CN115028648A - Tricyclic compound, and pharmaceutical composition and application thereof - Google Patents
Tricyclic compound, and pharmaceutical composition and application thereof Download PDFInfo
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- CN115028648A CN115028648A CN202110237007.5A CN202110237007A CN115028648A CN 115028648 A CN115028648 A CN 115028648A CN 202110237007 A CN202110237007 A CN 202110237007A CN 115028648 A CN115028648 A CN 115028648A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D498/14—Ortho-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- 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
Abstract
The invention belongs to the field of pharmaceutical chemistry, and relates to a tricyclic compound, a pharmaceutical composition and application thereof. The compound is shown in a formula I, has good PARP7 enzyme inhibition activity, and can be used as a PARP7 inhibitor for treating and/or preventing diseases or symptoms (such as cancer) caused by PARP7 overexpression.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a tricyclic compound, a pharmaceutical composition containing the tricyclic compound and application of the tricyclic compound in the field of medicines.
Background
PARP is known as poly-ADP-ribose polymerase, i.e., poly-ADP ribose polymerase, and is involved in a variety of important cellular processes including DNA repair, gene expression, protein degradation, cellular stress reaction, etc. The protein family is composed of 17 members, all of which comprise a common catalytic domain of about 230 amino acids, and are mainly divided into PARPs including four subtypes PARP1/2 and PARP5a/5b, and monoPARPs including twelve subtypes PARP3, PARP4, PARP6, PARP7, PARP8, PARP9, PARP10, PAPR11, PARP12, PAPR14, PARP15, and PARP 16. PARP1/2 inhibitors targeting PARP1/2 have been marketed as a number of drugs for the treatment of a number of different types of tumors.
The MonoPARP protein family plays a role in a variety of stress responses associated with the development of cancer, inflammatory diseases and neurodegenerative diseases, and its member PARP7 has been shown to be overactivated in tumors and to play a key role in cancer cell survival. It has been found that many cancer cells rely on PARP7 for intrinsic cell survival, that PARP7 is highly expressed in many tumor cells, and that over-activation or high expression of PARP7 over-proliferates tumor cells, inhibits T cell activation, and enables cancer cells to escape immune system surveillance. The PARP7 can inhibit the activity of TBK1 protein, thereby preventing interferon secretion, inhibit PARP7, effectively inhibit the growth of cancer cells, restore interferon signal transduction, effectively activate T cell mediated antitumor immune effect, and prevent tumor cells from escaping immune system surveillance. Therefore, PARP7 has great practical value as a target for tumor treatment.
Disclosure of Invention
Problems to be solved by the invention
The invention aims to provide a tricyclic compound serving as a PARP7 inhibitor with a novel structure, which shows good inhibitory activity on tumor cells, has good drug-forming property, is expected to be used for treating cancers such as non-small cell lung cancer, digestive tract cancer, pancreatic cancer and the like, and has a wide drug development prospect.
Means for solving the problems
In a first aspect, the present invention provides a compound represented by formula I or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, metabolite or prodrug thereof, wherein
A is selected from C 6 -C 10 Aryl and 6-10 membered heteroaryl;
R 1 selected from hydrogen, halogen, cyano, hydroxy, amino, C 1 -C 6 Alkyl radical, C 1 -C 6 Heteroalkyl group, C 3 -C 8 Cycloalkyl radical, C 3 -C 8 Heterocycloalkyl radical, C 1 -C 3 Alkoxy radical, C 1 -C 3 Haloalkoxy and C 1 -C 6 Haloalkyl, wherein said alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkoxy, haloalkoxy, and haloalkyl are each optionally substituted with at least 1R 8 Substitution;
R 2 selected from hydrogen, C 1 -C 6 Alkyl and C 3 -C 8 Cycloalkyl, wherein said alkyl and cycloalkyl are each optionally substituted with at least 1R 8 Substitution;
R 3 、R 4 、R 5 and R 6 Each independently selected from hydrogen, halogen, cyano, hydroxy, amino, nitro, C (O) R 9 、C(O)NR 9 R 10 、C(O)OR 9 、OC(O)R 9 、C 1 -C 6 Alkyl radical, C 1 -C 6 Heteroalkyl group, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 3 Alkoxy radical, C 1 -C 3 Haloalkoxy, C 3 -C 8 Cycloalkyl, C 3 -C 8 Heterocycloalkyl radical, C 6 -C 10 Aryl and 6-10 membered heteroaryl, wherein the alkyl, heteroalkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocycloalkyl, or alkoxy is substituted with one or more substituents selected from the group consisting of alkyl, heteroalkyl, alkenyl, alkynyl, haloalkyl, alkoxyEach of which is optionally substituted with at least 1R 8 Substitution;
R 7 selected from hydrogen, halogen, cyano, hydroxy, amino, C 1 -C 6 Alkyl radical, C 1 -C 6 Heteroalkyl group, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 3 Alkoxy radical, C 1 -C 3 Haloalkoxy, C 3 -C 8 Cycloalkyl radical, C 3 -C 8 Heterocycloalkyl radical, C 6 -C 10 Aryl and 6-10 membered heteroaryl, wherein said alkyl, heteroalkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each optionally substituted with at least 1R 8 Substitution;
L 1 、L 2 and L 3 Each independently selected from- (CH) 2 ) o -(A) p -(CH 2 ) q -, wherein A is selected from O, C (R) 8 ) 2 Or NR 8 O, p and q are each independently any integer of 0 to 3;
Y 1 、Y 2 and Y 3 Each independently selected from the group consisting of single bond, O, S, NR 10 、C(＝O)、C(＝O)O、C(＝O)NR 10 、S(＝O)、S(＝O) 2 、S(＝O)NR 10 、S(＝O) 2 NR 10 Or NR 10 C(＝O)NR 10 ；
X 1 Selected from O, C (R) 8 ) 2 And NR 8 ；
X 2 Selected from the group consisting of CR 8 And N;
m and n are each independently selected from 0, 1,2, 3, 4 and 5;
R 8 and R 9 Each independently selected from hydrogen, halogen, cyano, hydroxy, amino, C 1 -C 6 Alkyl radical, C 1 -C 6 Heteroalkyl group, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 3 -C 8 Cycloalkyl, C 3 -C 8 Heterocycloalkyl, C 3 -C 8 Cyclic alkoxy oxygenRadical and C 3 -C 8 Heterocycloalkoxy, wherein the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkoxy, and heterocycloalkoxy are each optionally substituted with at least 1R 10 Substitution;
R 1 to R 9 Wherein the heteroatom or heteroatom group contained in the heteroalkyl group, heterocycloalkyl group, heterocycloalkoxy group, heteroaryl group is independently selected from the group consisting of-C (═ O) N (R) 10 )-、-N(R 10 )-、-N＝、-O-、-S-、-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O) 2 -and-N (R) 10 )C(＝O)N(R 10 ) And the number of said heteroatoms or groups of heteroatoms is independently selected from 1,2 and 3, respectively;
R 10 selected from the group consisting of hydrogen, chloro, fluoro, cyano, hydroxy, amino, isopropyl, cyclopropyl, methyl, difluoromethyl, trifluoromethyl, methoxy, trifluoromethoxy, ethoxy, 2, 2-difluoroethoxy, 2,2, 2-trifluoroethoxy, and phenyl.
