WO2024109788A1 - Parp7抑制剂及其制备方法和用途 - Google Patents

Parp7抑制剂及其制备方法和用途 Download PDF

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WO2024109788A1
WO2024109788A1 PCT/CN2023/133125 CN2023133125W WO2024109788A1 WO 2024109788 A1 WO2024109788 A1 WO 2024109788A1 CN 2023133125 W CN2023133125 W CN 2023133125W WO 2024109788 A1 WO2024109788 A1 WO 2024109788A1
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alkyl
membered
ring
halogen
alkylene
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PCT/CN2023/133125
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French (fr)
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李进
瞿庆喜
郭安平
白晓光
农云宏
罗宇航
刘立川
洪新福
黄晓冬
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成都先导药物开发股份有限公司
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    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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    • A61K31/5375—1,4-Oxazines, e.g. morpholine
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    • A61K31/54—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 sulfur as the ring hetero atoms, e.g. sulthiame
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    • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
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Definitions

  • the present invention relates to the field of medicinal chemistry, and in particular to a class of compounds capable of inhibiting PARP7 activity, a pharmaceutical composition comprising the class of compounds, and applications thereof in the medical field.
  • PARP stands for poly-ADP-ribose polymerase, which is involved in many important cellular processes including DNA repair, gene expression, protein degradation, and cell stress response. This protein family consists of 17 members, all of which contain a common catalytic domain of about 230 amino acids.
  • the PARP family can be divided into three categories: monoPARPS (catalyzing the transfer of a single ADP-ribose unit to its substrate), including most PARP family members; polyPARPS (catalyzing the transfer of poly-ADP-ribose units to its substrate), including PARP1, PARP2, PARP5A, PARP5b; PARP13 is the only PARP family member whose catalytic activity cannot be demonstrated in vitro or in vivo.
  • the object of the present invention is to provide a compound as shown in Formula I, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
  • X, X1 , X4 , X5 , and X6 are independently selected from CRx , CRxRx1 , N, or NRx ;
  • X2 is selected from CH or N;
  • R X and R X1 are each independently selected from hydrogen, halogen, cyano, nitro, -OH, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl or halogen-substituted C 1-6 alkyl;
  • R c is selected from hydrogen, deuterium, halogen, cyano, nitro, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl , halogen-substituted C 1-6 alkyl, -C 0-2 alkylene-OH, -O(C 1-6 alkyl), -O(halogen-substituted C 1-6 alkyl), -NH 2 , -C 0-2 alkylene-NH(C 1-6 alkyl), -C 0-2 alkylene-N(C 1-6 alkyl)(C 1-6 alkyl) or -C(O)C 1-6 alkyl;
  • L1 is selected from -CO- or -CONH-;
  • L 2 is selected from -NHCR 2 R 3 -, -S(O)CR 2 R 3 -, -S(O) 2 CR 2 R 3 -, -S(O) NH CR 2 R 3 -, -S(O) 2 NH CR 2 R 3 -, 3-10 membered carbocyclic ring, 3-10 membered heterocyclic ring or 5-10 membered heteroaromatic ring; wherein the carbocyclic ring, heterocyclic ring or heteroaromatic ring is optionally substituted by one, two, three or four independent R d ;
  • R d is selected from hydrogen, halogen, cyano, oxo, nitro, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl , halogen-substituted C 1-6 alkyl, -C 0-2 alkylene-OH, -O(C 1-6 alkyl), -O(3-10 membered carbocycle), -O(halogen-substituted C 1-6 alkyl), -NH 2 , -C 0-2 alkylene-NH(C 1-6 alkyl), -C 0-2 alkylene-N(C 1-6 alkyl)(C 1-6 alkyl) or -C(O)C 1-6 alkyl ;
  • two R d together with the atoms to which they are attached form a 3- to 10-membered heterocyclic ring or a 3- to 10-membered carbocyclic ring;
  • R2 and R3 are independently selected from hydrogen, -C1-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, halogen-substituted C1-6 alkyl, -OH, -O( C1-6 alkyl), -O(halogen-substituted C1-6 alkyl), -NH2 , -C0-2 alkylene-NH( C1-6 alkyl), -C0-2 alkylene Alkyl-N(C 1-6 alkyl)(C 1-6 alkyl), -C(O)C 1-6 alkyl, 6-10 membered aromatic ring, 6-10 membered heteroaromatic ring, 3-10 membered heterocyclic ring or 3-10 membered carbocyclic ring; wherein the alkylene, carbocyclic ring, heterocyclic ring, aromatic ring or heteroaromatic ring is optionally substituted by one, two, three or four independent R 23 ;
  • R 2 , R 3 and the atoms to which they are connected together form a 3- to 10-membered heterocyclic ring or a 3- to 10-membered carbocyclic ring; wherein the heterocyclic ring or carbocyclic ring is optionally substituted by one, two, three or four independent R 23 ;
  • R 23 is selected from hydrogen, halogen, cyano, nitro, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, halogen-substituted C 1-6 alkyl, -C 0-2 alkylene-OH, -O(C 1-6 alkyl), -O(halogen-substituted C 1-6 alkyl), -NH 2 , -C 0-2 alkylene-NH(C 1-6 alkyl), -C 0-2 alkylene-N(C 1-6 alkyl)(C 1-6 alkyl) or -C(O)C 1-6 alkyl ;
  • Ring A 1 is selected from a 3- to 10-membered heterocyclic ring; wherein the heterocyclic ring is optionally substituted by one, two, three, four, five, six, seven or eight independent R 4 ;
  • R 4 is selected from hydrogen, deuterium, halogen, cyano, nitro, oxo, hydroxyl, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl , halogen-substituted C 1-6 alkyl, -O(C 1-6 alkyl), -O(3-6 membered carbocycle), -O(halogen-substituted C 1-6 alkyl), -NH 2 , -C 0-2 alkylene-NH(C 1-6 alkyl), -C 0-2 alkylene-N(C 1-6 alkyl)(C 1-6 alkyl) or -C(O)C 1-6 alkyl;
  • Ring A2 is selected from 5-10 heteroaromatic rings or 6-10 membered aromatic rings; wherein the aromatic ring or heteroaromatic ring is optionally substituted by one, two, three, or four independent R5 ;
  • R5 is selected from hydrogen, halogen, cyano, nitro, oxo, -C0 ⁇ 2 alkylene-hydroxy, -C1 ⁇ 6 alkyl, -C2 ⁇ 6 alkenyl, -C2 ⁇ 6 alkynyl, halogen-substituted C1 ⁇ 6 alkyl, -O(C1 ⁇ 6 alkyl), -S(C1 ⁇ 6 alkyl), -S(O)C1 ⁇ 6 alkyl, -S(O) 2C1 ⁇ 6 alkyl, -O(3 ⁇ 6 membered carbocycle), -O(halogen-substituted C1 ⁇ 6 alkyl), -C(O) NH2 , -NH2 , -C0 ⁇ 2 alkylene-NH(C1 ⁇ 6 alkyl), -C0 ⁇ 2 alkylene-N(C1 ⁇ 6 alkyl)(C1 ⁇ 6 alkyl), -
  • R 4 , R 5 together with Ring A 1 and Ring A 2 form an 11-17 membered fused heterocyclic ring; the fused heterocyclic ring is optionally substituted by one, two, three, or four independent R 52 ;
  • R 51 is selected from hydrogen, halogen, cyano, nitro, oxo, hydroxy, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl , halogen-substituted C 1-6 alkyl, -O(C 1-6 alkyl), -O(3-6 membered carbocycle), -O(halogen-substituted C 1-6 alkyl), -NH 2 , -C 0-2 alkylene-NH(C 1-6 alkyl) or -C 0-2 alkylene-N(C 1-6 alkyl)(C 1-6 alkyl);
  • R 52 is selected from hydrogen, halogen, cyano, nitro, oxo, thio, hydroxy, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl , halogen-substituted C 1-6 alkyl, -O(C 1-6 alkyl), -O(3-6 membered carbocyclic ring), -O(halogen-substituted C 1-6 alkyl), -NH 2 , - C0 ⁇ 2 alkylene-NH(C1 ⁇ 6 alkyl), -C0 ⁇ 2 alkylene-N(C1 ⁇ 6 alkyl)(C1 ⁇ 6 alkyl), -C2 ⁇ 6 alkenyl-CON(C1 ⁇ 6 alkyl)(C1 ⁇ 6 alkyl), -C0 ⁇ 2 alkylene-(3 ⁇ 10 membered carbocyclic ring), -C0 ⁇ 2 alkylene-(3 ⁇ 10 membere
  • L 2 is selected from -NHCR 2 R 3 -, a 3-membered carbocycle, a 4-membered carbocycle, a 5-membered carbocycle, a 6-membered carbocycle, a 4-membered monoheterocycle, a 5-membered monoheterocycle, a 6-membered monoheterocycle, a 7-membered monoheterocycle, an 8-membered monoheterocycle, a 9-membered monoheterocycle, a 10-membered monoheterocycle, a 7-membered spiroheterocycle, an 8-membered spiroheterocycle, a 9-membered spiroheterocycle, a 10-membered spiroheterocycle, a 6-membered fused heterocycle, a 7-membered fused heterocycle, an 8-membered fused heterocycle, a 9-membered fused heterocycle, a 10-membere
  • R 2 and R 3 are independently selected from hydrogen, -C 1-6 alkyl, 6-membered aromatic ring, 5-membered heteroaromatic ring or 6-membered heteroaromatic ring;
  • R 2 , R 3 and the atoms to which they are connected together form a 3-6-membered carbocyclic ring, a 4-membered heterocyclic ring, a 5-membered heterocyclic ring, a 6-membered heterocyclic ring or a 7-membered heterocyclic ring; wherein the carbocyclic ring or heterocyclic ring is optionally substituted by one, two, three or four independent R 23 ;
  • R d is selected from hydrogen, halogen, cyano, oxo, nitro, -C 1-3 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, halogen-substituted C 1-3 alkyl, -OH, -O(C 1-3 alkyl) or -O(3-6 membered carbocyclic ring);
  • Ring A2 is selected from a 5-membered heteroaromatic ring, a 6-membered heteroaromatic ring, a 9-membered fused heteroaromatic ring, a 10-membered fused heteroaromatic ring, a 5-membered heteroaromatic ring fused to a 6-membered saturated ring, a 6-membered heteroaromatic ring fused to a 6-membered saturated ring, a 6-membered heteroaromatic ring fused to a 6-membered saturated heterocyclic ring, a 6-membered heteroaromatic ring fused to a 5-membered saturated ring, a 5-membered heteroaromatic ring fused to a 6-membered saturated heterocyclic ring, or a 6-membered aromatic ring; wherein the aromatic ring or heteroaromatic ring is optionally substituted by one, two, three, or four independent R5 ;
  • Ring A1 is selected from
  • Ring A2 is selected from
  • R 4 , R 5 together with Ring A 1 and Ring A 2 , form a 12-membered fused heterocyclic ring, a 13-membered fused heterocyclic ring, a 14-membered fused heterocyclic ring, a 15-membered fused heterocyclic ring, or a 16-membered fused heterocyclic ring; the fused heterocyclic ring is optionally substituted by one, two, three, or four independent R 52 ;
  • R 52 is selected from hydrogen, halogen, cyano, nitro, oxo, thioxo, hydroxyl, -C 1-6 alkyl, -C 2-6 alkenyl , -C 2-6 alkynyl, halogen-substituted C 1-6 alkyl, -O(C 1-3 alkyl), -O(3-6 membered carbocycle), -O(halogen-substituted C 1-6 alkyl), -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl)(C 1-6 alkyl), -C 2-6 alkenyl-CON(C 1-6 alkyl)(C 1-6 alkyl ), -3-10 membered carbocycle, -3-10 membered heterocycle, -6-10 membered aromatic ring or -5-10 membered heteroaromatic ring.
  • n is selected from 1, 2 or 3;
  • X3 is independently selected from NH, N( C1-6 alkyl), N( C2-6 alkenyl), N(3-6 membered carbocyclic ring), N(3-6 membered heterocyclic ring), N(halogen substituted C1-6 alkyl), CR X31 , CR X31 RX32 , O, S,
  • R X31 and R X32 are each independently selected from hydrogen, halogen or -C 1-6 alkyl.
  • X3 are each independently selected from
  • the fused heterocyclic ring formed by R 4 , R 5 , Ring A 1 and Ring A 2 together is selected from:
  • X, X 1 , X 4 , X 5 and X 6 are each independently selected from CH, CH 2 , N or NCH 3 .
  • L 1 is selected from -CO- or Among them, the bb end is connected to ring A1 .
  • X is N, X1 is CH, X2 is N, X4 is N, X5 is N, and X6 is CH;
  • X is N, X1 is CH, X2 is N, X4 is N, X5 is CH, and X6 is CH;
  • X is N, X1 is CH, X2 is N, X4 is CH, X5 is CH, and X6 is CH;
  • X is N, X1 is CH, X2 is N, X4 is N, X5 is CH, and X6 is N;
  • X is N, X1 is CH, X2 is CH, X4 is CH, X5 is CH, and X6 is CH;
  • X is N
  • X1 is CH
  • X2 is N
  • X4 is NRX
  • X5 is CH2
  • X6 is N.
  • R 1 , RX , L 2 , L 1 , Ring A 1 and Ring A 2 are as described above.
  • R 1 , R d , R 4 and ring A 2 are as described above.
  • R 1 , R d , R 4 and ring A 2 are as described above.
  • each R d is independently selected from hydrogen, halogen, cyano, oxo, nitro, -C 1-3 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl , halogen-substituted C 1-3 alkyl, -OH, -O(C 1-3 alkyl) or -O(3-6 membered carbocyclic ring).
  • each R d is independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, fluorine, chlorine, oxo, -OH, -O(methyl), -O(cyclopropyl).
  • each R d is selected from hydrogen.
  • R 4 is selected from hydrogen, deuterium, halogen, oxo, hydroxyl, methyl, ethyl, n-propyl, isopropyl, -O(methyl). In some preferred embodiments, R 4 is hydrogen.
  • Ring A2 is selected from
  • the compound of formula I is as shown in formula II-1, formula II-2, formula II-3, formula II-4 or formula II-5:
  • Y 1 , Y 2 , Y 4 , Y 5 , Y 6 , Y 9 , Y 11 , and Y 12 are each independently selected from N, NR Y1 , CHR Y1 or CR Y1 ;
  • Y 3 , Y 7 , Y 8 , and Y 10 are independently selected from CR Y1 , CHR Y1 , O, S, N, or NR Y1 ;
  • Y13 is selected from N or CR Y1 ;
  • Each R Y1 is independently selected from hydrogen, halogen, cyano, nitro, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl or halogen-substituted C 1-6 alkyl;
  • R 1 , R d , R 4 , R 5 and X 1 are as described above.
  • the compound of formula I is as shown in formula II-1', formula II-2', formula II-3', formula II-4' or formula II-5':
  • Y 1 , Y 2 , Y 4 , Y 5 , Y 6 , Y 9 , Y 11 , and Y 12 are each independently selected from N, NR Y1 , CHR Y1 or CR Y1 ;
  • Y 3 , Y 7 , Y 8 , and Y 10 are independently selected from CR Y1 , CHR Y1 , O, S, N, or NR Y1 ;
  • Y13 is selected from N or CR Y1 ;
  • Each R Y1 is independently selected from hydrogen, halogen, cyano, nitro, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl or halogen-substituted C 1-6 alkyl;
  • R 1 , R d , R 4 , R 5 and X 1 are as described above.
  • each R d is independently selected from hydrogen, halogen, cyano, oxo, nitro, -C 1-3 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, halogen-substituted C 1-3 alkyl, -OH, -O (C 1-3 alkyl) or -O (3-6 membered carbocyclic ring).
  • each R d is independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, fluorine, chlorine, oxo, -OH, -O (methyl), -O (cyclopropyl). In some preferred embodiments, each R d is selected from hydrogen.
  • R 4 is selected from hydrogen, deuterium, halogen, oxo, hydroxyl, methyl, ethyl, n-propyl, isopropyl, -O(methyl). In some preferred embodiments, R 4 is hydrogen.
  • R 5 is selected from hydrogen, fluorine, chlorine, bromine, cyano, nitro, oxo, -C 0 ⁇ 2 alkylene-hydroxy, methyl, ethyl, n-propyl, isopropyl, vinyl, propenyl, monofluoromethyl, difluoromethyl, trifluoromethyl, -O(methyl), -O(ethyl), -O(n-propyl), -O(isopropyl), -O(3-membered carbocyclic ring), -O(4-membered carbocyclic ring), -O(5-membered carbocyclic ring), -O(6-membered carbocyclic ring), -O(monofluoromethyl), -O(difluoromethyl),
  • Y 4 and Y 5 are independently selected from N or CR Y1 ;
  • Y 3 is selected from CHR Y1 , O, S or NR Y1 ;
  • R L2 , R 3 and the atoms to which they are connected together form a 3- to 10-membered heterocyclic ring;
  • R 1 , R 2 , R 3 , R 4 and R 5 are as defined above.
  • R L2 , R 3 and the atoms to which they are attached together form a 4-membered heterocyclic ring, a 5-membered heterocyclic ring, a 6-membered heterocyclic ring, a 7-membered heterocyclic ring, an 8-membered heterocyclic ring, a 9-membered heterocyclic ring, or a 10-membered heterocyclic ring.
  • R 4 is selected from hydrogen, deuterium, halogen, oxo, hydroxy, methyl, ethyl, n-propyl, isopropyl, -O(methyl). In some preferred embodiments, R 4 is hydrogen.
  • the compound described in formula I of the present invention is specifically:
  • the present invention also provides a use of any of the above compounds, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating PARP7-mediated diseases.
  • the PARP7-mediated disease includes cancer or malignant tumors, including breast cancer, central nervous system cancer, endometrial cancer, kidney cancer, colorectal cancer, lung cancer, esophageal cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, head and neck cancer (upper aerodigestive tract cancer), urinary tract cancer or colon cancer.
  • the present invention also provides a pharmaceutical composition, which is a preparation prepared by adding any of the above-mentioned compounds, or their stereoisomers, or their pharmaceutically acceptable salts, and pharmaceutically acceptable excipients.
  • the compounds and derivatives provided in the present invention can be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) nomenclature system.
  • substituted refers to the replacement of a hydrogen atom in a molecule by another different atom or molecule.
  • C a-b alkyl indicates any alkyl group containing from “a” to "b” carbon atoms.
  • C 1-4 alkyl refers to an alkyl group containing 1 to 4 carbon atoms.
  • alkyl refers to a saturated hydrocarbon chain having a specified number of member atoms.
  • C 1-6 alkyl refers to an alkyl group having 1 to 6 member atoms, such as 1 to 4 member atoms.
  • the alkyl group can be straight or branched. Representative branched alkyl groups have one, two or three branches.
  • the alkyl group may be optionally substituted with one or more substituents as defined herein.
  • Alkyl includes methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl and tert-butyl), pentyl (n-pentyl, isopentyl and neopentyl) and hexyl.
  • the alkyl group may also be part of other groups, such as C 1 to C 6 alkoxy.
  • alkylene refers to a divalent saturated aliphatic hydrocarbon radical having a specified number of member atoms.
  • C a-b alkylene refers to an alkylene group having from a to b carbon atoms.
  • Alkylene groups include branched and straight chain hydrocarbon groups.
  • the term “propylene” can be exemplified by the following structure:
  • the term “dimethylbutylene” can be exemplified, for example, by any of the following structures:
  • the -C0 ⁇ 4 alkylene group of the present invention can be C0 alkylene, C1 alkylene (e.g. -CH2- ), C2 alkylene (e.g. -CH2CH2- , etc.), C3 alkylene or C4 alkylene;
  • C0 alkylene means that the group here does not exist and is connected in the form of a chemical bond, and
  • A0 alkylene-B means AB, that is, the A group and the B group are directly connected by a chemical bond.
  • the unsaturated mentioned in the present invention refers to the presence of carbon-carbon double bonds, carbon-carbon triple bonds, carbon-oxygen double bonds, carbon-sulfur double bonds, carbon-nitrogen triple bonds, etc. in the groups or molecules.
  • ( Ca - Cb )alkenyl refers to an alkenyl group having a to b carbon atoms and is meant to include, for example, ethenyl, propenyl, isopropenyl, 1,3-butadienyl, and the like.
  • alkynyl refers to a straight or branched monovalent hydrocarbon radical containing at least one triple bond.
  • alkynyl is also intended to include those hydrocarbon groups having one triple bond and one double bond.
  • (C 2 -C 6 )alkynyl is intended to include ethynyl, propynyl, and the like.
  • S or "thio" refers to a sulfur atom replacing two hydrogen atoms or a lone pair of electrons through a double bond.
  • -OR refers to the R group being connected to an oxygen atom or a nitrogen atom by a single bond.
  • -O(C 1-6 alkyl) means that a C 1-6 alkyl group is connected to an oxygen atom by a single bond.
  • -N(C 1-6 alkyl)(C 1-6 alkyl) means that two independent C 1-6 alkyl groups are connected to nitrogen atoms by single bonds.
  • CR refers to that the R group is connected to a carbon atom by a single bond, wherein the carbon atom includes but is not limited to an SP2 hybridized carbon atom or an SP3 hybridized carbon atom.
  • the oxygen atom is connected to the carbon atom or sulfur atom by a double bond
  • the R group is connected to the oxygen atom or sulfur atom by a single bond
  • “-S(O)(NH)R” means that the oxygen atom and the nitrogen atom are connected by a double bond
  • the R group is connected to the sulfur atom by a single bond.
  • halogen refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
  • halogen-substituted alkyl means that the hydrogen atoms in the alkyl group may be substituted by one or more halogen atoms.
  • the halogen-substituted C 1-4 alkyl group refers to an alkyl group containing 1 to 4 carbon atoms in which the hydrogen atoms are substituted by one or more halogen atoms.
  • deuterium-substituted alkyl refers to an alkyl group in which hydrogen atoms may be substituted by one or more deuterium atoms.
  • deuterium-substituted C 1-4 alkyl refers to an alkyl group containing 1 to 4 carbon atoms in which hydrogen atoms are substituted by one or more deuterium atoms.
  • carrier refers to saturated or partially saturated cyclic groups having carbon atoms and no ring heteroatoms and having a single ring or multiple rings (including fused, spiro and bridged rings).
  • the terms “carbocycle”, “cycloalkyl” e.g., 5,6,7,8,-tetrahydronaphthalene-5-yl
  • carrier include cycloalkenyl groups such as cyclohexenyl.
  • cycloalkyl groups include, for example, adamantyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclooctyl, cyclopentenyl and cyclohexenyl.
  • cycloalkyl groups including polybicycloalkyl ring systems are bicyclohexyl, bicyclopentyl, bicyclooctyl, etc.
  • carrier and “cycloalkyl” also include partially saturated cyclic groups formed by fusion of an aromatic ring with a non-aromatic ring, the attachment point of which can be located at a non-aromatic carbon atom or an aromatic carbon atom, examples of which include 1,2,3,4-tetrahydronaphthalen-5-yl.
  • bridged ring or “bridged cycloalkyl” refers to a saturated or non-aromatic partially saturated cyclic group formed by bridging multiple rings having multiple carbon atoms and no ring heteroatoms. Examples of bridged ring systems include Adamantyl, etc.
  • spirocycle or “spirocycloalkyl” refers to a saturated or non-aromatic partially saturated cyclic group formed by spiraling multiple rings with multiple carbon atoms and no ring heteroatoms. Examples of spirocyclic systems include wait.
  • fused ring refers to a saturated or non-aromatic partially saturated ring system formed by two or more cyclic structures sharing two adjacent atoms. Examples of fused ring systems include wait.
  • heterocycle refers to a saturated or partially unsaturated, monocyclic or polycyclic aliphatic hydrocarbon group containing at least one heteroatom; wherein the heteroatom refers to a nitrogen atom, an oxygen atom, or a sulfur atom; non-limiting examples of monocyclic heterocycloalkyls include, but are not limited to, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like.
  • Non-limiting examples of cycloalkyl groups include, but are not limited to, fused, spiro, or bridged heterocycloalkyl groups.
  • bridged heterocycle or “bridged heterocycloalkyl” refers to a saturated or non-aromatic partially saturated cyclic group formed by bridging multiple rings containing at least one heteroatom. Examples of bridged heterocycloalkyl systems include wait.
  • spiroheterocycle or “spiroheterocycloalkyl” refers to a saturated or non-aromatic partially saturated cyclic group formed by multiple spirocyclic groups containing at least one heteroatom. Examples of spiroheterocycloalkyl systems include wait.
  • fused heterocycle refers to a non-aromatic, saturated or partially unsaturated ring system formed by two or more cyclic structures sharing two adjacent atoms, wherein the ring atoms contain one or more heteroatoms independently selected from oxygen, nitrogen and sulfur, and the number of heteroatoms is 1, 2, 3 or more. Examples of fused heterocyclic ring systems include wait.
  • aromatic ring refers to a carbon ring system containing 6-14, preferably 6-10, more preferably 6 or 10 ring atoms.
  • heteroaryl or “heteroaromatic ring” refers to monocyclic, bicyclic and tricyclic ring systems containing 5-14, preferably 5-10 ring atoms, wherein at least one ring system is aromatic and at least one ring system contains one or more heteroatoms selected from nitrogen, oxygen or S(O) m (wherein m is 0, 1 or 2), wherein each ring system contains a ring consisting of 5-7 atoms and has one or more points of attachment to the rest of the molecule. Examples include, but are not limited to, furanyl, imidazolyl, pyridinyl, pyrimidinyl, thiazolyl, purinyl, quinolinyl, and the like.
  • stereoisomers refers to compounds which have identical chemical constitution, but differ in the way the atoms or groups are arranged in space.
  • the compounds of the present invention may contain asymmetric centers or chiral centers, and therefore exist in different stereoisomers. All stereoisomeric forms of the compounds of the present invention, including but not limited to, conformational isomers (rotamers), geometric isomers (cis/trans) isomers, atropisomers, etc., and their mixtures, such as racemic mixtures, constitute part of the present invention. Many organic compounds exist in optically active forms, that is, they have the ability to rotate the plane of plane polarized light. When describing optically active compounds, the prefixes D, L or R, S are used to indicate the absolute configuration of the chiral center of the molecule. The chemical structures of these stereoisomers are the same, but their stereostructures are different.
  • Stereoisomers can be enantiomers, isomers
  • a mixture of two enantiomers is often called a mixture of enantiomers.
  • a 50:50 mixture of enantiomers is called a racemic mixture or racemate, which may result in no stereoselectivity or stereospecificity during chemical reactions.
