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WO2021129841A1 - 用作ret激酶抑制剂的化合物及其应用 - Google Patents

用作ret激酶抑制剂的化合物及其应用 Download PDF

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Publication number
WO2021129841A1
WO2021129841A1 PCT/CN2020/139655 CN2020139655W WO2021129841A1 WO 2021129841 A1 WO2021129841 A1 WO 2021129841A1 CN 2020139655 W CN2020139655 W CN 2020139655W WO 2021129841 A1 WO2021129841 A1 WO 2021129841A1
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group
alkyl
compound
membered
cycloalkyl
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English (en)
French (fr)
Inventor
吴豫生
李钧
郑茂林
牛成山
梁阿朋
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TYK Medicines Inc
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TYK Medicines Inc
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Priority to AU2020410900A priority Critical patent/AU2020410900B2/en
Priority to US17/789,115 priority patent/US20230095530A1/en
Publication of WO2021129841A1 publication Critical patent/WO2021129841A1/zh
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • A61K31/50—Pyridazines; Hydrogenated pyridazines
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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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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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Definitions

  • the present invention relates to the field of medical technology, in particular to compounds used as RET kinase inhibitors, and their application in regulating RET kinase activity or treating RET-related diseases.
  • RET Rearranged during transfection
  • RET protein is located on chromosome 10
  • RTK receptor tyrosine kinase
  • Its mutation types mainly include KIF5B, Fusion mutations in genes such as TRIM33, CCDC6 and NCOA4, and point mutations in M918T alleles.
  • RET is a receptor tyrosine kinase, which is involved in the signal transduction of cell proliferation, migration, differentiation and survival of neural crest cells, formation of kidney organs, spermatogenesis and other processes.
  • RET gene KIF5B-RET and CCDC6-RET are closely related to the occurrence and development of a variety of cancers, such as papillary thyroid cancer, multiple endocrine neoplasia type 2, medullary thyroid cancer, pheochromocytoma and parathyroid adenoma, etc.;
  • the abnormal recombination of RET gene KIF5B-RET and CCDC6-RET is associated with about 1-2% of lung adenocarcinomas, of which KIF5B-RET accounts for 70-90% of them, and CCDC6-RET accounts for about 10- 25%;
  • the current treatment plan for RET gene modification is mainly to use multi-kinase inhibitor drugs, such as cabozantinib and vandetanib. Due to the low targeting, VEGFR inhibition related to off-target is usually serious. toxicity.
  • the purpose of the present invention is to provide a new class of compounds with RET kinase inhibitory activity and/or better pharmacodynamic/pharmacokinetic properties and uses thereof.
  • the first aspect of the present invention provides a compound of formula F, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof,
  • G is selected from: AZ 1 -or D;
  • Ar 1 is a substituted or unsubstituted 5-6 membered heteroaryl group containing 1 to 4 N atoms, wherein the substitution refers to substitution by one or more groups selected from the following group: H, CN, halogen, Methyl, ethyl or cyclopropyl;
  • K is selected from: C or N;
  • Q 2 is selected from the following group: saturated 4-7 membered monocyclic heterocyclic group, saturated 7-8 membered bridged heterocyclic group, saturated 7-11 membered spiro heterocyclic group, Wherein, the heterocyclic group contains 1, 2 or 3 nitrogen heteroatoms as the ring skeleton, and m, n, m'and n'are each independently 0, 1, 2, 3;
  • B is independently selected from the group of substituted or unsubstituted groups: 3-7 membered ring, C6-C14 aryl, 5-14 membered heteroaryl, 7-20 membered spiro ring or bridged ring, and the ring contains 0 -3 heteroatoms selected from N, O, S; the substitution refers to substitution by one or more substituents selected from the following group: deuterium, hydroxyl, halogen, cyano, ester, amide, carbonyl, Amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 thioalkyl, C1-C6 alkoxy, C1-C6 heteroalkyl, C1-C6 alkylamino, C3-C6 cycloalkyl , C3-C8 cycloalkylamino, C6-C14 aryl or 5-14 membered heteroaryl;
  • E is independently selected from substituted or unsubstituted groups: hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C1-C6 heteroalkyl, 3-6 membered heterocyclic group wherein said substituted refers 0-5 substituents R a;
  • Each R 5 is independently selected from substituted or unsubstituted groups: hydrogen, nitro, cyano, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy , C1-C6 heteroalkyl, C3-C12 cycloalkyl, C6-C14 aryl, 5-14 membered heteroaryl, C6-C14 aryloxy, C6-C14 aryl, C1-C6 alkyl, 3-12 Membered heterocyclic group, 3-12 membered heterocycloalkyl, -C(O)R 6 , -OC(O)R 6 , -C(O)OR 6 , -(C1-C6 alkylene)-C( O) R 6 , -SR 6 , -S(O) 2 R 6 , -S(O) 2 -N(R 6 )(R 7 ), -(C1-C
  • Z 1 is selected from the following group: NR b , -S-, -C(R b R c )- or -O-;
  • D is a 5-14 membered heteroaryl group, wherein the H on the heteroaryl group is optionally substituted by one or more substituents selected from the following group: deuterium, hydroxyl, halogen, cyano, ester, amide Group, oxo group, amino group, C1-C6 alkyl group, C1-C6 alkoxy group, C1-C6 heteroalkyl group, C3-C6 cycloalkyl group, C3-C8 cycloalkylamino group, C6-C14 aryl group or 5-14 membered heteroaryl; the C1-C6 alkyl, C1-C6 alkoxy, C1-C6 heteroalkyl, C3-C6 cycloalkyl, C3-C8 cycloalkylamino, C6-C14 aryl
  • the group or 5-14 membered heteroaryl group may be further substituted with one or more groups selected from the group consisting of halogen, cyano,
  • f 0, 1, 2, 3, 4, 5 or 6;
  • R a is independently selected from the group: O, C1-C6 alkyl, halogen, hydroxy, C1-C6 heteroalkyl, C1-C6 alkoxy, C3-C14 cycloalkyl, 3-14 membered heterocycloalkyl Or cyano.
  • R b and R c are independently selected from the following group: H, C1-C6 alkyl, halogen, hydroxyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C3-C14 cycloalkyl, 3-14 membered hetero Cycloalkyl or cyano;
  • Ar 2 is a 5-6 membered heteroaryl group, and Ar 2 passes through the N and Q 2 ring and/or Connection; wherein R x is selected from the following group: H, CN, halogen, methyl, ethyl or cyclopropyl; the H atom on Ar 2 can be replaced by CR a.
  • R x is selected from the following group: H, CN, halogen, methyl, ethyl or cyclopropyl: Y 3 , Y 4 , and Y 5 are N or CR a , and the definition of Ra is as described above.
  • R x is selected from the following group: H, CN, halogen, methyl, ethyl or cyclopropyl; Y 3 , Y 4 , and Y 5 are CH, N or CR a , and the definition of Ra is as described above.
  • Ar 2 is selected from among them, Is a six-membered heteroaryl group; Is a five-membered heteroaryl group; X 1 , X 2 , X 3 and X 4 are each independently CH, N or CR a , and 0 , 1, and 2 of X 1, X 2, X 3 and X 4 are N; Y '1 is N; Y 1 is C or N; Y 2 is N or C.
  • Ar 2 is selected from Wherein, Y 1 , Y 2 are CR a or N, X 1 , X 2 , X 3 and X 4 are each independently selected from CR a or N, and X 1 , X 2 , X 3 and X 4 have 0, 1 , 2 is N; R a is independently selected from the group: O, C1-C6 alkyl, halogen, hydroxy, C1-C6 heteroalkyl, C1-C6 alkoxy, C3-C14 cycloalkyl group, 3- 14-membered heterocycloalkyl or cyano.
  • Ar 2 is selected from Wherein, Y '1 is N, Y 2 is CR a or N; X 1, X 2, X 3 are each independently selected from CH, CR a or N, and X 1, X 2 and X 3 have 0,1, 2 is N; R a is independently selected from the group: O, C1-C6 alkyl, halogen, hydroxy, C1-C6 heteroalkyl, C1-C6 alkoxy, C3-C14 cycloalkyl, 3-14 Member heterocycloalkyl or cyano.
  • the compound, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof has formula (F-I), formula (F-II), formula (F -III)
  • F-I formula (F-II)
  • F -III formula (F-III)
  • R x is independently selected from the group consisting of H, CN, halogen, methyl, ethyl or cyclopropyl;
  • G, Q 2, E, B , R 5, f, R a is as defined above.
  • the compound, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof has formula (I), formula (II), formula (III), (IV), the structure shown in formula (V) or formula (VI),
  • X 1 , X 2 , X 3 and X 4 are each independently CH, N or CR a , and 0 , 1, and 2 of X 1, X 2, X 3 and X 4 are N;
  • Y 1 is C or N
  • Y 3 and Y 5 are each independently CH, N or CR a ; Y 2 is N or C;
  • Y 4 is CH, N or CR a ;
  • R x is independently selected from the group consisting of H, CN, halogen, methyl, ethyl or cyclopropyl;
  • E, R 5, f, A , Z 1, D, Q 2, B, R a is as defined above;
  • the limiting conditions are: in formula I and formula III, when Y 3 is N, Y 4 is CH or N, and Y 1 and/or Y 2 is N.
  • the compound, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof is characterized in that Ar 1 is a substituted or unsubstituted group of the following group: Wherein, the substitution refers to substitution by one or more groups selected from the following group; H, CN, halogen, methyl, ethyl or cyclopropyl.
  • A is independently selected from the following group:
  • R 1 and R 2 are each independently selected from: H or C1-C6 alkyl, wherein the alkyl group may be optionally substituted with 1-3 fluorines;
  • R 3 is a substituted or unsubstituted 5-6 membered heteroaryl group, which has 1-3 ring heteroatoms selected from N, O and S, and the substitution refers to substitution by one or more C1-C6 alkyl groups;
  • A is a C2-C6 alkyl group, which may be optionally substituted with one or more groups selected from the following group: -OH, F or C3-C6 cycloalkyl.
  • A is a dihydroxy C3-C6 alkyl group, which may optionally be C3-C6 cycloalkyl group.
  • X 1 is N.
  • Z 1 is O.
  • Y 4 is N.
  • Y 5 is C.
  • X 1 is N
  • X 2 , X 3 , and X 4 are C.
  • E is hydrogen or a substituted or unsubstituted C1-C6 alkyl, wherein said substituents means substituted with 0-5 R a, R a is as defined above.
  • A is substituted or unsubstituted C2-C6 alkyl-OH, wherein the substitution refers to substitution by one or more groups selected from the group consisting of fluorine or C3-C6 cycloalkyl .
  • Q 2 is Wherein, m, n, m', and n'are each independently 0, 1, 2, 3, and R 3 is defined as described above.
  • X 1 is N.
  • Q 2 is a saturated 5-6 membered monocyclic heterocyclic group, wherein the heterocyclic group contains one or two nitrogen ring heteroatoms, and the H on Q 2 can optionally be One or more substituents selected from the following group: deuterium, hydroxyl, halogen, cyano, ester, amido, oxo, carbonyl, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1- C6 thioalkyl, C1-C6 alkoxy, C1-C6 heteroalkyl, C1-C6 alkylamino, C3-C6 cycloalkyl, C3-C8 cycloalkylamino, C6-C14 aryl or 5- 14-membered heteroaryl.
  • Y 3 is N.
  • B is a 5-6 membered heteroaryl group
  • H on B can be optionally substituted with one or more substituents selected from the following group: deuterium, hydroxyl, halogen, cyano, ester group , Amido, carbonyl, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 thioalkyl, C1-C6 alkoxy, C1-C6 heteroalkyl, C1-C6 alkylamino, C3 -C6 cycloalkyl, C3-C8 cycloalkylamino, C6-C14 aryl or 5-14 membered heteroaryl.
