CN115702150A - CD73 inhibitor and application thereof in medicine - Google Patents
CD73 inhibitor and application thereof in medicine Download PDFInfo
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- CN115702150A CN115702150A CN202180043145.8A CN202180043145A CN115702150A CN 115702150 A CN115702150 A CN 115702150A CN 202180043145 A CN202180043145 A CN 202180043145A CN 115702150 A CN115702150 A CN 115702150A
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- 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
- A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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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
Abstract
Provided is a novel compound having a cancer therapeutic activity. Also provided are methods for the preparation of these compounds and pharmaceutical compositions comprising them.
Description
The present invention relates to a CD73 inhibitor having cancer therapeutic activity. The invention also relates to a preparation method of the compounds and a pharmaceutical composition containing the compounds.
Extracellular 5' -nucleotidase (CD 73) is a glycoprotein on the cell membrane, and is present on the surface of the cell membrane of various cell types, including endothelial cells, lymphocytes, stromal cells, tumor cells, and the like. CD73 catalyzes the production of adenosine from extracellular adenosine 5 '-phosphate (5' -AMP), which induces immunosuppressive effects and promotes tumor proliferation and/or metastasis. In addition, CD73 can also promote tumorigenesis by non-immune related mechanisms, such as promoting tumor angiogenesis, promoting adhesion of tumor cells to extracellular matrix proteins, and the like. Clinically, high levels of CD73 expression are associated with lymph node metastasis and poor prognosis for a variety of cancer types, and CD73 has been found to be an independent prognostic factor in prostate and triple negative breast cancer patients. The invention provides a micromolecular CD73 inhibitor with a novel structure, which has good anti-tumor activity.
Disclosure of Invention
The invention provides a compound shown as a general formula (I), a tautomer or a medicinal salt thereof:
wherein the content of the first and second substances,
R 1 selected from phenyl or 5-6 membered heteroaryl, said phenyl or 5-6 membered heteroaryl being unsubstituted or substituted by 1,2 or 3 substituents R 3 The substitution is carried out on the raw materials,
R 3 is selected from C 1-6 Alkyl, - (C) 1-4 Alkylene radical) 0-1 -Cyc、-O-(C 1-4 Alkylene radical) 0-1 -Cyc、-S-(C 1-4 Alkylene radical) 0-1 -Cyc、-NH-(C 1-4 Alkylene radical) 0-1 -Cyc、-NH-C 1-6 Alkyl, -N (C) 1-6 Alkyl radical) 2 、-O-C 1-6 Alkyl or-S-C 1-6 Alkyl radical, R 3 Optionally unsubstituted or further substituted by one or more R 4 Substituted by a substituent;
cyc is selected from C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 6-10 Aryl or 5-to 10-membered heteroaryl, said C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 6-10 Aryl or 5-to 10-membered heteroaryl unsubstituted or substituted by 1,2 or 3 substituents R 5 Substituted;
R 4 or R 5 Each of which isIndependently selected from H, hydroxy, amino, halogen, cyano, nitro, -OR a 、-SR a 、＝O、＝S、-C(O)R a 、-C(S)R a 、-C(O)OR a 、-C(S)OR a 、-C(O)N(R a ) 2 、-N(R a ) 2 、-S(O) 2 R a 、-O-S(O 2 )OR a 、-O-S(O) 2 R a Or R a Said R is a Each independently selected from H, C 1-6 Alkyl or C 3-6 Cycloalkyl radical, R a Unsubstituted or further substituted by one or more groups selected from halogen, hydroxy, C 1-3 Alkyl or cyano;
R 2 selected from hydrogen, halogen, cyano, C 1-3 Alkyl radical, C 1-3 Alkoxy radical, C 2-4 Alkenyl, halo C 2-4 Alkenyl or C 2-4 Alkynyl.
In some embodiments, R in formula (I) 1 Selected from phenyl or 5-6 membered heteroaryl, optionally containing 1 or 2 heteroatoms each independently selected from N, O or S, and said heteroaryl ring group is unsubstituted or substituted with 1,2 or 3 substituents R 3 Substituted; preferably R 1 Is selected from
The R is 1 Unsubstituted or substituted by 1,2 or 3 substituents R 3 And (4) substituting.
In some embodiments, R in formula (I) 3 Is substituted in meta position.
In some embodiments, R in formula (I) 3 Is selected from C 1-6 Alkyl, -C 1-3 Alkylene-phenyl, -C 1-3 alkylene-C 3-6 Cycloalkyl or-C 1-3 Alkylene- (5-to 10-membered heteroaryl), said R 3 Optionally selected from H, cyano, halogen, hydroxy, amino, C 1-3 Alkyl radical, C 1-3 Hydroxyalkyl radical, C 1-3 Haloalkyl, C 1-3 Alkoxy radical, C 1-3 Haloalkoxy, -C (= O) O-C 1-3 Alkyl or-S (= O) 2 -C 1-3 Alkyl substituent; preferably R 3 Is selected from C 1-6 Alkyl, aryl, heteroaryl, and heteroaryl,
The R is 3 Optionally substituted by a group selected from H, cyano, halogen, hydroxy, amino, C 1-3 Alkyl radical, C 1-3 Hydroxyalkyl radical, C 1-3 Haloalkyl, C 1-3 Alkoxy radical, C 1-3 Haloalkoxy, -C (= O) O-C 1-3 Alkyl or-S (= O) 2 -C 1-3 Alkyl substituents.
In some embodiments, R in formula (I) 2 Selected from halogen, C 1-3 Alkyl or C 1-3 An alkoxy group; preferably chlorine, methyl or methoxy.
In some embodiments, the compound of formula (I) is selected from compounds represented by general formula (IA):
wherein the content of the first and second substances,
X 1 is selected from N or CH;
X 2 is selected from N orCH；
R 3 Is selected from C 1-6 Alkyl, - (C) 1-4 Alkylene radical) 0-1 -Cyc、-O-(C 1-4 Alkylene radical) 0-1 -Cyc、-S-(C 1-4 Alkylene radical) 0-1 -Cyc、-NH-(C 1-4 Alkylene radical) 0-1 -Cyc、-NH-C 1-6 Alkyl, -N (C) 1-6 Alkyl radical) 2 、-O-C 1-6 Alkyl or-S-C 1-6 Alkyl radical, R 3 Optionally unsubstituted or further substituted by one or more R 4 Substituted by a substituent;
cyc is selected from C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 6-10 Aryl or 5-to 10-membered heteroaryl, said C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 6-10 Aryl or 5-to 10-membered heteroaryl unsubstituted or substituted by 1,2 or 3 substituents R 5 Substituted;
R 4 or R 5 Each independently selected from H, hydroxy, amino, halogen, cyano, nitro, -OR a 、-SR a 、＝O、＝S、-C(O)R a 、-C(S)R a 、-C(O)OR a 、-C(S)OR a 、-C(O)N(R a ) 2 、-N(R a ) 2 、-S(O) 2 R a 、-O-S(O 2 )OR a 、-O-S(O) 2 R a Or R a Said R is a Each independently selected from H, C 1-6 Alkyl or C 3-6 Cycloalkyl radical, R a Unsubstituted or further substituted by one or more groups selected from halogen, hydroxy, C 1-3 Alkyl or cyano;
R 2 selected from hydrogen, halogen, cyano, C 1-3 Alkyl radical, C 1-3 Alkoxy radical, C 2-4 Alkenyl, halo C 2-4 Alkenyl or C 2-4 Alkynyl.
In some embodiments, formula (I) is selected from:
in some embodiments, the method of synthesizing formula (I) comprises:
reacting the compound of the general formula (II) under an acidic condition to obtain a compound of the general formula (I),
wherein R is 1 And R 2 The definition of (A) is as described in formula (I).
The invention also provides a pharmaceutical composition, which is characterized by comprising at least one compound shown as the formula (I) in a therapeutically effective amount and at least one pharmaceutically acceptable auxiliary material.
The invention further provides a pharmaceutical composition, which is characterized in that the mass percentage of the therapeutically effective amount of at least one compound shown in the formula (I) and pharmaceutically acceptable auxiliary materials is 0.0001.
The invention provides application of a compound or a pharmaceutical composition shown in a structural formula (I) in preparation of a medicament.
The invention further provides a preferable technical scheme of the application:
preferably, the application is the application in preparing a medicament for treating and/or preventing cancer.
Preferably, the cancer is selected from breast cancer, multiple myeloma, bladder cancer, endometrial cancer, gastric cancer, cervical cancer, rhabdomyosarcoma, non-small cell lung cancer, pleomorphic lung cancer, ovarian cancer, esophageal cancer, melanoma, colorectal cancer, hepatoma, head and neck tumors, hepatobiliary cell carcinoma, myelodysplastic syndrome, glioblastoma, prostate cancer, thyroid cancer, xu Wangshi cell tumor, lung squamous cell carcinoma, lichenification keratosis, synovial sarcoma, skin cancer, pancreatic cancer, testicular cancer, or liposarcoma.
The invention also provides a method for treating and/or preventing diseases, which comprises the step of administering at least one compound shown in the structural formula (I) or a pharmaceutical composition containing the compound to a treated object in a therapeutically effective amount.
The present invention also provides a method for treating cancer, comprising administering to a subject a therapeutically effective amount of at least any one of the compounds of formula (I) or a pharmaceutical composition comprising the same.
Preferably, in the above method, the cancer is selected from breast cancer, multiple myeloma, bladder cancer, endometrial cancer, gastric cancer, cervical cancer, rhabdomyosarcoma, non-small cell lung cancer, pleomorphic lung cancer, ovarian cancer, esophageal cancer, melanoma, colorectal cancer, hepatoma, head and neck tumors, hepatobiliary cell carcinoma, myelodysplastic syndrome, glioblastoma, prostate cancer, thyroid cancer, xu Wangshi cell tumor, lung squamous cell carcinoma, lichenification keratosis, synovial sarcoma, skin cancer, pancreatic cancer, testicular cancer, or liposarcoma.
Unless otherwise indicated, general chemical terms used in the structural formulae have the usual meanings.
For example, the term "halogen" as used herein, unless otherwise specified, refers to fluorine, chlorine, bromine or iodine.
In the present invention, unless otherwise specified, "alkyl" includes straight or branched chain monovalent saturated hydrocarbon groups. For example, alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3- (2-methyl) butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-methylpentyl and the like. Similarly, "radical 1-8 Alkyl group "of" 1-8 By "meansGroups comprising 1,2,3,4, 5, 6, 7 or 8 carbon atoms arranged in a straight or branched chain.
“C 1-3 Alkylene "refers to a straight or branched chain divalent saturated hydrocarbon group. Such as methylene, 1,2-ethylene, 1,3-propylene or 1,2-isopropylene.
“C 2-6 Alkenyl "or" C 2-6 Alkynyl "refers to a straight or branched chain unsaturated hydrocarbon group.
"alkoxy" refers to the oxygen ether form of the straight or branched chain alkyl group previously described, i.e., -O-alkyl.
In the present invention, "a", "an", "the", "at least one" and "one or more" are used interchangeably. Thus, for example, a composition that includes "a" pharmaceutically acceptable excipient may be interpreted to mean that the composition includes "one or more" pharmaceutically acceptable excipients.
The term "aryl", as used herein, unless otherwise indicated, refers to an unsubstituted or substituted monocyclic or fused ring aromatic group comprising carbocyclic atoms. Preferably, aryl is a 6 to 10 membered monocyclic or bicyclic aromatic ring group. Preferably phenyl or naphthyl. Most preferred is phenyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl group, wherein the ring attached to the parent structure is an aryl ring, non-limiting examples include, but are not limited to, benzocyclopentyl.
The term "heterocyclyl", as used herein, unless otherwise specified, refers to an unsubstituted or substituted stabilizing ring system of carbon atoms and 1-3 heteroatoms selected from N, O or S, which is a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising from 3 to 20 carbon atoms in which the nitrogen or sulfur heteroatom may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. The heterocyclic group may be attached to any heteroatom or carbon atom to form a stable structure. Examples of such heterocyclyl groups include, but are not limited to, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, tetrahydrofuranyl, dioxolanyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, and tetrahydrooxadiazolyl.
The term "heteroaryl", in the present invention, unless otherwise indicated, refers to an unsubstituted or substituted stable 5-or 6-membered monocyclic aromatic ring system or an unsubstituted or substituted 9-or 10-membered benzo-fused heteroaromatic ring system or bicyclic heteroaromatic ring system, consisting of carbon atoms and 1 to 4 heteroatoms selected from N, O or S, and wherein said nitrogen or sulfur heteroatoms may be optionally oxidized and said nitrogen heteroatoms may be optionally quaternized. The heteroaryl group may be attached at any heteroatom or carbon atom to form a stable structure. Examples of heteroaryl groups include, but are not limited to, thienyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridazinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzisoxazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl adenine, quinolinyl, or isoquinolinyl. The heteroaryl group can be fused to an aryl, heterocyclyl, or cycloalkyl ring, wherein the ring attached to the parent structure is a heteroaryl ring.
The term "cycloalkyl" refers to a cyclic saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent having 3 to 10 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
The term "substituted" means that one or more hydrogen atoms in a group are replaced by the same or different substituents, respectively. Typical substituents include, but are not limited to, halogen (F, cl, br or I), C 1-8 Alkyl radical, C 3-12 Cycloalkyl, -OR 1 、-SR 1 、＝O、＝S、-C(O)R 1 、-C(S)R 1 、＝NR 1 、-C(O)OR 1 、-C(S)OR 1 、-NR 1 R 2 、-C(O)NR 1 R 2 Cyano, nitro, -S (O) 2 R 1 、-O-S(O 2 )OR 1 、-O-S(O) 2 R 1 、-OP(O)(OR 1 )(OR 2 ) (ii) a Wherein R is 1 And R 2 Independently selected from-H, C 1-6 Alkyl radical, C 1-6 A haloalkyl group. In some embodiments, the substituents are independently selected from the group consisting of-F, -Cl, -Br, -I, -OH, trifluoromethoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, -SCH 3 、-SC 2 H 5 Formaldehyde group, -C (OCH) 3 ) Cyano, nitro, -CF 3 、-OCF 3 Amino, dimethylamino, methylthio, sulfonyl and acetyl groups.
Examples of substituted alkyl groups include, but are not limited to, 2,3-dihydroxypropyl, 2-aminoethyl, 2-hydroxyethyl, pentachloroethyl, trifluoromethyl, methoxymethyl, pentafluoroethyl, phenylmethyl, dioxolanylmethyl, and piperazinylmethyl.
Examples of substituted alkoxy groups include, but are not limited to, 2-hydroxyethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 2-methoxyethoxy, 2-aminoethoxy, 2,3-dihydroxypropoxy, cyclopropylmethoxy, aminomethoxy, trifluoromethoxy, 2-diethylaminoethoxy, 2-ethoxycarbonylethoxy, 3-hydroxypropoxy.
