 ～C 8 Alkoxy, C 3 ～C 8 Cycloalkoxy, -OC (=o) C 1-8 Alkyl, -OC (=o) C 3 ～C 8 Cycloalkyl, -C (=o) OC 1-8 Alkyl, -C (=O) OC 3 ～C 8 Cycloalkyl group containingSaturated or unsaturated, halogenated or unhalogenated C of radicals 1-8 Alkyl group containing->Saturated or unsaturated, halogenated or unhalogenated C of radicals 3-8 Cycloalkyl, R f Substituted C 1 ～C 8 Alkyl, C 3 ～C 8 Cycloalkyl, C 1 ～C 8 Alkoxy, C 3 ～C 8 Substituents for cycloalkoxy groups, wherein R f Selected from deuterium, halogen, cyano, hydroxy, amino, saturated or unsaturated C 1 ～C 6 Alkyl, saturated or unsaturated C 3 ～C 6 Cycloalkyl, -S (O) m R c 、NR d R e Saturated or unsaturated C substituted by deuterium, halogen, hydroxy or amino 1 ～C 6 Alkyl, C substituted by deuterium, halogen, hydroxy or amino 3 ～C 6 Cycloalkyl, saturated or unsaturated C 1 ～C 6 Alkoxy, C 3 ～C 6 Cyclic alkoxy, saturated or unsaturated, substituted C by deuterium, halogen, hydroxy or amino 1 ～C 6 Alkoxy, C substituted by deuterium, halogen, hydroxy or amino 3 ～C 6 A cycloalkoxy group;
n is an integer of 0, 1, 2, 3, 4 or 5;
n1 is an integer of 0, 1 or 2;
m is an integer of 0, 1 or 2;
R c 、R g 、R h and R is i Each independently selected from hydrogen, hydroxy, amino, saturated or unsaturated substituted or unsubstituted C 1 -C 8 Alkyl, saturated or unsaturated substituted or unsubstituted C 3 -C 8 Cycloalkyl, -C (=o) C 1-8 Alkyl, -C (=o) C 3 -C 8 Cycloalkyl, -C (=o) OC 1 -C 8 Alkyl, -C (=o) OC 3 -C 8 Cycloalkyl, -C (=o) NC 1 -C 8 Alkyl, -C (=o) NC 3 -C 8 Cycloalkyl, C 1 -C 8 Sulfo, saturated or unsaturated substituted or unsubstituted C 1 -C 8 Sulfonyl, C 6 -C 14 Aryl, C 7 -C 14 Arylalkyl, 4 to 14 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S or 5 to 14 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S, wherein said "substituted" means substituted with 1 to 10 deuterium, or optionally containing 1 to 4 heteroatoms selected from hydroxy, halogen, cyano, sulfonyl, C 1 -C 8 Sulfo group, -NR d R e Saturated or unsaturated C 1 -C 8 Alkyl, saturated or unsaturated C 3 -C 8 Cycloalkyl, saturated or unsaturated C 1 -C 8 Alkoxy, saturated or unsaturated C 3 -C 8 Cycloalkoxy, -OC (=O) C 1 -C 8 Alkyl, -OC (=o) C 3 -C 8 Cycloalkyl, -C (=o) OC 1-8 Alkyl, -C (=o) O C 3 -C 8 Cycloalkyl, saturated or unsaturated C 1 -C 8 Sulfonyl, saturated or unsaturated C 1 -C 8 Acyl, saturated or unsaturated C 1 -C 8 Alkoxycarbonyl group, C 6 -C 14 Aryl, a 4 to 14 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, or a 5 to 14 membered heteroaryl substituent containing 1 to 3 heteroatoms selected from N, O and S, wherein R c Is not hydrogen;
R d and R is e Each independently selected from hydrogen, halogen, cyano, hydroxy, saturated or unsaturated C 1 ～C 3 Alkyl, C 3 ～C 6 Cycloalkyl, saturated or unsaturated C substituted by halogen or hydroxy 1 ～C 3 Alkyl, C substituted by halogen or hydroxy 3 ～C 6 Cycloalkyl, saturated or unsaturated C 1 ～C 3 Alkoxy, C 3 ～C 6 Cyclic alkoxy, saturated or unsaturated, substituted C by halogen or hydroxy 1 ～C 3 Alkoxy, C substituted by halogen or hydroxy 3 ～C 6 A cycloalkoxy group.