  • substituents selected from the following group: deuterium, hydroxyl, halogen, cyano, ester group , Amido, carbonyl, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 thioalkyl, C1-
  • the five-membered or six-membered heteroaryl group in Ar 2 is wherein, P 1 , P 2 , P 3 and P 4 are each independently selected from: N or CH, wherein 0, 1 , and 2 of P 1, P 2, P 3 and P 4 are N, L 1 , L 2 is each independently selected from: N or C.
  • Ar 2 is selected from:
  • the compound, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof has the formula (VII), formula (VIII) or formula (IX) Structure
  • A, Z 1 , D, R x , Q 2 , E, B, R 5 , and f are as defined above; Y 3 and Y 4 are each independently CH, N or CR a .
  • the compound, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof has a structure represented by formula (XI) or formula (XIII):
  • Y 4 , Y 5 each independently is CH, N or CR a ;
  • A, Z 1 , D, R x , Q 2 , E, B, R 5 , and f are as described above.
  • said B is selected from substituted or unsubstituted groups selected from the following group: C6-C10 aryl groups, 5-10 membered heteroaryl groups, and the substitution means that ground is selected from the group consisting of C6-C10 aryl groups and 5-10 membered heteroaryl groups. Substitution of one or more substituents of the group: deuterium, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, C3-C6 cycloalkyl, C3-C8 cycloalkylamino , C6-C14 aryl or 5-14 membered heteroaryl.
  • the compound, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof has a structure represented by formula (XIV):
  • h 0, 1 or 2;
  • G, B, Q2, R 5 and f are as described above.
  • Q2 is Wherein, l 1 and l 2 are each independently 0, 1, 2, 3, and l 1 + l 2 is an integer of 1-4;
  • y 0, 1, 2, 3;
  • G is selected from:
  • R 5 is selected from: C1-C3 alkoxy or Preferably, R 5 is selected from: methoxy,
  • Q2 is selected from:
  • B is a substituted or unsubstituted group from the following group: pyridyl, pyrimidinyl, and thiazolyl; wherein, the substitution refers to substitution by one or more substituents selected from the following group: deuterium , Hydroxy, halogen, cyano, ester, amide, carbonyl, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 thioalkyl, C1-C6 alkoxy, C1-C6 heteroalkane Group, C1-C6 alkylamino group, C3-C6 cycloalkyl group, C3-C8 cycloalkylamino group, C6-C14 aryl group or 5-14 membered heteroaryl group.
  • substituents selected from the following group: deuterium , Hydroxy, halogen, cyano, ester, amide, carbonyl, amino, C1-C6 alkyl, C1-
  • the compound, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof does not contain
  • G, K, Ar 1 , Ar 2 , Q2, E, B, R 5 , f, R x , A, Z 1 , X 1 , X 2 , X 3 , X 4 , Y 1 , Y 2 , Y 3 , Y 4 and Y 5 are the groups corresponding to the specific compounds in the examples.
  • the compound, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof is selected from the following group:
  • the compound is selected from the compounds shown in the examples.
  • the second aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound described in the first aspect, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof; and a pharmaceutically acceptable carrier .
  • the pharmaceutical composition further includes other cancer therapeutic agents.
  • the other cancer therapeutic agents include radioactive agents, cytotoxic agents, kinase inhibitors, immunotargeting inhibitors and angiogenesis inhibitors.
  • the pharmaceutical composition further includes:
  • PD-1 inhibitors such as nivolumab, pembrolizumab, JS-001, SHR-120, BGB-A317, IBI-308, GLS-010, GB-226, STW204, HX008, HLX10, BAT1306, AK105 , LZM 009 or biological analogues of the above drugs, etc.
  • PD-L1 inhibitors such as Devaluzumab, Atezolizumab, CS1001, KN035, HLX20, SHR-1316, BGB-A333, JS003, CS1003, KL-A167, F520, GR1405, MSB2311 or biological analogues of the above drugs, etc.
  • CD20 antibodies such as rituximab, obin utuzumab, ofatumumab, tositumomab, Titumomab, etc.
  • CD47 antibodies such as Hu5F9-G4, CC-90002, TTI-6
  • the third aspect of the present invention provides a compound according to the first aspect, its pharmaceutically acceptable salt, stereoisomer, solvate or prodrug, or the pharmaceutical composition according to the second aspect is prepared for inhibiting Use of RET kinase activity in a cell or subject in a medicine.
  • the compound described in the first aspect or the pharmaceutical composition described in the second aspect is used to prepare a medicine for the treatment of RET-related cancers.
  • the RET-related cancer is a cancer with the following characteristics: the expression or activity level of RET gene, RET kinase protein or any of the same proteins is disordered.
  • the RET-related cancer is selected from the group consisting of lung cancer, papillary thyroid cancer, medullary thyroid cancer, differentiated thyroid cancer, recurrent thyroid cancer, refractory differentiated thyroid cancer, multiple 2A or 2B Type endocrine tumors (MEN2A or MEN2B, respectively), pheochromocytoma, parathyroid hyperplasia, breast cancer, colorectal cancer, papillary renal cell carcinoma, gastrointestinal mucosal ganglion neuromatosis and cervical cancer.
  • MEN2A or MEN2B Type endocrine tumors
  • the drug is a drug for treating subjects who are resistant to cancer treatment.
  • the drug is a drug for treating a subject suffering from a condition mediated by abnormal RET activity.
  • the cell is a mammalian cell.
  • the subject is a mammal, preferably a human.
  • the fourth aspect of the present invention provides a method for inhibiting RET kinase activity in a cell or a subject, the method comprising contacting the cell or administering the compound of the first aspect to the subject Or the step of the pharmaceutical composition described in the second aspect.
  • the fifth aspect of the present invention provides a method of treating a subject suffering from a condition mediated by abnormal RET activity, the method comprising administering to the subject a therapeutically effective amount of the compound of the first aspect Or the pharmaceutical composition described in the second aspect.
  • the sixth aspect of the present invention provides a method of treating a subject who is resistant to cancer therapy, the method comprising administering to the subject a therapeutically effective amount of the compound of the first aspect or the second aspect The pharmaceutical composition.
  • C1-C6 alkyl refers to straight or branched chain alkyl, including from 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl N-butyl, tert-butyl, isobutyl (e.g. ), n-pentyl, isopentyl, n-hexyl, isohexyl.
  • Substituted alkyl means that one or more positions in the alkyl group are substituted, especially 1-4 substituents, which can be substituted at any position.
  • the "alkyl” in the present invention includes “substituted alkyl”.
  • heteroalkyl refers to a group in which a carbon atom in an alkyl group is substituted with an atom selected from, for example, oxygen, nitrogen, sulfur, phosphorus, or a combination thereof. Numerical ranges can be given, for example, C1-C6 heteroalkyl, which refers to the number of carbons in the chain, including 1 to 6 carbon atoms in this example. For example, the -CH 2 OCH 2 CH 3 group is referred to as "C 3 "heteroalkyl.
  • the connection to the rest of the molecule can be through a heteroatom or carbon in the heteroalkyl chain.
  • the term "3-7 membered ring” refers to a 3, 4, 5, 6, 7 membered ring, and the ring includes a saturated ring and an unsaturated ring.
  • the saturated ring includes a cycloalkyl, a heterocycloalkyl (containing 1-3 N, O, S heterocyclic atoms), cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl; heterocycloalkyl includes aziridinyl, azetidinyl , Azacyclopentyl, azacyclohexyl, oxanyl, oxetanyl, oxolan, oxanyl, etc.; unsaturated rings include cyclohexenyl, cyclohexadienyl , Cyclopentenyl, etc.
  • 5-membered aromatic group includes 5-membered heteroaryl groups, 6-membered heteroaryl groups, and phenyl groups.
  • the five-membered or six-membered heteroaryl group in Ar 1 can be Wait.
  • the five-membered or six-membered heteroaryl group in Ar 2 can be Wherein, P 1 , P 2 , P 3 and P 4 are each independently selected from: N or CH, wherein 0, 1 , and 2 of P 1, P 2, P 3 and P 4 are N, L 1 , L 2 is each independently selected from: N or C.
  • alkylene refers to a group formed by the removal of a hydrogen atom from the “alkyl” group, such as methylene, ethylene, propylene, isopropylene (such as ), butylene (e.g. ), pentylene (e.g. ), hexyl (e.g. ), Heptyl (e.g. )Wait.
  • cycloalkyl refers to a fully saturated cyclic hydrocarbon compound group
  • C3-C6 cycloalkyl and “C3-C12 cycloalkyl” refer to groups containing 3-6 and 3-12 carbon atoms, respectively .
  • Substituted cycloalkyl means that one or more positions in the cycloalkyl group are substituted, especially 1-4 substituents, which can be substituted at any position.
  • Typical substituents may be optionally substituted.
  • Typical substitutions also include spirocyclic, bridged or fused ring substituents, especially spirocyclic alkyl, spirocycloalkenyl, spirocyclic heterocycle (excluding heteroaromatic rings), bridged cycloalkyl, bridged cycloalkenyl, Bridged heterocyclic ring (excluding heteroaromatic ring), fused ring alkyl, fused ring alkenyl, fused ring heterocyclic group or fused ring aromatic ring group, the above-mentioned cycloalkyl, cycloalkenyl, heterocyclic group and heterocyclic aromatic The group can be optionally substituted.
  • heterocyclyl refers to a fully saturated or partially unsaturated cyclic group (including but not limited to, for example, 4-7 membered monocyclic ring, 7-11 membered spiro heterocyclic group, 7-8 membered bridged heterocyclic ring Group), in which at least one heteroatom is present in a ring with at least one carbon atom.
  • Each heterocyclic ring containing heteroatoms can have 1, 2, 3, or 4 heteroatoms. These heteroatoms are selected from nitrogen atoms, oxygen atoms or sulfur atoms.
  • the nitrogen atoms or sulfur atoms can be oxidized, and the nitrogen atoms can also be Is quaternized.
  • the heterocyclic group can be attached to any heteroatom or carbon atom residue of the ring or ring system molecule.
  • Typical monocyclic heterocycles include but are not limited to azetidinyl, pyrrolidinyl, oxetanyl, pyrazolinyl, imidazolinyl, imidazolidinyl, oxazolidinyl, isoxazolidine Group, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, hexahydroazepine Inyl group, 4-piperidinone group, tetrahydropyranyl group, morpholino group, thiomorpholino group, thiomorpholine sulfoxide group, thiomorpholine sulfone group, 1,3
  • Polycyclic heterocyclic groups include spiro, condensed and bridged heterocyclic groups; the spiro, condensed and bridged heterocyclic groups are optionally connected to other groups through a single bond, or through a ring Any two or more of the above atoms are further connected to other cycloalkyl groups, heterocyclic groups, aryl groups and heteroaryl groups; the heterocyclic group may be substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, Halogen, amino, nitro, hydroxy, mercapto, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylthio, oxo, carboxy, and carboxylate.
  • groups are independently selected from alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, Halogen, amino, nitro, hydroxy, mercapto, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylthio, oxo, carboxy, and carboxylate.
  • aryl refers to an aromatic cyclic hydrocarbon compound group
  • C6-C14 aryl refers to an aryl group containing 6-14 carbon atoms, especially monocyclic and bicyclic groups, such as phenyl and bicyclic groups. Phenyl or naphthyl. Where there are two or more aromatic rings (bicyclic, etc.), the aromatic ring of the aryl group can be connected by a single bond (such as biphenyl), or fused (such as naphthalene, anthracene, etc.).