Preferably, it is a compound represented by any one of the formulas I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11 or I-12,
more preferably, it is a compound represented by any one of the formulas I-1-1, I-2-1, I-3-1, I-4-1, I-5-1, I-6-1, I-7-1, I-8-1, I-9-1, I-10-1, I-11-1 or I-12-1,
in a second aspect, the present invention provides the following specific compounds:
in a third aspect, the present invention provides a pharmaceutical composition, which comprises one or more compounds shown as I, I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, -1-1, I-2-1, I-3-1, I-4-1, I-5-1, I-6-1, I-7-1, I-8-1, I-9-1, I-10-1, I-11-1 or I-12-1 or pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, tautomers, metabolites or prodrugs thereof.
Preferably, the pharmaceutical composition further comprises at least one pharmaceutically acceptable adjuvant.
In a fourth aspect, the present invention provides a compound represented by formula I, I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, -1-1, I-2-1, I-3-1, I-4-1, I-5-1, I-6-1, I-7-1, I-8-1, I-9-1, I-10-1, I-11-1 or I-12-1, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, metabolite or prodrug thereof, or a pharmaceutical composition comprising the same, for use in the preparation of a medicament for the prevention and/or treatment of a disease or disorder caused by overexpression of PARP7 The use of (1) in medicine.
In a fifth aspect, the present invention provides a compound represented by formula I, I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, -1-1, I-2-1, I-3-1, I-4-1, I-5-1, I-6-1, I-7-1, I-8-1, I-9-1, I-10-1, I-11-1 or I-12-1, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, metabolite or prodrug thereof, or a pharmaceutical composition comprising the same, for use in the prevention and/or treatment of a disease or condition caused by overexpression of PARP 7.
In a sixth aspect, the invention provides compounds of formula I, I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, -1-1, I-2-1, the use of a compound represented by I-3-1, I-4-1, I-5-1, I-6-1, I-7-1, I-8-1, I-9-1, I-10-1, I-11-1 or I-12-1, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, metabolite or prodrug thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for the treatment and/or prevention of cancer.
Preferably, the cancer is one or more of a hematologic tumor, pancreatic cancer, colorectal cancer and lung cancer.
In a seventh aspect, the present invention provides a method for the prevention and/or treatment of diseases or conditions caused by the overexpression of PARP7, comprising administering a prophylactically and/or therapeutically effective amount of a compound of formula I, I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, -1-1, I-2-1, I-3-1, I-4-1, I-5-1, I-6-1, I-7-1, I-8-1, I-9-1, I-10-1, I-11-1 or I-12-1, or a pharmaceutically acceptable salt thereof, to a subject in need thereof, The hydrate, solvate, stereoisomer, tautomer, metabolite or prodrug or a pharmaceutical composition comprising the same is administered to a subject in need thereof.
ADVANTAGEOUS EFFECTS OF INVENTION
The invention provides a series of tricyclic compounds with novel structures, and related enzyme and cell activity tests prove that the compounds of the invention not only have good PARP7 enzyme inhibition activity, but also have excellent cell proliferation inhibition activity, and IC for cell proliferation in vitro experiments 50 The value reaches nM level, and the method can be well applied to various tumors. The compounds of the present invention are suitable for the preparation of PARP7 inhibitors for the prevention and/or treatment of diseases or disorders associated with PARP7 activation, such as cancer (including but not limited to hematological tumors, pancreatic cancer, digestive tract tumors, colorectal cancer and lung cancer).
Detailed Description
General terms and definitions
Unless stated to the contrary, the terms used in the present invention have the following meanings.
"alkyl" refers to a saturated aliphatic hydrocarbon group, including straight and branched chain groups of 1 to 20 carbon atoms, such as straight and branched chain groups of 1 to 18 carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms. In the present invention, "alkyl" may be a monovalent, divalent or trivalent group. Non-limiting examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, various branched chain isomers thereof, and the like. Non-limiting examples also include, but are not limited to, methylene, methine, ethylene, ethylidene, propylidene, butylidene, and various branched chain isomers thereof. In addition, in the present invention, "alkyl" may be optionally substituted or unsubstituted.
"alkoxy" refers to a "-O-alkyl" group, wherein "alkyl" is as defined above.
"alkenyl" refers to an unsaturated aliphatic hydrocarbon group, straight and branched chain groups including 2 to 20 carbon atoms and at least 1 carbon-carbon double bond, such as straight and branched chain groups which may be 1 to 18 carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms. In the present invention, "alkenyl" may be a monovalent, divalent or trivalent group. Non-limiting examples include, but are not limited to, vinyl (-CH ═ CH) 2 ) Propen-1-yl (-CH ═ CH-CH) 3 ) Propen-2-yl (-C (CH) 3 )＝CH 2 ) Butene-1-yl (-CH-CH) 2 -CH 3 ) Butene-2-yl (-C (C) 2 H 5 )＝CH 2 ) 1-Methylpropen-1-yl (-C (CH) 3 )＝CH-CH 3 ) And various branched chain isomers thereof, and the like. Non-limiting examples also include, but are not limited to, 1-ethenylene (═ C ═ CH) 2 ) 1, 2-ethenylene (-CH ═ CH-), 1-propenylene (═ C ═ CH-), and their salts 3 ) 1, 2-propenylene (-CH. cndot. C (CH)) 3 ) -) and 1, 3-propenylene (-CH-CH) 2 -) and its various branchesChain isomers. In addition, in the present invention, "alkenyl" may be optionally substituted or unsubstituted.