  • the terms “racemic mixture” and “racemate” refer to an equimolar mixture of two enantiomers that lacks optical activity.
  • a heterocyclic group optionally substituted with an alkyl group means that an alkyl group may but need not be present, and the description includes situations where the heterocyclic group is substituted with an alkyl group and situations where the heterocyclic group is not substituted with an alkyl group.
  • pharmaceutical composition refers to a pharmaceutical composition that can be used for pharmaceutical purposes, which comprises one or more compounds as shown in Formula I or pharmaceutically acceptable forms thereof (such as salts, hydrates, solvates, stereoisomers, tautomers, metabolites, prodrugs, etc.), and other components (such as pharmaceutically acceptable excipients).
  • cancer refers to any of a variety of diseases characterized by uncontrolled abnormal proliferation of cells, the ability of affected cells to spread locally or via the bloodstream and lymphatic system to other parts of the body (i.e., metastasis), and any of a number of characteristic structural and/or molecular features.
  • a “cancer cell” refers to a cell that is undergoing an early, intermediate, or advanced stage of multistep tumor progression.
  • the “cancer” or “malignancy” is leukemia, liver cancer, brain tumor, myeloma, pancreatic cancer, breast cancer, colon cancer, prostate cancer, bladder cancer, or multiple endocrine carcinomas.
  • pharmaceutically acceptable excipients refer to auxiliary materials widely used in the field of drug production.
  • the main purpose of using excipients is to provide a pharmaceutical composition that is safe to use, stable in nature and/or has specific functionality, and also to provide a method so that after the drug is administered to the subject, the active ingredient can be dissolved at a desired rate, or to promote the effective absorption of the active ingredient in the subject receiving the drug.
  • Pharmaceutically acceptable excipients can be inert fillers, or they can be functional ingredients that provide a certain function for the pharmaceutical composition (for example, stabilizing the overall pH value of the composition or preventing the degradation of the active ingredient in the composition).
  • Non-limiting examples of pharmaceutically acceptable excipients include, but are not limited to, adhesives, suspending agents, emulsifiers, diluents (or fillers), granulating agents, adhesives, disintegrants, lubricants, anti-adhesive agents, glidants, wetting agents, gelling agents, absorption delay agents, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavoring agents, sweeteners, etc.
  • salts and “pharmaceutically acceptable salt” refer to acidic and/or basic salts of the above-mentioned compounds or their stereoisomers, formed with inorganic and/or organic acids and bases, and also include zwitterionic salts (inner salts), and also include quaternary ammonium salts, such as alkylammonium salts. These salts can be obtained directly in the final separation and purification of the compound. It can also be obtained by mixing the above-mentioned compound, or its stereoisomer, with a certain amount of acid or base appropriately (e.g., equivalent).
  • salts may form a precipitate in the solution and be collected by filtering, or be recovered after solvent evaporation, or be obtained by freeze-drying after reaction in an aqueous medium.
  • the salt described in the present invention can be a hydrochloride, sulfate, citrate, benzenesulfonate, hydrobromide, hydrofluoride, phosphate, acetate, propionate, succinate, oxalate, malate, succinate, fumarate, maleate, tartrate or trifluoroacetate of the compound.
  • the raw materials and equipment used in the specific embodiments of the present invention are all known products and are obtained by purchasing commercially available products.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS).
  • the NMR shift ( ⁇ ) is given in units of 15-0 (ppm).
  • the NMR is determined using (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic spectrometers, and the determination solvents are deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), and the internal standard is tetramethylsilane (TMS).
  • DMSO-d 6 deuterated dimethyl sulfoxide
  • CDCl 3 deuterated chloroform
  • CD 3 OD deuterated methanol
  • TMS tetramethylsilane
  • the LC-MS is determined using a Shimadzu LC-MS2020 (ESI) instrument.
  • the HPLC is determined using a Shimadzu high pressure liquid chromatograph (Shimadzu LC-20A).
  • Reverse phase preparative chromatography uses a Gilson GX-281 reverse phase preparative chromatograph.
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, and the specifications of the thin layer chromatography separation and purification product are 0.4mm ⁇ 0.5mm.
  • Column chromatography generally uses Yantai Huanghai silica gel 200 ⁇ 300 mesh silica gel as a carrier.
  • the known starting materials of the present invention can be synthesized by methods known in the art, or can be purchased from companies such as Anaiji Chemical, Aladdin Chemical, Chengdu Kelon Chemical, Shaoyuan Chemical Technology, and Bailingwei Technology.
  • Hydrogen atmosphere refers to a hydrogen balloon with a volume of about 1L connected to the reaction bottle.
  • the hydrogenation reaction is usually evacuated, filled with hydrogen, and repeated 3 times.
  • the reaction is carried out under a nitrogen atmosphere.
  • the solution refers to an aqueous solution.
  • the reaction temperature is room temperature.
  • M is moles per liter. Room temperature is the most suitable reaction temperature, which is 20°C ⁇ 30°C. Overnight is 12 ⁇ 2h.
  • PE petroleum ether
  • EA ethyl acetate
  • DCM dichloromethane
  • MeOH methanol
  • DMF N,N-dimethylformamide
  • DMSO dimethyl sulfoxide
  • DMAP 4-dimethylaminopyridine
  • DIPEA diisopropylethylamine
  • Boc tert-butyloxycarbonyl
  • TFA trifluoroacetic acid
  • DBU 1,8-diazabicycloundec-7-ene
  • HATU 2-(7-oxadiazole)-1,4-dihydro ...
  • NMP N-methylpyrrolidone
  • KF potassium fluoride
  • MePh toluene.
  • compound 5-bromo-2-chloropyrimidine A-1a (2.3 g, 10 mmol) was dissolved in NMP (20 mL). After the compound was completely dissolved, potassium carbonate (1.43 g, 10.34 mmol) and piperazine-1-carboxylic acid tert-butyl ester (1.44 g, 7.75 mmol) were added. After the addition, the mixture was heated in an oil bath at 80°C for 3 hours. After the reaction was completed as monitored by TLC, the mixture was cooled to room temperature. 100 mL of water and 50 mL of ethyl acetate were added, and the mixture was extracted and separated.
  • the intermediate A-1b (1.58g, 4.6mmol) was dissolved in dioxane/water (15mL/3mL/5:1), and then cyclopropylboronic acid pinacol ester (1.16g, 6.91mmol), Pd(dppf)Cl 2 (336.84mg, 0.46mmol) and cesium carbonate (3.01g, 9.21mmol) were added in sequence. After the addition, the nitrogen was fully replaced three times, and the oil bath was heated to 100°C and stirred for 16 hours. After the reaction was completed, the system was cooled to room temperature, and the reaction solution was concentrated to dryness under reduced pressure.
  • compound 2-chloropyrimidine-5-carboxylic acid methyl ester A-8a (1.02 g, 5.79 mmol) was dissolved in NMP (10 mL). After the compound was completely dissolved, potassium carbonate (1.6 g, 11.59 mmol) and piperazine-1-carboxylic acid tert-butyl ester (1.62 g, 8.69 mmol) were added. After the addition, the mixture was heated in an oil bath at 80°C for 3 hours. After the reaction was completed as monitored by TLC, the mixture was cooled to room temperature.
  • the intermediate A-8c (75mg, 0.23mmol) was dissolved in dry dichloromethane (3mL) and then replaced with nitrogen. Then, diethylaminosulfur trifluoride (113.2mg, 0.7mmol) was slowly added dropwise under an ice bath. After the addition was completed, the reaction was stirred at room temperature for 1 hour. After the reaction was completed by TLC spot plate monitoring, 30mL of glacial ammonium chloride saturated aqueous solution was added to quench the reaction, and then 10mL of dichloromethane was used to extract the liquid twice.
  • intermediate A-8 was prepared as a white solid, and the hydrochloride of the obtained product can be directly used in the next reaction without further purification.
  • MS (ESI) m/z 223 [M+H] + .
  • compound 2-chloro-5-(methylmercapto)pyrimidine A-9a (1.01 g, 6.23 mmol) was dissolved in NMP (10 mL). After the compound was completely dissolved, potassium carbonate (1.72 g, 6.23 mmol) and piperazine-1-carboxylic acid tert-butyl ester (1.74 g, 9.34 mmol) were added. After the addition, the mixture was heated in an oil bath at 80°C for 3 hours. After the reaction was completed as monitored by TLC, the mixture was cooled to room temperature.
  • intermediate A-9 was prepared as a white solid, and the hydrochloride of the obtained product can be directly used in the next reaction without further purification.
  • MS (ESI) m/z 227 [M+H] + .
  • intermediate A-10 was prepared as a white solid, and the hydrochloride of the obtained product can be directly used in the next reaction without further purification.
  • MS (ESI) m/z 243 [M+H] + .
  • compound 2-bromo-5-formaldehyde thiazole A-11a (1.01 g, 5.21 mmol) was dissolved in NMP (10 mL). After the compound was completely dissolved, potassium carbonate (1.44 g, 10.41 mmol) and piperazine-1-carboxylic acid tert-butyl ester (1.16 g, 6.25 mmol) were added. After the addition, the mixture was heated in an oil bath at 80°C for 3 hours. After the reaction was completed as monitored by TLC, the mixture was cooled to room temperature.
  • intermediate A-11 is prepared as a white solid.
  • the hydrochloride of the obtained product can be It was directly used in the next step without further purification.
  • MS (ESI) m/z 224 [M+H] + .
  • intermediate A-6c is the product of the second step of the synthesis of intermediate A-6, and is also the raw material for the synthesis of intermediate A-12.
  • the intermediate A-6c (320mg, 1.05mmol) was dissolved in dry dichloromethane (10mL) and the nitrogen was fully replaced. Then, diethylzinc toluene solution (5.3mL, 5.26mmol, 1M MePh solution) was slowly added dropwise under an ice bath. After the addition was completed, the reaction was stirred under an ice bath for 15 minutes, and chloroiodomethane (1.85g, 10.51mmol) was slowly added dropwise again. After the addition was completed, the ice bath was removed and the reaction was stirred at room temperature for 3 hours.
  • intermediate A-12 was prepared as a white solid, and the hydrochloride of the obtained product can be directly used in the next reaction without further purification.
  • MS (ESI) m/z 219 [M+H] + .
  • the intermediate A-1b (100 mg, 0.29 mmol) was dissolved in toluene/water (0.42 mL/0.2 mL, v/v 10:1), and then cyclobutylboronic acid pinacol ester (79.57 mg, 0.44 mmol), Pd(dppf)Cl 2 (21.32 mg, 29.14 ⁇ mol) and potassium hydroxide (49.04 mg, 0.87 mmol) were added in sequence. After the addition, nitrogen was fully blown in to replace the gas in the tube. Then, the reaction was stirred at 100°C in a microwave reactor for 3 hours.
  • intermediate A-13 was prepared as a white solid, and the hydrochloride of the obtained product can be directly used in the next reaction without further purification.
  • MS (ESI) m/z 219 [M+H] + .
  • the intermediate A-1b (100 mg, 0.29 mmol) was dissolved in toluene/water (2 mL/0.2 mL, v/v 10:1), and then cyclobutylboronic acid pinacol ester (79.57 mg, 0.44 mmol), Pd(dppf)Cl 2 (21.32 mg, 29.14 ⁇ mol) and potassium hydroxide (49.04 mg, 0.87 mmol) were added in sequence. After the addition, nitrogen was fully blown in to replace the gas in the tube. Then, the reaction was stirred at 100°C in a microwave reactor for 3 hours.
  • intermediate A-14 was prepared as a white solid, and the hydrochloride of the obtained product can be directly used in the next reaction without further purification.
  • MS (ESI) m/z 250 [M+H] + .
  • intermediate A-15 was prepared as a white solid, and the hydrochloride of the obtained product can be directly used in the next reaction without further purification.
  • MS (ESI) m/z 233 [M+H] + .
  • the intermediate A-17b (525mg, 1.73mmol) was dissolved in anhydrous tetrahydrofuran (10mL) and replaced with nitrogen. Then, bis(trimethylsilyl) lithium amide (4.2mL, 4.15mmol, 1M THF solution) was slowly added under an ice bath, and the reaction was continued to stir under an ice bath for 30 minutes. Then iodomethane (589.3mg, 4.15mmol) was slowly added, and the ice bath was removed after the addition, and the reaction was stirred at room temperature for 3 hours.
  • intermediate A-17 was prepared as a white solid, and the hydrochloride of the obtained product can be directly used in the next reaction without further purification.
  • MS (ESI) m/z 232 [M+H] + .
  • compound 2-chlorooxazole-5-carboxylic acid ethyl ester A-18a (175 mg, 1 mmol) was dissolved in NMP (5 mL). After the compound was completely dissolved, potassium carbonate (276.4 mg, 2 mmol) and piperazine-1-carboxylic acid tert-butyl ester (279.4 mg, 1.5 mmol) were added. After the addition, the mixture was heated in an oil bath at 80°C for 3 hours. After the reaction was completed as monitored by TLC, the mixture was cooled to room temperature.
  • intermediate A-18 was prepared as a white solid, and the hydrochloride of the obtained product can be directly used in the next reaction without further purification.
  • MS (ESI) m/z 197 [M+H] + .
  • the compound 3-chloro-6-hydrazine pyridazine B-1a (0.14 g, 1 mmol) was dissolved in trifluoroacetic acid (4 mL) and placed in a sealed tube. The oil bath was then heated to 120°C and stirred for 3 hours. The reaction was monitored by TLC spot plate. The reaction system was restored to room temperature. TFA was then dried under negative pressure. The resulting mixture was diluted with water and ethanol, and the pH value was adjusted to about 8-9 at 0°C with saturated sodium carbonate aqueous solution.
  • intermediate B-1 222.5 mg, 0.99 mmol
  • DMF 5 mL
  • N-chlorosuccinimide (NCS) (1.06 g, 7.96 mmol) was added. After the addition, the nitrogen was replaced, and the oil bath was heated to 80 ° C and stirred for 3 hours.
  • the intermediate B-1a (1.02 g, 7.06 mmol) was dissolved in anhydrous ethanol (10 mL), followed by the addition of diethyl oxalate (1.34 g, 8.99 mmol). After the addition, the nitrogen was replaced, and the oil bath was heated to 80 ° C. and stirred overnight. After the reaction was completed as monitored by LCMS, the ethanol was concentrated and removed, and 50 mL of ethyl acetate was added to dilute the reactant.
  • 2-amino-6-trifluoromethylquinazoline C-1a 105.2 mg, 0.49 mmol
  • copper bromide 220.3 mg, 0.99 mmol
  • Tert-butyl nitrite 102.1 mg, 0.99 mmol
  • the reaction mixture was heated to 60°C for 4 hours.
  • intermediate C-3 was prepared as an off-white solid, and the hydrochloride of the obtained product can be directly used in the next reaction without further purification.
  • MS (ESI) m/z 274 [M+H] + .
  • the intermediate C-6b (0.74 g, 1.99 mmol) was dissolved in THF (8 mL). After the compound was completely dissolved, sodium hydride (120 mg, 2.99 mmol, 60% purity) was added under ice bath. After addition, the reaction was continued to stir in the ice bath for 15 minutes, and then iodomethane (565.2 mg, 3.98 mmol) was slowly added. After the addition, the ice bath was removed and the reaction was stirred at room temperature for 3 hours.
  • intermediate C-6 is prepared as a yellow solid.
  • the hydrochloride of the obtained product can be It was directly used in the next step without further purification.
  • MS (ESI) m/z 287 [M+H] + .
  • intermediate IN-1 (0.33g, 0.9mmol) and intermediate B-1 (0.24g, 1.1mmol) were dissolved in DMSO (10mL), KF (504mg, 9mmol) was added and nitrogen was replaced, and then the oil bath was heated to 120°C and stirred for 3 hours. After the reaction was completed as monitored by TLC spot plate, the temperature was restored to room temperature, and the reaction solution was slowly added dropwise to the stirred ice water to precipitate a large amount of white solid, which was filtered, and the obtained solid was washed with water and transferred to dryness. Subsequently, the solid was dissolved in an appropriate amount of ethanol by heating to 50°C, and then naturally cooled to room temperature.
  • Example Compound 1 [(2S)-1-[3-(trifluoromethyl)-[1,2,4]triazol[4,3-b]pyridazine-6-yl]pyrrolidin-2-yl]-[4-[5-(trifluoromethyl)thiazol-2-yl]piperazine-1-yl]methanone (0.22 g, 0.42 mmol, white solid, yield 43%).
  • Example Compound 2 [(2S)-1-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6-yl]pyrrolidin-2-yl]-[4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazine-1-yl]methanone (3.45 g, 6.70 mmol, white solid, yield 61.49%).
  • step 1 the intermediate 2-bromo-5-trifluoromethylthiazole is replaced by the corresponding halogenated heterocyclic starting material in the table below, and the remaining reagents are operated in the same manner to obtain the corresponding structural compounds in the table below.
  • step 3 the intermediate (tert-butyloxycarbonyl)-L-proline is replaced by the corresponding carboxylic acid in the following table, and the remaining reagents are operated in the same manner to obtain the corresponding structural compounds in the following table.
  • the synthesis starts from step 3, and the intermediate IN-1b is replaced by the corresponding intermediate amine in the table below.
  • the remaining reagents and the subsequent steps are the same, and the corresponding structural compounds in the table below can be obtained.
  • step 1 the intermediate piperazine ring starting material corresponding to the intermediate piperazine ring in the table below is used to replace the intermediate piperazine-1-carboxylic acid tert-butyl ester, and the remaining reagents are operated in the same manner to obtain the corresponding structural compounds in the table below.
  • step 5 the intermediate B-1 is replaced by the corresponding intermediate and cyclic halide in the following table, and the remaining reagents are operated in the same manner to obtain the corresponding structural compounds in the following table.
  • the intermediate IN-1 (0.33g, 0.99mmol) and the intermediate B-12 (245.6mg, 1.09mmol) were dissolved in DMF (10mL), and N,N-diisopropylethylamine (255.4mg, 1.98mmol) was added to replace the nitrogen, and then the oil bath was heated to 40°C and stirred for 16 hours.
  • the intermediate 69b (100.6 mg, 0.21 mmol) was dissolved in dichloromethane (5 mL), and the nitrogen was replaced by the addition of Dess-Martin reagent (177 mg, 0.42 mmol), and then stirred at room temperature overnight. After the reaction was completed by TLC spot plate monitoring, 50 mL of saturated aqueous sodium bisulfite solution was added to quench the reaction, and then 20 mL of dichloromethane was added to extract the liquid, and the aqueous phase was extracted twice with dichloromethane.
  • intermediate 69c In a 50 mL single-necked reaction flask, intermediate 69c (50.5 mg, 0.11 mmol) was dissolved in dry dichloromethane (3 mL) and then replaced with nitrogen. Diethylaminosulfur trifluoride (84.8 mg, 0.53 mmol) was then slowly added dropwise under an ice bath. After the addition was complete, The reaction was stirred at room temperature for 1 hour.
  • the system is cooled to room temperature, the reaction solution is concentrated to dryness under reduced pressure, the obtained oil is dissolved in ethyl acetate, washed with saturated brine, separated, the organic phase is dried over sodium sulfate, filtered, and concentrated in vacuo to obtain a crude product.
  • intermediate B-1 (223mg, 1.00mmol) and intermediate C-2 (129.4mg, 1.00mmol) were dissolved in DMSO (10mL), KF (582.13mg, 10.02mmol) was added and nitrogen was replaced, and then the oil bath was heated to 120°C and stirred for 3 hours. After the reaction was completed by TLC plate monitoring, the temperature was restored to room temperature, and the reaction solution was poured into 100mL ice water, and then 50mL ethyl acetate was added to extract and separate the liquids, and the aqueous phase was extracted twice with ethyl acetate.
  • the intermediate IN-3a (305mg, 0.97mmol) was dissolved in a mixed solution of tetrahydrofuran, methanol and water (3mL/1mL/2mL/3:1:2). After the compound was completely dissolved, lithium hydroxide monohydrate (121.79mg, 2.90mmol) was added. After the addition, the reaction was stirred at room temperature for 3 hours.
  • the intermediate IN-3b (244mg, 0.81mmol) was dissolved in DMF (10mL). After the compound was completely dissolved, HATU (462mg, 1.22mmol) was added. After stirring at room temperature for 15 minutes, tert-butyl piperazine-1-carboxylate (181.04mg, 0.97mmol) and DIPEA (209.38mg, 1.62mmol) were added. The reaction was carried out at room temperature for 3 hours. After the reaction was completed by TLC plate monitoring, it was cooled to room temperature. 50mL of water and 30mL of ethyl acetate were added, and the liquid was extracted and separated.
  • the intermediate IN-3 (100 mg, 0.27 mmol) was dissolved in NMP (5 mL). After the compound was completely dissolved, potassium carbonate (74.8 mg, 0.54 mmol) and 2-chloro-7,8-dihydropyrido[4,3-D]pyrimidine-6(5H)-carboxylic acid tert-butyl ester (73.6 mg, 0.27 mmol) were added. After the addition, the mixture was heated in an oil bath at 80°C for 3 hours. After the reaction was completed as monitored by TLC, the mixture was cooled to room temperature.
  • 2-chloro-5-trifluoromethylpyrimidine is used to replace 2-bromo-5-trifluoromethylthiazole
  • 3-aminopyrrolidine-1-carboxylic acid tert-butyl ester is used to replace piperazine-1-carboxylic acid tert-butyl ester, and the other reagents and operations remain unchanged to obtain the implementation method.
  • the present invention quantitatively detects the binding of small molecule compounds to the active site of PARP7 by competitive binding TR-FRET (Time-resolved fluorescence resonance energy transfer).
  • TR-FRET Time-resolved fluorescence resonance energy transfer
  • the experiment was carried out in a 384-well plate (Corning, Cat# 3574), and the reaction buffer used was composed of: 20mM Hepes pH 8.0, 100mM NaCl, 0.1% BSA, 1mM DTT, 0.002% Tween20.
  • the specific experimental operation is as follows: 6 nM PARP7 (HitGen), different concentrations of the test compound (DMSO final concentration of 0.5%) and 6 nM Tracer (RBN011147, refer to Cell Chem Biol.
  • PHERAStar detected the fluorescence intensity at excitation wavelength 337nM and emission wavelength 620nM and 665nM, and calculated the FRET signal intensity (665nM fluorescence intensity/620nM fluorescence intensity*10000). The data were analyzed using GraphPad Prism 6 software log(inhibitor) vs.normalized response-Variable slope model to obtain IC50 values and compound fitting curves.
  • IC 50 data of the compounds of the present invention on PARP7 enzyme inhibition illustrate: ++:0.1nM ⁇ IC 50 ⁇ 10nM +:10nM ⁇ IC 50 ⁇ 1000nM
  • the present invention uses a cell proliferation assay to evaluate the biological activity of the compound on human lung cancer cell lines NCI-H1373 (Nanjing Kebai Biotechnology Co., Ltd.) and EBC-1 (Nanjing Kebai Biotechnology Co., Ltd.) cells.
  • NCI-H1373 cells were cultured in RPMI-1640 medium containing 10% fetal bovine serum and 100 ⁇ g/mL Normocin
  • EBC-1 cells were cultured in Minimum Essential Medium (MEM) containing 10% fetal bovine serum, 1% non-essential amino acids and 100 ⁇ g/mL Normocin.
  • MEM Minimum Essential Medium
  • NCI-H1373 cells and EBC-1 cells were seeded in 96-well plates, with 1000 cells per well of NCI-H1373 cells and 750 cells per well of EBC-1 cells.
  • the cells were cultured overnight at 37°C and 5% CO 2 to allow the cells to adhere to the wall.
  • the culture medium in the cells was removed, 150 ⁇ L of fresh culture medium was added first, and then 50 ⁇ L of culture medium containing 4 times the final concentration of the compound (final concentration range of 1nM to 10 ⁇ M) was added, and the cells were placed in an incubator and cultured for 6 days at 37°C and 5% CO 2 .
  • the culture medium in the cells was removed again, and 100 ⁇ L of serum-free RPMI-1640 basal medium containing 10% CCK8 reagent was added. After incubation at 37°C for 1 hour, the absorbance (OD) value was read at a wavelength of 450 nm using a microplate reader (BMG LABTECH). GraphPad Prism software was used to analyze the data and obtain the IC 50 value and compound fitting curve.
  • IC 50 data of the compounds of the present invention on the anti-proliferation experiment of NCI-H1373 cells illustrate: ++:0.01 ⁇ M ⁇ IC 50 ⁇ 1.00 ⁇ M +:1.0 ⁇ M ⁇ IC 50 ⁇ 100 ⁇ M
  • the above experimental data show that the compound of the present invention has a good inhibitory effect on the proliferation of NCI-H1373 cells and has a strong function of inhibiting the proliferation of tumor cells.