  • Substituted aryl means that one or more positions in the aryl group are substituted, especially 1-3 substituents, which can be substituted at any position.
  • Typical substituents may be optionally substituted.
  • Typical substitutions also include fused ring substituents, especially fused ring alkyl, fused ring alkenyl, fused ring heterocyclic group or fused ring aromatic ring group, the above-mentioned cycloalkyl, cycloalkenyl, heterocyclic group and heterocyclic aromatic The group can be optionally substituted.
  • 5-14 membered heteroaryl refers to a heteroaromatic system containing 1-4 heteroatoms and 5-14 ring atoms, where the heteroatoms are selected from oxygen, nitrogen and sulfur.
  • the heteroaryl group is preferably a 5- to 10-membered ring, more preferably 5-membered or 6-membered, such as pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl , Furyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazole and tetrazolyl, etc.
  • Heteroaryl may be substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from alkyl, deuterated alkyl, haloalkyl, alkoxy , Haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, halogen, amino, nitro, hydroxyl, mercapto, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkane Sulfur group, oxo group, carboxyl group and carboxylate group.
  • C1-C6 alkoxy refers to a straight-chain or branched-chain or cyclic alkoxy group having 1 to 6 carbon atoms, and includes, without limitation, methoxy, ethoxy, propoxy, isopropyl Oxy and butoxy, etc. Preferably it is a C1-C3 alkoxy group.
  • Alkoxyalkyl refers to a group in which a hydrogen atom in an alkyl group is replaced by an alkoxy group, such as CH 3 OCH 2 -and CH 3 OCH 2 CH 2 -.
  • halogen refers to chlorine, bromine, fluorine, and iodine.
  • deuterated refers to substitution by deuterium.
  • hydroxyl refers to a group with the structure OH.
  • nitro refers to a group bearing the structure NO 2.
  • cyano refers to a group bearing the structure CN.
  • ester group refers to a group with the structure -COOR, where R represents hydrogen, C1-C6 alkyl or substituted C1-C6 alkyl, C3-C8 cycloalkyl or substituted C3-C8 cycloalkyl , C4-C10 cycloalkenyl or substituted C4-C10 cycloalkenyl, aryl or substituted C6-C14 aryl, 3-8 heterocyclic group or substituted heterocyclic group.
  • amino refers to a group with the structure -NRR', where R and R'can independently represent hydrogen, C1-C6 alkyl or substituted C1-C6 alkyl, C3-C8 cycloalkyl (preferably C3-C6 cycloalkyl) or substituted C3-C8 cycloalkyl (preferably C3-C6 cycloalkyl), C4-C10 cycloalkenyl or substituted C4-C10 cycloalkenyl, aryl or substituted C6-C14 Aryl, 3-8 heterocyclic group or substituted heterocyclic group.
  • R and R' may be the same or different in the dialkylamine segment.
  • "C1-C6 alkylamino group” and "C3-C8 cycloalkylamino group” are C1-C6 alkyl NH- and C3-C8 cycloalkyl NH-, respectively.
  • amide group refers to a group with the structure -CONRR', where R and R'can independently represent hydrogen, C1-C6 alkyl or substituted C1-C6 alkyl, C3-C8 cycloalkyl or substituted C3-C8 cycloalkyl, C4-C10 cycloalkenyl or substituted C4-C10 cycloalkenyl, aryl or substituted C6-C14 aryl, 3-8 heterocyclic group or substituted heterocyclic group.
  • R and R' may be the same or different in the dialkylamine segment.
  • sulfonamido refers to a group with the structure -SO 2 NRR', where R and R'can independently represent hydrogen, C1-C6 alkyl or substituted C1-C6 alkyl, C3-C8 cycloalkane Group or substituted C3-C8 cycloalkyl, C4-C10 cycloalkenyl or substituted C4-C10 cycloalkenyl, aryl or substituted C6-C14 aryl, 3-8 heterocyclic group or substituted heterocyclic group .
  • R and R' may be the same or different in the dialkylamine segment.
  • C6-C14 aryl C1-C6 alkyl group refers to a group in which the hydrogen atom in the C1-C6 alkyl group is replaced by a C6-C14 aryl group, such as benzyl, phenethyl and the like.
  • substituted means that one or more hydrogen atoms on a specific group are replaced by a specific substituent.
  • the specific substituents are the substituents correspondingly described in the foregoing, or the substituents appearing in each embodiment.
  • a substituted group may have a substituent selected from a specific group at any substitutable position of the group, and the substituent may be the same or different in each position.
  • the groups for example: alkyl, alkylene, cycloalkyl, heteroalkyl, heterocyclyl, aryl, heteroaryl, etc.
  • substituents contemplated by the present invention are those that are stable or chemically achievable.
  • the substituents such as (but not limited to): halogen, hydroxyl, cyano, carboxy (-COOH), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 12-membered heterocyclic groups, aryl groups, heteroaryl groups, C1-C8 aldehyde groups, C2-C10 acyl groups, C2-C10 ester groups, amino groups, C1-C6 alkoxy groups, C1-C10 sulfonyl groups, and C1-C6 ureido and so on.
  • multiple generally refers to two or more.
  • a substituent is a non-terminal substituent, it is a subunit of the corresponding group, for example, an alkyl group corresponds to an alkylene group, a cycloalkyl group corresponds to a cycloalkylene group, a heterocyclic group corresponds to a heterocyclylene group, and an alkoxy group corresponds to Alkyleneoxy and so on.
  • the compound of the present invention refers to the compound represented by formula I, and also includes stereoisomers or optical isomers, pharmaceutically acceptable salts, prodrugs or solvates of the compound of formula F.
  • the compound of formula F has the following structure:
  • G, K, Ar 1 , Ar 2 , Q 2 , B, E, R 5 , and f are as defined above.
  • Ar 1 is a substituted or unsubstituted group from the following group: wherein, the substitution refers to substitution by one or more groups selected from the following group: H, CN, halogen, methyl, ethyl or cyclopropyl;
  • Q 2 is a saturated 5-6 membered monocyclic heterocyclic group, wherein the heterocyclic group contains one or two nitrogen ring heteroatoms, and the H on Q 2 can be optionally selected from one or Multiple substituent substitutions: deuterium, hydroxyl, halogen, cyano, ester, amide, oxo, carbonyl, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 thioalkyl, C1 -C6 alkoxy, C1-C6 heteroalkyl, C1-C6 alkylamino, C3-C6 cycloalkyl, C3-C8 cycloalkylamino, C6-C14 aryl or 5-14 membered heteroaryl;
  • B is a 5-6 membered heteroaryl group, and H on B can be optionally substituted with one or more substituents selected from the following group: deuterium, hydroxyl, halogen, cyano, ester, amido, carbonyl, amino , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 thioalkyl, C1-C6 alkoxy, C1-C6 heteroalkyl, C1-C6 alkylamino, C3-C6 cycloalkyl, C3 -C8 cycloalkylamino, C6-C14 aryl or 5-14 membered heteroaryl;
  • E is hydrogen or a substituted or unsubstituted C1-C6 alkyl, wherein said substituents means substituted with 0-5 R a, R a is as defined above.
  • Q2 is Wherein, l 1 and l 2 are each independently 0, 1, 2, 3, and l 1 + l 2 is an integer of 1-4;
  • y 0, 1, 2, 3;
  • Ar 1 is the following group of substituted or unsubstituted groups: Wherein, the substitution refers to substitution by one or more groups selected from the following group: H, CN, halogen, methyl, ethyl or cyclopropyl;
  • Ar 2 is selected from:
  • G is selected from:
  • R 5 is selected from: C1-C3 alkoxy or Preferably, R 5 is selected from: methoxy,
  • Q2 is selected from:
  • B is a substituted or unsubstituted group from the following group: pyridyl, pyrimidinyl, and thiazolyl; wherein, the substitution refers to substitution by one or more substituents selected from the group: deuterium, hydroxyl, halogen, cyano , Ester group, amide group, carbonyl group, amino group, C1-C6 alkyl group, C1-C6 haloalkyl group, C1-C6 thioalkyl group, C1-C6 alkoxy group, C1-C6 heteroalkyl group, C1-C6 alkyl group Amino, C3-C6 cycloalkyl, C3-C8 cycloalkylamino, C6-C14 aryl or 5-14 membered heteroaryl;
  • salts that may be formed by the compounds of the present invention also belong to the scope of the present invention. Unless otherwise specified, the compounds in the present invention are understood to include their salts.
  • the term "salt” as used herein refers to a salt formed into an acid or basic form with an inorganic or organic acid and a base.
  • the compound of the present invention contains a basic fragment, it includes but is not limited to pyridine or imidazole, and when it contains an acidic fragment, including but not limited to carboxylic acid, the zwitterion (“internal salt") that may be formed is contained in Within the scope of the term "salt”.
  • compositions are preferred, although other salts are also useful, for example, for separation or purification steps in the preparation process.
  • the compound of the present invention may form a salt.
  • the formula F can be obtained by reacting with a certain amount of acid or base, such as an equivalent amount of acid or base, and salting out in the medium, or by freeze-drying in an aqueous solution.
  • the basic fragments contained in the compounds of the present invention may form salts with organic or inorganic acids.
  • Typical acids that can form salts include acetate (such as acetic acid or trihaloacetic acid, such as trifluoroacetic acid), adipate, alginate, ascorbate, aspartate, and benzoate.
  • Benzene sulfonate hydrogen sulfate, borate, butyrate, citrate, camphor salt, camphor sulfonate, cyclopentane propionate, diglycolate, dodecyl sulfate, Ethane sulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, caproate, hydrochloride, hydrobromide, hydroiodide, isethionate (E.g. 2-hydroxyethanesulfonate), lactate, maleate, methanesulfonate, naphthalenesulfonate (e.g.
  • 2-naphthalenesulfonate nicotinate, nitrate, oxalic acid Salt, pectinate, persulfate, phenylpropionate (such as 3-phenylpropionate), phosphate, picrate, pivalate, propionate, salicylate, succinate, Sulfate (such as formed with sulfuric acid), sulfonate, tartrate, thiocyanate, toluenesulfonate such as p-toluenesulfonate, dodecanoate, etc.
  • the acidic fragments that some compounds of the present invention may contain, including but not limited to carboxylic acids, may form salts with various organic or inorganic bases.
  • Typical salts formed by bases include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, and salts formed by organic bases (such as organic amines) such as benzathine and bicyclohexyl.
  • Hypamine a salt formed with N,N-bis(dehydroabietyl)ethylenediamine
  • N-methyl-D-glucamine N-methyl-D-glucamide
  • tert-butyl Base amines and salts with amino acids such as arginine, lysine, etc.
  • Basic nitrogen-containing groups can be combined with halide quaternary ammonium salts, such as small molecular alkyl halides (such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides), dialkyl sulfates (Eg, dimethyl sulfate, diethyl, dibutyl and dipentyl sulfate), long-chain halides (such as chlorides and bromides of decyl, dodecyl, tetradecyl and tetradecyl And iodides), aralkyl halides (such as benzyl and phenyl bromides) and so on.
  • small molecular alkyl halides such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides
  • dialkyl sulfates Eg, dimethyl sulfate, diethyl, dibuty
  • prodrugs and solvates of the compounds of the present invention are also covered.
  • prodrug herein refers to a compound that undergoes metabolic or chemical transformation to produce the compound, salt, or solvate of the present invention when treating related diseases.
  • the compounds of the present invention include solvates, such as hydrates.
  • the compounds, salts or solvates of the present invention may exist in tautomeric forms (such as amides and imine ethers). All these tautomers are part of the invention.
