Polysubstituted aminoquinoline compound and use thereof

Abstract

Disclosed in the present invention are a polysubstituted aminoquinoline compound and the use thereof. Specifically disclosed in the present invention is a compound as represented by formula (I), or a stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof. The compound of the present invention is a CD38 inhibitor, and can be used in the preparation of a drug for treating and / or preventing diseases related to abnormal expression or activity of CD38.

Description

A multi-substituted aminoquinoline compound and its uses Technical Field

[0001] This invention relates to the field of pharmaceutical technology, specifically to a multi-substituted aminoquinoline compound and its uses. Background Technology

[0002] CD38 is a member of the ADP-ribosyl cyclase family, primarily responsible for the degradation of NAD+ (nicotinamide adenine dinucleotide), and is widely expressed on the surface of various cell types. It was initially thought to be a surface antigen on immune cells and also plays a role in cell signaling and intracellular calcium metabolism. 2+ CD38 plays an important role in regulation and cellular metabolism. It can convert NAD+ into ADPR (ADP-ribose) or cADPR (cyclic ADPR) and nicotinamide, participating in intracellular and extracellular metabolic regulation and signal transduction pathways.

[0003] NAD+ is an important intracellular redox carrier involved in cellular metabolism, energy balance, and cell signaling. Regulation of NAD+ levels is crucial for maintaining normal cellular function. CD38, as a consumer of NAD+, can increase NAD+ levels through inhibition, potentially offering therapeutic benefits for certain diseases associated with decreased NAD+ levels.

[0004] CD38 is a surface protein widely expressed in various cell types, including immune cells such as B cells, T cells, and natural killer (NK) cells. It plays a crucial role in cell signaling, cell proliferation, differentiation, and senescence. CD38 activity is associated with a variety of biological processes, including calcium regulation, cell cycle control, and age-related diseases. Studies have shown that CD38 knockout (KO) mice exhibit significantly reduced levels of endogenous cADPR in multiple tissues / organs, affecting the function of various cell types, including pancreatic islets, acinar cells, and neutrophils. Furthermore, CD38 expression is closely related to the immunosuppressive function of regulatory T cells (Tregs), tumor-associated macrophages (TAMs), and myeloid-derived suppressor cells (MDSCs). In the tumor microenvironment, CD38 expression is associated with tumor progression and may promote tumor escape from immune checkpoint inhibition by influencing T cell function.

[0005] The role of CD38 in tumorigenesis and immunosuppression is an active area of ​​research. Studies have reported that aberrant expression or activity of CD38 is associated with the development of various cancers, including non-small cell lung cancer, melanoma, cervical cancer, glioma, colorectal cancer, and esophageal cancer. Furthermore, CD38 is also associated with various diseases such as HIV / AIDS, adoptive T-cell therapy, and pancreatic cancer.

[0006] In summary, CD38 plays a crucial role not only in cellular physiological functions but is also closely related to the development and progression of various diseases. Inhibiting abnormal expression or activity of CD38 may provide new strategies for treating related diseases. However, the efficacy and selectivity of existing CD38 inhibitors do not meet clinical needs.

[0007] Therefore, there is an urgent need in the field for a CD38 inhibitor with excellent efficacy and high selectivity for the treatment of other diseases or conditions characterized by abnormal expression or activity of CD38.

[0008] Summary of the Invention

[0009] To address the above problems, this invention provides a CD38 inhibitor with excellent efficacy and high selectivity.

[0010] In a first aspect of the invention, a compound of formula (I), its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates, or prodrugs are provided.

[0011] in,

[0012] X is N or CR a ;

[0013] R a Selected from the following groups: H, D, halogens, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups;

[0014] Ring A is a 5-9 membered heteroaryl or a 4-9 membered heterocyclic group;

[0015] Ring B is selected from the following group: C 6-10 Aryl, 5-9 quinone heteroaryl, C 3-10 cycloalkyl groups, 4-9 membered heterocyclic groups;

[0016] n is 1, 2, 3, 4 or 5;

[0017] R1 is selected from the following group: deuterium, halogen, cyano, carboxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1- 6-alkoxy, C 1-6 Halogenated alkoxy groups, C 2-4 Ester group, -CONH2, -CONH-C 1-6 Alkyl group; the above groups are optionally surrounded by 1, 2 or 3 R groups. b replace;

[0018] R b Selected from the following group: -S(O)2-C 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Alkoxy, C 1-6 Alkylamino, -C(O)OC 1-6 Alkyl group, -C(O)NH-C 1-6 Alkyl, -C(O)N(C) 1-6 Alkyl)2;

[0019] R2, R3, and R4 are each independently selected from the following groups: H, D, halogens, C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, 3-8 membered cycloalkyl groups, and 4-7 membered heterocyclic groups.

[0020] In another preferred embodiment, R2, R3, and R4 are each independently selected from the group consisting of: H, D, F, Cl, Br, I, and C. 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, 3-6 membered cycloalkyl groups, and 5-6 membered heterocyclic groups.

[0021] In a preferred embodiment, X is N or CR a ;R a Selected from the following groups: H, D, halogens, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups;

[0022] Preferably, X is N or CR a The R a Selected from the following group: H, halogen, methyl, ethyl, n-propyl, isopropyl, C 1-3 Fluorinated alkyl groups;

[0023] More preferably, X is selected from the group consisting of: N, CH, CCH3, CCF3.

[0024] In a preferred embodiment, ring A is a 5-9 member sulfur-containing heteroaryl group;

[0025] Preferably, ring A is selected from the group consisting of 5-7 nucleotide sulfur-containing heteroaryl groups and 5-7 nucleotide oxygen-containing heteroaryl groups;

[0026] More preferably, the ring A is selected from the group consisting of 5-7 nucleotides containing sulfur and nitrogen, and 5-7 nucleotides containing oxygen and nitrogen.

[0027] More preferably, the ring A is selected from the group consisting of:

[0028] In a preferred embodiment, ring B is selected from the group consisting of: phenyl, naphthyl, 5-7 membered heteroaryl, C 3-8 cycloalkyl groups, 4-7 membered heterocyclic groups;

[0029] Preferably, ring B is selected from the group consisting of: phenyl, naphthyl, 5-7 member nitrogen-containing heteroaryl, C 3-6 cycloalkyl groups, 4-6 membered heterocyclic groups;

[0030] More preferably, the ring B is selected from the group consisting of: cyclopentane, cyclohexane, benzene ring, naphthalene, furan, pyran, dihydropyran, tetrahydropyran, thiophene, pyrrole, thiazole, thiadiazole, diazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetraazole, pyrazole, pyridine, pyrimidine, pyrazine, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine.

[0031] In a preferred embodiment, R1 is selected from the group consisting of: deuterium, halogen, cyano, carboxyl, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 2-4 Ester group, -CONH2, -CONH-C 1-4 Alkyl group; the above groups are optionally surrounded by 1, 2 or 3 R groups. b replace;

[0032] R b Selected from the following group: -S(O)2-C 1-4 Alkyl, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Alkoxy, C 1-4 Alkylamino, -C(O)OC 1-4 Alkyl group, -C(O)NH-C 1-4 Alkyl, -C(O)N(C) 1-4 Alkyl)2;

[0033] Preferably, R1 is selected from the group consisting of: deuterium, halogen, cyano, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1- 3-Hydroalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 Ester group, -CONH2, -CONH-C 1-3 Alkyl group; the above groups are optionally surrounded by 1, 2 or 3 R groups. b replace;

[0034] R b Selected from the following group: -S(O)2-C 1-3 Alkyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy groups, C 1-3 Alkoxy, C 1-3 Alkylamino, -C(O)OC 1-3 Alkyl group, -C(O)NH-C 1-3 Alkyl, -C(O)N(C) 1-3 Alkyl)2;

[0035] More preferably, R1 is selected from the group consisting of: F, Cl, Br, -OC. 1-3 Alkylene-R b ;

[0036] R b Selected from the following group: -S(O)2-C 1-3 Alkyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy groups, C 1-3 Alkoxy, C 1-3 Alkylamino, -C(O)OC 1-3 Alkyl group, -C(O)NH-C 1-3 Alkyl, -C(O)N(C) 1-3 Alkyl)2;

[0037] More preferably, R1 is selected from the group consisting of: F, Cl,

[0038] In a preferred embodiment, the Selected from the following group:

[0039] In another preferred embodiment, the compound has the structure shown in formula (I-1):

[0040] The definitions of X, n, R1, ring A, and ring B are as described above.

