CN115141202A - Pyrimidopyrazinone compounds and uses thereof - Google Patents

Pyrimidopyrazinone compounds and uses thereof Download PDF

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Publication number
CN115141202A
CN115141202A CN202210356402.XA CN202210356402A CN115141202A CN 115141202 A CN115141202 A CN 115141202A CN 202210356402 A CN202210356402 A CN 202210356402A CN 115141202 A CN115141202 A CN 115141202A
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substituted
cycloalkyl
alkyl
group
independently selected
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张学军
臧杨
李群
陈浩民
陈登辉
刘礼飞
安丹
刘哲
李莉娥
杨俊�
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Hubei Bio-Pharmaceutical Industrial Technological Institute Inc
Humanwell Healthcare Group Co ltd
Wuhan Humanwell Innovative Drug Research and Development Center Ltd Co
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Humanwell Healthcare Group Co ltd
Wuhan Humanwell Innovative Drug Research and Development Center Ltd Co
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D475/00—Heterocyclic compounds containing pteridine ring systems
    • 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
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Abstract

The invention provides a novel compound for effectively inhibiting MAT2A, which is a compound shown in a formula III, or a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug of the compound shown in the formula III:
Figure DDA0003571090800000011
wherein L is 1 Selected from-O-, -S-, -N (R) L1 ) -and a single bond; r L1 Selected from hydrogen and C 1 ‑C 6 An alkyl group; r 1 、R 2 、R 3 、R 4 Is determined byThe definition is as described in the specification; the compound can effectively inhibit the activity of MAT2A enzyme and has wide application prospect.

Description

Pyrimidopyrazinone compounds and uses thereof
The present invention claims priority to a prior application entitled "pyrimidopyridazinone compound and its use" filed on 29/3/2021 with the intellectual property office of the chinese national patent application No. 202110335375.3. The entire disclosure of this prior application is incorporated herein by reference.
Technical Field
The invention relates to the fields of chemistry and medicine, in particular to a pyrimidopyrazinone compound and application thereof.
Background
Methionine adenosyltransferase 2A (mat2a) is one of the members of the MAT family of proteins, widely distributed in vivo, expressed in non-parenchymal cells of the liver and in all extrahepatic tissues (Murray B, et al, world J Gastroenterol 2019 (31): 4300-4319.), as well as two members of the MAT family including MAT1A and MAT 2B. MAT2A inhibitors can reduce S-adenosylmethionine (SAM) levels, so MAT2A inhibitors are also known as SAM inhibitors. SAM is the main methyl donor in cells, protein arginine methyltransferase 5 (PRMT 5) is methylase of the methyl donor using SAM, SAM has important function in the PRMT5 pathway and can influence the activity of PRMT5, and researches show that MAT2A is the 'synthetic lethal' target of MTAP deletion type tumors. MAT2A and PRMT5 were determined to be susceptible genes in MTAP-deficient cells using shRNA screening, and metabolic and biochemical studies revealed the mechanistic basis for this synthetic lethality: MTA, a substrate for the MTAP enzyme reaction, accumulates in large amounts in MTAP-deficient cancers, MTA is a potent and selective inhibitor of PRMT5, resulting in a decrease in PRMT5 methylation activity in MTAP-deficient cells, MAT2A produces a SAM, a substrate for PRMT5, MAT2A deficiency selectively decreases the growth of MTAP-deficient cells and PRMT5 methylation activity, and MAT2A is selectively required in MTAP-deficient cancers (Marjon K, et al.cell Rep.2016;15 (3): 574-587). The MAT2A inhibitor provides a novel treatment method for MTAP-deficient tumor patients.
MAT2A is involved in the metabolism of tumor stem cells, which require large amounts of methionine to maintain self-histone methylation, which is critical for the growth and tumorigenic effects of tumor stem cells. The key enzyme MAT2A on the methionine cycle is inhibited, so that the growth of tumor stem cells and the formation of tumors can be greatly inhibited. And MAT2A protein is abnormally and highly expressed in human non-small cell lung cancer tissues. When non-small cell lung cancer tumor stem cells were transplanted into mice, the MAT2A inhibitor almost completely inhibited tumor growth, while the chemotherapeutic cisplatin had little effect (Wang Z, et al. Nature medicine,2019,25 (5): 1-13.).
MAT1A and MAT2A in liver cancer are converted. Many studies show that MAT plays an important role in the occurrence of chronic liver diseases and liver cancer, and under normal conditions, MAT2A is mainly expressed in fetal liver, and is gradually replaced by MAT1A along with growth and development after birth, and MAT1A maintains the differentiation state of liver cells. In normal liver cells, MAT1A and MAT2A have dynamic equilibrium, and the SAM homeostasis in the cells is maintained together. In hepatocellular carcinoma, down-regulation of the expression level of MAT1A and up-regulation of MAT2A occurred, referred to as MAT1A: MAT2A conversion, liver dedifferentiation, SAM biosynthesis reduction, liver proliferation signal enhancement. In human liver cancer, MAT1A: the expression ratio of MAT2A is negatively correlated with cell growth and genome instability, and is directly correlated with liver cancer cell apoptosis and overall DNA methylation; a decreased rate is a prognostic marker for higher malignancy and lower survival rate of liver cancer. It has been shown that the use of small interfering RNA to silence MAT2A gene can inhibit the growth of hepatoma cells and induce apoptosis (Liu Q, et al. Hepatol Res.2007;37 (5): 376-388.).
1810 thousands cancer cases are newly added in 2018 all over the world, and the number of deaths reaches 960 ten thousands. Approximately 15% of human cancer chromosomes 9p21 (chr 9p 21) are homozygous deleted for the genome, with deletion frequencies in glioblastoma multiforme as high as >50%. The chromosomal Chr9p21 locus comprises the CDKN2A gene, which encodes the key tumor suppressor p19-ARF and p16-INK4a, and Chr9p21 deletions often involve co-deletions of the CDKN2A proximal gene, the most important of which is the methylthioadenosine phosphorylase (MTAP) gene. Many human malignant cells have been found to lack MTAP activity. MTAP deficiency is not only present in tissue culture cells, but the deficiency is also present in primary leukemia, glioma, melanoma, pancreatic cancer, non-small cell lung cancer (NSLC), bladder cancer, astrocytoma, osteosarcoma, head and neck cancer, mucinous chondrosarcoma, ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcoma, non-hodgkin's lymphoma, and mesothelioma.
At present, the research of MAT2A inhibitor in the fields of cancer and the like has made a certain progress, but a novel medicament still needs to be further developed, the MAT2A medicament which is researched at present is optimized, and a new treatment selection is provided for the unmet clinical requirement in the field of cancer treatment.
Disclosure of Invention
The invention aims to provide a compound capable of effectively inhibiting MAT2A, which can be used as an improvement or replacement of the existing medicament or MAT2A inhibitor.
To this end, in a first aspect of the invention, the invention provides a compound of formula III, a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt, or a prodrug thereof:
Figure BDA0003571090790000021
wherein L is 1 Selected from-O-, -S-, -N (R) L1 ) -and a single bond; r L1 Selected from hydrogen and C 1 -C 6 An alkyl group;
R 1 is selected from C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 3 -C 6 Cycloalkyl, - (C) 1 -C 6 Alkylene group) - (C 3 -C 6 Cycloalkyl) and- (C) 1 -C 6 Alkylene group) - (C 3 -C 6 Cycloalkenyl group) of C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 3 -C 6 Cycloalkyl, - (C) 1 -C 6 Alkylene group) - (C 3 -C 6 Cycloalkyl) and- (C) 1 -C 6 Alkylene group) - (C 3 -C 6 Cycloalkenyl) is optionally substituted by one or more R 1a Substituted, said R 1a Selected from halogens; when R is 1a When there are plural, R is 1a The same or different;
or when L is 1 is-N (R) L1 ) When is, R L1 And R 1 May be combined with L to form optionally substituted by one or more R L1 Substituted 3 to 6 membered heterocycloalkyl; when R is L1 When there are plural, R is L1 The same or different; the 3-to 6-membered heterocycloalkyl wherein 1,2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, the remainder being carbon atoms;
R 2 selected from unsubstituted or substituted by R 2a Substituted C 6 -C 10 Aryl, unsubstituted or substituted by R 2a Substituted 5 to 10 membered heteroaryl; when R is 2a When there are plural, R is 2a The same or different; the 5 to 10 membered heteroaryl wherein 1,2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, the remainder being carbon atoms;
R 3 selected from unsubstituted or substituted by R 3a Substituted C 6 -C 10 Aryl, unsubstituted or substituted by R 3a Substituted 5-to 10-membered heteroaryl, unsubstituted or substituted by R 3a A substituted ring A; when R is 3a When there are plural, R is 3a The same or different; the ring A is
Figure BDA0003571090790000031
Wherein ring Cx and ring Cy are each independently selected from C 5 -C 6 -aryl, 5-to 6-membered heteroaryl, 5-to 6-membered cycloalkyl and 5-to 6-membered heterocycloalkyl, D and E are each independently selected from C, CH, N, G and J are each independently selected from C, CH 2 、N、NH、O、S；
The R is 2a Is selected from-R A 、-OR A Halogen, -N = N-R A 、NR A R B 、-(C 1 -C 6 Alkylene) -NR A R B 、-C(O)OR A 、-C(O)NR A R B 、-OC(O)R A and-CN;
the R is 3a Is selected from-R A 、-OR A Halogen, -N = N-R A 、NR A R B 、-(C 1 -C 6 Alkylene) -NR A R B 、-C(O)OR A 、-C(O)NR A R B 、-OC(O)R A 、-CN、-(C 1 -C 6 Alkylene) -5-6 membered heterocycloalkyl, - (C) 1 -C 6 Alkylene) -S (O) 2 -(C 1 -C 3 Alkyl), - (C) 1 -C 6 Alkylene) -C (O) -NR A R B ；
R A And R B Each independently selected from H, -CN, -OH, oxo, C 1 -C 6 Alkyl radical, C 3 -C 6 Cycloalkyl radical, C 1 -C 6 Alkoxy radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, -NH 2 、-S(O) 0-2 -(C 1 -C 6 Alkyl), -S (O) 0-2 -(C 6 -C 10 Aryl), -CO- (C) 1 -C 6 Alkyl), -CO- (C) 3 -C 14 Cycloalkyl), -C 3 -C 14 Cycloalkyl, - (C) 1 -C 6 Alkylene group) - (C 3 -C 14 Cycloalkyl), C 6 -C 10 Aryl, 3 to 14 membered heterocycloalkyl, 5 to 10 membered heteroaryl; the 3-to 14-membered heterocycloalkyl and 5-to 10-membered heteroaryl, wherein 1,2, 3, or 4 ring atoms are heteroatoms independently selected from O, S and N, the remainder being carbon atoms;
said R is A And R B Each C in 1 -C 6 Alkyl radical, C 3 -C 6 Cycloalkyl radical, C 1 -C 6 Alkoxy radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, -NH 2 、-S(O) 0-2 -(C 1 -C 6 Alkyl), -S (O) 0-2 -(C 6 -C 10 Aryl), -CO- (C) 1 -C 6 Alkyl), -CO- (C) 3 -C 14 Cycloalkyl), -C 3 -C 14 Cycloalkyl, - (C) 1 -C 6 Alkylene group) - (C 3 -C 14 Cycloalkyl), C 6 -C 10 Aryl, 3-to 14-membered heterocycloalkyl, 5-to 10-membered heteroaryl are each independently and optionally substituted with one or more R Aa Substitution; when R is Aa When there are plural, R is Aa The same or different;
the R is Aa Each independently selected from-OH, deuterium, halogen, C 1 -C 6 Alkyl, -N (R) An ) 2 Wherein each R is An Each independently selected from H, C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 6 -C 10 Aryl, 3-to 14-membered heterocycloalkyl, - (C) 1 -C 6 Alkylene) - (3-to 14-membered heterocycloalkyl), and 5-to 10-membered heteroaryl, -NHC (O) - (OC) 1 -C 6 Alkyl), -NO 2 -CN, oxo, -C (O) OH, -C (O) -O- (C) 1 -C 6 Alkyl), - (C) 1 -C 6 Alkylene group) - (C 1 -C 6 -alkoxy), -C (O) NH 2 、-C(O)-(C 1 -C 6 Alkyl), -O- (C) 1 -C 6 Alkyl), -Si (C) 1 -C 6 Alkyl radical) 3 、-S(O) 0-2 -(C 1 -C 6 Alkyl group), C 6 -C 10 Aryl, - (C) 1 -C 6 Alkylene group) - (C 6 -C 10 Aryl), 3-to 14-membered heterocycloalkyl, - (C) 1 -C 6 Alkylene) - (3 to 14 membered heterocycloalkyl), and-O (C) 6 -C 14 Aryl groups);
the R is Aa Each alkyl, alkenyl, aryl and heterocycloalkyl of (a) is independently and optionally substituted with one or more R Ab Substituted, said R Ab Each independently selected from-OH, -O- (C) 1 -C 6 Alkyl), halogen, -NH 2 、-(C 1 -C 6 Alkylene) -NH 2 -COOH, -CN and oxo;
R 4 selected from hydrogen, halogen, -OH, -CN, C 1 -C 6 Alkyl radical, C 3 -C 6 Cycloalkyl, and- (C) 1 -C 6 Alkylene group) - (C 3 -C 6 Cycloalkyl) of said C 1 -C 6 Alkyl radical, C 3 -C 6 Cycloalkyl, and- (C) 1 -C 6 Alkylene group) - (C 3 -C 6 Cycloalkyl) optionally substituted by one or more R 4a Substituted, said R 4a Selected from halogen; when R is 4a When there are plural, R is 4a The same or different.
The alkyl group includes straight-chain alkyl groups and branched-chain alkyl groups.
It will be understood by those skilled in the art that, according to the convention used in the art, in the structural formulae of the present application,
Figure BDA0003571090790000041
for delineating chemical bonds, which are the points at which moieties or substituents are attached to a core structure or a backbone structure.
According to certain embodiments of the invention, in the compound of formula III, L 1 Selected from-O-, -S-, -N (R) L1 ) -or a single bond; r L1 Selected from hydrogen, C 1 -C 3 An alkyl group; according to a preferred embodiment of the invention, R L1 Selected from hydrogen, methyl, ethyl. Preferably, L 1 Is selected from-O-, or-NH-.
According to certain embodiments of the invention, in the compound of formula III, R 1 Is selected from C 1 -C 6 Alkyl radical, C 3 -C 6 Cycloalkyl, - (C) 1 -C 6 Alkylene group) - (C 3 -C 6 Cycloalkyl groups); said C is 1 -C 6 Alkyl radical, C 3 -C 6 Cycloalkyl and- (C) 1 -C 6 Alkylene group) - (C 3 -C 6 Cycloalkyl) optionally substituted by one or more R 1a Substituted, said R 1a Selected from halogen; according to certain embodiments of the invention, R 1 Is selected from C 1 -C 3 Alkyl radical, C 3 -C 6 Cycloalkyl, - (C) 1 -C 3 Alkylene group) - (C 3 -C 6 Cycloalkyl), said C 1 -C 3 Alkyl radical, C 3 -C 6 Cycloalkyl, - (C) 1 -C 3 Alkylene group) - (C 3 -C 6 Cycloalkyl) optionally substituted by one or more R 1a Substitution; when R is 1a When there are plural, R is 1a The same or different; the R is 1a Selected from halogens; preferably, the halogen is F; according to a preferred embodiment of the invention, R 1 Selected from the group consisting of methyl, ethyl, propyl, fluoromethyl, fluoroethyl, fluoropropyl, cyclopropyl,
Figure BDA0003571090790000042
According to yet another preferred embodiment of the invention, R 1 Selected from methyl, ethyl, -CH 2 -CF 3 A cyclopropyl group,
Figure BDA0003571090790000043
According to a further preferred embodiment of the present invention, -L 1 -R 1 Selected from: -NH-cyclopropyl, -O-cyclopropyl, -NH-CH 2 CF 3 、-O-CH 2 CF 3 、-NH-CH 2 -cyclopropyl, -O-CH 2 -cyclopropyl.
According to certain embodiments of the invention, in the compound of formula III, R 2 Selected from unsubstituted or substituted by R 2a Substituted phenyl and unsubstituted or substituted by R 2a Substituted 5 toA 10 membered heteroaryl group, wherein one ring atom of the 5 to 10 membered heteroaryl group is N; according to a preferred embodiment of the invention, R 2 Selected from unsubstituted or substituted by R 2a Substituted phenyl, unsubstituted or substituted by R 2a Substituted pyridyl, unsubstituted or substituted by R 2a A substituted pyrimidinyl group.
According to certain embodiments of the invention, in the compound of formula III, R 3 Is as a quilt R 3a A substituted ring A; the R is 3a Is selected from-C 1 -C 6 Alkyl, - (C) 1 -C 6 Alkylene) -5-6 membered heterocycloalkyl, - (C) 1 -C 6 Alkylene) -S (O) 2 -CH 3 、-(C 1 -C 6 Alkylene) -C (O) -N (CH) 3 ) 2 (ii) a The ring A is
Figure BDA0003571090790000051
Wherein ring Cx is a 5-membered heteroaryl ring or a 5-membered heterocycloalkyl group; ring Cy is a benzene ring, a 5-6 membered heteroaromatic ring or a 5-6 membered heterocycloalkyl group; d and E are each independently selected from C, CH, N; preferably, the ring Cx is a 5 membered heteroaromatic ring containing 2N or 1N and 1S; preferably, the ring Cx is a 5-membered heterocycloalkyl, which contains 1O; preferably, the ring Cy contains 1 or 2N;
according to certain embodiments of the invention, in the compound of formula III, R 3 Selected from unsubstituted or substituted by R 3a Substituted phenyl, unsubstituted or substituted by R 3a Substituted pyridyl, unsubstituted or substituted by R 3a Substituted pyridonyl, unsubstituted or substituted by R 3a Substituted pyridazinyl, unsubstituted or substituted by R 3a Substituted isoxazolyl, unsubstituted or substituted by R 3a Substituted pyrazolyl, and unsubstituted or substituted by R 3a A substituted ring A selected from
Figure BDA0003571090790000052
Benzothiazolyl, benzisothiazolyl, benzoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, quinoxalinyl, quinolyl, quinazolinyl, imidazopyridinyl, pyrazolopyridyl, triazolopyridinyl, benzoxadiazolylPyridazinyl, benzofuranyl, dihydrobenzofuranyl, dihydrobenzodioxovinyl and tetrahydrobenzodioxovinyl groups, where n A Selected from the integers 1,2 or 3; according to a preferred embodiment of the present invention, ring a is selected from benzothiazolyl, benzimidazolyl, indazolyl, benzopiperidinyl, benzopiperazinyl, benzomorpholinyl, indane, chroman.
According to certain embodiments of the invention, in the compound of formula III, R 2a And R 3a Each independently selected from-R A 、-OR A Halogen and-CN.
According to certain embodiments of the invention, in the compound of formula III, R A Independently selected from H, -OH, C 1 -C 6 Alkyl radical, C 3 -C 6 Cycloalkyl, -CO- (C) 1 -C 6 Alkyl), - (C) 1 -C 6 Alkylene group) - (C 3 -C 14 Cycloalkyl), said C 1 -C 6 Alkyl radical, C 3 -C 6 Cycloalkyl, -CO- (C) 1 -C 6 Alkyl), - (C) 1 -C 6 Alkylene group) - (C 3 -C 14 Cycloalkyl) each independently and optionally substituted with one or more R Aa And (4) substitution.
According to certain embodiments of the invention, in the compound of formula III, R Aa Each independently selected from-OH, halogen, -N (R) An ) 2 Wherein each R is An Each independently selected from H, methyl, ethyl, isopropyl, n-propyl.
According to certain embodiments of the invention, in the compound of formula III, R 4 Independently selected from hydrogen, halogen, -OH, -CN, C 1 -C 6 Alkyl radical, C 3 -C 6 Cycloalkyl, and- (C) 1 -C 6 Alkylene group) - (C 3 -C 6 Cycloalkyl), said C 1 -C 6 Alkyl radical, C 3 -C 6 Cycloalkyl, and- (C) 1 -C 6 Alkylene group) - (C 3 -C 6 Cycloalkyl) optionally substituted by one or more R 4a Substituted, said R 4a Selected from fluorine and chlorine; when R is 4a When there are plural, R is 4a Same or differentThe same is true.
According to a preferred embodiment of the invention, in the compound of formula III, R 4 Selected from the group consisting of hydrogen, halogen, -OH, -CN, methyl, ethyl, n-propyl, fluoromethyl, fluoroethyl, fluoropropyl, cyclopropyl, fluorocyclopropyl, and,
Figure BDA0003571090790000061
Figure BDA0003571090790000062
Chloromethyl, chloroethyl chloropropyl, chlorocyclopropyl, methyl ethyl,
Figure BDA0003571090790000063
Preferably, R 4 Selected from hydrogen, halogen, methyl, ethyl, -CH 2 -CF 3 A cyclopropyl group,
Figure BDA0003571090790000064
R 4 Hydrogen is preferred.
According to certain embodiments of the invention, in the compound of formula III, R 2 Is selected from R 2a Substituted phenyl and substituted by R 2a Substituted pyridyl, and R 2a Independently selected from fluorine, chlorine, bromine, optionally substituted by one or more R Aa substituted-R A Optionally substituted by one or more R Aa substituted-OR A Said R is A Independently selected from the group consisting of one or more R Aa Substituted C 1 -C 6 Alkyl, by one or more R Aa Substituted C 3 -C 6 Cycloalkyl radical, each R Aa Independently selected from-OH, fluorine, chlorine, bromine; according to a preferred embodiment of the invention, R 2a Independently selected from-fluoro, chloro, bromo, methyl, ethyl, n-propyl, isopropyl cyclopropyl, methoxy, ethoxy, n-propoxy, isopropoxy,
Figure BDA0003571090790000065
A fluoromethoxy group; according to certain embodiments of the invention, R 2 Is composed of
Figure BDA0003571090790000066
R 2a Selected from: fluorine, chlorine, bromine, -O-C 1 -C 6 Alkyl or C 3 -C 6 A cycloalkyl group; said C is 1 -C 6 Alkyl optionally substituted with one or more halogens; preferably, the halogen is F; preferably, R 2a Selected from: fluorine, chlorine, -O-CF 2 H or cyclopropyl; according to yet another preferred embodiment of the invention, R 2 Is selected from
Figure BDA0003571090790000067
Figure BDA0003571090790000068
According to certain embodiments of the invention, in the compound of formula III, R 3 Is selected from R 3a A substituted ring A selected from
Figure BDA0003571090790000071
Figure BDA0003571090790000072
And R is 3a Independently selected from optionally substituted by one or more R Aa substituted-R A Said R is A Independently selected from the group consisting of one or more R Aa Substituted C 1 -C 6 Alkyl radical, each R Aa Each independently selected from-OH, fluorine, chlorine, bromine; according to a preferred embodiment of the invention, R 3a Independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, -CH 2 -OH、-(CH 2 ) 2 -OH、-(CH 2 ) 3 -OH、-(CH 2 ) 4 -OH、
Figure BDA0003571090790000073
According to certain embodiments of the invention, in the compound of formula III, R 3 Selected from:
Figure BDA0003571090790000074
Figure BDA0003571090790000075
Figure BDA0003571090790000076
R 3a selected from: -C 1 -C 6 Alkyl, -C 1 -C 6 Alkyl-5-6 membered heterocycloalkyl, -C 1 -C 6 alkyl-S (O) 2 -CH 3 、-C 1 -C 6 alkyl-C (O) -N (CH) 3 ) 2 (ii) a Preferably, C is 1 -C 6 The alkyl is straight-chain or branched-chain alkyl; said C is 1 -C 6 Alkyl is optionally substituted with-OH; preferably, the 5-6 membered heterocycloalkyl group is
Figure BDA0003571090790000077
Preferably, R 3a Selected from: -CH 3 、-
Figure BDA0003571090790000078
Figure BDA0003571090790000079
According to a preferred embodiment of the invention, in the compound of formula III, R 3 Is selected from
Figure BDA00035710907900000710
Figure BDA0003571090790000081
According to certain embodiments of the invention, the compound of formula III has the structure of formula II:
Figure BDA0003571090790000082
wherein R is 1 、R 2a 、R 3a 、R 4 、L 1 Having the definition given above, Y 1 、Y 2 、Y 3 Each independently selected from N, S, C, CH.
According to some embodiments of the invention, L 1 Selected from-O-, -S-, -N (R) L1 ) -and a single bond; r L1 Selected from hydrogen and C 1 -C 6 An alkyl group;
R 1 is selected from C 1 -C 6 Alkyl radical, C 3 -C 6 Cycloalkyl, - (C) 1 -C 6 Alkylene group) - (C 3 -C 6 Cycloalkyl) of said C 1 -C 6 Alkyl radical, C 3 -C 6 Cycloalkyl and- (C) 1 -C 6 Alkylene group) - (C 3 -C 6 Cycloalkyl) optionally substituted by one or more R 1a Substitution; when R is 1a When there are plural, R is 1a The same or different; the R is 1a Selected from halogens;
X 1 is selected from C (R) 2a )、N；
Y 1 、Y 2 、Y 3 Each independently selected from N, S, C, CH;
R 2a is independently selected from-R A 、-OR A And a halogen;
R 3a is independently selected from-R A ；
R A Independently selected from H, -CN, -OH, C 1 -C 6 Alkyl radical, C 3 -C 6 Cycloalkyl radicals, substituted by one or more R Aa Substituted C 1 -C 6 Alkyl, by one or more R Aa Substituted C 3 -C 6 A cycloalkyl group; when R is Aa When there are plural, R is Aa The same or different;
the R is Aa Each independently selected from-OH, deuterium, halogen;
R 4 selected from hydrogen, halogen, -OH, -CN, C 1 -C 6 Alkyl radical, C 3 -C 6 Cycloalkyl, and- (C) 1 -C 6 Alkylene group) - (C 3 -C 6 Cycloalkyl), said C 1 -C 6 Alkyl radical, C 3 -C 6 Cycloalkyl, and- (C) 1 -C 6 Alkylene group) - (C 3 -C 6 Cycloalkyl) optionally substituted by one or more R 4a Substituted, said R 4a Selected from halogens; when R is 4a When there are plural, R is 4a The same or different.
According to certain embodiments of the invention, in the compound of formula II, L 1 Selected from-O-, -S-, -N (R) L1 ) -or a single bond; r is L1 Selected from hydrogen, C 1 -C 3 An alkyl group; preferably, R L1 Selected from hydrogen, methyl, ethyl.
According to certain embodiments of the invention, in the compound of formula II, R 1 Selected from the group consisting of methyl, ethyl, propyl, fluoromethyl, fluoroethyl, fluoropropyl, cyclopropyl,
Figure BDA0003571090790000091
According to a preferred embodiment of the invention, R 1 Selected from methyl, ethyl, -CH 2 -CF 3 A cyclopropyl group,
Figure BDA0003571090790000092
According to certain embodiments of the invention, in the compound of formula II, X 1 Is selected from CH and N.
According to certain embodiments of the invention, in the compound of formula II, R 2a Independently selected from-fluoro, chloro, bromo, methyl, ethyl, n-propyl, isopropyl cyclopropyl, methoxy, ethoxy, n-propoxy, isopropoxy,
Figure BDA0003571090790000093
A fluoromethoxy group.
According to certain embodiments of the invention, in the compound of formula II, R 3a Independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, -CH 2 -OH、-(CH 2 ) 2 -OH、-(CH 2 ) 3 -OH、-(CH 2 ) 4 -OH、
Figure BDA0003571090790000094
According to certain embodiments of the invention, in the compound of formula II, R 4 Selected from the group consisting of hydrogen, halogen, -OH, -CN, methyl, ethyl, n-propyl, fluoromethyl, fluoroethyl, fluoropropyl, cyclopropyl, fluorocyclopropyl, and,
Figure BDA0003571090790000101
Chloromethyl, chloroethyl chloropropyl, chlorocyclopropyl, methyl ethyl,
Figure BDA0003571090790000102
Preferably, R 4 Selected from hydrogen, halogen, methyl, ethyl, -CH 2 -CF 3 A cyclopropyl group,
Figure BDA0003571090790000103
According to certain embodiments of the invention, the compound of formula II has a structure of formula II-a or II-b:
Figure BDA0003571090790000104
wherein R is 1 、L 1 、R 2a 、R 3a Having the definitions as described above.
According to certain embodiments of the invention, the compound of formula III may also have the structure of formula I:
Figure BDA0003571090790000105
wherein R is 1 、L 1 、R 2a 、R 3a 、R 4 、n A Having the definitions described above.
According to some embodiments of the invention, L 1 Selected from-O-, -S-, -N (R) L1 ) -and a single bond; r L1 Selected from hydrogen and C 1 -C 6 An alkyl group;
R 1 is selected from C 1 -C 6 Alkyl radical, C 3 -C 6 Cycloalkyl, - (C) 1 -C 6 Alkylene group) - (C 3 -C 6 Cycloalkyl) of said C 1 -C 6 Alkyl radical, C 3 -C 6 Cycloalkyl and- (C) 1 -C 6 Alkylene group) - (C 3 -C 6 Cycloalkyl) optionally substituted by one or more R 1a Substitution; when R is 1a When there are plural, R is 1a The same or different; the R is 1a Selected from halogens;
X 1 is selected from C (R) 2a )、N；
R 2a Is independently selected from-R A 、-OR A And halogen;
R 3a independently selected from-R A ；
R A Independently selected from H, -CN, -OH, C 1 -C 6 Alkyl radical, C 3 -C 6 Cycloalkyl radicals, substituted by one or more R Aa Substituted C 1 -C 6 Alkyl, by one or more R Aa Substituted C 3 -C 6 A cycloalkyl group; when R is Aa When there are plural, R is Aa The same or different;
the R is Aa Each independently selected from-OH, deuterium, halogen;
R 4 selected from hydrogen, halogen, -OH, -CN, C 1 -C 6 Alkyl radical, C 3 -C 6 Cycloalkyl, and- (C) 1 -C 6 Alkylene group) - (C 3 -C 6 Cycloalkyl) of said C 1 -C 6 Alkyl radical, C 3 -C 6 Cycloalkyl, and- (C) 1 -C 6 Alkylene group) - (C 3 -C 6 Cycloalkyl) optionally substituted by one or more R 4a Substituted, said R 4a Selected from halogen; when R is 4a When there are plural, R is 4a The same or different;
n A selected from the integers 1,2 or 3.