  • All stereoisomers of compounds (for example, those asymmetric carbon atoms that may exist due to various substitutions), including their enantiomeric and diastereomeric forms, fall within the scope of the present invention.
  • the independent stereoisomers of the compound in the present invention may not coexist with other isomers (for example, as a pure or substantially pure optical isomer with special activity), or may be a mixture, such as Racemates, or mixtures with all other stereoisomers or part of them.
  • the chiral center of the present invention has two configurations, S or R, defined by the International Union of Theoretical and Applied Chemistry (IUPAC) in 1974.
  • racemic form can be resolved by physical methods, such as fractional crystallization, or separation of crystallization by derivatization into diastereomers, or separation by chiral column chromatography.
  • Individual optical isomers can be obtained from racemates by suitable methods, including but not limited to traditional methods, such as salt formation with an optically active acid and then recrystallization.
  • the weight content of the compound obtained by successive preparation, separation and purification is equal to or greater than 90%, for example, equal to or greater than 95%, equal to or greater than 99% ("very pure" compound), as described in the text Listed.
  • very pure compounds of the invention are also part of the invention.
  • All configuration isomers of the compounds of the present invention are within the scope of coverage, whether in mixture, pure or very pure form.
  • the definition of the compound of the present invention includes two olefin isomers, cis (Z) and trans (E), as well as cis and trans isomers of carbocyclic and heterocyclic rings.
  • Certain compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • the present invention covers all compounds, including their cis and trans isomers, R and S enantiomers, diastereomers, (D) isomers, (L) isomers, and exogenous Spin mixtures and other mixtures.
  • the asymmetric carbon atom may represent a substituent, such as an alkyl group. All isomers and their mixtures are included in the present invention.
  • the ratio of the mixture of isomers containing the isomers can be varied.
  • a mixture of only two isomers can have the following combinations: 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98: 2,99:1, or 100:0, all ratios of isomers are within the scope of the present invention. Similar ratios, which are easily understood by those skilled in the art, and ratios that are mixtures of more complex isomers are also within the scope of the present invention.
  • the present invention also includes isotopically labeled compounds, which are equivalent to the original compounds disclosed herein. In practice, however, it usually occurs when one or more atoms are replaced by atoms whose atomic weight or mass number is different.
  • isotopes that can be classified as compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine isotopes, such as 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, and 18 O, respectively. , 17 O, 31 P, 32 P, 35 S, 18 F and 36 Cl.
  • the compounds of the present invention or enantiomers, diastereomers, isomers, or pharmaceutically acceptable salts or solvates, which contain isotopes or other isotopic atoms of the above compounds are all within the scope of the present invention.
  • Certain isotope-labeled compounds of the present invention such as radioisotopes of 3 H and 14 C, are also among them, which are useful in tissue distribution experiments of drugs and substrates.
  • Isotopically-labeled compounds can be prepared by general methods by replacing readily available isotope-labeled reagents with non-isotopic reagents, using the protocol disclosed in the example.
  • a specific enantiomer of the compound of the present invention can be prepared by asymmetric synthesis, or derivatized with a chiral adjuvant, separating the resulting diastereomeric mixture, and then removing the chiral adjuvant. Pure enantiomer.
  • a suitable optically active acid or base can be used to form a diastereomeric salt with it, and then through separation crystallization or chromatography, etc. After separation by conventional means, the pure enantiomers are obtained.
  • the compounds of the present invention can be combined with any number of substituents or functional groups to expand their scope of inclusion.
  • substituents or functional groups can be combined with any number of substituents or functional groups to expand their scope of inclusion.
  • the general formula including substituents in the formula of the present invention means that the substituents of the specified structure are substituted for hydrogen radicals.
  • each position of the substituents may be the same or different.
  • substitution as used herein includes all permissible substitution of organic compounds.
  • the permissible substituents include acyclic, cyclic, branched unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic organic compounds.
  • the heteroatom nitrogen may have a hydrogen substituent or any permitted organic compound as described above to supplement its valence.
  • the present invention is not intended to limit the permitted substitution of organic compounds in any way.
  • the present invention believes that the combination of substituents and variable groups is good in the treatment of diseases in the form of stable compounds, such as infectious diseases or proliferative diseases.
  • stable here refers to a compound that is stable and can be tested for a long enough time to maintain the structural integrity of the compound, preferably for a long enough time to be effective, and is used herein for the above purpose.
  • compound of the present invention refers to a compound represented by formula F.
  • the term also includes its pharmaceutically acceptable salts, stereoisomers, solvates or prodrugs.
  • the term "pharmaceutically acceptable salt” refers to a salt formed by the compound of the present invention and an acid or a base suitable for use as a medicine.
  • Pharmaceutically acceptable salts include inorganic salts and organic salts.
  • a preferred class of salts are the salts of the compounds of this invention with acids.
  • Acids suitable for salt formation include, but are not limited to: hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid and other inorganic acids; formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, Fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid and other organic acids; and Amino acids such as amino acid, phenylalanine, aspartic acid and glutamic acid.
  • a base such as alkali metal salt (such as sodium or potassium salt), alkaline earth metal salt (such as magnesium salt or calcium salt), ammonium salt (such as lower alkanolammonium Salt and other pharmaceutically acceptable amine salts), such as methylamine salt, ethylamine salt, propylamine salt, dimethylamine salt, trimethylamine salt, diethylamine salt, triethylamine salt, tert-butyl Base amine salt, ethylenediamine salt, hydroxyethylamine salt, dihydroxyethylamine salt, trihydroxyethylamine salt, and amine salts formed from morpholine, piperazine, and lysine, respectively.
  • alkali metal salt such as sodium or potassium salt
  • alkaline earth metal salt such as magnesium salt or calcium salt
  • ammonium salt such as lower alkanolammonium Salt and other pharmaceutically acceptable amine salts
  • methylamine salt such as sodium or potassium salt
  • alkaline earth metal salt such as magnesium salt or
  • solvate refers to a complex in which the compound of the present invention coordinates with solvent molecules to form a specific ratio.
  • “Hydrate” refers to a complex formed by coordination of the compound of the present invention with water.
  • the prodrugs include (but are not limited to) carboxylic acid esters, carbonate esters, phosphate esters, nitrate esters, sulfate esters, sulfone esters, sulfoxide esters, amino compounds, carbamates, and azo compounds of the compound , Phosphoramide, glucoside, ether, acetal and other forms.
  • the compounds of the present invention can be conveniently prepared by combining various synthetic methods described in this specification or known in the art, and such combinations can be easily performed by those skilled in the art to which the present invention belongs.
  • the compound of the present invention is carried out according to the following steps:
  • X and X' are each independently halogen, OTf or
  • G, K, Ar 1 , Ar 2 , Q2, E, B, R 5 and f are as described above.
  • the pharmaceutical composition of the present invention is used to prevent and/or treat the following diseases: inflammation, cancer, cardiovascular disease, infection, immune disease, and metabolic disease.
  • the compounds of the present invention can be used in combination with other drugs known to treat or improve similar conditions.
  • the mode and dosage of the original drug can be kept unchanged, while the compound of the present invention is administered at the same time or subsequently.
  • a pharmaceutical composition containing one or more known drugs and the compound of the present invention can be preferably used.
  • Drug combination also includes taking the compound of the present invention and one or more other known drugs in overlapping time periods.
  • the dose of the compound of the present invention or a known drug may be lower than the dose of the compound used alone.
  • the dosage form of the pharmaceutical composition of the present invention includes (but is not limited to): injection, tablet, capsule, aerosol, suppository, film, dripping pill, external liniment, controlled release or sustained release or nano preparation.
  • the pharmaceutical composition of the present invention contains a safe and effective amount of the compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier.
  • the "safe and effective amount” refers to: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per agent, and more preferably, contains 10-1000 mg of the compound of the present invention per agent.
  • the "one dose" is a capsule or tablet.
  • “Pharmaceutically acceptable carrier” refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use, and must have sufficient purity and sufficiently low toxicity. "Compatibility” here means that the components in the composition can be blended with the compound of the present invention and between them without significantly reducing the efficacy of the compound.
  • pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, and solid lubricants (such as stearic acid).
  • Magnesium stearate calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
  • vegetable oils such as soybean oil, sesame oil, peanut oil, olive oil, etc.
  • polyols such as propylene glycol, glycerin, mannitol, sorbitol, etc.
  • emulsifiers such as emulsifiers
  • wetting agents such as sodium lauryl sulfate
  • the method of administration of the compound or pharmaceutical composition of the present invention is not particularly limited.
  • Representative administration methods include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular, or subcutaneous), and topical administration .
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or mixed with the following ingredients: (a) fillers or compatibilizers, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) humectants, For example, glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) Absorption accelerators, such as quaternary amine compounds; (g) wetting agents, such as cetyl alcohol and glycty
  • Solid dosage forms such as tablets, sugar pills, capsules, pills and granules can be prepared with coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the active compound or the release of the compound in such a composition may be released in a certain part of the digestive tract in a delayed manner. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active compound can also be formed into microcapsules with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • the liquid dosage form may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-Butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.
  • composition may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.
  • the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
  • suspending agents for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
  • composition for parenteral injection may contain physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
  • the dosage form of the compound of the present invention for topical administration includes ointment, powder, patch, propellant and inhalant.
  • the active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required if necessary.
  • the treatment method of the present invention can be administered alone or in combination with other treatment means or therapeutic drugs.
  • a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment.
  • the dose administered is usually 1-2000 mg, preferably 50-1000 mg.
  • the specific dosage should also consider factors such as the route of administration and the patient's health status, which are all within the skill range of a skilled physician.
  • the present invention also provides a method for preparing a pharmaceutical composition, which comprises the steps of: subjecting a pharmaceutically acceptable carrier to the compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof. Mix to form a pharmaceutical composition.
  • the present invention also provides a treatment method, which comprises the steps of: administering the compound described in the present invention, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, or administering the compound described in the present invention to a subject in need of treatment.
  • the pharmaceutical composition of the invention is used to selectively inhibit RET.
  • the compounds of the present invention have good inhibitory ability on RET kinase
  • the compound has better pharmacodynamics, pharmacokinetic properties and lower toxic and side effects;
  • the structure of the compound of the present invention is determined by nuclear magnetic resonance (NMR) and liquid mass spectrometry (LC-MS).
  • the synthetic route is as follows:
  • the synthetic route is as follows:
  • the synthetic route is as follows:
  • the synthetic route is as follows:
  • the synthetic route is as follows:
  • the synthetic route is as follows:
  • the synthetic route is as follows:
  • the synthetic route is as follows:
  • the biological activity test of the compound of the present invention is carried out below.
  • the biological activity test experiment process is as follows:
  • Each sample was prepared into a solution with a concentration of 10 mM.
  • test compound was dissolved to a specific concentration in 100% dimethyl sulfoxide. Use Integra Viaflo Assist to assist DMSO for (serial) dilution.
  • Kinase activity data is expressed as the percentage of kinase activity remaining in the test sample compared to the vehicle (dimethyl sulfoxide) reaction.
  • Prism GRAPHPAD software was used to obtain IC50 values and curve fitting.
  • Table 1 shows the IC50 (nM) value of the obtained test sample's inhibitory activity against wild-type RET.