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Abstract

本发明涉及一种式I所示的PARP7抑制剂化合物和其制备方法，以及其用于治疗和/或预防PARP7介导的疾病中的用途。

Description

PARP7抑制剂及其制备方法和用途 技术领域
本发明涉及药物化学领域，具体涉及一类具有抑制PARP7活性的化合物，包含该类化合物的药物组合物及其在医药领域中的应用。
背景技术
PARP全称为poly-ADP-ribose polymerase，即多聚ADP核糖聚合酶，参与了包括DNA修复、基因表达、蛋白降解、细胞应激反应等多种重要的细胞过程。该蛋白家族由17个成员组成，它们都包含一个约230个氨基酸的共同催化结构域。根据催化活性的不同，PARP家族可分为三类：monoPARPS(催化单ADP-核糖单元转移到其底物上)，包括大部分PARP家族成员；polyPARPS(催化聚-ADP-核糖单元转移到其底物上)，包括PARP1、PARP2、PARP5A、PARP5b；PARP13是唯一一个在体外或体内都无法证明其催化活性的PARP家族成员。
monoPARP蛋白家族在与癌症、炎症性疾病和神经退行性疾病的发展相关的多种应激反应中发挥重要作用。PARP7作为monoPARP家族成员已被证明在肿瘤中过度活跃，并在癌细胞存活中起关键作用。研究发现，许多癌细胞依靠PARP7进行内部细胞生存，而PARP7允许癌细胞“躲避”免疫系统。抑制PARP7可有效抑制癌细胞的生长并恢复干扰素信号传导，有效激活T细胞介导的抗肿瘤免疫效应，防止肿瘤细胞逃脱免疫系统监视。目前，关于PARP7抑制剂的研究报道较少。因此，仍然需要开发用于治疗与PARP7相关的癌症的治疗化合物和方法。
发明内容
本发明的目的是提供了一种如式I所示的化合物、或其立体异构体、或其药学上可接受的盐：
其中，
表示单键或双键；
X、X1、X4、X5、X6分别独立地选自CRX、CRXRX1、N或NRX；
X2选自CH或N；
RX、RX1分别独立地选自氢、卤素、氰基、硝基、-OH、-C1～6烷基、-C2～6烯基、-C2～6炔基或卤素取代的C1～6烷基；
R1选自氢、卤素、氰基、硝基、＝O、-OH、-C1～6烷基、氘取代的C1～6烷基、卤素取代的C1～6烷基、-C2～6烯基、-O(C1～6烷基)、-O(卤素取代的C1～6烷基)、-NH2、-C0～2亚烷基-NH(C1～6烷基)、-C0～2亚烷基-N(C1～6烷基)(C1～6烷基)、-C(O)C1～6烷基、-C(O)NRaRb、-C(O)ORa、-S(O)Ra、-S(O)NRaRb、-S(O)ORa、-S(O)2Ra、-S(O)2NRaRb、-S(O)2ORa、-C0～2亚烷基-(3～10元碳环)、-C0～2亚烷基-(3～10元杂环)、-C0～2亚烷基-(6～10元芳环)或-C0～2亚烷基-(5～10元杂芳环)；其中，所述烷基、亚烷基、碳环、杂环、芳环、杂芳环任选地被一个、两个、三个或四个独立的Rc取代；
Ra、Rb分别独立选自氢、氘、卤素、氰基、硝基、-C1～6烷基、-C2～6烯基、-C2～6炔基、卤素取代的C1～6烷基、-C0～2亚烷基-OH、-O(C1～6烷基)、-O(卤素取代的C1～6烷基)、-NH2、-C0～2亚烷基-NH(C1～6烷基)或-C0～2亚烷基-N(C1～6烷基)(C1～6烷基)；
Rc选自氢、氘、卤素、氰基、硝基、-C1～6烷基、-C2～6烯基、-C2～6炔基、卤素取代的C1～6烷基、-C0～2亚烷基-OH、-O(C1～6烷基)、-O(卤素取代的C1～6烷基)、-NH2、-C0～2亚烷基-NH(C1～6烷基)、-C0～2亚烷基-N(C1～6烷基)(C1～6烷基)或-C(O)C1～6烷基；
L1选自-CO-或-CONH-；
L2选自-NHCR2R3-、-S(O)CR2R3-、-S(O)2CR2R3-、-S(O)NH CR2R3-、-S(O)2NH CR2R3-、3～10元碳环、3～10元杂环或5～10杂芳环；其中，所述碳环、杂环、杂芳环任选地被一个、两个、三个或四个独立的Rd取代；
Rd选自氢、卤素、氰基、氧代、硝基、-C1～6烷基、-C2～6烯基、-C2～6炔基、卤素取代的C1～6烷基、-C0～2亚烷基-OH、-O(C1～6烷基)、-O(3～10元碳环)、-O(卤素取代的C1～6烷基)、-NH2、-C0～2亚烷基-NH(C1～6烷基)、-C0～2亚烷基-N(C1～6烷基)(C1～6烷基)或-C(O)C1～6烷基；
或者，两个Rd与其相连的原子一起形成3～10元杂环或3～10元碳环；
R2、R3分别独立地选自氢、-C1～6烷基、-C2～6烯基、-C2～6炔基、卤素取代的C1～6烷基、-OH、-O(C1～6烷基)、-O(卤素取代的C1～6烷基)、-NH2、-C0～2亚烷基-NH(C1～6烷基)、-C0～2亚 烷基-N(C1～6烷基)(C1～6烷基)、-C(O)C1～6烷基、6～10元芳环、6～10元杂芳环、3～10元杂环或3～10元碳环；其中，所述亚烷基、碳环、杂环、芳环、杂芳环任选地被一个、两个、三个或四个独立的R23取代；
或者R2、R3与其相连的原子一起形成3～10元杂环或3～10元碳环；其中，所述杂环、碳环任选地被一个、两个、三个或四个独立的R23取代；
R23选自氢、卤素、氰基、硝基、-C1～6烷基、-C2～6烯基、-C2～6炔基、卤素取代的C1～6烷基、-C0～2亚烷基-OH、-O(C1～6烷基)、-O(卤素取代的C1～6烷基)、-NH2、-C0～2亚烷基-NH(C1～6烷基)、-C0～2亚烷基-N(C1～6烷基)(C1～6烷基)或-C(O)C1～6烷基；
环A1选自3～10元杂环；其中，所述杂环任选地被一个、两个、三个、四个、五个、六个、七个或八个独立的R4取代；
R4选自氢、氘、卤素、氰基、硝基、氧代、羟基、-C1～6烷基、-C2～6烯基、-C2～6炔基、卤素取代的C1～6烷基、-O(C1～6烷基)、-O(3～6元碳环)、-O(卤素取代的C1～6烷基)、-NH2、-C0～2亚烷基-NH(C1～6烷基)、-C0～2亚烷基-N(C1～6烷基)(C1～6烷基)或-C(O)C1～6烷基；
环A2选自5～10杂芳环或6～10元芳环；其中，所述芳环、杂芳环任选地被一个、两个、三个、或四个独立的R5取代；
R5选自氢、卤素、氰基、硝基、氧代、-C0～2亚烷基-羟基、-C1～6烷基、-C2～6烯基、-C2～6炔基、卤素取代的C1～6烷基、-O(C1～6烷基)、-S(C1～6烷基)、-S(O)C1～6烷基、-S(O)2C1～6烷基、-O(3～6元碳环)、-O(卤素取代的C1～6烷基)、-C(O)NH2、-NH2、-C0～2亚烷基-NH(C1～6烷基)、-C0～2亚烷基-N(C1～6烷基)(C1～6烷基)、-C(O)C1～6烷基、-C0～2亚烷基-(3～10元碳环)、-C0～2亚烷基-(3～10元杂环)、-C0～2亚烷基-(6～10元芳环)或-C0～2亚烷基-(5～10元杂芳环)；其中，所述烷基、亚烷基、碳环、杂环、芳环、杂芳环任选地被一个、两个、三个、或四个独立的R51取代；
或者R4、R5与环A1和环A2一起形成11～17元稠杂环；所述稠杂环任选地被一个、两个、三个、或四个独立的R52取代；
R51选自氢、卤素、氰基、硝基、氧代、羟基、-C1～6烷基、-C2～6烯基、-C2～6炔基、卤素取代的C1～6烷基、-O(C1～6烷基)、-O(3～6元碳环)、-O(卤素取代的C1～6烷基)、-NH2、-C0～2亚烷基-NH(C1～6烷基)或-C0～2亚烷基-N(C1～6烷基)(C1～6烷基)；
R52选自氢、卤素、氰基、硝基、氧代、硫代、羟基、-C1～6烷基、-C2～6烯基、-C2～6炔基、卤素取代的C1～6烷基、-O(C1～6烷基)、-O(3～6元碳环)、-O(卤素取代的C1～6烷基)、-NH2、- C0～2亚烷基-NH(C1～6烷基)、-C0～2亚烷基-N(C1～6烷基)(C1～6烷基)、-C2～6烯基-CON(C1～6烷基)(C1～6烷基)、-C0～2亚烷基-(3～10元碳环)、-C0～2亚烷基-(3～10元杂环)、-C0～2亚烷基-(6～10元芳环)或-C0～2亚烷基-(5～10元杂芳环)。
进一步地，
R1选自氢、卤素、氰基、＝O、-NH2、-C(O)NRaRb、氘取代的C1～6烷基、卤素取代的C1～6烷基、-C1～3烷基、-C2～4烯基、3元碳环、4元碳环、5元碳环、6元碳环、4元杂环、5元杂环、6元杂环、7元杂环、6元芳环、10元芳环、5元杂芳环、6元杂芳环、9元杂芳环或10元杂芳环；其中，所述碳环、杂环、芳环、杂芳环任选地被一个、两个、三个或四个独立的Rc取代；
L2选自-NHCR2R3-、3元碳环、4元碳环、5元碳环、6元碳环、4元单杂环、5元单杂环、6元单杂环、7元单杂环、8元单杂环、9元单杂环、10元单杂环、7元螺杂环、8元螺杂环、9元螺杂环、10元螺杂环、6元稠杂环、7元稠杂环、8元稠杂环、9元稠杂环、10元稠杂环或5元杂芳环；其中，所述碳环、单杂环、螺杂环、稠杂环、杂芳环任选地被一个、两个、三个或四个独立的Rd取代；
R2、R3分别独立地选自氢、-C1～6烷基、6元芳环、5元杂芳环或6元杂芳环；
或者，R2、R3与其相连的原子一起形成3～6元碳环、4元杂环、5元杂环、6元杂环或7元杂环；其中，所述碳环、杂环任选地被一个、两个、三个或四个独立的R23取代；
Rd选自氢、卤素、氰基、氧代、硝基、-C1～3烷基、-C2～6烯基、-C2～6炔基、卤素取代的C1～3烷基、-OH、-O(C1～3烷基)或-O(3～6元碳环)；
环A1选自5元单杂环、6元单杂环、7元单杂环、8元单杂环、9元单杂环、10元单杂环、7元螺杂环、8元螺杂环、9元螺杂环、10元螺杂环、6元稠杂环、7元稠杂环、8元稠杂环、9元稠杂环、10元稠杂环、7元桥杂环、8元桥杂环、9元桥杂环或10元桥杂环；其中，所述单杂环、螺杂环、稠杂环、桥杂环任选地被一个、两个、三个、四个、五个、六个、七个或八个独立的R4取代；
环A2选自5元杂芳环、6元杂芳环、9元稠杂芳环、10元稠杂芳环、5元杂芳环稠6元饱和环、6元杂芳环稠6元饱和环、6元杂芳环稠6元饱和杂环、6元杂芳环稠5元饱和环、5元杂芳环稠6元饱和杂环或6元芳环；其中，所述芳环、杂芳环任选地被一个、两个、三个、或四个独立的R5取代；
R5选自氢、卤素、氰基、硝基、氧代、羟基、-C1～3烷基、-C2～6烯基、-C2～6炔基、卤素 取代的C1～3烷基、-O(C1～6烷基)、-O(3～6元碳环)、-O(卤素取代的C1～6烷基)、-S(C1～6烷基)、-S(O)C1～6烷基、-S(O)2C1～6烷基、-NH2、-C0～2亚烷基-NH(C1～6烷基)、-C0～2亚烷基-N(C1～6烷基)(C1～6烷基)、-C(O)C1～6烷基、-C0～2亚烷基-(3～6元碳环)、3～10元杂环、6～10元芳环或5～10元杂芳环；其中，所述烷基、碳环、杂环、芳环、杂芳环任选地被一个、两个、三个、或四个独立的R51取代。
进一步具体地，
R1选自氢、Br、F、 氰基、甲基、＝O、 -NH2、
进一步具体地，
L2选自 其中，aa端与L1连接。
进一步具体地，
环A1选自
进一步具体地，
环A2选自
进一步地，
R4、R5与环A1和环A2一起形成12元稠杂环、13元稠杂环、14元稠杂环、15元稠杂环或16元稠杂环；所述稠杂环任选地被一个、两个、三个、或四个独立的R52取代；
R52选自氢、卤素、氰基、硝基、氧代、硫代、羟基、-C1～6烷基、-C2～6烯基、-C2～6炔基、卤素取代的C1～6烷基、-O(C1～3烷基)、-O(3～6元碳环)、-O(卤素取代的C1～6烷基)、-NH2、-NH(C1～6烷基)、-N(C1～6烷基)(C1～6烷基)、-C2～6烯基-CON(C1～6烷基)(C1～6烷基)、-3～10元碳环、-3～10元杂环、-6～10元芳环或-5～10元杂芳环。
进一步地，
R4、R5与环A1和环A2一起形成的稠杂环为
其中，
表示单键或双键；
n选自1，2或3；
X3各自独立地选自NH、N(C1～6烷基)、N(C2～6烯基)、N(3～6元碳环)、N(3～6元杂环)、N(卤素取代的C1～6烷基)、CRX31、CRX31RX32、O、S、
RX31、RX32分别独立地选自氢、卤素或-C1～6烷基。
进一步具体地，
X3各自独立地选自
进一步具体地，R4、R5环A1和环A2一起形成地稠杂环选自：