2. The 2-nitrogen substituted pyrimidine compound of formula I according to claim 1, wherein each of the optical isomers, deuterates, prodrugs or pharmaceutically acceptable salts thereof,
preferably, ring A is C 6～10 Aryl or a 5-to 8-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O and S.
3. The 2-nitrogen substituted pyrimidine compound of formula I according to claim 1, wherein each of the optical isomers, deuterates, prodrugs or pharmaceutically acceptable salts thereof,
preferably, R 1 And R is 2 Each independently is hydrogen, saturated or unsaturated substituted or unsubstituted C 1 -C 6 Alkyl, saturated or unsaturated substituted or unsubstituted C 3 -C 6 Cycloalkyl, -OC (=o) C 1-6 Alkyl, -OC (=o) C 3 -C 6 Cycloalkyl, -C (=o) OC 1 -C 6 Alkyl, -C (=o) C 3 -C 6 Cycloalkyl, -S (O) m R c Saturated or unsaturated substituted or unsubstituted C 1 -C 6 Sulfonyl, saturated or unsaturated substituted or unsubstituted C 1 -C 6 Acyl, C 6 -C 10 Aryl, 5-to 10-membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S or 5-to 10-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S, containingSaturated or unsaturated, halogenated or unhalogenated C of radicals 1-6 Alkyl group containing->Saturated or unsaturated, halogenated or unhalogenated C of radicals 3-6 Cycloalkyl, wherein said "substituted" means substituted with 1 to 10 deuterium groups or optionally containing 1 to 4 groups selected from hydroxy, halogen, cyano, -S (O) m R c 、-NR d R e Saturated or unsaturated C 1 -C 6 Alkyl, saturated or unsaturated C 3 -C 6 Cycloalkyl, saturated or unsaturated C 1 -C 6 Alkoxy, saturated or unsaturated C 3 -C 6 Cycloalkoxy, -OC (=O) C 1 -C 6 Alkyl, -OC (=o) C 3 -C 6 Cycloalkyl, -C (=o) OC 1-6 Alkyl, -C (=o) OC 3 -C 6 Cycloalkyl, containing->Saturated or unsaturated, halogenated or unhalogenated C of radicals 1-6 Alkyl group containing->Saturated or unsaturated, halogenated or unhalogenated C of radicals 3-6 Cycloalkyl, saturated or unsaturated C 1 -C 6 Acyl, saturated or unsaturated C 1 -C 6 Alkoxycarbonyl group, C 6 -C 10 Aryl, a 5 to 10 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, or a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S;
Or R is 1 And R is 2 Form, together with the N atom to which they are attached, a substituted or unsubstituted 5-to 10-membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, wherein said "substituted" means substituted with 1 to 10 deuterium, or optionally containing 1 to 4 heteroatoms selected from hydroxy, halogen, cyano, -S (O) m R c 、-NR d R e ，C 1 ～C 6 Alkyl, C 3 ～C 6 Cycloalkyl, C 1 ～C 6 Alkoxy, C 3 ～C 6 Cycloalkoxy, -OC (=o) C 1-6 Alkyl, -OC(＝O)C 3 ～C 6 Cycloalkyl, -C (=o) OC 1-6 Alkyl, -C (=O) OC 3 ～C 6 Cycloalkyl group containingSaturated or unsaturated, halogenated or unhalogenated C of radicals 1-6 Alkyl group containing->Saturated or unsaturated, halogenated or unhalogenated C of radicals 3-6 Cycloalkyl, R f Substituted C 1 ～C 6 Alkyl, C 3 ～C 6 Cycloalkyl, C 1 ～C 6 Alkoxy, C 3 ～C 6 Substituents for cycloalkoxy;