"alkynyl" refers to an unsaturated aliphatic hydrocarbon group, including straight and branched chain groups of 2 to 20 carbon atoms and at least 1 carbon-carbon triple bond, such as straight and branched chain groups of 1 to 18 carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms. In the present invention, "alkynyl" may be a monovalent, divalent or trivalent group. Non-limiting examples include, but are not limited to, ethynyl (-C ≡ CH), propynyl (-C ≡ C-CH) 3 ) Butynyl group
Pentynyl radical
And various branched chain isomers thereof, and the like. Non-limiting examples also include, but are not limited to, ethynylene (-C ≡ C-), propynyl
Butynylene radical
And various branched chain isomers thereof. In addition, in the present invention, "alkynyl group" may be optionally substituted or unsubstituted.
"Heteroalkyl" means a saturated aliphatic hydrocarbon group including straight and branched chain groups of 2 to 20 atoms, such as straight and branched chain groups of 2 to 18 atoms, 2 to 12 atoms, 2 to 8 atoms, 2 to 6 atoms, or 2 to 4 atoms, wherein one or more of the atoms is selected from nitrogen, oxygen, or S (O) m (wherein m is 0, 1 or 2) and the remainder are carbon. In the present invention, "heteroalkyl" may be a monovalent, divalent or trivalent group. Non-limiting examples include, but are not limited to, methoxymethyl (2-oxapropyl), methylthiomethyl (2-thiapropyl), methylaminomethyl (2-azapropyl), various branched isomers thereof, and the like. In addition, in the present invention, "heteroalkyl" may be optionally substituted or unsubstituted.
"cycloalkyl" refers to a saturated or partially unsaturated, monocyclic or polycyclic aliphatic hydrocarbon group comprising 3 to 12 ring atoms, which may be, for example, 3 to 12, 3 to 10, or 3 to 6 ring atoms (i.e., a 3 to 6 membered ring). Non-limiting examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like. In the present invention, "cycloalkyl" may be optionally substituted or unsubstituted.
"Heterocycloalkyl" means a saturated or partially unsaturated, monocyclic or polycyclic aliphatic hydrocarbon group containing 3 to 20 ring atoms, which may be, for example, 3 to 16, 3 to 12, 3 to 10 or 3 to 6 ring atoms, wherein one or more of the ring atoms is selected from nitrogen, oxygen or S (O) m (wherein m is 0, 1 or 2) and the remaining ring atoms are carbon; preferably 3 to 12 ring atoms, of which 1 to 4 ring atoms are heteroatoms; more preferably 3 to 10 ring atoms, most preferably 5 or 6 ring atoms, of which 1 to 4, preferably 1 to 3, more preferably 1 to 2 ring atoms are heteroatoms. Non-limiting examples of monocyclic heterocycloalkyl include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like. Non-limiting examples of polycyclic heterocycloalkyl groups include, but are not limited to, fused (fused), spiro, or bridged heterocycloalkyl groups.
"halogen" means fluorine, chlorine, bromine and iodine, preferably fluorine, chlorine and bromine.
"haloalkyl" or "haloalkoxy" means an alkyl or alkoxy group substituted with one or more of the same or different halogen atoms, examples of preferred alkyl or alkoxy groups include, but are not limited to, trifluoromethyl, trifluoroethyl, trifluoromethoxy, and the like.
"cyano" refers to the group "-CN".
"hydroxy" refers to an "-OH" group.
"amino" means "-NH 2 A "group.
"carbamoyl" refers to "- (C ═ O) -NH 2 "group".
"aryl" means a carbocyclic ring system containing 6 to 14, preferably 6 to 10, more preferably 6 to 7 ring atoms. Monocyclic, bicyclic and tricyclic carbon ring systems of ring atoms, wherein at least one ring system is aromatic, wherein each ring system comprises a ring of 3 to 7 atoms with one or more attachment points to the rest of the molecule. Examples include, but are not limited to, phenyl, naphthyl, anthracene, and the like.
"heteroaryl" means monocyclic, bicyclic and tricyclic ring systems containing 5 to 14, preferably 5 to 10 ring atoms, wherein at least one ring system is aromatic and at least one ring system contains one or more members selected from nitrogen, oxygen or S (O) m (wherein m is 0, 1 or 2), wherein each ring system comprises a ring of 5-7 atoms with one or more attachment points to the rest of the molecule. The term "heteroaryl" may be used interchangeably with the terms "heteroaromatic ring" or "heteroaromatic compound". Examples include, but are not limited to, furyl, imidazolyl, pyridyl, thiazolyl, purinyl, quinolinyl, and the like.
"optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs or does not. For example, "a heterocyclic group optionally substituted with an alkyl" means that an alkyl may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl and the heterocyclic group is not substituted with an alkyl.
By "substituted" is meant that one or more, preferably up to 5, more preferably 1 to 3, hydrogen atoms in the group are independently substituted with a corresponding number of substituents.
"pharmaceutically acceptable salt" refers to a salt prepared from a compound of the present invention with a relatively nontoxic acid or base. When the compounds of the present invention contain relatively acidic functional groups (e.g., carboxyl or sulfonic acid groups), base addition salts can be obtained by contacting the free form with a sufficient amount of a base in neat solution or in a suitable inert solvent. Non-limiting examples of pharmaceutically acceptable base addition salts include, but are not limited to, sodium, potassium, ammonium, calcium, magnesium, organic amine salts, or similar salts. When the compounds of the present invention contain relatively basic functional groups, such as amino or guanidino groups, acid addition salts may be obtained by contacting the free form with a sufficient amount of the acid in neat solution or in a suitable inert solvent. Non-limiting examples of pharmaceutically acceptable acid addition salts include, but are not limited to, inorganic acid salts (e.g., hydrochloride, hydrobromide, hydroiodide, nitrate, carbonate, bicarbonate, phosphate, monohydrogen phosphate, dihydrogen phosphate, phosphite, sulfate, hydrogen sulfate, etc.), organic acid salts (e.g., acetate, propionate, isobutyrate, malonate, succinate, suberate, maleate, fumarate, citrate, tartrate, lactate, mandelate, benzoate, phthalate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, glucuronic acid, etc.), and amino acid salts (e.g., arginate, etc.). Specific forms of pharmaceutically acceptable Salts can also be found in Berge et al, "Pharmaceutical Salts", Journal of Pharmaceutical Science,1977,66: 1-19). Certain specific compounds of the invention contain both basic and acidic functionalities and can thus be converted to either base addition salts or acid addition salts. Preferably, the neutral form of the compound is regenerated by contacting the salt with a base or acid and isolating the parent compound in a conventional manner. The parent form of the compound differs from its various salt forms in certain physical properties, such as solubility in polar solvents. According to an embodiment of the present invention, the pharmaceutically acceptable salt of the compound shown in formula I is preferably an acid addition salt, preferably a hydrochloride, a hydrobromide, a phosphate or a sulfate, more preferably a hydrochloride.