进一步地，
X、X1、X4、X5、X6分别独立地选自CH、CH2、N或NCH3。
进一步地，
L1选自-CO-或其中，bb端与环A1连接。
在本发明的一些实施方案中，
X为N，X1为CH、X2为N，X4为N，X5为N，X6为CH；
或者，X为N，X1为CH、X2为N，X4为N，X5为CH，X6为CH；
或者，X为N，X1为CH、X2为N，X4为CH，X5为CH，X6为CH；
或者，X为N，X1为CH、X2为N，X4为N，X5为CH，X6为N；
或者，X为N，X1为CH、X2为CH，X4为CH，X5为CH，X6为CH；
或者，X为N，X1为CH、X2为N，X4为NRX，X5为CH2，X6为N。
进一步地，式I所述化合物如式II、式III、式IV、式V、式VI或式VII所示：

其中，R1、RX、L2、L1、环A1、环A2如前所述。
作为优选：式I所述化合物如式I-1所示：
其中，R1、Rd、R4、环A2如前所述。
进一步优选地，式I所述化合物如式I-1’所示：
其中，R1、Rd、R4、环A2如前所述。
在本发明的一些实施方案中，式I-1或式I-1’中，R1选自氢、 Br、F、氰基、甲基、＝O、-NH2、
在本发明的一些实施方案中，式I-1或式I-1’中，每个Rd分别独立选自氢、卤素、氰基、氧代、硝基、-C1～3烷基、-C2～6烯基、-C2～6炔基、卤素取代的C1～3烷基、-OH、-O(C1～3烷基)或-O(3～6元碳环)。优选地，每个Rd分别独立选自氢、甲基、乙基、正丙基、异丙基、氟、氯、氧代、-OH、-O(甲基)、-O(环丙基)。在部分优选实施方案中，每个Rd均选自氢。
在本发明的一些实施方案中，式I-1或式I-1’中，R4选自氢、氘、卤素、氧代、羟基、甲基、乙基、正丙基、异丙基、-O(甲基)。在部分优选实施方案中，R4为氢。
在本发明的一些实施方案中，式I-1或式I-1’中，环A2选自
作为优选：式I所述化合物如式II-1、式II-2、式II-3、式II-4或式II-5所示：

其中，表示单键或双键；
Y1、Y2、Y4、Y5、Y6、Y9、Y11、Y12分别独立选自N、NRY1、CHRY1或CRY1；
Y3、Y7、Y8、Y10分别独立选自CRY1、CHRY1、O、S、N或NRY1；
Y13选自N或CRY1；
每个RY1分别独立地选自氢、卤素、氰基、硝基、-C1～6烷基、-C2～6烯基、-C2～6炔基或卤素取代的C1～6烷基；
R1、Rd、R4、R5、X1如前所述。
进一步优选地，式I所述化合物如式II-1’、式II-2’、式II-3’、式II-4’或式II-5’所示：

其中，表示单键或双键；
Y1、Y2、Y4、Y5、Y6、Y9、Y11、Y12分别独立选自N、NRY1、CHRY1或CRY1；
Y3、Y7、Y8、Y10分别独立选自CRY1、CHRY1、O、S、N或NRY1；
Y13选自N或CRY1；
每个RY1分别独立地选自氢、卤素、氰基、硝基、-C1～6烷基、-C2～6烯基、-C2～6炔基或卤素取代的C1～6烷基；
R1、Rd、R4、R5、X1如前所述。
在本发明的一些实施方案中，式II-1、式II-2、式II-3、式II-4、式II-5式、II-1’、式II-2’、式II-3’、式II-4’或式II-5’中，R1选自氢、Br、F、 氰基、甲基、＝O、-NH2、
在本发明的一些实施方案中，式II-1、式II-2、式II-3、式II-4、式II-5、式II-1’、式II-2’、式II-3’、式II-4’或式II-5’中，每个Rd分别独立选自氢、卤素、氰基、氧代、硝基、-C1～3烷基、-C2～6烯基、-C2～6炔基、卤素取代的C1～3烷基、-OH、-O(C1～3烷基)或-O(3～6元碳环)。优选地，每个Rd分别独立选自氢、甲基、乙基、正丙基、异丙基、氟、氯、氧代、-OH、-O(甲基)、-O(环丙基)。在部分优选实施方案中，每个Rd均选自氢。
在本发明的一些实施方案中，式II-1、式II-2、式II-3、式II-4、式II-5、式II-1’、式II-2’、式II-3’、式II-4’或式II-5’中，R4选自氢、氘、卤素、氧代、羟基、甲基、乙基、正丙基、异丙基、-O(甲基)。在部分优选实施方案中，R4为氢。
在本发明的一些实施方案中，式II-1、式II-2、式II-3、式II-4、式II-5、式II-1’、式II-2’、式II-3’、式II-4’或式II-5’中，R5选自氢、氟、氯、溴、氰基、硝基、氧代、-C0～2亚烷基-羟基、甲基、乙基、正丙基、异丙基、乙烯基、丙烯基、单氟甲基、二氟甲基、三氟甲基、-O(甲基)、-O(乙基)、-O(正丙基)、-O(异丙基)、-O(3元碳环)、-O(4元碳环)、-O(5元碳环)、-O(6元碳环)、-O(单氟甲基)、-O(二氟甲基)、-O(三氟甲基)、-C(O)NH2、-NH2、3元碳环、4元碳环、5元碳环、6元碳环、4元杂环、5元杂环、6元杂环、苯环、5元杂芳环、6元杂芳环。在部分优选实施方案中，R5为三氟甲基。
进一步地：式I所述化合物如式VIII所示：
其中，Y4、Y5分别独立选自N或CRY1；Y3选自CHRY1、O、S或NRY1；
同时，RL2、R3与其相连的原子一起形成3～10元杂环；
R1、R2、R3、R4、R5取代基定义如前所述。
在本发明的一些实施方案中，式VIII中，RL2、R3与其相连的原子一起形成4元杂环、5元杂环、6元杂环、7元杂环、8元杂环、9元杂环、10元杂环。优选地，式VIII中，RL2、R3与其相连的原子一起形成4元单杂环、5元单杂环、6元单杂环、7元单杂环、8元单杂环、6元稠杂环、7元稠杂环、8元稠杂环、9元稠杂环、10元稠杂环、7元螺杂环、8元螺 杂环、9元螺杂环、10元螺杂环。
在本发明的一些实施方案中，式VIII中，R1选自氢、Br、F、氰基、甲基、＝O、-NH2、
在本发明的一些实施方案中，式VIII中，R4选自氢、氘、卤素、氧代、羟基、甲基、乙基、正丙基、异丙基、-O(甲基)。在部分优选实施方案中，R4为氢。
优选地，本发明式I所述的化合物具体为：




















本发明还提供一种上述任一项所述的化合物、或其立体异构体、或其药学上可接受的盐在制备治疗PARP7介导的疾病的药物中的用途。
所述PARP7介导的疾病包括癌症或恶行肿瘤，所述癌症或恶行肿瘤包括乳腺癌、中枢神经系统癌、子宫内膜癌、肾癌、大肠癌、肺癌、食道癌、卵巢癌、胰腺癌、前列腺癌、胃癌、头颈癌(上呼吸消化道癌)、尿路癌或结肠癌。
本发明还提供一种药物组合物，它是以上述任一项所述的化合物、或其立体异构体、或其药学上可接受的盐，加上药学上可接受的辅料制备而成的制剂。
以下为对本发明的名词术语的解释和说明：
本发明中提供的化合物和衍生物可以根据IUPAC(国际纯粹与应用化学联合会)或CAS(化学文摘服务社，Columbus，OH)命名系统命名。
关于本发明的使用术语的定义：除非另有说明，本文中基团或者术语提供的初始定义适用于整篇说明书的该基团或者术语；对于本文没有具体定义的术语，应该根据公开内容和上下文，给出本领域技术人员能够给予它们的含义。
术语“取代”是指分子中的氢原子被其它不同的原子或分子所替换。
碳氢基团中碳原子含量的最小值和最大值通过前缀表示，例如，前缀Ca～b烷基表明任何含“a”至“b”个碳原子的烷基。因此，例如，“C1～4烷基”是指包含1～4个碳原子的烷基。
术语“烷基”是指具有指定数目的成员原子的饱和烃链。例如，C1～6烷基是指具有1至6个成员原子，例如1至4个成员原子的烷基基团。烷基基团可以是直链或支链的。代表性的支链烷基基团具有一个、两个或三个支链。烷基基团可任选地被一个或多个如本文所定义的取代基取代。烷基包括甲基、乙基、丙基(正丙基和异丙基)、丁基(正丁基、异丁基和叔丁基)、戊基(正戊基、异戊基和新戊基)和己基。烷基基团也可以是其他基团的一部分，所述其他基团为例如C1～C6烷氧基。
术语“亚烷基”是指具有指定数目的成员原子的二价饱和脂族烃基。Ca～b亚烷基是指具有a至b个碳原子的亚烷基基团。亚烷基基团包括支链和直链烃基基团。例如，术语“亚丙基”可以通过下列结构例举：同样地，术语“二甲基亚丁基”可以例如通过下列结构的任一种例举：
本发明的-C0～4亚烷基可以为C0亚烷基、C1亚烷基(例如-CH2-)、C2亚烷基(例如-CH2CH2-等)、C3亚烷基或C4亚烷基；C0亚烷基指的是此处的基团不存在，以化学键的形式连接，A-C0亚烷基-B指的是A-B，即A基团与B基团直接通过化学键连接。
本发明中所述的不饱和是指基团或者分子中含有碳碳双键、碳碳三键、碳氧双键、碳硫双键、碳氮三键等。
术语“烯基”是指具有2至10个碳原子和在一些实施方案中2至6个碳原子或2至4个碳原子且具有至少1个乙烯基不饱和位点(>C＝C<)的直链或支链烃基基团。例如，(Ca-Cb)烯基是指具有a至b个碳原子的烯基基团并且意在包括例如乙烯基、丙烯基、异丙烯基、1,3-丁二烯基等。
术语“炔基”是指含有至少一个三键的直链一价烃基或支链一价烃基。术语“炔基”还意在包括具有一个三键和一个双键的那些烃基基团。例如，(C2-C6)炔基意在包括乙炔基、丙炔基等。
术语“＝O”或“氧代”是指氧原子通过双键取代两个氢原子或孤对电子。
术语“＝S”或“硫代”是指硫原子通过双键取代两个氢原子或孤对电子。
本发明基团描述中的是用来描述基团取代的位置。例如是指四氢吡咯环通过的位置与结构中的其它环形成螺环。
术语“-OR”、“-NRR”等是指R基团与氧原子或氮原子以单键相连。例如，-O(C1～6烷基)表示C1～6烷基与氧原子以单键相连。又例如，-N(C1～6烷基)(C1～6烷基)表示两个独立的C1～6烷基分别与氮原子以单键相连。
术语“CR”、“CRR”等是指R基团与碳原子以单键相连，其中碳原子包括但不限于是SP2杂化碳原子或SP3杂化碳原子。
术语“-C(O)R”、“-CO-”、“-S(O)2R”、“-S(O)R”等中的氧原子是与碳原子或硫原子以双键相连，R基团与氧原子或硫原子以单键相连；又例如“-S(O)(NH)R”是指氧原子和氮原子以双 键与硫原子相连，R基团与硫原子以单键相连。
术语“卤素”为氟(F)、氯(Cl)、溴(Br)或碘(I)。
术语“卤素取代的烷基”指烷基中的氢原子可被一个或多个卤素原子取代。例如卤素取代的C1～4烷基指氢原子被一个或多个卤素原子取代的包含1～4个碳原子的烷基。
术语“氘取代的烷基”指烷基中的氢原子可被一个或多个氘原子取代。例如氘取代的C1～ 4烷基指氢原子被一个或多个氘原子取代的包含1～4个碳原子的烷基。
术语“碳环”、“环烷基”是指具有碳原子且没有环杂原子且具有单个环或多个环(包括稠合、螺和、桥环)的饱和或部分饱和的环状基团。对于具有不含环杂原子的芳族和非芳族环的多环体系，当连接点位于非芳族碳原子时，适用术语“碳环”、“环烷基”(例如5,6,7,8,-四氢化萘-5-基)。术语“碳环”、“环烷基”包括环烯基基团，诸如环己烯基。环烷基基团的实例包括例如，金刚烷基、环丙基、环丁基、环己基、环戊基、环辛基、环戊烯基和环己烯基。包括多双环烷基环体系的环烷基基团的实例是双环己基、双环戊基、双环辛基等。例如术语“碳环”、“环烷基”还包括芳香环与非芳香环稠合形成的部分饱和环状基团的情形，其连接位点可以位于非芳族碳原子或芳族碳原子，实例包括1,2,3,4-四氢化萘-5-基。
术语“桥环”、“桥环烷基”是指具有多个碳原子且没有环杂原子的多个环桥连形成的饱和或非芳香性的部分饱和的环状基团。桥环体系的的实例包括金刚烷基等。
术语“螺环”、“螺环烷基”是指具有多个碳原子且没有环杂原子的多个环螺合形成的饱和或非芳香性的部分饱和的环状基团。螺环体系的实例包括等。
术语“稠环”是指由两个或两个以上环状结构彼此共用两个相邻的原子所形成的饱和或非芳香性的部分饱和的环体系。稠环体系的实例包括等。
术语“杂环”、“杂环烷基”指包含至少一个杂原子的饱和或部分不饱和的、单环或多环的脂族烃基团；其中杂原子指氮原子、氧原子、硫原子；单环杂环烷基的非限制性实例包括但不限于吖丁啶基、吡咯烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基等。多环杂 环烷基的非限制性实例包括但不限于并环(稠环)、螺环或桥环的杂环烷基。
术语“桥杂环”、“桥杂环烷基”是指包含至少一个杂原子的多个环桥连形成的饱和或非芳香性的部分饱和的环状基团。桥杂环烷基体系的实例包含等。
术语“螺杂环”、“螺杂环烷基”是指包含至少一个杂原子的多个螺合连形成的饱和或非芳香性的部分饱和的环状基团。螺杂环烷基体系的实例包含等。
术语“稠杂环”是指由两个或两个以上环状结构彼此共用两个相邻的原子所形成的非芳香性的、饱和或部分不饱和的环体系，环原子包含一个或多个独立地选自氧、氮和硫的杂原子，杂原子个数为1个、2个、3个或更多个。稠杂环体系的实例包括等。
术语“芳环”、“芳基”是指含有6-14个，优选6-10个，更优选6个或10个环原子的碳环体系。环原子的单环、双环和三环的碳环体系、其中，至少一个环体系是芳香族的，其中每一个环体系包含3-7个原子组成的环，且有一个或多个连接点与分子的其余部分相连。实例包括但不限于苯基、萘基、蒽基等。
术语“杂芳基”、“杂芳环”是指含有5-14个，优选5-10个环原子的单环、双环和三环体系，其中，至少一个环体系是芳香族的，且至少一个环体系包含一个或多个选自氮、氧或S(O)m(其中m为0、1或2)的杂原子，其中每一个环体系包含5-7个原子组成的环，且有一个或多个连接点与分子的其余部分相连。实例包括但不限于呋喃基、咪唑基、吡啶基、嘧啶基、噻唑基、嘌呤基、喹啉基等。
术语“立体异构体”是指具有相同化学构造，但原子或基团在空间上排列方式不同的化合物。
本发明的化合物可以包含不对称中心或手性中心，因此存在不同的立体异构体。本发明的化合物所有的立体异构形式，包括但绝不限于，构象异构体(旋转异构体)、几何异构体(顺/反)异构体、阻转异构体等，和它们的混合物，如外消旋混合物，组成了本发明的一部分。很多有机化合物都以光学活性形式存在，即它们有能力旋转平面偏振光的平面。在描述光学活性化合物时，前缀D、L或R、S用来表示分子手性中心的绝对构型。这些立体异构体的化学结构是相同的，但是它们的立体结构不一样。特定的立体异构体可以是对映体，异构体 的混合物通常称为对映异构体混合物。50：50的对映体混合物被称为外消旋混合物或外消旋体，这可能导致化学反应过程中没有立体选择性或立体定向性。术语“外消旋混合物”和“外消旋体”是指等摩尔的两个对映异构体的混合物，缺乏光学活性。
术语“任选”或“任选地”意味着随后所描述地事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生的情形。例如，“任选被烷基取代的杂环基团”意味着烷基可以但并非必须存在，该说明包括杂环基团被烷基取代的情形和杂环基团不被烷基取代的情形。
术语“分别独立地”意味着随后所描述的事件或动作的主体具有相对独立性，其中一个(或一些)主体所经历的事件或发出的动作不会影响另一个(或另一些)主体所经历的事件或发出的动作。同时，需要说明的是，上述主体既可以是属于不同概念下或范畴内的个体，也可以是属于同一概念下或范畴内的不同个体。例如，“(每一个)A和B各自独立地为氢或甲基”意味着不但当只有一组A和B存在时，二者可以独立地为氢或甲基，而且当存在两组以上A和B时，不同组中的多个A(和/或不同组中的多个B)也可以独立地为氢或甲基。
术语“药物组合物”是指可供药用的组合物，其包含一种或多种如式I所示的化合物或其药学上可接受的形式(例如盐、水合物、溶剂化物、立体异构体、互变异构体、代谢产物、前药等)，以及其他组分(例如药学上可接受的辅料)。
术语“癌症”或“恶性肿瘤”是指以不受控制的细胞异常增殖为特征的多种疾病中的任何一种，受影响的细胞在局部或通过血流和淋巴系统扩散到其他部位的能力的身体(即转移)以及许多特征结构和/或分子特征中的任何一个。“癌细胞”是指经历多步骤肿瘤进展的早期，中期或晚期阶段的细胞。所述“癌症”或“恶性肿瘤”为白血病、肝癌、脑瘤、骨髓瘤、胰腺癌、乳腺癌、结肠癌、前列腺癌、膀胱癌或多发性内分泌腺癌。
在本发明中，“药学上可接受的辅料”是指在药物生产领域中广泛采用的辅助物料。使用辅料的主要目的在于提供一种使用安全、性质稳定和/或具有特定功能性的药物组合物，还在于提供一种方法，以便在为受试者施用药物之后，活性成分能够以所期望的速率溶出，或者促进活性成分在接受给药的受试者体内得到有效吸收。药学上可接受的辅料可以是具有惰性的填充剂，也可以是为药用组合物提供某种功能(例如稳定组合物的整体pH值或防止组合物中活性成分的降解)的功效成分。药学上可接受的辅料的非限制性实例包括但不限于粘合剂、助悬剂、乳化剂、稀释剂(或填充剂)、成粒剂、胶粘剂、崩解剂、润滑剂、抗粘着剂、助流剂、润湿剂、胶凝剂、吸收延迟剂、溶解抑制剂、增强剂、吸附剂、缓冲剂、螯合剂、防腐剂、着色剂、矫味剂、甜味剂等。
术语“盐”和“药学上可接受的盐”是指上述化合物或其立体异构体，与无机和/或有机酸和碱形成的酸式和/或碱式盐，也包括两性离子盐(内盐)，还包括季铵盐，例如烷基铵盐。这些盐可以是在化合物的最后分离和纯化中直接得到。也可以是通过将上述化合物，或其立体异构体，与一定数量的酸或碱适当(例如等当量)进行混合而得到。这些盐可能在溶液中形成沉淀而以过滤方法收集，或在溶剂蒸发后回收而得到，或在水介质中反应后冷冻干燥制得。本发明中所述盐可以是化合物的盐酸盐、硫酸盐、枸橼酸盐、苯磺酸盐、氢溴酸盐、氢氟酸盐、磷酸盐、乙酸盐、丙酸盐、丁二酸盐、草酸盐、苹果酸盐、琥珀酸盐、富马酸盐、马来酸盐、酒石酸盐或三氟乙酸盐。
具体实施方式
下面将结合具体实施例来阐述本发明的技术方案，下列实施例的提供旨在进一步说明本发明，而非用于限制本发明的范围。对于本领域技术人员而言，在不脱离本发明的精神和范围的情况下，针对本发明的具体实施例方式进行各种变化和改进将是显而易见的。
本发明具体实施方式中使用的原料、设备均为已知产品，通过购买市售产品获得。化合物的结构是通过核磁共振(NMR)或(和)质谱(MS)来确定的。NMR位移(δ)以15-0(ppm)的的单位给出。NMR的测定是用(BrukerAvanceIII 400和BrukerAvance 300)核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d6)，氘代氯仿(CDCl3)，氘代甲醇(CD3OD)，内标为四甲基硅烷(TMS)。LC-MS的测定用岛津液质联用仪(ShimadzuLC-MS2020(ESI))。HPLC的测定使用岛津高压液相色谱仪(ShimadzuLC-20A)。反相制备色谱使用GilsonGX-281反相制备色谱仪。薄层层析硅胶板用烟台黄海HSGF254或青岛GF254硅胶板，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。柱层析一般使用烟台黄海硅胶200～300目硅胶为载体。本发明的已知的起始原料可以采用或按照本领域已知的方法来合成，或可购买于安耐吉化学、阿拉丁化学、成都科龙化工、韶远化学科技、百灵威科技等公司。氢气氛围是指反应瓶连接一个约1L容积的氢气球。氢化反应通常抽真空，充入氢气，反复操作3次。实施例中无特殊说明，反应在氮气氛围下进行。实施例中无特殊说明，溶液是指水溶液。实施例中无特殊说明，反应的温度为室温。实施例中无特殊说明，M是摩尔每升。室温为最适宜的反应温度，为20℃～30℃。过夜为12±2h。
实施例中所述试剂缩写如下：
PE：石油醚；EA：乙酸乙酯；DCM：二氯甲烷；MeOH：甲醇；DMF：N,N-二甲基甲酰胺；DMSO：二甲基亚砜；DMAP：4-二甲氨基吡啶；DIPEA：二异丙基乙基胺；Boc：叔丁基氧羰基；TFA：三氟乙酸；DBU：1,8-二氮杂二环十一碳-7-烯；HATU：2-(7-偶 氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯；NMP：N-甲基吡咯烷酮；KF：氟化钾；MePh是指甲苯。
中间体A-1的合成
于100mL单口反应烧瓶中，将化合物5-溴-2-氯嘧啶A-1a(2.3g，10mmol)溶于NMP(20mL)中，待化合物溶解完全，加入碳酸钾(1.43g，10.34mmol)和哌嗪-1-羧酸叔丁酯(1.44g，7.75mmol)，加完后80℃油浴加热反应3小时，待TLC点板监测反应完成，冷却至室温。加入100mL水和50mL乙酸乙酯，萃取分液，并再用乙酸乙酯萃取两次，将有机相合并后用盐水洗涤，硫酸钠干燥，过滤，减压浓缩得固体粗品，正相纯化得到化合物A-1b(1.58g，4.6mmol，白色固体，产率89.04％)。MS(ESI)m/z＝344[M+H]+。
于100mL三口反应烧瓶中，将中间体A-1b(1.58g，4.6mmol)溶于二氧六环/水(15mL/3mL/5:1)中，再依次加入环丙基硼酸频哪醇酯(1.16g，6.91mmol)，Pd(dppf)Cl2(336.84mg，0.46mmol)和碳酸铯(3.01g，9.21mmol)。加毕，充分置换氮气三次，油浴升温至100℃搅拌反应16小时。待反应完成后，将体系冷却至室温，反应液减压浓缩至干，所得油状物用乙酸乙酯溶解后，用饱和食盐水洗涤，分液，有机相用硫酸钠干燥，过滤，减压浓缩得产物粗品。粗品经硅胶柱层析纯化得中间体A-1c(1.23g，4.04mmol，产率87.78％)。MS(ESI)m/z＝305[M+H]+。
于100mL单口反应烧瓶中，将中间体A-1c(1.23g,4.04mmol)溶于乙酸乙酯(2mL)中，待化合物溶解完全，冰浴下加入4M盐酸乙酸乙酯溶液(10mL)，随后撤走冰浴，于室温反应3小时。待TLC监测反应完成，减压浓缩得固体粗品，继续用石油醚洗涤，干燥，得中间体A-1(0.95g，盐酸盐，白色固体，产率97.66％)。MS(ESI)m/z＝205[M+H]+。
中间体A-2至中间体A-7的合成
参照中间体A-1的合成路线，用下表中相应的硼酸频哪醇酯替换环丙基硼酸频哪醇酯，其余试剂和操作不变，可得相应中间体。