[0041] In another preferred embodiment, the compound has the structure shown in formula (II), formula (III), or formula (IV):

[0042] The definitions of n, R1, and ring B are as described above.

[0043] In another preferred embodiment, the compound has the structure shown in formula (II-1), formula (III-1), or formula (IV-1):

[0044] Where, n, R b The definition of ring B is as described above.

[0045] In a preferred embodiment, the compound is selected from the group consisting of:

[0046] A second aspect of the present invention provides a pharmaceutical composition comprising:

[0047] (i) the compounds, stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates, or prodrugs as described in the first aspect of the invention; and

[0048] (ii) Pharmaceutically acceptable carriers, excipients or excipients.

[0049] A third aspect of the present invention provides the use of a compound, stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate, or prodrug as described in the first aspect of the present invention, or a pharmaceutical composition as described in the second aspect of the present invention, for the preparation of a medicament for treating and / or preventing diseases associated with abnormal expression or activity of CD38.

[0050] Preferably, the disease associated with abnormal expression or activity of CD38 is cancer or an immune disease;

[0051] More preferably, the cancer is selected from the group consisting of: leukemia, B-cell lymphoma, T-cell lymphoma, NK-cell lymphoma, plasma cell malignancy, myeloma, tumors of exhausted T cells, tumors defined as hot, variant, or cold immune tumors based on immune scores, breast cancer, central nervous system cancer, endometrial cancer, kidney cancer, colorectal cancer, lung cancer, esophageal cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, head and neck (upper respiratory and digestive tract) cancer, urinary tract cancer, colon cancer, Hodgkin's lymphoma, non-Hodgkin's lymphoma, multiple myeloma, B-cell lymphoma (e.g., diffuse large B-cell lymphoma (DLBCL)), chronic lymphocytic lymphoma (CLL), T-cell lymphoma, pilocellular lymphoma, Burkitt's lymphoma. Lymphoma, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), melanoma, colon cancer;

[0052] The immune diseases mentioned are selected from the following group: rheumatoid arthritis, systemic lupus erythematosus, asthma, inflammatory bowel disease, multiple sclerosis, Crohn's disease, gastritis, Hashimoto's thyroiditis, ankylosing spondylitis, graft-versus-host disease, and immune-mediated thrombocytopenic symptoms.

[0053] A fourth aspect of the present invention provides an intermediate compound, said compound being selected from the group consisting of:

[0054] The present invention also relates to pharmaceutical compositions comprising a compound of formula I or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier.

[0055] The present invention also relates to a method for inhibiting CD38 function by contacting CD38 with a compound of formula I or a pharmaceutically acceptable salt thereof.

[0056] The present invention also relates to a method for treating diseases associated with abnormal activity or expression of CD38, which is achieved by administering a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof to a patient in need.

[0057] The present invention further relates to compounds of the present invention or pharmaceutically acceptable salts thereof for the treatment of diseases associated with abnormal activity or expression of CD38.

[0058] The present invention further relates to the use of the compounds of the present invention or pharmaceutically acceptable salts thereof for the manufacture of medicaments for use in therapy.

[0059] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Detailed Implementation

[0060] Through long-term and in-depth research and extensive screening, the inventors have developed for the first time a multi-substituted aminoquinoline compound with excellent selective inhibition of CD38 activity. Based on this, the inventors completed this invention.

[0061] the term

[0062] As used herein, the terms “containing” or “including (comprise)” can be open-ended, semi-closed, or closed-ended. In other words, the terms also include “consistently made of” or “made of”.

[0063] As used herein, the term "alkyl" refers to a monovalent, straight-chain or branched saturated hydrocarbon group consisting of carbon and hydrogen atoms, for example, "C 1-6 "Alkyl" means an alkyl group having 1 to 6 carbon atoms (e.g., 1, 2, 3, 4, 5, or 6). Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tert-butyl. In this application, alkyl is also intended to include deuterated alkyl groups, examples of which include, but are not limited to, CD3, CD2CD3, and CD2CD2CD3.

[0064] As used herein, the term "cycloalkyl" refers to a monovalent saturated carbocyclic group consisting of carbon and hydrogen atoms, such as "C". 3- "8-cycloalkyl" refers to a cycloalkyl group containing 3 to 8 (e.g., 3, 4, 5, 6, 7, or 8) carbon atoms, preferably C64. 3-6 Cycloalkyl groups. Cycloalkyl groups can be monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or similar groups, or bicyclic, such as fused rings, bridged rings or spirocyclic rings.

[0065] As used herein, the term "alkoxy" refers to -O-alkyl, and examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, isopropoxy, tert-butoxy, etc.

[0066] As used herein, the term "alkylamino" refers to the formula -NR u R u 'group, wherein R u and R u Each is independently H or an alkyl group as defined herein, and R u and R u'Not both H. Alkylamino can be monoalkylamino or dialkylamino, and examples of alkylamino include, but are not limited to: N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino, etc.

[0067] As used herein, "halogen" refers to F, Cl, Br, I and their isotopes, including but not limited to F, 18 F, Cl, 32 Cl, Br, I.

[0068] As used in this article, the term "cyano" refers to -CN.

[0069] As used in this article, the term "carboxyl group" refers to -COOH.

[0070] As used herein, the term "ester group" refers to -COOR y , where R y It can be independently selected from the group consisting of: hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocyclic groups. Examples of ester groups include, but are not limited to: -COOCH3, -COOCH2CH3, -COOCH2CH2CH3, -COOCH2CH(CH3)2, etc.

[0071] As used herein, the term "haloalkyl" refers to a group obtained by substituting one or more hydrogen atoms in an alkyl group as described above with the same or different halogens. Specifically, "haloC" refers to a group obtained by substituting one or more hydrogen atoms in an alkyl group with the same or different halogens. 1-6 "alkyl" is preferably a halogenated C 1-4 Alkyl groups, examples of which include, but are not limited to: -CH2Cl, -CH2CF3, -CH2CCl3, perfluoroalkyl groups (e.g., -CF3-, -CF2CF3), etc.

[0072] As used herein, the term "haloalkoxy" refers to a group obtained by substituting one or more hydrogen atoms in an alkoxy group as described above with the same or different halogens. Examples of haloalkoxy groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, 2,2,2-trifluoroethoxy, etc.

[0073] As used herein, the term "heterocyclic" or "heterocyclic group" refers to a fully or partially saturated monocyclic, bicyclic, or polycyclic cyclic group on a ring backbone containing one or more heteroatoms selected from N, S, or O. For example, "4-7 membered heterocyclic group" refers to a group having 4-7 (e.g., 4, 5, 6, or 7) ring members. The nitrogen or sulfur atom may be oxidized, or the nitrogen atom may be quaternized. The heterocyclic group can be attached to any heteroatom or carbon residue in a ring or ring system molecule. Monocyclic heterocyclic groups include, but are not limited to: azacyclic butyl, pyrrolyl, oxacyclic butyl, pyrazolinyl, imidazolinyl, imidazoalkyl, oxazolinyl, isoxazolinyl, thiazoalkyl, isothiazolinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, 2-oxopiperidinyl, 2-oxopiperidinyl, 2-oxopiperylyl, hexahydroachenginyl, 4-piperidinoneyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1,3-dioxane, and tetrahydro-1,1-dioxothiophene, etc. Polycyclic heterocyclic groups include, but are not limited to, spirocyclic, fused-ring, and bridged-ring heterocyclic groups; wherein the spirocyclic, fused-ring, and bridged-ring heterocyclic groups involved are optionally connected to other groups by single bonds, or further cyclically linked to other cycloalkyl, heterocyclic, aryl, and heteroaryl groups by any two or more atoms on the ring.