According to certain embodiments of the invention, in the compounds of formula I, L 1 Selected from-O-, -S-, -N (R) L1 ) -or a single bond; r L1 Selected from hydrogen, C 1 -C 3 An alkyl group; preferably, R L1 Selected from hydrogen, methyl, ethyl.
According to certain embodiments of the invention, in the compounds of formula I, R 1 Selected from the group consisting of methyl, ethyl, propyl, fluoromethyl, fluoroethyl, fluoropropyl, cyclopropyl,
Figure BDA0003571090790000111
Preferably, R 1 Selected from methyl, ethyl, -CH 2 -CF 3 A cyclopropyl group,
Figure BDA0003571090790000112
According to certain embodiments of the invention, in the compounds of formula I, X 1 Is selected from CH and N.
According to certain embodiments of the invention, in the compounds of formula I, R 2a Independently selected from the group consisting of-fluoro, chloro, bromo, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, and tert-butoxy,
Figure BDA0003571090790000113
A fluoromethoxy group.
According to certain embodiments of the invention, in the compounds of formula I, R 3a Independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, -CH 2 -OH、-(CH 2 ) 2 -OH、-(CH 2 ) 3 -OH、-(CH 2 ) 4 -OH、
Figure BDA0003571090790000114
According to certain embodiments of the invention, in the compounds of formula I, R 4 Selected from the group consisting of hydrogen, halogen, -OH, -CN, methyl, ethyl, n-propyl, fluoromethyl, fluoroethyl, fluoropropyl, cyclopropyl, fluorocyclopropyl, and,
Figure BDA0003571090790000115
Chloro-substituted phenyl etherMethyl, chloroethyl, chloropropyl, chlorocyclopropyl,
Figure BDA0003571090790000121
Preferably, R 4 Selected from hydrogen, halogen, methyl, ethyl, -CH 2 -CF 3 A cyclopropyl group,
Figure BDA0003571090790000122
According to certain embodiments of the invention, the compound of formula III is selected from any one of the following:
Figure BDA0003571090790000123
Figure BDA0003571090790000131
in a second aspect of the invention, the invention provides intermediates M-1 and M-2:
Figure BDA0003571090790000141
wherein R is M Selected from halogen, L 1 、R 1 、R 2 、R 4 Having the definitions as described above.
According to some embodiments of the invention, L 1 Selected from-O-, -S-, -N (R) L1 ) -and a single bond; r is L1 Selected from hydrogen and C 1 -C 6 An alkyl group;
according to some embodiments of the invention, R 1 Is selected from C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 3 -C 6 Cycloalkyl, - (C) 1 -C 6 Alkylene group) - (C 3 -C 6 Cycloalkyl) and- (C) 1 -C 6 Alkylene group) - (C 3 -C 6 Cycloalkenyl groups);
said C is 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 3 -C 6 Cycloalkyl, - (C) 1 -C 6 Alkylene group) - (C 3 -C 6 Cycloalkyl) and- (C) 1 -C 6 Alkylene group) - (C 3 -C 6 Cycloalkenyl) is optionally substituted by one or more R 1a Substituted, said R 1a Selected from halogens; when R is 1a When there are plural, R is 1a The same or different;
or when L is 1 is-N (R) L1 ) When is, R L1 And R 1 May be combined with L to form optionally substituted by one or more R L1 Substituted 3 to 6 membered heterocycloalkyl; when R is L1 When there are plural, R is L1 The same or different; the 3-to 6-membered heterocycloalkyl wherein 1,2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, the remainder being carbon atoms;
according to certain embodiments of the invention, R 2 Selected from unsubstituted or substituted by R 2a Substituted C 6 -C 10 Aryl, unsubstituted or substituted by R 2a Substituted 5 to 10 membered heteroaryl; when R is 2a When there are plural, R is 2a The same or different; the 5 to 10 membered heteroaryl wherein 1,2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, the remainder being carbon atoms;
the R is 2a Is independently selected from-R A 、-OR A Halogen, -N = N-R A 、NR A R B 、-(C 1 -C 6 Alkylene) -NR A R B 、-C(O)OR A 、-C(O)NR A R B 、-OC(O)R A and-CN;
R A and R B Each independently selected from H, -CN, -OH, oxo, C 1 -C 6 Alkyl radical, C 3 -C 6 Cycloalkyl radical, C 1 -C 6 Alkoxy radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, -NH 2 、-S(O) 0-2 -(C 1 -C 6 Alkyl), -S (O) 0-2 -(C 6 -C 10 Aryl), -CO- (C) 1 -C 6 Alkyl), -CO- (C) 3 -C 14 Cycloalkyl), -C 3 -C 14 Cycloalkyl, - (C) 1 -C 6 Alkylene group) - (C 3 -C 14 Cycloalkyl), C 6 -C 10 Aryl, 3 to 14 membered heterocycloalkyl, 5 to 10 membered heteroaryl; the 3-to 14-membered heterocycloalkyl and 5-to 10-membered heteroaryl, wherein 1,2, 3, or 4 ring atoms are heteroatoms independently selected from O, S and N, the remainder being carbon atoms;
the R is A And R B Each C in 1 -C 6 Alkyl radical, C 3 -C 6 Cycloalkyl radical, C 1 -C 6 Alkoxy radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, -NH 2 、-S(O) 0-2 -(C 1 -C 6 Alkyl), -S (O) 0-2 -(C 6 -C 10 Aryl), -CO- (C) 1 -C 6 Alkyl), -CO- (C) 3 -C 14 Cycloalkyl), -C 3 -C 14 Cycloalkyl, - (C) 1 -C 6 Alkylene group) - (C 3 -C 14 Cycloalkyl), C 6 -C 10 Aryl, 3-to 14-membered heterocycloalkyl, 5-to 10-membered heteroaryl are each independently and optionally substituted with one or more R Aa Substitution; when R is Aa When there are plural, R is Aa The same or different;
the R is Aa Each independently selected from-OH, deuterium, halogen, -N (R) An ) 2 Wherein each R is An Each independently selected from H, C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 6 -C 10 Aryl, 3-to 14-membered heterocycloalkyl, - (C) 1 -C 6 Alkylene) - (3-to 14-membered heterocycloalkyl), and 5-to 10-membered heteroaryl, -NHC (O) - (OC) 1 -C 6 Alkyl), -NO 2 -CN, oxo, -C (O) OH, -C (O) -O- (C) 1 -C 6 Alkyl), - (C) 1 -C 6 Alkylene group) - (C 1 -C 6 -alkoxy), -C (O) NH 2 、-C(O)-(C 1 -C 6 Alkyl), -O- (C) 1 -C 6 Alkyl), -Si (C) 1 -C 6 Alkyl radical) 3 、-S(O) 0-2 -(C 1 -C 6 Alkyl group), C 6 -C 10 Aryl, - (C) 1 -C 6 Alkylene group) - (C 6 -C 10 Aryl), 3-to 14-membered heterocycloalkyl, - (C) 1 -C 6 Alkylene) - (3-to 14-membered heterocycloalkyl), and-O (C) 6 -C 14 Aryl groups);
the R is Aa Each alkyl, alkenyl, aryl and heterocycloalkyl of (a) is independently and optionally substituted with one or more R Ab Substituted, said R Ab Each independently selected from-OH, -O- (C) 1 -C 6 Alkyl), halogen, -NH 2 、-(C 1 -C 6 Alkylene) -NH 2 -COOH, -CN and oxo;
and said intermediate M-1 does not comprise the following compounds:
Figure BDA0003571090790000151
according to certain embodiments of the invention, R in intermediates M-1 and M-2 is M Selected from fluorine, chlorine, bromine, iodine; preferably, R M Selected from fluorine, chlorine, bromine.
According to certain embodiments of the invention, in intermediates M-1 and M-2, L 1 Selected from-O-, -S-, -N (R) L1 ) -or a single bond; r L1 Selected from hydrogen, C 1 -C 3 An alkyl group. According to certain preferred embodiments of the present invention, R L1 Selected from hydrogen, methyl, ethyl.
According to certain embodiments of the invention, R in intermediates M-1 and M-2 is 1 Is selected from C 1 -C 6 Alkyl radical, C 3 -C 6 Cycloalkyl, - (C) 1 -C 6 Alkylene group) - (C 3 -C 6 Cycloalkyl groups); said C is 1 -C 6 Alkyl radical, C 3 -C 6 Cycloalkyl and- (C) 1 -C 6 Alkylene group) - (C 3 -C 6 Cycloalkyl) optionally substituted by one or more R 1a Substituted, said R 1a Selected from halogens. According to certain preferred embodiments of the present invention, R 1 Selected from the group consisting of methyl, ethyl, propyl, fluoromethyl, fluoroethyl, fluoropropyl, cyclopropyl,
Figure BDA0003571090790000152
Preferably, R 1 Selected from methyl, ethyl, -CH 2 -CF 3 A cyclopropyl group,
Figure BDA0003571090790000153
According to certain embodiments of the invention, R in intermediates M-1 and M-2 is 2 Selected from unsubstituted or substituted by R 2a Substituted phenyl and unsubstituted or substituted by R 2a A substituted 5-to 10-membered heteroaryl, wherein one ring atom of the 5-to 10-membered heteroaryl is N; preferably, R 2 Selected from unsubstituted or substituted by R 2a Substituted phenyl, unsubstituted or substituted by R 2a Substituted pyridyl, unsubstituted or substituted by R 2a A substituted pyrimidinyl group.
According to certain embodiments of the invention, R in intermediates M-1 and M-2 is 2a Is independently selected from-R A 、-OR A Halogen and-CN.
According to certain embodiments of the invention, R in intermediates M-1 and M-2 is A Independently selected from H, -OH, C 1 -C 6 Alkyl radical, C 3 -C 6 Cycloalkyl, -CO- (C) 1 -C 6 Alkyl), - (C) 1 -C 6 Alkylene group) - (C 3 -C 14 Cycloalkyl) of said C 1 -C 6 Alkyl radical, C 3 -C 6 Cycloalkyl, -CO- (C) 1 -C 6 Alkyl), - (C) 1 -C 6 Alkylene group) - (C 3 -C 14 Cycloalkyl) each independently and optionally substituted with one or more R Aa And (4) substitution.
According to certain embodiments of the invention, R in intermediates M-1 and M-2 is Aa Each independently selected from-OH, halogen, -N (R) An ) 2 Wherein each R is An Each independently selected from H, methyl, ethyl, isopropyl, n-propyl.
According to certain embodiments of the invention, R in intermediates M-1 and M-2 is 2 Is selected from R 2a Substituted phenyl and substituted by R 2a Substituted pyridyl, and R 2a Independently selected from fluorine, chlorine, bromine, optionally substituted by one or more R Aa substituted-R A Optionally substituted by one or more R Aa substituted-OR A Said R is A Independently selected from the group consisting of one or more R Aa Substituted C 1 -C 6 Alkyl, by one or more R Aa Substituted C 3 -C 6 Cycloalkyl radical, each R Aa Independently selected from-OH, fluorine, chlorine, bromine; according to certain preferred embodiments of the present invention, R 2a Independently selected from the group consisting of-fluoro, chloro, bromo, methyl, ethyl, n-propyl, isopropyl cyclopropyl, methoxy, ethoxy, n-propoxy, isopropoxy,
Figure BDA0003571090790000161
A fluoromethoxy group; more preferably, R 2 Is selected from
Figure BDA0003571090790000162
Figure BDA0003571090790000163
According to certain embodiments of the invention, the intermediate M-1 is selected from any one of the following compounds:
Figure BDA0003571090790000164
Figure BDA0003571090790000171
according to certain embodiments of the invention, the intermediate M-2 is selected from any one of the following compounds:
Figure BDA0003571090790000172
in a third aspect of the invention, there is provided a process for the preparation of a compound of formula III, which comprises:
(1) Contacting said intermediate M-1 with a halogenating agent to obtain said intermediate M-2; and/or
Figure BDA0003571090790000181
(2) Reacting said intermediate M-2 with
Figure BDA0003571090790000182
Contacting to obtain the compound shown in the formula III,
Figure BDA0003571090790000183
wherein R is 1 、R 2 、R 3 、R 4 、L 1 Having the definition given above, R M Selected from fluorine, chlorine, bromine, iodine; preferably, R M Selected from fluorine, chlorine, bromine.
According to certain embodiments of the invention, in step (1), the halogenating agent is selected from N-chlorosuccinimide, N-bromosuccinimide.
According to some embodiments of the invention, in step (2), the intermediate M-2 is reacted with an inert gas under protection of an inert gas
Figure BDA0003571090790000184
Contacting a palladium catalyst with alkali to obtain the compound shown in the formula III.
In a fourth aspect of the invention, the invention provides a pharmaceutical composition comprising a therapeutically effective amount of at least one compound of formula III, a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt, or a prodrug thereof.
According to certain embodiments of the invention, the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients.
According to certain embodiments of the invention, the pharmaceutical composition may further comprise one or more additional therapeutic agents.
In a fifth aspect of the present invention, the present invention provides a compound represented by formula III, a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt, or a prodrug thereof, or a pharmaceutical composition thereof, for use in the preparation of a medicament for treating or preventing a disease associated with MAT2A, and also provides a pharmaceutical use of any compound described in the first aspect of the present invention or the pharmaceutical composition described in the fourth aspect of the present invention for treating or preventing a disease associated with MAT 2A.
According to certain embodiments of the invention, the medicament is for treating or preventing cancer.
According to certain embodiments of the invention, the cancer is a MTAP-deficient cancer.
According to certain embodiments of the invention, the cancer is selected from mesothelioma, neuroblastoma, rectal cancer, colon cancer, familiar adenomatous polyposis and hereditary non-polyposis colorectal cancer, esophageal cancer, lip cancer, laryngeal cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, stomach cancer, adenocarcinoma, medullary thyroid cancer, papillary thyroid cancer, kidney cancer, renal parenchymal cancer, ovarian cancer, cervical cancer, uterine corpus cancer, endometrial cancer, choriocarcinoma, pancreatic cancer, prostate cancer, bladder cancer, testicular cancer, breast cancer, urinary cancer, melanoma, brain tumor, lymphoma, head and neck cancer, acute Lymphoblastic Leukemia (ALL), chronic Lymphoid Leukemia (CLL), acute Myeloid Leukemia (AML), chronic Myelogenous Leukemia (CML), hepatocellular carcinoma, gall bladder cancer, bronchial carcinoma, small cell lung cancer, non-small cell lung cancer, multiple myeloma, basal sarcoma, teratocarcinoma, retinoblastoma, choroidal melanoma, ewingosing's cell tumor, rhabdomyosarcoma, osteosarcoma, chondrosarcoma, liposarcoma, fibrosarcoma, and sarcoma.
The present invention also provides a method of treating a disease associated with MAT2A, comprising administering to a patient a prophylactically or therapeutically effective amount of at least one compound of formula (I), a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt, or a prodrug thereof, or a pharmaceutical composition as described above.
According to certain embodiments of the invention, the patient is a mammal, preferably a human.
The invention also provides application of at least one of the compound shown in the formula (I), a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug thereof, or a pharmaceutical composition of the compound in treating or preventing MAT2A related diseases.
Advantageous effects
According to embodiments of the invention, the compounds and/or compositions thereof of the present invention are effective in inhibiting MAT2A enzymatic activity on HCT116 MTAP-/- The cell proliferation and SAM level in the cells have good inhibition effect and better pharmacokinetic property. Has wide application prospect in the aspect of preparing the medicine for treating MAT2A related diseases.
Additional aspects and advantages of the invention will be set forth in part in the description which follows and, in part, will be obvious from the description, or may be learned by practice of the invention.
Definition and description of terms
Unless otherwise indicated, the definitions of groups and terms described in the specification and claims of the present application, including definitions thereof as examples, exemplary definitions, preferred definitions, definitions described in tables, definitions of specific compounds in the examples, and the like, may be arbitrarily combined and coupled with each other. The definitions of the groups and the structures of the compounds in such combinations and after the combination are within the scope of the present specification.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs. All patents, patent applications, and publications cited herein are incorporated by reference in their entirety unless otherwise indicated. If there are multiple definitions of terms herein, the definition in this section controls.
Unless otherwise indicated, conventional methods within the skill of the art are employed, such as mass spectrometry, NMR, IR and UV/Vis spectroscopy, and pharmacological methods. Unless specific definitions are set forth, reference herein to analytical chemistry, organic synthetic chemistry, and pharmaceutical chemistryThe terminology used in the description is known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, pharmaceutical preparation, formulation and delivery, and treatment of patients. For example, the reaction and purification can be carried out using the manufacturer's instructions for use of the kit, or in a manner known in the art or as described herein. The techniques and methods described above can generally be practiced according to conventional methods well known in the art, as described in various general and more specific documents referred to and discussed in this specification. In the present specification, groups and substituents thereof may be selected by one skilled in the art to provide stable moieties and compounds. When a substituent is described by a general formula written from left to right, the substituent also includes chemically equivalent substituents obtained when the formula is written from right to left. For example, CH 2 O is equivalent to OCH 2 。
Where numerical ranges are recited in the specification and claims of this application, and where the numerical ranges are understood to be "integers," they are understood to recite both the endpoints of the ranges and each integer within the range. For example, "an integer of 1 to 6" should be understood to describe each integer of 0, 1,2, 3,4, 5, and 6. When a range of values is understood to be "a number," it is understood to recite both the endpoints of the range as well as each and every integer within the range and each and every decimal within the range. For example, "a number of 1 to 10" should be understood to recite not only each integer of 1,2, 3,4, 5,6,7, 8, 9, and 10, but also at least the sum of each integer and 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, respectively.
The term "pharmaceutically acceptable" is intended to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
The term "pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" refers to pharmaceutically acceptable salts of non-toxic acids or bases, including salts of inorganic acids and bases, organic acids and bases.
In addition to pharmaceutically acceptable salts, other salts are also contemplated by the present invention. They may serve as intermediates in the purification of the compounds or in the preparation of other pharmaceutically acceptable salts or may be used in the identification, characterization or purification of the compounds of the invention.
The term "stereoisomer" refers to an isomer resulting from the different arrangement of atoms in a molecule. The stereochemical definitions and conventions used in the present invention are generally in accordance with S.P. Parker, ed., mcGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, new York; and Eliel, E.and Wilen, S., "Stereochemistry of Organic Compounds", john Wiley & Sons, inc., new York, 1994. The compounds of the invention may contain asymmetric or chiral centers and thus exist in different stereoisomeric forms. It is contemplated that all stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers and atropisomers (atropisomers) and geometric (or conformational) isomers and mixtures thereof, such as racemic mixtures, are within the scope of the present invention.
Many organic compounds exist in an optically active form, i.e., they have the ability to rotate the plane of plane polarized light. When describing optically active compounds, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule with respect to the chiral center (or centers) in the molecule. The prefixes D and L or (+) and (-) are the symbols used to specify the rotation of plane polarized light by the compound, where (-) or L indicates that the compound is left-handed. Compounds prefixed with (+) or D are dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. A particular stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often referred to as a mixture of enantiomers. A 50.
Depending on the choice of starting materials and process, the compounds according to the invention may be present as one of the possible isomers or as a mixture thereof, for example as pure optical isomers, or as a mixture of isomers, for example as racemic and diastereomeric mixtures, depending on the number of asymmetric carbon atoms. Optically active (R) -or (S) -isomers can be prepared using chiral synthons or chiral preparations, or resolved using conventional techniques. If the compound contains a double bond, the substituents may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the substituents of the cycloalkyl group may be in the cis or trans (cis-or trans-) configuration.
When the bond to a chiral carbon in the general formula of the present invention is depicted in a straight line, it is understood that both the (R) and (S) configurations of the chiral carbon and the enantiomerically pure compounds and mixtures thereof resulting therefrom are included within the scope of the general formula. The illustrations of racemic or enantiomerically pure compounds herein are from Maehr, j.chem.ed.1985, 62. Unless otherwise indicated, the absolute configuration of a stereocenter is indicated by wedge bonds and dashed bonds.
The compounds of the present invention containing asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Resolution of racemic mixtures of compounds can be carried out by any of a number of methods known in the art. Exemplary methods include fractional recrystallization using chiral resolving acids, which are optically active salt-forming organic acids. Suitable resolving agents for use in the fractional recrystallization process are, for example, the D and L forms of optically active acids, such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or various optically active camphorsulfonic acids, such as β -camphorsulfonic acid. Other resolving agents suitable for fractional crystallization processes include stereoisomerically pure forms of α -methyl-benzylamine (e.g., S and R forms or diastereomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, and the like. Resolution of the racemic mixture can also be carried out by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). The method can be performed by High Performance Liquid Chromatography (HPLC) or Supercritical Fluid Chromatography (SFC). The choice of the particular method and the conditions of elution, the choice of the chromatography column can be selected by the person skilled in the art according to the structure of the compound and the results of the test. Further, any enantiomer or diastereomer of the compounds described herein may also be obtained by stereoorganic synthesis using optically pure starting materials or reagents of known configuration.
Many geometric isomers of olefins, C = N double bonds, and the like may also be present in the compounds described herein, and all such stable isomers are contemplated herein. When compounds described herein contain olefinic double bonds, such double bonds include both E and Z geometric isomers, unless otherwise specified.
The term "tautomer" refers to an isomer of a functional group resulting from the rapid movement of an atom in two positions in a molecule. The compounds of the invention may exhibit tautomerism. Tautomeric compounds may exist in two or more interconvertible species. Prototropic tautomers result from the migration of a covalently bonded hydrogen atom between two atoms. Tautomers generally exist in equilibrium, and attempts to isolate a single tautomer often result in a mixture whose physicochemical properties are consistent with the mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the keto form predominates; whereas in phenol the enol type predominates. The present invention encompasses all tautomeric forms of the compounds.
The term "pharmaceutical composition" denotes a mixture of one or more compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof with other chemical components, such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate the administration of the compound to an organism.
The term "solvate" means that the compound of the present invention or a salt thereof includes a stoichiometric or non-stoichiometric amount of solvent bonded with non-covalent intermolecular forces, and when the solvent is water, it is a hydrate.
The term "prodrug" refers to a compound of the invention that can be converted to a biologically active compound under physiological conditions or by solvolysis. Prodrugs of the invention are prepared by modifying functional groups in the compounds, which modifications may be routinely made or removed in vivo to provide the parent compound. Prodrugs include compounds of the present invention wherein a hydroxy or amino group is attached to any group that, when the prodrug is administered to a mammalian subject, cleaves to form a free hydroxy or a free amino group, respectively.
The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compound may be labeled with a radioisotope, such as tritium (A) 3 H) Iodine-125 ( 125 I) Or C-14 ( 14 C) .1. The All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.
The term "adjuvant" refers to a pharmaceutically acceptable inert ingredient. Examples of classes of the term "excipient" include, without limitation, binders, disintegrants, lubricants, glidants, stabilizers, fillers, diluents, and the like.
The term "C 1 -C 6 Alkyl "is understood to mean a straight-chain or branched saturated monovalent hydrocarbon radical having 1,2, 3,4, 5 or 6 carbon atoms, a branched saturated monovalent hydrocarbon radical having 3 to 6 carbon atoms. The alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, or the like or isomers thereof. In particular, the radicals have 1,2 or 3 carbon atoms ("C) 1 -C 3 Alkyl radicals), such as the methyl, ethyl, n-propyl or isopropyl radical. One skilled in the art will recognize that the term "alkyl" may include "alkylene" groups.
The term "alkylene" is understood to mean a straight-chain saturated divalent hydrocarbon radical having from 1 to 6 carbon atoms or a branched-chain saturated divalent hydrocarbon radical having from 3 to 6 carbon atoms, such as methylene, ethylene, propylene, 1-methylpropylene, butylene, and the like, unless otherwise specified.
The term "C 2 -C 6 Alkenyl "is understood to mean a straight-chain monovalent hydrocarbon radical having 2,3, 4,5 or 6 carbon atoms or a branched monovalent hydrocarbon radical having 3 to 6 carbon atoms with a double bond of propenyl, butenyl and the like, containing one or more carbon-carbon double bonds.
The term "C 2 -C 6 Alkynyl "is understood to mean a straight-chain, branched or cyclic hydrocarbon radical containing from 2 to 6 carbon atoms and at least one carbon-carbon triple bond, such as ethynyl, propynyl, butynyl, 3-methylbutynyl and the like.
The term "C 3 -C 6 Cycloalkyl "is understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3 to 6 carbon atoms, including fused or bridged polycyclic ring systems. Such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
The term "C 1 -C 6 Alkoxy "is to be understood as meaning-O- (C) 1-6 Alkyl) in which "C" is 1-6 Alkyl "has the above definition.
The term "halo" or "halogen" refers to fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.
The term "haloalkyl" is meant to include both branched and straight chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms substituted with one or more halogens (e.g., -CvFw, where v =1 to 3, w =1 to (2v + 1)). Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl.
The term "C 6 -C 10 Aryl "means a monovalent monocyclic or bicyclic aromatic hydrocarbon radical of 6 to 10 ring atoms, such as phenyl or naphthyl.
The term "5-to 10-membered heteroaryl" refers to a monovalent monocyclic or bicyclic aromatic group having 5 to 10 ring atoms, comprising one or two aromatic rings, wherein one or more (in certain embodiments 1,2, 3, or 4) ring atoms are heteroatoms independently selected from O, S and N, the remainder being carbon atoms.
In the case of bicyclic rings, the term "bicyclic ring" or "fused" refers to two rings joined together via a bond between two atoms (e.g., naphthalene), joined together via a series of atoms to form a bridge (e.g., quinuclidine) or joined together via a single atom to form a spiro compound (e.g., 1,4-dioxa-8-aza-spiro [4.5] decane and N,3,3-dimethyl-1,5-dioxaspiro [5.5] undecan-9-yl).
The term "3 to 6 membered heterocycloalkyl" refers to a saturated monocyclic group of 3 to 6 ring atoms, wherein 1,2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, the remainder being carbon atoms; in addition, one or two ring carbon atoms in the heterocyclyl ring may be optionally substituted with a-CO-group.
"oxo", as used herein alone or in combination, means = O.
Figure BDA0003571090790000231
Represents a five-membered heteroaromatic ring containing 2N atoms, wherein
Figure BDA0003571090790000232
Representing delocalized large pi bonds.
The term "patient" refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or primates, most preferably humans.
The term "therapeutically effective amount" means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response that is being sought by a researcher, veterinarian, medical doctor or other clinician in a tissue, system, animal, individual, or human, which includes one or more of the following: (1) prevention of diseases: for example, preventing a disease, disorder or condition in an individual who is susceptible to the disease, disorder or condition but has not experienced or developed disease pathology or symptomatology. (2) inhibition of disease: for example, inhibiting the disease, disorder or condition (i.e., arresting the further development of the pathology and/or condition) in an individual who is experiencing or presenting the pathology or condition of the disease, disorder or condition. (3) relieving the diseases: such as relieving the disease, disorder or condition (i.e., reversing the pathology and/or symptomatology) in an individual who is experiencing or developing the pathology or symptomatology of the disease, disorder or condition.
Detailed Description
The technical solution of the present invention will be further described in detail with reference to specific embodiments. It is to be understood that the following examples are only illustrative and explanatory of the present invention and should not be construed as limiting the scope of the present invention. All the technologies realized based on the above-mentioned contents of the present invention are covered in the protection scope of the present invention.
Unless otherwise indicated, the raw materials and reagents used in the following examples are all commercially available products or can be prepared by known methods.
Unless otherwise specified, the compounds of the invention are identified by Nuclear Magnetic Resonance (NMR) and/or Mass Spectrometry (MS). NMR shift in units of 10 -6 (ppm). Solvents for NMR measurement are deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol and the like, and internal standard is Tetramethylsilane (TMS).
The abbreviations of the present invention are defined as follows:
reagent:
DIPEA: also can be written as DIEA, diisopropylethylamine, i.e., N-diisopropylethylamine
THF: tetrahydrofuran (THF)
DMSO, DMSO: dimethyl sulfoxide
NCS: n-chlorosuccinimide, i.e. chlorosuccinimide
NBS: n-bromosuccinimide
Pd(dppf)Cl 2 : [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride
EA: acetic acid ethyl ester
EtOH: ethanol
AcOH: acetic acid
MeOH: methanol
Symbol or unit:
EC 80 : concentration for 80% of maximum effect
IC 50 : the median inhibitory concentration is the concentration at which half of the maximum inhibitory effect is achieved
M: mol/L, molar concentration, e.g. 1M hydrochloric acid for 1mol/L hydrochloric acid solution
N: equivalent concentration, e.g. 2N hydrochloric acid means 2mol/L hydrochloric acid solution
RT: retention time
The test method comprises the following steps:
LC-MS: liquid chromatography-mass spectrometry
SFC: supercritical fluid chromatography
TLC: thin layer chromatography
Unless indicated to the contrary, the compounds exemplified herein are named and numbered using ChemBioDraw Ultra 13.0.