The term "pharmaceutically acceptable salt" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids.
Since the compounds of formula (I) are intended for pharmaceutical use, it is preferred to use them in a certain purity, for example, at least 60% pure, more suitably at least 75% pure, and especially at least 98% pure (% by weight).
Prodrugs of the compounds of the invention are included within the scope of the invention. In general, the prodrug refers to a functional derivative that is readily converted in vivo to the desired compound. For example, any pharmaceutically acceptable salt, ester, salt of an ester, or other derivative of a compound of the present application, which upon administration to a subject is capable of providing, directly or indirectly, a compound of the present application or a pharmaceutically active metabolite or residue thereof.
The compounds of the present invention may contain one or more asymmetric centers and may thus give rise to diastereomers and optical isomers. The present invention includes all possible diastereomers and racemic mixtures thereof, substantially pure resolved enantiomers thereof, all possible geometric isomers thereof, and pharmaceutically acceptable salts thereof.
Certain therapeutic advantages may be provided when compounds of formula (I) are replaced with heavier isotopes such as deuterium, for example, which may be attributed to greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements.
When solvates or polymorphs exist of the compounds of formula (I) and pharmaceutically acceptable salts thereof, the present invention includes any possible solvates and polymorphs. The type of solvent for forming the solvate is not particularly limited as long as the solvent is pharmaceutically acceptable. For example, water, ethanol, propanol, acetone, and the like can be used.
The term "composition," as used herein, is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. Accordingly, pharmaceutical compositions containing the compounds of the invention as active ingredients as well as methods for preparing the compounds of the invention are also part of the invention. In addition, some crystalline forms of the compounds may exist as polymorphs and as such are included in the present invention. In addition, some compounds may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates also fall within the scope of the present invention.
The pharmaceutical composition provided by the invention comprises a compound shown in formula (I) (or pharmaceutically acceptable salt thereof) as an active component, a pharmaceutically acceptable excipient and other optional therapeutic components or auxiliary materials.
In order to make the above clear and definite, the present invention will be further illustrated by the following examples. The following examples are intended only to illustrate specific embodiments of the present invention so as to enable those skilled in the art to understand the present invention, but not to limit the scope of the present invention. In the embodiments of the present invention, technical means or methods not specifically described are conventional in the art.
All parts and percentages herein are by weight and all temperatures are in degrees Celsius, unless otherwise indicated.
The synthesis scheme is as follows:
reacting the compound of the general formula (II) under an acidic condition to obtain the compound of the general formula (I).
Preparation of intermediate Compound M1
The method comprises the following steps:
4,6-dichloro-3-methylpyridazine (1.3 g), 2,4-dimethoxy-5-pyrimidineboronic acid (1.6 g), pd (dppf) Cl 2 -CH 2 Cl 2 (325.64 mg) and Cs 2 CO 3 (3.75 g) was mixed with dioxane (25 mL) and water (5 mL) and the mixture was heated to 70 ℃ under nitrogen. After 2h, TLC monitoring indicated complete reaction. Pouring the reaction solution into a proper amount of water, mixing uniformly, extracting with ethyl acetate for three times, washing with saturated saline solution, drying and concentrating to obtain a crude product. Column chromatography purification (PE: EA = 1:1) to obtain 1.1g white solid, i.e. compound M1 (M + H) + :267、269)。
Preparation of intermediate compound M2
Step 1:
3-amino-4-bromo-6-chloropyridazine (2 g), 3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1- (triisopropylsilyl) -1H-pyrrole (1.6 g), pd (dppf) Cl 2 -CH 2 Cl 2 (289.45 mg) and K 2 CO 3 (2.20 g) was mixed with dioxane (25 mL) and water (5 mL), and the mixture was heated to 70 ℃ under nitrogen atmosphere to react. After 2h, TLC monitoring indicated complete reaction. Pouring the reaction solution into a proper amount of water, mixing uniformly, extracting with ethyl acetate for three times, washing with saturated saline solution, drying and concentrating to obtain a crude product. Column chromatography purification (DCM: meOH = 30) + :352、354)。
Step 2
The compound M2-1 (3.1 g), 2,4-dimethoxy-5-pyrimidineboronic acid (3.25 g), pd (dppf) Cl 2 -CH 2 Cl 2 (341.28 mg) and Cs 2 CO 3 (8.69 g) was mixed with dioxane (50 mL) and water (10 mL), and the mixture was heated to 90 ℃ under nitrogen atmosphere to react. After 12h, TLC monitoring indicated complete reaction. Pouring the reaction solution into a proper amount of water, mixing uniformly, extracting with ethyl acetate for three times, washing with saturated saline solution, drying and concentrating to obtain a crude product. Column chromatography purification (DCM: meOH = 20) + :299)。
Step 3
Compound M2-2 (1.1 g) and cuprous chloride (730.83 mg) were mixed in acetonitrile (50 mL), tert-butyl nitrite was added dropwise, and the temperature was raised to 70 ℃ under nitrogen protection to react. After 2h, TLC monitoring indicated complete reaction. Filtering the reaction solution with diatomaceous earth, washing the filter cake with ethyl acetate, and purifying the filtrate by column chromatography (PE: EA = 1:5) to obtain 212mg of yellow solid, i.e., compound M2 (M + H) + :318,320)。
Example 1: synthesis of Compound 1 (4- ((5- (6- (2,4-dioxy-1,2,3,4-tetrahydropyrimidin-5-yl) -3-methylpyridazin-4-yl) -1H-pyrazol-1-yl) methyl) benzonitrile)
Step 1: synthesis of Compound 1-1
The compound 1H-pyrazole-3-boronic acid pinacol ester (109 mg), p-cyanobenzyl bromide (100 mg) and K 2 CO 3 (211 mg) was mixed with acetonitrile (5 mL), and the mixture was heated to 70 ℃ to react overnight. LCMS monitoring indicated complete reaction. Directly evaporating the reaction solution to dryness to obtain white viscous substance 100mg, i.e. compound 1-1 (M + H) + :228)。
Step 2: synthesis of Compound 1-2
Compounds M1 (129 mg), 1-1 (100 mg), K 2 CO 3 (152mg)、Pd(dppf)Cl 2 -CH 2 Cl 2 (36 mg) was mixed with dioxane (5 mL) and water (1 mL), and the mixture was heated to 70 ℃ under nitrogen atmosphere to react. After 4h, LCMS monitoring indicated complete reaction. The reaction solution was directly evaporated to dryness. Separating and purifying by column chromatography (PE: EA = 1:1) to obtain 70mg of white solid, i.e. compound 1-2 (M + H) + :413)。
And step 3: synthesis of Compound 1
Compound 1-2 (70 mg) was mixed with 1M dilute hydrochloric acid solution (2 mL), and the mixture was heated to 70 ℃ to react. After 5h, LCMS monitoring indicated complete reaction. Filtering to obtain crude product, pulping acetonitrile to obtain 50mg white solid, i.e. compound 1 (M + H) + :386)。
Example 2: synthesis of Compound 2 (4- ((3- (6- (2,4-dioxy-1,2,3,4-tetrahydropyrimidin-5-yl) -3-methylpyridazin-4-yl) -1H-pyrazol-1-yl) methyl) benzonitrile)
Step 1: synthesis of Compound 2-1
The compound 1H-pyrazole-3-boronic acid pinacol ester (109 mg), p-cyanobenzyl bromide (100 mg) and K 2 CO 3 (211 mg) was mixed with acetonitrile (5 mL), and the mixture was heated to 70 ℃ to react overnight. LCMS monitoring indicated complete reaction. Direct steaming of reaction liquidDrying to obtain white viscous substance 100mg, i.e. compound 2-1 (M + H) + :228)。
Step 2: synthesis of Compound 2-2
Compounds M1 (129 mg), 2-1 (100 mg), K 2 CO 3 (152mg)、Pd(dppf)Cl 2 -CH 2 Cl 2 (36 mg) was mixed with dioxane (5 mL) and water (1 mL), and the mixture was heated to 70 ℃ under nitrogen atmosphere to react. After 4h, TLC monitoring indicated complete reaction. The reaction solution was directly evaporated to dryness. Separating and purifying by column chromatography (PE: EA = 1:1) to obtain 60mg of white solid, i.e. compound 2-2 (M + H) + :413)。
And step 3: synthesis of Compound 2
Compound 2-2 (60 mg) was mixed with 1M dilute hydrochloric acid solution (2 mL), and the mixture was heated to 70 ℃ to react. After 5h, LCMS monitoring indicated complete reaction. Filtering to obtain crude product, pulping acetonitrile to obtain 40mg white solid, i.e. compound 2 (M + H) + :386)。
Example 3: synthesis of Compound 3 (5- (6-methyl-5- (1- (4-methylbenzyl) -1H-pyrazol-3-yl) pyridazin-3-yl) pyrimidine-2,4 (1H, 3H) -dione)
Step 1: synthesis of Compound 3-1
The compound 1H-pyrazole-3-boronic acid pinacol ester (109 mg), p-methylbenzyl bromide (100 mg) and K 2 CO 3 (211 mg) was mixed with acetonitrile (5 mL), and the mixture was heated to 70 ℃ to react overnight. LCMS monitoring indicated complete reaction. Directly evaporating the reaction solution to dryness to obtain white viscous substance 100mg, i.e. compound 3-1 (M + H) + :217)。
Step 2: synthesis of Compound 3-2
Mixing compound M1 (129 mg), 3-1 (100 mg), and K 2 CO 3 (152mg)、Pd(dppf)Cl 2 -CH 2 Cl 2 (36 mg) was mixed with dioxane (5 mL) and water (1 mL) and the mixture was heated to 70 ℃ under nitrogen atmosphere for reaction overnight.The reaction solution was directly evaporated to dryness. Separating and purifying by column chromatography (PE: EA = 1:1) to obtain 70mg of white solid, i.e. compound 3-2 (M + H) + :403)。
And step 3: synthesis of Compound 3
Compound 3-2 (70 mg) was mixed with 1M dilute hydrochloric acid solution (2 mL), and the mixture was heated to 70 ℃ to react. After 5h, LCMS monitoring indicated complete reaction. Filtering to obtain crude product, pulping acetonitrile to obtain 50mg white solid, i.e. compound 3 (M + H) + :375)。
Example 4: synthesis of Compound 4 (5- (5- (1-benzyl-1H-pyrazol-3-yl) -6-methylpyridazin-3-yl) pyrimidine-2,4 (1H, 3H) -dione)
Step 1: synthesis of Compound 4-1
The compound 1H-pyrazole-3-boronic acid pinacol ester (109 mg), bromobenzyl (95 mg) and K 2 CO 3 (211 mg) was mixed with acetonitrile (5 mL), and the mixture was heated to 70 ℃ to react overnight. TLC monitoring indicated complete reaction. Directly evaporating the reaction solution to dryness to obtain white viscous substance 100mg, i.e. compound 4-1 (M + H) + :203)。
Step 2: synthesis of Compound 4-2
Mixing compound M1 (129 mg), 4-1 (100 mg), and K 2 CO 3 (152mg)、Pd(dppf)Cl 2 -CH 2 Cl 2 (36 mg) was mixed with dioxane (5 mL) and water (1 mL), and the mixture was heated to 70 ℃ under nitrogen atmosphere to react. After 2h, TLC monitoring indicated complete reaction. The reaction solution was directly evaporated to dryness. Separating and purifying by column chromatography (PE: EA = 1:1) to obtain 70mg of white solid, i.e. compound 4-2 (M + H) + :389)。
And step 3: synthesis of Compound 4
Compound 4-2 (70 mg) was mixed with 1M dilute hydrochloric acid solution (2 mL), and the mixture was heated to 70 ℃ to react. After 5h, LCMS monitoring indicated complete reaction. Filtering to obtain crude product, pulping acetonitrile to obtain 50mg white solid, i.e. compound 4 (M + H) + :361)。
Example 5: synthesis of Compound 5 (5- (5- (1- (4-chlorobenzyl) -1H-pyrazol-3-yl) -6-methylpyridazin-3-yl) pyrimidine-2,4 (1H, 3H) -dione)
Step 1: synthesis of Compound 5-1
Mixing compound M1 (70 mg), 1H-pyrazole-3-boronic acid pinacol ester (76.40 mg) and K 2 CO 3 (72.55mg)、Pd(dppf)Cl 2 -CH 2 Cl 2 (10.72 mg) was mixed with dioxane (2 mL) and water (0.4 mL), and the mixture was heated to 70 ℃ under nitrogen atmosphere to react. After 2h, TLC monitoring showed the reaction was complete. Pouring the reaction solution into a proper amount of water, mixing uniformly, extracting with ethyl acetate for three times, washing with saturated saline solution, drying and concentrating to obtain a crude product. Pulping dichloromethane/petroleum ether (V: V = 1/1) to obtain 70mg white solid, i.e. compound 5-1 (M + H) + :299)。
Step 2: synthesis of Compound 5-2
Compound 5-1 (70 mg), benzyl p-chlorobromide (50.60 mg) and K 2 CO 3 (64.86 mg) was mixed with DMF (2 mL) and the mixture was heated to 50 ℃ for reaction. After 1h, TLC monitoring indicated complete reaction. Pouring the reaction solution into a proper amount of water, mixing uniformly, extracting with ethyl acetate for three times, washing with saturated saline solution, drying and concentrating to obtain a crude product. Pulping acetonitrile to obtain 70mg of white solid, i.e. compound 5-2 (M + H) + :423、425)。
And step 3: synthesis of Compound 5
Compound 5-2 (90 mg) was mixed with 1M dilute hydrochloric acid solution (2 mL), and the mixture was heated to 70 ℃ to react. After 5h, LCMS monitoring indicated complete reaction. Filtering to obtain crude product, pulping acetonitrile to obtain 63mg of white solid, i.e. compound 5 (M + H) + :395、397)。
Example 6: synthesis of Compound 6 (5- (6-methyl-5- (1-methyl-1H-pyrazol-3-yl) pyridazin-3-yl) pyrimidine-2,4 (1H, 3H) -dione)
Step 1: synthesis of Compound 6-1