more preferably, R 1 And R is 2 Each independently is hydrogen, saturated or unsaturated substituted or unsubstituted C 1 -C 4 Alkyl, saturated or unsaturated substituted or unsubstituted C 3 -C 6 Cycloalkyl, -OC (=o) C 1-4 Alkyl, -OC (=o) C 3 -C 6 Cycloalkyl, -C (=o) OC 1 -C 4 Alkyl, -C (=o) C 3 -C 6 Cycloalkyl, -S (O) m R c Saturated or unsaturated substituted or unsubstituted C 1 -C 4 Acyl, C 6 -C 10 Aryl, 5-to 8-membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S or 5-to 8-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S, containing Saturated or unsaturated, halogenated or unhalogenated C of radicals 1-4 Alkyl group containingSaturated or unsaturated, halogenated or unhalogenated C of radicals 3-6 Cycloalkyl, wherein the "substitution" refers to substitution with 1 to 10 deuterium, or optionallyContaining 1 to 3 groups selected from hydroxy, halogen, cyano, -S (O) m R c 、-NR d R e Saturated or unsaturated C 1 -C 4 Alkyl, saturated or unsaturated C 3 -C 6 Cycloalkyl, saturated or unsaturated C 1 -C 4 Alkoxy, saturated or unsaturated C 3 -C 6 Cycloalkoxy, -OC (=O) C 1 -C 4 Alkyl, -OC (=o) C 3 -C 6 Cycloalkyl, -C (=o) OC 1-4 Alkyl, -C (=o) OC 3 -C 6 Cycloalkyl, containing->Saturated or unsaturated, halogenated or unhalogenated C of radicals 1-4 Alkyl group containing->Saturated or unsaturated, halogenated or unhalogenated C of radicals 3-6 Cycloalkyl, saturated or unsaturated C 1 -C 4 Acyl, saturated or unsaturated C 1 -C 4 Alkoxycarbonyl group, C 6 -C 10 Aryl, a 5 to 8 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, or a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S;
or R is 1 And R is 2 Form, together with the N atom to which they are attached, a substituted or unsubstituted 5-to 8-membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, wherein said "substituted" means substituted with 1 to 10 deuterium, or optionally containing 1 to 3 heteroatoms selected from hydroxy, halogen, cyano, -S (O) m R c 、-NR d R e ，C 1 ～C 4 Alkyl, C 3 ～C 6 Cycloalkyl, C 1 ～C 4 Alkoxy, C 3 ～C 6 Cycloalkoxy, -OC (=o) C 1-4 Alkyl, -OC (=o) C 3 ～C 6 Cycloalkyl, -C (=o) OC 1-4 Alkyl, -C (=O) OC 3 ～C 6 Cycloalkyl group containingSaturated or unsaturated, halogenated or unhalogenated C of radicals 1-4 Alkyl group containing->Saturated or unsaturated, halogenated or unhalogenated C of radicals 3-6 Cycloalkyl, R f Substituted C 1 ～C 4 Alkyl, C 3 ～C 6 Cycloalkyl, C 1 ～C 4 Alkoxy, C 3 ～C 6 Substituents for cycloalkoxy groups, wherein R f Selected from deuterium, halogen, cyano, hydroxy, amino, saturated or unsaturated C 1 ～C 4 Alkyl, saturated or unsaturated C 3 ～C 6 Cycloalkyl, -S (O) m R c 、NR d R e Saturated or unsaturated C substituted by deuterium, halogen, hydroxy or amino 1 ～C 4 Alkyl, C substituted by deuterium, halogen, hydroxy or amino 3 ～C 6 Cycloalkyl, saturated or unsaturated C 1 ～C 4 Alkoxy, C 3 ～C 6 Cyclic alkoxy, saturated or unsaturated, substituted C by deuterium, halogen, hydroxy or amino 1 ～C 4 Alkoxy, C substituted by deuterium, halogen, hydroxy or amino 3 ～C 6 A cycloalkoxy group;