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Abstract

涉及用作RET激酶抑制剂的化合物及其应用，其具有式F所示结构，所述化合物对RET激酶均有很好的抑制能力，且具有较好的药效学、药代动力学性能和更低的毒副作用。

Description

用作RET激酶抑制剂的化合物及其应用 技术领域
本发明涉及医药技术领域，具体涉及用作RET激酶抑制剂的化合物，及其在调节RET激酶活性或治疗RET相关疾病方面的应用。
背景技术
RET(Rearranged during transfection，转染期间重排)基因位于10号染色体，它所编码的RET蛋白是一种存在于细胞膜上的受体酪氨酸激酶(RTK)，其变异类型主要包括与KIF5B、TRIM33、CCDC6和NCOA4等基因的融合突变，以及M918T等位点的点突变。RET是一种受体酪氨酸激酶，与细胞增殖、迁移、分化及神经嵴细胞的生存、肾脏器官的形成、精子发生等过程的信号转导有关。其异常表达、突变和重组与多种癌症的发生发展密切相关，如乳突状甲状腺癌、多发性内分泌腺瘤病2型、髓样甲状腺癌、嗜铬细胞瘤和甲状腺旁腺瘤等；在肺癌方面，RET基因的异常重组KIF5B-RET和CCDC6-RET与约1-2％的肺腺癌相关，其中KIF5B-RET更是占到了其中70-90％的比例，CCDC6-RET约占10-25％；目前对于RET基因改变的治疗方案主要是使用多激酶抑制剂类药物，比如卡博替尼、凡德他尼，由于靶向性不高，通常会发生脱靶导致的VEGFR抑制相关的严重毒性。
蓝图药品公司(Blueprint)和莱德克斯制药公共有限公司(Loxo Oncology)公布了其开发的高效且具有选择性的口服RET抑制剂BLU-667和LOXO-292。Blueprint I期临床数据结果显示BLU-667表现出广泛的抗肿瘤活性，在具有RET融合和突变的肿瘤患者中总体缓解率(ORR)为45％，其中非小细胞肺癌和甲状腺髓样癌患者的ORR分别为50％和40％。最近美国FDA授予Loxo Oncology公司的在研药物LOXO-292突破性疗法认定，用于治疗携带RET基因变异的非小细胞肺癌(NSCLC)和甲状腺髓样癌(MTC)患者。
无论是BLU-667还是LOXO-292，目前还均处于临床试验阶段。因此，开发新的具有RET激酶抑制活性的、具有更好药效学、药代动力学性能的化合物已成为开发新型抗肿瘤药物的重要研究项目，并最终用于人类肿瘤等疾病的治疗中。
发明内容
本发明的目的是提供一类新型的具有RET激酶抑制活性和/或具有更好药效学/药代动力学性能的化合物及其用途。
本发明的第一方面，提供一种式F化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药，
Figure PCTCN2020139655-appb-000001
其中，
G选自：A-Z 1-或D；
Ar 1为含1～4个N原子的取代或未取代5-6元杂芳基，其中，所述取代是指被选自下组的一个或多个基团取代：H、CN、卤素、甲基、乙基或环丙基；
Ar 2选自取代或未取代的下组基团：5-6元芳基或5-6元杂芳基，其中，所述取代是指被选自下组的一个或多个基团取代：C1-C6烷基、卤素、羟基、氧代基(＝O)、C1-C6杂烷基、C1-C6烷氧基、C3-C14环烷基、3-14元杂环烷基或氰基；
K选自：C或N；
Q 2选自下组：饱和4-7元单环杂环基、饱和7-8元桥连杂环基、饱和7-11元螺杂环基、
Figure PCTCN2020139655-appb-000002
其中，所述杂环基中含有1、2或3个作为环骨架的氮杂原子，m、n、m’和n’各自独立地为0、1、2、3；
且Q 2上的H可以任选地被选自下组的一个或多个取代基取代：氘、羟基、卤素、氰基、酯基、酰胺基、羰基、氧代基(＝O)、氨基、C1-C6烷基、C1-C6卤代烷基、C1-C6硫代烷基、C1-C6烷氧基、C1-C6杂烷基、C1-C6烷胺基、C3-C6环烷基、C3-C8环烷胺基、C6-C14芳基或5-14元杂芳基；R 3为取代或未取代5-6元杂芳基、C1-C6烷基或C1-C6杂烷基，其可任选地被一个或多个C1-C6烷基取代；
B独立地选自取代或未取代下组基团：3-7元环、C6-C14芳基、5-14元杂芳基、7-20元螺环或桥环，且所述环含有0-3个选自N、O、S的杂原子；所述取代是指被选自下组的一个或多个取代基取代：氘、羟基、卤素、氰基、酯基、酰胺基、羰基、氨基、C1-C6烷基、C1-C6卤代烷基、C1-C6硫代烷基、C1-C6烷氧基、C1-C6杂烷基、C1-C6烷基胺基、C3-C6环烷基、C3-C8环烷基胺基、C6-C14芳基或5-14元杂芳基；
E独立地选自取代或未取代下组基团：氢、C1-C6烷基、C1-C6烷氧基、C3-C6环烷基、C1-C6杂烷基、3-6元杂环基，其中，所述取代是指被0-5个R a取代；
各R 5独立地选自取代或未取代下组基团：氢、硝基、氰基、卤素、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6烷氧基、C1-C6杂烷基、C3-C12环烷基、C6-C14芳基、5-14元杂芳基、C6-C14芳氧基、C6-C14芳基C1-C6烷基、3-12元杂环基、3-12元杂环烷基、-C(O)R 6、 -OC(O)R 6、-C(O)OR 6、-(C1-C6亚烷基)-C(O)R 6、-SR 6、-S(O) 2R 6、-S(O) 2-N(R 6)(R 7)、-(C1-C6亚烷基)-S(O) 2R 6、-(C1-C6亚烷基)-S(O) 2-N(R 6)(R 7)、-N(R 6)(R 7)、-C(O)-N(R 6)(R 7)、-N(R 6)-C(O)R 7、-N(R 6)-C(O)OR 7、-(C1-C6亚烷基)-N(R 6)-C(O)R 7、-N(R 6)S(O) 2R 7和-P(O)(R 6)(R 7)；其中，所述取代是指被0、1、2、3、4或5个R a取代；R 6和R 7各自独立地选自下组：C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6烷氧基、C1-C6杂烷基、C3-C6环烷基、C6-C14芳基、5-14元杂芳基、C6-C14芳氧基、C6-C14芳基C1-C6烷基、C3-C6杂环烷基、C1-C6烷胺基、C3-C6环烷基胺基；或R 6和R 7与其相邻的N原子一起构成取代或未取代3-6元杂环基；其中，所述取代是指被0、1、2、3、4或5个R a取代；
A独立地选自下组：H、取代或未取代C1-C6烷基、取代或未取代4-6元杂环基、(R 1R 2N)C(＝O)-；其中，所述取代选自下组的一个或多个基团：卤素、-OH、C1～C6烷氧基、C1～C6烷基、胺基、5-6元杂芳基、4-6元杂环基、C3-C6环烷基、酰胺基、(R 1R 2N)C(＝O)-、羟基C1-C6烷基、(C1-C6烷基)C(＝O)-、C1-C6烷氧基、氧代基和(C1-C6烷氧基)C(＝O)-；R 1和R 2各自独立的选自：H或C1-C6烷基，其中，烷基可任选地被1-3个氟取代；
Z 1选自下组：NR b、-S-、-C(R bR c)-或-O-；
D为5-14元杂芳基，其中，所述杂芳基上的H任选地被一个或多个选自下组的取代基取代：氘、羟基、卤素、氰基、酯基、酰胺基、氧代基、氨基、C1-C6烷基、C1-C6烷氧基、C1-C6杂烷基、C3-C6环烷基、C3-C8环烷基胺基、C6-C14芳基或5-14元杂芳基；所述C1-C6烷基、C1-C6烷氧基、C1-C6杂烷基、C3-C6环烷基、C3-C8环烷基胺基、C6-C14芳基或5-14元杂芳基可进一步被一个或多个选自下组的基团取代：卤素、氰基、羟基；
f为0、1、2、3、4、5或6；
R a独立地选自下组：O、C1-C6烷基、卤素、羟基、C1-C6杂烷基、C1-C6烷氧基、C3-C14环烷基、3-14元杂环烷基或氰基。
R b、R c独立地选自下组：H、C1-C6烷基、卤素、羟基、C1-C6杂烷基、C1-C6烷氧基、C3-C14环烷基、3-14元杂环烷基或氰基；
限定条件为：
当
Figure PCTCN2020139655-appb-000003
为
Figure PCTCN2020139655-appb-000004
时，Ar 2为5-6元杂芳基，且Ar 2通过N与Q 2环和/或
Figure PCTCN2020139655-appb-000005
连接；其中，R x选自下组：H、CN、卤素、甲基、乙基或环丙基；Ar 2上的H原子可以被CR a取代。
在另一优选例中，
Figure PCTCN2020139655-appb-000006
选自
Figure PCTCN2020139655-appb-000007
其中，R x选自 下组：H、CN、卤素、甲基、乙基或环丙基：Y 3、Y 4、Y 5为N或CR a，R a的定义如上所述。
在另一优选例中，
Figure PCTCN2020139655-appb-000008
选自
Figure PCTCN2020139655-appb-000009
其中，R x选自下组：H、CN、卤素、甲基、乙基或环丙基；Y 3、Y 4、Y 5为CH、N或CR a，R a的定义如上所述。
在另一优选例中，Ar 2选自
Figure PCTCN2020139655-appb-000010
其中，
Figure PCTCN2020139655-appb-000011
为六元杂芳基；
Figure PCTCN2020139655-appb-000012
为五元杂芳基；X 1、X 2、X 3和X 4各自独立地为CH、N或CR a，且X 1、X 2、X 3和X 4中有0、1、2个为N；Y' 1为N；Y 1为C或N；Y 2为N或C。
在另一优选例中，Ar 2选自
Figure PCTCN2020139655-appb-000013
其中，Y 1、Y 2为CR a或N，X 1、X 2、X 3和X 4各自独立的选自CR a或N，且X 1、X 2、X 3和X 4有0、1、2个为N；R a独立地选自下组：O、C1-C6烷基、卤素、羟基、C1-C6杂烷基、C1-C6烷氧基、C3-C14环烷基、3-14元杂环烷基或氰基。
在另一优选例中，Ar 2选自
Figure PCTCN2020139655-appb-000014
其中，Y' 1为N，Y 2为CR a或N；X 1、X 2、X 3各自独立的选自CH、CR a或N，且X 1、X 2和X 3有0、1、2个为N；R a独立地选自下组：O、C1-C6烷基、卤素、羟基、C1-C6杂烷基、C1-C6烷氧基、C3-C14环烷基、3-14元杂环烷基或氰基。
在另一优选例中，所述化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药，其具有式(F-Ⅰ)、式(F-Ⅱ)、式(F-Ⅲ)所示结构，
Figure PCTCN2020139655-appb-000015
X 1、X 2、X 3和X 4各自独立地选自：N或CR a，且X 1、X 2、X 3和X 4中有0、1、2个为N；Y 1、Y 3、Y 5各自独立地选自：N或CR a，Y 2、Y 4各自独立地为N或C；
R x独立地选自下组：H、CN、卤素、甲基、乙基或环丙基；
G、Q 2、E、B、R 5、f、R a的定义如上所述。