"pharmaceutical composition" refers to a pharmaceutically acceptable composition comprising one or more compounds of formula I or pharmaceutically acceptable forms thereof (e.g., salts, hydrates, solvates, stereoisomers, tautomers, metabolites, prodrugs, etc.), as well as other components (e.g., pharmaceutically acceptable excipients).
In the present invention, "pharmaceutically acceptable auxiliary materials" refer to auxiliary materials widely used in the field of pharmaceutical production. The main purpose of the use of excipients is to provide a pharmaceutical composition that is safe to use, stable in nature and/or has a specific functionality, and to provide a method for dissolving the active ingredient at a desired rate after administration of the drug to a subject, or for promoting an efficient absorption of the active ingredient in the subject to whom it is administered. Pharmaceutically acceptable excipients may be inert fillers or may be functional ingredients that provide some function to the pharmaceutical composition (e.g., stabilize the overall pH of the composition or prevent degradation of the active ingredients in the composition). Non-limiting examples of pharmaceutically acceptable excipients include, but are not limited to, binders, suspending agents, emulsifiers, diluents (or fillers), granulating agents, adhesives, disintegrating agents, lubricants, antiadherents, glidants, wetting agents, gelling agents, absorption delaying agents, dissolution inhibitors, enhancers, adsorbents, buffering agents, chelating agents, preservatives, coloring agents, flavoring agents, sweetening agents, and the like.
The pharmaceutical compositions of the present invention may be prepared using any method known to those skilled in the art. For example, conventional mixing, dissolving, granulating, emulsifying, levigating, encapsulating, entrapping and/or lyophilizing processes.
In the present invention, the pharmaceutical composition is used for the purpose of promoting administration to a living body, facilitating absorption of an active ingredient, and exerting biological activity. The pharmaceutical compositions of the present invention may be administered in any form, including injection (intra-arterial, intravenous, intramuscular, intraperitoneal, subcutaneous), mucosal, oral (solid oral, liquid oral), rectal, inhalation, implant, topical (e.g., ocular) administration, and the like. Non-limiting examples of oral solid formulations include, but are not limited to, powders, capsules, lozenges, granules, tablets, and the like. Non-limiting examples of liquid formulations for oral or mucosal administration include, but are not limited to, suspensions, tinctures, elixirs, solutions and the like. Non-limiting examples of formulations for topical administration include, but are not limited to, emulsions, gels, ointments, creams, patches, pastes, foams, lotions, drops, or serum formulations. Non-limiting examples of parenteral formulations include, but are not limited to, injectable solutions, injectable dry powders, injectable suspensions, injectable emulsions, and the like. The pharmaceutical compositions of the present invention may also be formulated as controlled release or delayed release dosage forms (e.g., liposomes or microspheres).
Preferably, the compound of the present invention or the pharmaceutical composition comprising the same is administered to an individual in need thereof by oral or intravenous administration. Other routes of administration may also be applied and even preferred depending on the particular circumstances of the subject. For example, for patients who are forgetful or have irritability to oral medications, transdermal administration would be a very important mode of administration. In the present invention, the route of administration can be varied or adjusted in any suitable manner to meet the needs of the nature of the drug, the convenience of the patient and the medical staff, and other relevant factors.
The compound or the pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, metabolite or prodrug thereof or the pharmaceutical composition containing the compound or the pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, metabolite or prodrug thereof have excellent PARP7 enzyme inhibition activity and cell proliferation inhibition activity, can be used as a PARP7 inhibitor, is used for preventing and/or treating diseases or symptoms caused by PARP7 overexpression, and has good clinical application and medical application. Preferably, non-limiting examples of diseases or conditions caused by overexpression of PARP7 are cancers, including but not limited to hematologic tumors, pancreatic cancer, colorectal cancer, and lung cancer.
The technical solutions of the present invention will be illustrated below with reference to specific examples, which are provided to further illustrate the present invention and are not intended to limit the scope of the present invention. It will be apparent to those skilled in the art that various changes and modifications can be made in the specific embodiments of the present invention without departing from the spirit and scope of the invention.
The preparation of the compounds of the present invention may be accomplished by synthetic methods well known to those skilled in the art, including but not limited to the specific embodiments listed below, embodiments formed by combinations with other chemical synthetic methods, and equivalents known to those skilled in the art, with preferred embodiments including but not limited to the examples of the present invention. Known starting materials for use in the present invention may be synthesized by methods known in the art or purchased by conventional commercial means (e.g., from Shaosha remote chemical technology, Beijing coupling technology, etc.). Unless otherwise specified, the reaction was carried out under an argon atmosphere or a nitrogen atmosphere. The hydrogenation reaction was usually evacuated and charged with hydrogen and repeated 3 times. The reaction temperature is room temperature and the temperature range is 20-30 ℃. Monitoring of the progress of the reaction can be accomplished by synthetic methods well known to those skilled in the art, including but not limited to Thin Layer Chromatography (TLC). Thin layer chromatography silica gel plates using Qingdao ocean GF254 silica gel plates, developer systems include but are not limited to A: dichloromethane and methanol systems; b: petroleum ether and ethyl acetate, the volume ratio of the solvent can be adjusted according to the polarity of the compound.
The isolation and purification of the compounds of the present invention can be accomplished by synthetic methods well known to those skilled in the art, including but not limited to Column Chromatography (CC), High Performance Liquid Chromatography (HPLC), ultra high performance liquid chromatography (UPLC), and the like. Column chromatography typically uses Qingdao ocean 200-: dichloromethane and methanol systems; b: the volume ratio of the petroleum ether to the ethyl acetate system can be adjusted according to the polarity of the compound, and a small amount of acidic or alkaline tailing-preventing agent can also be added for adjustment. The HPLC profile was determined using an Agilent1200DAD HPLC chromatograph (column: Sunfire C18,150X 4.6mm,5 μm) or a Waters 2695-2996HPLC chromatograph (column: Gimini C18,150X 4.6mm,5 μm).
Structural identification of the compounds of the invention can be accomplished by methods well known to those skilled in the art, including but not limited to Nuclear Magnetic Resonance (NMR), Mass Spectrometry (MS), and the like. NMR spectrum is measured by Bruker AVANCE-400 or Varian Oxford-300 nuclear magnetic instrument, and the measuring solvent is deuterated dimethyl sulfoxide (DMSO-d) 6 ) Deuterated chloroform (CDC 1) 3 ) Or deuterated methanol (CD) 3 OD), internal standard Tetramethylsilane (TMS), chemical shifts at 10 -6 (ppm). MS spectra were measured using an Agilent SQD (ESI) mass spectrometer (model: 6110) or Shimadzu SQD (ESI) mass spectrometer (model: 2020).