preferably, R 3 Selected from deuterium, halogen, nitro, cyano, carboxyl, hydroxyl, -NR d R e 、-OR g 、-CO 2 R g 、-S(O) m R c Or by 1 to 3R h Substituted C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy radicals C 1-6 Alkoxycarbonyl group, C 1-6 Alkylcarbonyl, C 1-6 Alkylcarboxy, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl;
More preferably, R 3 Selected from deuterium, halogen, nitro, cyano, carboxyl, hydroxyl, -NR d R e 、-OR g 、-CO 2 R g 、-S(O) m R c Or by 1 to 3R h Substituted C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 3-6 Cycloalkoxy radicals C 1-4 Alkoxycarbonyl group, C 1-4 Alkylcarbonyl, C 1-4 Alkylcarboxy, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl;
preferably, R a 、R b Each independently selected from saturated or unsaturated substituted or unsubstituted C 3 -C 6 Cycloalkyl, saturated or unsaturated substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted 6-10 membered aryl or substituted or unsubstituted 5-8 membered heteroaryl containing from 1 to 3 heteroatoms selected from N, O and S, wherein "substituted" means substituted with 1 to 10 deuterium, or optionally containing 1 to 3 heteroatoms selected from hydroxy, halogen, cyano, -S (O) m R c 、-NR d R e Saturated or unsaturated C 1 -C 6 Alkyl, saturated or unsaturated C 3 -C 6 Cycloalkyl, saturated or unsaturated C 1 -C 6 Alkoxy, saturated or unsaturated C 3 -C 6 Cycloalkoxy, -OC (=O) C 1 -C 6 Alkyl, -OC (=o) C 3 -C 6 Cycloalkyl, -C (=o) OC 1-6 Alkyl, -C (=o) OC 3 -C 6 Cycloalkyl, saturated or unsaturated C 1 -C 6 Acyl, saturated or unsaturated C 1 -C 6 Alkoxycarbonyl group containingSaturated or unsaturated, halogenated or unhalogenated C of radicals 1-6 Alkyl group containing->Saturated or unsaturated, halogenated or unhalogenated C of radicals 3-6 Cycloalkyl, C 6 -C 10 Aryl, 5 to 10 membered containing 1 to 3 heteroatoms selected from N, O and SA heterocycloalkyl or a substituent of a 5 to 10 membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O and S;
or R is a And R is b Form, together with the N atom to which they are attached, a substituted or unsubstituted 4 to 10 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, a substituted or unsubstituted 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S, wherein said "substituted" means substituted with 1 to 10 deuterium, or optionally containing 1 to 4 heteroatoms selected from hydroxy, halogen, cyano, sulfonyl, carboxy, -S (O) m R c 、-NR d R e ，C 1 ～C 6 Alkyl, C 3 ～C 6 Cycloalkyl, C 1 ～C 6 Alkoxy, C 3 ～C 6 Cycloalkoxy, -OC (=o) C 1-6 Alkyl, -OC (=o) C 3 ～C 6 Cycloalkyl, -C (=o) OC 1-6 Alkyl, -C (=O) OC 3 ～C 6 Cycloalkyl group containingSaturated or unsaturated, halogenated or unhalogenated C of radicals 1-6 Alkyl group containing->Saturated or unsaturated, halogenated or unhalogenated C of radicals 3-6 Cycloalkyl, R f Substituted C 1 ～C 6 Alkyl, C 3 ～C 6 Cycloalkyl, C 1 ～C 6 Alkoxy, C 3 ～C 6 Substituents for cycloalkoxy;