Compound M1 (70 mg), 1-methyl-3-pyrazoleboronic acid pinacol ester (76.40 mg), K 2 CO 3 (72.55mg)、Pd(dppf)Cl 2 -CH 2 Cl 2 (10.72 mg) was mixed with dioxane (2 mL) and water (0.4 mL), and the mixture was heated to 70 ℃ under nitrogen atmosphere to react. After 2h, TLC monitoring indicated complete reaction. The reaction solution was directly evaporated to dryness. Separating and purifying by column chromatography (PE: EA = 1:1) to obtain 70mg of white solid, i.e. compound 6-1 (M + H) + :313)。
Step 2: synthesis of Compound 6
Compound 6-1 (70 mg) was mixed with 1M dilute hydrochloric acid solution (2 mL), and the mixture was heated to 70 ℃ to react. After 5h, LCMS monitoring indicated complete reaction. Filtering to obtain crude product, pulping acetonitrile to obtain 50mg white solid, i.e. compound 6 (M + H) + :285)。
Example 7: synthesis of Compound 7 (5- (5- (1-isopropyl-1H-pyrazol-3-yl) -6-methylpyridazin-3-yl) pyrimidine-2,4 (1H, 3H) -dione)
Step 1: synthesis of Compound 7-1
Compound M1 (70 mg), 1-isopropyl-3-pyrazoleboronic acid pinacol ester (77.40 mg), K 2 CO 3 (72.55mg)、Pd(dppf)Cl 2 -CH 2 Cl 2 (10.72 mg) was mixed with dioxane (2 mL) and water (0.4 mL), and the mixture was heated to 70 ℃ under nitrogen atmosphere to react. After 2h, TLC monitoring indicated complete reaction. The reaction solution was directly evaporated to dryness. Column chromatography separation and purification (PE: EA = 1:1) to obtain 70mg of white solid, namely compound 7-1 (M + H) + :341)。
Step 2: synthesis of Compound 7
Compound 7-1 (70 mg) was mixed with 1M dilute hydrochloric acid solution (2 mL), and the mixture was heated to 70 ℃ to react. After 5h, LCMS monitoring indicated complete reaction. Filtering to obtain crude product, pulping acetonitrile to obtain 50mg white solid, i.e. compound 7 (M + H) + :313)。
Example 8: synthesis of Compound 8 (5- (5- (1- (cyclopropylmethyl) -1H-pyrazol-4-yl) -6-methylpyridazin-3-yl) pyrimidine-2,4 (1H, 3H) -dione)
Step 1: synthesis of Compound 8-1
Compound M1 (70 mg), 4-pyrazoleboronic acid pinacol ester (76.40 mg), and K 2 CO 3 (72.55mg)、Pd(dppf)Cl 2 -CH 2 Cl 2 (10.72 mg) was mixed with dioxane (2 mL) and water (0.4 mL), and the mixture was heated to 70 ℃ under nitrogen atmosphere to react. After 2h, TLC monitoring indicated complete reaction. Pouring the reaction solution into a proper amount of water, mixing uniformly, extracting with ethyl acetate for three times, washing with saturated saline solution, drying and concentrating to obtain a crude product. Pulping dichloromethane/petroleum ether (V: V = 1:1) to obtain 70mg white solid, i.e. compound 8-1 (M + H) + :299)。
Step 2: synthesis of Compound 8-2
Compound 8-1 (70 mg), bromomethylcyclopropane (30.10 mg) and K 2 CO 3 (64.86 mg) was mixed with DMF (2 mL) and the mixture was heated to 50 ℃ for reaction. After 1h, TLC monitoring indicated complete reaction. Pouring the reaction solution into a proper amount of water, mixing uniformly, extracting with ethyl acetate for three times, washing with saturated saline solution, drying and concentrating to obtain a crude product. Pulping acetonitrile to obtain 60mg of white solid, i.e. compound 8-2 (M + H) + :353)。
And step 3: synthesis of Compound 8
Compound 8-2 (60 mg) was mixed with 1M dilute hydrochloric acid solution (2 mL), and the mixture was heated to 70 ℃ to react. After 5h, LCMS monitoring indicated complete reaction. Filtering to obtain crude product, pulping acetonitrile to obtain 50mg white solid, i.e. compound 8 (M + H) + :325)。
Example 9: synthesis of Compound 9 (5- (5- (1- (4-chlorobenzyl) -1H-pyrazol-4-yl) -6-methylpyridazin-3-yl) pyrimidine-2,4 (1H, 3H) -dione)
Step 1: synthesis of Compound 9-1
Compound 8-1 (70 mg), p-chlorobenzyl bromide (50.30 mg) and K 2 CO 3 (64.86 mg) was mixed with DMF (2 mL) and the mixture was heated to 50 ℃ for reaction. After 1h, TLC monitoring showed the reaction was complete. Pouring the reaction solution into a proper amount of water, mixing uniformly, extracting with ethyl acetate for three times, washing with saturated saline solution, drying and concentrating to obtain a crude product. Pulping acetonitrile to obtain 75mg of white solid, i.e. compound 9-1 (M + H) + :423)。
Step 2: synthesis of Compound 9
Compound 9-1 (75 mg) was mixed with 1M dilute hydrochloric acid solution (2 mL), and the mixture was heated to 70 ℃ to react. After 5h, LCMS monitoring indicated complete reaction. Filtering to obtain crude product, pulping acetonitrile to obtain 50mg white solid, i.e. compound 9 (M + H) + :395)。
Example 10: synthesis of Compound 10 (4- ((4- (6- (2,4-dioxy-1,2,3,4-tetrahydropyrimidin-5-yl) -3-methylpyridazin-4-yl) -1H-pyrazol-1-yl) methyl) benzonitrile)
Step 1: synthesis of Compound 10-1
Compound 8-1 (70 mg), p-cyanobenzyl bromide (50.60 mg) and K 2 CO 3 (64.86 mg) was mixed with DMF (2 mL) and the mixture was heated to 50 ℃ for reaction. After 1h, TLC monitoring indicated complete reaction. Pouring the reaction solution into a proper amount of water, mixing uniformly, extracting with ethyl acetate for three times, washing with saturated saline solution, drying and concentrating to obtain a crude product. Pulping acetonitrile to obtain 90mg of white solid, i.e. compound 10-1(M+H + :414)。
And 3, step 3: synthesis of Compound 10
Compound 10-1 (90 mg) was mixed with 1M dilute hydrochloric acid solution (2 mL), and the mixture was heated to 70 ℃ to react. After 5h, LCMS monitoring indicated complete reaction. Filtering to obtain crude product, pulping with acetonitrile to obtain 50mg white solid, i.e. compound 10 (M + H) + :386)。
Example 11: synthesis of Compound 11 (5- (5- (furan-3-yl) -6-methylpyridazin-3-yl) pyrimidine-2,4 (1H, 3H) -dione)
Step 1: synthesis of Compound 11-1
Compound M1 (100 mg), 3-furanboronic acid (84 mg), and K 2 CO 3 (77.74mg)、Pd(dppf)Cl 2 -CH 2 Cl 2 (21.95 mg) was mixed with dioxane (4 mL) and water (1 mL), and the mixture was heated to 70 ℃ under nitrogen atmosphere to react. After 1h, TLC monitoring indicated complete reaction. Pouring the reaction solution into appropriate amount of water, mixing, extracting with ethyl acetate for three times, washing with saturated saline solution, drying, mixing with silica gel, separating by column chromatography, and pulping with petroleum ether/ethyl acetate (V: V = 5:1-1:3) as eluent to obtain 80mg yellow solid, i.e. compound 11-1 (M + H) + :299)。
Step 2: synthesis of Compound 11
Compound 11-1 (80 mg) was mixed with 1M dilute hydrochloric acid solution (3 mL), and the mixture was heated to 70 ℃ to react. After 5h, LCMS monitoring indicated complete reaction. Filtering to obtain crude product, pulping acetonitrile to obtain 26mg white solid, i.e. compound 11 (M + H) + :271)。
Example 12: synthesis of Compound 12 (5- (6-methyl-5- (1H-pyrrol-3-yl) pyridazin-3-yl) pyrimidine-2,4 (1H, 3H) -dione)
Step 1: synthesis of Compound 16-1
Compound M1 (70 mg), 3- (tetramethyl-1,3,2-dioxaborolan-2-yl) -1- [ tris (propan-2-yl) silyl]-1H-pyrrole (157.22 mg), K 2 CO 3 (103.65 mg) and Pd (dppf) Cl 2 -CH 2 Cl 2 (12.25 mg) was mixed with dioxane (2.5 mL) and water (0.5 mL), and the mixture was heated to 70 ℃ under nitrogen atmosphere to react. After 2h, TLC monitoring indicated complete reaction. Pouring the reaction solution into a proper amount of water, mixing uniformly, extracting with ethyl acetate for three times, washing with saturated saline, drying, and concentrating to obtain brown solid (136 mg), namely the compound 16-1 (M + H) + 298, 454). Used in the next step without purification.
Step 2: synthesis of Compound 16-2
Compound 16-1 (136 mg) and tetrabutylammonium fluoride (224.78 mg) were mixed in THF (5 mL) and stirred at room temperature. After 0.5h, TLC monitoring indicated complete reaction. Pouring the reaction solution into appropriate amount of water, mixing, extracting with ethyl acetate for three times, washing with saturated saline, drying, and concentrating to obtain brown solid (90 mg), i.e. compound 16-2 (M + H) + :298). Used in the next step without purification.
And step 3: synthesis of Compound 12
Compound 16-2 (30 mg) was mixed with 1M dilute hydrochloric acid solution (2 mL), and the mixture was heated to 70 ℃ to react. After 5h, LCMS monitoring indicated complete reaction. Filtering to obtain crude product, pulping DMF/methanol (V: V = 1/2) to obtain 11.8mg light green solid, i.e. compound 12 (M + H) + :270)。
Example 13: synthesis of Compound 13 (5- (5- (1- (cyclopropylmethyl) -1H-pyrrol-3-yl) -6-methylpyridazin-3-yl) pyrimidine-2,4 (1H, 3H) -dione)
Step 1: synthesis of Compound 13-1
Compound 16-2 (59 mg) and bromomethylcyclopropane (40.1)9mg)、Cs 2 CO 3 (129.31 mg) was mixed with DMF (6 mL) and the mixture was heated to 50 ℃ for reaction. After 10h, TLC monitoring indicated complete reaction. The reaction solution was poured into an appropriate amount of water and mixed well, extracted three times with ethyl acetate, washed with saturated brine, dried and concentrated to give yellow oil (65 mg), i.e., compound 13-1 (M + H) + :352). Used in the next step without purification.
And 2, step: synthesis of Compound 13
Compound 13-1 (90 mg) was mixed with 1M dilute hydrochloric acid solution (2 mL), and the mixture was heated to 70 ℃ to react. After 5h, LCMS monitoring indicated complete reaction. The reaction was spun dry to give crude and preparative TLC purification (DCM/MeOH = 10/1) afforded 36.9mg of a yellow solid, compound 13 (M + H) + :324)。
Example 14: synthesis of Compound 14 (5- (5- (1- (4-chlorobenzyl) -1H-pyrrol-3-yl) -6-methylpyridin-3-yl) pyrimidine-2,4 (1H, 3H) -dione)
Step 1: synthesis of Compound 14-1
Compound 16-2 (59 mg), benzyl p-chlorobromide (61.16 mg) and Cs 2 CO 3 (129.31 mg) was mixed with DMF (6 mL) and the mixture was heated to 50 ℃ for reaction. After 1.5h, TLC monitoring indicated complete reaction. Mixing the reaction solution with appropriate amount of water, extracting with ethyl acetate for three times, washing with saturated saline, drying, and concentrating to obtain yellow solid (80 mg), i.e. compound 14-1 (M + H) + 421, 423). Used in the next step without purification.
Step 2: synthesis of Compound 14
Compound 14-1 (80 mg) was mixed with 1M dilute hydrochloric acid solution (2 mL), and the mixture was heated to 70 ℃ to react. After 5h, LCMS monitoring indicated complete reaction. Filtering to obtain crude product, pulping with DCM/MeOH (1/1) to obtain 7.6mg of light yellow solid, i.e. compound 14 (M + H) + :394、396)。
Example 15: synthesis of Compound 15 (5- (5- (1- (4-methoxybenzyl) -1H-pyrrol-3-yl) -6-methylpyridazin-3-yl) pyrimidine-2,4 (1H, 3H) -dione)
Step 1: synthesis of Compound 15-1
Mixing compound 16-2 (59 mg), p-methoxybenzyl chloride (59.85 mg) and Cs 2 CO 3 (129.31 mg) was mixed with DMF (6 mL) and the mixture was heated to 50 ℃ for reaction. After 1.5h, TLC monitoring indicated complete reaction. Mixing the reaction solution with appropriate amount of water, extracting with ethyl acetate for three times, washing with saturated saline, drying, and concentrating to obtain yellow solid (80 mg), i.e. compound 15-1 (M + H) + :418). Used in the next step without purification.
Step 2: synthesis of Compound 15
Compound 15-1 (80mg, 191.64umol) was mixed with 1M dilute hydrochloric acid solution (2 mL) and the mixture was heated to 70 ℃ for reaction. After 5h, LCMS monitoring indicated complete reaction. Filtering to obtain crude product, separating the prepared liquid phase to obtain 12.3mg white solid, i.e. compound 15 (M + H) + :390)。
Example 16: synthesis of Compound 16 (4- ((3- (6- (2,4-dioxy-1,2,3,4-tetrahydropyrimidin-5-yl) -3-methylpyridazin-4-yl) -1H-pyrrol-1-yl) methyl) benzonitrile)
The method comprises the following steps: synthesis of Compound 16-3
Compound 16-2 (60 mg), p-cyanobenzyl bromide (47.48 mg) and K 2 CO 3 (55.78 mg) was mixed with DMF (2 mL) and the mixture was heated to 50 ℃ for reaction. After 10h, TLC monitoring indicated complete reaction. Pouring the reaction solution into a proper amount of water, mixing uniformly, extracting with ethyl acetate for three times, washing with saturated saline solution, drying and concentrating to obtain a crude product. Preparative TLC purification (PE/EA = 3/1) yielded 60mg of a yellow solid, compound 16-3 (M + H) + :413)。
And 4, step 4: synthesis of Compound 16
Compound 16-3 (60 mg) was mixed with 1M dilute hydrochloric acid solution (2 mL), and the mixture was heated to 70 ℃ to react. After 5h, LCMS monitoring indicated complete reaction. The crude product was spin-dried to prepare a liquid phase and 3.2mg of a yellow solid, compound 16 (M + H) + :385)。
Example 17: synthesis of Compound 17 (5- (5- (1-benzyl-1H-pyrrol-3-yl) -6-methylpyridazin-3-yl) pyrimidine-2,4 (1H, 3H) -dione)
Step 1: synthesis of Compound 17-1
Mixing compound 16-2 (60 mg), benzyl bromide (46.48 mg) and Cs 2 CO 3 (131.72 mg) was mixed with DMF (2 mL) and the mixture was heated to 50 ℃ for reaction. After 3h, LCMS monitoring indicated complete reaction. Pouring the reaction solution into a proper amount of water, mixing uniformly, extracting with ethyl acetate for three times, washing with saturated saline solution, drying and concentrating to obtain a crude product. Column chromatography separation and purification (DCM: meOH = 15) + :388)。
And 4, step 4: synthesis of Compound 17
Compound 17-2 (60mg, 145.47umol) was mixed with 1M dilute hydrochloric acid solution (2 mL) and reacted at an elevated temperature to 70 ℃. After 5h, LCMS monitoring indicated complete reaction. Filtering to obtain crude product, pulping with ethanol to obtain 30mg white solid, i.e. compound 17 (M + H) + :360)。
1 H-NMR(500MHz,DMSO-d 6 )δ11.50-11.37(m,2H),8.28(d,J＝5.9Hz,1H),8.22(s,1H),7.49(s,1H),7.38-7.35(m,2H),7.31-7.28(m,3H),7.03(s,1H),6.52(s,1H),5.21(s,2H),2.76(s,3H).