中间体A-8的合成
于100mL单口反应烧瓶中，将化合物2-氯嘧啶-5-羧酸甲酯A-8a(1.02g，5.79mmol)溶于NMP(10mL)中，待化合物溶解完全，加入碳酸钾(1.6g，11.59mmol)和哌嗪-1-羧酸叔丁酯(1.62g，8.69mmol)，加完后80℃油浴加热反应3小时，待TLC点板监测反应完成，冷却至室温。加入100mL水和50mL乙酸乙酯，萃取分液，并再用乙酸乙酯萃取两次，将有机相合并后用盐水洗涤，硫酸钠干燥，过滤，减压浓缩得固体粗品，正相纯化得到化合物A-8b(1.62g，5.03mmol，油状物，产率86.72％)。MS(ESI)m/z＝323[M+H]+。
于50mL三口反应烧瓶中，将中间体A-8b(161mg，0.49mmol)和钛酸四异丙酯(198.73mg，0.79mmol)溶于干燥四氢呋喃(5mL)中并充分置换氮气。随后在冰浴下缓慢滴加乙基溴化镁溶液(1.4mL，2.8mmol)，加毕，室温下搅拌反应过夜。待TLC点板监测反应完成后，加入50mL冰水淬灭反应，随后用20mL乙酸乙酯，萃取两次分液，将有机相合并后用盐水洗涤，硫酸钠干燥，过滤，减压浓缩得产物粗品。粗品经硅胶柱层析纯化得中间体A-8c(75mg，0.23mmol，产率46.87％)。MS(ESI)m/z＝321[M+H]+。
于50mL单口反应烧瓶中，将中间体A-8c(75mg，0.23mmol)溶于干燥二氯甲烷(3mL)后置换氮气。随后在冰浴下缓慢滴加二乙胺基三氟化硫(113.2mg，0.7mmol)，加毕，室温下搅拌反应1小时。待TLC点板监测反应完成后，加入30mL冰氯化铵饱和水溶液淬灭反应，随后用10mL二氯甲烷，萃取两次分液，将有机相合并后用盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩得粗品。粗品经反相柱层析纯化得中间体A-8d(62mg，0.19mmol，产率82.16％)。MS(ESI)m/z＝323[M+H]+。
参考中间体A-1的合成方法，制备得到中间体A-8为白色固体，所得产物的盐酸盐可直接用于下一步反应，无需进一步纯化。MS(ESI)m/z＝223[M+H]+。
中间体A-9的合成
于100mL单口反应烧瓶中，将化合物2-氯-5-(甲巯基)嘧啶A-9a(1.01g，6.23mmol)溶于NMP(10mL)中，待化合物溶解完全，加入碳酸钾(1.72g，6.23mmol)和哌嗪-1-羧酸叔丁酯(1.74g，9.34mmol)，加完后80℃油浴加热反应3小时，待TLC点板监测反应完成，冷却至室温。加入100mL水和50mL乙酸乙酯，萃取分液，并再用乙酸乙酯萃取两次，将有机相合并后用盐水洗涤，硫酸钠干燥，过滤，减压浓缩得粗品，正相纯化得化合物A-9b(1.58g，5.03mmol，白色固体，产率81.76％)。MS(ESI)m/z＝311[M+H]+。
于50mL单口反应烧瓶中，将中间体A-9b(580mg，1.87mmol)溶于干燥二氯甲烷(5mL)中，待化合物溶解完全，加入间氯过氧苯甲酸(322.43mg，1.87mmol)，加毕，室温下搅拌反应3小时。待TLC点板监测反应完成后，缓慢加入50mL硫代硫酸钠水溶液淬灭反应，随后用20mL乙酸乙酯，萃取两次分液，将有机相合并后用盐水洗涤，硫酸钠干燥，过滤，减压浓缩得粗品。粗品经反相柱层析纯化得中间体A-9c(422mg，1.29mmol，产率69.19％)。MS(ESI)m/z＝327[M+H]+。
参考中间体A-1的合成方法，制备得到中间体A-9为白色固体，所得产物的盐酸盐可直接用于下一步反应，无需进一步纯化。MS(ESI)m/z＝227[M+H]+。
中间体A-10的合成
于50mL单口反应烧瓶中，将中间体A-9b(634mg，2.04mmol)溶于干燥二氯甲烷(5mL)中，待化合物溶解完全，加入间氯过氧苯甲酸(1.06g，6.13mmol)，加毕，室温下搅拌反应16小时。待TLC点板监测反应完成后，缓慢加入100mL硫代硫酸钠水溶液淬灭反应，随后用20mL乙酸乙酯，萃取两次分液，将有机相合并后用盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩得粗品。粗品经反相柱层析纯化得中间体A-10a(410mg，1.81mmol，产率69.19％)。MS(ESI)m/z＝343[M+H]+。
参考中间体A-1的合成方法，制备得到中间体A-10为白色固体，所得产物的盐酸盐可直接用于下一步反应，无需进一步纯化。MS(ESI)m/z＝243[M+H]+。
中间体A-11的合成
于100mL单口反应烧瓶中，将化合物2-溴-5-甲醛基噻唑A-11a(1.01g，5.21mmol)溶于NMP(10mL)中，待化合物溶解完全，加入碳酸钾(1.44g，10.41mmol)和哌嗪-1-羧酸叔丁酯(1.16g，6.25mmol)，加完后80℃油浴加热反应3小时，待TLC点板监测反应完成，冷却至室温。加入100mL水和50mL乙酸乙酯，萃取分液，并再用乙酸乙酯萃取两次，将有机相合并后用盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩得粗品，经正相纯化得到化合物A-11b(1.22g，4.11mmol，白色固体，产率78.78％)。MS(ESI)m/z＝298[M+H]+。
于50mL三口反应烧瓶中，将中间体A-11b(502mg，1.68mmol)溶于干燥四氢呋喃(5mL)中并充分置换氮气。随后在冰浴下缓慢滴加环丙基基溴化镁溶液(3.4mL，3.36mmol，1M的THF溶液)，加毕，室温下搅拌反应3小时。待LCMS监测反应完成后，加入50mL冰水淬灭反应，随后用20mL乙酸乙酯，萃取两次分液，将有机相合并后用盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩得粗品。粗品经硅胶柱层析纯化得中间体A-11c(385.4mg，1.13mmol，产率67.45％)。MS(ESI)m/z＝340[M+H]+。
于50mL单口反应烧瓶中，将中间体A-11c(200mg，0.59mmol)溶于二氯甲烷(5mL)，再依次加入三乙基硅烷(102.76mg，0.88mmol)，三氟乙酸(100.77mg，0.88mmol)。加毕，于室温在氮气保护下继续搅拌反应1小时。待反应完成后，将体系冷却至室温，反应液减压浓缩至干，所得油状物用甲醇溶解后，粗品经反相柱层析纯化得中间体A-11d(135.5mg，0.42mmol，产率70.84％)。MS(ESI)m/z＝324[M+H]+。
参考中间体A-1的合成方法，制备得到中间体A-11为白色固体，所得产物的盐酸盐可 直接用于下一步反应，无需进一步纯化。MS(ESI)m/z＝224[M+H]+。
中间体A-12的合成
在合成中间体A-6的过程中，中间体A-6c为中间体A-6合成第二步的产品，此处也是中间体A-12合成的原料。
于50mL三口反应烧瓶中，将中间体A-6c(320mg，1.05mmol)溶于干燥二氯甲烷(10mL)中并充分置换氮气。随后在冰浴下缓慢滴加二乙基锌甲苯溶液(5.3mL，5.26mmol，1M的MePh溶液)，加毕，冰浴下搅拌反应15分钟后，再次缓慢滴加氯碘甲烷(1.85g，10.51mmol)，加完后撤走冰浴，在室温下搅拌反应3小时。待LCMS监测反应完成后，加入50mL冰氯化铵饱和水溶液淬灭反应，随后用乙酸乙酯(20mL*2)萃取。合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩得粗品。粗品经硅胶柱层析纯化得中间体A-12a(120.5mg，0.38mmol，产率35.85％)。MS(ESI)m/z＝319[M+H]+。
继续参考中间体A-1的合成方法，制备得到中间体A-12为白色固体，所得产物的盐酸盐可直接用于下一步反应，无需进一步纯化。MS(ESI)m/z＝219[M+H]+。
中间体A-13的合成
于微波反应管中，将中间体A-1b(100mg，0.29mmol)溶于甲苯/水(0.42mL/0.2mL,v/v 10:1)中，再依次加入环丁基硼酸频哪醇酯(79.57mg，0.44mmol)，Pd(dppf)Cl2(21.32mg，29.14μmol)和氢氧化钾(49.04mg，0.87mmol)。加毕，充分吹入氮气，置换管内气体。随后于微波反应器中100℃搅拌反应3小时。反应液减压浓缩至干，所得油状物用乙酸乙酯溶解后，用饱和食盐水洗涤，分液，有机相用无水硫酸钠干燥，过滤，减压浓缩得粗品。粗品经硅胶柱层析纯化得中间体A-13a(25.5mg，78.51μmol，产率26.95％)。MS(ESI)m/z＝319[M+H]+。
参考中间体A-1的合成方法，制备得到中间体A-13为白色固体，所得产物的盐酸盐可直接用于下一步反应，无需进一步纯化。MS(ESI)m/z＝219[M+H]+。
中间体A-14的合成
于微波反应管中，将中间体A-1b(100mg,0.29mmol)溶于甲苯/水(2mL/0.2mL,v/v10:1)中，再依次加入环丁基硼酸频哪醇酯(79.57mg,0.44mmol)，Pd(dppf)Cl2(21.32mg,29.14μmol)和氢氧化钾(49.04mg,0.87mmol)。加毕，充分吹入氮气，置换管内气体。随后于微波反应器中100℃搅拌反应3小时。反应液用乙酸乙酯溶解后，用饱和食盐水洗涤，分液，有机相用硫酸钠干燥，过滤，减压浓缩得粗品。粗品经硅胶柱层析纯化得中间体A-14a(25.5mg,78.51μmol,产率26.95％)。MS(ESI)m/z＝350[M+H]+。
参考中间体A-1的合成方法，制备得到中间体A-14为白色固体，所得产物的盐酸盐可直接用于下一步反应，无需进一步纯化。MS(ESI)m/z＝250[M+H]+。
中间体A-15的合成
于100mL三口反应烧瓶中，将中间体A-1b(1.02g，2.94mmol)溶于二氧六环/水(15mL/3mL,v/v 5:1)中，再依次加入1-环戊烯硼酸频哪醇酯(856.68mg，4.41mmol)，Pd(dppf)Cl2(215.25mg，0.29mmol)和碳酸铯(1.92g，5.89mmol)。加毕，充分置换氮气3次，油浴升温至100℃搅拌反应16小时。待反应完成后，将体系冷却至室温，反应液减压浓缩至干，所得油状物用乙酸乙酯溶解后，用饱和食盐水洗涤，分液，有机相用无水硫酸钠干燥，过滤，减压浓缩得粗品。粗品经硅胶柱层析纯化得中间体A-15a(789.1mg，2.39mmol，产率81.14％)。MS(ESI)m/z＝331[M+H]+。
于100mL单口反应烧瓶中，将中间体A-15a(0.79g，2.39mmol)溶于甲醇(10mL)中，加入10％钯/碳(95.37mg，0.36mmol，60％水)。加毕，充分置换氢气，使反应瓶处 于氢气环境下，室温下搅拌反应3小时。待反应完成后，过滤，滤液减压浓缩至干得中间体A-15b(760mg，2.29mmol，产率95.74％)。MS(ESI)m/z＝333[M+H]+。
参考中间体A-1的合成方法，制备得到中间体A-15为白色固体，所得产物的盐酸盐可直接用于下一步反应，无需进一步纯化。MS(ESI)m/z＝233[M+H]+。
中间体A-16的合成
参考中间体A-15的合成方法，将第一步中的1-环戊烯硼酸频哪醇酯，换为2,5-二氢呋喃-3-频哪醇硼酸酯，其它操作相同，制备得到中间体A-16为白色固体，所得产物的盐酸盐可直接用于下一步反应，无需进一步纯化。MS(ESI)m/z＝235[M+H]+。
中间体A-17的合成
于100mL三口反应烧瓶中，将中间体A-1b(1.01g，2.91mmol)溶于MePh(20mL)中，再依次加入氰基乙酸乙酯(659.1mg，5.83mmol)，Pd2(dba)3(134.8mg，0.15mmol)，2-双环己基膦-2',4',6'-三异丙基联苯(140.3mg，0.29mmol)和磷酸钾(1.87g，8.83mmol)。加毕，充分置换氮气3次，油浴升温至110℃搅拌反应16小时。待反应完成后，将体系冷却至室温，反应液减压浓缩至干，所得油状物用乙酸乙酯溶解后，用饱和食盐水洗涤，分液，有机相用硫酸钠干燥，过滤，真空浓缩，得产物粗品。粗品经硅胶柱层析纯化得中间体A-17a(700mg，1.87mmol，产率63.63％)。MS(ESI)m/z＝376[M+H]+。
于100mL单口反应烧瓶中，将中间体A-17a(700mg，1.87mmol)溶于DMSO(20mL)中，待化合物溶解完全，加入氯化锂(158.5mg，3.74mmol)和水(50.4mg，2.81mmol)，加完后120℃油浴反应过夜，待TLC点板监测反应完成，冷却至室温。加入100mL水和50mL乙酸乙酯，萃取分液，并再用乙酸乙酯萃取两次，将有机相合并后用盐水洗涤，硫酸钠干燥，过滤，真空浓缩，去除溶剂得粗品，正相纯化得到化合物A-17b(525mg，1.73mmol，产率92.75％)。MS(ESI)m/z＝304[M+H]+。
于100mL三口反应烧瓶中，将中间体A-17b(525mg，1.73mmol)溶于无水四氢呋喃(10mL)中，并置换氮气。随后在冰浴下缓慢加入双(三甲硅基)氨基锂(4.2mL，4.15mmol，1M的THF溶液)，并在冰浴下继续搅拌反应30分钟。然后缓慢加入碘甲烷(589.3mg，4.15mmol)，加完后撤走冰浴，室温下搅拌反应3小时。待LCMS监测反应完成，加入50mL冰氯化铵饱和水溶液淬灭反应，随后加入20mL乙酸乙酯，萃取分液，并再用乙酸乙酯萃取水相两次，将有机相合并后用盐水洗涤，硫酸钠干燥，过滤，真空浓缩，去除溶剂得粗品，正相纯化得到化合物A-17c(322mg，0.97mmol，产率56.26％)。MS(ESI)m/z＝332[M+H]+。
参考中间体A-1的合成方法，制备得到中间体A-17为白色固体，所得产物的盐酸盐可直接用于下一步反应，无需进一步纯化。MS(ESI)m/z＝232[M+H]+。
中间体A-18的合成
于50mL单口反应烧瓶中，将化合物2-氯噁唑-5-羧酸乙酯A-18a(175mg，1mmol)溶于NMP(5mL)中，待化合物溶解完全，加入碳酸钾(276.4mg，2mmol)和哌嗪-1-羧酸叔丁酯(279.4mg，1.5mmol)，加完后80℃油浴加热反应3小时，待TLC点板监测反应完成，冷却至室温。加入50mL水和20mL乙酸乙酯，萃取分液，并再用乙酸乙酯萃取两次，将有机相合并后用盐水洗涤，硫酸钠干燥，过滤，真空浓缩，去除溶剂得固体粗品，正相纯化得到化合物A-18b(285mg，0.87mmol，产率87.42％)，MS(ESI)m/z＝326[M+H]+。
于15mL封管中将中间体A-18b(285mg，0.87mmol)溶于氨甲醇溶液(3mL)，随后密封好后油浴升温至80℃搅拌反应过夜。待TLC点板监测反应完成后，将氨甲醇于真空下浓缩去除，所得粗品用甲醇溶解，反相柱层析纯化得到中间体A-18c(180.1mg，0.61mmol， 产率69.77％)。MS(ESI)m/z＝297[M+H]+。
参考中间体A-1的合成方法，制备得到中间体A-18为白色固体，所得产物的盐酸盐可直接用于下一步反应，无需进一步纯化。MS(ESI)m/z＝197[M+H]+。
中间体B-1的合成
将化合物3-氯-6-肼基哒嗪B-1a(0.14g,1mmol)溶于三氟乙酸(4mL)后，置于封管中，随后油浴升温至120℃搅拌反应3小时。TLC点板监测反应完成，将反应体系恢复至室温，随后将TFA在负压下旋干，所得混合物用水和乙醇溶解稀释，并用饱和碳酸钠水溶液，在0℃下调节pH值到8～9左右，然后用二氯甲烷和甲醇(10：1)有机液萃取三次，分液，合并的有机相用饱和食盐水洗涤两次，干燥，旋干得到产物粗品。用甲醇溶解粗品后，中压反相柱纯化，得中间体B-1(0.16g，咖啡色固体，产率90.25％)。MS(ESI)m/z＝223[M+H]+。
中间体B-2至中间体B-9的合成
参照中间体B-1的合成路线，用下表中相应的酸替换三氟乙酸，其余试剂和操作不变，可得相应中间体。