more preferably, R a 、R b Each independently selected from saturated or unsaturated substituted or unsubstituted C 3 -C 6 Cycloalkyl, saturated or unsaturated substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted 6-10 membered aryl or substituted or unsubstituted 5-8 membered heteroaryl containing from 1 to 3 heteroatoms selected from N, O and S, wherein "substituted" means substituted with from 1 to 10 deuterium, or optionally containing from 1 to 3 heteroatomsFrom hydroxy, halogen, cyano, -S (O) m R c 、-NR d R e Saturated or unsaturated C 1 -C 4 Alkyl, saturated or unsaturated C 3 -C 6 Cycloalkyl, saturated or unsaturated C 1 -C 4 Alkoxy, saturated or unsaturated C 3 -C 6 Cycloalkoxy, -OC (=O) C 1 -C 4 Alkyl, -OC (=o) C 3 -C 6 Cycloalkyl, -C (=o) OC 1-4 Alkyl, -C (=o) OC 3 -C 6 Cycloalkyl, saturated or unsaturated C 1 -C 4 Acyl, saturated or unsaturated C 1 -C 4 Alkoxycarbonyl group containingSaturated or unsaturated, halogenated or unhalogenated C of radicals 1-4 Alkyl group containing->Saturated or unsaturated, halogenated or unhalogenated C of radicals 3-6 Cycloalkyl, C 6 -C 10 Aryl, a 5 to 10 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, or a 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S;
or R is a And R is b And form together with the N atom to which they are attached a substituted or unsubstituted 5-to 8-membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, a substituted or unsubstituted 5-to 6-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S, wherein said "substituted" means substituted with 1 to 10 deuterium, or optionally containing 1 to 3 heteroatoms selected from hydroxy, halogen, cyano, sulfonyl, carboxy, -S (O) m R c 、-NR d R e ，C 1 ～C 4 Alkyl, C 5 ～C 6 Cycloalkyl, C 1 ～C 4 Alkoxy, C 5 ～C 6 Cycloalkoxy, -OC (=o) C 1-4 Alkyl, -OC (=o) C 5 ～C 6 Cycloalkyl, -C (=o) OC 1-4 Alkyl, -C (=O)OC 5 ～C 6 Cycloalkyl group containingSaturated or unsaturated, halogenated or unhalogenated C of radicals 1-4 Alkyl group containing->Saturated or unsaturated, halogenated or unhalogenated C of radicals 3-6 Cycloalkyl, R f Substituted C 1 ～C 4 Alkyl, C 5 ～C 6 Cycloalkyl, C 1 ～C 4 Alkoxy, C 5 ～C 6 Substituents for cycloalkoxy;
preferably, R c 、R f 、R g 、R h And R is i Each independently selected from hydrogen, hydroxy, amino, saturated or unsaturated substituted or unsubstituted C 1 -C 6 Alkyl, saturated or unsaturated substituted or unsubstituted C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, -C (=o) C 1-6 Alkyl, -C (=o) C 3 -C 6 Cycloalkyl, -C (=o) OC 1 -C 6 Alkyl, -C (=o) OC 3 -C 6 Cycloalkyl, -C (=o) NC 1 -C 6 Alkyl, -C (=o) NC 3 -C 6 Cycloalkyl, saturated or unsaturated substituted or unsubstituted C 1 -C 6 Sulfonyl, C 6 -C 10 Aryl, C 7 -C 11 Arylalkyl, a 5-to 10-membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, or a 5-to 