Example 18: synthesis of Compound 18 (5- (5- (1- (3-methoxybenzyl) -1H-pyrrol-3-yl) -6-methylpyridazin-3-yl) pyrimidine-2,4 (1H, 3H) -dione)
Step 1: synthesis of Compound 18-1
Mixing compound 16-2 (20 mg), m-methoxybenzyl bromide (41 mg) and Cs 2 CO 3 (66.2 mg) was mixed with DMF (2 mL), and the mixture was heated to 50 ℃ to react. After 3h, LCMS monitoring indicated complete reaction. Pouring the reaction solution into a proper amount of water, mixing uniformly, extracting with ethyl acetate for three times, washing with saturated saline solution, drying and concentrating to obtain a crude product. Column chromatography separation and purification (DCM: meOH = 15) + :418)。
Step 2: synthesis of Compound 18
Compound 18-2 (11 mg) was mixed with 1M dilute hydrochloric acid solution (1.5 mL), and the mixture was heated to 70 ℃ to react. After 5h, LCMS monitoring indicated complete reaction. Filtering to obtain crude product, pulping with ethanol to obtain 4.2mg yellow solid, i.e. compound 18 (M + H) + :390)。
Example 19: synthesis of Compound 19 (5- (6-methyl-5- (1- (3- (trifluoromethyl) benzyl) -1H-pyrrol-3-yl) pyridazin-3-yl) pyrimidine-2,4 (1H, 3H) -dione)
Step 1: synthesis of Compound 19-1
Mixing compound 16-2 (50 mg), 1-chloromethyl-3-trifluoromethylbenzene (118 mgl) and Cs 2 CO 3 (198 mg) was mixed with DMF (4 mL) and the mixture was heated to 50 ℃ for reaction. After 3h, LCMS monitoring indicated complete reaction. Pouring the reaction solution into a proper amount of water, mixing uniformly, extracting with ethyl acetate for three times, washing with saturated saline solution, drying and concentrating to obtain a crude product. Column chromatography purification (DCM: meOH = 15) + :456)。
Step 2: synthesis of Compound 19
Compound 19-2 (60 mg) was mixed with 1M dilute hydrochloric acid solution (5 mL), and the mixture was heated to 70 ℃ to react. After the reaction time of 5 hours,LCMS monitoring showed reaction completion. Filtering to obtain crude product, pulping with ethanol to obtain 41.48mg yellow solid, i.e. compound 19 (M + H) + :428)。
Example 20: synthesis of Compound 20 (5- (6-methyl-5- (1- (2- (trifluoromethyl) benzyl) -1H-pyrrol-3-yl) pyridazin-3-yl) pyrimidine-2,4 (1H, 3H) -dione)
Step 1: synthesis of Compound 20-1
Compound 16-2 (50 mg), 2-trifluoromethylbenzyl chloride (118 mg) and Cs 2 CO 3 (198 mg) was mixed with DMF (4 mL) and the mixture was heated to 50 ℃ for reaction. After 3h, LCMS monitoring indicated complete reaction. Pouring the reaction solution into a proper amount of water, mixing uniformly, extracting with ethyl acetate for three times, washing with saturated saline solution, drying and concentrating to obtain a crude product. Column chromatography purification (DCM: meOH = 15) + :456)。
Step 2: synthesis of Compound 20
Compound 20-1 (50 mg) was mixed with 1M dilute hydrochloric acid solution (5 mL), and the mixture was heated to 70 ℃ to react. After 5h, LCMS monitoring indicated complete reaction. Filtering to obtain crude product, pulping with ethanol to obtain 32.83mg yellow solid, i.e. compound 20 (M + H) + :428)。
Example 21: synthesis of Compound 21 (5- (6-methyl-5- (1- (quinolin-4-ylmethyl) -1H-pyrrol-3-yl) pyridazin-3-yl) pyrimidine-2,4 (1H, 3H) -dione)
Step 1: synthesis of Compound 21-1
Compound 16-2 (40 mg), 4-chloromethylquinoline (56.97 mg) and Cs 2 CO 3 (159 mg) was mixed with DMF (3 mL), and the mixture was heated to 50 ℃ for reaction. After 3h, LCMS monitoring indicated complete reaction. Inverse directionPouring the reaction solution into a proper amount of water, mixing uniformly, extracting with ethyl acetate for three times, washing with saturated saline solution, drying and concentrating to obtain a crude product. Column chromatography separation and purification (DCM: meOH = 15) + :439)。
Step 2: synthesis of Compound 21
Compound 21-1 (30 mg) was mixed with 1M dilute hydrochloric acid solution (3 mL), and the mixture was heated to 70 ℃ to react. After 5h, LCMS monitoring indicated complete reaction. Filtering to obtain crude product, pulping with ethanol to obtain 18.35mg yellow solid, i.e. compound 21 (M + H) + :411)。
Example 22: synthesis of Compound 22 (5- (6-methyl-5- (1- (1-phenylethyl) -1H-pyrrol-3-yl) pyridazin-3-yl) pyrimidine-2,4 (1H, 3H) -dione)
Step 1: synthesis of Compound 22-1
Compound 16-2 (30 mg), 1-chloro-1-phenylethane (51.1 mg) and Cs 2 CO 3 (119 mg) was mixed with DMF (2 mL), and the mixture was heated to 50 ℃ to react. After 3h, LCMS monitoring indicated complete reaction. Pouring the reaction solution into a proper amount of water, mixing uniformly, extracting with ethyl acetate for three times, washing with saturated saline solution, drying and concentrating to obtain a crude product. Column chromatography separation and purification (DCM: meOH = 15) + :402)。
Step 2: synthesis of Compound 22
Compound 22-1 (20 mg) was mixed with 1M dilute hydrochloric acid solution (2 mL), and the mixture was heated to 70 ℃ to react. After 5h, LCMS monitoring indicated complete reaction. Filtering to obtain crude product, pulping with ethanol to obtain 8.3mg yellow solid, i.e. compound 22 (M + H) + :374)。
Example 23: synthesis of Compound 23 (5- (5- (1- (cyclopentylmethyl) -1H-pyrrol-3-yl) -6-methylpyridazin-3-yl) pyrimidine-2,4 (1H, 3H) -dione)
Step 1: synthesis of Compound 23-1
Compound 16-2 (30 mg), chloromethylcyclopentane (43.1 mg) and Cs 2 CO 3 (119 mg) was mixed with DMF (2 mL), and the mixture was heated to 50 ℃ to react. After 3h, LCMS monitoring indicated complete reaction. Pouring the reaction solution into a proper amount of water, mixing uniformly, extracting with ethyl acetate for three times, washing with saturated saline solution, drying and concentrating to obtain a crude product. Column chromatography separation and purification (DCM: meOH = 15) + :380)。
Step 2: synthesis of Compound 23
Compound 23-1 (20 mg) was mixed with 1M dilute hydrochloric acid solution (2 mL), and the mixture was heated to 70 ℃ to react. After 5h, LCMS monitoring indicated complete reaction. Filtering to obtain crude product, pulping with ethanol to obtain 16.94mg yellow solid, i.e. compound 23 (M + H) + :352)。
Example 24: synthesis of Compound 24 (5- (5- (1- (cyclohexylmethyl) -1H-pyrrol-3-yl) -6-methylpyridazin-3-yl) pyrimidine-2,4 (1H, 3H) -dione)
Step 1: synthesis of Compound 24-1
Compound 16-2 (20 mg), chloromethylcyclohexane (28 mg) and Cs 2 CO 3 (66.2 mg) was mixed with DMF (2 mL), and the mixture was heated to 50 ℃ to react. After 3h, LCMS monitoring indicated complete reaction. Pouring the reaction solution into a proper amount of water, mixing uniformly, extracting with ethyl acetate for three times, washing with saturated saline solution, drying and concentrating to obtain a crude product. Column chromatography separation and purification (DCM: meOH = 15) + :394)。
Step 2: synthesis of Compound 24
Compound 24-1 (10 mg) was mixed with 1M dilute hydrochloric acid solution (2 mL), and the mixture was heated to 70 ℃ to react. After 5h, LCMS monitoring indicated complete reactionAnd (4) completing. Filtering to obtain crude product, pulping with ethanol to obtain 5.92mg yellow solid, i.e. compound 24 (M + H) + :366)。
Example 25: synthesis of compound 25 (4- ((3- (6- (2,4-dioxy-1,2,3,4-tetrahydropyrimidin-5-yl) -3-methylpyridazin-4-yl) -1H-pyrrol-1-yl) methyl) -3-fluorobenzonitrile)
Step 1: synthesis of Compound 25-1
Compound 16-2 (20 mg), 4- (chloromethyl) -3-fluorobenzonitrile (36 mg) and Cs 2 CO 3 (66.2 mg) was mixed with DMF (2 mL), and the mixture was heated to 50 ℃ for reaction. After 3h, LCMS monitoring indicated complete reaction. Pouring the reaction solution into a proper amount of water, mixing uniformly, extracting with ethyl acetate for three times, washing with saturated saline solution, drying and concentrating to obtain a crude product. Column chromatography separation and purification (DCM: meOH = 15) + :431)。
Step 2: synthesis of Compound 25
Compound 25-1 (20 mg) was mixed with 1M dilute hydrochloric acid solution (3 mL), and the mixture was heated to 70 ℃ to react. After 5h, LCMS monitoring indicated complete reaction. Filtering to obtain crude product, pulping with ethanol to obtain 10.54mg yellow solid, i.e. compound 25 (M + H) + :403)。
Example 26: synthesis of Compound 26 (5- (5- (1- (2,4-difluorobenzyl) -1H-pyrrol-3-yl) -6-methylpyridazin-3-yl) pyrimidine-2,4 (1H, 3H) -dione)
Step 1: synthesis of Compound 26-1
The compounds 16-2 (100 mg), 2,4-difluorobenzyl chloride (113 mg) and Cs 2 CO 3 (228.7 mg) was mixed with DMF (5 mL) and the mixture was heated to 50 ℃ for reaction. After 3h, LCMS monitoring indicated complete reaction. Reaction solutionPouring into proper amount of water, mixing, extracting with ethyl acetate for three times, washing with saturated saline solution, drying, and concentrating to obtain crude product. Column chromatography separation and purification (DCM: meOH = 15) + :424)。
Step 2: synthesis of Compound 26
Compound 26-1 (80 mg) was mixed with 1M dilute hydrochloric acid solution (5 mL), and the mixture was heated to 70 ℃ to react. After 5h, LCMS monitoring indicated complete reaction. Filtering to obtain crude product, pulping with ethanol to obtain 69.51mg yellow solid, i.e. compound 26 (M + H) + :396)。
Example 27: synthesis of Compound 27 (5- (6-methyl-5- (1- (pyridin-2-ylmethyl) -1H-pyrrol-3-yl) pyridazin-3-yl) pyrimidine-2,4 (1H, 3H) -dione)
Step 1: synthesis of Compound 27-1
Compound 16-2 (40 mg), 2-chloromethylpyridine (35.58 mg) and Cs 2 CO 3 (91.50 mg) was mixed with DMF (3 mL) and the mixture was heated to 50 ℃ for reaction. After 3h, LCMS monitoring indicated complete reaction. Pouring the reaction solution into a proper amount of water, mixing uniformly, extracting with ethyl acetate for three times, washing with saturated saline solution, drying and concentrating to obtain a crude product. Column chromatography separation and purification (DCM: meOH = 15) + :389)。
Step 2: synthesis of Compound 27
Compound 27-1 (30 mg) was mixed with 1M dilute hydrochloric acid solution (3 mL), and the mixture was heated to 70 ℃ to react. After 5h, LCMS monitoring indicated complete reaction. Filtering to obtain crude product, pulping with ethanol to obtain 24.8mg yellow solid, i.e. compound 27 (M + H) + :361)。
Example 28: synthesis of Compound 28 (5- (6-methyl-5- (1- ((1-methyl-1H-pyrazol-3-yl) methyl) -1H-pyrrol-3-yl) pyridazin-3-yl) pyrimidine-2,4 (1H, 3H) -dione)
Step 1: synthesis of Compound 28-1
The compound 16-2 (30 mg), 3- (chloromethyl) -1-methyl-1H-pyrazole (47.5 mg) and Cs 2 CO 3 (119 mg) was mixed with DMF (3 mL), and the mixture was heated to 50 ℃ to react. After 3h, LCMS monitoring indicated complete reaction. Pouring the reaction solution into a proper amount of water, mixing uniformly, extracting with ethyl acetate for three times, washing with saturated saline solution, drying and concentrating to obtain a crude product. Column chromatography isolation and purification (DCM: meOH = 15) + :392)。
Step 2: synthesis of Compound 28
Compound 28-1 (25 mg) was mixed with 1M dilute hydrochloric acid solution (3 mL), and the mixture was heated to 70 ℃ to react. After 5h, LCMS monitoring indicated complete reaction. Filtering to obtain crude product, pulping with ethanol to obtain 19.81mg yellow solid, i.e. compound 28 (M + H) + :364)。
Example 29: synthesis of Compound 29 (5- (5- (1- (4-ethoxybenzyl) -1H-pyrrol-3-yl) -6-methylpyridazin-3-yl) pyrimidine-2,4 (1H, 3H) -dione)
Step 1: synthesis of Compound 29-1
Compound 16-2 (20 mg), 1-chloromethyl-4-ethoxybenzene (36 mg) and Cs 2 CO 3 (66.2 mg) was mixed with DMF (2 mL), and the mixture was heated to 50 ℃ to react. After 3h, LCMS monitoring indicated complete reaction. Pouring the reaction solution into a proper amount of water, mixing uniformly, extracting with ethyl acetate for three times, washing with saturated saline solution, drying and concentrating to obtain a crude product. Column chromatography separation and purification (DCM: meOH = 15) + :432)。
Step 2: synthesis of Compound 29
Compound 29-1 (20 mg) was mixed with 1M dilute hydrochloric acid solution (3 mL), and the temperature was raised to 70 deg.CAnd (4) reacting. After 5h, LCMS monitoring indicated complete reaction. Filtering to obtain crude product, pulping with ethanol to obtain 13.00mg yellow solid, i.e. compound 29 (M + H) + :404)。
Example 30: synthesis of Compound 30 (5- (6-methyl-5- (1- ((5-methylpyridin-2-yl) methyl) -1H-pyrrol-3-yl) pyridazin-3-yl) pyrimidine-2,4 (1H, 3H) -dione)
Step 1: synthesis of Compound 30-1
Compound 16-2 (100 mg), 2- (chloromethyl) -5-methylpyridine (98.75 mg) and Cs 2 CO 3 (228.7 mg) was mixed with DMF (5 mL) and the mixture was heated to 50 ℃ for reaction. After 3h, LCMS monitoring showed reaction complete. Pouring the reaction solution into a proper amount of water, mixing uniformly, extracting with ethyl acetate for three times, washing with saturated saline solution, drying and concentrating to obtain a crude product. Column chromatography purification (DCM: meOH = 15) + :403)。
Step 2: synthesis of Compound 30
Compound 30-1 (80 mg) was mixed with 1M dilute hydrochloric acid solution (5 mL), and the mixture was heated to 70 ℃ to react. After 5h, LCMS monitoring indicated complete reaction. Filtering to obtain crude product, pulping with ethanol to obtain 67.23mg yellow solid, i.e. compound 30 (M + H) + :375)。
Example 31: synthesis of compound 31 (4- ((3- (3-chloro-6- (2,4-dioxy-1,2,3,4-tetrahydropyrimidin-5-yl) pyridazin-4-yl) -1H-pyrrol-1-yl) methyl) benzonitrile)
Step 1: synthesis of Compound 31-1
Compound M2 (10 mg), 4- (chloromethyl) benzonitrile (14.35 mg) and Cs 2 CO 3 (31.05 mg) was mixed with DMF (1 mL) and the mixture was heated to 50 ℃ and the reaction mixture was cooledShould be used. After 3h, LCMS monitoring showed reaction complete. Pouring the reaction solution into a proper amount of water, mixing uniformly, extracting with ethyl acetate for three times, washing with saturated saline solution, drying and concentrating to obtain a crude product. Column chromatography separation and purification (DCM: meOH = 40) + :418,420)。
Step 2: synthesis of Compound 31
Compound 31-1 (8 mg) was mixed with 1M dilute hydrochloric acid solution (2 mL), and the mixture was heated to 70 ℃ to react. After 3h, LCMS monitoring indicated complete reaction. Direct reverse phase column preparation liquid phase freeze-drying to obtain 0.87mg white solid, namely compound 31 (M + H) + :405,407)。
Example 32: synthesis of Compound 32 (4- ((3- (6- (2,4-dioxy-1,2,3,4-tetrahydropyrimidin-5-yl) -3-methoxypyridazin-4-yl) -1H-pyrrol-1-yl) methyl) benzonitrile)
Step 1: synthesis of Compound 32-1
Compound 31-1 (10 mg) and sodium methoxide (12.95 mg) were mixed in methanol (2 mL), and the mixture was heated to 70 ℃ to react. After 12h, LCMS monitoring indicated complete reaction. Spin-drying methanol, dissolving the product with ethyl acetate, filtering to remove insoluble salt, and spin-drying the filtrate to obtain 6mg yellow solid, i.e. compound 32-1 (M + H) + :429)。
Step 2: synthesis of Compound 35
Compound 32-1 (6 mg) was mixed with 1M diluted hydrochloric acid solution (2 mL), and the mixture was heated to 40 ℃ to react. After 10h, LCMS monitoring indicated complete reaction. Direct reverse phase column preparation liquid phase freeze-drying to obtain 0.86mg white solid, namely compound 32 (M + H) + :401)。
Example 33: synthesis of compound 33 (5- (5- (1- (4-hydroxybenzyl) -1H-pyrrol-3-yl) -6-methylpyridazin-3-yl) pyrimidine-2,4 (1H, 3H) -dione)
Step 1: synthesis of Compound 33
A25 ml three-necked flask was charged with Compound 15 (25 mg) dissolved in DCM (5 ml), N 2 Protecting, cooling in ice bath, and dropwise adding BBr into the reaction solution 3 (0.1 ml), and reacted for 3 hours under ice bath. The reaction was quenched by slowly dropping saturated sodium bicarbonate solution into the reaction solution, the reaction solution was evaporated to dryness, and the product was isolated by column chromatography (DCM: meOH = 10).