中间体B-10的合成
于100mL单口反应烧瓶中，将中间体B-3(1.55g，0.01mol)溶于无水四氢呋喃(15mL)中，并置换氮气。随后在冰浴下分批次加入N-溴代丁二酰亚胺(NBS)(2.67g，15.1mmol)，加完后撤走冰浴，室温下搅拌反应3小时。待LCMS监测反应完成，加入50mL乙酸乙酯稀释反应液，随后将有机相用饱和碳酸氢钠，以及盐水洗涤，硫酸钠干燥，过滤，真空浓缩，去除溶剂得粗品，正相纯化得到中间体B-10(1.41g，6.08mmol，白色固体，产率60.34％)。MS(ESI)m/z＝233[M+H]+。
中间体B-11的合成
于100mL单口反应烧瓶中，将中间体B-1(222.5mg，0.99mmol)溶于DMF(5mL)中，随后加入N-氯代丁二酰亚胺(NCS)(1.06g，7.96mmol)，加完后置换氮气，油浴升温至80℃搅拌反应3小时。待LCMS监测反应完成，加入50mL乙酸乙酯稀释反应液，随后 将有机相用饱和碳酸氢钠，以及盐水洗涤，硫酸钠干燥，过滤，真空浓缩，去除溶剂得粗品，正相纯化得到中间体B-11(112.2mg，0.44mmol，油状物，产率44.27％)。MS(ESI)m/z＝257[M+H]+。
中间体B-12的合成
于100mL单口反应烧瓶中，将中间体B-1a(1.02g，7.06mmol)溶于无水乙醇(10mL)中，随后加入草酸二乙酯(1.34g，8.99mmol)，加完后置换氮气，油浴升温至80℃搅拌反应过夜。待LCMS监测反应完成，将乙醇浓缩去除，加入50mL乙酸乙酯稀释反应物，随后将有机相用盐水洗涤，硫酸钠干燥，过滤，真空浓缩，去除溶剂得粗品，正相纯化得到中间体B-12(1.31g，5.8mmol，白色固体，产率86.67％)。MS(ESI)m/z＝227[M+H]+。
中间体B-13的合成
于100mL单口反应烧瓶中，将中间体B-1a(1.01g，6.99mmol)溶于乙醇(10mL)和水(2mL)的混合物中。随后在搅拌状态下逐滴加入溴乙腈(2.8mL，13.98mmol)，加毕，室温下反应过夜。LCMS监测反应完成后，冷冻静置反应液，有固体析出，抽滤，将所得滤饼用适量乙醇洗涤，母液加入适量饱和碳酸钠溶液碱化，再次析出固体，抽滤，将所得滤饼用适量乙醇洗涤，合并干燥后，得中间体B-13(651mg，3.84mmol，黄色固体，产率42.76％)。MS(ESI)m/z＝170[M+H]+。
中间体C-1的合成
于100mL干燥三口反应烧瓶中，将2-氨基-6-三氟甲基喹唑啉C-1a(105.2mg，0.49mmol)和溴化铜(220.3mg，0.99mmol)溶于超干乙腈(5mL)中，并充分置换氮气，将亚硝酸叔丁酯(102.1mg，0.99mmol)溶于超干乙腈(2mL)中，用注射器缓慢打入反应体 系中，随后再次升温至60℃反应4小时。待TLC点板监测反应完成，降温，将反应体系中的溶剂旋干，加入50mL乙酸乙酯稀释反应液，随后将有机相过滤，用乙酸乙酯洗涤，有机相合并后用盐水洗涤，硫酸钠干燥，过滤，真空浓缩，去除溶剂得粗品，正相纯化得到中间体C-1(48.2mg，0.17mmol，黄色固体，产率35.56％)。MS(ESI)m/z＝277[M+H]+。
中间体C-2的合成
于100mL干燥三口反应烧瓶中，将化合物(叔丁氧羰基)-L-脯氨酸(2.15g，9.99mmol)溶于无水甲醇(20mL)中，并充分置换氮气，冰浴下缓慢滴加二氯亚砜(3.54g，29.9mmol)，加毕，撤走冰浴，油浴升温至70℃下搅拌反应3小时，待TLC点板监测反应完成，降至室温，将反应体系中多余的二氯亚砜和溶剂旋干，所得油状物用水和乙醇溶解稀释，并用饱和碳酸钠水溶液，在0℃下调节pH值到8～9左右，然后用二氯甲烷和甲醇(10：1)有机液萃取三次，分液，有机相合并后用盐水洗涤，硫酸钠干燥，过滤，真空浓缩，去除溶剂得到中间体C-2(855mg，6.63mmol，油状物，产率65.76％)。MS(ESI)m/z＝130[M+H]+。
中间体C-3的合成
于50mL单口反应烧瓶中，将化合物2,3-二氟-5-(三氟甲基)吡啶(278mg，1.52mmol)和3-(2-羟基乙基)哌嗪-1-羧酸叔丁酯(200mg，0.87mmol)溶于DMSO(2mL)中，待化合物溶解完全，加入DIPEA(254mg，1.96mmol)，加完后100℃油浴搅拌反应2小时，待TLC点板监测反应完成，冷却至室温。加入50mL水和20mL乙酸乙酯，萃取分液，并再用乙酸乙酯萃取两次，将有机相合并后用盐水洗涤，硫酸钠干燥，过滤，真空浓缩，去除溶剂得固体粗品，正相纯化得到中间体C-3a(252mg，0.64mmol，产率73.77％)。MS(ESI)m/z＝394[M+H]+。
于50mL三口反应烧瓶中，将中间体C-3a(252mg，0.64mmol)溶于无水DMF(4mL)中，并置换氮气。随后在冰浴下缓慢加入氢化钠(31mg，0.77mmol，60％purity)，并在冰浴下继续搅拌反应10分钟。然后撤走冰浴，升温至50℃搅拌反应3小时。待LCMS监测反 应完成，加入50mL冰氯化铵饱和水溶液淬灭反应，随后加入20mL乙酸乙酯，萃取分液，并再用乙酸乙酯萃取水相两次，将有机相合并后用盐水洗涤，硫酸钠干燥，过滤，真空浓缩，去除溶剂得粗品，正相纯化得到化合物C-3b(185mg，0.50mmol，产率77.4％)。MS(ESI)m/z＝374[M+H]+。
参考中间体A-1的合成方法，制备得到中间体C-3为类白色固体，所得产物的盐酸盐可直接用于下一步反应，无需进一步纯化。MS(ESI)m/z＝274[M+H]+。
中间体C-4的合成
参考中间体C-1的合成路线，第一步中用3,5,6-三氯-[1,2,4]-噻嗪替换2,3-二氟-5-(三氟甲基)吡啶，同时用2-(羟甲基)-1,4-哌嗪二羧酸二叔丁酯替换3-(2-羟基乙基)哌嗪-1-羧酸叔丁酯，其余试剂和操作不变，即可制备得到中间体C-4为黄色固体，所得产物的盐酸盐可直接用于下一步反应。MS(ESI)m/z＝228[M+H]+。
中间体C-5的合成
参考中间体C-1的合成路线，第一步中用2-(羟甲基)-1,4-哌嗪二羧酸二叔丁酯替换3-(2-羟基乙基)哌嗪-1-羧酸叔丁酯，其余试剂和操作不变，即可制备得到中间体C-5为淡黄色固体，所得产物的盐酸盐可直接用于下一步反应。MS(ESI)m/z＝260[M+H]+。
中间体C-6的合成
于50mL单口反应烧瓶中，将化合物4-Boc-哌嗪-2-羧酸(1.38g，6.0mmol)和5-(三氟甲基)-3-硝基-2-氯吡啶(0.91g，4.0mmol)溶于THF和DMF(8mL/2mL)混合溶剂中，待化合物溶解完全，加入TEA(1.21g，12.0mmol)，加完后室温下搅拌反应过夜，待TLC点板监测反应完成，冷却至室温。加入50mL水和适量1M盐酸水溶液，调节pH值至小于7，随后加入20mL乙酸乙酯，萃取分液，并再用乙酸乙酯萃取两次，将有机相合并后用盐水洗涤，硫酸钠干燥，过滤，真空浓缩，去除溶剂得固体粗品，正相纯化得到中间体C-6a(1.45g，3.45mmol，产率85.8％)。MS(ESI)m/z＝421[M+H]+。
于50mL单口反应烧瓶中，将中间体C-6a(1.45g，3.45mmol)溶于冰醋酸(15mL)中，待化合物溶解完全，加入铁粉(19.3mg，0.34mmol)和锌粉(2.2g，34.5mmol)，加完后充分置换氮气，并在室温下搅拌反应过夜。待LCMS监测反应完成，加入50mL乙酸乙酯稀释反应液，过滤，适量乙酸乙酯洗涤滤饼，随后加入至200mL水中，洗涤萃取分液，并再用乙酸乙酯萃取两次，将有机相合并后再用盐水洗涤，硫酸钠干燥，过滤，真空浓缩，去除溶剂得固体粗品，用乙腈溶解后，酸性体系(TFA)下反相柱层析纯化得到中间体C-6b(0.74g，1.99mmol，产率57.82％)。MS(ESI)m/z＝373[M+H]+。
于50mL单口反应烧瓶中，将中间体C-6b(0.74g，1.99mmol)溶于THF(8mL)中，待化合物溶解完全，冰浴下加入氢化钠(120mg，2.99mmol，60％purity)，加入后，在冰浴中继续搅拌反应15分钟，随后缓慢加入碘甲烷(565.2mg，3.98mmol)，加完后撤走冰浴，反应在室温下搅拌反应3小时。待TLC点板监测反应完成，加入50mL冰氯化铵饱和水溶液淬灭反应，随后加入20mL乙酸乙酯，萃取分液，并再用乙酸乙酯萃取水相两次，将有机相合并后用盐水洗涤，硫酸钠干燥，过滤，真空浓缩，去除溶剂得粗品，正相纯化得到中间体C-6c(442mg，1.15mmol，产率57.64％)。MS(ESI)m/z＝387[M+H]+。
参考中间体A-1的合成方法，制备得到中间体C-6为黄色固体，所得产物的盐酸盐可 直接用于下一步反应，无需进一步纯化。MS(ESI)m/z＝287[M+H]+。
实施例1：化合物1的制备
于100mL单口反应烧瓶中，将化合物2-溴-5-三氟甲基噻唑(2.3g，9.91mmol)溶于NMP(20mL)中，待化合物溶解完全，加入碳酸钾(2.74g，19.82mmol)和哌嗪-1-羧酸叔丁酯(2.78g，14.87mmol)，加完后80℃油浴回流反应2小时，待TLC点板监测反应完成，冷却至室温。加入100mL水和50mL乙酸乙酯，萃取分液，并再用乙酸乙酯萃取两次，将有机相合并后用盐水洗涤，硫酸钠干燥，过滤，真空浓缩，去除溶剂得固体粗品，正相纯化得到中间体IN-1a(3.01g，8.93mmol，产率89.85％)。MS(ESI)m/z＝338[M+H]+。
于100mL单口反应烧瓶中，将化合物中间体IN-1a(2.7g，8.01mmol)溶于乙酸乙酯(10mL)中，随后冰浴下，滴入4M盐酸乙酸乙酯溶液(20mL)，加毕，升至室温反应3小时，TLC点板监测反应完成，将体系冰浴至0℃左右，析出大量白色固体，抽滤，石油醚洗涤，干燥，得到中间体IN-1b(1.84g，盐酸盐，白色固体，产率84.13％)。MS(ESI)m/z＝238[M+H]+。
于100mL单口反应烧瓶中，将化合物(叔丁氧羰基)-L-脯氨酸(0.645g，3mmol)溶于DMF(10mL)中，待化合物溶解完全，加入HATU(1.71g，4.49mmol)，随后升至室温搅拌15分钟后，加入中间体IN-1b(0.474g，2mmol)和DIPEA(1.4mL，8mmol)，室温反应3小时，待TLC点板监测反应完成，冷却至室温。加入50mL的水和30mL的乙酸乙酯，萃取分液，并再用乙酸乙酯萃取两次，将有机相合并后用盐水洗涤，硫酸钠干燥，过滤，真空浓缩，去除溶剂得固体粗品，正相纯化得到中间体IN-1c(0.792g，1.84mmol，产率91.24％)。MS(ESI)m/z＝435[M+H]+。
于100mL单口反应烧瓶中，将中间体IN-1c(0.792g，1.84mmol)溶于乙酸乙酯(2mL)中，待化合物溶解完全，冰浴下加入4M盐酸乙酸乙酯溶液(5mL)，随后撤走冰浴，于室温反应3小时。待TLC监测反应完成，减压浓缩得固体粗品，继续用石油醚洗涤，干燥，得中间体IN-1(0.61g，盐酸盐，白色固体，产率91.04％)。MS(ESI)m/z＝335[M+H]+。
于100mL单口反应烧瓶中，将中间体IN-1(0.33g，0.9mmol)与中间体B-1(0.24g，1.1mmol)溶于DMSO(10mL)中，加入KF(504mg，9mmol)后置换氮气，随后油浴升温至120℃搅拌反应3小时。待TLC点板监测反应完成，恢复至室温，将反应液缓慢向搅动的冰水里滴加，析出大量白色固体，抽滤，所得固体用水洗涤，转移干燥。随后固体用适量乙醇升温至50℃溶解，再自然降温至室温，等待固体结晶析出，抽滤，所得固体用乙腈分散，加水冻干得实施例化合物1：[(2S)-1-[3-(三氟甲基)-[1，2，4]三唑[4，3-b]哒嗪-6-基]吡咯烷-2-基]-[4-[5-(三氟甲基)噻唑-2-基]哌嗪-1-基]甲酮(0.22g，0.42mmol，白色固体，产率43％)。1H NMR(400MHz,Methanol-d4)δ8.05(d,J＝10.1Hz,1H),7.60(q,J＝1.4Hz,1H),7.30(s,1H),5.18-5.00(m,1H),3.93(dtd,J＝12.6,10.1,8.4,4.6Hz,2H),3.85-3.71(m,6H),3.59(h,J＝7.6Hz,2H),2.61-2.36(m,1H),2.15(s,3H).MS(ESI)m/z＝521[M+H]+。
实施例2：化合物2的制备

于250mL单口反应烧瓶中，将化合物2-氯-5-三氟甲基嘧啶(4.1g，22.5mmol)溶于NMP(40mL)中，待化合物溶解完全，加入碳酸钾(6.23g，45.1mmol)和哌嗪-1-羧酸叔丁酯(6.28g，33.8mmol)，加完后80℃油浴回流反应2小时，待TLC点板监测反应完成，冷却至室温。加入200mL水和50mL乙酸乙酯，萃取分液，并再用乙酸乙酯萃取两次，将有机相合并后用盐水洗涤，硫酸钠干燥，过滤，真空浓缩，去除溶剂得固体粗品，正相纯化得到中间体IN-2a(5.62g，16.9mmol，产率75.13％)。MS(ESI)m/z＝333[M+H]+。
于250mL单口反应烧瓶中，将化合物中间体IN-2a(5.62g，16.9mmol)溶于乙酸乙酯(20mL)中，随后冰浴下，滴入4M盐酸乙酸乙酯溶液(40mL)，加毕，升至室温反应3小时，TLC点板监测反应完成，将体系冰浴至0℃左右，析出大量白色固体，抽滤，石油醚洗涤，干燥，得到中间体IN-2b(4.32g，盐酸盐，白色固体，产率95.15％)。MS(ESI)m/z＝233[M+H]+。
于250mL单口反应烧瓶中，将化合物(叔丁氧羰基)-L-脯氨酸(4.15g，19.3mmol)溶于DMF(50mL)中，待化合物溶解完全，分三批次加入HATU(9.13g，24.2mmol)将合理控制在0℃左右，随后升至室温搅拌15分钟后，加入中间体IN-2b(4.32g，16.1mmol)和DIPEA(11.1mL，64.4mmol)，室温反应3小时，待TLC点板监测反应完成，冷却至室温。加入200mL的水和50mL的乙酸乙酯，萃取分液，并再用乙酸乙酯萃取两次，将有机相合并后用盐水洗涤，硫酸钠干燥，过滤，真空浓缩，去除溶剂得固体粗品，正相纯化得到中间体IN-2c(5.21g，12.1mmol，产率76.62％)。MS(ESI)m/z＝430[M+H]+。
于250mL单口反应烧瓶中，将中间体IN-2c(5.21g，12.1mmol)溶于乙酸乙酯(20 mL)中，待化合物溶解完全，冰浴下加入4M盐酸乙酸乙酯溶液(50mL)，随后撤走冰浴，于室温反应3小时。待TLC监测反应完成，减压浓缩得固体粗品，继续用石油醚洗涤，干燥，得中间体IN-2d(3.98g，盐酸盐，白色固体，产率89.03％)。MS(ESI)m/z＝330[M+H]+。
于250mL单口反应烧瓶中，将中间体IN-2d(3.98g，10.9mmol)与中间体B-1(2.87g，12.9mmol)溶于DMSO(50mL)中，加入KF(6.25g，107.6mmol)后置换氮气，随后油浴升温至120℃搅拌反应3小时。待TLC点板监测反应完成，恢复至室温，将反应液缓慢向搅动的冰水里滴加，析出大量白色固体，抽滤，所得固体用水洗涤，转移干燥。随后固体用适量乙醇升温至50℃溶解，再自然降温至室温，等待固体结晶析出，抽滤，所得固体用乙腈分散，加水冻干得实施例化合物2：[(2S)-1-[3-(三氟甲基)-[1，2，4]三唑并[4，3-b]哒嗪-6-基]吡咯烷-2-基]-[4-[5-(三氟甲基)嘧啶-2-基]哌嗪-1-基]甲酮(3.45g，6.70mmol，白色固体，产率61.49％)。1H NMR(400MHz,DMSO-d6)δ8.77(d,J＝0.9Hz,2H),8.26(s,1H),7.36(s,1H),4.96(s,1H),4.03(dt,J＝13.1,4.9Hz,1H),3.97-3.88(m,2H),3.87-3.76(m,2H),3.73(s,2H),3.59-3.45(m,2H),2.47-2.29(m,1H),2.03(s,3H).MS(ESI)m/z＝516[M+H]+
实施例3至实施例23的制备
参照实施例1的合成方法，在步骤1中用下表中相应的卤代杂环起始原料替代中间体2-溴-5-三氟甲基噻唑，其余试剂操作相同，可得下表中相应结构化合物。






实施例24至实施例36的制备
参照实施例1的合成方法，在步骤3中用下表中相应的羧酸替代中间体(叔丁氧羰基)-L-脯氨酸，其余试剂操作相同，可得下表中相应结构化合物。



实施例37至实施例53的制备
参照实施例1的合成方法，合成从步骤3开始，并用下表中相应的中间体胺替代中间体IN-1b，其余试剂和后几步操作相同，可得下表中相应结构化合物。





实施例54和实施例55的制备
参照实施例1的合成方法，在步骤1中用下表中相应的中间体哌嗪环起始原料替代中间体哌嗪-1-羧酸叔丁酯，其余试剂操作相同，可得下表中相应结构化合物。