[0074] As used herein, the term "aromatic ring" or "aryl" refers to an aromatic cyclic hydrocarbon group (including monocyclic, bicyclic, or polycyclic groups), such as "C 6-12 "Aryl" refers to an aromatic cyclic hydrocarbon group having 6-12 (6, 7, 8, 9, 10, 11, or 12) ring carbon atoms. It contains two or more aromatic rings (such as bicyclic rings), and the aromatic rings of the aryl group can be linked by single bonds (such as biphenyl) or fused (such as naphthalene, anthracene, etc.). Examples of aryl groups (especially monocyclic and bicyclic groups) include, but are not limited to, phenyl, biphenyl, or naphthyl. Aryl groups can be fused with heterocyclic groups through single bonds or any two adjacent ring carbon atoms, for example: benzotetrahydrofuranyl, benzotetrahydropyranyl, benzodioxane, etc. wait.

[0075] As used herein, the term “heteroaromatic ring” or “heteroaryl” refers to an aromatic cyclic group (including monocyclic, bicyclic, or polycyclic groups) whose ring skeleton contains 1, 2, 3, or 4 heteroatoms selected from N, S, or O. For example, “5-12-membered heteroaryl” refers to a monocyclic, bicyclic, or tricyclic group having 5 to 12 (5, 6, 7, 8, 9, 10, 11, or 12) ring atoms. Examples of heteroaryl groups include, but are not limited to: imidazole, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, thiophene, furanyl, pyranyl, pyridinyl, pyrroleyl, pyrazolyl, pyrimidinyl, quinolinyl, isoquinolinyl, benzofuranyl, benzothiophene, benzothiaranyl, benzoimidazolyl, benzooxazolyl, benzooxadiazolyl, benzothiazolyl, benzothiazolyl, benzopyranyl, indoleyl, isoindoleyl, triazolyl, triazinyl, quinoxolinyl, purine, quinazolinyl, quinazinyl, naphridinyl, pteridinyl, carbazoleyl, and azazolyl. basalt, diazoxide acridine group, etc.

[0076] As used in this article, the term "multi-substitution" refers to a substance that includes two or more substitutions.

[0077] As used herein, “deuterated” means that one or more hydrogen atoms in a compound or group are replaced by deuterium. Deuteration can be monosubstituted, disubstituted, polysubstituted, or total substituted. The terms “one or more deuterated” and “one or more deuterated” are used interchangeably.

[0078] As used herein, the term "deuterated compound" refers to a compound in which one or more hydrogen atoms (H) are replaced by a deuterium atom (D).

[0079] When a group loses one hydrogen atom, it becomes a subunit of the corresponding group, and it is a divalent group. For example, an alkyl group loses one hydrogen atom to become an alkylene group (e.g., methylene, ethylene, propylene, isopropylene). ), butylide (such as) ), pentylene (e.g.) ), hexyl (such as) ), subheptagen (such as ) etc.; cycloalkyl corresponds to cyclohexane (e.g.: (etc.); heterocyclic groups correspond to subheterocyclic groups (e.g.: Alkoxy groups correspond to alkoxy groups (e.g., -CH2O-, -CH2CH2O-, -OCH2CH2CH2-), and heteroalkyl groups correspond to heteroalkyl groups (e.g., -CH2-O-CH2CH2-, -CH2-O-(CH2)2CH2-, -CH2CH2-O-CH2CH2-, -CH2-O-CH2CH2CH2-, -CH2-S-CH2CH2-, -CH2-S-(CH2)2CH2-, -CH2CH2-S-CH2CH2-, -CH2-S-CH2CH2CH2-, -CH2-NH-CH2CH2-, -CH2-NH-(CH2)2CH2-, -CH2CH2-NH-CH2CH2-, -CH2-NH-CH2CH2CH2-, etc.).

[0080] In this invention, the alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups, unless otherwise specified, include substituted alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups. The substituents include, but are not limited to, halogen, hydroxyl, cyano, acyl, sulfonyl, ester, sulfinyl, alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, acyl, and ester groups.

[0081] As used herein, the term "substitution" refers to the replacement of one or more hydrogen atoms on a particular group by a particular substituent. The particular substituent is either the substituent described accordingly above or the substituent appearing in the various embodiments. Unless otherwise specified, a substituted group may have a substituent selected from a particular group at any substituted site of that group, and the substituents may be the same or different at each position. Those skilled in the art will understand that the combinations of substituents contemplated in this invention are those that are stable or chemically feasible.

[0082] Unless otherwise specified, the groups described in this invention may be substituted with substituents selected from the group consisting of: D, halogen, cyano, nitro, hydroxyl, amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, 3-12 membered heterocyclic groups, C3-C6 alkyl, ... 12 cycloalkyl, 5-10 heteroaryl and C6-C 10 Aryl.

[0083] In this document, “optionally” means that the event or condition described below may, but is not required to, occur, and the description includes both the possibility that the event or condition occurs and the possibility that the event or condition does not occur.

[0084] In this article, the term "multiple" refers to 2, 3, 4, 5, or a positive integer greater than 5.

[0085] Active ingredients

[0086] As used herein, “compound of the present invention” means a compound of formula (I), and also includes its stereoisomers, its optical isomers, its pharmaceutically acceptable salts, its crystal forms, its isotopic derivatives, its prodrugs, its metabolites, its solvates or hydrates thereof.

[0087] Unless otherwise specified, the structural formulas described in this invention are intended to include all stereoisomers (such as cis-trans isomers, enantiomers, diastereomers, and conformational isomers): R and S configurations containing an asymmetric center, (Z) and (E) isomers of double bonds, cis-trans isomers of cycloalkanes, etc. Therefore, any single stereochemical isomer of the compounds of this invention, or a mixture of its enantiomers, diastereomers, or conformational isomers, is within the scope of this invention.

[0088] The compounds of this invention may contain cis-trans isomers, one or more chiral carbon atoms, and thus can produce cis-trans isomers, chiral isomers, enantiomers, diastereomers, and other combinations of stereoisomers. Cis-trans isomerism refers to the diastereomeric phenomenon in which different functional groups in a compound molecule are arranged differently in space due to a restrictive factor that limits free rotation. This restrictive factor is generally caused by non-rotating functional groups in the structure of organic compounds, such as C=C double bonds, C=N double bonds, C=S double bonds, N=N double bonds, heterocycles, or cycloalkanes. Organic molecules containing such isomers, such as alkenes, azo compounds, and cycloalkanes, are considered cis-trans isomers. Cis refers to the same ligands being in adjacent positions, generally denoted by "cis" or "cis-"; trans refers to the same ligands being in diagonal positions, generally denoted by "trans" or "trans-". Each chiral carbon atom can be defined as (R)- or (S)- based on stereochemistry. This invention aims to include all possible isomers, their racemic and optically pure forms. The compounds of this invention can be prepared using racemic, cis-trans, chiral, diastereomer, or enantiomers as starting materials or intermediates. Optically active isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as crystallization and chiral chromatography.

[0089] Conventional techniques for preparing / separating individual optical isomers (i.e., cis-trans isomers and chiral isomers) include chiral synthesis from suitable cis-trans precursors or optically pure precursors, or resolution of racemates (or racemates of salts or derivatives) using, for example, chiral high-performance liquid chromatography.

[0090] To design the synthesis of a specific stereoisomer of the compound of this invention, it can be prepared asymmetrically or derivatized with a chiral auxiliary. The resulting stereo mixture is then separated, and the chiral auxiliary is removed to obtain pure cis-trans monomers, chiral monomers, or mixed stereoisomers. If the molecule contains a cis-trans isomer center, it can be purified by column chromatography (normal-phase silica gel column or reverse-phase high-performance liquid chromatography) to obtain pure cis or trans products. Alternatively, if the molecule contains a basic functional group, such as an amino acid, or an acidic functional group, such as a carboxyl group, it can be formed with a suitable optically active acid or base to form a diastereomeric salt, which is then separated by conventional methods such as separation crystallization or chromatography to obtain pure enantiomers.