LCMS：[M+H] + ＝376.13
Example 34: synthesis of Compound 34 (5- (5- (1- (3-hydroxybenzyl) -1H-pyrrol-3-yl) -6-methylpyridazin-3-yl) pyrimidine-2,4 (1H, 3H) -dione)
Step 1: synthesis of Compound 34
Compound 18 (30 mg) was added to a 25ml three-necked flask, dissolved in DCM (5 ml), and N 2 Protecting, cooling in ice bath, and dropwise adding BBr into the reaction solution 3 (0.15 ml), and reacted for 3 hours under ice bath. The reaction was quenched by slowly dropping saturated sodium bicarbonate solution into the reaction solution, the reaction solution was evaporated to dryness, and the product was isolated by column chromatography (DCM: meOH = 10).
LCMS：[M+H] + ＝376.13
Example 35: synthesis of Compound 35 (5- (5- (3-benzyl-1H-pyrrol-1-yl) -6-methylpyridazin-3-yl) pyrimidine-2,4 (1H, 3H) -dione)
Step 1: synthesis of Compound 35-1
In a 100ml three-necked flask, compound M1 (200 mg) and phenyl (1H-pyridine) were addedPyrrol-3-yl) methanone (154 mg), cuI (15 mg), cs 2 CO 3 (500 mg) in DMSO (10 mL), N 2 Protection, and oil bath reaction at 70 ℃ for 4h. Cooling to room temperature, diluting the reaction solution with water, extracting with ethyl acetate, drying the organic phase with anhydrous sodium sulfate, and separating the product by column chromatography (PE: EA = 1:1) to obtain 150mg of a pale yellow solid, i.e., compound 35-1.
Step 2: synthesis of Compound 35-2
A50 mL single-necked flask was charged with Compound 35-1 (150 mg) and NaBH 4 (200 mg) was dissolved in THF (10 mL) and reacted at room temperature for 12h. The reaction solution was quenched by adding water, evaporated to dryness, and the product was isolated by column chromatography (DCM: meOH = 15.
And step 3: synthesis of Compound 35-3
A50 mL single-neck flask was charged with Compound 35-2 (100 mg), dissolved in DCM (10 mL), cooled in ice bath, and Et was added dropwise to the reaction mixture 3 SiH (0.2 ml), and finally TFA (0.5 ml) was added dropwise and reacted for 0.5h in ice bath. The reaction solution was quenched by adding saturated sodium bicarbonate solution. The reaction solution was directly evaporated to dryness and the product was isolated by column chromatography (DCM: meOH = 20).
And 4, step 4: synthesis of Compound 35
In a 25mL single-necked flask, 35-3 (50 mg) was added and dissolved in 1M hydrochloric acid (4 mL) and reacted at 70 ℃ for 3 hours. Cooling to room temperature, regulating the pH of the reaction solution to be neutral by using a saturated sodium bicarbonate solution, separating out a white solid, carrying out suction filtration, washing a filter cake with water, and drying. 15mg of a white solid, compound 35 (purity 99.16%) was obtained.
LCMS：[M+H] + ＝360.14
Example 36: synthesis of Compound 36 (5- (5- (3- (4-fluorobenzyl) -1H-pyrrol-1-yl) -6-methylpyridazin-3-yl) pyrimidine-2,4 (1H, 3H) -dione)
Step 1: synthesis of Compound 36-1
Adding AlCl into a 100ml three-mouth bottle 3 (1.7 g), suspended in DCM (50 mL), N 2 After protection, 4-fluorobenzoyl chloride (0.7 g) was added dropwise to the reaction mixture at room temperature, and after 15 minutes of reaction, a solution of 1- (benzenesulfonyl) -1H-pyrrole in DCM was added dropwise and the reaction was carried out at room temperature for 2 hours. 50ml of ice water is added into the reaction solution, the mixture is stirred vigorously for 30 minutes, DCM is used for extraction, the organic phase is dried by anhydrous sodium sulfate, and the organic phase is evaporated to dryness to obtain 1.3g of white solid, namely the compound 36-1.
Step 2: synthesis of Compound 36-2
Compound 36-1 (1.3 g) was added to a 250mL single-necked flask and dissolved in 1,4-dioxane (40 mL) and 4M NaOH (40 mL) and reacted at room temperature for 12h. Diluting the reaction solution with water, extracting with EA for three times, drying the organic phase with anhydrous sodium sulfate, and evaporating the reaction solution to dryness to obtain 0.6g of light yellow solid, namely the compound 36-2.
And step 3: synthesis of Compound 36-3
A100 ml three-necked flask was charged with Compound M1 (200 mg), 4-fluorophenyl (1H-pyrrol-3-yl) methanone (154 mg), cuI (15 mg), cs 2 CO 3 (500 mg) in DMSO (10 mL), N 2 Protection, and oil bath reaction at 70 ℃ for 4h. Cooling to room temperature, diluting the reaction solution with water, extracting with ethyl acetate, drying the organic phase with anhydrous sodium sulfate, and separating the product by column chromatography (PE: EA = 1:1) to obtain 150mg of a pale yellow solid, i.e., compound 36-3.
And 4, step 4: synthesis of Compound 36-4
A50 mL single-necked flask was charged with Compound 36-3 (150 mg) and NaBH 4 (200 mg) was dissolved in THF (10 mL) and reacted at room temperature for 12h. The reaction solution was quenched by adding water, the reaction solution was evaporated to dryness, and the product was isolated by column chromatography (DCM: meOH = 15.
And 5: synthesis of Compound 36-5
Compound 36-4 (100 mg) was added to a 50mL single-necked flask, dissolved in DCM (10 mL), cooled in ice bath, and Et was added dropwise to the reaction mixture 3 SiH (0.2 ml), and finally TFA (0.5 ml) was added dropwise and reacted for 0.5h in ice bath. The reaction solution was quenched by adding saturated sodium bicarbonate solution. Directly evaporating to drynessThe product was isolated by column chromatography (DCM: meOH = 20) as a white solid, compound 36-5, 90 mg.
And 6: synthesis of Compound 36
In a 25mL single-necked flask, compound 36-5 (50 mg) was dissolved in 1M hydrochloric acid (4 mL) and reacted at 70 ℃ for 3 hours. Cooling to room temperature, adjusting the pH of the reaction solution to be neutral by using a saturated sodium bicarbonate solution, separating out a white solid, performing suction filtration, washing a filter cake with water, and drying. 15mg of a white solid, compound 36 (purity 99.16%) is obtained.
LCMS：[M+H] + ＝378.13
Example 37: synthesis of Compound 37 (5- (5- (3- (4-methoxybenzyl) -1H-pyrrol-1-yl) -6-methylpyridazin-3-yl) pyrimidine-2,4 (1H, 3H) -dione)
Step 1: synthesis of Compound 37-1
Adding AlCl into a 100ml three-mouth bottle 3 (1.7 g), suspended in DCM (50 mL), N 2 After the protection, 4-methoxybenzoyl chloride (0.7 g) was added dropwise to the reaction mixture at room temperature, and after 15 minutes of reaction, a solution of 1- (benzenesulfonyl) -1H-pyrrole in DCM was added dropwise and the reaction was carried out at room temperature for 2 hours. 50ml of ice water was added to the reaction solution, stirred vigorously for 30 minutes, extracted with DCM, dried over anhydrous sodium sulfate of the organic phase and evaporated to dryness to obtain 1.3g of a white solid, compound 37-1.
Step 2: synthesis of Compound 37-2
A250 mL single-necked flask was charged with compound 37-1 (1.3 g), dissolved in 1,4-dioxane (40 mL) and 4M NaOH (40 mL), and reacted at room temperature for 12h. And (3) diluting the reaction solution by adding water, extracting by EA (ethylene-acetic acid) for three times, drying the organic phase by anhydrous sodium sulfate, and evaporating the reaction solution to dryness to obtain 0.7g of light yellow solid, namely the compound 37-2.
And step 3: synthesis of Compound 37-3
In a 100ml three-necked flask, compound M1 (200 mg), 4-methoxyphenyl (1H-pyrrol-3-yl) methanone (154 mg), cuI (15 mg), cs 2 CO 3 (500 mg) in DMSO (10 mL), N 2 Protection, and oil bath reaction at 70 ℃ for 4h. Cooling to room temperature, diluting the reaction solution with water, extracting with ethyl acetate, drying the organic phase with anhydrous sodium sulfate, and separating the product by column chromatography (PE: EA = 1:1) to obtain 150mg of a pale yellow solid, i.e., compound 37-3.
And 4, step 4: synthesis of Compound 37-4
A50 mL single-necked flask was charged with Compound 37-3 (150 mg) and NaBH 4 (200 mg) was dissolved in THF (10 mL) and reacted at room temperature for 12h. The reaction solution was quenched by adding water, evaporated to dryness, and the product was isolated by column chromatography (DCM: meOH = 15.
And 5: synthesis of Compound 37-5
A50 mL single vial was charged with compound 37-4 (100 mg), dissolved in DCM (10 mL), cooled in ice bath, and Et was added dropwise to the reaction mixture 3 SiH (0.2 ml), and finally TFA (0.5 ml) was added dropwise and reacted for 0.5h in ice bath. The reaction was quenched by adding saturated sodium bicarbonate solution to the reaction solution. The reaction was directly evaporated to dryness and the product was isolated by column chromatography (DCM: meOH = 20).
Step 6: synthesis of Compound 37
A25 mL single vial was charged with 37-5 (90 mg) of compound, dissolved in 1M hydrochloric acid (4 mL) and reacted at 70 ℃ for 3h. Cooling to room temperature, regulating the pH of the reaction solution to be neutral by using a saturated sodium bicarbonate solution, separating out a white solid, carrying out suction filtration, washing a filter cake with water, and drying. 55mg of a white solid, compound 37 (purity 99.16%) was obtained.
LCMS：[M+H] + ＝390.15
Example 38: synthesis of Compound 38 (5- (5- (3- (4-hydroxybenzyl) -1H-pyrrol-1-yl) -6-methylpyridazin-3-yl) pyrimidine-2,4 (1H, 3H) -dione)
Step 1: synthesis of Compound 38
25ml of threeCompound 37 (25 mg) was added to the vial, dissolved in DCM (5 ml), N 2 Protecting, cooling in ice bath, and dropwise adding BBr into the reaction solution 3 (0.1 ml), and reacted for 3 hours in an ice bath. The reaction was quenched by slowly dropping saturated sodium bicarbonate solution into the reaction solution, the reaction solution was evaporated to dryness, and the product was isolated by column chromatography (DCM: meOH = 10).