Example 1: preparation of Compound I-1
2- (cyclopropylamino) -8- (4- (difluoromethoxy) phenyl) -6- (2-methyl-2H-indazol-5-yl) pteridin-7 (8H) -one (Compound I-1)
Figure BDA0003571090790000251
The synthetic route for compound I-1 is shown below:
Figure BDA0003571090790000261
the first step is as follows: synthesis of 2-chloro-N- (4- (difluoromethoxy) phenyl) -5-nitropyrimidin-4-amine (I-1B)
Figure BDA0003571090790000262
2,4-dichloro-5-nitropyrimidine (5.00g, 25.8mmol) and 4- (difluoromethoxy) aniline (4.51g, 28.3mmol) were dissolved in tetrahydrofuran (40 mL), cooled to-40 ℃ and N, N-diisopropylethylamine (6.66g, 51.5mmol) was added slowly and reacted at-40 ℃ for 2 hours. After the reaction was completed, water (80 mL) was added and quenched, warmed to room temperature, extracted with ethyl acetate (160 mL), then washed with saturated brine (160 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and concentrated to give 2-chloro-N- (4- (difluoromethoxy) phenyl) -5-nitropyrimidin-4-amine (I-1B) (7.8 g, 88.4% yield) as a yellow solid.
LC-MS,M/Z(ESI):317.0(M+H) +
The second step is that: n is a radical of 2 -cyclopropyl-N 4 Synthesis of- (4- (difluoromethoxy) phenyl) -5-nitropyrimidine-2,4-diamine (I-1C)
Figure BDA0003571090790000271
2-chloro-N- (4- (difluoromethoxy) phenyl) -5-nitropyrimidin-4-amine (4.00g, 12.6 mmol), cyclopropylamine (865.4mg, 15.2mmol), N, N-diisopropylethylamine (4.08g, 31.6 mmol) and cesium fluoride (1.92g, 12.63mmol) were added to dimethyl sulfoxide (15 mL), nitrogen was replaced, and the mixture was heated to 80 ℃ and stirred for 3 hours. Cooling the reaction solution to room temperature, pouring the reaction solution into water (50 mL), filtering, collecting solid, and drying to obtain yellow solid N 2 -cyclopropyl-N 4 - (4- (difluoromethoxy) phenyl) -5-nitropyrimidine-2,4-diamine (I-1C) (4.00 g, 65.7% yield).
LC-MS,M/Z(ESI):338.0(M+H) +
The third step: n is a radical of hydrogen 2 -cyclopropyl-N 4 Synthesis of- (4- (difluoromethoxy) phenyl) pyrimidine-2,4,5-triamine (I-1D)
Figure BDA0003571090790000272
N is made of 2 -cyclopropyl-N 4 - (4- (difluoromethoxy) phenyl) -5-nitropyrimidine-2,4-diamine (3.50g, 7.26mmol) and palladium on carbon (0.35 g,10% in content) were added to methanol (30 mL), the hydrogen was replaced, and the reaction was stirred at 30 ℃ under 50psi for 3 hours. The reaction solution was cooled to room temperature and filteredConcentrating the filtrate to obtain a red solid N 2 -cyclopropyl-N 4 - (4- (difluoromethoxy) phenyl) pyrimidine-2,4,5-triamine (I-1D) (2.1 g, 94.0% yield).
LC-MS,M/Z(ESI):308.1(M+H) +
The fourth step: synthesis of 2- (cyclopropylamino) -8- (4- (difluoromethoxy) phenyl) pteridin-7 (8H) -one (I-1E)
Figure BDA0003571090790000273
Handle N 2 -cyclopropyl-N 4 - (4- (difluoromethoxy) phenyl) pyrimidine-2,4,5-triamine (1.00g, 3.25mmol), ethyl glyoxylate (431.8mg, 4.23mmol) and acetic acid (195.4mg, 3.25mmol) were added to ethanol (20 mL), the nitrogen gas was replaced, and the mixture was heated to 80 ℃ for reaction for 3 hours. The reaction mixture was cooled to room temperature, water (30 mL) was added, extraction was performed with ethyl acetate (90 mL. Times.3), and the organic phases were combined, washed with saturated brine (90 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column (petroleum ether: ethyl acetate (V/V) = 100-1:1) to give 2- (cyclopropylamino) -8- (4- (difluoromethoxy) phenyl) pteridin-7 (8H) -one (I-1E) (520 mg, yield 46.2%) as a red solid.
LC-MS,M/Z(ESI):346.1(M+H) +
The fifth step: synthesis of 6-chloro-2- (cyclopropylamino) -8- (4- (difluoromethoxy) phenyl) pteridin-7 (8H) -one (I-1F)
Figure BDA0003571090790000281
2- (cyclopropylamino) -8- (4- (difluoromethoxy) phenyl) pteridin-7 (8H) -one (400mg, 1.16mmol) and chlorosuccinimide (232.0 mg, 1.74mmol) were added to N, N-dimethylformamide (10 mL), nitrogen was replaced, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was extracted with water (30 mL) and ethyl acetate (90 mL. Times.3), and the organic phases were combined and washed with saturated brine (90 mL. Times.2). The residue was purified by silica gel column (petroleum ether: ethyl acetate (V/V): 100-3:1) to give 6-chloro-2- (cyclopropylamino) -8- (4- (difluoromethoxy) phenyl) pteridin-7 (8H) -one (I-1F) (400 mg, 90.9% yield) as a yellow solid.
LC-MS,M/Z(ESI):380.1(M+H) +
And a sixth step: 2- (cyclopropylamino) -8- (4- (difluoromethoxy) phenyl) -6- (2-methyl-2H-indazol-5-yl) pteridin-7 (8H) -one (title compound I-1)
Figure BDA0003571090790000282
6-chloro-2- (cyclopropylamino) -8- (4- (difluoromethoxy) phenyl) pteridin-7 (8H) -one (380mg, 1.00mmol), 2-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl) -2H-indazole (387.4mg, 1.50mmol), 1,1' -bis (diphenylphosphino) ferrocene palladium chloride (73.2mg, 100.0. Mu. Mol) and potassium carbonate (414.8mg, 3.00mmol) were dissolved in 1,4-dioxane (10 mL) and water (1 mL) under nitrogen, replaced with nitrogen, and warmed to 90 ℃ for 2 hours. The reaction mixture was cooled to room temperature, and the mixture was added dropwise to water (30 mL) and extracted with ethyl acetate (90 mL). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The solid was then slurried with methanol (20 mL) at 60 ℃ and filtered hot to give the compound 2- (cyclopropylamino) -8- (4- (difluoromethoxy) phenyl) -6- (2-methyl-2H-indazol-5-yl) pteridin-7 (8H) -one (176 mg, 36.2% yield) as a yellow solid.
LC-MS,M/Z(ESI):476.2[M+H] +
1 H NMR(400MHz,DMSO-d 6 ):δ8.80-8.82(m,2H),8.49(s,1H),8.09(d,1H),7.65(d,1H),7.17-7.57(m,6H),4.19(s,3H),2.45-2.47(m,1H),0.51-0.65(m,1H),0.42-0.49(m,3H).
Example 2: preparation of target Compound I-2
The synthetic route is as follows:
Figure BDA0003571090790000291
the first step is as follows: synthesis of 2-cyclopropoxy-N- (4- (difluoromethoxy) phenyl) -5-nitropyrimidin-4-amine
To a solution of 2-chloro-N- (4- (difluoromethoxy) phenyl) -5-nitropyrimidin-4-amine (1.00g, 3.16mmol) in dimethyl sulfoxide (10.0 mL) under nitrogen were added, under nitrogen, cyclopropanol (500mg, 8.61mmol) and N, N-diisopropylethylamine (1.04g, 8.04mmol) and cesium fluoride (480mg, 3.16mmol), and the reaction was stirred at 50 ℃ for 10 hours. After completion of the reaction, the reaction mixture was diluted with water (50.0 mL), then extracted with ethyl acetate (30.0 mL × 3), the organic layers were combined, washed with water (30.0 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified with a silica gel column (petroleum ether: ethyl acetate (V/V) =30 to 10) to obtain the compound 2-cyclopropoxy-N- (4- (difluoromethoxy) phenyl) -5-nitropyrimidin-4-amine (550mg, 1.63mmol, yellow solid, yield 51.5%).
LC-MS,M/Z(ESI):339.0(M+H) + 。
1 H NMR(400MHz,CDCl 3 )δ10.31(s,1H),9.25(s,1H),7.69-7.76(m,2H),7.15-7.22(m,2H),6.29-6.78(m,1H),4.29-4.34(m,1H),0.88-0.96(m,2H),0.81-0.88(m,2H)。
The second step is that: 2-Cyclopropoxy-N 4 Synthesis of- (4- (difluoromethoxy) phenyl) pyrimidine-4,5-diamine
To a solution of 2-cyclopropoxy-N- (4- (difluoromethoxy) phenyl) -5-nitropyrimidin-4-amine (550mg, 1.63mmol) in methanol (10.0 mL) was added platinum vanadium carbon (500mg, 192. Mu. Mol, content 10%) under nitrogen, and the reaction was replaced 3 times with hydrogen, and the reaction was stirred at 15 ℃ for 5 hours under a hydrogen pressure of 15 psi. After completion of the reaction, the reaction mixture was filtered, washed with methanol (30.0 mL. Multidot.2), and concentrated to give 2-cyclopropoxy-N 4 - (4- (difluoromethoxy) phenyl) pyrimidine-4,5-diamine (520 mg yellow solid). Was used directly in the next step.
The third step: synthesis of 2-cyclopropoxy-8- (4- (difluoromethoxy) phenyl) pteridin-7 (8H) -one
Under the protection of nitrogen, to 2-cyclopropoxy-N 4 To a solution of- (4- (difluoromethoxy) phenyl) pyrimidine-4,5-diamine (500mg, 1.62mmol) in ethanol (5.00 mL) were added a toluene solution of ethyl glyoxylate (431mg, 2.11mmol, 50.0% concentration) and glacial acetic acid (97.4 mg, 1.62mmol), and the reaction was stirred at 80 ℃ for 10 hours. After the reaction is completed, the reaction is carried outThe reaction mixture was diluted with water (20.0 mL), then extracted with ethyl acetate (20.0 mL × 3), the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give the compound 2-cyclopropoxy-8- (4- (difluoromethoxy) phenyl) pteridin-7 (8H) -one (500mg, 1.44mmol, yellow solid, yield 89.0%).
LC-MS,M/Z(ESI):347.1(M+H) +
The fourth step: synthesis of 6-chloro-2-cyclopropoxy-8- (4- (difluoromethoxy) phenyl) pteridin-7 (8H) -one
To a solution of 2-cyclopropoxy-8- (4- (difluoromethoxy) phenyl) pteridin-7 (8H) -one (300mg, 866. Mu. Mol) in N, N-dimethylformamide (1.00 mL) was added N-chlorosuccinimide (174mg, 1.30mmol) and the reaction was stirred at 25 ℃ for 10H. After completion of the reaction, the reaction mixture was diluted with water (10.0 mL), followed by extraction with ethyl acetate (10.0 mL × 3), and the organic layers were combined, washed with water (10.0 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to give the compound 6-chloro-2-cyclopropoxy-8- (4- (difluoromethoxy) phenyl) pteridin-7 (8H) -one (280 mg yellow solid). Used directly in the next step.
LC-MS,M/Z(ESI):381.2(M+H) +
The fifth step: synthesis of 2-cyclopropoxy-8- (4- (difluoromethoxy) phenyl) -6- (2-methyl-2H-indazol-5-yl) pteridin-7 (8H) -one (I-2)
Figure BDA0003571090790000311
To a solution of 6-chloro-2-cyclopropoxy-8- (4- (difluoromethoxy) phenyl) pteridin-7 (8H) -one (180mg, 473. Mu. Mol) in 1,4-dioxane (1.00 mL) and water (200. Mu.L) was added 2-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2H-indazole (183mg, 709. Mu. Mol), potassium carbonate (196mg, 1.42mmol) and 1,1-bis (diphenylphosphino) ferrocene palladium dichloride (34.6 mg, 47.3. Mu. Mol) under nitrogen, and the reaction was stirred at 75 ℃ for 3 hours. After the reaction was completed, the reaction mixture was diluted with water (10.0 mL), then extracted with ethyl acetate (10.0 mL × 3), the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the residue was separated and purified with a silica gel column (petroleum ether: ethyl acetate (V/V) =5:1 to 1:3), then slurried with methanol (5.00 mL) to give the compound 2-cyclopropoxy-8- (4- (difluoromethoxy) phenyl) -6- (2-methyl-2H-indazol-5-yl) pteridin-7 (8H) -one (I-2) (147mg, 296 μmol, yellow solid, yield 62.6%).
LC-MS,M/Z(ESI):477.0(M+H) +
1 H NMR(400MHz,DMSO_d 6 )δ9.11(s,1H),8.89(s,1H),8.53(s,1H),8.11(dd,1H),7.68(d,1H),7.19-7.56(m,5H),4.15-4.25(m,4H),0.69(d,4H).
Example 3: preparation of Compound I-3
The synthetic route is as follows:
Figure BDA0003571090790000312
the first step is as follows: synthesis of N- (4- (difluoromethoxy) phenyl) -5-nitro-2- (2,2,2-trifluoroethoxy) pyrimidin-4-amine
To a solution of 2-chloro-N- (4- (difluoromethoxy) phenyl) -5-nitropyrimidin-4-amine (1.20g, 3.79mmol) in dimethyl sulfoxide (10.0 mL) under nitrogen protection were added 2,2,2-trifluoroethanol (1.14g, 11.4mmol) and N, N-diisopropylethylamine (980mg, 7.58mmol) and cesium fluoride (576mg, 3.79mmol), and the reaction was stirred at 20 ℃ for 5 hours. After completion of the reaction, the reaction mixture was diluted with water (50.0 mL), followed by extraction with ethyl acetate (30.0 mL × 3), the organic layers were combined, washed with water (30.0 mL × 3), dried over anhydrous sodium sulfate, filtered, and the residue was separated and purified with a silica gel column (petroleum ether: ethyl acetate (V/V) = 30.
LC-MS,M/Z(ESI):381.1(M+H) +
1 H NMR(400MHz,CDCl 3 )δ10.24(s,1H),9.26(s,1H),7.53-7.61(m,2H),7.19-7.25(m,2H),6.35-6.77(m,1H),4.77(q,2H).
The second step is that: n is a radical of 4 Synthesis of- (4- (difluoromethoxy) phenyl) -2- (2,2,2-trifluoroethoxy) pyrimidine-4,5-diamine
Under the protection of nitrogen, toTo a solution of N- (4- (difluoromethoxy) phenyl) -5-nitro-2- (2,2,2-trifluoroethoxy) pyrimidin-4-amine (900mg, 2.37mmol) in methanol (20.0 mL) was added platinum vanadium carbon (501mg, 192. Mu. Mol, content 10%), followed by replacing the reaction system with hydrogen 3 times, and the reaction was stirred under a hydrogen pressure of 15psi at 15 ℃ for 5 hours. After completion of the reaction, the reaction solution was filtered, washed with methanol (30.0 mL. Multidot.2), and concentrated to give N 4 - (4- (difluoromethoxy) phenyl) -2- (2,2,2-trifluoroethoxy) pyrimidine-4,5-diamine (920 mg yellow solid). Used directly in the next step.
The third step: synthesis of 8- (4- (difluoromethoxy) phenyl) -2- (2,2,2-trifluoroethoxy) pteridin-7 (8H) -one
Under the protection of nitrogen, to N 4 To a solution of- (4- (difluoromethoxy) phenyl) -2- (2,2,2-trifluoroethoxy) pyrimidine-4,5-diamine (500mg, 1.43mmol) in ethanol (5.00 mL) were added a solution of ethyl glyoxylate in toluene (379mg, 1.86mmol,50.0% strength) and glacial acetic acid (85.7mg, 1.43mmol), and the reaction was stirred at 90 ℃ for 10 hours. After completion of the reaction, the reaction mixture was diluted with water (30.0 mL), followed by extraction with ethyl acetate (30.0 mL × 3), and the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give the compound 8- (4- (difluoromethoxy) phenyl) -2- (2,2,2-trifluoroethoxy) pteridin-7 (8H) -one (550 mg yellow solid). Used directly in the next step.
LC-MS,M/Z(ESI):389.1(M+H) +
The fourth step: synthesis of 6-chloro-8- (4- (difluoromethoxy) phenyl) -2- (2,2,2-trifluoroethoxy) pteridin-7 (8H) -one
To a solution of 8- (4- (difluoromethoxy) phenyl) -2- (2,2,2-trifluoroethoxy) pteridin-7 (8H) -one (250mg, 644. Mu. Mol) in N, N-dimethylformamide (2.00 mL) was added N-chlorosuccinimide (112mg, 837. Mu. Mol), and the reaction was stirred at 25 ℃ for 10 hours. After completion of the reaction, the reaction mixture was diluted with water (20.0 mL), followed by extraction with ethyl acetate (20.0 mL _ 3), the organic layers were combined, washed with water (20.0 mL _ 3), dried over anhydrous sodium sulfate, filtered, and the residue was separated and purified with a silica gel plate (petroleum ether: ethyl acetate (V/V) = 1:3) to give a compound
6-chloro-8- (4- (difluoromethoxy) phenyl) -2- (2,2,2-trifluoroethoxy) pteridin-7 (8H) -one (260 mg yellow oil). Was used directly in the next step.
LC-MS,M/Z(ESI):422.9(M+H) +
The fifth step: synthesis of 8- (4- (difluoromethoxy) phenyl) -6- (2-methyl-2H-indazol-5-yl) -2- (2,2,2-trifluoroethoxy) pteridin-7 (8H) -one (I-3)
Figure BDA0003571090790000331
To a solution of 6-chloro-8- (4- (difluoromethoxy) phenyl) -2- (2,2,2-trifluoroethoxy) pteridin-7 (8H) -one (220mg, 520. Mu. Mol) in 1,4-dioxane (3.00 mL) and water (500. Mu.L) was added 2-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2H-indazole (202mg, 781. Mu. Mol), potassium carbonate (216mg, 1.56mmol) and 1,1-bis (diphenylphosphino) ferrocene palladium dichloride (19.0mg, 26.0. Mu. Mol) under nitrogen, and the reaction was stirred at 70 ℃ for 3 hours. After completion of the reaction, the reaction mixture was diluted with water (10.0 mL), followed by extraction with ethyl acetate (15.0 mL × 3), the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the residue was separated and purified by a silica gel column (petroleum ether: ethyl acetate (V/V) =5:1 to 1:3), followed by beating with methanol (5.00 mL) to give the compound 8- (4- (difluoromethoxy) phenyl) -6- (2-methyl-2H-indazol-5-yl) -2- (2,2,2-trifluoroethoxy) pteridin-7 (8H) -one (I-3) (10.9mg, 20.2 μmol, yellow solid, yield 3.89%).
LC-MS,M/Z(ESI):519.1(M+H) +
1 H NMR(400MHz,DMSO_d 6 )δ9.15(s,1H),8.91(s,1H),8.55(s,1H),8.11(dd,1H),7.69(d,1H),7.53(d,2H),7.20-7.44(m,3H),4.97(q,2H)4.19(s,3H).
Example 4: preparation of Compound I-4
The synthetic route is shown as follows:
Figure BDA0003571090790000341
the first step is as follows: synthesis of 2-chloro-N- (4- (difluoromethoxy) phenyl) -5-nitropyrimidin-4-amine
2,4-dichloro-5-nitropyrimidine (5.00g, 25.8mmol) and 4- (difluoromethoxy) aniline (4.51g, 28.3mmol) were dissolved in tetrahydrofuran (30 mL), cooled to-40 deg.C, N-diisopropylethylamine (6.66g, 51.5 mmol) was added slowly, and the reaction was continued at-40 deg.C for 2 hours. After the reaction was completed, water (80 mL) was added to quench, and the mixture was warmed to room temperature, extracted with ethyl acetate (160 mL), then washed with saturated brine (160ml × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to give 2-chloro-N- (4- (difluoromethoxy) phenyl) -5-nitropyrimidin-4-amine (8.00 g, yellow solid, yield 98.0%).
LC-MS,M/Z(ESI):317.2(M+H) +
The second step is that: n is a radical of 4 - (4- (difluoromethoxy) phenyl) -5-nitro-N 2 Synthesis of- (2,2,2-trifluoroethyl) pyrimidine-2,4-diamine 2-chloro-N- (4- (difluoromethoxy) phenyl) -5-nitropyrimidin-4-amine (1.00g, 3.16mmol), 2,2,2-trifluoroethylamine (375.4mg, 3.79mmol), N, N-diisopropylethylamine (1.02g, 7.90mmol) and cesium fluoride (479.7mg, 3.169mmol) were added to dimethyl sulfoxide (5 mL), replaced with nitrogen, heated to 80 ℃ and the reaction stirred for 3 hours. Cooling the reaction solution to room temperature, pouring the reaction solution into water (50 mL), filtering, collecting the solid, and drying to obtain N 4 - (4- (difluoromethoxy) phenyl) -5-nitro-N 2 - (2,2,2-trifluoroethyl) pyrimidine-2,4-diamine (1.00 g, yellow solid, 83.5% yield).
LC-MS,M/Z(ESI):380.1(M+H) +
The third step: n is a radical of hydrogen 4 - (4- (difluoromethoxy) phenyl) -N 2 Synthesis of- (2,2,2-trifluoroethyl) pyrimidine-2,4,5-triamine
N is made of 4 - (4- (difluoromethoxy) phenyl) -5-nitro-N 2 - (2,2,2-trifluoroethyl) pyrimidine-2,4-diamine (1.00g, 2.64mmol) and palladium on carbon (0.10 g,10% by weight) were added to methanol (10 mL), the hydrogen was replaced, and the reaction was heated to 30 ℃ and stirred under a pressure of 50psi for 3 hours. Cooling the reaction solution to room temperature, filtering, and concentrating the filtrate to obtain N 4 - (4- (difluoromethoxy) phenyl) -N 2 - (2,2,2-trifluoroethyl) pyrimidine-2,4,5-triamine (800 mg, yellow solid, yield 86.9%).
LC-MS,M/Z(ESI):350.1(M+H) +
The fourth step: synthesis of 8- (4- (difluoromethoxy) phenyl) -2- ((2,2,2-trifluoroethyl) amino) pteridin-7 (8H) -one
N is made of 4 - (4- (difluoromethoxy) phenyl) -N 2 - (2,2,2-trifluoroethyl) pyrimidine-2,4,5-triamine (700mg, 2.00mmol), ethyl glyoxylate (613.8mg, 3.01mmol) and acetic acid (120.4mg, 2.00mmol) were added to ethanol (5 mL), nitrogen was replaced, and the mixture was heated to 80 ℃ for reaction for 3 hours. The reaction mixture was cooled to room temperature, water (20 mL) was added, and extraction was performed with ethyl acetate (20ml _ 3), and the organic phases were combined, washed with saturated brine (30ml _ 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column (petroleum ether: ethyl acetate (V/V) =100: 0-1:1) to give 8- (4- (difluoromethoxy) phenyl) -2- ((2,2,2-trifluoroethyl) amino) pteridin-7 (8H) -one (650 mg, red solid, 83.7% yield).
LC-MS,M/Z(ESI):388.1(M+H) +
The fifth step: synthesis of 6-chloro-8- (4- (difluoromethoxy) phenyl) -2- ((2,2,2-trifluoroethyl) amino) pteridin-7 (8H) -one
8- (4- (difluoromethoxy) phenyl) -2- ((2,2,2-trifluoroethyl) amino) pteridin-7 (8H) -one (600mg, 1.55mmol) and chlorosuccinimide (310.3mg, 2.32mmol) were added to N, N-dimethylformamide (5 mL), nitrogen was replaced, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was extracted with water (20 mL) and ethyl acetate (20mL. Multidot.3), and the organic phases were combined and washed with saturated brine (30mL. Multidot.2). Dried over anhydrous sodium sulfate, filtered, and concentrated to give 6-chloro-8- (4- (difluoromethoxy) phenyl) -2- ((2,2,2-trifluoroethyl) amino) pteridin-7 (8H) -one (480 mg, yellow solid, 73.5% yield).
LC-MS,M/Z(ESI):422.0(M+H) +
And a sixth step: 8- (4- (difluoromethoxy) phenyl) -6- (2-methyl-2H-indazol-5-yl) -2- ((2,2,2-trifluoroethyl) amino) pteridin-7 (8H) -one (Compound I-4)
Figure BDA0003571090790000351
6-chloro-8- (4- (difluoromethoxy) phenyl) -2- ((2,2,2-trifluoroethyl) amino) pteridin-7 (8H) -one (100mg, 237.1. Mu. Mol), 2-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2H-indazole (91.8mg, 355.7. Mu. Mol), 1,1-bis (diphenylphosphino) ferrocene palladium dichloride (17.4mg, 23.7. Mu. Mol) and potassium carbonate (98.3mg, 711.4. Mu. Mol) were dissolved in dioxane (1 mL) and water (0.2 mL) under nitrogen blanket, nitrogen was replaced, and the temperature was raised to 60 ℃ for 2 hours. The reaction mixture was cooled to room temperature, and the mixture was added dropwise to water (30 mL) and extracted with ethyl acetate (90 mL). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The solid was then slurried with ethyl acetate (20 mL) at 65 ℃, cooled and filtered to give compound 8- (4- (difluoromethoxy) phenyl) -6- (2-methyl-2H-indazol-5-yl) -2- ((2,2,2-trifluoroethyl) amino) pteridin-7 (8H) -one (compound I-4) (36.4 mg, yellow solid, 28.5% yield).
LC-MS,M/Z(ESI):518.1(M+H) +
1 H NMR(400MHz,DMSO-d 6 ):δ8.81-8.95(m,2H),8.51(s,1H),8.14-8.47(m,1H),8.09(dd,1H),7.66(d,1H),7.16-7.59(m,5H),4.19(s,4H),3.71-3.87(m,1H).
Example 5: preparation of Compound I-5
The synthetic route is as follows:
Figure BDA0003571090790000361
the first step is as follows: synthesis of 2-chloro-N- (4- (difluoromethoxy) phenyl) -5-nitropyrimidin-4-amine
2,4-dichloro-5-nitropyrimidine (5.00g, 25.8mmol) and 4- (difluoromethoxy) aniline (4.51g, 28.3mmol) were dissolved in tetrahydrofuran (40 mL), cooled to-40 ℃ and N, N-diisopropylethylamine (6.66g, 51.5mmol) was added slowly and reacted at-40 ℃ for 2 hours. After the reaction was completed, water (80 mL) was added to quench, and the mixture was warmed to room temperature, extracted with ethyl acetate (160 mL), then washed with saturated brine (160ml × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to give 2-chloro-N- (4- (difluoromethoxy) phenyl) -5-nitropyrimidin-4-amine (7.8 g, yellow solid, yield 88.4%).
LC-MS,M/Z(ESI):317.1(M+H) +
The second step is that: n is a radical of 2 - (cyclopropylmethyl) -N 4 Synthesis of- (4- (difluoromethoxy) phenyl) -5-nitropyrimidine-2,4-diamine
2-chloro-N- (4- (difluoromethoxy) phenyl) -5-nitropyrimidin-4-amine (1.00g, 3.16mmol), cyclopropylmethylamine (269.5mg, 297.9. Mu. Mol), N, N-diisopropylethylamine (1.02g, 7.90mmol) and cesium fluoride (497.7mg, 3.16mmol) were added to dimethyl sulfoxide (5 mL), the nitrogen gas was replaced, and the mixture was heated to 80 ℃ and stirred for reaction for 3 hours. Cooling the reaction solution to room temperature, pouring the reaction solution into water (50 mL), filtering, collecting the solid, and drying to obtain N 2 - (cyclopropylmethyl) -N 4 - (4- (difluoromethoxy) phenyl) -5-nitropyrimidine-2,4-diamine (1.00 g, yellow solid, 90.1% yield).
LC-MS,M/Z(ESI):352.1(M+H) +
The third step: n is a radical of hydrogen 2 - (cyclopropylmethyl) -N 4 Synthesis of- (4- (difluoromethoxy) phenyl) pyrimidine-2,4,5-triamine
N is made of 2 - (cyclopropylmethyl) -N 4 - (4- (difluoromethoxy) phenyl) -5-nitropyrimidine-2,4-diamine (1.00g, 2.85mmol) and palladium on carbon (0.10 g,10% content) were added to methanol (10 mL), the hydrogen was replaced, and the reaction was heated to 30 ℃ and stirred under 50psi pressure for 3 hours. Cooling the reaction solution to room temperature, filtering, and concentrating the filtrate to obtain N 2 - (cyclopropylmethyl) -N 4 - (4- (difluoromethoxy) phenyl) pyrimidine-2,4,5-triamine (700 mg, red solid, 76.5% yield).