[0091] This invention also includes isotopically labeled compounds (i.e., isotopic derivatives), equivalent to the original compounds disclosed herein. However, it is common practice to see one or more atoms replaced by atoms with different atomic weights or mass numbers. Examples of isotopes in the isotopic derivatives of this invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine isotopes, respectively as follows: 2 H, 3 H, 13 C 11 C 14 C 15 N、 18 O、 17 O、 31 P, 32 P, 35 S, 18 F and 36 Cl. Isotope derivatives of the compounds of this invention are all within the scope of protection of this invention. In this document, 3 H-labeled compounds and 14 C-labeled compounds are useful in tissue distribution experiments of drugs and substrates. Tritium (i.e., 3 H) and carbon-14 (i.e. 14 C) Labeled compounds are relatively easy to prepare and detect, making them the preferred choice among isotopes. Furthermore, heavier isotope substitutions, such as deuterium, are also possible. 2 H, due to its excellent metabolic stability, offers advantages in certain therapies, such as increasing half-life or reducing dosage in vivo, and therefore may be preferred in some cases. Isotopically labeled compounds can be prepared using general methods, by replacing the non-isotopic reagent with an readily available isotopically labeled reagent, according to the scheme disclosed in the examples.

[0092] As used herein, the term "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0093] "Pharmaceutically acceptable acid addition salts" refer to salts formed with inorganic or organic acids that retain the bioavailability of the free base without other side effects. Inorganic acid salts include, but are not limited to, hydrochlorides, hydrobroms, sulfates, nitrates, and phosphates; organic acid salts include, but are not limited to, formates, acetates, 2,2-dichloroacetate, trifluoroacetate, propionates, hexanoates, octanoates, decanoates, undecenoates, glycolates, gluconates, lactates, sebates, adipates, glutarate, malonates, oxalates, maleates, succinates, fumarates, tartrates, citrates, palmitates, stearates, oleates, cinnamates, laurates, malates, glutamates, pyroglutamates, aspartate, benzoates, methanesulfonates, benzenesulfonates, p-toluenesulfonates, alginates, ascorbic acid salts, salicylates, 4-aminosalicylic acid salts, and naphthalene disulfonates. These salts can be prepared using methods known in this field.

[0094] "Pharmaceutically acceptable base addition salts" refer to salts formed with inorganic or organic bases that retain the bioavailability of the free acid without other side effects. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Preferred inorganic salts are ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, the following: primary amines, secondary amines, and tertiary amines; substituted amines, including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucosamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. These salts can be prepared by methods known in the art.

[0095] Metabolites of the compound represented by formula (I) and its pharmaceutically acceptable salts, as well as prodrugs that can be converted in vivo into the compound represented by formula (I) and its pharmaceutically acceptable salts, are also included within the scope of protection of this invention.

[0096] As used herein, the term "solvent" refers to a complex of a compound of formula (I) coordinated with a solvent molecule in a specific ratio.

[0097] As used herein, the term "hydrate" refers to a complex of the compound represented by formula (I) coordinated with water molecules in a specific ratio.

[0098] As described herein, the compounds of the present invention can be substituted with any number of substituents or functional groups to broaden their scope. Generally, the term "substitution" refers to replacing a hydrogen radical with a substituent of a specified structure. When multiple positions in a particular structure are substituted by multiple specific substituents, each position of the substituent can be the same or different. The term "substitution" as used herein includes all permissible organic group substitutions. In a broad sense, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic organic groups. As described herein, heteroatomic nitrogen may be supplemented with a hydrogen substituent or any permissible organic group described above to complete its valence state. Furthermore, the present invention is not intended to limit permissible substituted organic groups in any way. The present invention considers the combination of substituents and variable groups to be beneficial in the treatment of diseases in the form of stable compounds. The term "stable" here means having a stable compound that, when tested over a sufficiently long period, maintains sufficient integrity of the compound structure, preferably remaining effective for a sufficiently long period, and is used herein for the purposes described above.

[0099] Pharmaceutical Compositions and Administration

[0100] Because the compounds of the present invention can inhibit CD38 and are used to treat diseases such as cancer, the compounds of the present invention, their stereoisomers, their optical isomers, their pharmaceutically acceptable salts, their crystal forms, their isotopic derivatives, their prodrugs, their metabolites, their solvates or hydrates thereof, and pharmaceutical compositions containing the compounds of the present invention as the main active ingredient can be used to prevent and / or treat (stabilize, alleviate or cure) diseases related to abnormal expression or activity of CD38, such as cancer.

[0101] The pharmaceutical compositions of the present invention comprise the compound of the present invention within a safe and effective range and a pharmaceutically acceptable excipient or carrier. "Safe and effective range" refers to an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably, 10-200 mg of the compound of the present invention per dose. Preferably, "one dose" is one capsule or tablet.

[0102] "Pharmaceutically acceptable carriers" refer to one or more compatible solid or liquid fillers or gelling substances that are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with and with the compounds of the present invention without significantly reducing the efficacy of the compounds. Examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), and emulsifiers (such as Tween). Wetting agents (such as sodium dodecyl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0103] There are no particular limitations on the administration of the compounds or pharmaceutical compositions of the present invention. Representative administration methods include, but are not limited to, oral administration and parenteral administration (intravenous, intramuscular, or subcutaneous).

[0104] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following components: (a) fillers or compatibilizers, such as starch, lactose, sucrose, glucose, mannitol, and silica; (b) binders, such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants, such as glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or cassava starch, alginate, certain complex silicates, and sodium carbonate; (e) slowing agents, such as paraffin; (f) absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, such as kaolin; and (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, or mixtures thereof. Buffers may also be included in capsules, tablets, and pills.

[0105] Solid dosage forms such as tablets, sugar pills, capsules, pellets, and granules can be prepared using coatings and shells, such as casings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compound from such compositions can be delayed in a portion of the digestive tract. Examples of encapsulating components that can be used are polymeric substances and waxes. If necessary, the active compound may also be formed into microcapsules with one or more of the excipients described above.

[0106] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, e.g., ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures of these substances.

[0107] In addition to these inert diluents, the composition may also contain auxiliaries such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and fragrances.

[0108] In addition to the active ingredient, the suspension may contain suspending agents, such as ethoxylated isooctadecyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0109] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents, or excipients include water, ethanol, polyols, and suitable mixtures thereof.

[0110] Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays, and inhalers. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants as needed.

[0111] The compounds of this invention can be administered alone or in combination with other pharmaceutically acceptable compounds.

[0112] When administered in combination, the pharmaceutical composition further comprises one or more (two, three, four, or more) other pharmaceutically acceptable compounds. One or more (two, three, four, or more) of these other pharmaceutically acceptable compounds may be used simultaneously, separately, or sequentially with the compounds of the present invention for the prevention and / or treatment of CD38-related diseases.

[0113] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is administered to the mammal (such as a human) requiring treatment. The dosage at the time of administration is the pharmaceutically considered effective dose. For a person weighing 60 kg, the daily dose is typically 1-2000 mg, preferably 20-500 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the patient's health condition, which are all within the scope of the skill of a skilled physician.

[0114] use

[0115] The compounds, stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates, or prodrugs described in this invention, or pharmaceutical compositions as described in this invention, are used to prepare medicaments for the treatment and / or prevention of diseases associated with abnormal expression or activity of CD38.

[0116] In some implementations, the disease associated with abnormal expression or activity of CD38 is cancer or an immune disease.

[0117] The compounds of this invention can be used to treat various diseases associated with abnormal expression or activity of CD38. For example, the compounds of this invention can be used to treat cancer. In some embodiments, the cancer is characterized by abnormal expression or activity of CD38, such as increased expression or activity compared to normal cells. In some embodiments, cancers treatable according to this invention include breast cancer, central nervous system cancer, endometrial cancer, kidney cancer, colorectal cancer, lung cancer, esophageal cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, head and neck (upper respiratory and digestive tract) cancer, urinary tract cancer, and colon cancer.