LCMS：[M+H] + ＝376.13
Example 39: synthesis of Compound 39 (4- ((1- (6- (2,4-dioxy-1,2,3,4-tetrahydropyrimidin-5-yl) -3-methylpyridazin-4-yl) -1H-pyrrol-3-yl) methyl) benzonitrile)
Step 1: synthesis of Compound 39-1
Adding AlCl into a 100ml three-mouth bottle 3 (1.7 g), suspended in DCM (50 mL), N 2 After the protection, 4-cyanobenzoyl chloride (0.7 g) was added dropwise to the reaction mixture at room temperature, and the reaction was carried out for 15 minutes, then a solution of 1- (benzenesulfonyl) -1H-pyrrole in DCM was added dropwise thereto, and the reaction was carried out for 2 hours at room temperature. 50ml of ice water was added to the reaction solution, stirred vigorously for 30 minutes, extracted with DCM, dried over anhydrous sodium sulfate of the organic phase and evaporated to dryness to obtain 1.3g of a white solid, compound 39-1.
Step 2: synthesis of Compound 39-2
A250 mL single-necked flask was charged with compound 39-1 (1.3 g), dissolved in 1,4-dioxane (40 mL) and 4M NaOH (40 mL), and reacted at room temperature for 12h. Diluting the reaction solution with water, extracting with EA for three times, drying the organic phase with anhydrous sodium sulfate, and evaporating the reaction solution to dryness to obtain 0.7g of light yellow solid, namely the compound 39-2.
And step 3: synthesis of Compound 39-3
In a 100ml three-necked flask, compound M1 (200 mg), 4-cyanophenyl (1H-pyrrol-3-yl) methanone (154 mg), cuI (15 mg), cs 2 CO 3 (500 mg) in DMSO (10 mL), N 2 Protection, and oil bath reaction at 70 ℃ for 4h.Cooling to room temperature, diluting the reaction solution with water, extracting with ethyl acetate, drying the organic phase with anhydrous sodium sulfate, and separating the product by column chromatography (PE: EA = 1:1) to obtain 150mg of a pale yellow solid, i.e., compound 39-3.
And 4, step 4: synthesis of Compound 39-4
A50 mL single-necked flask was charged with Compound 7-3 (150 mg) and NaBH 4 (200 mg) was dissolved in THF (10 mL) and reacted at room temperature for 12h. The reaction solution was quenched by adding water, the reaction solution was evaporated to dryness, and the product was isolated by column chromatography (DCM: meOH = 15.
And 5: synthesis of Compound 39-5
A50 mL single vial was charged with 39-4 (100 mg) dissolved in DCM (10 mL), cooled in ice bath, and Et was added dropwise to the reaction mixture 3 SiH (0.2 ml), and finally TFA (0.5 ml) was added dropwise and reacted for 0.5h in ice bath. The reaction was quenched by adding saturated sodium bicarbonate solution to the reaction solution. The reaction was directly evaporated to dryness and the product was isolated by column chromatography (DCM: meOH = 20).
And 7: synthesis of Compound 39
A25 mL single vial was charged with 39-5 (50 mg) dissolved in 1M hydrochloric acid (4 mL) and reacted at 70 ℃ for 3h. Cooling to room temperature, adjusting the pH of the reaction solution to be neutral by using a saturated sodium bicarbonate solution, separating out a white solid, performing suction filtration, washing a filter cake with water, and drying. 15mg of a white solid, compound 39 (purity 99.16%) was obtained.
LCMS：[M+H] + ＝385.13
Example 40: synthesis of Compound 40 (5- (5- (1- (4-methoxybenzyl) -1H-pyrazol-3-yl) -6-methylpyridazin-3-yl) pyrimidine-2,4 (1H, 3H) -dione)
Step 1: synthesis of Compound 40-1
A50 ml three-necked flask was charged with Compound M1 (100 mg), 3- (4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl) -1H-pyrazole (110 mg), pd(dppf)Cl 2 (30mg)、K 2 CO 3 (100 mg) in 1,4-dioxane (10 mL), water (2 mL), N 2 Protection, and oil bath reaction at 70 ℃ for 4h. Cooling to room temperature, diluting the reaction solution with water, extracting with ethyl acetate, drying the organic phase with anhydrous sodium sulfate, and separating the product by column chromatography (PE: EA = 1:2) to obtain 100mg of a yellow solid, i.e., compound 40-1.
Step 2: synthesis of Compound 40-2
A50 ml single-necked flask was charged with compound 40-2 (100 mg), p-methoxybenzyl chloride (110 mg), and K 2 CO 3 (100 mg) in DMF (10 ml) and reacted in an oil bath at 60 ℃ for 2h. Cooling to room temperature, diluting the reaction solution with water, extracting with ethyl acetate, drying the organic phase with anhydrous sodium sulfate, and separating the product by column chromatography (PE: EA = 1:1) to obtain 70mg of yellow solid, i.e., compound 40-2.
And step 3: synthesis of Compound 40
A25 mL single vial was charged with Compound 40-2 (70 mg) dissolved in 1M hydrochloric acid (4 mL) and reacted at 70 ℃ for 3h. Cooling to room temperature, regulating the pH of the reaction solution to be neutral by using a saturated sodium bicarbonate solution, separating out a white solid, carrying out suction filtration, washing a filter cake with water, and drying. 45mg of a white solid, compound 40 (purity 99.16%) was obtained.
LCMS：[M+H] + ＝391.14
Example 41: synthesis of Compound 41 (5- (6-methyl-5- (1- (2- (trifluoromethoxy) benzyl) -1H-pyrrol-3-yl) pyridazin-3-yl) pyrimidine-2,4 (1H, 3H) -dione)
Step 1: synthesis of Compound 41-1
A50 ml single-necked flask was charged with intermediate M2 (50 mg), 1- (bromomethyl) -2- (trifluoromethoxy) benzene (74 mg), and K 2 CO 3 (100 mg) in DMF (5 ml) and reacted in an oil bath at 50 ℃ for 2h. Cooling to room temperature, diluting the reaction solution with water, extracting with ethyl acetate, and drying the organic phase with anhydrous sodium sulfateThe product was dried and isolated by column chromatography (PE: EA = 1:1) to yield 30mg of a yellow solid, compound 41-1.
Step 2: synthesis of Compound 41
A25 mL single vial was charged with Compound 41-1 (30 mg) dissolved in 1M hydrochloric acid (3 mL) and reacted at 70 ℃ for 3h. Cooling to room temperature, adjusting the pH of the reaction solution to be neutral by using a saturated sodium bicarbonate solution, separating out a white solid, performing suction filtration, washing a filter cake with water, and drying. 15mg of a white solid, compound 41 (purity 99.16%) was obtained.
LCMS：[M+H] + ＝444.12
Example 42: synthesis of Compound 42 (5- (6-methyl-5- (1- (3- (trifluoromethoxy) benzyl) -1H-pyrrol-3-yl) pyridazin-3-yl) pyrimidine-2,4 (1H, 3H) -dione)
Step 1: synthesis of Compound 42-1
A50 ml single-necked flask was charged with intermediate M2 (50 mg), 1- (bromomethyl) -3- (trifluoromethoxy) benzene (74 mg), and K 2 CO 3 (100 mg) in DMF (5 ml) and reacted in an oil bath at 50 ℃ for 2h. Cooling to room temperature, diluting the reaction solution with water, extracting with ethyl acetate, drying the organic phase with anhydrous sodium sulfate, and separating the product by column chromatography (PE: EA = 1:1) to obtain 30mg of a yellow solid, i.e., compound 42-1.
Step 2: synthesis of Compound 42
A25 mL single vial was charged with compound 42-1 (30 mg) dissolved in 1M hydrochloric acid (3 mL) and reacted at 70 ℃ for 3h. Cooling to room temperature, regulating the pH of the reaction solution to be neutral by using a saturated sodium bicarbonate solution, separating out a white solid, carrying out suction filtration, washing a filter cake with water, and drying. 15mg of a white solid, compound 42 (purity 99.16%) was obtained.
LCMS：[M+H] + ＝444.12
Example 43: synthesis of Compound 43 (methyl 4- ((3- (6- (2,4-dioxy-1,2,3,4-tetrahydropyrimidin-5-yl) -3-methylpyridazin-4-yl) -1H-pyrrol-1-yl) methyl) benzoate)
Step 1: synthesis of Compound 43-1
A50 ml single-necked flask was charged with intermediate M2 (50 mg), methyl 4- (bromomethyl) benzoate (57 mg), and Cs 2 CO 3 (120 mg) in DMF (5 ml) and reacted in an oil bath at 50 ℃ for 2h. Cooling to room temperature, diluting the reaction solution with water, extracting with ethyl acetate, drying the organic phase with anhydrous sodium sulfate, and separating the product by column chromatography (PE: EA = 1:1) to obtain 35mg of a yellow solid, i.e., compound 43-1.
Step 2: synthesis of Compound 43
A25 mL single vial was charged with Compound 43-1 (35 mg) dissolved in 1M hydrochloric acid (3 mL) and reacted at 70 ℃ for 3h. Cooling to room temperature, regulating the pH of the reaction solution to be neutral by using a saturated sodium bicarbonate solution, separating out a white solid, carrying out suction filtration, washing a filter cake with water, and drying. 20mg of a white solid, compound 43 (purity 99.16%) was obtained.
LCMS：[M+H] + ＝418.14
Example 44: synthesis of Compound 44 (methyl 3- ((3- (6- (2,4-dioxy-1,2,3,4-tetrahydropyrimidin-5-yl) -3-methylpyridazin-4-yl) -1H-pyrrol-1-yl) methyl) benzoate)
Step 1: synthesis of Compound 44-1
A50 ml single-necked flask was charged with intermediate M2 (50 mg), methyl 3- (bromomethyl) benzoate (57 mg), and Cs 2 CO 3 (120 mg) in DMF (5 ml) and reacted in an oil bath at 50 ℃ for 2h. Cooling to room temperature, diluting the reaction solution with water, extracting with ethyl acetate, drying the organic phase with anhydrous sodium sulfate, and separating the product by column chromatography (PE: EA = 1:1) to obtain 35mg of a yellow solid, i.e., compound 44-1.
Step 2: synthesis of Compound 44
A25 mL single vial was charged with compound 44-1 (35 mg) dissolved in 1M hydrochloric acid (3 mL) and reacted at 70 ℃ for 3h. Cooling to room temperature, adjusting the pH of the reaction solution to be neutral by using a saturated sodium bicarbonate solution, separating out a white solid, performing suction filtration, washing a filter cake with water, and drying. 20mg of white solid, compound 44 (purity 99.16%) was obtained.
LCMS：[M+H] + ＝418.14
Example 45: synthesis of Compound 45 (5- (5- (1- (3- (hydroxymethyl) benzyl) -1H-pyrrol-3-yl) -6-methylpyridazin-3-yl) pyrimidine-2,4 (1H, 3H) -dione)
Step 1: synthesis of Compound 45
A25 mL three-necked flask was charged with Compound 44 (20 mg), naBH 4 (10 mg) in THF (3 mL), N 2 To the reaction solution, meOH (0.3 ml) was added dropwise under protection and oil bath at 50 ℃. The reaction was carried out at 50 ℃ for 3h. Cooling to room temperature, and dropwise adding water into the reaction liquid to quench the reaction. The reaction was evaporated to dryness directly and the product isolated by column chromatography (DCM: meOH = 10.
LCMS：[M+H] + ＝390.15
Example 46: synthesis of Compound 46 (5- (5- (1- (4- (difluoromethyl) benzyl) -1H-pyrrol-3-yl) -6-methylpyridazin-3-yl) pyrimidine-2,4 (1H, 3H) -dione)
A50 ml single-necked flask was charged with intermediate M2 (100 mg), methyl 4- (bromomethyl) benzoate (120 mg), and Cs 2 CO 3 (300 mg), dissolved in DMF (10 ml) and reacted in an oil bath at 50 ℃ for 2h. Cooling to room temperature, diluting the reaction mixture with water, extracting with ethyl acetate, andthe organic phase was dried over anhydrous sodium sulfate and the product was isolated by column chromatography (PE: EA = 1:1) to yield 80mg of a yellow solid, compound 46-1.
Step 2: synthesis of Compound 46-2
A50 mL three-necked flask was charged with 46-1 (80 mg) of Compound and NaBH 4 (50 mg) in THF (10 mL), N 2 To the reaction mixture MeOH (1 ml) was added dropwise under oil bath at 50 ℃. The reaction was carried out at 50 ℃ for 3h. Cooling to room temperature, and dropwise adding water into the reaction solution to quench the reaction. The reaction solution was directly evaporated to dryness, and the product was isolated by column chromatography (DCM: meOH = 10.
And step 3: synthesis of Compound 46-3
Compound 46-2 (45 mg) and PCC (50 mg) were added to a 50mL one-neck flask, dissolved in DCM (10 mL) and reacted at room temperature for 3h. The reaction was evaporated to dryness directly and the product was isolated by column chromatography (DCM: meOH = 15.
And 4, step 4: synthesis of Compound 46-4
A25 mL single-neck flask was charged with 46-3 (30 mg) dissolved in DCM (5 mL), cooled in ice bath, and DSAT (0.5 mL) was added dropwise to the reaction mixture, after the addition, the reaction mixture was slowly warmed to room temperature and reacted for 3h. The reaction solution was quenched by dropwise addition of saturated sodium bicarbonate solution, the reaction solution was directly evaporated to dryness, and the product was isolated by column chromatography (DCM: meOH = 15).
And 5: synthesis of Compound 46
In a 25mL single-necked flask, compound 46-4 (20 mg) was added, dissolved in MeOH (2 mL) and 1M hydrochloric acid (2 mL), and reacted at 40 ℃ for 5h. After cooling to room temperature, the reaction solution was adjusted to neutral pH with sodium bicarbonate, evaporated to dryness, and the product was isolated by column chromatography (DCM: meOH =10 1) to give 10mg of a white solid, compound 46 (purity 99.16%).
LCMS：[M+H] + ＝410.14
Example 47: synthesis of Compound 47 (5- (5- (1- (3- (difluoromethyl) benzyl) -1H-pyrrol-3-yl) -6-methylpyridin-3-yl) pyrimidine-2,4 (1H, 3H) -dione)
Step 1: synthesis of Compound 47-1
A50 ml single-necked flask was charged with intermediate M2 (100 mg), methyl 3- (bromomethyl) benzoate (120 mg), and Cs 2 CO 3 (300 mg) in DMF (10 ml) and reacted in an oil bath at 50 ℃ for 2h. Cooling to room temperature, diluting the reaction solution with water, extracting with ethyl acetate, drying the organic phase with anhydrous sodium sulfate, and separating the product by column chromatography (PE: EA = 1:1) to obtain 80mg of a yellow solid, i.e., compound 47-1.