LC-MS,M/Z(ESI):322.1(M+H) +
The fourth step: synthesis of 2- ((cyclopropylmethyl) amino) -8- (4- (difluoromethoxy) phenyl) pteridin-7 (8H) -one
Handle N 2 - (cyclopropylmethyl) -N 4 - (4- (difluoromethoxy) phenyl) pyrimidine-2,4,5-triamine (600mg, 1.87mmol), ethyl glyoxylate (571.9 mg, 2.80mmol) and acetic acid (112.1mg, 1.87mmol) were added to ethanol (5 mL), the nitrogen gas was replaced, and the mixture was heated to 80 ℃ for reaction for 3 hours. The reaction mixture was cooled to room temperature, water (20 mL) was added, and extraction was performed with ethyl acetate (20ml _ 3), and the organic phases were combined, washed with saturated brine (30ml _ 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by a silica gel column (petroleum ether: ethyl acetate (V/V) = 10)0:0-1:1) to give 2- ((cyclopropylmethyl) amino) -8- (4- (difluoromethoxy) phenyl) pteridin-7 (8H) -one (600 mg, red solid, 89.4% yield).
LC-MS,M/Z(ESI):360.1(M+H) +
The fifth step: synthesis of 6-chloro-2- ((cyclopropylmethyl) amino) -8- (4- (difluoromethoxy) phenyl) pteridin-7 (8H) -one
2- ((cyclopropylmethyl) amino) -8- (4- (difluoromethoxy) phenyl) pteridin-7 (8H) -one (550.0mg, 1.53mmol) and chlorosuccinimide (306.6mg, 2.30mmol) were added to N, N-dimethylformamide (5 mL), nitrogen was replaced, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was extracted with water (20 mL) and ethyl acetate (20mL. Multidot.3), and the organic phases were combined and washed with saturated brine (30mL. Multidot.2). Dried over anhydrous sodium sulfate, filtered, and concentrated to give 6-chloro-2- ((cyclopropylmethyl) amino) -8- (4- (difluoromethoxy) phenyl) pteridin-7 (8H) -one (460 mg, yellow solid, 76.3% yield).
LC-MS,M/Z(ESI):394.0(M+H) +
And a sixth step: 2- ((cyclopropylmethyl) amino) -8- (4- (difluoromethoxy) phenyl) -6- (2-methyl-2H-indazol-5-yl) pteridin-7 (8H) -one (Compound I-5)
Figure BDA0003571090790000381
6-chloro-2- ((cyclopropylmethyl) amino) -8- (4- (difluoromethoxy) phenyl) pteridin-7 (8H) -one (100mg, 253.9. Mu. Mol), 2-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2H-indazole (98.3mg, 380.9. Mu. Mol), 1,1-bis (diphenylphosphino) ferrocene dichloropalladium (18.6mg, 25.4. Mu. Mol) and potassium carbonate (105.3mg, 761.9. Mu. Mol) were dissolved in dioxane (1 mL) and water (0.2 mL) under nitrogen blanket, replaced with nitrogen, and allowed to warm to 60 ℃ for 2 hours. The reaction mixture was cooled to room temperature, and the mixture was added dropwise to water (30 mL) and extracted with ethyl acetate (90 mL). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The solid was then slurried with methanol (20 mL) at 60 ℃, cooled and filtered to give the compound 2- ((cyclopropylmethyl) amino) -8- (4- (difluoromethoxy) phenyl) -6- (2-methyl-2H-indazol-5-yl) pteridin-7 (8H) -one (74.6 mg, yellow solid, 94.3% yield).
LC-MS,M/Z(ESI):490.2(M+H) +
1 H NMR(400MHz,DMSO-d 6 ):δ8.81-8.90(m,2H),8.54(s,1H),8.14(d,1H),7.80-8.10(m,1H),7.70(d,1H),7.22-7.60(m,5H),4.24(s,3H),2.89(t,2H),0.82-1.19(m,1H),0.23-0.47(m,3H),0.00(s,1H).
Example 6: preparation of target Compound I-6
The synthetic route is as follows:
Figure BDA0003571090790000391
the first step is as follows: synthesis of 2-chloro-N- (4-chlorophenyl) -5-nitropyrimidine-4-amine
To a solution of 2,4-dichloro-5-nitropyrimidine (2.50g, 12.9mmol) in tetrahydrofuran (50.0 mL) at-40 deg.C were added 4-chloroaniline (1.69g, 13.3mmol) and N, N-diisopropylethylamine (3.33g, 25.8mmol) and the reaction stirred at-40 deg.C for 2 hours. After completion of the reaction, the reaction mixture was diluted with water (50.0 mL), followed by extraction with ethyl acetate (50.0 mL × 3), and the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give the compound 2-chloro-N- (4-chlorophenyl) -5-nitropyrimidin-4-amine (6.50g, 22.8mmol, yellow solid, yield 88.5%).
LC-MS,M/Z(ESI):285.2(M+H) +
1 H NMR(400MHz,DMSO_d 6 )δ10.48(s,1H),9.14-9.19(m,1H),7.54-7.60(m,2H),7.48-7.53(m,2H).
The second step is that: n is a radical of 4 - (4-chlorophenyl) -N 2 Synthesis of (E) -cyclopropyl-5-nitropyrimidine-2,4-diamine
To a solution of 2-chloro-N- (4-chlorophenyl) -5-nitropyrimidin-4-amine (2.50g, 8.77mmol) in dimethyl sulfoxide (30.0 mL) at room temperature were added cyclopropylamine (601mg, 10.5 mmol), N, N-diisopropylethylamine (2.83g, 21.9 mmol) and cesium fluoride (1.33g, 8.77mmol), followed by stirring at 80 ℃ for 3 hours. After completion of the reaction, the reaction mixture was diluted with water (150 mL) to precipitate a solid, and the reaction mixture was filtered to dry the solidDrying to obtain N 4 - (4-chlorophenyl) -N 2 -cyclopropyl-5-nitropyrimidine-2,4-diamine (2.80 g yellow solid). Used directly in the next step.
LC-MS,M/Z(ESI):306.1(M+H) +
The third step: n is a radical of 4 - (4-chlorophenyl) -N 2 Synthesis of (E) -cyclopropylpyrimidine-2,4,5-triamine
Under the protection of nitrogen, to N 4 - (4-chlorophenyl) -N 2 To a solution of-cyclopropyl-5-nitropyrimidine-2,4-diamine (1.50g, 4.91mmol) in methanol (20.0 mL) was added platinum vanadium carbon (500mg, 4.91mmol,10.0% purity) and the reaction was stirred under 15psi of hydrogen at 20 ℃ for 10 hours. After completion of the reaction, the reaction mixture was filtered, the filter cake was washed with methanol (30.0 ml _ 2), and the filtrate was concentrated under reduced pressure to give N 4 - (4-chlorophenyl) -N 2 Cyclopropyl pyrimidine-2,4,5-triamine (1.30g, 4.71mmol, yellow solid, 96.1% yield). Used directly in the next step.
LC-MS,M/Z(ESI):276.0(M+H) +
The fourth step: synthesis of 8- (4-chlorophenyl) -2- (cyclopropylamino) pteridin-7 (8H) -one
To N 4 - (4-chlorophenyl) -N 2 To a solution of (E) -cyclopropylpyrimidine-2,4,5-triamine (1.10g, 3.99mmol) in ethanol (5.00 mL) were added ethyl glyoxylate (1.06g, 5.19mmol) and glacial acetic acid (240mg, 3.99mmol), and the reaction was stirred at 80 ℃ for 5 hours under nitrogen. After completion of the reaction, the reaction mixture was diluted with water (30.0 mL), then extracted with ethyl acetate/tetrahydrofuran (1/1, 30.0mL × 4), the organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was slurried with methyl tert-butyl ether (15.0 mL) to give the compound 8- (4-chlorophenyl) -2- (cyclopropylamino) pteridin-7 (8H) -one (1.20 g yellow solid). Used directly in the next step.
LC-MS,M/Z(ESI):314.3(M+H) +
The fifth step: synthesis of 6-chloro-8- (4-chlorophenyl) -2- (cyclopropylamino) pteridin-7 (8H) -one
To a solution of 8- (4-chlorophenyl) -2- (cyclopropylamino) pteridin-7 (8H) -one (600mg, 1.91mmol) in N, N-dimethylformamide (5.00 mL) was added N-chlorosuccinimide (380mg, 2.85mmol) under nitrogen, followed by stirring at 25 ℃ for 2 hours. The reaction mixture was diluted with water (30.0 mL) and a solid precipitated, the reaction was filtered and the solid dried to give the compound 6-chloro-8- (4-chlorophenyl) -2- (cyclopropylamino) pteridin-7 (8H) -one (450mg, 1.29mmol, 67.6% yield) as a yellow solid.
LC-MS,M/Z(ESI):348.0(M+H) +
And a sixth step: synthesis of 8- (4-chlorophenyl) -2- (cyclopropylamino) -6- (2-methyl-2H-indazol-5-yl) pteridin-7 (8H) -one (I-6)
Figure BDA0003571090790000401
To a solution of 6-chloro-8- (4-chlorophenyl) -2- (cyclopropylamino) pteridin-7 (8H) -one (200mg, 574. Mu. Mol) in 1,4-dioxane (5.00 mL) and water (1.00 mL) under nitrogen was added 2-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2H-indazole (222mg, 862. Mu. Mol), 1,1-bis (diphenylphosphino) ferrocene dichloropalladium (21.0mg, 28.7. Mu. Mol) and potassium carbonate (238mg, 1.72mmol), and the reaction was stirred at 80 ℃ for 2 hours. After completion of the reaction, the reaction mixture was diluted with water (20.0 mL), a solid precipitated, the reaction solution was filtered, the solid was dried, and the residue was slurried with methanol (10.0 mL), followed by separation and purification by high performance liquid chromatography (column: phenomenex luna C18 250 x 50mm 10um; solvent: a = water +0.225 vol% formic acid (99.0%), B = acetonitrile; gradient: 38% -68%,19 minutes) to give 8- (4-chlorophenyl) -2- (cyclopropylamino) -6- (2-methyl-2H-indazol-5-yl) pteridin-7 (8H) -one (I-6) (36.8mg, 81.9 μmol, yellow solid, yield 14.3%).
LC-MS,M/Z(ESI):444.0(M+H) +
1 H NMR(400MHz,DMSO_d6)δ8.70-8.95(m,2H),8.49(s,1H),8.05-8.11(m,1H),7.57-7.86(m,4H),7.43-7.55(m,2H),4.18(s,3H),2.73-2.96(m,1H),0.38-0.68(m,4H).
Example 7: preparation of Compound I-7
The synthetic route is as follows:
Figure BDA0003571090790000411
Figure BDA0003571090790000421
the first step is as follows: synthesis of 2- (difluoromethoxy) -5-nitropyridine (1 a-2)
Figure BDA0003571090790000422
To a solution of 5-nitropyridine-2-phenol (1 a-1) (3.50g, 25.0mmol) in acetonitrile (30.0 mL) at 0 ℃ were added sodium carbonate (5.30g, 50.0mmol) and 2,2-difluoro-2- (fluorosulfonyl) acetic acid (6.67g, 37.5mmol), and the reaction was stirred at 30 ℃ for 10 hours. After completion of the reaction, the reaction mixture was diluted with saturated aqueous sodium bicarbonate (150 mL), followed by extraction with ethyl acetate (100ml × 3), the organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified with a silica gel column (petroleum ether: ethyl acetate (V/V) =1:0 to 50) to give 2- (difluoromethoxy) -5-nitropyridine (1 a-2) (3.10g, 16.3mmol, yellow oil, yield 32.6%).
1 H NMR(400MHz,DMSO_d 6 )δ9.15(d,1H),8.69(dd,1H),7.61-8.03(m,1H),7.35(d,1H).
The second step is that: synthesis of 6- (difluoromethoxy) pyridin-3-amine (1 a)
Figure BDA0003571090790000431
To a solution of 2- (difluoromethoxy) -5-nitropyridine (1 a-2) (2.00g, 10.5 mmol) in methanol (20.0 mL) under nitrogen was added platinum vanadium carbon (500mg, 10% purity) and the reaction was stirred at 30 ℃ for 10 hours under a pressure of 15psi of hydrogen. After completion of the reaction, the reaction mixture was filtered, the filter cake was washed with methanol (50.0 ml × 2), and the filtrate was concentrated under reduced pressure to give 6- (difluoromethoxy) pyridin-3-amine (1 a) (1.65g, 10.3mmol, brown oil, yield 97.9%). Used directly in the next step.
LC-MS,M/Z(ESI):161.0(M+H) +
Figure BDA0003571090790000432
The third step: synthesis of 2-chloro-N- (6- (difluoromethoxy) pyridin-3-yl) -5-nitropyrimidin-4-amine
Figure BDA0003571090790000433
To a solution of 2,4-dichloro-5-nitropyrimidine (2.70g, 13.9 mmol) in tetrahydrofuran (30.0 mL) at-40 deg.C were added 6- (difluoromethoxy) pyridin-3-amine (2.23g, 13.9 mmol) and N, N-diisopropylethylamine (3.60g, 27.8mmol), and the reaction was stirred at-40 deg.C for 2 hours. After the reaction was completed, the reaction mixture was diluted with water (50.0 mL), then extracted with ethyl acetate (50.0 mL × 3), and the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 2-chloro-N- (6- (difluoromethoxy) pyridin-3-yl) -5-nitropyrimidin-4-amine (4.80 g, crude brown solid). Used directly in the next step.
LC-MS,M/Z(ESI):318.0(M+H) +
1 H NMR(400MHz,DMSO_d 6 )δ10.58(s,1H),9.15-9.23(m,1H),8.38(d,1H),8.04(dd,1H),7.49-7.95(m,1H),7.20(d,1H).
The fourth step: n is a radical of 2 -cyclopropyl-N 4 Synthesis of- (6- (difluoromethoxy) pyridin-3-yl) -5-nitropyrimidine-2,4-diamine
Cyclopropylamine (539mg, 9.44mmol), N, N-diisopropylethylamine (2.54g, 19.7 mmol) and cesium fluoride (1.20g, 7.87mmol) were added to a solution of 2-chloro-N- (6- (difluoromethoxy) pyridin-3-yl) -5-nitropyrimidin-4-amine (2.50g, 7.87mmol) in dimethyl sulfoxide (20.0 mL) under nitrogen protection, followed by stirring at 80 ℃ for 5 hours. After completion of the reaction, the reaction mixture was diluted with water (150 mL) to precipitate a solid, the reaction solution was filtered, the solid was dried, and then slurried with methyl t-butyl ether (30.0 mL) to obtain N 2 -cyclopropyl-N 4 - (6- (difluoromethoxy) pyridin-3-yl) -5-Nitropyrimidine-2,4-diamine (2.30g, 6.80mmol, yellow solid, 86.4% yield).
LC-MS,M/Z(ESI):339.3(M+H) +
1 H NMR(400MHz,DMSO_d 6 )δ10.37(s,1H),8.96(s,1H),8.70(d,1H),8.64(d,1H),8.42(dd,1H),7.47-7.91(m,1H),7.08-7.17(m,1H),2.66(td,1H),0.67-0.76(m,2H),0.48-0.61(m,2H).
The fifth step: n is a radical of 2 -cyclopropyl-N 4 Synthesis of (6- (difluoromethoxy) pyridin-3-yl) pyrimidine-2,4,5-triamine
Under the protection of nitrogen, to N 2 -cyclopropyl-N 4 - (6- (Difluoromethoxy) pyridin-3-yl) -5-nitropyrimidine-2,4-diamine (2.30g, 6.80mmol) in methanol (20.0 mL) platinum vanadium carbon (500mg, 10% purity) was added and the reaction was stirred under a pressure of hydrogen of 15psi at 20 ℃ for 10 hours. After completion of the reaction, the reaction mixture was filtered, the filter cake was washed with methanol (30.0 ml _ 2), and the filtrate was concentrated under reduced pressure to give N 2 -cyclopropyl-N 4 - (6- (difluoromethoxy) pyridin-3-yl) pyrimidine-2,4,5-triamine (1.90g, 6.16mmol, yellow solid, 90.6% yield). Used directly in the next step.
LC-MS,M/Z(ESI):309.1(M+H) +
And a sixth step: synthesis of 2- (cyclopropylamino) -8- (6- (difluoromethoxy) pyridin-3-yl) pteridin-7 (8H) -one
To N 2 -cyclopropyl-N 4 Ethyl glyoxylate (775mg, 3.80mmol) and glacial acetic acid (175mg, 2.92mmol) were added to a solution of- (6- (difluoromethoxy) pyridin-3-yl) pyrimidine-2,4,5-triamine (900mg, 2.92mmol) in ethanol (10.0 mL) and the reaction was stirred at 70 ℃ for 2 hours under nitrogen. After completion of the reaction, the reaction mixture was diluted with water (60.0 mL), followed by extraction with ethyl acetate/tetrahydrofuran (1/1, 50.0mL × 3), and the organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was slurried with methyl tert-butyl ether (20.0 mL) to give the compound 2- (cyclopropylamino) -8- (6- (difluoromethoxy) pyridin-3-yl) pteridin-7 (8H) -one (900mg, 2.60mmol, yellow solid, 89.0% yield). Used directly in the next step.
LC-MS,M/Z(ESI):347.1(M+H) +
The seventh step: synthesis of 6-chloro-2- (cyclopropylamino) -8- (6- (difluoromethoxy) pyridin-3-yl) pteridin-7 (8H) -one
To a solution of 2- (cyclopropylamino) -8- (6- (difluoromethoxy) pyridin-3-yl) pteridin-7 (8H) -one (300mg, 866. Mu. Mol) in N, N-dimethylformamide (2.00 mL) was added N-chlorosuccinimide (174mg, 1.30mmol) under nitrogen, followed by stirring at 60 ℃ for 4 hours. The reaction mixture was diluted with water (20.0 mL), then extracted with ethyl acetate (20.0 mL × 3), and the organic layers were combined, washed with water (20.0 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to give the compound 6-chloro-2- (cyclopropylamino) -8- (6- (difluoromethoxy) pyridin-3-yl) pteridin-7 (8H) -one (330 mg yellow solid). Used directly in the next step.
LC-MS,M/Z(ESI):381.0(M+H) +
Eighth step: synthesis of 2- (cyclopropylamino) -8- (6- (difluoromethoxy) pyridin-3-yl) -6- (2-methyl-2H-indazol-5-yl) pteridin-7 (8H) -one (I-7)
Figure BDA0003571090790000451
To a solution of 6-chloro-2- (cyclopropylamino) -8- (6- (difluoromethoxy) pyridin-3-yl) pteridin-7 (8H) -one (330mg, 867. Mu. Mol) in dioxane (5.00 mL) and water (1.00 mL) was added 2-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2H-indazole (336mg, 1.30mmol), 1,1-bis (diphenylphosphino) ferrocene dichloropalladium (63.4mg, 86.7. Mu. Mol) and potassium carbonate (359mg, 2.60mmol) under nitrogen, and the reaction was stirred at 70 ℃ for 2 hours. After completion of the reaction, the reaction mixture was diluted with water (30.0 mL), a solid precipitated, the reaction solution was filtered, the solid was dried, slurried with ethyl acetate (10.0 mL), and then separated and purified by high performance liquid chromatography (column: phenomenex Luna C18150 × 25mm × 10um; solvent: a = water +0.225 vol% formic acid (99.0%), B = acetonitrile; gradient: 58% -88%,10 minutes) to give 2- (cyclopropylamino) -8- (6- (difluoromethoxy) pyridin-3-yl) -6- (2-methyl-2H-indazol-5-yl) pteridin-7 (8H) -one (I-7) (125mg, 262 μmol, yellow solid yield, 30.2%).
LC-MS,M/Z(ESI):477.1(M+H) +
1 H NMR(400MHz,DMSO_d 6 ) δ 8.82 (br s, 2H), 8.49 (s, 1H), 8.32-8.43 (m, 1H), 7.96-8.23 (m, 3H), 7.76-7.90 (m, 1H), 7.65 (d, 1H), 7.32 (d, 1H), 4.18 (s, 3H), 2.69-3.13 (m, 1H), 0.40-0.69 (m, 4H). Example 8: preparation of Compound I-8
The synthetic route is as follows:
Figure BDA0003571090790000461
the first step is as follows: synthesis of 2-chloro-N- (4-cyclopropylphenyl) -5-nitropyrimidin-4-amine
2,4-dichloro-5-nitropyrimidine (1.19g, 6.14mmol) and 4-cyclopropylaniline (900mg, 6.76mmol) were dissolved in tetrahydrofuran (20.0 mL), cooled to-40 deg.C, and N, N-diisopropylethylamine (1.59g, 12.2mmol) was added slowly and reacted at-40 deg.C for 2 hours. After the reaction was completed, water (10.0 mL) was added and quenched, warmed to room temperature, extracted with ethyl acetate (45.0 mL), then washed with saturated brine (20.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product, 2-chloro-N- (4-cyclopropylphenyl) -5-nitropyrimidin-4-amine (1.60 g, crude yellow solid).
1 H NMR(400MHz,CDCl 3 )δ10.17(br s,1H),9.17(s,1H),7.48-7.51(m,2H),7.13-7.16(m,2H),1.91-1.98(m,1H),1.00–1.11(m,2H),0.72-0.75(m,2H).
The second step is that: n is a radical of 2 -cyclopropyl-N 4 Synthesis of- (4-cyclopropylphenyl) -5-nitropyrimidine-2,4-diamine
2-chloro-N- (4-cyclopropylphenyl) -5-nitropyrimidin-4-amine (1.60 g, crude), cyclopropylamine (377mg, 6.60mmol), N, N-diisopropylethylamine (1.78g, 13.7mmol) and cesium fluoride (836 g, 5.50mmol) were dissolved in dimethyl sulfoxide (10.0 mL), and the mixture was heated to 80 ℃ under nitrogen exchange and stirred for 3 hours. The reaction was cooled to room temperature, poured into water (30.0 mL), filtered and the solid collected. To obtain N 2 -cyclopropyl-N 4 - (4-cyclopropylphenyl) -5-nitropyrimidine-2,4-diamine (1.60 g, yellow solid, 93.3% yield).
LC-MS,M/Z(ESI):312.2(M+H) +
The third step: n is a radical of 2 -cyclopropyl-N 4 Synthesis of- (4-cyclopropylphenyl) pyrimidine-2,4,5-triamine
Handle N 2 -cyclopropyl-N 4 - (4-cyclopropylphenyl) -5-nitropyrimidine-2,4-diamine (1.60g, 5.14mmol) and platinum vanadium carbon (160mg, 10.0% content) were added to methanol (16.0 mL) to displace hydrogen, heated to 30 ℃ and stirred at 50psi for 3 hours. Cooling the reaction solution to room temperature, filtering, and spin-drying the filtrate. To obtain N 2 -cyclopropyl-N 4 - (4-cyclopropylphenyl) pyrimidine-2,4,5-triamine (1.35 g, tan solid, 93.3% yield).
LC-MS,M/Z(ESI):282.1(M+H) +
The fourth step: synthesis of 2- (cyclopropylamino) -8- (4-cyclopropylphenyl) pteridin-7 (8H) -one
Handle N 2 -cyclopropyl-N 4 - (4-Cyclopropylphenyl) pyrimidine-2,4,5-triamine (1.20g, 4.27mmol), ethyl glyoxylate (1.13g, 5.54mmol) and acetic acid (256mg, 4.27mmol) were added to ethanol (12.0 mL), nitrogen was replaced, and the mixture was heated to 80 ℃ and stirred at 80 ℃ for 3 hours. The reaction mixture was cooled to room temperature, water (20.0 mL) was added thereto, extraction was performed with ethyl acetate (45.0 mL _ 3), and the organic phases were combined, washed with saturated brine (30.0 mL _ 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by a silica gel column (petroleum ether: ethyl acetate (V/V) =100:1 to 1:1), and the fraction was concentrated to give 2- (cyclopropylamino) -8- (4-cyclopropylphenyl) pteridin-7 (8H) -one (360 mg, yellow solid, yield 26.4%).
LC-MS,M/Z(ESI):320.1(M+H) +
1 H NMR(400MHz,DMSO-d6)δ8.67-8.86(m,1H),7.93(s,1H),7.34-7.12(m,4H),2.53(d,1H),1.81-2.09(m,1H),0.97-1.13(m,2H),0.69-0.85(m,2H),0.63(br s,1H),0.32-0.58(m,3H).
The fifth step: synthesis of 6-chloro-2- (cyclopropylamino) -8- (4-cyclopropylphenyl) pteridin-7 (8H) -one
2- (cyclopropylamino) -8- (4-cyclopropylphenyl) pteridin-7 (8H) -one (400mg, 1.16mmol) and chlorosuccinimide (232mg, 1.74mmol) were added to N, N-dimethylformamide (10.0 mL), nitrogen was replaced, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was added to water (30.0 mL), extracted with ethyl acetate (90.0 mL _ 3), and the organic phases were combined, washed with saturated brine (30.0 mL _ 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by a silica gel column (petroleum ether: ethyl acetate (V/V) =100:1 to 3:1), and the fraction was concentrated to give 6-chloro-2- (cyclopropylamino) -8- (4-cyclopropylphenyl) pteridin-7 (8H) -one (400 mg, yellow solid, yield 90.9%).
LC-MS,M/Z(ESI):354.0(M+H) +
And a sixth step: 2- (cyclopropylamino) -8- (4-cyclopropylphenyl) -6- (2-methyl-2H-indazol-5-yl) pteridin-7 (8H) -one (Compound I-8)
Figure BDA0003571090790000481
6-chloro-2- (cyclopropylamino) -8- (4-cyclopropylphenyl) pteridin-7 (8H) -one (160mg, 452. Mu. Mol), 2-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) indazole (140mg, 542. Mu. Mol), 1,1-bis (diphenylphosphino) ferrocene palladium dichloride (18.4 mg, 22.6. Mu. Mol) and potassium carbonate (187mg, 1.36mmol) were dissolved in dioxane (2.00 mL) and water (0.20 mL) to displace nitrogen, warm to 60 ℃ and stir for 2 hours under nitrogen blanket. The reaction mixture was cooled to room temperature, added dropwise to water (10.0 mL), extracted with ethyl acetate (20.0 mL), and the organic phase was washed with saturated brine (15.0 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by high performance liquid chromatography by (column: phenomenex Luna C18150 × 25mm 10um; solvent: a = water +0.225 vol% formic acid (99%), B = acetonitrile; gradient: 44% -74%,10 min) to give compound 2- (cyclopropylamino) -8- (4-cyclopropylphenyl) -6- (2-methyl-2H-indazol-5-yl) pteridin-7 (8H) -one (I-8) (18.4 mg, yellow solid, yield 8.54%).
LC-MS,M/Z(ESI):450.2(M+H) +
1 H NMR(400MHz,DMSO-d6)δ8.83-8.87(m,1H),8.80(s,1H),8.48(s,1H),8.07(dd,1H),7.69-7.78(m,1H),7.64(d,1H),7.17-7.31(m,4H),4.18(s,3H),1.95-2.08(m,1H),1.23(s,1H),0.98-1.07(m,2H),0.70-0.78(m,2H),0.37-0.67(m,4H).
Example 9: preparation of Compound I-9
The synthetic route is shown as follows:
Figure BDA0003571090790000491
the first step is as follows: synthesis of (2-methylimidazo [1,2-a ] pyridin-6-yl) boronic acid (6 a)
Figure BDA0003571090790000492
6-bromo-2-methylimidazo [1,2-a ] pyridine (1.00g, 4.74mmol), bis (pinacolato) borate (1.80g, 7.11mmol), 1,1-bis (diphenylphosphino) ferrocene palladium dichloride (173mg, 236.9. Mu. Mol) and potassium acetate (1.40g, 14.2mmol) were dissolved in dioxane (20 mL), replaced with nitrogen, and stirred at 90 ℃ for 1 hour. Cooling to room temperature, filtering the reaction solution, and spin-drying the mother solution to obtain a crude product. The crude product obtained was purified with petroleum ether: ethyl acetate (10.
LC-MS,M/Z(ESI):177.0(M+H) +
The second step is that: synthesis of 2- (cyclopropylamino) -8- (4- (difluoromethoxy) phenyl) -6- (2-methylimidazo [1,2-a ] pyridin-6-yl) pteridin-7 (8H) -one (I-9)
Figure BDA0003571090790000493
6-chloro-2- (cyclopropylamino) -8- (4- (difluoromethoxy) phenyl) pteridin-7 (8H) -one (100mg, 263.3. Mu. Mol), (2-methylimidazo [1,2-a ] pyridin-6-yl) boronic acid (101.9mg, 395.0. Mu. Mol), 1,1-bis (diphenylphosphino) ferrocene palladium dichloride (10.8mg, 13.2. Mu. Mol) and potassium carbonate (109.2mg, 790.0. Mu. Mol) were dissolved in dioxane (2 mL) and water (0.4 mL), nitrogen was replaced, the temperature was raised to 90 ℃ and stirring was continued for 2 hours under nitrogen. The reaction mixture was cooled to room temperature, and the mixture was added dropwise to water (10 mL) and extracted with ethyl acetate (30 mL). The organic phase was washed twice with saturated brine (30 mL), dried over anhydrous sodium sulfate, concentrated and the residue was separated by reverse phase high performance liquid chromatography by (column: 3. Mu. Phenomenex Luna C18 x 30mm 3 μm; solvent: A = water +0.225% vol formic acid (99%), B = acetonitrile; gradient: 15% -45%,10 min) to give the compound 2- (cyclopropylamino) -8- (4- (difluoromethoxy) phenyl) -6- (2-methylimidazo [1,2-a ] pyridin-6-yl) pteridin-7 (8H) -one (45 mg, yellow solid, yield 35.8%) after lyophilization.