Preparation of intermediates
Preparation of intermediate INT-1
The synthetic route is as follows:
the preparation method comprises the following steps:
the first step is as follows: synthesis of Compound INT-1B
Compound INT-1A (25.4g,100mmol) was dissolved in DMF (250mL), cooled to 5 ℃ under ice bath, then sodium hydrogen (6g,150mmol, mass fraction 60%) was added in portions, after the addition, reaction was carried out at 25 ℃ for 1 hour, cooled to 5 ℃ under ice bath, 4-methoxybenzyl chloride (23.4g,150mmol) was added dropwise, and then the reaction was kept at 25 ℃ for reaction for 3 hours. TLC showed the reaction was complete, 1L of water was added, solid precipitated, filtered, collected, washed with ice methanol and dried to give Compound INT-1B (28.5g, grey solid, 76% yield).
MS(ESI):m/z 375[M+1] + 。
The second step: synthesis of Compound INT-1C
Compound INT-1B (28.0g,74.6mmol) was dissolved in MeOH (300mL), potassium hydroxide (12.5g,225mmol) was added at 25 deg.C, and the reaction was held at 25 deg.C for 3 h. TLC showed the reaction was complete, after methanol was spun off, the resulting solid was added to water (200mL), stirred well, filtered to give a solid, which was washed with ice methanol and dried to give compound INT-1C (22.3g, white solid, 92% yield).
MS(ESI):m/z 325[M+1] + 。
The third step: synthesis of Compound INT-1D
Compound INT-1C (22g,67.6mmol) was added to NMP (220mL), methyl fluorosulfonyldifluoroacetate (39g,203mmol, cas:680-15-9) and cuprous iodide (6.4g,33.8mmol) were then added, the reaction was performed at 100 ℃ for 3 hours under nitrogen after the addition was completed, after TLC showed the completion of the reaction, the reaction solution was cooled, 1L of water was added and extracted with ethyl acetate (500mL × 3), the combined organic phases were washed with water (500mL × 2) and saturated aqueous sodium chloride solution (500mL × 2), the organic phase was dried over sodium sulfate and then spin-dried, and the obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate ═ 3:1 (volume ratio)) to obtain compound INT-1D (15.3g, yellow oil, yield 72%).
MS(ESI):m/z 315[M+1] + 。
The fourth step: synthesis of Compound INT-1E
Compound INT-1D (15g,47.7mmol) was added to DMF (150mL), then TMSI (12.3g,62mmol) was added dropwise, after completion of the addition, the temperature was raised to 85 ℃ and the reaction was carried out for 24 hours, after TLC showed the completion of the reaction, the reaction solution was cooled, 1L of water was added and extracted with DCM (500mL × 3), the combined organic phase was washed with water (500mL × 2) and saturated aqueous sodium chloride solution (500mL × 2) in this order, the organic phase was dried over sodium sulfate and then spin-dried, the obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate ═ 3:1 (volume ratio)) to obtain a crude compound, which was then slurried with methyl t-butyl ether to obtain compound INT-1E (10.3g, white solid, yield 74%).
MS(ESI):m/z 301[M+1] + 。
The fifth step: synthesis of Compound INT-1F
Compound INT-1E (10g,33.2mmol) was added to DMF (50mL) then cooled under ice bath at 5 ℃ and oxalyl chloride (8.5g,66.5mmol) was slowly added dropwise. After the addition was complete, the ice bath was removed, the temperature was raised to 25 ℃ and the reaction was allowed to proceed for 8 hours, after TLC showed the completion of the reaction, the reaction mixture was slowly added to water (300ml), and a large amount of solid was precipitated, filtered, collected, and dried to give Compound INT-1F (9.85g, white solid, 93% yield).
MS(ESI):m/z 319[M+1] + 。
And a sixth step: synthesis of Compound INT-1G
Compound INT-1F (5g,15.6mmol) was added to THF (50mL), followed by triethylamine (4.7g,47mmol) and DL-aminopropanol (1.4g,18.72 mmol). Then heated to 65 ℃ for reaction for 2 h. After TLC showed the reaction was complete, the reaction was cooled, added to water (250ml), extracted with ethyl acetate (100ml × 3), the combined organic phases were washed with saturated aqueous sodium chloride (100ml × 2), the organic phase was dried over sodium sulfate and then dried by spin drying, and the resulting residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate 3:1 (vol.%)) to give compound INT-1G (4.6G, yellow oil, 82% yield).
MS(ESI):m/z 358[M+1] + 。
The seventh step: synthesis of Compound INT-1H
Compound INT-1G (4.5G,12.6mmol) was added to acetonitrile (50mL), followed by cesium carbonate (4.9G,15mmol) and ethyl acrylate (12.6G,126mmol), and the reaction was reacted at 25 ℃ for 12 h. TLC showed the reaction was complete, the reaction was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate 3:1 (vol.%)) to give compound INT-1H (3.6g, light yellow liquid, 63% yield).
MS(ESI):m/z 458[M+1] + 。
Eighth step: synthesis of Compound INT-1
Compound INT-1H (3.5g,7.6mmol) was added to a mixed solvent of 3N hydrochloric acid (35mL) and isopropanol (3.5mL) at room temperature, and then heated to 90 ℃ for reaction for 16H. TLC showed the reaction was complete, the reaction was diluted with ethyl acetate, extracted with water, washed with brine, the organic phase was dried over anhydrous sodium sulfate and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate 1:2 (vol.%)) to give compound INT-1(2.2g, pale yellow liquid, 66% yield).
MS(ESI):m/z 428[M-1] + 。
Preparation of the Compounds
Example 1:compound 1(5- ((1- (3-oxo-3- (3- (trifluoromethyl) -6a,7,9, 10-tetrahydropyrazino [1, 2-d)]Pyrido [3,2-b][1,4]Preparation of oxazin-8 (6H) -yl) propoxy) propan-2-yl) amino) -4- (trifluoromethyl) pyridazin-3 (2H) -one)
The synthetic route is as follows:
the preparation method comprises the following steps:
the first step is as follows: synthesis of Compound 1C
Compound 1A (2.6g,10mmol) and tert-butyl 3- (hydroxymethyl) piperazine-1-carboxylate (2.6g,12mmol) were dissolved in DMSO (30mL), followed by addition of cesium fluoride (3g,20mmol) and reaction at 100 ℃ for 2 hours. After TLC showed the reaction was complete, the reaction was cooled, added to water (150ml), extracted with ethyl acetate (100ml × 3), the combined organic phases were washed with saturated aqueous sodium chloride (100ml × 2), the organic phase was dried over sodium sulfate and then dried by spin drying, and the resulting residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate 1:1 (volume ratio)) to give compound 1C (2.9g, yellow solid, yield 67%).