And 2, step: synthesis of Compound 47-2
A50 mL three-necked flask was charged with 47-1 (80 mg) of NaBH 4 (50 mg) in THF (10 mL), N 2 To the reaction solution, meOH (1 ml) was added dropwise under protection and oil bath at 50 ℃. The reaction was carried out at 50 ℃ for 3h. Cooling to room temperature, and dropwise adding water into the reaction liquid to quench the reaction. The reaction solution was directly evaporated to dryness, and the product was isolated by column chromatography (DCM: meOH = 10.
And step 3: synthesis of Compound 47-3
Compound 47-2 (45 mg) and PCC (50 mg) were added to a 50mL single-necked flask, dissolved in DCM (10 mL) and reacted at room temperature for 3h. The reaction was evaporated to dryness directly and the product was isolated by column chromatography (DCM: meOH = 15.
And 4, step 4: synthesis of Compound 47-4
A25 mL single-neck flask was charged with 47-3 (30 mg) dissolved in DCM (5 mL), cooled in ice bath, and DSAT (0.5 mL) was added dropwise to the reaction mixture, after the addition, the reaction mixture was slowly warmed to room temperature and reacted for 3h. The reaction solution was quenched by dropwise addition of saturated sodium bicarbonate solution, the reaction solution was directly evaporated to dryness, and the product was isolated by column chromatography (DCM: meOH = 15).
And 5: synthesis of Compound 47
In a 25mL single-necked flask, compound 47-4 (20 mg) was added, dissolved in MeOH (2 mL) and 1M hydrochloric acid (2 mL), and reacted at 40 ℃ for 5h. After cooling to room temperature, the reaction solution was adjusted to neutral pH with sodium bicarbonate, evaporated to dryness, and the product was isolated by column chromatography (DCM: meOH =10 1) to give 10mg of a white solid, compound 47 (purity 99.16%).
LCMS：[M+H] + ＝410.14
Example 48: synthesis of Compound 48 (5- (6-methyl-5- (1- (pyridin-4-ylmethyl) -1H-pyrrol-3-yl) pyridin-3-yl) pyrimidine-2,4 (1H, 3H) -dione)
Step 1: synthesis of Compound 48-1
Compound 16-2 (59 mg), 4- (bromomethyl) pyridine (40.96 mg), cs 2 CO 3 (129.31 mg) was mixed in DMF (6 mL) and reacted at room temperature. After 2h, TLC monitoring indicated complete reaction. The reaction solution was poured into appropriate amount of water and mixed well, extracted three times with ethyl acetate, washed with saturated brine, dried, concentrated, and purified by preparative TLC (DCM/MeOH = 20/1) to give 30mg of yellow solid, i.e. compound 48-1 (M + H) + :389)。
Step 2: synthesis of Compound 48
Compound 48-1 (30 mg) was mixed with 1M dilute hydrochloric acid solution (2 mL), and the mixture was heated to 70 ℃ to react. After 5h, LCMS monitoring indicated complete reaction. The reaction solution was spun dry and slurried with dichloromethane to give 4.4mg of a yellow solid, compound 48 (M + H) + :361)。
1 H NMR(600MHz,DMSO-d6)δ11.89(s,1H),11.72(s,1H),8.77(d,J＝5.7Hz,2H),8.55(s,1H),8.44(d,J＝5.8Hz,1H),7.82(s,1H),7.55(d,J＝5.6Hz,2H),7.19(t,J＝2.5Hz,1H),6.83(s,1H),5.53(s,2H),2.84(s,3H).
Example 49: synthesis of Compound 49 (5- (6-methyl-5- (1- (4-methylbenzyl) -1H-pyrrol-3-yl) pyridazin-3-yl) pyrimidine-2,4 (1H, 3H) -dione)
Step 1: synthesis of Compound 49-1
Mixing compound 16-2 (59 mg), 4-methyl benzyl chloride (41.85 mg), and Cs 2 CO 3 (129.31 mg) was mixed with DMF (6 mL) and the mixture was heated to 50 ℃ for reaction. After 2h, TLC monitoring indicated complete reaction. Pouring the reaction solution into a proper amount of water, mixing uniformly, extracting with ethyl acetate for three times, washing with saturated saline, drying, concentrating, and purifying by preparative TLC (PE/EA = 1/1) to obtain 70mg of yellow solid, namely the compound 49-1 (M + H) + :402)。
Step 2: synthesis of Compound 49
Compound 49-1 (70 mg) was mixed with 1M dilute hydrochloric acid solution (2 mL), and the mixture was heated to 70 ℃ to react. After 5h, LCMS monitoring indicated complete reaction. The reaction solution was spun dry and slurried with dichloromethane to give 15.2mg of a white solid, compound 49 (M + H) + :374)。
1 H NMR(600MHz,Methanol-d4)δ8.73(s,1H),8.66(s,1H),7.76(d,J＝2.1Hz,1H),7.18(s,4H),7.02(t,J＝2.6Hz,1H),6.87(t,J＝2.5Hz,1H),5.20(s,2H),2.90(s,3H),2.32(s,3H).
Example 50: synthesis of Compound 50 (6- ((3- (6- (2,4-dioxy-1,2,3,4-tetrahydropyrimidin-5-yl) -3-methylpyridazin-4-yl) -1H-pyrrol-1-yl) methyl) nicotinonitrile)
Step 1: synthesis of Compound 50-1
Compound 16-2 (59 mg), 6- (bromomethyl) nicotinonitrile (58.64 mg), cs 2 CO 3 (129.31 mg) was mixed in DMF (6 mL) and reacted at room temperature. After 2h, TLC monitoring showed the reaction was complete. The reaction solution was poured into appropriate amount of water and mixed well, extracted three times with ethyl acetate, washed with saturated brine, dried, concentrated, and purified by preparative TLC (DCM/MeOH = 20/1) to give 75mg of yellow solid, i.e. compound 50-1 (M + H) + :414)。
Step 2: synthesis of Compound 50
Compound 50-1 (75 mg)) Mixed with 1M diluted hydrochloric acid solution (2 mL), and heated to 70 ℃ for reaction. After 5h, LCMS monitoring indicated complete reaction. The reaction solution was spun dry and slurried with dichloromethane to give 62.6mg of a yellow solid, compound 50 (M + H) + :386)。
1 H NMR(600MHz,DMSO-d6)δ11.46(s,1H),11.43(s,1H),9.02(d,J＝2.1Hz,1H),8.31(dd,J＝8.2,2.2Hz,1H),8.28(d,J＝3.6Hz,1H),8.24(s,1H),7.52(d,J＝2.1Hz,1H),7.23(d,J＝8.2Hz,1H),7.07(t,J＝2.5Hz,1H),6.58(dd,J＝2.9,1.9Hz,1H),5.44(s,2H),2.76(s,3H).
Example 51: synthesis of Compound 51 (5- (6-methyl-5- (1- (3-methylbenzyl) -1H-pyrrol-3-yl) pyridazin-3-yl) pyrimidine-2,4 (1H, 3H) -dione)
Step 1: synthesis of Compound 51-1
Mixing the compound 16-2 (59 mg), 3-methylbenzyl chloride (41.67 mg) and Cs 2 CO 3 (129.31 mg) was mixed with DMF (6 mL) and the mixture was heated to 50 ℃ for reaction. After 2h, TLC monitoring showed the reaction was complete. Pouring the reaction solution into a proper amount of water, mixing uniformly, extracting with ethyl acetate for three times, washing with saturated saline, drying, concentrating, and purifying by preparative TLC (PE/EA = 1/1) to obtain 72mg of yellow solid, namely the compound 51-1 (M + H) + :402)。
Step 2: synthesis of Compound 51
Compound 51-1 (72 mg) was mixed with 1M dilute hydrochloric acid solution (2 mL), and the mixture was heated to 70 ℃ to react. After 5h, LCMS monitoring indicated complete reaction. The reaction solution was spun dry and slurried with dichloromethane to give 58.3mg of a white solid, compound 51 (M + H) + :374)。
1 H NMR(600MHz,DMSO-d6)δ12.04(s,1H),11.80(s,1H),8.61(s,1H),8.48(d,J＝5.6Hz,1H),7.87(d,J＝2.1Hz,1H),7.25(t,J＝7.5Hz,1H),7.17–7.08(m,4H),6.80(t,J＝2.4Hz,1H),5.21(s,2H),2.86(s,3H),2.29(s,3H).
Example 52: synthesis of Compound 52 (5- (6-methyl-5- (1- (2-methylbenzyl) -1H-pyrrol-3-yl) pyridin-3-yl) pyrimidine-2,4 (1H, 3H) -dione)
Step 1: synthesis of Compound 52-1
Compound 16-2 (59 mg), 2-methylbenzyl chloride (41.67 mg), cs 2 CO 3 (129.31 mg) was mixed with DMF (6 mL) and the mixture was heated to 50 ℃ for reaction. After 2h, TLC monitoring indicated complete reaction. Pouring the reaction solution into a proper amount of water, mixing uniformly, extracting with ethyl acetate for three times, washing with saturated saline, drying, concentrating, and purifying by preparative TLC (PE/EA = 1/1) to obtain 68mg of yellow solid, namely the compound 52-1 (M + H) + :402)。
And 2, step: synthesis of Compound 52
Compound 52-1 (72 mg) was mixed with 1M dilute hydrochloric acid solution (2 mL), and the mixture was heated to 70 ℃ to react. After 5h, LCMS monitoring indicated complete reaction. The reaction solution was spun dry and slurried with dichloromethane to give 63.1mg of a white solid, compound 52 (M + H) + :374)。
1 H NMR(600MHz,DMSO-d6)δ11.99(s,1H),11.78(s,1H),8.59(s,1H),8.47(d,J＝5.9Hz,1H),7.76(s,1H),7.25–7.21(m,2H),7.18(dq,J＝8.7,3.9Hz,1H),7.05(t,J＝2.5Hz,1H),6.93(d,J＝7.4Hz,1H),6.81(t,J＝2.4Hz,1H),5.29(s,2H),2.84(s,3H),2.31(s,3H).
Example 53: synthesis of Compound 53 (5- (5- (1- (4-aminobenzyl) -1H-pyrrol-3-yl) -6-methylpyridazin-3-yl) pyrimidine-2,4 (1H, 3H) -dione)
Step 1: synthesis of Compound 53-1
Mixing compound 16-2 (59 mg), 4-nitrobenzyl chloride (50.90 mg), cs 2 CO 3 (129.31 mg) was mixed in DMF (6 mL) and reacted at room temperature. After the reaction time of 2 hours, the reaction solution is stirred,TLC monitoring indicated complete reaction. Pouring the reaction solution into a proper amount of water, mixing uniformly, extracting with ethyl acetate for three times, washing with saturated saline, drying, concentrating, and performing TLC purification (PE/EA = 1/1) to obtain 77mg of yellow solid, namely a compound 53-1 (M + H) + :433)。
Step 2: synthesis of Compound 53-2
Compound 53-1 (72 mg) and palladium on carbon (10 mg) were mixed with absolute ethanol (5 mL), and the mixture was heated to 80 ℃ to react. After 2h, LCMS monitoring showed reaction complete. The reaction mixture was spin-dried, filtered to remove palladium on carbon, and spin-dried to give 63.5mg of a white solid, i.e., compound 53-2 (M + H) + :403)。
And step 3: synthesis of Compound 53
Compound 53-2 (63.5 mg) was mixed with 1M dilute hydrochloric acid solution (2 mL), and the mixture was heated to 70 ℃ to react. After 5h, LCMS monitoring indicated complete reaction. The reaction solution was spun dry and slurried with dichloromethane to give 6.9mg of a white solid, compound 53 (M + H) + :375)。
1 H NMR(600MHz,DMSO-d6)δ11.77(s,1H),11.66(s,1H),8.41(d,J＝16.2Hz,2H),7.68(s,1H),7.27–7.20(m,2H),7.06(t,J＝2.5Hz,1H),6.95(s,2H),6.68(s,1H),5.14(s,2H),2.80(s,2H),1.24(s,3H).
Example 54: synthesis of Compound 54 (5- (6-methyl-5- (1- (4- (methylsulfonyl) benzyl) -1H-pyrrol-3-yl) pyridazin-3-yl) pyrimidine-2,4 (1H, 3H) -dione)
Step 1: synthesis of Compound 54-1
Mixing compound 16-2 (59 mg), 4-methanesulfonyl chlorobenzyl (60.58 mg), cs 2 CO 3 (129.31 mg) was mixed in DMF (6 mL) and reacted at room temperature. After 2h, TLC monitoring indicated complete reaction. Pouring the reaction solution into a proper amount of water, mixing uniformly, extracting with ethyl acetate for three times, washing with saturated saline, drying, concentrating, and performing preparative TLC purification (PE/EA = 1/1) to obtain 62mg of white solid, namely the compound 54-1 (M + H) + :466)。
Step 2: synthesis of Compound 54
Compound 54-1 (62 mg) was mixed with 1M dilute hydrochloric acid solution (2 mL), and the mixture was heated to 70 ℃ to react. After 5h, LCMS monitoring indicated complete reaction. The reaction solution was spun dry and slurried with dichloromethane to give 21.8mg of a white solid, compound 54 (M + H) + :438)。
1 H NMR(600MHz,DMSO-d6)δ11.95(s,1H),11.76(s,1H),8.57(s,1H),8.46(d,J＝6.0Hz,1H),7.96–7.91(m,2H),7.87(s,1H),7.56–7.52(m,2H),7.18(dd,J＝3.0,2.0Hz,1H),6.81(t,J＝2.4Hz,1H),5.40(s,2H),3.20(s,3H),2.85(s,3H).