LC-MS,M/Z(ESI):476.2(M+H) +
1 H NMR(400MHz,DMSO-d 6 )δ9.64(s,1H),8.91(d,1H),8.03(d,1H),7.17-7.89(m,8H),3.28-3.32(m,1H),2.33(s,3H),0.39-0.65(m,4H).
Example 10: preparation of Compound I-10
2- (cyclopropylamino) -8- (4- (difluoromethoxy) phenyl) -6- (2-methylbenzo [ d ] thiazol-6-yl) pteridin-7 (8H) -one (I-10)
Figure BDA0003571090790000501
Synthetic route to Compound I-10 referring to the synthetic method of I-1, 2- (cyclopropylamino) -8- (4- (difluoromethoxy) phenyl) -6- (2-methylbenzo [ d ] thiazol-6-yl) pteridin-7 (8H) -one (I-10) is obtained
LC-MS,M/Z(ESI):493.1[M+H] +
Example 11: preparation of Compound I-11
The synthetic route is as follows:
Figure BDA0003571090790000511
the first step is as follows: synthesis of 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2H-indazole
5-bromo-2H-indazole (2.00g, 10.1mmol) was dissolved in N, N-dimethylformamide (20.0 mL) at room temperature, and a mixture of bis-pinacolboronic acid ester (3.87g, 15.2mmol), potassium acetate (2.99g, 30.4 mmol) and 1,1-bis (diphenylphosphino) ferrocene palladium dichloride dichloromethane (828mg, 1.02mmol) was added, stirred well, and reacted at 100 ℃ for 12 hours. After completion of the reaction, water (30.0 mL) was added and the mixture was quenched, extracted with ethyl acetate (90.0 mL), then washed with saturated brine (90.0 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by a silica gel column (petroleum ether: ethyl acetate (V/V) = 5:1) to give 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2H-indazole (1.64 g, tan oil, 66.1% yield).
LC-MS,M/Z(ESI):244.9(M+H) +
The second step is that: synthesis of 2-methyl-1- (5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2H-indazol-2-yl) propan-2-ol
Figure BDA0003571090790000512
5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2H-indazole (1.64g, 6.72mmol) was dissolved in N, N-dimethylformamide (16.0 mL), 2,2-dimethyloxirane (1.21g, 16.8mmol) and potassium carbonate (1.39g, 10.0mmol) were added, and nitrogen was replaced, and the mixture was stirred at 100 ℃ for 2 hours. After the reaction was completed, water (10.0 mL) was added to quench, extraction was performed with ethyl acetate (30.0 mL), followed by washing with saturated brine (30.0 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by high performance liquid chromatography by (column: welch Ultimate XB-SiOH 250 x 50 x 10 μm; solvent: a = cyclohexane, B = ethanol; gradient: 1% -20%,15 minutes) to give 2-methyl-1- (5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2H-indazol-2-yl) propan-2-ol (186 mg, colorless transparent oil, yield 2.12%).
LC-MS,M/Z(ESI):317.1(M+H) +
The third step: synthesis of 2- (cyclopropylamino) -8- (4- (difluoromethoxy) phenyl) -6- (2- (2-hydroxy-2-methylpropyl) -2H-indazol-5-yl) pteridin-7 (8H) -one (I-11)
Figure BDA0003571090790000521
2-methyl-1- (5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2H-indazol-2-yl) propan-2-ol (135mg, 426. Mu. Mol) was dissolved in 1,4-dioxane (4.00 mL), 6-chloro-2- (cyclopropylamino) -8- [4- (difluoromethoxy) phenyl ] pteridine-7-one (147mg, 388. Mu. Mol), potassium carbonate (160mg, 1.00 mmol) in water (1.00 mL), 1,1-bis (diphenylphosphino) ferrocene dichloropalladium chloride dichloromethane mixture (15.8mg, 19.4. Mu. Mol), stirred well and reacted at 25 ℃ for 12 hours. After the reaction was completed, water (15.0 mL) was added to quench, and extraction was performed with ethyl acetate (30.0 mL), followed by washing with saturated brine (30.0 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated, and the residue was separated and purified by high performance liquid chromatography by (column: waters Xbridge 150 × 25mm 5 μm; solvent: a = water +0.225 vol% formic acid (99%), B = acetonitrile; gradient: 38% -68%,7 min) to give 2- (cyclopropylamino) -8- (4- (difluoromethoxy) phenyl) -6- (2- (2-hydroxy-2-methylpropyl) -2H-indazol-5-yl) pteridin-7 (8H) -one (I-11) (75.0 mg, yellow solid, yield 34.8%).
LC-MS,M/Z(ESI):534.2(M+H) +
1 H NMR(400MHz,CDCl 3 )δ8.98(s,1H),8.83-8.95(m,1H),8.26(d,1H),8.02(s,1H),7.78(d,1H),7.30-7.38(m,4H),6.40-6.80(m,1H),5.34-5.63(m,1H),4.37(s,2H),4.25-4.35(m,1H),1.21(s,7H),0.41-0.60(m,4H)
Example 12: preparation of Compound I-12
The synthetic route is as follows:
Figure BDA0003571090790000531
the first step is as follows: synthesis of 2- (cyclopropylmethoxy) -N- (4- (difluoromethoxy) phenyl) -5-nitropyrimidin-4-amine
To a solution of 2-chloro-N- (4- (difluoromethoxy) phenyl) -5-nitropyrimidin-4-amine (1.00g, 3.16mmol) in dimethyl sulfoxide (10.0 mL) under nitrogen protection were added cyclopropylmethanol (600mg, 8.32mmol) and N, N-diisopropylethylamine (1.04g, 8.04mmol) and cesium fluoride (480mg, 3.16mmol), and the reaction was stirred at 30 ℃ for 10 hours. After completion of the reaction, the reaction mixture was diluted with water (50.0 mL), followed by extraction with ethyl acetate (30.0 mL × 3), and the organic layers were combined, washed with water (30.0 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified with a silica gel column (petroleum ether: ethyl acetate (V/V) =1 to 15) to obtain compound 2- (cyclopropylmethoxy) -N- (4- (difluoromethoxy) phenyl) -5-nitropyrimidin-4-amine (500mg, 1.42mmol, yellow solid, yield 44.9%).
LC-MS,M/Z(ESI):353.0(M+H) +
1 H NMR(400MHz,CDCl 3 )δ10.27(s,1H),9.24(s,1H),7.58-7.66(m,2H),7.17-7.24(m,2H),6.33-6.75(m,1H),4.21(d,2H),1.22-1.39(m,1H),0.60-0.68(m,2H),0.30-0.42(m,2H).
The second step: 2- (cyclopropylmethoxy) -N 4 Synthesis of- (4- (difluoromethoxy) phenyl) pyrimidine-4,5-diamine
To a solution of 2- (cyclopropylmethoxy) -N- (4- (difluoromethoxy) phenyl) -5-nitropyrimidin-4-amine (500mg, 1.42mmol) in methanol (10.0 mL) was added platinum vanadium carbon (500mg, 192. Mu. Mol, content: 10%) under a nitrogen blanket, and the reaction was replaced 3 times with hydrogen, and the reaction was stirred at 15 ℃ for 10 hours under a hydrogen pressure of 15 psi. After completion of the reaction, the reaction mixture was filtered, washed with methanol (15.0 ml _ 2), and concentrated to give 2- (cyclopropylmethoxy) -N 4 - (4- (difluoromethoxy) phenyl) pyrimidine-4,5-diamine (470 mg yellow solid). Used directly in the next step.
LC-MS,M/Z(ESI):323.1(M+H) +
The third step: synthesis of 2- (cyclopropylmethoxy) -8- (4- (difluoromethoxy) phenyl) pteridin-7 (8H) -one
Under the protection of nitrogen, to 2- (cyclopropyl methoxy) -N 4 - (4- (Difluoromethoxy) phenyl) pyrimidine-4,5-diamine (450mg, 1.40mmol) in ethanol (5.00 mL) was added a toluene solution of ethyl glyoxylate (371mg, 1.82mmol,50.0% concentration) and glacial acetic acid (83.8mg, 1.40mmol), and the reaction was stirred at 90 ℃ for 10 hours. After completion of the reaction, the reaction mixture was diluted with water (20.0 mL), followed by extraction with ethyl acetate (20.0 mL × 3), and the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give the compound 2- (cyclopropylmethoxy) -8- (4- (difluoromethoxy) phenyl) pteridin-7 (8H) -one (450mg, 1.25mmol, yellow solid, yield 89.5%).
LC-MS,M/Z(ESI):361.1(M+H) +
The fourth step: synthesis of 6-chloro-2- (cyclopropylmethoxy) -8- (4- (difluoromethoxy) phenyl) pteridin-7 (8H) -one
To a solution of 2- (cyclopropylmethoxy) -8- (4- (difluoromethoxy) phenyl) pteridin-7 (8H) -one (350mg, 971. Mu. Mol) in N, N-dimethylformamide (1.00 mL) was added N-chlorosuccinimide (195mg, 1.46mmol), and the reaction was stirred at 25 ℃ for 10 hours. After completion of the reaction, the reaction mixture was diluted with water (10.0 mL), followed by extraction with ethyl acetate (10.0 mL × 3), and the organic layers were combined, washed with water (10.0 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to give 6-chloro-2- (cyclopropylmethoxy) -8- (4- (difluoromethoxy) phenyl) pteridin-7 (8H) -one (300 mg of a yellow oily compound). Was used directly in the next step.
LC-MS,M/Z(ESI):394.8(M+H) +
The fifth step: synthesis of 2- (cyclopropylmethoxy) -8- (4- (difluoromethoxy) phenyl) -6- (2-methyl-2H-indazol-5-yl) pteridin-7 (8H) -one (I-12)
Figure BDA0003571090790000541
To a solution of 6-chloro-2- (cyclopropylmethoxy) -8- (4- (difluoromethoxy) phenyl) pteridin-7 (8H) -one (200mg, 507. Mu. Mol) in 1,4-dioxane (1.00 mL) and water (200. Mu.L) was added 2-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2H-indazole (196mg, 760. Mu. Mol), potassium carbonate (210mg, 1.52mmol) and 1,1-bis (diphenylphosphino) ferrocenedipalladium dichloride (37.1mg, 50.7. Mu. Mol) under nitrogen, and the reaction was stirred at 75 ℃ for 3 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was separated and purified by silica gel plate (petroleum ether: ethyl acetate (V/V) = 1:2), followed by beating with methanol (3.00 mL) to give compound 2- (cyclopropylmethoxy) -8- (4- (difluoromethoxy) phenyl) -6- (2-methyl-2H-indazol-5-yl) pteridin-7 (8H) -one (I-12) (3.67mg, 7.04 μmol, yellow solid, yield 1.39%).
LC-MS,M/Z(ESI):491.1(M+H) +
1 H NMR(400MHz,CDCl 3 )δ8.98-9.13(m,2H),8.28(br d,1H),8.01(s,1H),7.78(d,1H),7.33-7.43(m,4H),6.38-6.87(m,1H),4.26(s,3H),4.08(d,2H),1.18-1.29(m,1H),0.48-0.65(m,2H),0.18-0.37(m,2H).
Example 13: preparation of Compound I-13
The synthetic route is shown as follows:
Figure BDA0003571090790000551
to a solution of 6-chloro-2- (cyclopropylamino) -8- (4- (difluoromethoxy) phenyl) pteridin-7 (8H) -one (200mg, 527. Mu. Mol) in N, N-dimethylformamide (2.00 mL) was added 2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo [4,3-c ] pyridine hydrochloride (133mg, 632. Mu. Mol) and cesium carbonate (515mg, 1.58mmol) under nitrogen, and the reaction was stirred at 50 ℃ for 10 hours. After completion of the reaction, the reaction mixture was diluted with water (20.0 mL), followed by extraction with ethyl acetate (20.0 mL × 3), the organic layers were combined, washed with water (20.0 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by high performance liquid chromatography by (column: phenomenex Gemini-NX C18 75 × 30mm 3 μm; solvent: a = water +0.225 vol% formic acid (99.0%), B = acetonitrile; gradient: 35% -65%,7 minutes), followed by beating with methanol (5.00 mL) to give the compound 2- (cyclopropylamino) -8- (4- (difluoromethoxy) phenyl) -6- (2-methyl-6,7-dihydro-2H-pyrazolo [4,3-C ] pyridin-5 (4H) -yl) pteridin-7 (8H) -one (I-13) (43.10 mg,85.3 μmol, yield, 2.16 mol of yellow solid).
LC-MS,M/Z(ESI):481.1(M+H) +
1 H NMR(400MHz,DMSO_d 6 )δ8.45(s,1H),7.47-7.57(m,1H),7.38-7.46(m,2H),7.05-7.38(m,4H),4.63(s,2H),3.93(t,2H),3.75(s,3H),3.41-3.52(m,1H),2.69-2.82(m,2H),0.22-0.66(m,4H).
Example 14: preparation of Compound I-14
The synthetic route is as follows:
Figure BDA0003571090790000561
the first step is as follows: synthesis of 3-amino-2-methyl-2,6-dihydropyrrolo [3,4-c ] pyrazole-5 (4H) -carboxylic acid tert-butyl ester
Tert-butyl 3-cyano-4-oxopyrrolidine-1-carboxylate (3.00g, 14.2mmol) was dissolved in ethanol (30.0 mL) at room temperature, methylhydrazine (788mg, 17.1mmol) was added thereto, and the mixture was stirred well and reacted at 85 ℃ for 17 hours. After the reaction was completed, the reaction mixture was directly filtered and concentrated, and the residue was purified by HPLC by (column: phenomenex luna C18150 × 40mm × 15 μm; solvent: A = water +0.225 vol% ammonia (30%), B = acetonitrile; gradient: 25% -55%,10 min) to give 3-amino-2-methyl-2,6-dihydropyrrolo [3,4-C ] pyrazole-5 (4H) -carboxylic acid tert-butyl ester as a yellow solid (1.90 g, yield 55.8%).
LC-MS,M/Z(ESI):239.2(M+H) +
The second step: synthesis of 2-methyl-2,6-dihydropyrrolo [3,4-c ] pyrazole-5 (4H) -carboxylic acid tert-butyl ester
3-amino-2-methyl-2,6-dihydropyrrolo [3,4-c ] pyrazole-5 (4H) -carboxylic acid tert-butyl ester (1.90g, 7.97mmol) was dissolved in 1,4-dioxane (20.0 mL), isoamyl nitrite (0.87g, 15.9 mmol) was added, nitrogen was replaced, and the mixture was stirred at 100 ℃ for 2 hours. After the reaction was completed, water (10.0 mL) was added and quenched, extracted with ethyl acetate (60.0 mL), then washed with saturated brine (60.0 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give 2-methyl-2,6-dihydropyrrolo [3,4-c ] pyrazole-5 (4H) -carboxylic acid tert-butyl ester as a yellow oil (1.20 g, 67.4% yield).
LC-MS,M/Z(ESI):224.5(M+H) +
The third step: synthesis of 2-methyl-2,4,5,6-tetrahydropyrrolo [3,4-c ] pyrazole
Tert-butyl 2-methyl-2,6-dihydropyrrolo [3,4-c ] pyrazole-5 (4H) -carboxylate (1.20g, 5.37mmol) was dissolved in methylene chloride (12.0 mL), trifluoroacetic acid (30.6g, 268mmol) was added, and the mixture was reacted at 25 ℃ for 12 hours with thorough stirring. After the reaction was complete, concentration gave the crude product 2-methyl-2,4,5,6-tetrahydropyrrolo [3,4-c ] pyrazole as a yellow solid (435 mg, 65.7% yield).
LC-MS,M/Z(ESI):124.1(M+H) +
1 H NMR(400MHz,DMSO-d6)δ7.58(s,1H),4.27(t,4H),3.84(s,3H).
The fourth step: synthesis of 2- (cyclopropylamino) -8- (4- (difluoromethoxy) phenyl) -6- (2-methyl-2,6-dihydropyrrolo [3,4-c ] pyrazol-5 (4H) -yl) pteridin-7 (8H) -one (I-14)
Figure BDA0003571090790000571
2-methyl-2,4,5,6-tetrahydropyrrolo [3,4-c ] pyrazole (50.0mg, 405. Mu. Mol) was dissolved in dimethyl sulfoxide (1.00 mL), diisopropylethylamine ((262mg, 2.03mmol), 6-chloro-2- (cyclopropylamino) -8- [4- (difluoromethoxy) phenyl ] pteridin-7 (8H) -one (154mg, 405. Mu. Mol) was added, nitrogen was replaced, the reaction was stirred well, and at 95 ℃ for 2 hours, after the reaction was completed, water (15.0 mL) was added and quenched, filtered, a solid was collected, and then the solid was recrystallized in a methanol solution at 60 ℃ to give 2- (cyclopropylamino) -8- (4- (difluoromethoxy) phenyl) -6- (2-methyl-2,6-dihydropyrrolo [3,4-c ] pyrazol-5 (4H) -yl) pteridin-7 (8H) -one (I-14) (40.0 mg, yellow solid yield, 20.0%).
LC-MS,M/Z(ESI):467.1(M+H) +
1 H NMR(400MHz,DMSO-d6)δ8.41(s,1H),7.52-7.56(m,1H),7.43(d,2H),7.30-7.35(m,3H),7.11-7.17(m,1H),4.86(s,4H),3.84(s,3H),3.30(s,1H),0.48(d,2H),0.36(s,2H).
Example 15: preparation of Compound I-15
The synthetic route is as follows:
Figure BDA0003571090790000581
the first step is as follows: synthesis of 2-methyl-1- (5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-indazol-2-yl) propan-2-ol
5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2H-indazole (1.64g, 6.72mmol) was dissolved in N, N-dimethylformamide (16.0 mL), 2,2-dimethyloxirane (1.21g, 16.8mmol) and potassium carbonate (1.39g, 10.0mmol) were added, and nitrogen was replaced, and the mixture was stirred at 100 ℃ for 2 hours. After the reaction was completed, water (10.0 mL) was added to quench, extraction was performed with ethyl acetate (30.0 mL), followed by washing with saturated brine (30.0 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by high performance liquid chromatography by (column: welch Ultimate XB-SiOH 250 x 50 x 10um; solvent: a = cyclohexane, B = ethanol; gradient: 1% -20%,15 minutes) to give 2-methyl-1- (5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-indazol-2-yl) propan-2-ol (450 mg, colorless transparent oil, yield 14.3%).
LC-MS,M/Z(ESI):317.1(M+H) +
The second step is that: synthesis of 2- (cyclopropylamino) -8- (4- (difluoromethoxy) phenyl) -6- (1- (2-hydroxy-2-methylpropyl) -1H-indazol-5-yl) pteridin-7 (8H) -one (I-15)
Figure BDA0003571090790000582
2-methyl-1- (5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-indazol-2-yl) propan-2-ol (223mg, 706. Mu. Mol) was dissolved in 1,4 dioxane (4.00 mL), an aqueous solution of 6-chloro-2- (cyclopropylamino) -8- [4- (difluoromethoxy) phenyl ] pteridin-7 (8H) -one (244mg, 642. Mu. Mol), potassium carbonate (266mg, 1.93mmol) (1.00 mL), 1,1-bis (diphenylphosphino) ferrocene palladium dichloride dichloromethane mixture (26.2mg, 32.1. Mu. Mol), stirred well and reacted at 25 ℃ for 12 hours. After the reaction was completed, water (15.0 mL) was added to quench, and extraction was performed with ethyl acetate (30.0 mL), followed by washing with saturated brine (30.0 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by high performance liquid chromatography by the method of (column: phenomenex Gemini-NX C18 75 x 30mm 3um; solvent: a = water +0.225 vol% formic acid (99%), B = acetonitrile; gradient: 40% -70%,7 min) to give 2- (cyclopropylamino) -8- (4- (difluoromethoxy) phenyl) -6- (1- (2-hydroxy-2-methylpropyl) -1H-5-yl) pteridin-7 (8H) -one (I-15) (88.0 mg, yellow solid, yield 24.6%).
LC-MS,M/Z(ESI):534.1(M+H) +
1 H NMR(400MHz,CDCl 3 )δ8.85-8.94(m,2H),8.36(dd,1H),8.12(s,1H),7.51(dd,1H),7.34(s,4H),6.42-6.80(m,1H),5.43-5.75(m,1H),4.36(s,2H),3.57-3.64(m,1H),1.23(s,6H),0.45-0.85(m,4H).
Example 16: preparation of Compound I-16
The synthetic route is as follows:
Figure BDA0003571090790000591
the first step is as follows: synthesis of (Z) -3- ((dimethylamino) methylene) -4-oxopyrrolidine-1-carboxylic acid tert-butyl ester
Tert-butyl 3-oxopyrrolidine-1-carboxylate (4.00g, 21.6 mmol) was dissolved in tetrahydrofuran (10.0 mL) at room temperature, N-dimethylformamide dimethyl acetal (7.72g, 64.9 mmol) was added, nitrogen gas was replaced, the mixture was stirred well, and the reaction was carried out at 70 ℃ for 16 hours. After the reaction was completed, the reaction mixture was directly concentrated, and the residue was purified by HPLC separation (column: welch Ultimate XB-CN 250 × 70 × 10um; solvent: A = cyclohexane, B = ethanol; gradient: 1% -40%,15 minutes) to obtain (Z) -3- ((dimethylamino) methylene) -4-oxopyrrolidine-1-carboxylic acid tert-butyl ester (1.40 g, yellow oil, yield 26.9%).
LC-MS,M/Z(ESI):241.2(M+H) +
1 H NMR(400MHz,CDCl 3 )δ7.37(s,1H),4.58(s,2H),3.83(s,2H),3.11(s,6H),1.48(s,9H).
The second step is that: synthesis of 1-methyl-4,6-dihydropyrrolo [3,4-c ] pyrazole-5 (1H) -carboxylic acid tert-butyl ester
(Z) -3- ((dimethylamino) methylene) -4-oxopyrrolidine-1-carboxylic acid tert-butyl ester (1.00g, 4.16mmol) was dissolved in ethanol (10.0 mL), methylhydrazine (230mg, 4.99mmol) was added thereto, nitrogen gas was replaced, and the mixture was stirred at 85 ℃ for 17 hours. After the reaction was completed, the reaction mixture was filtered, dissolved in petroleum ether (20.0 mL), washed with a saturated ammonium chloride solution (25.0 mL) and then with a saturated sodium bicarbonate solution (25.0 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by hplc using a separation method (column: phenomenex luna C18150 x 40mm 15um; solvent: a = water +0.225 vol% formic acid (99%), B = acetonitrile; gradient: 25% -55%,10 min) to give brown 1-methyl-4,6-dihydropyrrolo [3,4-C ] pyrazole-5 (1H) -carboxylic acid tert-butyl ester (260 mg, brown oil, yield 27.4%).
LC-MS,M/Z(ESI):224.1(M+H) +
1 H NMR(400MHz,CDCl 3 )δ7.31(d,1H),4.40-4.53(m,4H),3.88(s,3H),1.51(s,9H).
The third step: synthesis of 1-methyl-1,4,5,6-tetrahydropyrrolo [3,4-c ] pyrazole
1-methyl-4,6-dihydropyrrolo [3,4-c ] pyrazole-5 (1H) -carboxylic acid tert-butyl ester (135mg, 426. Mu. Mol) was added to trifluoroacetic acid (2.55g, 22.3mmol), stirred well, and reacted at 25 ℃ for 12 hours. After the reaction was completed, the reaction mixture was directly concentrated to give 1-methyl-1,4,5,6-tetrahydropyrrolo [3,4-c ] pyrazole (80.0 mg, tan oil, crude).
LC-MS,M/Z(ESI):124.1(M+H) +
The fourth step: synthesis of 2- (cyclopropylamino) -8- (4- (difluoromethoxy) phenyl) -6- (1-methyl-4,6-dihydropyrrolo [3,4-c ] pyrazol-5 (1H) -yl) pteridin-7 (8H) -one (I-16)
Figure BDA0003571090790000601
1-methyl-1,4,5,6-tetrahydropyrrolo [3,4-c ] pyrazole (80.0mg, 649. Mu. Mol) was dissolved in dimethyl sulfoxide (1.00 mL), diisopropylethylamine (419mg, 3.25mmol), 6-chloro-2- (cyclopropylamino) -8- [4- (difluoromethoxy) phenyl ] pteridin-7 (8H) -one (246mg, 649. Mu. Mol) was added, nitrogen was replaced, and the mixture was sufficiently stirred and reacted at 95 ℃ for 2 hours. After the reaction was complete, quenched with water (15.0 mL), filtered, the solid was collected and then recrystallized from 60 ℃ methanol solution to give 2- (cyclopropylamino) -8- (4- (difluoromethoxy) phenyl) -6- (1-methyl-4,6-dihydropyrrolo [3,4-c ] pyrazol-5 (1H) -yl) pteridin-7 (8H) -one (I-16) (4.08 mg, yellow solid, 1.35% yield).
LC-MS,M/Z(ESI):467.1(M+H) +
1 H NMR(400MHz,DMSO-d 6 )δ8.41(s,1H),7.43(d,2H),7.31-7.37(m,3H),7.25(s,1H),7.16(s,1H),4.92-5.10(m,2H),4.78-4.92(m,2H),3.80(s,3H),3.30(s,1H),0.48(dd,2H),0.36(s,2H).
Example 17: preparation of target Compound I-17
The synthetic route is shown as follows:
Figure BDA0003571090790000611
the first step is as follows: synthesis of (2-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2,3-dihydrobenzofuran-2-yl) methanol
(5-bromo-2-methyl-2,3-dihydrobenzofuran-2-yl) methanol (100mg, 411. Mu. Mol), potassium acetate (121mg, 1.23mmol), bis-pinacol boronate (157mg, 617. Mu. Mol) and 1,1-bis (diphenylphosphino) ferrocene palladium dichloride (30.1mg, 41.1. Mu. Mol) were added to 1,4-dioxane (2.00 mL) at room temperature, reacted at 90 ℃ for 2 hours under nitrogen protection, and the reaction solution was filtered and concentrated to give compound (2-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2,3-dihydrobenzofuran-2-yl) methanol (115 mg, crude yellow solid).
LC-MS,M/Z(ESI):291.1(M+H) +
The second step is that: 2- (cyclopropylamino) -8- (4- (difluoromethoxy) phenyl) -6- (2- (hydroxymethyl) -2-methyl-2,3-dihydrobenzofuran-5-yl) pteridin-7 (8H) -one (I-17)
Figure BDA0003571090790000612
(2-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2,3-dihydrobenzofuran-2-yl) methanol (115mg, 396. Mu. Mol), potassium carbonate (164mg, 1.91mmol), 6-chloro-2- (cyclopropylamino) -8- (4- (difluoromethoxy) phenyl) pteridin-7 (8H) -one (151mg, 3.96mmol) 1,1-bis (diphenylphosphine) ferrocene palladium dichloride (29.0 mg, 39.6. Mu. Mol) were added to 1,4-dioxane (1.00 mL) and water (0.30 mL) under nitrogen protection, reacted at 35 ℃ for 12 hours, the reaction solution was filtered and concentrated to give a crude product. The crude product was then purified by high performance liquid chromatography, using a separation procedure of (column: phenomenex synergy C18 75 x 30mm 4um; solvent: a = water +0.1 vol% trifluoroacetic acid (99%), B = acetonitrile; gradient: 46% -66% B,6 min) to give the compound 2- (cyclopropylamino) -8- (4- (difluoromethoxy) phenyl) -6- (2- (hydroxymethyl) -2-methyl-2,3-dihydrobenzofuran-5-yl) pteridin-7 (8H) -one (I-17) (58.5mg, 22.7% yield).
LC-MS,M/Z(ESI):508.3(M+H) +
1 H NMR(400MHz,CDCl 3 )δ9.45(br,1H),8.51(s,1H),8.17-8.19(m,2H),7.30-7.34(m,4H),6.42-6.83(m,2H),3.65-3.77(m,2H),3.34-3.38(d,1H),2.96-3.00(d,1H),2.48-2.51(br,1H),1.48(s,3H),0.55-0.64(m,4H).
Example 18: preparation of Compound I-18
The synthetic route is as follows:
Figure BDA0003571090790000621
the first step is as follows: synthesis of 1- (4-bromo-1H-pyrazol-1-yl) -2-methylpropan-2-ol
At room temperature, 4-bromopyrazole (1.00g, 6.80mmol), 2,2-dimethyloxirane (981mg, 13.6mmol) and cesium carbonate (2.22g, 6.80mmol) were added to dioxane (20.0 mL) and reacted at 80 ℃ for 2 hours under nitrogen protection, and the reaction solution was filtered and concentrated to give the compound 1- (4-bromo-1H-pyrazol-1-yl) -2-methylpropan-2-ol (1.20 g, crude white solid).
LC-MS,M/Z(ESI):219.0(M+H) +
The second step is that: synthesis of 2-methyl-1- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) propan-2-ol
1- (4-bromo-1H-pyrazol-1-yl) -2-methylpropan-2-ol (500mg, 2.28mmol), potassium acetate (672mg, 6.85mmol), bis-pinacol boronate (580mg, 2.28mmol) and 1,1-bis (diphenylphosphino) ferrocene palladium dichloride (167mg, 228. Mu. Mol) were added to 1,4-dioxane (10.0 mL) at room temperature, reacted at 80 ℃ for 2 hours under nitrogen protection, and the reaction solution was filtered and concentrated to give 2-methyl-1- (4- (4,4,5,5-tetramethyl-1,3,2-dioxacyclopentane-2-yl) -1H-pyrazol-1-yl) propan-2-ol (500 mg, crude yellow oil).