[0118] In some embodiments, the compounds of the present invention can be used to treat tumors with exhausted T cells and tumors defined as hot, variable, and cold immune tumors based on immune scores.

[0119] In some embodiments, the cancers treatable according to the present invention include hematopoietic malignancies such as leukemia and lymphoma. Examples of lymphomas include Hodgkin's lymphoma or non-Hodgkin's lymphoma, multiple myeloma, B-cell lymphoma (e.g., diffuse large B-cell lymphoma (DLBCL)), chronic lymphocytic lymphoma (CLL), T-cell lymphoma, pilocellular lymphoma, and Burkitt's lymphoma. Examples of leukemias include acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), and chronic myeloid leukemia (CML).

[0120] In some embodiments, other cancers that can be treated by applying the compounds of the present invention include bladder cancer, bone cancer, glioma, breast cancer, cervical cancer, colon cancer, endometrial cancer, epithelial cancer, esophageal cancer, Ewing's sarcoma, pancreatic cancer, gallbladder cancer, gastric cancer, gastrointestinal tumors, glioma, head and neck cancer (upper respiratory and digestive tract cancers), intestinal cancer, Kaposi's sarcoma, kidney cancer, laryngeal cancer, liver cancer (e.g., hepatocellular carcinoma), lung cancer (e.g., non-small cell lung cancer, adenocarcinoma), melanoma, prostate cancer, rectal cancer, clear cell renal cell carcinoma, skin cancer, gastric cancer, testicular cancer, thyroid cancer, and uterine cancer.

[0121] In some embodiments, cancers that can be treated by applying the compounds of the present invention are multiple myeloma, diffuse large B-cell lymphoma (DLBCL), hepatocellular carcinoma, bladder cancer, esophageal cancer, head and neck cancer (upper respiratory and digestive tract cancer), kidney cancer, prostate cancer, rectal cancer, stomach cancer, thyroid cancer, uterine cancer, and breast cancer.

[0122] Other cancers that can be treated by applying the compounds of this invention include cancers treated with checkpoint therapy, checkpoint-resistant cancers, adenosine-dependent tumors, Treg-invasive tumors, and MDSC-invasive tumors.

[0123] The compounds of this invention can also be used to treat the following diseases or conditions: HIV / AIDS, adoptive T-cell therapy, acute lung injury, acute respiratory distress syndrome (ARDS), hyperphosphatemia, alcohol intolerance, lupus, rheumatoid arthritis, ataxia-telangiectasia, sleep disorders, epilepsy, exercise intolerance, hypertension, hypoxic pulmonary vasoconstriction, Hansen's disease, tuberculosis, leishmaniasis, cardiomegaly, congestive heart failure (CHF), muscular dystrophy, stroke, organ reperfusion injury, idiopathic pulmonary fibrosis, pancreatitis, cystic fibrosis, asthma, chronic obstructive pulmonary disease (COPD), irritable bowel syndrome (IBS), colitis, gout, obesity, sarcopenic obesity, metabolic syndrome, end-stage renal disease, dyslipidemia, hearing loss, liver disease, fatty degeneration, non-alcoholic steatohepatitis (NASH / NAFLD), Alzheimer's disease. Diseases including multiple sclerosis, neurocognitive impairment, optic neuropathy, postmenopausal osteoporosis, bipolar disorder, schizophrenia, Huntington's disease, diabetes, Hartnup disease, hyperpigmentation, diabetic neuropathy, radiation exposure, UV skin damage, psoriasis, periodontitis, chronic lymphocytic leukemia, amyotrophic lateral sclerosis, Parkinson's disease, Leber's hereditary amaurosis insulin resistance, and type 1 diabetes.

[0124] The CD38 inhibitor of the present invention may also have therapeutic use in CD38-related conditions, particularly in disease areas characterized by overexpression or increased activity of CD38 (e.g., cardiology, virology, neurodegeneration, inflammation, and pain).

[0125] Preparation method

[0126] 1) Preparation of the compounds of the present invention

[0127] Where X and ring A are defined as described above; R is

[0128] S1. Compounds of formula III and IV undergo a condensation dehydration reaction to obtain compound of formula II;

[0129] S2. In the presence of TFA, compound II undergoes a deprotection reaction to yield compound I.

[0130] 2) Intermediate compound IV

[0131] 3) Intermediate compound III

[0132] Where X is defined as described above

[0133] 4) Preparation of intermediate compound III

[0134] 4.1 When X is CR a (Preferably, X is CH, CCH3, or CCF3):

[0135] 4.1 When X is nitrogen:

[0136] The main advantage of this invention is that the compounds of this invention have excellent activity in inhibiting CD38.

[0137] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, were generally performed under conventional conditions or as recommended by the manufacturer. Unless otherwise stated, percentages and parts are weight percentages and parts by weight.

[0138] Synthesis of intermediates

[0139] 1. Amine intermediate (IV)

[0140] The amine intermediate (IV) used in the following examples are known compounds, which were synthesized directly from commercially available reagents or by referring to relevant literature. Experimental methods not specifically described in the examples were performed using conventional methods and conditions, or according to the product instructions.

[0141] 2. Acid intermediate

[0142] 2.1 2-(bis(4-methoxybenzyl)amino)-4-methyl-8-(thiazo-5-yl)quinoline-6-carboxylic acid (IIIa)

[0143] Step 1: Methyl 4-acetamido-3-bromobenzoate

[0144] Under nitrogen protection, methyl 4-amino-3-bromobenzoate (7.50 g, 32.60 mmol) and triethylamine (4.97 mL, 35.86 mmol) were dissolved in tetrahydrofuran (THF, 100 mL), cooled to 0 °C, and acetyl chloride (4.62 mL, 65.20 mmol) was added. The mixture was stirred for 2 hours and then concentrated under vacuum. The residue was purified by rapid column chromatography (PE / EtOAc) to give the target compound IIIa-1 (5.51 g, yellow solid). LCMS (ESI, m / z): 272 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ9.57(s,1H),8.13(s,1H),7.93(s,2H),3.85(s,3H),2.15(s,3H).

[0145] Step 2: Methyl 8-bromo-4-methyl-2-oxo-1,2-dihydroquinoline-6-carboxylate

[0146] Under nitrogen protection, compound IIIa-1 (5.10 g, 18.82 mmol) was dissolved in glacial acetic acid (150 mL), followed by the addition of ethyl propargylate (3.17 g, 28.23 mmol), silver hexafluoroantimonate (1.29 g, 3.76 mmol), and dichlorobis(4-methylisopropylphenyl)ruthenium(II) (578 mg, 0.94 mmol). The reaction temperature was then raised to 130 °C, and the mixture was stirred for 60 hours. After cooling, the mixture was concentrated under vacuum, and the residue was purified by rapid column chromatography (PE / EtOAc) to give the target compound IIIa-2 (500 mg, red solid). LCMS (ESI, m / z): 296 [M+H] + ; 1 H NMR (400MHz, MeOD) δ8.43(d,1H),8.40(d,1H),6.62(s,1H),3.95(s,3H),2.58(d,3H).

[0147] Step 3: Methyl 8-bromo-2-chloro-4-methylquinoline-6-carboxylate

[0148] Compound IIIa-2 (1.50 g, 5.07 mmol) was dissolved in acetonitrile (20.0 mL), and phosphorus oxychloride (1.16 g, 7.60 mmol) was added at 25 °C. The reaction mixture was stirred at 90 °C for 3 hours. The mixture was concentrated under vacuum, and the crude product was alkalized to pH 7 with saturated sodium bicarbonate solution, then extracted with ethyl acetate. The combined organic phases were dried and concentrated under vacuum. The residue was purified by rapid column chromatography (PE / EtOAc) to give the target compound IIIa-3 (1.50 g, pale yellow solid). LCMS (ESI, m / z): 314 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ8.67(d,1H),8.52(d,1H),7.74(s,1H),3.96(s,3H),2.79(s,3H).