实施例56至实施例68的制备
参照实施例1的合成方法，在步骤5中用下表中相应的中间体并环卤代物替代中间体B-1，其余试剂操作相同，可得下表中相应结构化合物。



实施例69：化合物69的制备
于100mL单口反应烧瓶中，将中间体IN-1(0.33g，0.99mmol)与中间体B-12(245.6mg，1.09mmol)溶于DMF(10mL)中，加入N,N-二异丙基乙胺(255.4mg，1.98mmol)后置换氮气，随后油浴升温至40℃搅拌反应16小时。待TLC点板监测反应完成，恢复至室温，将反应液倒入100mL水中后，用20mL二氯甲烷萃取，萃取水相，分液，将所得有机相合并，用饱和食盐水洗涤，硫酸钠干燥，真空浓缩，得产物粗品。随后粗品用乙醇溶解后，经反相柱层析纯化得中间体69a(381.2mg，0.73mmol，产率73.48％)。MS(ESI)m/z＝525[M+H]+。
于100mL单口反应烧瓶中，将中间体69a(381.2mg，0.73mmol)溶于无水乙醇(5mL)中，加入硼氢化钠(82.8mg，2.18mmol)后置换氮气，随后室温下搅拌反应3小时。待TLC点板监测反应完成，加入50mL冰氯化铵饱和水溶液淬灭反应，随后加入20mL二氯甲烷，萃取分液，并再用二氯甲烷萃取水相两次，将有机相合并后用盐水洗涤，硫酸钠干燥，过滤，真空浓缩，去除溶剂得粗品，用甲醇溶解后，反相柱层析纯化得中间体69b(281.4mg，0.58mmol，产率80.17％)。MS(ESI)m/z＝483[M+H]+。
于100mL单口反应烧瓶中，将中间体69b(100.6mg，0.21mmol)溶于二氯甲烷(5mL)中，加入戴斯-马丁试剂(177mg，0.42mmol)后置换氮气，随后室温下搅拌反应过夜。待TLC点板监测反应完成，加入50mL亚硫酸氢钠饱和水溶液淬灭反应，随后加入20mL二氯甲烷，萃取分液，并再用二氯甲烷萃取水相两次，将有机相合并后用盐水洗涤，硫酸钠干燥，过滤，真空浓缩，去除溶剂得中间体69c(50.5mg，0.11mmol，产率50.18％)，并迅速用于下一步反应，不再进一步纯化。MS(ESI)m/z＝481[M+H]+。
于50mL单口反应烧瓶中，将中间体69c(50.5mg，0.11mmol)溶于干燥二氯甲烷(3mL)后置换氮气。随后在冰浴下缓慢滴加二乙胺基三氟化硫(84.8mg，0.53mmol)，加毕， 室温下搅拌反应1小时。待TLC点板监测反应完成后，加入30mL冰氯化铵饱和水溶液淬灭反应，随后用10mL二氯甲烷，萃取两次分液，将有机相合并后用盐水洗涤，硫酸钠干燥，过滤，真空浓缩，去除溶剂得产物粗品。所得粗品用甲醇溶解，反相柱层析纯化得到油状产物，用少量乙腈分散溶解，并加水冻干得实施例69：[(2S)-1-[3-(二氟甲基)-[1，2，4]三唑[4，3-b]哒嗪-6-基]吡咯烷-2-基]-[4-[5-(三氟甲基)噻唑-2-基]哌嗪-1-基]甲酮(10.5mg，0.42mmol，白色固体，产率19.89％)，MS(ESI)m/z＝503[M+H]+。1H NMR(400MHz,Methanol-d4)δ7.91(d,J＝10.1Hz,1H),7.50(q,J＝1.5Hz,1H),7.11(s,2H),4.98(dd,J＝8.8,3.5Hz,1H),3.80-3.69(m,4H),3.65-3.57(m,2H),3.51-3.36(m,4H),2.37(dd,J＝12.0,8.1Hz,1H),2.09-1.93(m,3H).
实施例70：化合物70的制备
于15mL封管中将中间体69a(100.5mg，0.19mmol)溶于氨甲醇溶液(3mL)，随后密封好后油浴升温至80℃搅拌反应过夜。待TLC点板监测反应完成后，将氨甲醇于真空下浓缩去除，所得粗品用甲醇溶解，反相柱层析纯化得到油状产物，用少量乙腈分散溶解，并加水冻干得实施例70：6-[(2S)-2-[4-[5-(三氟甲基)噻唑-2-基]哌嗪-1-羰基]吡咯烷-1-基]-[1，2，4]三唑并[4，3-b]哒嗪-3-甲酰胺(42.4mg，85.66μmol，白色固体，产率44.68％)，MS(ESI)m/z＝496[M+H]+。1H NMR(400MHz,Methanol-d4)δ7.95(d,J＝10.1Hz,1H),7.49(q,J＝1.4Hz,1H),7.15(s,1H),5.01(d,J＝8.2Hz,1H),3.87-3.65(m,6H),3.51(d,J＝48.2Hz,4H),2.50-2.35(m,1H),2.06(d,J＝8.4Hz,3H).
实施例71：化合物71的制备
于50mL三口反应烧瓶中，将化合物66(50mg，94.10μmol)溶于二氧六环/水(4mL/1mL/4:1)中，再依次加入环丙基硼酸频哪醇酯(23.8mg，0.14mmol)，Pd(dppf)Cl2(7.3mg，9.41μmol)和碳酸铯(61.5mg，0.19mmol)。加毕，充分置换氮气3次，油浴升温至100℃搅拌反应16小时。待反应完成后，将体系冷却至室温，反应液减压浓缩至干，所得油状物用乙酸乙酯溶解后，用饱和食盐水洗涤，分液，有机相用硫酸钠干燥，过滤，真空浓缩，得产物粗品，粗品经反相柱层析纯化得到油状产物，用少量乙腈分散溶解，并加水冻干得实施例71：[(2S)-1-(3-环丙基-[1，2，4]三唑并[4，3-b]哒嗪-6-基)吡咯烷-2-基]-[4-[5-(三氟甲基)噻唑-2-基]哌嗪-1-基]甲酮(23.2mg，47.15μmol，产率50.01％)，MS(ESI)m/z＝493[M+H]+。1H NMR(400MHz,Methanol-d4)δ7.87(d,J＝10.1Hz,1H),7.51(q,J＝1.4Hz,1H),7.22(s,1H),5.08-4.95(m,1H),3.84(d,J＝5.0Hz,2H),3.79-3.62(m,6H),3.52(t,J＝5.4Hz,2H),2.49-2.34(m,1H),2.24(s,1H),2.13-1.97(m,3H),1.32-1.16(m,2H),1.02(d,J＝24.5Hz,2H).
实施例72：化合物72的制备
参照实施例71的合成路线，用异丙烯基硼酸频哪醇酯替换环丙基硼酸频哪醇酯，其余试剂和操作不变，即可得实施例72：[(2S)-1-(3-异丙烯基-[1，2，4]三唑并[4，3-b]哒嗪-6-基)吡咯烷-2-基]-[4-[5-(三氟甲基)噻唑-2-基]哌嗪-1-基]甲酮，MS(ESI)m/z＝493[M+H]+。1H NMR(400MHz,Methanol-d4)δ7.85(d,J＝10.0Hz,1H),7.51(q,J＝1.4Hz,1H),7.04(s,1H),6.44(s,1H),5.51(d,J＝2.1Hz,1H),5.02-4.92(m,1H),3.78(ddd,J＝26.2,19.7,6.3Hz,4H),3.68-3.30(m,6H),2.40(td,J＝8.1,3.3Hz,1H),2.21(s,3H),2.03(tq,J＝10.7,5.6,5.0Hz,3H).
实施例73：化合物73的制备
于50mL三口反应烧瓶中，将化合物66(50mg，94.10μmol)和氰化亚铜(8.43mg，94.10μmol)溶于DMF(2mL)中，充分置换氮气，油浴升温至160℃搅拌反应8小时。待反应完成后，将体系冷却至室温，用乙酸乙酯稀释溶解后，用饱和食盐水洗涤，分液，有机相用硫酸钠干燥，过滤，真空浓缩，得产物粗品，粗品经反相柱层析纯化得到油状产物，用少量乙腈分散溶解，并加水冻干得实施例73：6-[rac-(2S)-2-[4-[5-(三氟甲基)噻唑-2-基]哌嗪-1-羰基]吡咯烷-1-基]-[1，2，4]三唑并[4，3-b]哒嗪-3-碳腈(8.2mg，17.19μmol，产率17.78％)，MS(ESI)m/z＝478[M+H]+。1H NMR(400MHz,Chloroform-d)δ8.12(s,1H),7.52(d,J＝2.8Hz,1H),7.01(d,J＝10.6Hz,1H),5.01(s,1H),4.02(s,2H),3.96-3.85(m,2H),3.81-3.56(m,6H),2.35(d,J＝14.0Hz,2H),2.14(d,J＝36.6Hz,2H).
实施例74：化合物74的制备
参照实施例1的合成路线，第一步中用2-氯-5三氟甲基嘧啶替换2-溴-5-三氟甲基噻唑，第三步中用叔丁氧羰基-D-丙氨酸替换(叔丁氧羰基)-L-脯氨酸，其余试剂和操作不变，即可得实施例74：(2R)-1-[4-[5-(三氟甲基)嘧啶-2-基]哌嗪-1-基]-2-[[3-(三氟甲酯)-[1，2，4]三唑并[4，3-b]哒嗪-6-基]氨基]丙-1-酮，MS(ESI)m/z＝490[M+H]+。1H NMR(400MHz,Methanol-d4)δ8.63(d,J＝0.9Hz,2H),7.96(d,J＝10.0Hz,1H),7.08(d,J＝10.0Hz,1H),4.90(d,J＝7.2Hz,1H),4.19-4.01(m,2H),3.95(q,J＝4.8Hz,2H),3.84(t,J＝5.4Hz,2H),3.77-3.63(m,2H),1.49(d,J＝7.1Hz,3H).
实施例75：化合物75的制备
参照实施例1的合成路线，第一步中用2-氯-5三氟甲基嘧啶替换2-溴-5-三氟甲基噻唑，第三步中用叔丁氧羰基-L-丙氨酸替换(叔丁氧羰基)-L-脯氨酸，其余试剂和操作不变，即可得实施例75：(2S)-1-[4-[5-(三氟甲基)嘧啶-2-基]哌嗪-1-基]-2-[[3-(三氟甲酯)-[1，2，4]三唑并[4，3-b]哒嗪-6-基]氨基]丙-1-酮，MS(ESI)m/z＝490[M+H]+。1H NMR(400MHz,Methanol-d4)δ8.63(d,J＝0.9Hz,2H),7.96(d,J＝9.9Hz,1H),7.08(d,J＝9.9Hz,1H),4.90(d,J＝7.1Hz,1H),4.18-4.04(m,2H),3.95(q,J＝4.8Hz,2H),3.84(t,J＝5.3Hz,2H),3.70(dt,J＝11.8,5.3Hz,2H),1.49(d,J＝7.1Hz,3H).
实施例76：化合物76的制备
参照实施例1的合成路线，省去前两步，从第三步中用中间体A-1替换IN-1b，第五步中用中间体B-10替换中间体B-1，其余试剂和操作不变，即可得实施例76：[4-(5-环丙基嘧啶-2-基)哌嗪-1-基]-[rac-(2S)-1-(3-溴-[1，2，4]三唑并[4，3-b]哒嗪-6-基)吡咯烷-2-基]甲酮，MS(ESI)m/z＝498[M+H]+。1H NMR(400MHz,Methanol-d4)δ8.09(s,2H),7.81(d,J＝10.1Hz,1H),7.07(s,1H),4.98(dd,J＝8.8,3.7Hz,1H),4.03-3.86(m,2H),3.85-3.78(m,1H),3.78-3.59(m,6H),3.54(dt,J＝13.0,5.1Hz,1H),2.36(dt,J＝12.3,8.1Hz,1H),2.16-1.92(m,3H),1.70(tt,J＝8.5,5.1Hz,1H),0.94-0.78(m,2H),0.60-0.50(m,2H).
实施例77：化合物77的制备
参照实施例71的合成方法，用化合物76替换化合物66，其余试剂和操作不变，即可得实施例77：[4-(5-环丙基嘧啶-2-基)哌嗪-1-基]-[rac-(2S)-1-(3-环丙基-[1，2，4]三唑并[4，3-b]哒嗪-6-基)吡咯烷-2-基]甲酮，MS(ESI)m/z＝460[M+H]+。1H NMR(400MHz,Methanol-d4)δ8.09(s,2H),7.73(d,J＝10.0Hz,1H),6.96(s,1H),4.96(dd,J＝8.8,3.4Hz,1H),3.92-3.84(m,1H),3.83-3.76(m,2H),3.72(dd,J＝7.4,3.6Hz,4H),3.65-3.54(m,3H),2.36(dt,J＝12.1,8.2Hz,1H),2.16(s,1H),2.08-1.93(m,3H),1.70(tt,J＝8.5,5.1Hz,1H),1.21-1.03(m,2H),0.95-0.73(m,4H),0.55(dt,J＝6.5,4.6Hz,2H).
实施例78：化合物78的制备
参照实施例1的合成路线，省去前两步，从第三步中用中间体A-1替换IN-1b，N-Boc-4,4-二氟-L-脯氨酸替换(叔丁氧羰基)-L-脯氨酸，其余试剂和操作不变，即可得实施例78：[4-(5-环丙基嘧啶-2-基)哌嗪-1-基]-[(2S)-4,4-二氟-1-[3-(三氟甲基)-[1,2,4]三唑并[4,3-b]哒嗪-6-基]吡咯烷-2-基]甲酮，MS(ESI)m/z＝524[M+H]+。1H NMR(400MHz,Methanol-d4)δ8.08(s,2H),8.02(d,J＝10.1Hz,1H),7.15(d,J＝10.2Hz,1H),5.27(dd,J＝9.7,4.9Hz,1H),4.22-3.99(m,2H),3.88-3.76(m,2H),3.74-3.61(m,4H),3.55(t,J＝5.3Hz,2H),2.99(tt,J＝14.3,6.9Hz,1H),2.48(qd,J＝13.8,4.8Hz,1H),1.68(tt,J＝8.5,5.2Hz,1H),0.88-0.79(m,2H),0.54(dt,J＝6.4,4.6Hz,2H).
实施例79：化合物79的制备
参照实施例1的合成路线，第一步中用2-氯-5三氟甲基嘧啶替换2-溴-5-三氟甲基噻唑，第三步中N-Boc-4,4-二氟-L-脯氨酸替换(叔丁氧羰基)-L-脯氨酸，其余试剂和操作不变，即可得实施例79：[(2S)-4,4-二氟-1-[3-(三氟甲基)-[1,2,4]三唑[4,3-b]哒嗪-6-基]吡咯烷- 2-基]-[4-[5-(三氟甲基)嘧啶-2-基]哌嗪-1-基]甲酮，MS(ESI)m/z＝552[M+H]+。
1H NMR(400MHz,Methanol-d4)δ8.53(d,J＝0.9Hz,2H),8.04(d,J＝10.1Hz,1H),7.17(d,J＝10.1Hz,1H),5.29(dd,J＝9.5,4.9Hz,1H),4.24-4.03(m,2H),4.00(t,J＝5.3Hz,2H),3.88(qt,J＝13.5,5.2Hz,2H),3.71(tq,J＝13.6,8.1,6.6Hz,2H),3.59(t,J＝5.4Hz,2H),2.99(td,J＝14.3,9.6Hz,1H),2.50(qd,J＝13.8,4.9Hz,1H).
实施例80：化合物80的制备
参照实施例1的合成路线，省去前两步，从第三步中用中间体A-18替换IN-1b，N-Boc-4,4-二氟-L-脯氨酸替换(叔丁氧羰基)-L-脯氨酸，其余试剂和操作不变，即可得实施例80：2-[4-[(2R)-4,4-二氟-1-[3-(三氟甲基)-[1,2,4]三唑并[4,3-b]哒嗪-6-基]吡咯烷-2-羰基]哌嗪-1-基]恶唑-5-甲酰胺，MS(ESI)m/z＝516[M+H]+。1H NMR(600MHz,Methanol-d4)δ8.14(d,J＝10.1Hz,1H),7.52(s,1H),7.27(s,1H),5.38(dd,J＝10.0,4.9Hz,1H),4.33-4.11(m,2H),3.84(t,J＝5.2Hz,2H),3.80-3.69(m,4H),3.66(ddd,J＝20.8,9.1,5.5Hz,2H),3.10(dt,J＝14.7,7.5Hz,1H),2.60(dd,J＝13.5,4.7Hz,1H).
实施例81：化合物81的制备
参照实施例1的合成路线，第一步中用2-氯-5三氟甲基嘧啶替换2-溴-5-三氟甲基噻唑，第五步中用中间体B-10替换中间体B-1，其余试剂和操作不变，即可得实施例81：[(2S)-1-(3-溴-[1，2，4]三唑并[4，3-b]哒嗪-6-基)吡咯烷-2-基]-[4-[5-(三氟甲基)嘧啶-2-基]哌嗪-1-基]甲酮，MS(ESI)m/z＝526[M+H]+。1H NMR(400MHz,Methanol-d4)δ8.62(d,J＝0.9Hz,2H),7.92(d,J＝10.1Hz,1H),7.18(s,1H),5.10(dd,J＝8.7,3.7Hz,1H),4.20(s,1H),4.16-4.08(m,1H),4.08-4.00(m,2H),3.97(dd,J＝13.5,3.8Hz,1H),3.87-3.81(m,2H),3.81-3.73 (m,2H),3.68(ddd,J＝17.5,8.8,5.2Hz,1H),2.48(dq,J＝11.9,8.1Hz,1H),2.20-2.03(m,3H).
实施例82：化合物82的制备
参照实施例1的合成路线，第一步中用2-氯-5三氟甲基嘧啶替换2-溴-5-三氟甲基噻唑，用顺式-3,5-二甲基哌嗪-1-羧酸叔丁酯替换哌嗪-1-羧酸叔丁酯，其余试剂和操作不变，即可得实施例82：。[rac-(3S，5R)-3,5-二甲基-4-[5-(三氟甲基)嘧啶-2-基]哌嗪-1-基]-[rac-(2S)-1-[3-(三氟甲基)-[1，2，4]三唑[4，3-b]哒嗪-6-基]吡咯烷-2-基]甲酮，MS(ESI)m/z＝544[M+H]+。1H NMR(400MHz,Methanol-d4)δ8.55(s,2H),7.97(t,J＝9.6Hz,1H),7.22(s,1H),5.17-4.85(m,3H),4.46-3.90(m,2H),3.79-3.36(m,3H),3.08-2.84(m,1H),2.42(d,J＝38.5Hz,1H),2.25-1.84(m,3H),1.35(dd,J＝50.5,6.9Hz,3H),1.15(dd,J＝6.9,4.2Hz,3H).
实施例83：化合物83的制备

于50mL单口反应烧瓶中，将中间体B-1(223mg，1.00mmol)与中间体C-2(129.4mg，1.00mmol)溶于DMSO(10mL)中，加入KF(582.13mg，10.02mmol)后置换氮气，随后油浴升温至120℃搅拌反应3小时。待TLC点板监测反应完成，恢复至室温，将反应液倒入100mL冰水中，随后加入50mL乙酸乙酯，萃取分液，并再用乙酸乙酯萃取水相两次，将有机相合并后用盐水洗涤，硫酸钠干燥，过滤，真空浓缩，去除溶剂得固体粗品，正相纯化得到中间体IN-3a(305mg，0.97mmol，产率：96.56％)。MS(ESI)m/z＝316[M+H]+。
于50mL单口反应烧瓶中，将中间体IN-3a(305mg，0.97mmol)溶于四氢呋喃，甲醇和水的混合溶液(3mL/1mL/2mL/3:1:2)中，待化合物溶解完全，加入氢氧化锂一水合物(121.79mg，2.90mmol)，加完后室温下搅拌反应3小时。待TLC点板监测反应完成，加入50mL稀释反应液，并在0℃下加入适量1N盐酸水溶液，调节pH值至小于7，并加入20mL乙酸乙酯萃取分液，并再用乙酸乙酯萃取两次，将有机相合并后用盐水洗涤，硫酸钠干燥，过滤，真空浓缩，去除溶剂得到中间体IN-3b(244mg，0.81mmol，产率：83.73％)。MS(ESI)m/z＝302[M+H]+。
于50mL单口反应烧瓶中，将中间体IN-3b(244mg，0.81mmol)溶于DMF(10mL)中，待化合物溶解完全，加入HATU(462mg，1.22mmol)，室温搅拌15分钟后，加入哌嗪-1-羧酸叔丁酯(181.04mg，0.97mmol)和DIPEA(209.38mg，1.62mmol)，室温反应3小时，待TLC点板监测反应完成，冷却至室温。加入50mL的水和30mL的乙酸乙酯，萃取分液，并再用乙酸乙酯萃取两次，将有机相合并后用盐水洗涤，硫酸钠干燥，过滤，真空浓缩，去除溶剂得固体粗品，正相纯化得到中间体IN-3c(360mg，0.77mmol，产率94.67％)。MS(ESI)m/z＝470[M+H]+
于100mL单口反应烧瓶中，将化合物中间体IN-3c(360mg，0.77mmol，)溶于乙酸乙 酯(3mL)中，随后冰浴下，滴入4M盐酸乙酸乙酯溶液(10mL)，加毕，升至室温反应3小时，TLC点板监测反应完成，将体系冰浴至0℃左右，析出大量白色固体，抽滤，石油醚洗涤，干燥，得到中间体IN-3(275mg，0.74mmol，白色固体，产率：97.10％)。MS(ESI)m/z＝370[M+H]+。
于100mL单口反应烧瓶中，将中间体IN-3(100mg，0.27mmol)溶于NMP(5mL)中，待化合物溶解完全，加入碳酸钾(74.8mg，0.54mmol)和2-氯-7,8-二氢吡啶并[4,3-D]嘧啶-6(5H)-甲酸叔丁酯(73.6mg，0.27mmol)，加完后80℃油浴加热反应3小时，待TLC点板监测反应完成，冷却至室温。加入50mL水和20mL乙酸乙酯，萃取分液，并再用乙酸乙酯萃取两次，将有机相合并后用盐水洗涤，硫酸钠干燥，过滤，真空浓缩，去除溶剂得固体粗品，正相纯化得到化合物IN-3d(85mg，0.14mmol，白色固体，产率：51.92％)。MS(ESI)m/z＝603[M+H]+。
于100mL单口反应烧瓶中，将化合物中间体IN-3d(85mg，0.14mmol)溶于乙酸乙酯(2mL)中，随后冰浴下，滴入4M盐酸乙酸乙酯溶液(5mL)，加毕，升至室温反应3小时，TLC点板监测反应完成，将体系冰浴至0℃左右，析出大量白色固体，过滤，将固体用甲醇溶解后，在碱性体系下反相柱层析纯化得油状产物，用乙腈分散，并加入纯水稀释后，冻干得到实施例83：[4-(4a，5,6,7,8,8a-六氢吡啶并[4,3-d]嘧啶-2-基)哌嗪-1-基]-[1-[3-(三氟甲基)-[1,2,4]三唑[4,3-b]哒嗪-6-基]吡咯烷-2-基]甲酮(45mg，89.2μmol，白色固体，产率：63.45％)，MS(ESI)m/z＝503[M+H]+。1H NMR(400MHz,Methanol-d4)δ8.08(d,J＝17.7Hz,2H),7.30(s,1H),5.14-5.02(m,1H),4.05-3.90(m,2H),3.83(d,J＝10.3Hz,4H),3.75(d,J＝8.6Hz,4H),3.65(s,2H),3.14(t,J＝5.9Hz,2H),2.77(t,J＝6.1Hz,2H),2.46(d,J＝10.1Hz,1H),2.15(s,3H).
实施例84：化合物84的制备
参照实施例83的合成路线，第五步中用2-氯-5H,6H,7H,8H-吡啶并[3,4-D]嘧啶-7-羧酸叔丁酯替换2-氯-7,8-二氢吡啶并[4,3-D]嘧啶-6(5H)-甲酸叔丁酯，其余试剂和操作不变，即可得实施例84：[4-(4a，5,6,7,8,8a-六氢吡啶并[3,4-d]嘧啶-2-基)哌嗪-1-基]-[1-[3-(三氟甲基) -[1,2,4]三唑[4,3-b]哒嗪-6-基]吡咯烷-2-基]甲酮，MS(ESI)m/z＝503[M+H]+。1H NMR(400MHz,Methanol-d4)δ8.27(s,1H),8.06(d,J＝10.1Hz,1H),7.31(s,1H),5.11-5.04(m,1H),4.10(s,2H),4.03-3.92(m,2H),3.83(p,J＝4.5Hz,4H),3.75(dt,J＝9.5,7.3Hz,2H),3.65(t,J＝5.3Hz,2H),3.38(t,J＝6.1Hz,2H),2.89(t,J＝6.1Hz,2H),2.47(dd,J＝12.1,7.9Hz,1H),2.15(d,J＝6.8Hz,2H),2.10-2.03(m,1H).
实施例85：化合物85的制备
参照实施例1的合成路线，第一步中用4-叔丁氧羰基氨基哌啶替换哌嗪-1-羧酸叔丁酯，用反-N-(叔丁氧羰基)-4-羟基-L-脯氨酸替换(叔丁氧羰基)-L-脯氨酸，其余试剂和操作不变，即可得实施例85：(2S，4R)-4-羟基-N-[1-[5-(三氟甲基)噻唑-2-基]-4-哌啶基]-1-[3-(三氟甲基)-[1，2，4]三唑并[4，3-b]哒嗪-6-基]吡咯烷-2-甲酰胺，MS(ESI)m/z＝551[M+H]+。1H NMR(400MHz,DMSO-d6)δ8.25-8.23(m,J＝0.8Hz,1H),7.69(m,1H),6.78(s,1H),4.22(s,1H),3.69-3.6(m,2H),3.38-3.13(m,6H),2.11-2.05(m,2H),1.85-1.74(m,2H),1.70-1.60(m,2H).
实施例86：化合物86的制备
参照实施例1的合成路线，第一步中用2-氯-5三氟甲基嘧啶替换2-溴-5-三氟甲基噻唑，用3-氨基吡咯烷-1-羧酸叔丁酯替换哌嗪-1-羧酸叔丁酯，其余试剂和操作不变，即可得实施 例86：[rac-(2S)-1-[3-(三氟甲基)-[1，2，4]三唑并[4，3-b]哒嗪-6-基]吡咯烷-2-基]-[3-[[5-(三氟甲酯)嘧啶-2-基]氨基]吡咯烷-1-基]甲酮，MS(ESI)m/z＝516[M+H]+。1H NMR(400MHz,DMSO-d6)δ8.77(d,J＝0.9Hz,2H),8.26(s,1H),7.36(s,1H),4.06(s,1H),3.88(dt,J＝13.1,4.9Hz,1H),3.82-3.59(m,3H),3.57-3.41(m,3H),2.44(s,1H),2.19-1.99(m,2H),1.88-1.66(m,3H).
实施例87至实施例91的制备
参照实施例1的合成路线，省去前两步，从第三步中用相应的中间体三并环胺替代中间体IN-1b，其余试剂操作相同，可得下表中相应结构化合物。