LC-MS,M/Z(ESI):267.2(M+H) +
The third step: 2- (cyclopropylamino) -8- (4- (difluoromethoxy) phenyl) -6- (1- (2-hydroxy-2-methylpropyl) -1H-pyrazol-4-yl) pteridin-7 (8H) -one (I-18)
Figure BDA0003571090790000631
Under the protection of nitrogen, 2-methyl-1- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) propan-2-ol (350mg, 1.32mmol), potassium carbonate (545mg, 3.95mmol), 6-chloro-2- (cyclopropylamino) -8- (4- (difluoromethoxy) phenyl) pteridine-7 (8H) -one (250mg, 658. Mu. Mol), 1,1-bis (diphenylphosphino) ferrocene palladium dichloride (48.1mg, 65.8. Mu. Mol) were added to 1,4-dioxane (8.00 mL) and water (1.00 mL), reacted at 25 ℃ under the protection of nitrogen for 6 hours, and the reaction solution was filtered and concentrated to obtain a crude product. The crude product was purified by hplc using column: phenomenex synergy C18 x 50mm 3um, solvent: a = water +0.1 vol% formic acid (99%), B = acetonitrile, gradient: 30% -60%,15 min) to give 2- (cyclopropylamino) -8- (4- (difluoromethoxy) phenyl) -6- (1- (2-hydroxy-2-methylpropyl) -1H-pyrazol-4-yl) pteridin-7 (8H) -one (I-18) (26.1 mg, yellow compound, 4.08% yield).
LC-MS,M/Z(ESI):484.2(M+H) +
1 H NMR(400MHz,CDCl 3 )δ8.79(br,1H),8.48(s,1H),8.41(s,1H),7.29-7.36(m,4H),6.42-6.78(t,1H),4.11(s,2H),1.60-1.67(m,1H),1.20(s,6H),0.43-0.57(m,4H).
Example 19: preparation of target Compound I-19
The synthetic route is as follows:
Figure BDA0003571090790000641
the first step is as follows: synthesis of 4- (4-bromo-1H-pyrazol-1-yl) -2-methylbutan-2-ol
4-bromopyrazole (2.00g, 13.6 mmol) and 4-bromo-2-methylbutan-2-ol (3.41g, 20.4 mmol) were added to N, N-dimethylformamide (10 mL), potassium carbonate (3.76g, 27.2mmol) was added, nitrogen was replaced, and the mixture was stirred at 25 ℃ for 12 hours. The reaction mixture was extracted with water (30 mL) and ethyl acetate (30ml × 3), and the organic phases were combined, washed with saturated brine (45ml × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to give 4- (4-bromo-1H-pyrazol-1-yl) -2-methylbutan-2-ol (3.00 g, yellow oil, yield 94.6%).
LC-MS,M/Z(ESI):233.1(M+H) +
The second step is that: synthesis of 2-methyl-4- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) butan-2-ol
4- (4-bromo-1H-pyrazol-1-yl) -2-methylbutan-2-ol (2.80g, 12.0mmol), bis-pinacol boronate (4.58g, 18.0mmol), 1,1-bis (diphenylphosphino) ferrocene palladium dichloride (879mg, 1.20. Mu. Mol) and potassium acetate (2.36g, 24.0mmol) were added to 1,4-dioxane (20 mL), nitrogen was replaced, and stirring was performed at 80 ℃ for 1 hour. The reaction was concentrated to give 2-methyl-4- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) butan-2-ol (2.80 g, yellow oil, 83.2% yield). Used directly in the next step.
LC-MS,M/Z(ESI):281.1(M+H) +
The third step: 2- (cyclopropylamino) -8- (4- (difluoromethoxy) phenyl) -6- (1- (3-hydroxy-3-methylbutyl) -1H-pyrazol-4-yl) pteridin-7 (8H) -one (title compound I-19)
Figure BDA0003571090790000642
6-chloro-2- (cyclopropylamino) -8- (4- (difluoromethoxy) phenyl) pteridin-7 (8H) -one (500mg, 1.32mmol), 2-methyl-4- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) butan-2-ol (553mg, 1.97mmol), 1,1-bis (diphenylphosphino) ferrocene palladium (107mg, 132. Mu. Mol) and potassium carbonate (364mg, 2.63mmol) were dissolved in 1,4-dioxane (4 mL) and water (1 mL) under nitrogen blanket, nitrogen was replaced, and the reaction was carried out at 25 ℃ for 2 hours. The reaction mixture was added dropwise to water (20 mL), and extracted with ethyl acetate (60 mL). The organic phase was washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by reverse phase high performance liquid chromatography by (column: waters Xbridge 150 x 25mm x 5um; solvent: a = water +0.225 volume of formic acid (99%), B = acetonitrile; gradient: 34% -64%,10 min), lyophilized to give the compound 2- (cyclopropylamino) -8- (4- (difluoromethoxy) phenyl) -6- (1- (3-hydroxy-3-methylbutyl) -1H-pyrazol-4-yl) pteridin-7 (8H) -one (I-19) (18.0 mg, yellow solid, yield 2.71%).
LC-MS,M/Z(ESI):498.2(M+H) +
1 H NMR(400MHz,DMSO-d 6 )δ8.62-8.91(m,1H),8.52(s,1H),8.16(s,1H),7.15-7.55(m,5H),4.47(s,1H),4.21-4.30(m,2H),2.70-2.88(m,1H),1.89-1.98(m,2H),1.12(s,6H),0.31-0.71(m,4H).
Example 20: preparation of Compound I-20
The synthetic route is shown as follows:
Figure BDA0003571090790000651
the first step is as follows: synthesis of 1- (5-bromo-2H-indazol-2-yl) propan-2-ol
To a solution of 5-bromo-2H-indazole (1.00g, 5.08mmol) in N, N-dimethylformamide (10.0 mL) were added 1-bromopropan-2-ol (1.31g, 6.60mmol,70.0% purity) and cesium carbonate (3.31g, 10.2mmol) and sodium iodide (76.1mg, 508. Mu. Mol), and the reaction was stirred at 80 ℃ for 10 hours. After completion of the reaction, the reaction mixture was diluted with water (50.0 mL), followed by extraction with ethyl acetate (30.0 mL × 3), organic layers were combined, washed with water (30.0 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified twice with high performance liquid chromatography by (column: welch Ultimate XB-CN 250 × 10um; solvent: a = n-hexane, B = ethanol +0.1 vol% aqueous ammonia (30.0%); gradient: 1% -35%,15 minutes) and (column: welch Ultimate XB-SiOH 250 × 70 × 10um; solvent: a = n-hexane, B = ethanol +0.1 vol% aqueous ammonia (30.0%); gradient: 1% -40%,20 minutes) to give compound 1- (5-bromo-2H-indazol-2-yl) propan-2-ol (500500mg, 1.9638.6 mmol, white solid, 38.6%).
LC-MS,M/Z(ESI):255.1(M+H) +
1 H NMR(400MHz,DMSO_d 6 )δ8.32(d,1H),7.97(dd,1H),7.58(d,1H),7.30(dd,1H),5.00(d,1H),4.24-4.39(m,2H),4.07-4.19(m,1H),1.08(d,3H).
The second step: synthesis of 1- (5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2H-indazol-2-yl) propan-2-ol to a solution of 1- (5-bromo-2H-indazol-2-yl) propan-2-ol (450mg, 1.76mmol) in 1,4-dioxane (1.00 mL) was added bis pinacol boronate (538mg, 2.12mmol), potassium acetate (519mg, 5.29mmol) and 1,1-bis (diphenylphosphino) ferrocene palladium dichloride (64.5mg, 88.2. Mu. Mol) under nitrogen, and the reaction was stirred at 85 ℃ for 10 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was separated and purified by a silica gel column (petroleum ether: ethyl acetate (V/V) =50 to 10.
LC-MS,M/Z(ESI):303.1(M+H) +
The third step: synthesis of 2- (cyclopropylamino) -8- (4- (difluoromethoxy) phenyl) -6- (2- (2-hydroxypropyl) -2H-indazol-5-yl) pteridin-7 (8H) -one (I-20)
Figure BDA0003571090790000661
To a solution of 1,4-dioxane (1.00 mL) and water (200 uL) of 1- (5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2H-indazol-2-yl) propan-2-ol (200mg, 662. Mu. Mol) was added 6-chloro-2- (cyclopropylamino) -8- (4- (difluoromethoxy) phenyl) pteridin-7 (8H) -one (350mg, 922. Mu. Mol), potassium carbonate (274mg, 1.99mmol) and 1,1-bis (diphenylphosphino) ferrocene palladium dichloride (24.2mg, 33.1. Mu. Mol) under nitrogen protection and the reaction was stirred at 25 ℃ for 10 hours. After completion of the reaction, the reaction mixture was diluted with water (10.0 mL), followed by extraction with ethyl acetate (10.0 mL × 3), and the organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified with a silica gel plate (petroleum ether: ethyl acetate (V/V) = 0:1) to give compound 2- (cyclopropylamino) -8- (4- (difluoromethoxy) phenyl) -6- (2- (2-hydroxypropyl) -2H-indazol-5-yl) pteridin-7 (8H) -one (I-20) (100mg, 183 μmol, yellow solid, 27.6% yield).
LC-MS,M/Z(ESI):520.1(M+H) +
1 H NMR(400MHz,DMSO_d 6 )δ8.65-9.02(m,2H),8.46(s,1H),8.08(dd,1H),7.42-7.84(m,4H),7.12-7.40(m,3H),5.03(d,1H),4.24-4.40(m,2H),4.09-4.21(m,1H),2.52-3.00(m,1H),1.10(d,3H),0.34-0.71(m,4H).
Example 21: preparation of target Compound I-21
The synthetic route is as follows:
Figure BDA0003571090790000671
the first step is as follows: synthesis of methyl 2- (5-bromo-2H-indazol-2-yl) propionate
To a solution of 5-bromo-2H-indazole (5.00g, 25.4 mmol) in acetonitrile (50.0 mL) were added methyl 2-bromopropionate (5.00g, 30.0 mmol) and potassium carbonate (7.01g, 50.8 mmol), and the reaction was stirred at 25 ℃ for 5 hours and then at 80 ℃ for 10 hours. After completion of the reaction, the reaction mixture was diluted with water (100 mL), followed by extraction with ethyl acetate (100ml × 3), and the organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was isolated and purified with a silica gel column (petroleum ether: ethyl acetate (V/V) = 30.
LC-MS,M/Z(ESI):282.9(M+H) +
1 H NMR(400MHz,DMSO_d 6 )δ8.49(s,1H),7.94-8.07(m,1H),7.60(d,1H),7.33(d,1H),5.67(q,1H),3.65(s,3H),1.79(d,3H).
The second step is that: synthesis of methyl 2- (5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2H-indazol-2-yl) propanoate to a solution of methyl 2- (5-bromo-2H-indazol-2-yl) propanoate (2.00g, 7.06mmol) in 1,4-dioxane (10.0 mL) under nitrogen were added bis pinacol boronate (2.15g, 8.48mmol), potassium acetate (2.08g, 21.2mmol), and 1,1-bis (diphenylphosphino) ferrocene dichloropalladium (258mg, 353. Mu. Mol), and the reaction was stirred at 85 ℃ for 10 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was separated and purified by a silica gel column (petroleum ether: ethyl acetate (V/V) =30 to 5:1) to give methyl 2- (5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2H-indazol-2-yl) propionate (2.30g, 6.97mmol, yellow oil, yield 98.6%).
LC-MS,M/Z(ESI):331.0(M+H) +
The third step: synthesis of 2- (5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2H-indazol-2-yl) propan-1-ol
To a solution of methyl 2- (5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2H-indazol-2-yl) propionate (600mg, 1.82mmol) in tetrahydrofuran (10.0 mL) at 0 ℃ under nitrogen protection was added a solution of lithium aluminum hydride in tetrahydrofuran (2.50m, 1.82ml) and the reaction was stirred at 25 ℃ for 2 hours. After completion of the reaction, the reaction was quenched with sodium sulfate decahydrate (3.00 g), filtered, washed with ethyl acetate (20.0 mL), and the filtrate was concentrated to give 2- (5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2H-indazol-2-yl) propan-1-ol (320mg, 1.06mmol, yellow oil, yield 58.3%) at 0 ℃.
The fourth step: synthesis of 2- (cyclopropylamino) -8- (4- (difluoromethoxy) phenyl) -6- (2- (1-hydroxypropan-2-yl) -2H-indazol-5-yl) pteridin-7 (8H) -one (I-21)
Figure BDA0003571090790000681
To a solution of 6-chloro-2- (cyclopropylamino) -8- (4- (difluoromethoxy) phenyl) pteridin-7 (8H) -one (120mg, 316. Mu. Mol) in 1,4-dioxane (5.00 mL) and water (1.00 mL) was added 2- (5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2H-indazol-2-yl) propan-1-ol (153mg, 506. Mu. Mol), potassium carbonate (131mg, 948. Mu. Mol) and 1,1-bis (diphenylphosphino) ferrocene dichloropalladium (23.1mg, 31.6. Mu. Mol) under nitrogen, and the reaction was stirred at 25 ℃ for 10 hours. After completion of the reaction, the reaction mixture was diluted with water (20.0 mL), followed by extraction with ethyl acetate (20.0 mL × 3), the organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was slurried with acetonitrile (20.0 mL) and dichloromethane (20.0 mL) to give compound 2- (cyclopropylamino) -8- (4- (difluoromethoxy) phenyl) -6- (2- (1-hydroxypropan-2-yl) -2H-indazol-5-yl) pteridin-7 (8H) -one (I-21) (45.8mg, 88.1 μmol, yellow solid, yield 27.9%).
LC-MS,M/Z(ESI):520.3(M+H) +
1 H NMR(400MHz,DMSO_d 6 )δ8.83(s,2H),8.51(s,1H),8.08(dd,1H),7.44-7.90(m,4H),7.14-7.42(m,3H),5.01(t,1H),4.61-4.75(m,1H),3.70-3.88(m,2H),2.62-2.97(m,1H),1.52(d,3H),0.28-0.76(m,4H).
Example 22: preparation of target Compound I-22
The synthetic route is as follows:
Figure BDA0003571090790000691
the first step is as follows: synthesis of 1- (5-bromo-2H-indazol-2-yl) -2-methylpropan-2-ol
At room temperature, 5-bromo-2H indazole (1.00g, 5.08mmol), 2,2-dimethyloxirane (732mg, 10.2mmol) and cesium carbonate (1.65g, 5.08mmol) were added to 1,4-dioxane (20.0 mL), reacted at 80 ℃ for 2 hours under nitrogen protection, and the reaction solution was filtered and concentrated to give a crude product. The crude product was then prepared in the normal phase by separation (column: phenomenex synergy XB-SiOH 250 x 70mm x 10um; solvent: a = n-hexane, B = ethanol; gradient: 1% -25%,20 min) to give compound 1- (5-bromo-2H-indazol-2-yl) -2-methylpropan-2-ol (400 mg, white solid, yield 29.3%).
LC-MS,M/Z(ESI):269.1(M+H) +
The second step is that: synthesis of 2-methyl-1- (5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2H-indazol-2-yl) propan-2-ol
1- (5-bromo-2H-indazol-2-yl) -2-methylpropan-2-ol (350mg, 1.30mmol), potassium acetate (383mg, 3.90mmol), bis-pinacol boronate (396mg, 1.56mmol) and 1,1-bis (diphenylphosphino) ferrocene palladium dichloride (95.2mg, 130. Mu. Mol) were added to 1,4-dioxane (15.0 mL) at room temperature, reacted under nitrogen protection for 4 hours at 80 ℃, and the reaction solution was filtered and concentrated to give 2-methyl-1- (5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2H-pyrazol-1-yl) propan-2-ol (400 mg, crude yellow oily compound).
LC-MS,M/Z(ESI):317.0(M+H) +
The third step: 8- (4- (difluoromethoxy) phenyl) -6- (2- (2-hydroxy-2-methylpropyl) -2H-indazol-5-yl) -2- ((2,2,2-trifluoroethyl) amino) pteridin-7 (8H) -one (I-22)
Figure BDA0003571090790000701
Under the protection of nitrogen, 2-methyl-1- (5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2H-pyrazol-1-yl) propan-2-ol (400mg, 1.27mmol), potassium carbonate (525mg, 3.80mmol), 6-chloro-2- (cyclopropylamino) -8- (4- (difluoromethoxy) phenyl) pteridine-7 (8H) -one (533mg, 1.27mmol) 1,1-bis (diphenylphosphino) ferrocene palladium dichloride (92.6mg, 127. Mu. Mol) were added to 1,4-dioxane (8.00 mL) and water (1.00 mL), reacted at 25 ℃ under the protection of nitrogen for 8 hours, and the reaction solution was filtered and concentrated to give a crude product. The crude product was then purified by hplc using separation (column: phenomenex synergy C18 x 25mm x 10um; solvent: a = water +0.1 vol% formic acid (99%), B = acetonitrile; gradient: 38% -68%,10 min) to give compound 8- (4- (difluoromethoxy) phenyl) -6- (2- (2-hydroxy-2-methylpropyl) -2H-indazol-5-yl) -2- ((2,2,2-trifluoroethyl) amino) pteridin-7 (8H) -one (I-22) (45.4 mg, yellow solid, 6.24% yield).
LC-MS,M/Z(ESI):576.3(M+H) +
1 H NMR(400MHz,CDCl 3 )δ8.99(s,1H),8.92(s,1H),8.25-8.27(d,1H),8.03(s,1H),7.77-7.79(m,1H),7.34(s,4H),6.44-6.80(t,1H),5.47-5.86(m,1H),4.22(s,2H),4.20(s,1H),3.83(s,1H),1.21(s,6H).
Example 23: preparation of target Compound I-23
The synthetic route is shown as follows:
Figure BDA0003571090790000711
the first step is as follows: synthesis of 5-bromo-2- (2- (methylsulfonyl) ethyl) -2H-indazole
To a solution of 5-bromo-2H-indazole (2.00g, 10.2 mmol) in acetonitrile (20.0 mL) was added 1-bromo-2- (methylsulfonyl) ethane (1.90g, 10.2 mmol) and potassium carbonate (2.81g, 20.3 mmol), and the reaction was stirred at 80 ℃ for 10 hours. After completion of the reaction, the reaction mixture was diluted with water (50.0 mL), followed by extraction with ethyl acetate (50.0 mL × 3), the organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified with a silica gel column (petroleum ether: ethyl acetate (V/V) =15 to 5:1) to give compound 5-bromo-2- (2- (methylsulfonyl) ethyl) -2H-indazole (600mg, 1.98mmol, white solid, yield 19.5%).
1 H NMR(400MHz,DMSO_d 6 )δ8.47(s,1H),8.00(d,1H),7.60(d,1H),7.33(dd,1H),4.88(t,2H),3.86(t,2H),2.93(s,3H).
The second step is that: synthesis of 2- (2- (methylsulfonyl) ethyl) -5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2H-indazole
To a solution of 5-bromo-2- (2- (methylsulfonyl) ethyl) -2H-indazole (300mg, 990. Mu. Mol) in 1,4-dioxane (10.0 mL) was added bis pinacolboronic acid ester (302mg, 1.19mmol), potassium acetate (291mg, 2.97mmol), and 1,1-bis (diphenylphosphino) ferrocene dichloropalladium (36.2mg, 49.5. Mu. Mol) under nitrogen, and the reaction was stirred at 85 ℃ for 10 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was separated and purified by a silica gel column (petroleum ether: ethyl acetate (V/V) =5:1 to dichloromethane: methanol (V/V) = 10) to give 2- (2- (methylsulfonyl) ethyl) -5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2H-indazole (320mg, 914 μmol, off-white solid, yield 92.3%).
LC-MS,M/Z(ESI):351.2(M+H) +
The third step: synthesis of 2- (cyclopropylamino) -8- (4- (difluoromethoxy) phenyl) -6- (2- (2- (methylsulfonyl) ethyl) -2H-indazol-5-yl) pteridin-7 (8H) -one (I-23)
Figure BDA0003571090790000721
To a solution of 6-chloro-2- (cyclopropylamino) -8- (4- (difluoromethoxy) phenyl) pteridin-7 (8H) -one (300mg, 790. Mu. Mol) in 1,4-dioxane (5.00 mL) and water (1.00 mL) was added 2- (2- (methylsulfonyl) ethyl) -5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2H-indazole (300mg, 857. Mu. Mol) (3), potassium carbonate (328mg, 2.37mmol) and 1,1-bis (diphenylphosphino) ferrocene dichloropalladium (57.8mg, 79.0. Mu. Mol) under nitrogen, and the reaction was stirred at 25 ℃ for 10 hours. After completion of the reaction, the reaction mixture was diluted with water (10.0 mL), then extracted with dichloromethane/methanol (10/1, 10.0mL × 3), the organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was slurried sequentially with methanol (20.0 mL), acetonitrile (20.0 mL), and dichloromethane (20.0 mL) to give the compound 2- (cyclopropylamino) -8- (4- (difluoromethoxy) phenyl) -6- (2- (2- (methylsulfonyl) ethyl) -2H-indazol-5-yl) pteridin-7 (8H) -one (I-23) (94.5 mg,153 μmol, yellow solid, yield 19.4%).
LC-MS,M/Z(ESI):568.3(M+H) +
1 H NMR(400MHz,DMSO_d 6 )δ8.69-9.02(m,2H),8.62(s,1H),8.10(dd,1H),7.58-7.94(m,2H),7.13-7.57(m,5H)4.89(t,2H),3.89(t,2H),2.69-3.04(m,4H),0.27-0.87(m,4H).
Example 24: preparation of target Compound I-24
The synthetic route is shown as follows:
Figure BDA0003571090790000722
the first step is as follows: synthesis of 2- (5-bromo-2H-indazol-2-yl) -N, N-dimethylacetamide
At room temperature, 5-bromo-2H-indazole (1.00g, 5.08mmol), N, N-dimethyl-2-chloroacetamide (925mg, 7.61mmol) and cesium carbonate (3.31g, 10.2mmol) were added to 1,4-dioxane (15.0 mL), reacted at 70 ℃ for 8 hours under nitrogen protection, and the reaction solution was filtered and concentrated to give a crude product. The crude product was then purified by normal phase preparative purification using (column: phenomenex Synergi XB-SiOH 250 x 70mm x 10um; solvent: a = N-hexane, B =99.9% ethanol +0.1% ammonia; gradient: 1% -40%,20 min) to give compound 2- (5-bromo-2H-indazol-2-yl) -N, N-dimethylacetamide (350 mg, white solid, 24.4% yield).
LC-MS,M/Z(ESI):282.1(M+H) +
The second step is that: synthesis of N, N-dimethyl-2- (5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2H-indazol-2-yl) acetamide
At room temperature, 2- (5-bromo-2H-indazol-2-yl) -N, N-dimethylacetamide (300mg, 1.06mmol), potassium acetate (313mg, 3.19mmol), bis-pinacol boronate (405mg, 1.59mmol), and 1,1-bis (diphenylphosphino) ferrocene palladium dichloride (77.8mg, 106. Mu. Mol) were added to 1,4-dioxane (3.00 mL) and reacted at 85 ℃ for 7 hours under nitrogen protection, and the reaction solution was filtered and concentrated to give the compound N, N-dimethyl-2- (5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2H-indazol-2-yl) acetamide (300 mg, crude yellow oil).
LC-MS,M/Z(ESI):330.2(M+H) +
The third step: 2- (5- (2- (cyclopropylamino) -8- (4- (difluoromethoxy) phenyl) -7-oxo-7,8-dihydropteridin-6-yl) -2H-indazol-2-yl) -N, N-dimethylacetamide (I-24)
Figure BDA0003571090790000731
N, N-dimethyl-2- (5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2H-indazol-2-yl) acetamide (300mg, 911. Mu. Mol), potassium carbonate (504mg, 3.65mmol), 6-chloro-2- (cyclopropylamino) -8- (4- (difluoromethoxy) phenyl) pteridin-7 (8H) -one (242mg, 638. Mu. Mol), 1,1-bis (diphenylphosphino) ferrocenepalladium (66.7mg, 91.1. Mu. Mol) were added to tetrahydrofuran (6.00 mL) and water (1.00 mL) under nitrogen protection, reacted at 25 ℃ for 8 hours, and the reaction solution was filtered and concentrated to give a crude product. The crude product was then purified by hplc using column: phenomenex synergy C18 x 30mm 7um, solvent: a = water +0.1 vol% hydrochloric acid (99%), B = acetonitrile, gradient: 40% -60%,7 min) to give compound 2- (5- (2- (cyclopropylamino) -8- (4- (difluoromethoxy) phenyl) -7-oxo-7,8-dihydropteridin-6-yl) -2H-indazol-2-yl) -N, N-dimethylacetamide (I-24) (71.2 mg, yellow solid, 14.2% yield).
LC-MS,M/Z(ESI):547.4(M+H) +
1 H NMR(400MHz,CDCl 3 )δ8.78-8.90(m,2H),8.44(s,1H),7.93-8.10(m,2H),7.63-7.65(d,1H),7.18-7.54(m,5H),5.46(s,2H),3.09(s,3H),2.87(s,3H),2.81-2.82(s,1H),0.40-0.66(m,4H).
Example 25: preparation of Compound I-25
The synthetic route is as follows:
Figure BDA0003571090790000741
the first step is as follows: synthesis of 5-bromo-1- (3-methylbut-2-en-1-yl) pyridin-2 (1H) -one
To a solution of 5-bromopyridin-2 (1H) -one (2.00g, 11.5 mmol) in tetrahydrofuran (20.0 mL) at 0 deg.C under nitrogen was added sodium hydrogen (690mg, 17.3mmol, content 60.0%) and the reaction stirred at 0 deg.C for 1 hour, followed by addition of 1-bromo-3-methylbut-2-ene (2.23g, 14.9 mmol) and stirring at 25 deg.C for 10 hours. After the reaction was completed, the reaction mixture was diluted with water (50.0 mL), then extracted with ethyl acetate (50.0 mL × 3), the organic layers were combined, washed with water (50.0 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified with a silica gel column (petroleum ether: ethyl acetate (V/V) =10 to 3:1) to give 5-bromo-1- (3-methylbut-2-en-1-yl) pyridin-2 (1H) -one (2.20g, 9.09mmol, yellow oil, yield 79.1%).
LC-MS,M/Z(ESI):242.1(M+H) +
1 H NMR(400MHz,CDCl 3 )δ6.99-7.89(m,2H),6.48(d,1H),5.29(br s,1H),4.51(d,2H),1.55-2.00(m,6H).
The second step is that: synthesis of 5-bromo-1- (3-hydroxy-3-methylbutyl) pyridin-2 (1H) -one
To a solution of 5-bromo-1- (3-methylbut-2-en-1-yl) pyridin-2 (1H) -one (1.00g, 4.13mmol) in 1,4-dioxane (20.0 mL) was added a solution of sulfuric acid (7.36g, 37.5mmol,50.0% concentration) and the reaction was stirred at 80 ℃ for 10 hours. After the reaction was completed, the reaction mixture was quenched with aqueous sodium hydroxide (4.00m, 30.0 ml) at 0 ℃, then extracted with ethyl acetate (20.0 ml × 3), the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give 5-bromo-1- (3-hydroxy-3-methylbutyl) pyridin-2 (1H) -one (800mg, 3.08mmol, gray oil, yield 74.5%).
LC-MS,M/Z(ESI):244.1(M-18+H) +
1 H NMR(400MHz,CDCl 3 )δ7.48(d,1H),7.35(dd,1H),6.49(d,1H),4.03-4.11(m,2H),1.87-1.95(m,2H),1.28(s,6H).
The third step: synthesis of 1- (3-hydroxy-3-methylbutyl) -5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2 (1H) -one
To a solution of 5-bromo-1- (3-hydroxy-3-methylbutyl) pyridin-2 (1H) -one (300mg, 1.15mmol) in 1,4-dioxane (2.00 mL) was added bis pinacol boronate (360mg, 1.42mmol), potassium acetate (340mg, 3.46mmol), and 1,1-bis (diphenylphosphino) ferrocene dichloropalladium (42.2mg, 57.7. Mu. Mol) under nitrogen, and the reaction was stirred at 85 ℃ for 10 hours. After completion of the reaction, the reaction mixture was diluted with water (20.0 mL), then extracted with ethyl acetate (20.0 mL × 3), and the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give 1- (3-hydroxy-3-methylbutyl) -5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2 (1H) -one (350 mg brown oil). Used directly in the next step.
LC-MS,M/Z(ESI):308.2(M+H) +
The fourth step: synthesis of 2- (cyclopropylamino) -8- (4- (difluoromethoxy) phenyl) -6- (1- (3-hydroxy-3-methylbutyl) -6-oxo-1,6-dihydropyridin-3-yl) pteridin-7 (8H) -one (I-25)
Figure BDA0003571090790000751
To a solution of 6-chloro-2- (cyclopropylamino) -8- (4- (difluoromethoxy) phenyl) pteridin-7 (8H) -one (340mg, 895. Mu. Mol) in 1,4-dioxane (4.00 mL) and water (1.00 mL) was added 1- (3-hydroxy-3-methylbutyl) -5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2 (1H) -one (4) (340mg, 1.11mmol), potassium carbonate (371mg, 2.68mmol) and 1,1-bis (diphenylphosphine) ferrocene dichloropalladium (65.5mg, 89.5. Mu. Mol) under nitrogen, and the reaction was stirred at 25 ℃ for 10 hours. After completion of the reaction, the reaction mixture was diluted with water (20.0 mL), followed by extraction with ethyl acetate (20.0 mL × 3), the organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by high performance liquid chromatography by (column: phenomenex luna C18150 × 40mm 15um; solvent: a = water +0.225 vol% formic acid (99.0%), B = acetonitrile; gradient: 35% -65%,10 min) to give the compound 2- (cyclopropylamino) -8- (4- (difluoromethoxy) phenyl) -6- (1- (3-hydroxy-3-methylbutyl) -6-oxo-1,6-dihydropyridin-3-yl) pteridine-7 (8H) -one (I-25) (104mg, 183 μmol, yellow solid, yield 20.4%).