[0149] Step 4: Methyl 2-(bis(4-methoxybenzyl)amino)-8-bromo-4-methylquinoline-6-carboxylate

[0150] Compound IIIa-3 (1.50 g, 4.77 mmol) was mixed with bis[(4-methoxyphenyl)methyl]amine (12.20 g, 47.7 mmol), and the mixture was stirred at 140 °C for 1 hour. After cooling, the crude product was purified by rapid column chromatography (PE / EtOAc) to give the target compound IIIa-4 (2.11 g, white solid). LCMS (ESI, m / z): 535 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ8.38(d,1H),8.31(d,1H),7.30(s,4H),7.11(s,1H),6.88(d,4H),4.89(s,4H),3.89(s,3H),3.72(s,6H),2.56(s,3H).

[0151] Step 5: Methyl 2-(bis(4-methoxybenzyl)amino)-4-methyl-8-(thiazo-5-yl)quinoline-6-carboxylate

[0152] Under nitrogen protection, compound IIIa-4 (600 mg, 1.12 mmol) was dissolved in 1,4-dioxane / water (3.0 mL, V / V = 5 / 1), followed by the addition of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)thiazole (355 mg, 1.68 mmol), potassium phosphate (714 mg, 3.36 mmol), and 1,1-bis(diphenylphosphine)diberberine palladium dichloride (Pd(dppf)Cl2, 82 mg, 0.112 mmol). The reaction was heated to 90 °C and reacted for 3 hours. After cooling and dilution with water, the mixture was extracted with ethyl acetate, and the combined organic phases were concentrated under vacuum. The residue was purified by rapid column chromatography (dichloromethane / methanol) to give the target compound IIIa-5 (0.45 g, yellow solid). LCMS (ESI, m / z): 540 [M+H] + ; 1 HNMR(400MHz,DMSO-d6)δ9.04(s,1H),8.56-8.52(m,2H),8.42(d,1H),7.23-7 .16(m,5H),6.88(d,4H),4.93(s,4H),3.92(s,3H),3.71(s,6H),2.60(s,3H).

[0153] Step 6: 2-(bis(4-methoxybenzyl)amino)-4-methyl-8-(thiazolyl-5-yl)quinoline-6-carboxylic acid was dissolved in water / tetrahydrofuran / methanol (6.0 mL, V / V / V = 1 / 1 / 1) at 25 °C. Lithium hydroxide (100 mg, 4.15 mmol) was added, and the mixture was heated to 50 °C and stirred for 1 hour. The reaction was monitored for completeness, neutralized to pH 3 with 10% hydrochloric acid, extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the target compound IIIa (350 mg, yellow oil). LCMS (ESI, m / z): 526 [M+H] + .

[0154] 1 H NMR(400MHz,DMSO-d6)δ12.46(s,1H),9.03(s,1H),8.56–8.51(m,2H),8.42(d,1H) ),7.20(d,4H),7.17(s,1H),6.88(d,4H),4.93(s,4H),3.71(s,6H),1.91(s,3H).

[0155] 2.2 2-Amino-8-(1,3-thiazo-5-yl)quinoline-6-carboxylic acid (IIIb)

[0156] By replacing ethyl propargyl ester with ethyl ethinyl ester, the synthetic method was exactly the same as that used for compound IIIa, yielding compound IIIb-5 protected by bis(p-methoxybenzyl) ester, LCMS (ESI, m / z): 512 [M+H] + .

[0157] Compound IIIb-5 was further protected with trifluoroacetic acid to yield compound IIIb. LCMS (ESI, m / z): 272 [M+H] + .

[0158] 1 H NMR (400MHz, DMSO-d6) δ12.96(s,1H),9.14(s,1H),8.70(s,1H),8.44(d,1H),8.30(s,1H),8.14(s,1H),7.12(s,2H),6.90(d,1H).

[0159] 2.3 2-(bis(4-methoxybenzyl)amino)-8-(1H-imidazol-1-yl)-4-methylquinoline-6-carboxylic acid (IIIc)

[0160] Compound IIIa-4 (860 mg, 1.61 mmol) was dissolved in dimethyl sulfoxide (20 mL), and methyl[2-(methylamino)cyclohexyl]amine (137 mg, 0.96 mmol), 1H-imidazole (219 mg, 3.21 mmol), cesium carbonate (1.57 g, 4.82 mmol), and cuprous iodide (CuI, 61.18 mg, 0.32 mmol) were added. The reaction mixture was then heated to 120 °C and stirred for 16 hours. The mixture was diluted with water, extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under vacuum, and the residue was purified by rapid column chromatography (DCM / MeOH) to give the target compound IA-5 (0.45 g, yellow oil). LCMS (ESI, m / z): 509 [M+H] + .

[0161] 2.4 2-Amino-8-(1,3-thiazolyl-5-yl)quinoxaloline-6-carboxylic acid (IIId)

[0162] Step 1: Methyl 8-bromo-2-oxo-1H-quinoxaline-6-carboxylic acid

[0163] Methyl 3,4-diamino-5-bromobenzoate (10.0 g, 40.80 mmol) was dissolved in methanol (130 mL) and cooled to -40 °C. A solution of glyoxylic acid hydrate (5.3 g, 57.58 mmol) in water (10 mL) was added dropwise. The mixture was then heated to room temperature and stirred for 4 hours. LC-MS analysis confirmed the reaction was complete. The reaction solution was filtered, and the filter cake was washed with methyl tert-butyl ether and dried to obtain the target product IIId-1 (10.0 g, yellow solid). LC-MS (ESI, m / z): 283 [M+H] + .

[0164] Step 2: Methyl 8-bromo-2-chloroquinoxaline-6-carboxylate

[0165] Compound IIId-1 (10.0 g, 35.33 mmol) was dissolved in phosphorus oxychloride (130 mL) at room temperature, then heated to 80 °C and stirred for 6 hours. The reaction mixture was cooled to room temperature, concentrated, and then mixed with cold dichloromethane and water. The mixture was separated, the organic phase was dried, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to give the target product IIId-2 (7.0 g, 23.22 mmol, yellow solid). LCMS (ESI, m / z): 301 [M+H] + . 1 H NMR(DMSO-d6)δ9.17(s,1H),8.61(d,1H),8.57(d,1H),3.97(s,3H).

[0166] Step 3: 2-{bis[(4-methoxyphenyl)methyl]amino}-8-bromoquinoxaline-6-carboxylic acid methyl ester

[0167] Compound IIId-2 (7.0 g, 23.22 mmol) and bis-(4-methoxybenzyl)-amine (50.0 g, 194.30 mmol) were mixed at room temperature and then heated to 140 °C for 1 hour. LC-MS analysis showed that the reaction proceeds were completely reacted. After cooling, dichloromethane (300 mL) was added, resulting in the precipitation of a white solid. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was slurried with ethyl acetate / petroleum ether (V / V = 1 / 4, 300 mL) to obtain the target compound IIId-3 (7.0 g, yellow solid). LC-MS (ESI, m / z): 522 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.69(s,1H),8.33(d,1H),8.31(d,1H),7.36(s,4H),6.90(d,4H),4.99(s,4H),3.90(s,3H),3.72(s,6H).

[0168] Step 4: Methyl 2-{bis[(4-methoxyphenyl)methyl]amino}-8-(1,3-thiazolyl-5-yl)quinoxaline-6-carboxylate

[0169] At room temperature, compound IIId-3 (7.0 g, 13.21 mmol), Pd(dppf)Cl2.CH2Cl2 (4.11 g, 5.02 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)thiazole (5.86 g, 27.74 mmol), and potassium phosphate (14.02 g, 66.04 mmol) were dissolved in 1,4-dioxane and water (150 mL / 50 mL). The mixture was purged with nitrogen three times, then heated to 90 °C and stirred for 18 hours. The reaction mixture was confirmed to be complete by LC-MS. The reaction solution was concentrated, and ethyl acetate (200 mL) and water (100 mL) were added. The mixture was separated, the organic phase was dried, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain the target product IIId-4 (5.0 g, yellow solid). LC-MS (ESI, m / z): 527 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ9.12(s,1H),8.79(s,1H),8.63(s,1H),8.59(d,1H),8 .34(d,1H),7.26(d,4H),6.89(d,4H),5.02(s,4H),3.93(s,3H),3.72(s,6H).