Example 55: synthesis of Compound 55 (5- (6-methoxy-5- (1- (4-methoxybenzyl) -1H-pyrrol-3-yl) pyridazin-3-yl) pyrimidine-2,4 (1H, 3H) -dione)
Step 1: synthesis of Compound 55-1
4-bromo-1,2-dihydropyridazine-3,6-dione (2.00 g), 3- (4,4,5,5-tetramethyl-1,3,2-dioxaboron-2-yl) -1- (triisopropylsilyl) -1H-pyrrole (7.30 g), [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride dichloromethane complex (0.42 g), cs 2 CO 3 (17.06 g) was mixed with dioxane (100 mL) and water (30 mL) and heated to 70 ℃ under nitrogen atmosphere. After 3h, LCMS monitoring indicated complete reaction. Pouring the reaction solution into a proper amount of water, mixing uniformly, extracting with ethyl acetate for three times, washing with saturated saline, drying, concentrating, and purifying by column chromatography (DCM/MeOH = 20/1) to obtain 0.83g of yellow liquid, namely a compound 55-1 (M + H) + :334)。
Step 2: synthesis of Compound 55-2
Compound 55-1 (0.83 g) was dissolved in phosphorus oxychloride (10 mL) and reacted by warming to 100 ℃. After 1h, LCMS monitoring indicated complete reaction. Slowly adding the reaction solution into water, quenching phosphorus oxychloride, extracting with ethyl acetate for three times, washing with saturated saline solution, drying, concentrating, and purifying with columnChromatographic purification (PE/EA = 1/1) gave 0.23g of a white solid, i.e. compound 55-2 (M + H) + :215)。
And step 3: synthesis of Compound 55-3
Compounds 55-2 (0.25 g), (2,4-dimethoxypyrimidin-5-yl) boronic acid (0.25 g), [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride dichloromethane complex (0.05 g), K 2 CO 3 (0.32 g) was mixed with a mixed solvent of dioxane (10 mL) and water (2 mL), and the mixture was heated to 60 ℃ under nitrogen atmosphere to react. After 1h, LCMS monitoring indicated complete reaction. The reaction solution was poured into appropriate amount of water and mixed well, extracted three times with ethyl acetate, washed with saturated brine, dried, concentrated, and purified by preparative TLC (DCM/MeOH = 20/1) to obtain 0.14g of white solid, i.e. compound 55-3 (M + H) + :319)。
And 4, step 4: synthesis of Compound 55-4
Mixing compound 55-3 (0.14 g), 4-methoxy benzyl chloride (0.13 g), cs 2 CO 3 (0.27 g) was mixed with DMF (10 mL), and the mixture was heated to 50 ℃ for reaction. After 2h, TLC monitoring indicated complete reaction. The reaction solution was poured into appropriate amount of water and mixed well, extracted three times with ethyl acetate, washed with saturated brine, dried, concentrated, and purified by preparative TLC (DCM/MeOH = 20/1) to give 143mg of white solid, i.e. compound 55-4 (M + H) + :439)。
And 5: synthesis of Compound 55-5
Compound 55-4 (0.14 g) and sodium methoxide (0.18 g) were mixed in methanol (20 mL), and the mixture was heated to 60 ℃ to carry out a tube-sealing reaction. After 12h, LCMS monitoring indicated complete reaction. The reaction solution was poured into appropriate amount of water and mixed well, extracted three times with dichloromethane, washed with saturated brine, dried, concentrated, and purified by preparative TLC (DCM/MeOH = 20/1) to give 48mg of white solid, i.e. compound 55-5 (M + H) + :434)。
Step 6: synthesis of Compound 55
Compound 55-5 (48 mg) was mixed with 1M diluted hydrochloric acid solution (2 mL), and the mixture was heated to 50 ℃ to react. After 5h, LCMS monitoring indicated complete reaction. The reaction solution was spun dry and the preparative liquid phase was purified to give 30mg of a gray solid, compound 55 (M + H) + :406)。
1 H NMR(600MHz,DMSO-d6)δ11.43(s,1H),8.24(s,1H),8.12(s,1H),7.66(s,1H),7.23(d,J＝8.2Hz,2H),6.97(s,1H),6.92(d,J＝8.2Hz,2H),6.63(s,1H),5.11(s,2H),4.13(s,3H),3.73(s,3H).
The following examples were synthesized using the methods described above, or analogous methods using the corresponding intermediates.
Comparative example 1
Comparative compound 1 was synthesized according to the procedure of WO2019168744A1 example 2,
pharmacological experiments
Example 1: detection of enzymatic Activity at cellular level
Calu-6 cells were digested using TM buffer (25mM Tris,5mM MgCl) 2 pH 7.5) and plated at 25000 cells in 96-well plates at 100. Mu.L/well. TM buffer was used to prepare gradient concentration compound solutions, and 50. Mu.L of DMSO solutions of test compounds were added to each well at respective concentrations of 20000, 6666.7, 2222.2, 740.7, 246.9, 82.3, 27.4, 9.1, 3.0, 1.0, 0.3, 0nM (final DMSO concentration was 0.625%). Pre-incubating for 30min at 37 ℃ by using a constant-temperature horizontal shaking table, adding 50 mu L of 800 mu M AMP solution into each hole, continuing incubating for 120min by using a constant-temperature horizontal shaking table at 37 ℃, centrifuging a 96-well plate, transferring 50 mu L of supernate into a new 96-well plate for each hole, adding 50 mu L of 130 mu M ATP solution and 100 mu L of Cell-tilt Glo working solution into each hole, oscillating, uniformly mixing, incubating for 10min at room temperature, and labeling with multifunctional enzymeLuminescence values were read by the luminometer and Luminescence readings were converted to percent inhibition:
percent inhibition = (1-reading/max) × 100.
"maximum" is DMSO control.
Curve fitting was performed using GraphPad Prism software and IC50 values were obtained.
The enzymatic IC50 data of the compounds of the examples at the cellular level of Calu-6 are shown in Table 1.
TABLE 1
| Name of Compound | IC50(nM) | Name of Compound | IC50(nM) |
| 1 | 2084 | 29 | 114 |
| 2 | 54.4 | 30 | 12.4 |
| 3 | 49 | 31 | 4.8 |
| 4 | 37.4 | 32 | 4.6 |
| 5 | 25.1 | 33 | 5.7 |
| 6 | 455 | 34 | 8.2 |
| 7 | 462 | 35 | 95 |
| 8 | 617 | 36 | 73 |
| 9 | 28 | 37 | 96 |
| 10 | 9.4 | 38 | 71 |
| 11 | 173 | 39 | 79 |
| 12 | 308 | 40 | 50 |
| 13 | 239 | 41 | 63 |
| 14 | 3.1 | 42 | 30 |
| 15 | 2.1 | 43 | 10.3 |
| 16 | 9.5 | 44 | 7.3 |
| 17 | 22.2 | 45 | 31.6 |
| 18 | 10.2 | 46 | 24.2 |
| 19 | 59 | 47 | 34.7 |
| 20 | 83 | 48 | 39.8 |
| 21 | 23 | 49 | 14 |
| 22 | 49 | 50 | 21.8 |
| 23 | 376 | 51 | 16 |
| 24 | 121 | 52 | 19.5 |
| 25 | 26.6 | 53 | 18 |
| 26 | 14.7 | 54 | 21.4 |
| 27 | 13.5 | 55 | 96.3 |
| 28 | 32.6 | D1 | 49.1 |
The compounds of the present invention have good activity and unexpectedly, the present invention R 3 The substituent meta-substituted compound has significantly enhanced activity compared to ortho-substituted compound (table 2).
TABLE 2
While the present invention has been fully described by way of embodiments thereof, it is to be noted that various changes and modifications will be apparent to those skilled in the art. Such changes and modifications are intended to be included within the scope of the appended claims.
Claims (11)
- A compound of formula (I), a tautomer, a deuteron, or a pharmaceutically acceptable salt thereof:
wherein, the first and the second end of the pipe are connected with each other,R 1 selected from phenyl or 5-6 membered heteroaryl, said phenyl or 5-6 membered heteroaryl being unsubstituted or substituted by 1,2 or 3 substituents R 3 The substitution is carried out on the raw materials,R 3 is selected from C 1-6 Alkyl, - (C) 1-4 Alkylene radical) 0-1 -Cyc、-O-(C 1-4 Alkylene radical) 0-1 -Cyc、-S-(C 1-4 Alkylene radical) 0-1 -Cyc、-NH-(C 1-4 Alkylene radical) 0-1 -Cyc、-NH-C 1-6 Alkyl, -N (C) 1-6 Alkyl radical) 2 、-O-C 1-6 Alkyl or-S-C 1-6 Alkyl radical, R 3 Optionally unsubstituted or further substituted by one or more R 4 Substituted by a substituent;cyc is selected from C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 6-10 Aryl or 5-to 10-membered heteroaryl, said C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 6-10 Aryl or 5-to 10-membered heteroaryl unsubstituted or substituted by 1,2 or 3 substituents R 5 Substituted;R 4 or R 5 Each independently selected from H, hydroxy, amino, halogen, cyano, nitro, -OR a 、-SR a 、＝O、＝S、-C(O)R a 、-C(S)R a 、-C(O)OR a 、-C(S)OR a 、-C(O)N(R a ) 2 、-N(R a ) 2 、-S(O) 2 R a 、-O-S(O 2 )OR a 、-O-S(O) 2 R a Or R a Said R is a Each independently selected from H, C 1-6 Alkyl or C 3-6 Cycloalkyl radical, R a Unsubstituted or further substituted by one or more groups selected from halogen, hydroxy, C 1-3 Alkyl or cyano;R 2 selected from hydrogen, halogen, cyano, C 1-3 Alkyl radical, C 1-3 Alkoxy radical, C 2-4 Alkenyl, halo C 2-4 Alkenyl or C 2-4 Alkynyl. - The compound, tautomer, deuteron, or pharmaceutically acceptable salt thereof according to claim 1, wherein R is 1 Selected from phenyl or 5-6 membered heteroaryl, optionally containing 1 or 2 heteroatoms each independently selected from N, O or S, and said heteroaryl ring group being unsubstituted or substituted with 1,2 or 3 substituents R 3 Substituted; preferably R 1 Is selected from
The R is 1 Unsubstituted or substituted by 1,2 or 3 substituents R 3 And (4) substituting.
- The compound, tautomer, deuteron or pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein R is 3 Is substituted in meta position.
- The compound, tautomer, deuteron or pharmaceutically acceptable salt thereof according to any one of claims 1-3, wherein R is 3 Is selected from C 1-6 Alkyl, -C 1-3 Alkylene-phenyl, -C 1-3 alkylene-C 3-6 Cycloalkyl or-C 1-3 Alkylene- (5-to 10-membered heteroaryl), said R 3 Optionally selected from H, cyano, halogen, hydroxy, amino, C 1-3 Alkyl radical, C 1-3 Hydroxyalkyl radical, C 1-3 Haloalkyl, C 1-3 Alkoxy radical, C 1-3 Haloalkoxy, -C (= O) O-C 1-3 Alkyl or-S (= O) 2 -C 1-3 Alkyl substituent substitution; preferably R 3 Is selected from C 1-6 Alkyl, aryl, heteroaryl, and heteroaryl,
The R is 3 Optionally selected from H, cyano, halogen, hydroxy, amino, C 1-3 Alkyl radical, C 1-3 Hydroxyalkyl radical, C 1-3 Haloalkyl, C 1-3 Alkoxy radical, C 1-3 Haloalkoxy, -C (= O) O-C 1-3 Alkyl or-S (= O) 2 -C 1-3 Alkyl substituents.
- The compound, tautomer, deuteron or pharmaceutically acceptable salt thereof according to any one of claims 1-5, wherein R is 2 Selected from halogen, C 1-3 Alkyl or C 1-3 An alkoxy group; preferably chlorine, methyl or methoxy.
- The compound of any one of claims 1-6, a tautomer, a deutero-compound, or a pharmaceutically acceptable salt thereof, selected from compounds represented by general formula (IA):
wherein the content of the first and second substances,X 1 is selected from N or CH;X 2 is selected from N or CH;R 3 is selected from C 1-6 Alkyl, - (C) 1-4 Alkylene radical) 0-1 -Cyc、-O-(C 1-4 Alkylene radical) 0-1 -Cyc、-S-(C 1-4 Alkylene radical) 0-1 -Cyc、-NH-(C 1-4 Alkylene radical) 0-1 -Cyc、-NH-C 1-6 Alkyl, -N (C) 1-6 Alkyl radical) 2 、-O-C 1-6 Alkyl or-S-C 1-6 Alkyl radical, R 3 Optionally unsubstituted or further substituted by one or more R 4 Substituted by a substituent;cyc is selected from C 3-10 Cycloalkyl, 3-to 10-membered heterocyclic group, C 6-10 Aryl or 5-to 10-membered heteroaryl, said C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 6-10 Aryl or 5-to 10-membered heteroaryl unsubstituted or substituted by 1,2 or 3 substituents R 5 Substituted;R 4 or R 5 Each independently selected from H, hydroxy, amino, halogen, cyano, nitro, -OR a 、-SR a 、＝O、＝S、-C(O)R a 、-C(S)R a 、-C(O)OR a 、-C(S)OR a 、-C(O)N(R a ) 2 、-N(R a ) 2 、-S(O) 2 R a 、-O-S(O 2 )OR a 、-O-S(O) 2 R a Or R a Said R is a Each independently selected from H, C 1-6 Alkyl or C 3-6 Cycloalkyl radical, R a Unsubstituted or further substituted by one or more groups selected from halogen, hydroxy, C 1-3 Alkyl or cyano;R 2 selected from hydrogen, halogen, cyano, C 1-3 Alkyl radical, C 1-3 Alkoxy radical, C 2-4 Alkenyl, halo C 2-4 Alkenyl or C 2-4 Alkynyl. - A compound, tautomer, deuteron, or pharmaceutically acceptable salt thereof, selected from:
- a process for the preparation of a compound of general formula (I), a tautomer, a deuteron, or a pharmaceutically acceptable salt thereof, as claimed in claim 1, which comprises:
reacting the compound of the general formula (II) under an acidic condition to obtain a compound of the general formula (I),wherein R is 1 And R 2 Is as defined in claim 1. - A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 8 and at least one pharmaceutically acceptable excipient.
- Use of a compound according to any one of claims 1 to 8 or a pharmaceutical composition according to claim 9 for the manufacture of a medicament.
- A method of treating and/or preventing a disease comprising administering to a subject a therapeutically effective amount of a compound of any one of claims 1-8 or a pharmaceutical composition of claim 9.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2020106465629 | 2020-07-07 | ||
| CN202010646562 | 2020-07-07 | ||
| CN202010768662 | 2020-08-03 | ||
| CN2020107686629 | 2020-08-03 | ||
| PCT/CN2021/103508 WO2022007677A1 (en) | 2020-07-07 | 2021-06-30 | Cd73 inhibitor and application in pharmaceutical use |
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| Publication Number | Publication Date |
|---|---|
| CN115702150A true CN115702150A (en) | 2023-02-14 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN202180043145.8A Pending CN115702150A (en) | 2020-07-07 | 2021-06-30 | CD73 inhibitor and application thereof in medicine |
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| Country | Link |
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| CN (1) | CN115702150A (en) |
| WO (1) | WO2022007677A1 (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2023201267A1 (en) | 2022-04-13 | 2023-10-19 | Gilead Sciences, Inc. | Combination therapy for treating trop-2 expressing cancers |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| MX2018008350A (en) * | 2016-01-08 | 2019-05-30 | Arcus Biosciences Inc | Modulators of 5'-nucleotidase, ecto and the use thereof. |
| TWI702954B (en) * | 2018-03-01 | 2020-09-01 | 美商美國禮來大藥廠 | Cd73 inhibitors |
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- 2021-06-30 CN CN202180043145.8A patent/CN115702150A/en active Pending
- 2021-06-30 WO PCT/CN2021/103508 patent/WO2022007677A1/en active Application Filing
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| Publication number | Publication date |
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| WO2022007677A1 (en) | 2022-01-13 |
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