LC-MS,M/Z(ESI):525.3(M+H) +
1 H NMR(400MHz,DMSO_d 6 )δ8.99(br s,1H),8.68-8.89(m,1H),8.28(dd,1H),7.15-7.58(m,6H),6.53(d,1H),4.47(s,1H),3.92-4.13(m,2H),2.67-2.98(m,1H),1.61-1.91(m,2H),1.13(s,6H),0.35-0.71(m,4H).
Example 26: preparation of Compound I-26
The synthetic route is as follows:
Figure BDA0003571090790000761
the first step is as follows: synthesis of 4- (2- (5-bromo-2H-indazol-2-yl) ethyl) morpholine
To a solution of 5-bromo-2H-indazole (16.0 g, 81.2mmol) in acetonitrile (400 mL) were added 4- (2-chloroethyl) morpholine (14.6 g,97.4 mmol) and potassium carbonate (22.4 g, 162mmol), and the reaction was stirred at 80 ℃ for 10 hours, then at 95 ℃ for 10 hours. After completion of the reaction, the reaction mixture was concentrated, and the residue was diluted with water (300 mL), followed by extraction with ethyl acetate (300ml × 3), combined with organic layers, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was isolated and purified with a silica gel column (petroleum ether: ethyl acetate (V/V) =10 to 3:1) to give compound 4- (2- (5-bromo-2H-indazol-2-yl) ethyl) morpholine (7.00g, 22.6mmol, off-white solid, yield 27.8%).
LC-MS,M/Z(ESI):310.1(M+H) +
1 H NMR(400MHz,CDCl 3 )δ7.97(s,1H),7.82(d,1H),7.58(d,1H),7.33(dd,1H),4.51(t,2H),3.62-3.75(m,4H),2.94(t,2H),2.42-2.57(m,4H).
The second step is that: synthesis of 4- (2- (5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2H-indazol-2-yl) ethyl) morpholine
To a solution of 4- (2- (5-bromo-2H-indazol-2-yl) ethyl) morpholine (6.00g, 19.3 mmol) in 1,4-dioxane (70.0 mL) was added bis pinacol boronate (5.89g, 23.2 mmol), potassium acetate (5.70g, 58.0mmol) and 1,1-bis (diphenylphosphino) ferrocene palladium dichloride (708mg, 967. Mu. Mol) under nitrogen, and the reaction was stirred at 85 ℃ for 10 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column separation (petroleum ether: ethyl acetate (V/V) =20 to 5:1) to give 4- (2- (5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2H-indazol-2-yl) ethyl) morpholine (6.50g, 18.2mmol, yellow oily substance, yield 94.1%).
LC-MS,M/Z(ESI):358.2(M+H) +
The third step: synthesis of 2- (cyclopropylamino) -8- (4- (difluoromethoxy) phenyl) -6- (2- (2-morpholinoethyl) -2H-indazol-5-yl) pteridin-7 (8H) -one (I-26)
Figure BDA0003571090790000771
To a solution of 4- (2- (5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2H-indazol-2-yl) ethyl) morpholine (2.50g, 7.00mmol) in 1,4-dioxane (30.0 mL) and water (5.00 mL) was added 6-chloro-2- (cyclopropylamino) -8- (4- (difluoromethoxy) phenyl) pteridin-7 (8H) -one (2.66g, 7.00mmol), potassium carbonate (2.90g, 21.0mmol) and 1,1-bis (diphenylphosphino) ferrocene palladium dichloride (256mg, 350. Mu. Mol) under nitrogen, and the reaction was stirred at 25 ℃ for 10 hours. After completion of the reaction, the reaction mixture was diluted with water (50.0 mL), then extracted with ethyl acetate (50.0 mL × 3), the organic layers were combined, washed with brine (50.0 mL × 2), dried, and the residue was slurried with ethyl acetate/methanol/dichloromethane (5/1/1, 70.0 mL) to give compound 2- (cyclopropylamino) -8- (4- (difluoromethoxy) phenyl) -6- (2- (2-morpholinoethyl) -2H-indazol-5-yl) pteridin-7 (8H) -one (I-26) (1.97g, 3.29mmol, yellow solid, yield 47.0%).
LC-MS,M/Z(ESI):575.4(M+H) +
1 H NMR(400MHz,DMSO_d 6 )δ8.60-9.07(m,2H),8.54(s,1H),8.08(dd,1H),7.15-7.89(m,7H),4.55(t,2H),3.52-3.54(m,4H),2.65-3.01(m,3H),2.44(br s,4H),0.35-0.73(m,4H).
The preparation of the reference compounds in the test examples according to the invention was obtained with reference to patent WO2019/191470A1 and the structure is shown below:
Figure BDA0003571090790000781
test example 1: MAT2A enzyme activity inhibition assay
IC of compound for inhibiting MAT2A enzyme activity is detected by adopting BPS Bioscience MAT2A inhibitor screening kit 50 First, the test compounds are dissolved in DMSO and all compounds are diluted in DMSO to startInitial concentration was 1mM,3 fold dilution, 10 concentration gradients. 200nL of diluted compound was transferred to reaction plates (784075, greiner) per well using Echo 550, and the plates were sealed with a sealing plate membrane and centrifuged at 1000g for 1 min at a final DMSO concentration of 1%. 2X MAT2A enzyme solution was prepared by preparing 1X enzyme reaction buffer, adding 10. Mu.L of 2X MAT2A enzyme solution to each well of 384-reaction plates (Corning 3702), sealing the plates with a sealing plate membrane, centrifuging at 1000g for 60 seconds, and incubating at room temperature for 10 minutes. A mixture of 2X L-Methionine and ATP was prepared in 1X MAT2A kinase reaction buffer, 10. Mu.L of a mixture of 2X L-Methionine and ATP was added to each well of the 384-reaction plate, and the plate was sealed with a sealing plate membrane to obtain 20. Mu.L of total reaction system. Centrifuge at 1000g for 60 seconds and incubate at room temperature for 60 minutes. mu.L of Detection buffer, colorimetric Detection Reagent, was added to each well, centrifuged at 1000g for 30 seconds, and reacted at room temperature for 15 minutes. The 630nm fluorescence signal was read by Envision 2104 and the inhibition was calculated by the following formula:
Figure BDA0003571090790000782
note: signal Ave_PC Fluorescence signal of positive control wells in the reaction plate; signal Ave_VC Fluorescence signal of negative control wells in the reaction plate.
IC of the compound was obtained using the following non-linear fit equation 50 (median inhibitory concentration):
Y＝Bottom+(Top-Bottom)/(1+10^((LogIC 50 -X)*HillSlope))
note: x is the log value of the concentration of the compound; y is Inhibition%
The inhibitory effect of the control compound and the compound of the present invention on the activity of MAT2A enzyme was measured according to the above-mentioned experimental method, and the results are shown in table 1 below:
TABLE 1 test Compound inhibition of MAT2A enzyme Activity
Test compounds IC 50 (nM)
Control Compounds 89.04
I-1 14.9
I-2 33.49
I-3 32.93
I-4 57.18
I-5 52.13
I-6 38.33
I-7 137.3
I-8 41.34
I-11 20.50
I-12 74.61
I-17 21.1
I-20 23.23
I-21 25.26
I-22 32.22
I-23 22.53
I-24 23.78
I-25 128.4
I-26 39.98
Experimental results show that the compound has good inhibitory activity on MAT2A enzyme and is superior to a control compound.
Test example 2: compound pair HCT116 MTAP-/- Effect of cell proliferation
The control and invention compounds were tested for HCT116 as described below MTAP-/- The effect of cell proliferation.
HCT116 MTAP-/- The cells were cultured in MCCOYS 5A medium, supplemented with 10% FBS and 1% Penicilin-Streptomyces at 37 ℃ 5% 2 Culturing under the condition. And (4) conventionally culturing the cells until the saturation degree of the cells is 80% -90%, and collecting the cells. And (4) resuspending the cells with a corresponding culture medium to prepare a cell suspension with a proper density. Transfer the diluted compounds to 150nL to 384 cell culture plates with Echo 550; cells were plated in 384 cell culture plates, 400/well, 30uL. Final upper concentration limit starting concentration of Compound20 μ M, 10 concentrations in a 4-fold gradient, and 30 μ M starting concentration of the control compound AGI-2452 in a 3-fold gradient. Placing the plate in a cell culture incubator at 37 ℃ and 5% 2 The culture was carried out for 5 days in the environment. The cell assay plate was allowed to stand at room temperature for 30 minutes, 30. Mu.L of CTG reagent (CelltiterGlo kit) was added to each well, and after 30 minutes of standing in the dark at room temperature, the chemiluminescence signal value was read by an Envision instrument. Calculation of Compound Pair HCT116 by measuring luminescence MTAP-/- Inhibitory Activity of cell proliferation IC 50 。
Table 2 test compound vs HCT116 MTAP-/- Inhibition of cell proliferation
Test compounds IC 50 (nM)
Control Compounds 266
I-1 27
I-11 87
I-20 115
I-22 100
The experimental results show that the compound of the invention is applied to HCT116 MTAP-/- Has good inhibition on cell proliferationThe inhibitory activity was superior to that of the control compound.
Test example 3: compound pair HCT116 MTAP-/- SAM level Effect in cells
The control and invention compounds were tested for HCT116 as described below MTAP-/- SAM level effects in cells.
HCT116 MTAP-/- The cells were cultured in MCCOYS 5A medium, supplemented with 10% FBS and 1% Penicilin-Streptomyces at 37 ℃ 5% 2 Culturing under the condition. And conventionally culturing the cells until the saturation degree of the cells is 80% -90%, and collecting the cells. Resuspending in appropriate medium to prepare cell suspension of appropriate density, inoculating in 96-well culture dish for 24 hr, and mixing with test compound at 37 deg.C and 5% CO 2 Incubated under conditions for 4 hours. SAM levels were measured in cells after compound treatment: cells were gently washed once in ammonium carbonate buffer (75mM, pH 7.4), placed on dry ice, and lysed with metabolite extraction buffer (80% cold methanol and 20% acetic acid containing 50ng/ml deuterated d3 SAM). After centrifugation at 3200rpm for 30 min at 4 ℃, the supernatant was collected and stored at-80 ℃ until the level of SAM was analyzed by LC/MS.
TABLE 3 inhibition of SAM levels in HCT116 MTAP-/-cells by 80nM compounds
Test compounds IC 50 (nM)
I-11 31.35
I-26 32.96
The experimental results show that the compound is applied to HCT116 MTAP-/- The SAM level in the cells has a significant inhibitory effect and is superior to the control compound.
Test example 4: human liver microsome stability
The stability of human liver microsomes of control compounds and compounds of the invention was determined according to the following experimental procedure. The liver microsome stability test of the compound adopts the in-vitro co-incubation of the compound and human liver microsome for detection. Test compounds were first formulated in DMSO solvent as 10mM stock solutions, followed by dilution of the compounds to 0.5mM using acetonitrile. Liver microsomes (Corning) were diluted with PBS to give a microsome/buffer solution, and 0.5mM of the compound was diluted with this solution to give a working solution in which the compound concentration was 1.5. Mu.M and the liver microsomes concentration was 0.75mg/ml. The reaction was initiated by adding 30. Mu.L of the working solution to each well of a deep-well plate, and then 15. Mu.L of a preheated 6mM NADPH solution, and incubated at 37 ℃. At 0, 5, 15, 30, 45 minutes of incubation, the reaction was stopped by adding 135 μ L of acetonitrile to the corresponding wells. After terminating the reaction with acetonitrile at the last 45 minute time point, the deep well plate was vortexed for 10 minutes (600 rpm/min) and then centrifuged for 15 minutes. Centrifuging, taking the supernatant, adding purified water into 1:1, performing LC-MS/MS detection to obtain the peak area ratio of the compound to the internal standard peak area at each time point, comparing the peak area ratios of the compound at 5, 15, 30 and 45 minutes with the peak area ratio at 0 minute, calculating the residual percentage of the compound at each time point, and calculating T by using Graphpad 5 software 1/2 。
Results of hepatic microsomal stability for Table 4 Compounds
Compound (I) Species T 1/2 (minute) Cl int (mL/min/kg)
I-1 Human being >1200 ≤0.01
The experimental result shows that the compound I has better stability, slow metabolism and good druggability in human liver microsomes. Test example 5: evaluation of toxicity of Compounds on human Normal liver cells
Toxicity of the control compounds and compounds of the invention to human normal liver cells was determined according to the following experimental method.
Human normal hepatocytes LO2 were cultured in DMEM medium containing 10% FBS, and seeded in 384-well plates at a density of 3000/well and 30. Mu.L/well when the cell growth state was good. Put at 37 ℃ and 5% CO 2 The incubator was overnight.
Gradient dilutions of compound or DMSO were added to each well and wells not seeded with cell addition medium were set as blanks. Put at 37 ℃ and 5% CO 2 After 20 hours in an incubator according to CytoTox-Glo TM Cytotoxicity Assay kit (Promega, cat. No. G9290) instruction book preparation Cytotox-Glo TM Cytotoxin detection reagents and lysis reagents. CytoTox-Glo was added at 10. Mu.L/well TM The cytotoxin detection reagent is placed for 15 minutes at room temperature, and dead cell luminescence signals are read on a multifunctional microplate reader. Lysis reagents were added at 10. Mu.L/well and the total luminescence signal was read on a multifunctional microplate reader after 15 minutes at room temperature. Viable cell signal = total signal-dead cell signal. Calculating the cell viability inhibition rate:
cell viability inhibition = (DMSO group-test compound)/(DMSO group-blank control group) × 100%
IC calculation Using Graphpad 5 software 50 The value is obtained.
The experimental result shows that the compound has no inhibitory activity on normal human liver cells LO2, and the compound has no toxic risk on the normal human liver cells.
Test example 6: pharmacokinetics in mice
The mouse pharmacokinetic properties of the control compounds and the compounds of the invention were determined according to the following experimental method.
3 male CD-1 mice were used, dose 10mg/kg, route of administration was intragastric, vehicle 5% DMSO +5% NMP +10% Solutol +80% (40% HB-CD), fasted overnight, blood sampling time points before and 15, 30 minutes and 1,2, 4,6, 8, 24 hours post-dose. Blood samples 6800g were centrifuged at 2-8 ℃ for 6 minutes, and plasma was collected and stored at-80 ℃.30 μ L of plasma at each time point was taken and 300 μ L of methanol containing 100ng/mL internal standard was added, vortexed, mixed and centrifuged at 18000g for 7 minutes at 2-8 ℃.200 μ L of the sample was transferred to a 96-well plate for LC-MS/MS quantitative analysis. The major pharmacokinetic parameters were analyzed using WinNonlin 7.0 software, a non-compartmental model.
TABLE 5 major pharmacokinetic parameters (mean) for gavage administration in mice
Compound (I) T 1/2 (h) T max (h) C max (ng/mL) AUC (0-t) (h·ng/mL)
I-1 2.37 0.5 11631 51974
The experimental result shows that the compound of the invention shows excellent pharmacokinetic properties in mice.
The embodiments of the present invention have been described above by way of example. It should be understood that the scope of the present invention is not limited to the above-described embodiments. Any modification, equivalent replacement, improvement or the like made by those skilled in the art within the spirit and principle of the present invention should be included in the protection scope of the claims of the present application.

Claims (28)

1. A compound of formula III, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, or prodrug thereof:
Figure FDA0003571090780000011
wherein L is 1 Selected from-O-, -S-, -N (R) L1 ) -and a single bond; r L1 Selected from hydrogen and C 1 -C 6 An alkyl group;
R 1 is selected from C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 3 -C 6 Cycloalkyl, - (C) 1 -C 6 Alkylene group) - (C 3 -C 6 Cycloalkyl) and- (C) 1 -C 6 Alkylene group) - (C 3 -C 6 Cycloalkenyl group) of C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 3 -C 6 Cycloalkyl, - (C) 1 -C 6 Alkylene group) - (C 3 -C 6 Cycloalkyl) and- (C) 1 -C 6 Alkylene group) - (C 3 -C 6 Cycloalkenyl) is optionally substituted by one or more R 1a Substituted, said R 1a Selected from halogens; when R is 1a When there are plural, R is 1a The same or different;
or when L is 1 is-N (R) L1 ) When is, R L1 And R 1 May be combined with L to form optionally substituted by one or more R L1 Substituted 3 to 6 membered heterocycloalkyl; when R is L1 When there are plural, R is L1 The same or different; the 3-to 6-membered heterocycloalkyl wherein 1,2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, the remainder being carbon atoms;
R 2 selected from unsubstituted or substituted by R 2a Substituted C 6 -C 10 Aryl, unsubstituted or substituted by R 2a Substituted 5 to 10 membered heteroaryl; when R is 2a When there are plural, R is 2a The same or different; the 5 to 10 membered heteroaryl wherein 1,2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, the remainder being carbon atoms;
R 3 selected from unsubstituted or substituted by R 3a Substituted C 6 -C 10 Aryl, unsubstituted or substituted by R 3a Substituted 5-to 10-membered heteroaryl, unsubstituted or substituted by R 3a A substituted ring A; when R is 3a When there are plural, R is 3a The same or different; the ring A is
Figure FDA0003571090780000012
Wherein ring Cx and ring Cy are each independently selected from C 5 -C 6 -aryl, 5-to 6-membered heteroaryl, 5-to 6-membered cycloalkyl and 5-to 6-membered heterocycloalkyl, D and E are each independently selected from C, CH, N, G and J are each independently selected from C, CH 2 、N、NH、O、S；
The R is 2a Is selected from-R A 、-OR A Halogen, -N = N-R A 、NR A R B 、-(C 1 -C 6 Alkylene) -NR A R B 、-C(O)OR A 、-C(O)NR A R B 、-OC(O)R A and-CN;
the R is 3a Is selected from-R A 、-OR A Halogen, -N = N-R A 、NR A R B 、-(C 1 -C 6 Alkylene) -NR A R B 、-C(O)OR A 、-C(O)NR A R B 、-OC(O)R A 、-CN、-(C 1 -C 6 Alkylene) -5-6 membered heterocycloalkyl, - (C) 1 -C 6 Alkylene) -S (O) 2 -(C 1 -C 3 Alkyl), - (C) 1 -C 6 Alkylene) -C (O) -NR A R B ；
R A And R B Each independently selected from H, -CN, -OH, oxo, C 1 -C 6 Alkyl radical, C 3 -C 6 Cycloalkyl radical, C 1 -C 6 Alkoxy radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, -NH 2 、-S(O) 0-2 -(C 1 -C 6 Alkyl), -S (O) 0-2 -(C 6 -C 10 Aryl), -CO- (C) 1 -C 6 Alkyl), -CO- (C) 3 -C 14 Cycloalkyl), -C 3 -C 14 Cycloalkyl, - (C) 1 -C 6 Alkylene group) - (C 3 -C 14 Cycloalkyl), C 6 -C 10 Aryl, 3 to 14 membered heterocycloalkyl, 5 to 10 membered heteroaryl; the 3 to 14 membered heterocycloalkyl and 5 to 10 membered heteroaryl, wherein 1,2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, the remainder being carbon atoms;
the R is A And R B Each C in 1 -C 6 Alkyl radical, C 3 -C 6 Cycloalkyl, C 1 -C 6 Alkoxy radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, -NH 2 、-S(O) 0-2 -(C 1 -C 6 Alkyl), -S (O) 0-2 -(C 6 -C 10 Aryl), -CO- (C) 1 -C 6 Alkyl), -CO- (C) 3 -C 14 Cycloalkyl), -C 3 -C 14 Cycloalkyl, - (C) 1 -C 6 Alkylene group) - (C 3 -C 14 Cycloalkyl), C 6 -C 10 Aryl, 3-to 14-membered heterocycloalkyl, 5-to 10-membered heteroaryl are each independently and optionally substituted with one or more R Aa Substitution; when R is Aa When there are plural, R is Aa The same or different;
said R is Aa Each independently selected from-OH,Deuterium, halogen, C 1 -C 6 Alkyl, -N (R) An ) 2 Wherein each R is An Each independently selected from H, C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 6 -C 10 Aryl, 3-to 14-membered heterocycloalkyl, - (C) 1 -C 6 Alkylene) - (3-to 14-membered heterocycloalkyl), and 5-to 10-membered heteroaryl, -NHC (O) - (OC) 1 -C 6 Alkyl), -NO 2 -CN, oxo, -C (O) OH, -C (O) -O- (C) 1 -C 6 Alkyl), - (C) 1 -C 6 Alkylene group) - (C 1 -C 6 -alkoxy), -C (O) NH 2 、-C(O)-(C 1 -C 6 Alkyl), -O- (C) 1 -C 6 Alkyl), -Si (C) 1 -C 6 Alkyl radical) 3 、-S(O) 0-2 -(C 1 -C 6 Alkyl group), C 6 -C 10 Aryl, - (C) 1 -C 6 Alkylene group) - (C 6 -C 10 Aryl), 3-to 14-membered heterocycloalkyl, - (C) 1 -C 6 Alkylene) - (3-to 14-membered heterocycloalkyl), and-O (C) 6 -C 14 Aryl groups);
the R is Aa Each alkyl, alkenyl, aryl and heterocycloalkyl of (a) is independently and optionally substituted with one or more R Ab Substituted, said R Ab Each independently selected from-OH, -O- (C) 1 -C 6 Alkyl), halogen, -NH 2 、-(C 1 -C 6 Alkylene) -NH 2 -COOH, -CN and oxo;
R 4 selected from hydrogen, halogen, -OH, -CN, C 1 -C 6 Alkyl radical, C 3 -C 6 Cycloalkyl, and- (C) 1 -C 6 Alkylene group) - (C 3 -C 6 Cycloalkyl), said C 1 -C 6 Alkyl radical, C 3 -C 6 Cycloalkyl, and- (C) 1 -C 6 Alkylene group) - (C 3 -C 6 Cycloalkyl) optionally substituted by one or more R 4a Substituted, said R 4a Selected from halogen; when R is 4a When there are plural, R is 4a The same or different.
2. The compound of claim 1,
L 1 selected from-O-, -S-, -N (R) L1 ) -and a single bond; r L1 Selected from hydrogen and C 1 -C 6 An alkyl group;
R 1 is selected from C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 3 -C 6 Cycloalkyl, - (C) 1 -C 6 Alkylene group) - (C 3 -C 6 Cycloalkyl) and- (C) 1 -C 6 Alkylene group) - (C 3 -C 6 Cycloalkenyl group) of C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 3 -C 6 Cycloalkyl, - (C) 1 -C 6 Alkylene group) - (C 3 -C 6 Cycloalkyl) and- (C) 1 -C 6 Alkylene group) - (C 3 -C 6 Cycloalkenyl) is optionally substituted by one or more R 1a Substituted, said R 1a Selected from halogens; when R is 1a When there are plural, R is 1a The same or different;
or when L is 1 is-N (R) L1 ) When is, R L1 And R 1 May be combined with L to form optionally substituted by one or more R L1 Substituted 3 to 6 membered heterocycloalkyl; when R is L1 When there are plural, R is L1 The same or different; the 3-to 6-membered heterocycloalkyl wherein 1,2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, the remainder being carbon atoms;
R 2 selected from unsubstituted or substituted by R 2a Substituted C 6 -C 10 Aryl, unsubstituted or substituted by R 2a Substituted 5 to 10 membered heteroaryl; when R is 2a When there are plural, R is 2a The same or different; the 5 to 10 membered heteroaryl wherein 1,2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, the remainder being carbon atoms;
R 3 selected from unsubstituted or substituted by R 3a Substituted C 6 -C 10 Aryl, unsubstituted or substituted by R 3a Substituted 5-to 10-membered heteroaryl, unsubstituted or substituted by R 3a A substituted ring A; when R is 3a When a plurality ofSaid R is 3a The same or different; the ring A is
Figure FDA0003571090780000031
Wherein ring Cx and ring Cy are each independently selected from C 5 -C 6 -aryl, 5-to 6-membered heteroaryl, 5-to 6-membered cycloalkyl and 5-to 6-membered heterocycloalkyl, D and E are each independently selected from C, CH, N, G and J are each independently selected from C, CH 2 、N、NH、O、S；
The R is 2a And R 3a Each independently selected from-R A 、-OR A Halogen, -N = N-R A 、NR A R B 、-(C 1 -C 6 Alkylene) -NR A R B 、-C(O)OR A 、-C(O)NR A R B 、-OC(O)R A and-CN;
R A and R B Each independently selected from H, -CN, -OH, oxo, C 1 -C 6 Alkyl radical, C 3 -C 6 Cycloalkyl, C 1 -C 6 Alkoxy radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, -NH 2 、-S(O) 0-2 -(C 1 -C 6 Alkyl), -S (O) 0-2 -(C 6 -C 10 Aryl), -CO- (C) 1 -C 6 Alkyl), -CO- (C) 3 -C 14 Cycloalkyl), -C 3 -C 14 Cycloalkyl, - (C) 1 -C 6 Alkylene group) - (C 3 -C 14 Cycloalkyl), C 6 -C 10 Aryl, 3 to 14 membered heterocycloalkyl, 5 to 10 membered heteroaryl; the 3 to 14 membered heterocycloalkyl and 5 to 10 membered heteroaryl, wherein 1,2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, the remainder being carbon atoms;
the R is A And R B Each C in 1 -C 6 Alkyl radical, C 3 -C 6 Cycloalkyl radical, C 1 -C 6 Alkoxy radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, -NH 2 、-S(O) 0-2 -(C 1 -C 6 Alkyl), -S (O) 0-2 -(C 6 -C 10 Aryl), -CO- (C) 1 -C 6 Alkyl), -CO- (C) 3 -C 14 Cycloalkyl), -C 3 -C 14 Cycloalkyl, - (C) 1 -C 6 Alkylene group) - (C 3 -C 14 Cycloalkyl), C 6 -C 10 Aryl, 3-to 14-membered heterocycloalkyl, 5-to 10-membered heteroaryl are each independently and optionally substituted with one or more R Aa Substitution; when R is Aa When there are plural, R is Aa The same or different;
the R is Aa Each independently selected from-OH, deuterium, halogen, -N (R) An ) 2 Wherein each R is An Each independently selected from H, C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 6 -C 10 Aryl, 3-to 14-membered heterocycloalkyl, - (C) 1 -C 6 Alkylene) - (3-to 14-membered heterocycloalkyl), and 5-to 10-membered heteroaryl, -NHC (O) - (OC) 1 -C 6 Alkyl), -NO 2 -CN, oxo, -C (O) OH, -C (O) -O- (C) 1 -C 6 Alkyl), - (C) 1 -C 6 Alkylene group) - (C 1 -C 6 -alkoxy), -C (O) NH 2 、-C(O)-(C 1 -C 6 Alkyl), -O- (C) 1 -C 6 Alkyl), -Si (C) 1 -C 6 Alkyl radical) 3 、-S(O) 0-2 -(C 1 -C 6 Alkyl group), C 6 -C 10 Aryl, - (C) 1 -C 6 Alkylene group) - (C 6 -C 10 Aryl), 3-to 14-membered heterocycloalkyl, - (C) 1 -C 6 Alkylene) - (3-to 14-membered heterocycloalkyl), and-O (C) 6 -C 14 Aryl groups);
said R is Aa Each alkyl, alkenyl, aryl and heterocycloalkyl of (a) is independently and optionally substituted with one or more R Ab Substituted, said R Ab Each independently selected from-OH, -O- (C) 1 -C 6 Alkyl), halogen, -NH 2 、-(C 1 -C 6 Alkylene) -NH 2 -COOH, -CN and oxo;
R 4 selected from hydrogen, halogen, -OH, -CN, C 1 -C 6 Alkyl radical, C 3 -C 6 Cycloalkyl, and- (C) 1 -C 6 Alkylene group) - (C 3 -C 6 Cycloalkyl), said C 1 -C 6 Alkyl radical, C 3 -C 6 Cycloalkyl, and- (C) 1 -C 6 Alkylene group) - (C 3 -C 6 Cycloalkyl) optionally substituted by one or more R 4a Substituted, said R 4a Selected from halogens; when R is 4a When there are plural, R is 4a The same or different.