[0170] Step 5: 2-{bis[(4-methoxyphenyl)methyl]amino}-8-(1,3-thiazolyl-5-yl)quinoxaline-6-carboxylic acid

[0171] Compound IIId-4 (5.0 g, 9.02 mmol) was dissolved in water / methanol / tetrahydrofuran (60 mL, V / V / V = 1 / 1 / 1) at room temperature. Lithium hydroxide (1.08 g, 45.10 mmol) was added, and the mixture was heated to 50 °C and reacted for 1 hour. The reaction solution was directly concentrated to remove most of the solvent, and water (20 mL) was added. The pH was adjusted to 3 with dilute hydrochloric acid (2 M). The mixture was filtered, and the filter cake was washed three times with water and dried to give compound IIId-5 (3 g, 5.6 mmol, yellow solid). LCMS (ESI, m / z): 513 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ13.21(s,1H),9.11(s,1H),8.78(s,1H),8.62(s,1H), 8.59(d,1H),8.33(d,1H),7.26(d,4H),6.89(d,4H),5.02(s,4H),3.72(s,6H).

[0172] Step 6: 2-Amino-8-(1,3-thiazolyl-5-yl)quinoxaline-6-carboxylic acid

[0173] Compound IIId-5 (3 g, 5.56 mmol) was dissolved in trifluoroacetic acid (50 mL), and the mixture was stirred at 90 °C for 1 hour. The reaction was monitored by LCMS until complete. The reaction solution was concentrated, and the crude product was slurryed with ethyl acetate to give the title compound (1.6 g, yellow solid). LCMS (ESI, m / z): 273 [M+H] + .

[0174] Example 1. Synthesis of 2-amino-N-[(1r,4r)-4-[(2-methoxyethyl)oxy]cyclohexyl]-4-methyl-8-(1,3-thiazolyl-5-yl)quinoline-6-carboxamide (I-1)

[0175] Step 1: 2-{bis[(4-methoxyphenyl)methyl]amino}-N-[(1r,4r)-4-[(2-methoxyethyl)oxy]cyclohexyl]-4-methyl-8-(1,3-thiazolyl-5-yl)quinoline-6-carboxamide (I-1-1)

[0176] Compound IIIa (300 mg, 570.75 μmol) was dissolved in anhydrous acetonitrile (15 mL) at 25 °C, followed by the addition of N,N,N',N'-tetramethylchloromethamphexane hexafluorophosphate (176 mg, 627.83 μmol) and N-methylimidazole (94 mg, 1.14 mmol). After stirring for 10 minutes, trans-4-(2-methoxyethoxy)-cyclohexylamine (280 mg, 1.51 mmol) was added, and the reaction was continued for 1 hour. LCMS analysis confirmed the reaction was complete. The reaction mixture was extracted with water and ethyl acetate, the organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to give I-1-1 (296 mg). LCMS (ESI, m / z): 681 [M+H] + .

[0177] Step 2: 2-Amino-N-[(1r,4r)-4-[(2-methoxyethyl)oxy]cyclohexyl]-4-methyl-8-(1,3-thiazolyl-5-yl)quinoline-6-carboxamide (I-1)

[0178] Compound I-1-1 (290 mg, 425.93 μmol) was dissolved in 5 mL of trifluoroacetic acid and stirred at 90 °C for 1 hour. After the reaction was complete, the reaction solution was concentrated under vacuum. The crude product was purified by reversed-phase silica gel column chromatography (column: Welch-Xtimate-C18-10 μm-21.2*150 mm; mobile phase A: 10 mM ammonium bicarbonate / water, mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: B: 35%–65%, 9 min) to obtain the target compound I-1 (103 mg, white solid). LCMS (ESI, m / z): 441 [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.88(s,1H),8.50(s,1H),8.23(dd,2H),6.66(s,1H),6.02(d,1H),4.91(s,2H),4.18-3.89(m,1 H),3.65(dd,2H),3.55(dd,2H),3.38-3.29(m,1H),2.66(s,3H),2.17(dd,4H),1.54-1.44(m,3H),1.42-1.30(m,2H).

[0179] The synthesis of the compounds in the examples in Table 1 below is the same as that in Example 1. The corresponding acid intermediates are condensed with amine intermediates, and then deprotected to obtain the corresponding target compounds. The amine intermediates are all known compounds that can be obtained from reagent companies.

[0180] Table 1

[0181] Example 12 2-Amino-N-{4-[(2-methoxyethyl)oxy]phenyl}-8-(1,3-thiazolyl)quinoline-6-carboxamide

[0182] Compound IIIb (400 mg, 1.31 mmol) was dissolved in acetonitrile (5 mL) at 25 °C. N,N,N',N'-tetramethylchloromethacin hexafluorophosphate (800 mg, 2.85 mmol) and N-methylimidazole (1.2 mL, 15.05 mmol) were added, and the mixture was stirred for 10 minutes. Then, 4-(2-methoxyethoxy)aniline (230 mg, 1.38 mmol) was added, and the reaction was continued for 1 hour. LC-MS analysis confirmed the reaction was complete. The reaction solution was then diluted with water. Extracted with ethyl acetate, the organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by reversed-phase high-performance liquid chromatography (RP-HPLC) (column: Nouryon-Kromasil-C18-10um-25*250mm; mobile phase: [water (ammonium bicarbonate)-acetonitrile]; B%: 30%-95%, 8min) to obtain the target product I-12 (103.87 mg, 0.25 mmol, purity 100%, yield 18.87%, white solid). 1 H NMR(400MHz,DMSO-d6)δ10.20(s,1H),9.13(s,1H),8.77(s,1H),8.57(d,1H),8.28(d,1H),8.09(d,1H) ,7.70(d,2H),7.02–6.93(m,4H),6.90(d,1H),4.12–4.05(m,2H),3.71–3.61(m,2H),3.32–3.32(m,3H).

[0183] The synthesis of the compounds in the examples in Table 2 below is the same as that in Example 12. The corresponding target compounds are obtained by condensation of the corresponding acid intermediates and amine intermediates. The amine intermediates are all known compounds that can be obtained from reagent companies.

[0184] Table 2

[0185] Example 1: Inhibitory activity of the compound of the present invention against human CD38 enzyme.

[0186] The method described in this invention (J.Med.Chem.2015,58,17,7021–7056) uses recombinant human CD38 protein (R&D, catalog number 2404-AC-010) to test the inhibitory activity of the compound in the examples against human CD38 enzyme activity. The enzyme activity assay was performed in a small-volume 384-well plate (Perkin Elmer, catalog number 6007279) with a total volume of 20 μL. A series of concentrations of the test compound were fed into the wells of the plate in 200 nL of dimethyl sulfoxide. Columns 6 and 18 of the plate contained no compound in dimethyl sulfoxide and served as high-signal and low-signal controls (without CD38), respectively.

[0187] All reagents added to the plate were performed using Multidrop Combi, with the plate shaken for 3–5 seconds after each addition. CD38 (0.8 nM) and the test compound were pre-incubated in 10 μL of a solution containing 100 mM HEPES (pH 7.4), 4 mM EDTA, and 1 mM CHAPS for 30 minutes before initiating the reaction. The reaction was initiated by adding 10 μL of a solution containing 5 mM sodium acetate (pH 4.5), 1 mM CHAPS, 200 μM NAD (Sigma, catalog number N2630), and 500 μM GW323424X. Solutions of both additives were freshly prepared daily from concentrated stockpiles of each component. The final concentrations used in the experiment were 50 mM HEPES, 2 mM EDTA, 1 mM CHAPS, 2.5 mM sodium acetate, 100 μM NAD, 250 μM GW323434X and 0.4 nM CD38.