限定条件：在式F-Ⅰ中，当Y 3为N时，Y 4为C时，Y 1和/或Y 2为N。
在另一优选例中，所述的化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药，其具有式(Ⅰ)、式(Ⅱ)、式(Ⅲ)、式(Ⅳ)、式(V)或式(VI)所示结构，
Figure PCTCN2020139655-appb-000016
其中：
Figure PCTCN2020139655-appb-000017
为六元杂芳基；
Figure PCTCN2020139655-appb-000018
为五元杂芳基；
X 1、X 2、X 3和X 4各自独立地为CH、N或CR a，且X 1、X 2、X 3和X 4中有0、1、2个为N；
Y' 1为N；
Y 1为C或N；
Y 3、Y 5各自独立地为CH、N或CR a；Y 2为N或C；
Y 4为CH、N或CR a；
R x独立地选自下组：H、CN、卤素、甲基、乙基或环丙基；
E、R 5、f、A、Z 1、D、Q 2、B、R a的定义如上所述；
限定条件为：在式Ⅰ和式Ⅲ中，当Y 3为N时，Y 4为CH或N时，Y 1和/或Y 2为N。
在另一优选例中，所述的化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药，其特征在于，Ar 1为取代或未取代的下组基团：
Figure PCTCN2020139655-appb-000019
Figure PCTCN2020139655-appb-000020
其中，所述取代是指被选自下组的一个或多个基团取代；H、CN、卤素、甲基、乙基或环丙基。
在另一优选例中，A独立地选自下组：
a)H；
b)C1-C6烷基，其可任选地被1～3个选自下组的基团取代：F、OH、R 3、R 4、C3-C6环烷基、(R 1R 2N)C(＝O)-、R 1R 2N-；其中，C3-C6环烷基可任选地进一步被OH取代；
c)R 4；或
d)(R 1R 2N)C(＝O)-；
R 1和R 2各自独立的选自：H或C1-C6烷基，其中，烷基可任选地被1-3个氟取代；
R 3为取代或未取代5-6元杂芳基，其具有1-3个选自N、O和S环杂原子，并且所述取代是指被一个或多个C1-C6烷基取代；
R 4为4-6元杂环基，所述杂环基具有1-2个独立地选自N和O的环杂原子，且可任选地被一个或多个独立地选自下组的取代基取代：OH、C1-C6烷基(任选被1-3个氟取代)、羟基C1-C6烷基、卤素、(C1-C6烷基)C(＝O)-、C1-C6烷氧基、氧代基或(C1-C6烷氧基)C(＝O)-。
在另一优选例中，A为C2-C6烷基，其可任选地被选自下组的一个或多个基团取代：-OH、F或C3～C6环烷基。
在另一优选例中，A为-C1-C3烷基，其可任选地被选自下组的一个或多个基团取代：C3-C6环烷基、C1-C6烷氧基、R 4；其中，C1-C6烷氧基可进一步被1～3个F取代；R 4为4-6元杂环基，所述杂环基具有1-2个独立地选自N和O的环杂原子，且可任选地被一个或多个独立地选自下组的取代基取代：OH、C1-C6烷基(任选被1-3个氟取代)、羟基C1-C6烷基、卤素、(C1-C6烷基)C(＝O)-、C1-C6烷氧基、氧代基或(C1-C6烷氧基)C(＝O)-。
在另一优选例中，A为二羟基C3-C6烷基，其可任选地被C3-C6环烷基。
在另一优选例中，X 1为N。
在另一优选例中，Z 1为O。
在另一优选例中，Y 4为N。
在另一优选例中，Y 5为C。
在另一优选例中，X 1为N，X 2、X 3、X 4为C。
在另一优选例中，E为氢或取代或未取代C1-C6烷基，其中，所述取代是指被0-5个R a取代，R a的定义如上所述。
在另一优选例中，A为取代或未取代C2-C6烷基-OH，其中，所述取代是指被选自下组的一个或多个基团取代：氟或C3-C6环烷基。
在另一优选例中，Q 2为饱和4-7元单环杂环基，其中，所述杂环基中含有一个或两个氮环杂原子，且Q 2上的H可以任选地被选自下组的一个或多个取代基取代：氘、羟基、 卤素、氰基、酯基、酰胺基、羰基、氧代基(＝O)、氨基、C1-C6烷基、C1-C6卤代烷基、C1-C6硫代烷基、C1-C6烷氧基、C1-C6杂烷基、C1-C6烷胺基、C3-C6环烷基、C3-C8环烷胺基、C6-C14芳基或5-14元杂芳基；优选地Q2环为5-6元单环含氮杂环。
在另一优选例中，Q 2为饱和7-8元桥杂环基，其中，所述杂环基中含有一个或两个氮环杂原子，且Q 2上的H可以任选地被选自下组的一个或多个取代基取代：氘、羟基、卤素、氰基、酯基、酰胺基、羰基、氧代基(＝O)、氨基、C1-C6烷基、C1-C6卤代烷基、C1-C6硫代烷基、C1-C6烷氧基、C1-C6杂烷基、C1-C6烷胺基、C3-C6环烷基、C3-C8环烷胺基、C6-C14芳基或5-14元杂芳基；优选地Q 2为7-8元桥环含氮杂环。
在另一优选例中，Q 2为饱和7-11元螺杂环基，其中，所述杂环基中含有一个或两个氮环杂原子，且Q 2上的H可以任选地被选自下组的一个或多个取代基取代：氘、羟基、卤素、氰基、酯基、酰胺基、羰基、氧代基(＝O)、氨基、C1-C6烷基、C1-C6卤代烷基、C1-C6硫代烷基、C1-C6烷氧基、C1-C6杂烷基、C1-C6烷胺基、C3-C6环烷基、C3-C8环烷胺基、C6-C14芳基或5-14元杂芳基。
在另一优选例中，Q 2为
Figure PCTCN2020139655-appb-000021
其中，m、n、m’和n’各自独立地为0、1、2、3，R 3的定义如上所述。
在另一优选例中，X 1为N。
在另一优选例中，Q 2为饱和5-6元单环杂环基，其中，所述杂环基中含有一个或两个氮环杂原子，且Q 2上的H可以任选地被选自下组的一个或多个取代基取代：氘、羟基、卤素、氰基、酯基、酰胺基、氧代基、羰基、氨基、C1-C6烷基、C1-C6卤代烷基、C1-C6硫代烷基、C1-C6烷氧基、C1-C6杂烷基、C1-C6烷胺基、C3-C6环烷基、C3-C8环烷胺基、C6-C14芳基或5-14元杂芳基。
在另一优选例中，Y 3为N。
在另一优选例中，B为5-6元杂芳基，且B上H可以任选地被选自下组的一个或多个取代基取代：氘、羟基、卤素、氰基、酯基、酰胺基、羰基、氨基、C1-C6烷基、C1-C6卤代烷基、C1-C6硫代烷基、C1-C6烷氧基、C1-C6杂烷基、C1-C6烷胺基、C3-C6环烷基、C3-C8环烷胺基、C6-C14芳基或5-14元杂芳基。
在另一优选例中，Ar 2中五元或六元杂芳基为
Figure PCTCN2020139655-appb-000022
其中，P 1、P 2、P 3和P 4各自独立地选自：N或CH，其中，P 1、P 2、P 3和P 4中有0、1、2个为N，L 1、L 2各自独立地选自：N或C。
在另一优选例中，Ar 2选自：
Figure PCTCN2020139655-appb-000023
在另一优选例中，所述的化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药，其具有式(VII)、式(VIII)或式(Ⅸ)所示的结构
Figure PCTCN2020139655-appb-000024
其中，A、Z 1、D、R x、Q 2、E、B、R 5、f的定义如上所述；Y 3和Y 4各自独立地为CH、N或CR a。
在另一优选例中，所述的化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药，其具有式(Ⅺ)或式(XIII)所示的结构：
Figure PCTCN2020139655-appb-000025
其中，Y 4、Y 5、各自独立地为CH、N或CR a；
A、Z 1、D、R x、Q 2、E、B、R 5、f的定义如上所述。
在另一优选例中，所述的B选自取代或未取代的选自下组的基团：C6-C10芳基、5-10元杂芳基，所述取代是指地被选自下组的一个或多个取代基取代：氘、卤素、C1-C6烷基、C1-C6烷氧基、C1-C6烷基胺基、C3-C6环烷基、C3-C8环烷基胺基、C6-C14芳基或5-14元杂芳基。
在另一优选例中，所述的化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药，其具有式(XIV)所示的结构：
Figure PCTCN2020139655-appb-000026
其中，
各R m独立地选自：C1-C6烷基、卤素、羟基、氧代基(＝O)、C1-C6杂烷基、C1-C6烷氧基、C3-C14环烷基、3-14元杂环烷基或氰基；
h为0、1或2；
G、B、Q2、R 5、f的定义如上所述。
在另一优选例中，Q2为
Figure PCTCN2020139655-appb-000027
其中，l 1和l 2各自独立地为0、1、2、3，且l 1+l 2为1-4的整数；
y为0、1、2、3；
Rn选自：氘、羟基、卤素、氰基、酯基、酰胺基、羰基、氧代基(＝O)、氨基、C1-C6烷基、C1-C6卤代烷基、C1-C6硫代烷基、C1-C6烷氧基、C1-C6杂烷基、C1-C6烷胺基、C3-C6环烷基、C3-C8环烷胺基、C6-C14芳基或5-14元杂芳基。
在另一优选例中，G选自：
Figure PCTCN2020139655-appb-000028
在另一优选例中，R 5选自：C1-C3烷氧基或
Figure PCTCN2020139655-appb-000029
优选地，R 5选自：甲氧基、
Figure PCTCN2020139655-appb-000030
在另一优选例中，Q2选自：
Figure PCTCN2020139655-appb-000031
在另一优选例中，B为取代或未取代的下组基团：吡啶基、嘧啶基、噻唑基；其中，所述取代是指被选自下组的一个或多个取代基取代：氘、羟基、卤素、氰基、酯基、酰胺基、羰基、氨基、C1-C6烷基、C1-C6卤代烷基、C1-C6硫代烷基、C1-C6烷氧基、C1-C6杂烷基、C1-C6烷基胺基、C3-C6环烷基、C3-C8环烷基胺基、C6-C14芳基或5-14元杂芳基。
在另一优选例中，
Figure PCTCN2020139655-appb-000032
部分选自：
Figure PCTCN2020139655-appb-000033
Figure PCTCN2020139655-appb-000034
在另一优选例中，所述所述的化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药，不包含
Figure PCTCN2020139655-appb-000035
在另一优选例中，G、K、Ar 1、Ar 2、Q2、E、B、R 5、f、R x、A、Z 1、X 1、X 2、 X 3、X 4、Y 1、Y 2、Y 3、Y 4和Y 5为实施例中各具体化合物所对应基团。
在另一优选例中，所述的化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药，所述化合物选自下组：
Figure PCTCN2020139655-appb-000036
Figure PCTCN2020139655-appb-000037
Figure PCTCN2020139655-appb-000038
在另一优选例中，所述化合物选自实施例中所示化合物。