MS(ESI):m/z 440[M+1] + 。
The second step: synthesis of Compound 1D
Compound 1C (2.2g,5mmol) was dissolved in dioxane (25mL), cesium carbonate (3.26g,10mmol), xanthphos (289mg,0.5mmol, cas:161265-03-8), and palladium acetate (112mg,0.5mmol) were added in this order, then the temperature was raised to 100 ℃ under nitrogen protection for 16 hours, TLC showed the reaction to be complete, the reaction solution was spin-dried, and the resulting residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate 3:1 (volume ratio)) to give compound 1D (1.16g, yellow solid, 62% yield).
MS(ESI):m/z 360[M+1] + 。
The third step: synthesis of Compound 1E
Compound 1D (1.1g,3mmol) was added to EA (10mL), 8% HCl-EA (10mL) was added dropwise over ice and reacted at room temperature for 12 h. TLC showed the reaction was complete, and the reaction was spin-dried to give Compound 1E (0.7g, yellow solid, 94% yield).
MS(ESI):m/z 260[M+1] + 。
The fourth step: synthesis of Compound 1F
Compound INT-1(200mg,0.47mmol) was added to DMF (3mL), followed by DIEA (129mg,1mmol) and HATU (380mg,1mmol), and the reaction was allowed to warm up for 20 min. Compound 1E (146mg,0.56mmol) obtained in the previous step was added again, reacted at room temperature for 3 hours, TLC showed the reaction was completed, the reaction solution was added to water (20ml), extracted with ethyl acetate (10 ml. times.3), the combined organic phases were washed with saturated aqueous sodium chloride solution (10 ml. times.2), the organic phase was dried over sodium sulfate and then dried by spin-drying, and the obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate 1:2 (volume ratio)) to obtain compound 1F (177mg, yellow solid, yield 56%).
MS(ESI):m/z 671[M+1] + 。
The fifth step: synthesis of Compound 1
Compound F (150mg,0.22mmol) was added to trifluoroacetic acid (2mL) at room temperature, followed by trifluoromethanesulfonic acid (0.3 mL). After the addition was complete, the reaction was carried out at room temperature for 2 hours. After TLC indicated the reaction was complete, water (10ml) was added, the pH adjusted to 8-9 with saturated aqueous potassium carbonate and extracted with ethyl acetate (10 ml. times.3), the combined organic phases were washed with saturated aqueous sodium chloride (10 ml. times.2), the organic phases were dried over sodium sulfate and spun to give crude yellow solid, which was purified by preparative silica gel plate (developer: petroleum ether/ethyl acetate 1:2 (vol.) to give pure compound 1(53mg, white solid, 44% yield).
MS(ESI):m/z 551[M+1] + 。
1 H-NMR(400MHz,DMSO-d6):12.44(s,1H),8.07(s,1H),7.91(s,1H),7.28(s,1H),6.25(s,1H),4.51-4.29(m,3H),4.16-4.13(m,1H),4.03-3.95(m,2H),3.77-3.65(m,2H),3.49-3.47(m,2H),3.43-3.40(m,1H),3.17-3.11(m,1H),2.91-2.85(m,1H),2.79-2.71(m,1H),2.68-2.60(m,2H),1.15(d,J＝8H,3H)。
Using the different chiral starting materials obtained by purchase, using the route and conditions for the synthesis of compound 1, the compounds shown in table 1 are obtained:
TABLE 1
Test example 1: PARP7 enzyme Activity test experiment
This assay was used to examine the efficacy of compounds to inhibit PARP7 enzyme activity with lower IC 50 Values represent the high potency of compounds as PARP7 inhibitors in the following assay setup.
1. Experimental materials:
the PARP7 chemiluminescence detection kit was purchased from BPS Bioscience.
2. The experimental method comprises the following steps:
PBST buffer solution preparation: 0.05% Tween 20 was contained in 1 XPBS, i.e., 5. mu.L of 100% Tween 20 was added to 10mL of PBS.
The histone solution in the kit is added with 4 parts of PBS according to 1 part of solution, and 25 mu L/hole dilution is taken and incubated overnight at 4 ℃. The dilutions were removed before use, plates were washed 3 times with 100. mu.L/well PBST, 100. mu.L/well blocking solution was added, and incubated at 25 ℃ for 90 min. After the incubation was completed, the plate was washed 3 times with 100. mu.L/well PBST, and the residual liquid in the wells was discarded.
1X test buffer formulation: diluting 10 XPARP test buffer solution with double distilled water by 10 times;
preparing a compound solution: test compounds were diluted 3-fold with DMSO solution to 8 th concentration, i.e., from 300 μ M to 137 nM. The test compounds were then diluted in 1 Xassay buffer to working solutions with 10% DMSO in each gradient. 2.5. mu.L/well was added to the corresponding well. Add 12.5. mu.L/well bottom mix solution (1.25. mu.L 10 XPARP assay buffer; 1.25. mu.L 10 XPARP assay mix; 10. mu.L double distilled water) per well. The PARP7 enzyme was diluted to 6 ng/. mu.L, 10. mu.L/well was added to the corresponding wells at a final compound concentration gradient of 3. mu.M to 1.37nM, PARP7(60ng), and the reaction was incubated at 25 ℃ for 60 min;
after finishing incubation, discarding the liquid in the hole, taking 100 mu L/hole PBST to wash the plate for 3 times, and discarding the residual liquid in the hole; performing 50-fold dilution on Streptavidin-HRP by using a confining liquid, then taking 25 mu L/hole to a corresponding hole, and incubating for 30 minutes at 25 ℃; after finishing incubation, discarding the liquid in the hole, taking 100 mu L/hole PBST to wash the plate for 3 times, and discarding the residual liquid in the hole; ELISA ECL substrate A and ELISA ECL substrate B were mixed well at 1:1(v/v) on ice, 50. mu.L/well was put into the corresponding well, and the chemiluminescence values were read.
3. Experimental data processing method
Calculating the inhibition rate by using the luminescence information value, and performing nonlinear regression curve fitting on the concentration and the inhibition rate by using Graphpad Prism software to obtain IC 50 The value is obtained.
Wherein, the inhibitory effect of the compounds 1-5 prepared by the invention and a PARP7 enzyme inhibitor RBN-2397 commonly used in the field on the activity of PARP7 enzyme is shown in Table 2.