生物学评价试验
实验例1：PARP7酶抑制活性检测
本发明通过竞争性结合TR-FRET(Time-resolved fluorescence resonance energy transfer)定量检测小分子化合物与PARP7活性位点的结合作用。实验在384孔板(Corning，Cat# 3574)中进行，使用的反应缓冲液成分为：20mM Hepes pH 8.0,100mM NaCl，0.1％BSA，1mM DTT，0.002％Tween20。具体实验操作如下：在384孔板中加入6nM PARP7(HitGen)，不同浓度的待测化合物(DMSO终浓度为0.5％)和6nM Tracer(RBN011147，参考Cell Chem Biol.2020Jul 16；27(7):877-887.e14.)，反应总体积18μL，混匀后室温孵育30分钟；再加入0.5nM Eu-W1024labeled streptavidin(PerKinElmer，Cat#AD0062)和6nM ULight anti-FLAG(PerKinElmer，Cat# TRF0059D)，反应终体积24μL，混匀后室温孵育60分钟，用BMG PHERAStar检测激发波长337nM发射波长620nM和665nM的荧光强度，计算FRET信号强度(665nM荧光强度/620nM荧光强度*10000)。使用GraphPad Prism 6软件log(inhibitor)vs.normalized response-Variable slope模型对数据进行分析，得到IC50值和化合物拟合曲线。
其中本发明制备得到的部分化合物以及已公开PARP7抑制剂RBN-2397(CAS NO.2381037-82-5)对于PARP7酶活性的抑制效果如表1所示。
表1.本发明的化合物对PARP7酶抑制的IC50数据




说明：
++:0.1nM＜IC50＜10nM
+:10nM＜IC50＜1000nM
上述实验数据表明，本发明的化合物对PARP7酶具有良好的抑制作用。
实验例2：细胞增殖试验
本发明运用细胞增殖实验法来评价化合物对人肺癌细胞系NCI-H1373(南京科佰生物科技有限公司)细胞和EBC-1(南京科佰生物科技有限公司)细胞的生物活性。NCI-H1373细 胞使用含10％胎牛血清和100μg/mL Normocin的RPMI-1640培养基培养，EBC-1细胞使用含10％胎牛血清，1％非必须氨基酸和100μg/mL Normocin的最低必需培养基(Minimum Essential Medium,MEM)培养。分别将NCI-H1373细胞和EBC-1细胞接种于96孔板中，其中NCI-H1373细胞每孔接种1000个细胞，EBC-1细胞每孔接种750个细胞。在37℃及5％CO2条件下培养过夜，使细胞附着贴壁。次日，移除细胞中的培养基，先加入150μL新鲜培养基，再加入50μL含有4倍终浓度化合物(终浓度范围为1nM～10μM)的培养基，放入培养箱中，在37℃及5％CO2条件下继续培养6天。培养6天后再次移除细胞中的培养基，加入100μL含有10％CCK8试剂的无血清RPMI-1640基础培养基。在37℃条件下孵育1h后使用酶标仪(BMG LABTECH)于450nm波长下读取吸光度(OD)值。使用GraphPad Prism软件对数据进行分析，并得到IC50值和化合物拟合曲线。
其中本发明制备得到的部分化合物以及已公开PARP7抑制剂RBN-2397(CAS NO.2381037-82-5)对于NCI-H1373细胞抗增殖的抑制效果如表2所示。
表2.本发明的化合物对NCI-H1373细胞抗增殖实验的IC50数据


说明：
++:0.01μM＜IC50＜1.00μM
+:1.0μM＜IC50＜100μM
上述实验数据表明，本发明的化合物对NCI-H1373细胞抗增殖有较好的抑制，具有强大的抑制肿瘤细胞增殖的功能。

Claims (20)

  1. 式I所示的化合物、或其立体异构体、或其药学上可接受的盐：
    其中，
    表示单键或双键；
    X、X1、X4、X5、X6分别独立地选自CRX、CRXRX1、N或NRX；
    X2选自CH或N；
    RX、RX1分别独立地选自氢、卤素、氰基、硝基、-OH、-C1～6烷基、-C2～6烯基、-C2～6炔基或卤素取代的C1～6烷基；
    R1选自氢、卤素、氰基、硝基、＝O、-OH、-C1～6烷基、氘取代的C1～6烷基、卤素取代的C1～6烷基、-C2～6烯基、-O(C1～6烷基)、-O(卤素取代的C1～6烷基)、-NH2、-C0～2亚烷基-NH(C1～6烷基)、-C0～2亚烷基-N(C1～6烷基)(C1～6烷基)、-C(O)C1～6烷基、-C(O)NRaRb、-C(O)ORa、-S(O)Ra、-S(O)NRaRb、-S(O)ORa、-S(O)2Ra、-S(O)2NRaRb、-S(O)2ORa、-C0～2亚烷基-(3～10元碳环)、-C0～2亚烷基-(3～10元杂环)、-C0～2亚烷基-(6～10元芳环)或-C0～2亚烷基-(5～10元杂芳环)；其中，所述烷基、亚烷基、碳环、杂环、芳环、杂芳环任选地被一个、两个、三个或四个独立的Rc取代；
    Ra、Rb分别独立选自氢、氘、卤素、氰基、硝基、-C1～6烷基、-C2～6烯基、-C2～6炔基、卤素取代的C1～6烷基、-C0～2亚烷基-OH、-O(C1～6烷基)、-O(卤素取代的C1～6烷基)、-NH2、-C0～2亚烷基-NH(C1～6烷基)或-C0～2亚烷基-N(C1～6烷基)(C1～6烷基)；
    Rc选自氢、氘、卤素、氰基、硝基、-C1～6烷基、-C2～6烯基、-C2～6炔基、卤素取代的C1～6烷基、-C0～2亚烷基-OH、-O(C1～6烷基)、-O(卤素取代的C1～6烷基)、-NH2、-C0～2亚烷基-NH(C1～6烷基)、-C0～2亚烷基-N(C1～6烷基)(C1～6烷基)或-C(O)C1～6烷基；
    L1选自-CO-或-CONH-；
    L2选自-NHCR2R3-、-S(O)CR2R3-、-S(O)2CR2R3-、-S(O)NHCR2R3-、-S(O)2NHCR2R3-、3～10元碳环、3～10元杂环或5～10杂芳环；其中，所述碳环、杂环、杂芳环任选地被一个、 两个、三个或四个独立的Rd取代；
    Rd选自氢、卤素、氰基、氧代、硝基、-C1～6烷基、-C2～6烯基、-C2～6炔基、卤素取代的C1～6烷基、-C0～2亚烷基-OH、-O(C1～6烷基)、-O(3～10元碳环)、-O(卤素取代的C1～6烷基)、-NH2、-C0～2亚烷基-NH(C1～6烷基)、-C0～2亚烷基-N(C1～6烷基)(C1～6烷基)或-C(O)C1～6烷基；
    或者，两个Rd与其相连的原子一起形成3～10元杂环或3～10元碳环；
    R2、R3分别独立地选自氢、-C1～6烷基、-C2～6烯基、-C2～6炔基、卤素取代的C1～6烷基、-OH、-O(C1～6烷基)、-O(卤素取代的C1～6烷基)、-NH2、-C0～2亚烷基-NH(C1～6烷基)、-C0～2亚烷基-N(C1～6烷基)(C1～6烷基)、-C(O)C1～6烷基、6～10元芳环、6～10元杂芳环、3～10元杂环或3～10元碳环；其中，所述亚烷基、碳环、杂环、芳环、杂芳环任选地被一个、两个、三个或四个独立的R23取代；
    或者R2、R3与其相连的原子一起形成3～10元杂环或3～10元碳环；其中，所述杂环、碳环任选地被一个、两个、三个或四个独立的R23取代；
    R23选自氢、卤素、氰基、硝基、-C1～6烷基、-C2～6烯基、-C2～6炔基、卤素取代的C1～6烷基、-C0～2亚烷基-OH、-O(C1～6烷基)、-O(卤素取代的C1～6烷基)、-NH2、-C0～2亚烷基-NH(C1～6烷基)、-C0～2亚烷基-N(C1～6烷基)(C1～6烷基)或-C(O)C1～6烷基；
    环A1选自3～10元杂环；其中，所述杂环任选地被一个、两个、三个、四个、五个、六个、七个或八个独立的R4取代；
    R4选自氢、氘、卤素、氰基、硝基、氧代、羟基、-C1～6烷基、-C2～6烯基、-C2～6炔基、卤素取代的C1～6烷基、-O(C1～6烷基)、-O(3～6元碳环)、-O(卤素取代的C1～6烷基)、-NH2、-C0～2亚烷基-NH(C1～6烷基)、-C0～2亚烷基-N(C1～6烷基)(C1～6烷基)或-C(O)C1～6烷基；
    环A2选自5～10杂芳环或6～10元芳环；其中，所述芳环、杂芳环任选地被一个、两个、三个、或四个独立的R5取代；
    R5选自氢、卤素、氰基、硝基、氧代、-C0～2亚烷基-羟基、-C1～6烷基、-C2～6烯基、-C2～6炔基、卤素取代的C1～6烷基、-O(C1～6烷基)、-S(C1～6烷基)、-S(O)C1～6烷基、-S(O)2C1～6烷基、-O(3～6元碳环)、-O(卤素取代的C1～6烷基)、-C(O)NH2、-NH2、-C0～2亚烷基-NH(C1～6烷基)、-C0～2亚烷基-N(C1～6烷基)(C1～6烷基)、-C(O)C1～6烷基、-C0～2亚烷基-(3～10元碳环)、-C0～2亚烷基-(3～10元杂环)、-C0～2亚烷基-(6～10元芳环)或-C0～2亚烷基-(5～10元杂芳环)；其中，所述烷基、亚烷基、碳环、杂环、芳环、杂芳环任选地被一个、两个、三个、或四个独立的R51取代；
    或者R4、R5与环A1和环A2一起形成11～17元稠杂环；所述稠杂环任选地被一个、两个、三个、或四个独立的R52取代；
    R51选自氢、卤素、氰基、硝基、氧代、羟基、-C1～6烷基、-C2～6烯基、-C2～6炔基、卤素取代的C1～6烷基、-O(C1～6烷基)、-O(3～6元碳环)、-O(卤素取代的C1～6烷基)、-NH2、-C0～2亚烷基-NH(C1～6烷基)或-C0～2亚烷基-N(C1～6烷基)(C1～6烷基)；
    R52选自氢、卤素、氰基、硝基、氧代、硫代、羟基、-C1～6烷基、-C2～6烯基、-C2～6炔基、卤素取代的C1～6烷基、-O(C1～6烷基)、-O(3～6元碳环)、-O(卤素取代的C1～6烷基)、-NH2、-C0～2亚烷基-NH(C1～6烷基)、-C0～2亚烷基-N(C1～6烷基)(C1～6烷基)、-C2～6烯基-CON(C1～6烷基)(C1～6烷基)、-C0～2亚烷基-(3～10元碳环)、-C0～2亚烷基-(3～10元杂环)、-C0～2亚烷基-(6～10元芳环)或-C0～2亚烷基-(5～10元杂芳环)。
  2. 根据权利要求1所述化合物，其特征在于：
    R1选自氢、卤素、氰基、＝O、-NH2、-C(O)NRaRb、氘取代的C1～6烷基、卤素取代的C1～6烷基、-C1～3烷基、-C2～4烯基、3元碳环、4元碳环、5元碳环、6元碳环、4元杂环、5元杂环、6元杂环、7元杂环、6元芳环、10元芳环、5元杂芳环、6元杂芳环、9元杂芳环或10元杂芳环；其中，所述碳环、杂环、芳环、杂芳环任选地被一个、两个、三个或四个独立的Rc取代；
    L2选自-NHCR2R3-、3元碳环、4元碳环、5元碳环、6元碳环、4元单杂环、5元单杂环、6元单杂环、7元单杂环、8元单杂环、9元单杂环、10元单杂环、7元螺杂环、8元螺杂环、9元螺杂环、10元螺杂环、6元稠杂环、7元稠杂环、8元稠杂环、9元稠杂环、10元稠杂环或5元杂芳环；其中，所述碳环、单杂环、螺杂环、稠杂环、杂芳环任选地被一个、两个、三个或四个独立的Rd取代；
    R2、R3分别独立地选自氢、-C1～6烷基、6元芳环、5元杂芳环或6元杂芳环；
    或者，R2、R3与其相连的原子一起形成3～6元碳环、4元杂环、5元杂环、6元杂环或7元杂环；其中，所述碳环、杂环任选地被一个、两个、三个或四个独立的R23取代；
    Rd选自氢、卤素、氰基、氧代、硝基、-C1～3烷基、-C2～6烯基、-C2～6炔基、卤素取代的C1～3烷基、-OH、-O(C1～3烷基)或-O(3～6元碳环)；
    环A1选自5元单杂环、6元单杂环、7元单杂环、8元单杂环、9元单杂环、10元单杂环、7元螺杂环、8元螺杂环、9元螺杂环、10元螺杂环、6元稠杂环、7元稠杂环、8元稠杂环、9元稠杂环、10元稠杂环、7元桥杂环、8元桥杂环、9元桥杂环或10元桥杂环；其 中，所述单杂环、螺杂环、稠杂环、桥杂环任选地被一个、两个、三个、四个、五个、六个、七个或八个独立的R4取代；
    环A2选自5元杂芳环、6元杂芳环、9元稠杂芳环、10元稠杂芳环、5元杂芳环稠6元饱和环、6元杂芳环稠6元饱和环、6元杂芳环稠6元饱和杂环、6元杂芳环稠5元饱和环、5元杂芳环稠6元饱和杂环或6元芳环；其中，所述芳环、杂芳环任选地被一个、两个、三个、或四个独立的R5取代；
    R5选自氢、卤素、氰基、硝基、氧代、羟基、-C1～3烷基、-C2～6烯基、-C2～6炔基、卤素取代的C1～3烷基、-O(C1～6烷基)、-O(3～6元碳环)、-O(卤素取代的C1～6烷基)、-S(C1～6烷基)、-S(O)C1～6烷基、-S(O)2C1～6烷基、-NH2、-C0～2亚烷基-NH(C1～6烷基)、-C0～2亚烷基-N(C1～6烷基)(C1～6烷基)、-C(O)C1～6烷基、-C0～2亚烷基-(3～6元碳环)、3～10元杂环、6～10元芳环或5～10元杂芳环；其中，所述烷基、碳环、杂环、芳环、杂芳环任选地被一个、两个、三个、或四个独立的R51取代。
  3. 根据权利要求1所述化合物，其特征在于：
    R1选自氢、Br、F、 氰基、甲基、＝O、 -NH2、
  4. 根据权利要求1所述化合物，其特征在于：
    L2选自 其中，aa端与L1连接。
  5. 根据权利要求1所述化合物，其特征在于：
    环A1选自
  6. 根据权利要求1所述化合物，其特征在于：
    环A2选自
  7. 根据权利要求1所述化合物，其特征在于：
    R4、R5与环A1和环A2一起形成12元稠杂环、13元稠杂环、14元稠杂环、15元稠杂环或16元稠杂环；所述稠杂环任选地被一个、两个、三个、或四个独立的R52取代；
    R52选自氢、卤素、氰基、硝基、氧代、硫代、羟基、-C1～6烷基、-C2～6烯基、-C2～6炔基、卤素取代的C1～6烷基、-O(C1～3烷基)、-O(3～6元碳环)、-O(卤素取代的C1～6烷基)、-NH2、-NH(C1～6烷基)、-N(C1～6烷基)(C1～6烷基)、-C2～6烯基-CON(C1～6烷基)(C1～6烷基)、-3～10元碳环、-3～10元杂环、-6～10元芳环或-5～10元杂芳环。
  8. 根据权利要求7所述化合物，其特征在于：
    R4、R5与环A1和环A2一起形成的稠杂环为
    其中，
    表示单键或双键；
    n选自1，2或3；
    X3各自独立地选自NH、N(C1～6烷基)、N(C2～6烯基)、N(3～6元碳环)、N(3～6元杂环)、 N(卤素取代的C1～6烷基)、CRX31、CRX31RX32、O、S、
    RX31、RX32分别独立地选自氢、卤素或-C1～6烷基。
  9. 根据权利要求8所述化合物，其特征在于：
    X3各自独立地选自
  10. 根据权利要求1所述化合物，其特征在于：R4、R5与环A1和环A2一起形成的稠杂环选自：

  11. 根据权利要求1所述化合物，其特征在于：
    X、X1、X4、X5、X6分别独立地选自CH、CH2、N或NCH3。
  12. 根据权利要求1所述化合物，其特征在于：
    L1选自-CO-或其中，bb端与环A1连接。
  13. 根据权利要求1所述化合物，其特征在于：式I所述化合物如式II、式III、式IV、式V、式VI或式VII所示：
    其中，R1、RX、L2、L1、环A1、环A2如权利要求1所述。
  14. 根据权利要求1所述化合物，其特征在于：式I所述化合物如式I-1所示：
    其中，R1、Rd、R4、环A2取代基定义如权利要求1所述。
  15. 根据权利要求1所述化合物，其特征在于：式I所述化合物如式II-1、式II-2、式II-3、式II-4或式II-5所示：

    其中，表示单键或双键；
    Y1、Y2、Y4、Y5、Y6、Y9、Y11、Y12分别独立选自N、NRY1、CHRY1或CRY1；
    Y3、Y7、Y8、Y10分别独立选自CRY1、CHRY1、O、S、N或NRY1；
    Y13选自N或CRY1；
    每个RY1分别独立地选自氢、卤素、氰基、硝基、-C1～6烷基、-C2～6烯基、-C2～6炔基或卤素取代的C1～6烷基；
    R1、Rd、R4、R5、X1如权利要求1所述。
  16. 根据权利要求1所述化合物，其特征在于：式I所述化合物如式VIII所示：

    其中，Y4、Y5分别独立选自N或CRY1；Y3选自CHRY1、O、S或NRY1；
    同时，RL2、R3与其相连的原子一起形成3～10元杂环；
    R1、R2、R3、R4、R5取代基定义如权利要求1所述。
  17. 根据权利要求1所述化合物，其特征在于：所述化合物具体选自：



















  18. 权利要求1-17任一项所述的化合物、或其立体异构体、或其药学上可接受的盐在制备治疗PARP7介导的疾病的药物中的用途。
  19. 权利要求18所述的用途，其特征在于：所述PARP7介导的疾病包括：乳腺癌、中枢神经系统癌、子宫内膜癌、肾癌、大肠癌、肺癌、食道癌、卵巢癌、胰腺癌、前列腺癌、胃癌、头颈癌、尿路癌或结肠癌。
  20. 一种药物组合物，其特征在于：它是以权利要求1～17任一项所述的化合物、或其立体异构体、或其药学上可接受的盐，加上药学上可接受的辅料制备而成的制剂。
PCT/CN2023/133125 2022-11-23 2023-11-22 Parp7抑制剂及其制备方法和用途 WO2024109788A1 (zh)

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