本发明第二方面，提供一种药物组合物，其包含第一方面所述的化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药；和药学上可接受的载体。
在另一优选例中，所述药物组合物还包括其他癌症治疗剂。
在另一优选例中，所述的其他癌症治疗剂包括放射剂、细胞毒试剂、激酶抑制剂、免疫靶向抑制剂和血管生成抑制剂。
在另一优选例中，所述药物组合物还包括：
PD-1抑制剂(如纳武单抗、派姆单抗、JS-001、SHR-120、BGB-A317、IBI-308、GLS-010、GB-226、STW204、HX008、HLX10、BAT1306、AK105、LZM 009或上述药物的生物类似药等)、PD-L1抑制剂(如德瓦鲁单抗、阿特珠单抗、CS1001、KN035、HLX20、SHR-1316、BGB-A333、JS003、CS1003、KL-A167、F 520、GR1405、MSB2311或上述药物的生物类似药等)、CD20抗体(如利妥昔单抗、奥滨尤妥珠单抗、奥法木单抗、托西莫单抗、替伊莫单抗等)、CD47抗体(如Hu5F9-G4、CC-90002、TTI-621、TTI-622、OSE-172、SRF-231、ALX-148、NI-1701、SHR-1603、IBI188、IMM01)、ALK抑制剂(如色瑞替尼、艾乐替尼、布加替尼、劳拉替尼、奥卡替尼)、PI3K抑制剂(如艾代拉里斯、Dactolisib、Taselisib、Buparlisib等)、BTK抑制剂(如依鲁替尼、Tirabrutinib、Acalabrutinib等)、EGFR抑制剂(如阿法替尼、吉非替尼、厄洛替尼、拉帕替尼、达克替尼、埃克替尼、卡奈替尼等)、VEGFR抑制剂(如索拉非尼、帕唑帕尼、瑞伐替尼、卡博替尼、舒尼替尼、多纳非尼等)、HDAC抑制剂(如Givinostat、Droxinostat、恩替诺特、达西司特、泰克地那林等)、CDK抑制剂(如帕博西尼、瑞博西尼、Abemaciclib、Lerociclib等)、MEK抑制剂(如司美替尼(AZD6244)、曲美替尼(GSK1120212)、PD0325901、U0126、AS-703026、PD184352(CI-1040)等)、Akt抑制剂(如MK-2206、Ipatasertib、Capivasertib、Afuresertib、Uprosertib等)、mTOR抑制剂(如Vistusertib等)、SHP2抑制剂(如RMC-4630、JAB-3068、TNO155等)、IGF-1R抑制剂(如Ceritinib、奥卡替尼、linsitinib、BMS-754807、GSK1838705A等)或其组合。
本发明第三方面，提供一种第一方面所述的化合物、其药学上可接受的盐、立体异构体、溶剂化物或前药或第二方面所述的药物组合物在制备用于抑制细胞或受试者中的RET激酶活性的药物中的用途。
在另一优选例中，第一方面所述的化合物或第二方面所述的药物组合物用于制备治 疗与RET相关癌症的药物。
在另一优选例中，所述与RET相关癌症是具有以下特征的癌症：RET基因、RET激酶蛋白或任何相同蛋白的表达或活性水平的失调。
在另一优选例中，RET相关癌症选自下组：肺癌、甲状腺乳头状癌、甲状腺髓样癌、分化型甲状腺癌、复发性甲状腺癌、难治性分化型甲状腺癌、多发性2A或2B型内分泌肿瘤(分别为MEN2A或MEN2B)、嗜铬细胞瘤、甲状旁腺增生、乳腺癌、结肠直肠癌、乳头状肾细胞癌、胃肠粘膜神经节神经瘤病和宫颈癌。
在另一优选例中，所述药物为治疗对癌症治疗产生抗性的受试者的药物。
在另一优选例中，所述药物为治疗患有由异常RET活性介导的病状的受试者的药物。
在另一优选例中，所述细胞为哺乳动物细胞。
在另一优选例中，所述受试者为哺乳动物，优选为人。
本发明第四方面，提供了一种用于抑制细胞或受试者中的RET激酶活性的方法，所述方法包括使所述细胞接触或向所述受试者施用第一方面所述的化合物或第二方面所述的药物组合物的步骤。
本发明第五方面，提供了一种治疗患有由异常RET活性介导的病状的受试者的方法，所述方法包括向所述受试者施用治疗有效量的第一方面所述的化合物或第二方面所述的药物组合物。
本发明第六方面，提供了一种治疗对癌症治疗产生抗性的受试者的方法，所述方法包括向所述受试者施用治疗有效量的第一方面所述的化合物或第二方面所述的药物组合物。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
具体实施方式
术语
在本发明中，除非特别指出，所用术语具有本领域技术人员公知的一般含义。
术语“C1-C6烷基”指的是直链或支链烷基，包括从1-6个碳原子，如甲基、乙基、丙基、异丙基
Figure PCTCN2020139655-appb-000039
正丁基、叔丁基、异丁基(如
Figure PCTCN2020139655-appb-000040
)、正戊基、异戊基、正己基、异己基。“取代烷基”是指烷基中的一个或多个位置被取代，尤其是1-4个取代基，可在任何位置上取代。本发明中所述的“烷基”包括“取代的烷基”。典型的取代包括但不限于一个或多个以下基团：如氢、氘、卤素(例如，单卤素取代基或多卤素取代基，后者如三氟 甲基或包含Cl 3的烷基)、腈基、硝基、氧(如＝O)、三氟甲基、三氟甲氧基、环烷基、烯基、环烯基、炔基、杂环、芳环、OR a、SR a、S(＝O)R e、S(＝O) 2R e、P(＝O) 2R e、S(＝O) 2OR e,P(＝O) 2OR e、NR bR c、NR bS(＝O) 2R e、NR bP(＝O) 2R e、S(＝O) 2NR bR c、P(＝O) 2NR bR c、C(＝O)OR d、C(＝O)R a、C(＝O)NR bR c、OC(＝O)R a、OC(＝O)NR bR c、NR bC(＝O)OR e,NR dC(＝O)NR bR c、NR dS(＝O) 2NR bR c、NR dP(＝O) 2NR bR c、NR bC(＝O)R a、或NR bP(＝O) 2R e，其中在此出现的R a可以独立表示氢、氘、烷基、环烷基、烯基、环烯基、炔基、杂环或芳环，R b、R c和R d可以独立表示氢、氘、烷基、环烷基、杂环或芳环，或者说R b和R c与N原子一起可以形成杂环；R e可以独立表示氢、烷基、环烷基、烯基、环烯基、炔基、杂环或芳环。上述典型的取代基，如烷基、环烷基、烯基、环烯基、炔基、杂环或芳环可以任选取代。
术语“杂烷基”是指烷基中的碳原子被选自，例如，氧、氮、硫、磷或其组合的原子取代的基团。可以给出数值范围，例如，C1-C6杂烷基，其是指链中的碳数目，在此实例中包括1至6个碳原子。例如，-CH 2OCH 2CH 3基团被称为“C 3”杂烷基。与分子其余部分的连接可以通过杂烷基链中的杂原子或碳。
术语“3-7元环”是指3、4、5、6、7元环，且所述环包括饱和环和不饱和环，饱和环包括环烷基、杂环烷基(含有1-3个N、O、S杂环原子)，环烷基包括环丙基、环丁基、环戊基、环己基、环庚基；杂环烷基包括氮杂环丙基、氮杂环丁基、氮杂环戊基、氮杂环己基、氧杂环丙基、氧杂环丁基、氧杂环戊基、氧杂环己基等；不饱和环包括环己烯基、环己二烯基、环戊烯基等。
术语“5或6元芳香基”包括5元杂芳基、6元杂芳基、苯基。
本发明中，Ar 1中五元或六元杂芳基可以是
Figure PCTCN2020139655-appb-000041
Figure PCTCN2020139655-appb-000042
等。
本发明中，Ar 2中五元或六元杂芳基可以是
Figure PCTCN2020139655-appb-000043
其中，P 1、P 2、P 3和P 4各自独立地选自：N或CH，其中，P 1、P 2、P 3和P 4中有0、1、2个为N，L 1、L 2各自独立地选自：N或C。
术语“亚烷基”是指“烷基”再脱掉一个氢原子所形成的基团，如亚甲基、亚乙基、亚丙基、亚异丙基(如
Figure PCTCN2020139655-appb-000044
)、亚丁基(如
Figure PCTCN2020139655-appb-000045
)、亚戊基(如
Figure PCTCN2020139655-appb-000046
)、亚己基(如
Figure PCTCN2020139655-appb-000047
)、亚庚基(如
Figure PCTCN2020139655-appb-000048
)等。
术语“环烷基”是指完全饱和的环状烃类化合物基团，“C3-C6环烷基”和“C3-C12环 烷基”分别指含有3-6个和3-12个碳原子。“取代环烷基”是指环烷基中的一个或多个位置被取代，尤其是1-4个取代基，可在任何位置上取代。典型的取代包括但不限于一个或多个以下基团：如氢，氘，卤素(例如，单卤素取代基或多卤素取代基，后者如三氟甲基或包含Cl 3的烷基)、腈基、硝基、氧(如＝O)、三氟甲基、三氟甲氧基、环烷基、烯基、环烯基、炔基、杂环、芳环、OR a、SR a、S(＝O)R e、S(＝O) 2R e、P(＝O) 2R e、S(＝O) 2OR e,P(＝O) 2OR e、NR bR c、NR bS(＝O) 2R e、NR bP(＝O) 2R e、S(＝O) 2NR bR c、P(＝O) 2NR bR c、C(＝O)OR d、C(＝O)R a、C(＝O)NR bR c、OC(＝O)R a、OC(＝O)NR bR c、NR bC(＝O)OR e,NR dC(＝O)NR bR c、NR dS(＝O) 2NR bR c、NR dP(＝O) 2NR bR c、NR bC(＝O)R a、或NR bP(＝O) 2R e，其中在此出现的R a可以独立表示氢、氘、烷基、环烷基、烯基、环烯基、炔基、杂环或芳环，R b、R c和R d可以独立表示氢、氘、烷基、环烷基、杂环或芳环，或者说R b和R c与N原子一起可以形成杂环；R e可以独立表示氢、氘、烷基、环烷基、烯基、环烯基、炔基、杂环或芳环。上述典型的取代基可以任选取代。典型的取代还包括螺环、桥环或稠环取代基，尤其是螺环烷基、螺环烯基、螺环杂环(不包括杂芳环)、桥环烷基、桥环烯基、桥环杂环(不包括杂芳环)、稠环烷基、稠环烯基、稠环杂环基或稠环芳环基，上述环烷基、环烯基、杂环基和杂环芳基可以任选取代。
术语“杂环基”是指完全饱和的或部分不饱和的的环状基团(包含但不限于如4-7元单环、7-11元螺杂环基、7-8元桥杂环基)，其中至少有一个杂原子存在于至少有一个碳原子的环中。每个含有杂原子的杂环可以带有1、2、3或4个杂原子，这些杂原子选自氮原子、氧原子或硫原子，其中氮原子或硫原子可以被氧化，氮原子也可以被季铵化。杂环基团可以连接到环或环系分子的任何杂原子或碳原子的残基上。典型的单环杂环包括但不限于氮杂环丁烷基、吡咯烷基、氧杂环丁烷基、吡唑啉基、咪唑啉基、咪唑烷基、噁唑烷基、异噁唑烷基、噻唑烷基、异噻唑烷基、四氢呋喃基、哌啶基、哌嗪基、2-氧代哌嗪基、2-氧代哌啶基、2-氧代吡咯烷基、六氢吖庚因基、4-哌啶酮基、四氢吡喃基、吗啡啉基、硫代吗啡啉基、硫代吗啡啉亚砜基、硫代吗啡啉砜基、1,3-二噁烷基和四氢-1,1-二氧噻吩等。多环杂环基包括螺环、稠环和桥环的杂环基；其中涉及到的螺环、稠环和桥环的杂环基任选与其他基团通过单键相连接，或者通过环上的任意两个或两个以上的原子与其他环烷基、杂环基、芳基和杂芳基进一步并环连接；杂环基团可以是取代的或者未取代的，当被取代时，取代基优选为一个或多个一下基团，其独立地选自烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、烯基、炔基、烷硫基、烷基氨基、卤素、氨基、硝基、羟基、巯基、氰基、环烷基、杂环基、芳基、杂芳基、环烷硫基、氧代基、羧基和羧酸酯基。