10-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S, wherein said "substituted" means substituted with 1 to 10 deuterium, or optionally containing 1 to 4 heteroatoms selected from hydroxy, halogen, cyano, sulfonyl, C 1 -C 6 Sulfo group, -NR d R e Saturated or unsaturated C 1 -C 6 Alkyl, saturated or unsaturated C 3 -C 6 Cycloalkyl, saturated or unsaturated C 1 -C 6 Alkoxy, saturated or unsaturated C 3 -C 6 Cycloalkoxy, -OC (=O) C 1 -C 6 Alkyl, -OC (=o) C 3 -C 8 Cycloalkyl, -C (=o) OC 1-6 Alkyl, -C (=o) OC 3 -C 6 Cycloalkyl, saturated or unsaturated C 1 -C 6 Sulfonyl, saturated or unsaturated C 1 -C 6 Acyl, saturated or unsaturated C 1 -C 6 Alkoxycarbonyl group, C 6 -C 10 Aryl, a 5-to 10-membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, or a 5-to 10-membered heteroaryl substituent containing 1 to 3 heteroatoms selected from N, O and S, wherein R c Is not hydrogen;
more preferably, R c 、R f 、R g 、R h And R is i Each independently selected from hydrogen, hydroxy, amino, saturated or unsaturated substituted or unsubstituted C 1 -C 4 Alkyl, saturated or unsaturated substituted or unsubstituted C 1 -C 4 Alkyl, C 4 -C 6 Cycloalkyl, -C (=o) C 1-4 Alkyl, -C (=o) C 4 -C 6 Cycloalkyl, -C (=o) OC 1 -C 4 Alkyl, -C (=o) OC 4 -C 8 Cycloalkyl, -C (=o) NC 1 -C 4 Alkyl, -C (=o) NC 4 -C 6 Cycloalkyl, saturated or unsaturated substituted or unsubstituted C 1 -C 4 Sulfonyl, C 6 -C 10 Aryl, C 7 -C 11 Arylalkyl, a 5-to 8-membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, or a 5-to 10-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S, wherein said "substituted" means substituted with 1 to 10 deuterium, or optionally containing 1 to 3 heteroatoms selected from hydroxy, halogen, cyano, sulfonyl, C 1 -C 4 Sulfo group, -NR d R e Saturated or unsaturated C 1 -C 4 Alkyl, saturated or unsaturated C 4 -C 6 Cycloalkyl, saturated or unsaturated C 1 -C 4 Alkoxy, saturated or unsaturated C 4 -C 6 Cycloalkoxy, -OC (=O) C 1 -C 4 Alkyl, -OC (=o) C 4 -C 6 Cycloalkyl radicals、-C(＝O)OC 1-4 Alkyl, -C (=o) OC 4 -C 6 Cycloalkyl, saturated or unsaturated C 1 -C 4 Sulfonyl, saturated or unsaturated C 1 -C 4 Acyl, saturated or unsaturated C 1 -C 4 Alkoxycarbonyl group, C 6 -C 10 Aryl, a 5-to 8-membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, or a 5-to 10-membered heteroaryl substituent containing 1 to 3 heteroatoms selected from N, O and S, wherein R c Is not hydrogen;
more preferably, R f Selected from deuterium, halogen, cyano, hydroxy, amino, saturated or unsaturated C 1 ～C 6 Alkyl, saturated or unsaturated C 3 ～C 6 Cycloalkyl, -S (O) m R c 、NR d R e Saturated or unsaturated C substituted by deuterium, halogen, hydroxy or amino 1 ～C 6 Alkyl, C substituted by deuterium, halogen, hydroxy or amino 3 ～C 6 Cycloalkyl, saturated or unsaturated C 1 ～C 6 Alkoxy, C 3 ～C 6 Cyclic alkoxy, saturated or unsaturated, substituted C by deuterium, halogen, hydroxy or amino 1 ～C 6 Alkoxy, C substituted by deuterium, halogen, hydroxy or amino 3 ～C 6 A cycloalkoxy group.