3. A compound according to claim 1 or 2, wherein:
L 1 selected from-O-, -S-, -N (R) L1 ) -or a single bond; r L1 Selected from hydrogen, C 1 -C 3 An alkyl group; preferably, R L1 Selected from hydrogen, methyl, ethyl;
and/or, R 1 Is selected from C 1 -C 6 Alkyl radical, C 3 -C 6 Cycloalkyl, - (C) 1 -C 6 Alkylene group) - (C 3 -C 6 Cycloalkyl radicals); said C is 1 -C 6 Alkyl radical, C 3 -C 6 Cycloalkyl and- (C) 1 -C 6 Alkylene group) - (C 3 -C 6 Cycloalkyl) optionally substituted by one or more R 1a Substituted, said R 1a Selected from halogen;
and/or, R 2 Selected from unsubstituted or substituted by R 2a Substituted phenyl and unsubstituted or substituted by R 2a A substituted 5-to 10-membered heteroaryl, wherein one ring atom of the 5-to 10-membered heteroaryl is N; preferably, R 2 Selected from unsubstituted or substituted by R 2a Substituted phenyl, unsubstituted or substituted by R 2a Substituted pyridyl, unsubstituted or substituted by R 2a A substituted pyrimidinyl group;
and/or, R 3 Selected from unsubstituted or substituted by R 3a Substituted phenyl, unsubstituted or substituted by R 3a Substituted pyridyl, unsubstituted or substituted by R 3a Substituted pyridonyl, unsubstituted or substituted by R 3a Substituted pyridazinyl, unsubstituted or substituted by R 3a Substituted isoxazolyl, unsubstituted or substituted by R 3a Substituted pyrazolyl, and unsubstituted or substituted by R 3a A substituted ring A selected from
Figure FDA0003571090780000041
Benzothiazolyl, benzisothiazolyl, benzoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, quinoxalinyl, quinolyl, quinazolinyl, imidazopyridinyl, pyrazolopyridinyl, triazolopyridinyl, benzopyrazinyl, benzofuranyl, dihydrobenzofuranyl, dihydrobenzodioxovinyl, and tetrahydrobenzodioxovinyl, wherein n is A Selected from the integers 1,2 or 3; preferably, said ring a is selected from benzothiazolyl, benzimidazolyl, indazolyl, benzopiperidinyl, benzopiperazinyl, benzomorpholinyl, indane, chroman;
and/or, R 2a And R 3a Each independently selected from-R A 、-OR A Halogen and-CN;
and/or, R A Independently selected from H, -OH, C 1 -C 6 Alkyl radical, C 3 -C 6 Cycloalkyl, -CO- (C) 1 -C 6 Alkyl), - (C) 1 -C 6 Alkylene group) - (C 3 -C 14 Cycloalkyl), said C 1 -C 6 Alkyl radical, C 3 -C 6 Cycloalkyl, -CO- (C) 1 -C 6 Alkyl), - (C) 1 -C 6 Alkylene group) - (C 3 -C 14 Cycloalkyl) each independently and optionally substituted with one or more R Aa Substitution;
and/or, R Aa Each independently selected from-OH, halogen, -N (R) An ) 2 Wherein each R is An Each independently selected from H, methyl, ethyl, isopropyl, n-propyl;
and/or, R 4 Independently selected from hydrogen, halogen, -OH, -CN, C 1 -C 6 Alkyl radical, C 3 -C 6 Cycloalkyl, and- (C) 1 -C 6 Alkylene group) - (C 3 -C 6 Cycloalkyl) of said C 1 -C 6 Alkyl radical, C 3 -C 6 Cycloalkyl, and- (C) 1 -C 6 Alkylene group) - (C 3 -C 6 Cycloalkyl radicals) Optionally substituted by one or more R 4a Substituted, said R 4a Selected from fluorine and chlorine; when R is 4a When there are plural, R is 4a The same or different.
4. A compound according to any one of claims 1 to 3, wherein:
L 1 selected from-O-, -S-, -N (R) L1 ) -or a single bond; r L1 Selected from hydrogen, methyl, ethyl;
and/or, R 1 Selected from the group consisting of methyl, ethyl, propyl, fluoromethyl, fluoroethyl, fluoropropyl, cyclopropyl,
Figure FDA0003571090780000051
Preferably, R 1 Selected from methyl, ethyl, -CH 2 -CF 3 A cyclopropyl group,
Figure FDA0003571090780000052
And/or, R 2 Is selected from R 2a Substituted phenyl and substituted by R 2a Substituted pyridyl, and R 2a Independently selected from fluorine, chlorine, bromine, optionally substituted by one or more R Aa substituted-R A Optionally substituted by one or more R Aa substituted-OR A Said R is A Independently selected from the group consisting of one or more R Aa Substituted C 1 -C 6 Alkyl, by one or more R Aa Substituted C 3 -C 6 Cycloalkyl radical, each R Aa Independently selected from-OH, fluorine, chlorine, bromine; preferably, R 2a Independently selected from-fluoro, chloro, bromo, methyl, ethyl, n-propyl, isopropyl cyclopropyl, methoxy, ethoxy, n-propoxy, isopropoxy,
Figure FDA0003571090780000053
A fluoromethoxy group; more preferably, R 2 Is selected from
Figure FDA0003571090780000054
Figure FDA0003571090780000055
And/or, R 3 Is selected from the group consisting of 3a A substituted ring A selected from
Figure FDA0003571090780000056
Figure FDA0003571090780000057
Figure FDA0003571090780000058
And R is 3a Independently selected from the group optionally substituted by one or more R Aa substituted-R A Said R is A Independently selected from the group consisting of one or more R Aa Substituted C 1 -C 6 Alkyl radical, each R Aa Each independently selected from-OH, fluorine, chlorine, bromine; preferably, R 3a Independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, -CH 2 -OH、-(CH 2 ) 2 -OH、-(CH 2 ) 3 -OH、-(CH 2 ) 4 -OH、
Figure FDA0003571090780000061
And/or, R 4 Selected from the group consisting of hydrogen, halogen, -OH, -CN, methyl, ethyl, n-propyl, fluoromethyl, fluoroethyl, fluoropropyl, cyclopropyl, fluorocyclopropyl, and,
Figure FDA0003571090780000062
Chloromethyl, chloroethyl, chloropropyl, chlorocyclopropyl,
Figure FDA0003571090780000063
Preferably, R 4 Selected from hydrogen, halogen, methyl, ethyl, -CH 2 -CF 3 Cyclopropyl group、
Figure FDA0003571090780000064
5. A compound according to any one of claims 1 to 4 wherein R is 4 Is hydrogen;
R 2 is composed of
Figure FDA0003571090780000065
R 2a Selected from: fluorine, chlorine, bromine, -O-C 1 -C 6 Alkyl or C 3 -C 6 A cycloalkyl group; said C is 1 -C 6 Alkyl optionally substituted with one or more halogens;
R 3 is as a quilt R 3a A substituted ring A;
the R is 3a Is selected from-C 1 -C 6 Alkyl, - (C) 1 -C 6 Alkylene) -5-6 membered heterocycloalkyl, - (C) 1 -C 6 Alkylene) -S (O) 2 -CH 3 、-(C 1 -C 6 Alkylene) -C (O) -N (CH) 3 ) 2 ；
The ring A is
Figure FDA0003571090780000066
Wherein ring Cx is a 5-membered heteroaryl ring or a 5-membered heterocycloalkyl group;
ring Cy is a benzene ring, a 5-6 membered heteroaromatic ring or a 5-6 membered heterocycloalkyl group;
d and E are each independently selected from C, N;
preferably, the ring Cx is a 5 membered heteroaromatic ring containing 2N or 1N and 1S;
preferably, the ring Cx is a 5-membered heterocycloalkyl group containing 1O;
preferably, the cyclic Cy contains 1 or 2N;
preferably, the halogen is F.
6. A compound according to any one of claims 1 to 5 wherein R is 2 Is composed of
Figure FDA0003571090780000067
Figure FDA0003571090780000071
R 2a Selected from the group consisting of: fluorine, chlorine, -O-CF 2 H or cyclopropyl;
preferably, R 2 Is selected from
Figure FDA0003571090780000072
Figure FDA0003571090780000073
7. A compound according to any one of claims 1 to 6 wherein R is 3 Selected from:
Figure FDA0003571090780000074
Figure FDA0003571090780000075
R 3a selected from the group consisting of: -C 1 -C 6 Alkyl, -C 1 -C 6 Alkyl-5-6 membered heterocycloalkyl, -C 1 -C 6 alkyl-S (O) 2 -CH 3 、-C 1 -C 6 alkyl-C (O) -N (CH) 3 ) 2 ；
Preferably, C is 1 -C 6 The alkyl is straight-chain or branched-chain alkyl; said C is 1 -C 6 Alkyl is optionally substituted with-OH.
8. The compound of any one of claims 1-7, wherein: r 3 Is selected from
Figure FDA0003571090780000076
Figure FDA0003571090780000077
Figure FDA0003571090780000081
9. The compound of any one of claims 1-8, wherein the compound is a compound of formula II or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, or prodrug of the compound of formula II:
Figure FDA0003571090780000082
wherein R is 1 、R 2a 、R 3a 、R 4 、L 1 Having the definition of any one of claims 1 to 8;
preferably, L 1 Selected from-O-, -S-, -N (R) L1 ) -and a single bond; r L1 Selected from hydrogen and C 1 -C 6 An alkyl group;
R 1 is selected from C 1 -C 6 Alkyl radical, C 3 -C 6 Cycloalkyl, - (C) 1 -C 6 Alkylene group) - (C 3 -C 6 Cycloalkyl), said C 1 -C 6 Alkyl radical, C 3 -C 6 Cycloalkyl and- (C) 1 -C 6 Alkylene group) - (C 3 -C 6 Cycloalkyl) optionally substituted by one or more R 1a Substitution; when R is 1a When there are plural, R is 1a The same or different; said R is 1a Selected from halogen;
X 1 is selected from C (R) 2a )、N；
Y 1 、Y 2 、Y 3 Each independently selected from N, S, C;
R 2a independently selected from-R A 、-OR A And halogen;
R 3a independently selected from-R A ；
R A Independently selected from H, -CN, -OH, C 1 -C 6 Alkyl radical, C 3 -C 6 Cycloalkyl radicals, substituted by one or more R Aa Substituted C 1 -C 6 Alkyl, by one or more R Aa Substituted C 3 -C 6 A cycloalkyl group; when R is Aa When there are plural, R is Aa The same or different;
the R is Aa Each independently selected from-OH, deuterium, halogen;
R 4 selected from hydrogen, halogen, -OH, -CN, C 1 -C 6 Alkyl radical, C 3 -C 6 Cycloalkyl, and- (C) 1 -C 6 Alkylene group) - (C 3 -C 6 Cycloalkyl), said C 1 -C 6 Alkyl radical, C 3 -C 6 Cycloalkyl, and- (C) 1 -C 6 Alkylene group) - (C 3 -C 6 Cycloalkyl) optionally substituted by one or more R 4a Substituted, said R 4a Selected from halogen; when R is 4a When there are plural, R is 4a The same or different.
10. The compound of any one of claims 1-9,
L 1 selected from-O-, -S-, -N (R) L1 ) -or a single bond; r L1 Selected from hydrogen, C 1 -C 3 An alkyl group; preferably, R L1 Selected from hydrogen, methyl, ethyl;
and/or, R 1 Selected from the group consisting of methyl, ethyl, propyl, fluoromethyl, fluoroethyl, fluoropropyl, cyclopropyl,
Figure FDA0003571090780000091
Preferably, R 1 Selected from methyl, ethyl, -CH 2 -CF 3 A cyclopropyl group,
Figure FDA0003571090780000092
And/or, X 1 Selected from CH, N;
and/or, R 2a Independently selected from-fluoro, chloro, bromo, methyl, ethyl, n-propyl, isopropyl cyclopropyl, methoxy, ethoxy, n-propoxy, isopropoxy,
Figure FDA0003571090780000093
A fluoromethoxy group;
and/or, R 3a Independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, -CH 2 -OH、-(CH 2 ) 2 -OH、-(CH 2 ) 3 -OH、-(CH 2 ) 4 -OH、
Figure FDA0003571090780000094
And/or, R 4 Selected from the group consisting of hydrogen, halogen, -OH, -CN, methyl, ethyl, n-propyl, fluoromethyl, fluoroethyl, fluoropropyl, cyclopropyl, fluorocyclopropyl,
Figure FDA0003571090780000095
Chloromethyl, chloroethyl chloropropyl, chlorocyclopropyl,
Figure FDA0003571090780000096
Preferably, R 4 Selected from hydrogen, halogen, methyl, ethyl, -CH 2 -CF 3 A cyclopropyl group,
Figure FDA0003571090780000097
11. The compound of any one of claims 1-10, wherein the compound has the structure shown in structure II-a or II-b:
Figure FDA0003571090780000098
wherein R is 1 、L 1 、R 2a 、R 3a Having the definitions set forth in claims 1-10.
12. A compound according to any one of claims 1 to 11 wherein L is 1 Is selected from-O-, or-NH-;
R 1 selected from C1-C3 alkyl, - (C1-C3 alkylene) - (C3-C6 cycloalkyl), said C1-C3 alkyl, C3-C6 cycloalkyl, - (C1-C3 alkylene) - (C3-C6 cycloalkyl) optionally substituted by one or more R 1a Substitution; when R is 1a When there are plural, R is 1a The same or different; the R is 1a Selected from halogen;
preferably, the halogen is F;
preferably, R is 1 Selected from the group consisting of: methyl, ethyl, propyl, fluoromethyl, fluoroethyl, fluoropropyl, cyclopropyl,
Figure FDA0003571090780000101
More preferably, R 1 Selected from: methyl, ethyl, -CH 2 -CF 3 A cyclopropyl group,
Figure FDA0003571090780000102
Preferably, -L 1 -R 1 Selected from the group consisting of: -NH-cyclopropyl, -O-cyclopropyl, -NH-CH 2 CF 3 、-O-CH 2 CF 3 、-NH-CH 2 -cyclopropyl, -O-CH 2 -cyclopropyl.
13. The compound of any one of claims 1-12, wherein R is 3a Selected from: -C 1 -C 6 Alkyl, -C 1 -C 6 Alkyl-5-6 membered heterocycloalkyl, -C 1 -C 6 alkyl-S (O) 2 -CH 3 、-C 1 -C 6 alkyl-C (O) -N (CH) 3 ) 2 ；
Said C is 1 -C 6 The alkyl being straight-chain or branchedA chain alkyl group;
said C is 1 -C 6 Alkyl is optionally substituted with-OH;
preferably, the 5-6 membered heterocycloalkyl group is
Figure FDA0003571090780000103
Preferably, R 3a Selected from: -CH 3 、
Figure FDA0003571090780000104
Figure FDA0003571090780000105
14. The compound of any one of claims 1-13, wherein the compound is a compound of formula I or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, or prodrug of a compound of formula I:
Figure FDA0003571090780000111
wherein R is 1 、L 1 、R 2a 、R 3a 、R 4 、n A Having the definitions of claims 1-13;
preferably, L 1 Selected from-O-, -S-, -N (R) L1 ) -and a single bond; r is L1 Selected from hydrogen and C 1 -C 6 An alkyl group;
R 1 is selected from C 1 -C 6 Alkyl radical, C 3 -C 6 Cycloalkyl, - (C) 1 -C 6 Alkylene group) - (C 3 -C 6 Cycloalkyl), said C 1 -C 6 Alkyl radical, C 3 -C 6 Cycloalkyl and- (C) 1 -C 6 Alkylene group) - (C 3 -C 6 Cycloalkyl) optionally substituted by one or more R 1a Substitution; when R is 1a When there are plural, R is 1a The same or different; the R is 1a Selected from halogens;
X 1 is selected from C (R) 2a )、N；
R 2a Independently selected from-R A 、-OR A And halogen;
R 3a independently selected from-R A ；
R A Independently selected from H, -CN, -OH, C 1 -C 6 Alkyl radical, C 3 -C 6 Cycloalkyl radicals, substituted by one or more R Aa Substituted C 1 -C 6 Alkyl, by one or more R Aa Substituted C 3 -C 6 A cycloalkyl group; when R is Aa When there are plural, R is Aa The same or different;
the R is Aa Each independently selected from-OH, deuterium, halogen;
R 4 selected from hydrogen, halogen, -OH, -CN, C 1 -C 6 Alkyl radical, C 3 -C 6 Cycloalkyl, and- (C) 1 -C 6 Alkylene group) - (C 3 -C 6 Cycloalkyl) of said C 1 -C 6 Alkyl radical, C 3 -C 6 Cycloalkyl, and- (C) 1 -C 6 Alkylene group) - (C 3 -C 6 Cycloalkyl) optionally substituted by one or more R 4a Substituted, said R 4a Selected from halogens; when R is 4a When there are plural, R is 4a The same or different;
n A selected from the integers 1,2 or 3.
15. The compound according to any one of claims 1 to 14,
L 1 selected from-O-, -S-, -N (R) L1 ) -or a single bond; r is L1 Selected from hydrogen, C 1 -C 3 An alkyl group; preferably, R L1 Selected from hydrogen, methyl, ethyl;
and/or, R 1 Selected from the group consisting of methyl, ethyl, propyl, fluoromethyl, fluoroethyl, fluoropropyl, cyclopropyl,
Figure FDA0003571090780000112
Preferably, R 1 Selected from methyl, ethyl, -CH 2 -CF 3 A cyclopropyl group,
Figure FDA0003571090780000113
And/or, X 1 Selected from CH, N;
and/or, R 2a Independently selected from-fluoro, chloro, bromo, methyl, ethyl, n-propyl, isopropyl cyclopropyl, methoxy, ethoxy, n-propoxy, isopropoxy,
Figure FDA0003571090780000121
A fluoromethoxy group;
and/or, R 3a Independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, -CH 2 -OH、-(CH 2 ) 2 -OH、-(CH 2 ) 3 -OH、-(CH 2 ) 4 -OH、
Figure FDA0003571090780000122
And/or, R 4 Selected from the group consisting of hydrogen, halogen, -OH, -CN, methyl, ethyl, n-propyl, fluoromethyl, fluoroethyl, fluoropropyl, cyclopropyl, fluorocyclopropyl, and,
Figure FDA0003571090780000123
Chloromethyl, chloroethyl chloropropyl, chlorocyclopropyl, methyl ethyl,
Figure FDA0003571090780000124
Preferably, R 4 Selected from hydrogen, halogen, methyl, ethyl, -CH 2 -CF 3 A cyclopropyl group,
Figure FDA0003571090780000125
16. The compound of any one of claims 1-15, wherein the compound is selected from the group consisting of a compound shown below, or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, or prodrug of a compound shown below:
Figure FDA0003571090780000126
Figure FDA0003571090780000131
Figure FDA0003571090780000141
17. intermediates M-1 and M-2 shown below:
Figure FDA0003571090780000142
wherein the content of the first and second substances,
R M selected from halogen; l is a radical of an alcohol 1 、R 1 、R 2 、R 4 Having the definition set forth in any one of claims 1 to 16;
preferably, L 1 、R 1 、R 2 As defined in claim 1;
preferably, L 1 Selected from-O-, -S-, -N (R) L1 ) -and a single bond; r L1 Selected from hydrogen and C 1 -C 6 An alkyl group;
preferably, R 1 Is selected from C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 3 -C 6 Cycloalkyl, - (C) 1 -C 6 Alkylene group) - (C 3 -C 6 Cycloalkyl) and- (C) 1 -C 6 Alkylene group) - (C 3 -C 6 CycloalkenesRadical);
said C is 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 3 -C 6 Cycloalkyl, - (C) 1 -C 6 Alkylene group) - (C 3 -C 6 Cycloalkyl) and- (C) 1 -C 6 Alkylene group) - (C 3 -C 6 Cycloalkenyl) is optionally substituted by one or more R 1a Substituted, said R 1a Selected from halogen; when R is 1a When there are plural, R is 1a The same or different;
or when L is 1 is-N (R) L1 ) When is, R L1 And R 1 May be combined with L to form an optionally substituted one or more R L1 Substituted 3 to 6 membered heterocycloalkyl; when R is L1 When there are plural, R is L1 The same or different; the 3-to 6-membered heterocycloalkyl wherein 1,2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, the remainder being carbon atoms;
preferably, R 2 Selected from unsubstituted or substituted by R 2a Substituted C 6 -C 10 Aryl, unsubstituted or substituted by R 2a Substituted 5 to 10 membered heteroaryl; when R is 2a When there are plural, R is 2a The same or different; the 5 to 10 membered heteroaryl, wherein 1,2, 3, or 4 ring atoms are heteroatoms independently selected from O, S and N, the remainder being carbon atoms;
the R is 2a Is independently selected from-R A 、-OR A Halogen, -N = N-R A 、NR A R B 、-(C 1 -C 6 Alkylene) -NR A R B 、-C(O)OR A 、-C(O)NR A R B 、-OC(O)R A and-CN;
R A and R B Each independently selected from H, -CN, -OH, oxo, C 1 -C 6 Alkyl radical, C 3 -C 6 Cycloalkyl radical, C 1 -C 6 Alkoxy radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, -NH 2 、-S(O) 0-2 -(C 1 -C 6 Alkyl), -S (O) 0-2 -(C 6 -C 10 Aryl), -CO- (C) 1 -C 6 Alkyl radical)、-CO-(C 3 -C 14 Cycloalkyl), -C 3 -C 14 Cycloalkyl, - (C) 1 -C 6 Alkylene group) - (C 3 -C 14 Cycloalkyl), C 6 -C 10 Aryl, 3 to 14 membered heterocycloalkyl, 5 to 10 membered heteroaryl; the 3-to 14-membered heterocycloalkyl and 5-to 10-membered heteroaryl, wherein 1,2, 3, or 4 ring atoms are heteroatoms independently selected from O, S and N, the remainder being carbon atoms;
said R is A And R B Each C in 1 -C 6 Alkyl radical, C 3 -C 6 Cycloalkyl radical, C 1 -C 6 Alkoxy radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, -NH 2 、-S(O) 0-2 -(C 1 -C 6 Alkyl), -S (O) 0-2 -(C 6 -C 10 Aryl), -CO- (C) 1 -C 6 Alkyl), -CO- (C) 3 -C 14 Cycloalkyl), -C 3 -C 14 Cycloalkyl, - (C) 1 -C 6 Alkylene group) - (C 3 -C 14 Cycloalkyl), C 6 -C 10 Aryl, 3-to 14-membered heterocycloalkyl, 5-to 10-membered heteroaryl are each independently and optionally substituted with one or more R Aa Substitution; when R is Aa When there are plural, R is Aa The same or different;
the R is Aa Each independently selected from-OH, deuterium, halogen, -N (R) An ) 2 Wherein each R is An Each independently selected from H, C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 6 -C 10 Aryl, 3-to 14-membered heterocycloalkyl, - (C) 1 -C 6 Alkylene) - (3-to 14-membered heterocycloalkyl), and 5-to 10-membered heteroaryl, -NHC (O) - (OC) 1 -C 6 Alkyl), -NO 2 -CN, oxo, -C (O) OH, -C (O) -O- (C) 1 -C 6 Alkyl), - (C) 1 -C 6 Alkylene group) - (C 1 -C 6 -alkoxy), -C (O) NH 2 、-C(O)-(C 1 -C 6 Alkyl), -O- (C) 1 -C 6 Alkyl), -Si (C) 1 -C 6 Alkyl radical) 3 、-S(O) 0-2 -(C 1 -C 6 Alkyl group), C 6 -C 10 Aryl, - (C) 1 -C 6 Alkylene group) - (C 6 -C 10 Aryl), 3-to 14-membered heterocycloalkyl, - (C) 1 -C 6 Alkylene) - (3-to 14-membered heterocycloalkyl), and-O (C) 6 -C 14 Aryl);
the R is Aa Each alkyl, alkenyl, aryl and heterocycloalkyl of (a) is independently and optionally substituted with one or more R Ab Substituted, said R Ab Each independently selected from-OH, -O- (C) 1 -C 6 Alkyl), halogen, -NH 2 、-(C 1 -C 6 Alkylene) -NH 2 -COOH, -CN and oxo;
and said intermediate M-1 does not comprise the following compounds:
Figure FDA0003571090780000151
18. intermediates M-1 and M-2 according to claim 17, wherein:
R M selected from fluorine, chlorine, bromine, iodine; preferably, R M Selected from fluorine, chlorine, bromine;
L 1 selected from-O-, -S-, -N (R) L1 ) -or a single bond; r L1 Selected from hydrogen, C 1 -C 3 An alkyl group; preferably, R L1 Selected from hydrogen, methyl, ethyl;
and/or, R 1 Is selected from C 1 -C 6 Alkyl radical, C 3 -C 6 Cycloalkyl, - (C) 1 -C 6 Alkylene group) - (C 3 -C 6 Cycloalkyl groups); said C is 1 -C 6 Alkyl radical, C 3 -C 6 Cycloalkyl and- (C) 1 -C 6 Alkylene group) - (C 3 -C 6 Cycloalkyl) optionally substituted by one or more R 1a Substituted, said R 1a Selected from halogen;
and/or, R 2 Selected from unsubstituted or substituted by R 2a Substituted phenyl and unsubstituted or substituted by R 2a A substituted 5-to 10-membered heteroaryl, wherein one ring atom of the 5-to 10-membered heteroaryl is N; preferably, R 2 Selected from unsubstituted or substituted by R 2a Substituted phenyl, unsubstituted or substituted by R 2a Substituted pyridyl, unsubstituted or substituted by R 2a A substituted pyrimidinyl group;
and/or, R 2a Independently selected from-R A 、-OR A Halogen and-CN;
and/or, R A Independently selected from H, -OH, C 1 -C 6 Alkyl radical, C 3 -C 6 Cycloalkyl, -CO- (C) 1 -C 6 Alkyl), - (C) 1 -C 6 Alkylene group) - (C 3 -C 14 Cycloalkyl), said C 1 -C 6 Alkyl radical, C 3 -C 6 Cycloalkyl, -CO- (C) 1 -C 6 Alkyl), - (C) 1 -C 6 Alkylene group) - (C 3 -C 14 Cycloalkyl) each independently and optionally substituted with one or more R Aa Substitution;
and/or, R Aa Each independently selected from-OH, halogen, -N (R) An ) 2 Wherein each R is An Each independently selected from H, methyl, ethyl, isopropyl, n-propyl.
19. Intermediates M-1 and M-2 according to claim 17 or 18, wherein:
L 1 selected from-O-, -S-, -N (R) L1 ) -or a single bond; r L1 Selected from hydrogen, methyl, ethyl;
and/or, R 1 Selected from the group consisting of methyl, ethyl, propyl, fluoromethyl, fluoroethyl, fluoropropyl, cyclopropyl,
Figure FDA0003571090780000161
Preferably, R 1 Selected from methyl, ethyl, -CH 2 -CF 3 A cyclopropyl group,
Figure FDA0003571090780000162
And/or, R 2 Is selected fromBy R 2a Substituted phenyl and substituted by R 2a Substituted pyridyl, and R 2a Independently selected from fluorine, chlorine, bromine, optionally substituted by one or more R Aa substituted-R A Optionally substituted by one or more R Aa substituted-OR A Said R is A Independently selected from the group consisting of one or more R Aa Substituted C 1 -C 6 Alkyl, by one or more R Aa Substituted C 3 -C 6 Cycloalkyl radical, each R Aa Independently selected from-OH, fluorine, chlorine, bromine; preferably, R 2a Independently selected from-fluoro, chloro, bromo, methyl, ethyl, n-propyl, isopropyl cyclopropyl, methoxy, ethoxy, n-propoxy, isopropoxy,
Figure FDA0003571090780000163
A fluoromethoxy group; more preferably, R 2 Is selected from
Figure FDA0003571090780000164
Figure FDA0003571090780000165
20. Intermediate M-1 according to any one of claims 17 to 19, selected from any one of the following compounds:
Figure FDA0003571090780000171
21. intermediate M-2 according to any one of claims 17 to 19, selected from any one of the following compounds:
Figure FDA0003571090780000172
Figure FDA0003571090780000181
22. a process for the preparation of a compound according to any one of claims 1 to 16, which comprises:
(1) Contacting intermediate M-1 with a halogenating agent to provide said intermediate M-2; and/or
Figure FDA0003571090780000182
(2) Reacting said intermediate M-2 with
Figure FDA0003571090780000183
Contacting to obtain the compound shown in the formula III,
Figure FDA0003571090780000184
wherein R is 1 、R 2 、R 3 、R 4 、L 1 Having the definition as set forth in any of claims 1 to 16, R M Selected from fluorine, chlorine, bromine, iodine; preferably, R M Selected from fluorine, chlorine, bromine.
23. The method of claim 22, wherein:
in the step (1), the halogenating reagent is selected from N-chlorosuccinimide and N-bromosuccinimide; and/or
In the step (2), the intermediate M-2 is reacted with the intermediate M-2 under the protection of inert gas
Figure FDA0003571090780000185
Contacting a palladium catalyst with alkali to obtain the compound shown in the formula III.
24. A pharmaceutical composition comprising a therapeutically effective amount of at least one of a compound of any one of claims 1-16, a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt, or a prodrug thereof.
25. Use of a compound according to any one of claims 1 to 16 or a pharmaceutical composition according to claim 24 in the manufacture of a medicament for the treatment or prevention of MAT 2A-associated diseases.
26. Use of a compound according to any one of claims 1 to 16 or a pharmaceutical composition according to claim 24 in the manufacture of a medicament for the treatment or prophylaxis of cancer.
27. The use of claim 26, wherein the cancer is an MTAP-deficient cancer.
28. The use of claim 26, wherein the cancer is selected from mesothelioma, neuroblastoma, rectal cancer, colon cancer, familiar adenomatous polyposis and hereditary non-polyposis colorectal cancer, esophageal cancer, lip cancer, larynx cancer, hypopharynx cancer, tongue cancer, salivary gland cancer, stomach cancer, adenocarcinoma, medullary thyroid cancer, papillary thyroid cancer, kidney cancer, renal parenchymal cancer, ovarian cancer, cervical cancer, corpus uteri cancer, endometrial cancer, choriocarcinoma, pancreatic cancer, prostate cancer, bladder cancer, testicular cancer, breast cancer, urinary cancer, melanoma, brain tumor, lymphoma, head and neck cancer, acute Lymphoblastic Leukemia (ALL), chronic Lymphoid Leukemia (CLL), acute Myeloid Leukemia (AML), chronic Myelogenous Leukemia (CML), hepatocellular carcinoma, gallbladder cancer, bronchial cancer, small cell lung cancer, non-small cell lung cancer, multiple myeloma, basal sarcoma, teratocarcinoma, retinoblastoma, choroidal melanoma, ewing's germ cell tumor, rhabdomyosarcoma, osteosarcoma, chondrosarcoma, liposarcoma, fibrosarcoma, and sarcoma.
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