TABLE 2 IC inhibition of PARP7 enzyme by compounds of the present invention 50 Data of
| Compound number | IC 50 (nM) |
| RBN-2397 | 31.31 |
| Compound 1 | 38.74 |
| Compound 2 | 30.80 |
| Compound 3 | 28.25 |
| Compound 4 | 19.36 |
| Compound 5 | 23.67 |
As shown in Table 2, the compounds (specifically, compounds 1 to 5) of the present invention have good inhibitory effect on PARP7 enzyme, especially the PARP7 enzyme inhibitory activity of compound 4 is better than that of RBN-2397, and the compounds are extremely excellent lead compounds.
Test example 2: NCI-H1373 cell antiproliferation assay
1. Experimental materials:
cell line NCI-H1373 was purchased from Kyobo. RPMI1640 medium, penicillin/streptomycin antibiotics were purchased from prenocidin. Fetal bovine serum was purchased from Biosera. CellTiter-Glo (cell viability chemiluminescence detection reagent) reagent was purchased from Promega. The EnVision multi-label analyzer was purchased from PerkinElmer.
2. The experimental method comprises the following steps:
NCI-H1373 cells were plated in white 96-well plates, 80. mu.L of cell suspension/well, containing 2000 NCI-H1373 cells. The cell plates were placed in a carbon dioxide incubator overnight. The test compounds were diluted 3-fold with a calandria to the 9 th concentration, i.e. from 600 μ M to 91.45nM, setting up a double-well experiment. Add 78. mu.L of medium to the intermediate plate, transfer 2. mu.L/well of the gradient diluted compound to the intermediate plate according to the corresponding position, mix well and transfer 20. mu.L/well to the cell plate. The concentration of compound transferred to the cell plate ranged from 3. mu.M to 0.46 nM. The cell plate was cultured in a carbon dioxide incubator for 6 days. A separate cell plate was prepared, and the signal values were read on the day of drug addition as maximum values (Max values in the following equation) for data analysis. To each well of the cell plate, 25. mu.L of a cell viability chemiluminescence detection reagent was added, and the plate was incubated at room temperature for 10 minutes to stabilize the luminescence signal. Reading with a multi-label analyzer. After the incubation of the cell plate added with the compound is finished, 25 μ L of cell viability chemiluminescence detection reagent is added into each well of the cell plate, and the cell plate is incubated at room temperature for 10 minutes to stabilize the luminescence signal. Reading with a multi-label analyzer.
3. Experimental data processing method
Calculating the inhibition rate by using the luminescence information value, and performing nonlinear regression curve fitting on the concentration and the inhibition rate by using Graphpad Prism software to obtain IC 50 The value is obtained.
Wherein the inhibitory effect of the compounds 1-5 prepared by the present invention and the PARP7 enzyme inhibitor RBN-2397 commonly used in the art on the anti-proliferation of NCI-H1373 cells is shown in Table 3.
TABLE 3 IC of the antiproliferation experiments on NCI-H1373 cells by the compounds of the invention 50 Data of
| Compound number | IC 50 (nM) |
| RBN-2397 | 271 |
| Compound 1 | 349 |
| Compound 2 | 595 |
| Compound 3 | 516 |
| Compound 4 | 263 |
| Compound 5 | 283 |
As can be seen from Table 3, the compounds (specifically, compounds 1 to 5) of the present invention have good inhibition effect on NCI-H1373 cell proliferation, especially the anti-proliferation activity of compound 4 is superior to that of RBN-2397, and the compounds are extremely excellent compounds, have very large anti-tumor potential, and have good clinical application prospects.
Test example 3: drug metabolism test
Using compound RBN-2397 and compound 4 of the present invention, the oral drug was formulated into a 1.0mg/mL clear solution (DMSO: PEG 300: tween 80: water ═ 6.25:28.75:2:63(v/v/v/v)), and the intravenous drug was formulated into a 0.2mg/mL clear solution (DMSO: PEG 300: tween 80: water ═ 6.25:28.75:2:63 (v/v/v/v)).
Male CD-1 mice, 3 each per group, weighing 27-28g, were provided by Shanghai Si Laike laboratory animal responsibility Co., Ltd. The test mice are given an environmental adaptation period of 2-4 days before the experiment, are fasted for 8-12h before the administration, are fed with water after the administration for 2h, and are fed with food after 4 h.
After the mice are fasted but can drink water freely for 12 hours, blank plasma at 0 moment is adopted; taking mice, and orally administering 10mg/kg of the compound to be tested (PO); intravenous (IV) administration of 1mg/kg of test compound; continuously taking blood from fundus venous plexus 5min, 15min, 30min, 1h, 2h, 4h, 8h, 10h and 24h after oral administration, placing in an EP tube distributed with heparin, centrifuging at 8000rpm for 5min, taking upper layer plasma, freezing at-20 deg.C, and analyzing by LC-MS/MS; according to the obtained blood concentration-time data, pharmacokinetic parameters are calculated by adopting WinNonlin software, and specific data are shown in a table 4.
Table 4: pharmacokinetic data for the Compounds of the invention
The pharmacokinetic experimental data are shown in table 4, and the results show that after the compound 4 is orally or intravenously administered to mice, the compound has very high exposure and very good half-life, area under the curve and bioavailability in animal plasma, has good drug forming property, has higher apparent distribution volume and longer half-life compared with a clinical compound RBN-2397, and has good clinical application prospect.
While embodiments of the present invention have been shown and described above, it should be understood that the above embodiments are exemplary and should not be taken as limiting the invention. Variations, modifications, substitutions and changes to the above-described embodiments can be made by those skilled in the art within the scope of the present invention without departing from the principle and spirit of the invention, and these variations, modifications, substitutions and changes are intended to be included within the scope of the present invention.