[0188] GW323434X is a 4-pyridyl compound that acts as a nucleophile in a base exchange reaction with nicotinamide on NAD, forming a novel dinucleotide with absorption at 405 nm. The catalytic formation of this novel chromophore was tracked using an Envision microplate reader by reading absorbance at two time points, typically 30 minutes apart within 45 minutes of the reaction initiation. These time points were empirically determined to ensure that the measured rate was within the linear range of product formation.

[0189] Data analysis was performed using Abase XE in the following ways:

[0190] The 15-minute and 45-minute readings were processed by subtracting the 15-minute reading from the 45-minute reading for each well. For the results displayed for non-control wells, the inhibition rate was converted in Excel using the following formula: Inhibition Rate % = 100 * ((U - C1) / (C2 - C1))

[0191] Where U is the value of the test hole, C1 is the average value of the high signal (column 6) control hole values, and C2 is the average value of the low signal (column 18) control hole values.

[0192] Plot the inhibition percentage (Y) against the inhibitor concentration (X), use XL-Fit and fit the data according to formula (2) to obtain the IC50 value, and use the following four-parameter equation for curve fitting to obtain the IC50 value: Y=A+((BA) / (1+(IC 50 / X)*C)),

[0193] Where A is the minimum response, B is the maximum response, and C is the slope.

[0194] The inhibitory activity (IC50) of the compounds in this invention on human CD38 50 The results are shown in the table below.

[0195] Therefore, the compounds of the present invention have excellent activity in inhibiting CD38 and have excellent development prospects.

[0196] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A compound of formula (I), its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates, or prodrugs, in, X is N or CR a ; R a Selected from the following groups: H, D, halogens, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups; Ring A is a 5-9 membered heteroaryl or a 4-9 membered heterocyclic group; Ring B is selected from the following group: C 6-10 Aryl, 5-9 quinone heteroaryl, C 3-10 cycloalkyl groups, 4-9 membered heterocyclic groups; n is 1, 2, 3, 4 or 5; R1 is selected from the following group: deuterium, halogen, cyano, carboxyl, C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1- 6-alkoxy, C 1-6 Halogenated alkoxy groups, C 2-4 Ester group, -CONH2, -CONH-C 1-6 Alkyl group; the above groups are optionally surrounded by 1, 2 or 3 R groups. b replace; R b Selected from the following group: -S(O)2-C 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Alkoxy, C 1-6 Alkylamino, -C(O)OC 1-6 Alkyl group, -C(O)NH-C 1-6 Alkyl, -C(O)N(C) 1-6 Alkyl)2; R2, R3, and R4 are each independently selected from the following groups: H, D, halogens, C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, 3-8 membered cycloalkyl groups, and 4-7 membered heterocyclic groups.

2. The compound, its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates, or prodrugs as claimed in claim 1, characterized in that, X is N or CR a ;R a Selected from the following groups: H, D, halogens, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups; Preferably, X is N or CR a The R a Selected from the following group: H, halogen, methyl, ethyl, n-propyl, isopropyl, C 1-3 Fluorinated alkyl groups; More preferably, X is selected from the group consisting of: N, CH, CCH3, CCF3.

3. The compound, its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates, or prodrugs as described in claim 1, characterized in that, The ring A is a 5-9 member sulfur-containing heteroaryl group; Preferably, ring A is selected from the group consisting of 5-7 nucleotide sulfur-containing heteroaryl groups and 5-7 nucleotide oxygen-containing heteroaryl groups; More preferably, the ring A is selected from the group consisting of 5-7 nucleotides containing sulfur and nitrogen, and 5-7 nucleotides containing oxygen and nitrogen. More preferably, the ring A is selected from the group consisting of:

4. The compound, its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates, or prodrugs as described in claim 1, characterized in that, The ring B is selected from the group consisting of: phenyl, naphthyl, 5-7 membered heteroaryl, C 3-8 cycloalkyl groups, 4-7 membered heterocyclic groups; Preferably, ring B is selected from the group consisting of: phenyl, naphthyl, 5-7 member nitrogen-containing heteroaryl, C 3-6 cycloalkyl, 4-6 member hetero Cyclic groups; More preferably, the ring B is selected from the group consisting of: cyclopentane, cyclohexane, benzene ring, naphthalene, furan, pyran, dihydropyran, tetrahydropyran, thiophene, pyrrole, thiazole, thiadiazole, diazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetraazole, pyrazole, pyridine, pyrimidine, pyrazine, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine.

5. The compound of claim 1, its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates, or prodrugs, characterized in that, The R1 is selected from the group consisting of: deuterium, halogen, cyano, carboxyl, and C. 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 2-4 Ester group, -CONH2, -CONH-C 1-4 Alkyl group; the above groups are optionally surrounded by 1, 2 or 3 R groups. b replace; R b Selected from the following group: -S(O)2-C 1-4 Alkyl, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Alkoxy, C 1-4 Alkylamino, -C(O)OC 1-4 Alkyl group, -C(O)NH-C 1-4 Alkyl, -C(O)N(C) 1-4 Alkyl)2; Preferably, R1 is selected from the group consisting of: deuterium, halogen, cyano, carboxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 Ester group, -CONH2, -CONH-C 1-3 Alkyl group; the above groups are optionally surrounded by 1, 2 or 3 R groups. b replace; R b Selected from the following group: -S(O)2-C 1-3 Alkyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy groups, C 1-3 Alkoxy, C 1-3 Alkylamino, -C(O)OC 1-3 Alkyl group, -C(O)NH-C 1-3 Alkyl, -C(O)N(C) 1-3 Alkyl)2; More preferably, R1 is selected from the group consisting of: F, Cl, Br, -OC. 1-3 Alkylene-R b ; R b Selected from the following group: -S(O)2-C 1-3 Alkyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy groups, C 1-3 Alkoxy, C 1-3 Alkylamino, -C(O)OC 1-3 Alkyl group, -C(O)NH-C 1-3 Alkyl, -C(O)N(C) 1-3 Alkyl)2; More preferably, R1 is selected from the group consisting of: F, Cl, 6. The compound, its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates, or prodrugs as claimed in claim 1, characterized in that, The Selected from the following group:

7. The compound of claim 1, its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates, or prodrugs, characterized in that, The compounds are selected from the group consisting of:

8. A pharmaceutical composition, characterized in that, The composition comprises: (i) The compound, stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug as described in any one of claims 1-7; and (ii) Pharmaceutically acceptable carriers, excipients or excipients.

9. The use of the compound, stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate, or prodrug as claimed in any one of claims 1-7, or the pharmaceutical composition as claimed in claim 8, characterized in that, Used to prepare drugs for the treatment and / or prevention of diseases associated with abnormal expression or activity of CD38; Preferably, the disease associated with abnormal expression or activity of CD38 is cancer or an immune disease; More preferably, the cancer is selected from the group consisting of: leukemia, B-cell lymphoma, T-cell lymphoma, NK-cell lymphoma, plasma cell malignancy, myeloma, tumors of exhausted T cells, tumors defined as hot, variant, or cold immune tumors based on immune scores, breast cancer, central nervous system cancer, endometrial cancer, kidney cancer, colorectal cancer, lung cancer, esophageal cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, head and neck (upper respiratory and digestive tract) cancer, urinary tract cancer, colon cancer, Hodgkin's lymphoma, non-Hodgkin's lymphoma, multiple myeloma, B-cell lymphoma (e.g., diffuse large B-cell lymphoma (DLBCL)), chronic lymphocytic lymphoma (CLL), T-cell lymphoma, pilocellular lymphoma, Burkitt's lymphoma. Lymphoma, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), melanoma, colon cancer; The immune diseases mentioned are selected from the following group: rheumatoid arthritis, systemic lupus erythematosus, asthma, inflammatory bowel disease, multiple sclerosis, Crohn's disease, gastritis, Hashimoto's thyroiditis, ankylosing spondylitis, graft-versus-host disease, and immune-mediated thrombocytopenic symptoms.

10. An intermediate compound, characterized in that, The compounds are selected from the group consisting of:

Images