4. The 2-nitrogen substituted pyrimidine compound of formula I according to claim 1, wherein each of the optical isomers, deuterates, prodrugs or pharmaceutically acceptable salts thereof,
More preferably, R in formula I 1 And R is 2 The structure formed with the N atom to which they are attached is selected from the group consisting of:
5. the 2-nitrogen substituted pyrimidine compound of formula I according to claim 1, wherein each of the optical isomers, deuterates, prodrugs or pharmaceutically acceptable salts thereof,
more preferably, R in formula I a And R is b The structure formed with the N atom to which they are attached is selected from the group consisting of:
wherein R is j And R is k Each occurrence is independently hydroxy, halogen, cyano, sulfonyl, amino, C 1 ～C 8 Alkyl, C 3 ～C 8 Cycloalkyl, C 1 ～C 8 Alkoxy, C 3 ～C 8 Cycloalkoxy, -OC (=o) C 1-8 Alkyl, -OC (=o) C 3 ～C 8 Cycloalkyl, -C (=o) OC 1-8 Alkyl, -C (=O) OC 3 ～C 8 Cycloalkyl, R f Substituted C 1 ～C 8 Alkyl, C 3 ～C 8 Cycloalkyl, C 1 ～C 8 Alkoxy, C 3 ～C 8 Substituents for cycloalkoxy; n2 is an integer of 0, 1, 2, 3, 4 or 5;
preferably, R j And R is k Each occurrence is independently hydroxy, halogen, cyano, sulfonyl, amino C 1 ～C 6 Alkyl, C 3 ～C 6 Cycloalkyl, C 1 ～C 6 Alkoxy, C 3 ～C 6 Cycloalkoxy, -OC (=o) C 1-6 Alkyl, -OC (=o) C 3 ～C 6 Cycloalkyl, -C (=o) OC 1-6 Alkyl, -C (=O) OC 3 ～C 6 Cycloalkyl, R f Substituted C 1 ～C 6 Alkyl, C 3 ～C 6 Cycloalkyl, C 1 ～C 6 Alkoxy, C 3 ～C 6 Substituents for cycloalkoxy;
more preferably, R j And R is k Each occurrence is independently hydroxy, halogen, cyano, sulfonyl, amino C 1 ～C 4 Alkyl, C 4 ～C 6 Cycloalkyl, C 1 ～C 4 Alkoxy, C 4 ～C 6 Cycloalkoxy, -OC (=o) C 1-4 Alkyl, -OC (=o) C 4 ～C 6 Cycloalkyl, -C (=o) OC 1-4 Alkyl, -C (=O) OC 4 ～C 6 Cycloalkyl, substituted by halogen, hydroxy, amino or R f Substituted C 1 ～C 4 Alkyl, C 4 ～C 6 Cycloalkyl, C 1 ～C 4 Alkoxy, C 4 ～C 6 Substituents for cycloalkoxy groups.
6. 2-nitrogen substituted pyrimidines of formula i according to any one of claims 1 to 5, which are each optical isomers, deuterates, prodrugs or pharmaceutically acceptable salts thereof, characterized in that the 2-nitrogen substituted pyrimidines are selected from the following compounds:
7. a pharmaceutical composition comprising a therapeutically effective amount of a 2-nitrogen substituted pyrimidine compound of formula i according to any one of claims 1 to 6, each of which is an optical isomer, deuterate, prodrug or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.
8. Use of a 2-nitrogen substituted pyrimidine compound of formula i according to any one of claims 1 to 6, each of which is an optical isomer, deuterate, prodrug or pharmaceutically acceptable salt thereof for the preparation of an AHR disorder inhibitor.
9. Use of a 2-nitrogen substituted pyrimidine compound of formula i according to any one of claims 1 to 6, each of which is an optical isomer, deuterate, prodrug or pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of a tumor associated with an AHR disorder.
10. A method of treating a tumor associated with an AHR disorder, the method comprising administering to a subject in need thereof an effective amount of a 2-nitrogen substituted pyrimidine of formula i according to any one of claims 1 to 6, each of which is an optical isomer, deuterate, prodrug or pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 7.
CN202211003425.9A 2022-08-19 2022-08-19 2-nitrogen substituted pyrimidine compound, and preparation method and application thereof Pending CN117624135A (en)

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US20060178388A1 (en) * 2005-02-04 2006-08-10 Wrobleski Stephen T Phenyl-substituted pyrimidine compounds useful as kinase inhibitors
WO2006127588A2 (en) * 2005-05-24 2006-11-30 Vertex Pharmaceuticals Incorporated Modulators of atp-binding cassette transporters
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