Claims (10)
1. A compound of formula I or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, metabolite, or prodrug thereof, wherein
A is selected from C 6 -C 10 Aryl and 6-10 membered heteroaryl;
R 1 selected from hydrogen, halogen, cyano, hydroxy, amino, C 1 -C 6 Alkyl radical, C 1 -C 6 Heteroalkyl group, C 3 -C 8 Cycloalkyl radical, C 3 -C 8 Heterocycloalkyl radical, C 1 -C 3 Alkoxy radical, C 1 -C 3 Haloalkoxy and C 1 -C 6 Haloalkyl, wherein said alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkoxy, haloalkoxy, and haloalkyl are each optionally substituted with at least 1R 8 Substitution;
R 2 selected from hydrogen, C 1 -C 6 Alkyl and C 3 -C 8 Cycloalkyl, wherein said alkyl and cycloalkyl are each optionally substituted with at least 1R 8 Substitution;
R 3 、R 4 、R 5 and R 6 Each independently selected from hydrogen, halogen, cyano, hydroxy, amino, nitro, C (O) R 9 、C(O)NR 9 R 10 、C(O)OR 9 、OC(O)R 9 、C 1 -C 6 Alkyl radical, C 1 -C 6 Heteroalkyl group, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 3 Alkoxy radical, C 1 -C 3 Alkyl halidesOxy radical, C 3 -C 8 Cycloalkyl radical, C 3 -C 8 Heterocycloalkyl radical, C 6 -C 10 Aryl, 6-10 membered heteroaryl, wherein said alkyl, heteroalkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is each optionally substituted with at least 1R 8 Substitution;
R 7 selected from hydrogen, halogen, cyano, hydroxy, amino, C 1 -C 6 Alkyl radical, C 1 -C 6 Heteroalkyl group, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 3 Alkoxy radical, C 1 -C 3 Haloalkoxy, C 3 -C 8 Cycloalkyl radical, C 3 -C 8 Heterocycloalkyl radical, C 6 -C 10 Aryl, 6-10 membered heteroaryl, wherein said alkyl, heteroalkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is each optionally substituted with at least 1R 8 Substitution;
L 1 、L 2 and L 3 Each independently selected from- (CH) 2 ) o -(A) p -(CH 2 ) q -, wherein A is selected from O, C (R) 8 ) 2 Or NR 8 O, p and q are independently any integer from 0 to 3;
Y 1 、Y 2 and Y 3 Each independently selected from the group consisting of a single bond, O, S, NR 10 、C(＝O)、C(＝O)O、C(＝O)NR 10 、S(＝O)、S(＝O) 2 、S(＝O)NR 10 、S(＝O) 2 NR 10 And NR 10 C(＝O)NR 10 ；
X 1 Selected from O, C (R) 8 ) 2 And NR 8 ；
X 2 Selected from the group consisting of CR 8 And N;
m and n are each independently selected from 0, 1,2, 3, 4 or 5;
R 8 and R 9 Each independently selected from hydrogen, halogen, cyano, hydroxy, amino, C 1 -C 6 Alkyl radical, C 1 -C 6 Heteroalkyl group, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 3 -C 8 Cycloalkyl radical, C 3 -C 8 Heterocycloalkyl radical, C 3 -C 8 Cycloalkoxy or C 3 -C 8 Heterocycloalkoxy, wherein the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkoxy, and heterocycloalkoxy are each optionally substituted with at least 1R 10 Substitution;
R 1 to R 9 Wherein the heteroatom or heteroatom group contained in the heteroalkyl group, heterocycloalkyl group, heterocycloalkoxy group, heteroaryl group is independently selected from the group consisting of-C (═ O) N (R) 10 )-、-N(R 10 )-、-N＝、-O-、-S-、-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O) 2 -and-N (R) 10 )C(＝O)N(R 10 ) And the number of said heteroatoms or groups of heteroatoms is independently selected from 1,2 and 3, respectively;
R 10 selected from the group consisting of hydrogen, chloro, fluoro, cyano, hydroxy, amino, isopropyl, cyclopropyl, methyl, difluoromethyl, trifluoromethyl, methoxy, trifluoromethoxy, ethoxy, 2, 2-difluoroethoxy, 2,2, 2-trifluoroethoxy, and phenyl.
2. The compound of claim 1, which is a compound of any one of formulae I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, or I-12,
3. the compound of claim 2, which is a compound represented by any one of formulas I-1-1, I-2-1, I-3-1, I-4-1, I-5-1, I-6-1, I-7-1, I-8-1, I-9-1, I-10-1, I-11-1 or I-12-1,
4. the following compounds:
5. a pharmaceutical composition comprising a compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, metabolite, or prodrug thereof.
6. The pharmaceutical composition of claim 5, further comprising at least one pharmaceutically acceptable excipient.
7. Use of a compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, metabolite or prodrug thereof or a pharmaceutical composition according to claim 5 or 6 for the manufacture of a medicament for the prevention and/or treatment of a disease or condition caused by overexpression of PARP 7.
8. Use of a compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, metabolite or prodrug thereof, or a pharmaceutical composition according to claim 5 or 6, for the preparation of a PARP7 inhibitor.
9. Use of a compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, metabolite or prodrug thereof, or a pharmaceutical composition according to claim 5 or 6, for the manufacture of a medicament for the treatment and/or prevention of cancer.
10. Use according to claim 9, wherein the cancer is one or more of a hematological tumor, pancreatic cancer, colorectal cancer and lung cancer.
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| US20180037576A1 (en) * | 2015-03-06 | 2018-02-08 | Nanjing Sanhome Pharmaceutical Co., Ltd. | Substituted pyrimidine compounds as phosphatidylinositol 3-kinase delta inhibitor and use thereof |
| CN109761986A (en) * | 2017-11-10 | 2019-05-17 | 上海翰森生物医药科技有限公司 | Three simultaneously ring analog derivative inhibitor, preparation method and applications |
| CN110546145A (en) * | 2017-05-24 | 2019-12-06 | 上海和誉生物医药科技有限公司 | Azaaryl derivative, preparation method and pharmaceutical application thereof |
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| CA3075727A1 (en) * | 2017-09-18 | 2019-03-21 | Goldfinch Bio, Inc. | Pyridazinones and methods of use thereof |
| RS62872B1 (en) * | 2017-09-27 | 2022-02-28 | Incyte Corp | Salts of pyrrolotriazine derivatives useful as tam inhibitors |
| FI3788040T3 (en) * | 2018-04-30 | 2023-06-13 | Ribon Therapeutics Inc | Pyridazinones as parp7 inhibitors |
| WO2020223229A1 (en) * | 2019-04-29 | 2020-11-05 | Ribon Therapeutics, Inc. | Solid forms of a parp7 inhibitor |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US20180037576A1 (en) * | 2015-03-06 | 2018-02-08 | Nanjing Sanhome Pharmaceutical Co., Ltd. | Substituted pyrimidine compounds as phosphatidylinositol 3-kinase delta inhibitor and use thereof |
| CN110546145A (en) * | 2017-05-24 | 2019-12-06 | 上海和誉生物医药科技有限公司 | Azaaryl derivative, preparation method and pharmaceutical application thereof |
| CN109761986A (en) * | 2017-11-10 | 2019-05-17 | 上海翰森生物医药科技有限公司 | Three simultaneously ring analog derivative inhibitor, preparation method and applications |
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