术语“芳基”是指芳香环状烃类化合物基团，“C6-C14芳基”是指含有6-14个碳原子的芳基，尤其指单环和双环基团，如苯基、联苯基或萘基。凡含有两个或两个以上芳香环(双环等)，芳基基团的芳香环可由单键联接(如联苯)，或稠合(如萘、蒽等等)。“取代芳基”是指芳基中的一个或多个位置被取代，尤其是1-3个取代基，可在任何位置上取代。典型的取代包括但不限于一个或多个以下基团：如氢、氘、卤素(例如，单卤素取代基或 多卤素取代基，后者如三氟甲基或包含Cl 3的烷基)、腈基、硝基、氧(如＝O)、三氟甲基、三氟甲氧基、环烷基、烯基、环烯基、炔基、杂环、芳环、OR a、SR a、S(＝O)R e、S(＝O) 2R e、P(＝O) 2R e、S(＝O) 2OR e,P(＝O) 2OR e、NR bR c、NR bS(＝O) 2R e、NR bP(＝O) 2R e、S(＝O) 2NR bR c、P(＝O) 2NR bR c、C(＝O)OR d、C(＝O)R a、C(＝O)NR bR c、OC(＝O)R a、OC(＝O)NR bR c、NR bC(＝O)OR e,NR dC(＝O)NR bR c、NR dS(＝O) 2NR bR c、NR dP(＝O) 2NR bR c、NR bC(＝O)R a、或NR bP(＝O) 2R e，其中在此出现的R a可以独立表示氢、氘、烷基、环烷基、烯基、环烯基、炔基、杂环或芳环，R b、R c和R d可以独立表示氢、氘、烷基、环烷基、杂环或芳环，或者说R b和R c与N原子一起可以形成杂环；R e可以独立表示氢、氘、烷基、环烷基、烯基、环烯基、炔基、杂环或芳环。上述典型的取代基可以任选取代。典型的取代还包括稠环取代基，尤其是稠环烷基、稠环烯基、稠环杂环基或稠环芳环基，上述环烷基、环烯基、杂环基和杂环芳基可以任选取代。
术语“5-14元杂芳基”指包含1-4个杂原子、5-14个环原子的杂芳族体系，其中杂原子选自氧、氮和硫。杂芳基优选5至10元环，更优选为5元或6元，例如吡咯基、吡唑基、咪唑基、噁唑基、异噁唑基、噻唑基、噻二唑基、异噻唑基、呋喃基、吡啶基、吡嗪基、嘧啶基、哒嗪基、三氮嗪基、三氮唑基及四氮唑基等。“杂芳基”可以是取代的或者未取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、烯基、炔基、烷硫基、烷基氨基、卤素、氨基、硝基、羟基、巯基、氰基、环烷基、杂环基、芳基、杂芳基、环烷硫基、氧代基、羧基和羧酸酯基。
术语“C1-C6烷氧基”是指具有1至6个碳原子的直链或支链或环状烷氧基，非限制性地包括甲氧基、乙氧基、丙氧基、异丙氧基和丁氧基等。优选为C1-C3烷氧基。“烷氧基烷基”是指，烷基中的氢原子被烷氧基基取代的基团，例如CH 3OCH 2-和CH 3OCH 2CH 2-。
术语“卤素”或“卤”是指氯、溴、氟、碘。
术语“氘代”是指被氘取代。
术语“羟基”是指带有结构OH的基团。
术语“硝基”是指带有结构NO 2的基团。
术语“氰基”是指带有结构CN的基团。
术语“酯基”是指带有结构-COOR的基团，其中R代表氢、C1-C6烷基或取代的C1-C6烷基、C3-C8环烷基或取代的C3-C8环烷基、C4-C10环烯基或取代的C4-C10环烯基、芳基或取代的C6-C14芳基、3-8杂环基或取代的杂环基。
术语“胺基”是指带有结构-NRR'的基团，其中R和R'可以独立的代表氢、C1-C6烷基或取代的C1-C6烷基、C3-C8环烷基(优选C3-C6环烷基)或取代的C3-C8环烷基(优选C3-C6环烷基)、C4-C10环烯基或取代的C4-C10环烯基、芳基或取代的C6-C14芳基、3-8杂环基或取代的杂环基。R和R'在二烷基胺片段中可以相同或不同。“C1-C6烷基胺基”和“C3-C8环烷基胺基”分别为C1-C6烷基NH-、C3-C8环烷基NH-。
术语“酰胺基”是指带有结构-CONRR'的基团，其中R和R'可以独立的代表氢、C1-C6 烷基或取代的C1-C6烷基、C3-C8环烷基或取代的C3-C8环烷基、C4-C10环烯基或取代的C4-C10环烯基、芳基或取代的C6-C14芳基、3-8杂环基或取代的杂环基。R和R'在二烷基胺片段中可以相同或不同。
术语“磺酰胺基”是指带有结构-SO 2NRR'的基团，其中R和R'可以独立的代表氢、C1-C6烷基或取代的C1-C6烷基、C3-C8环烷基或取代的C3-C8环烷基、C4-C10环烯基或取代的C4-C10环烯基、芳基或取代的C6-C14芳基、3-8杂环基或取代的杂环基。R和R'在二烷基胺片段中可以相同或不同。
术语“C6-C14芳基C1-C6烷基”是指C1-C6烷基中的氢原子被C6-C14芳基取代的基团，如苄基、苯乙基等。
在本发明中，术语“取代”指特定的基团上的一个或多个氢原子被特定的取代基所取代。特定的取代基为在前文中相应描述的取代基，或各实施例中所出现的取代基。除非特别说明，某个取代的基团可以在该基团的任何可取代的位点上具有一个选自特定组的取代基，所述的取代基在各个位置上可以是相同或不同的。在本发明中，所述基团(例如：烷基、亚烷基、环烷基、杂烷基、杂环基、芳基、杂芳基等)包括其相应基团上的H被取代的基团。本领域技术人员应理解，本发明所预期的取代基的组合是那些稳定的或化学上可实现的组合。所述取代基例如(但并不限于)：卤素、羟基、氰基、羧基(-COOH)、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、3-至12元杂环基、芳基、杂芳基、C1-C8醛基、C2-C10酰基、C2-C10酯基、胺基、C1-C6烷氧基、C1-C10磺酰基、及C1-C6脲基等。
本发明中，多个通常指两个以上。
除非另外说明，假定任何不满价态的杂原子有足够的氢原子补充其价态。
当取代基为非末端取代基时，其为相应基团的亚基，例如烷基对应于亚烷基、环烷基对应亚环烷基、杂环基对亚杂环基、烷氧基对应亚烷氧基等。
活性成分
如本文所用，“本发明化合物”指式I所示的化合物，并且还包括及式F化合物的立体异构体或光学异构体、药学上可接受的盐、前药或溶剂化物。
所述式F化合物具有如下结构：
Figure PCTCN2020139655-appb-000049
式中，G、K、Ar 1、Ar 2、Q 2、B、E、R 5、f的定义如上所述。
优选地，式F中，Ar 1为取代或未取代的下组基团：
Figure PCTCN2020139655-appb-000050
Figure PCTCN2020139655-appb-000051
其中，所述取代是指被选自下组的一个或多个基团取代：H、CN、卤素、甲基、乙基或环丙基；
Ar 2为取代或未取代的5元杂芳基，其中，所述取代是指被选自下组的一个或多个基团取代：C1-C6烷基、卤素、羟基、氧代基(＝O)、C1-C6杂烷基、C1-C6烷氧基、C3-C14环烷基、3-14元杂环烷基或氰基；
Q 2为饱和5-6元单环杂环基，其中，所述杂环基中含有一个或两个氮环杂原子，且Q 2上的H可以任选地被选自下组的一个或多个取代基取代：氘、羟基、卤素、氰基、酯基、酰胺基、氧代基、羰基、氨基、C1-C6烷基、C1-C6卤代烷基、C1-C6硫代烷基、C1-C6烷氧基、C1-C6杂烷基、C1-C6烷胺基、C3-C6环烷基、C3-C8环烷胺基、C6-C14芳基或5-14元杂芳基；
B为5-6元杂芳基，且B上H可以任选地被选自下组的一个或多个取代基取代：氘、羟基、卤素、氰基、酯基、酰胺基、羰基、氨基、C1-C6烷基、C1-C6卤代烷基、C1-C6硫代烷基、C1-C6烷氧基、C1-C6杂烷基、C1-C6烷胺基、C3-C6环烷基、C3-C8环烷胺基、C6-C14芳基或5-14元杂芳基；
E为氢或取代或未取代C1-C6烷基，其中，所述取代是指被0-5个R a取代，R a的定义如上所述。
优选地，Q2为
Figure PCTCN2020139655-appb-000052
其中，l 1和l 2各自独立地为0、1、2、3，且l 1+l 2为1-4的整数；
y为0、1、2、3；
Rn选自：氘、羟基、卤素、氰基、酯基、酰胺基、羰基、氧代基(＝O)、氨基、C1-C6烷基、C1-C6卤代烷基、C1-C6硫代烷基、C1-C6烷氧基、C1-C6杂烷基、C1-C6烷胺基、C3-C6环烷基、C3-C8环烷胺基、C6-C14芳基或5-14元杂芳基。
优选地，式F中，
Ar 1为取代或未取代的下组基团：
Figure PCTCN2020139655-appb-000053
其中，所述取代是指被选自下组的一个或多个基团取代：H、CN、卤素、甲基、乙基或环丙基；
Ar 2选自：
Figure PCTCN2020139655-appb-000054
G选自：
Figure PCTCN2020139655-appb-000055
R 5选自：C1-C3烷氧基或
Figure PCTCN2020139655-appb-000056
优选地，R 5选自：甲氧基、
Figure PCTCN2020139655-appb-000057
Q2选自：
Figure PCTCN2020139655-appb-000058
B为取代或未取代的下组基团：吡啶基、嘧啶基、噻唑基；其中，所述取代是指被选自下组的一个或多个取代基取代：氘、羟基、卤素、氰基、酯基、酰胺基、羰基、氨基、C1-C6烷基、C1-C6卤代烷基、C1-C6硫代烷基、C1-C6烷氧基、C1-C6杂烷基、C1-C6烷基胺基、C3-C6环烷基、C3-C8环烷基胺基、C6-C14芳基或5-14元杂芳基；
Figure PCTCN2020139655-appb-000059
部分选自：
Figure PCTCN2020139655-appb-000060
本发明中的化合物可能形成的盐也是属于本发明的范围。除非另有说明，本发明中的化合物被理解为包括其盐类。在此使用的术语“盐”，指用无机或有机酸和碱形成酸式或碱式的盐。此外，当本发明中的化合物含一个碱性片段时，它包括但不限于吡啶或咪唑，含一个酸性片段时，包括但不限于羧酸，可能形成的两性离子(“内盐”)包含在术语“盐”的范围内。药学上可接受的(即无毒，生理可接受的)盐是首选，虽然其他盐类也有用，例如可以用在制备过程中的分离或纯化步骤。本发明的化合物可能形成盐，例如，式F与一定量如等当量的酸或碱反应，在介质中盐析出来，或在水溶液中冷冻干燥得来。
本发明中的化合物含有的碱性片段，包括但不限于胺或吡啶或咪唑环，可能会和有机或无机酸形成盐。可以成盐的典型的酸包括醋酸盐(如用醋酸或三卤代醋酸，如三氟乙酸)、己二酸盐、藻朊酸盐、抗坏血酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、硫酸氢盐、硼酸盐、丁酸盐、柠檬酸盐、樟脑盐、樟脑磺酸盐、环戊烷丙酸盐、二甘醇酸盐、十二烷基硫酸盐、乙烷磺酸盐、延胡索酸盐、葡庚糖酸盐、甘油磷酸盐、半硫酸盐、庚酸盐、己酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、羟基乙磺酸盐(如，2-羟基乙磺酸盐)、乳酸盐、马来酸盐、甲磺酸盐、萘磺酸盐(如，2-萘磺酸盐)、烟酸盐、硝酸盐、草酸盐、果胶酸盐、过硫酸盐、苯丙酸盐(如3-苯丙酸盐)、磷酸盐、苦味酸盐、新戊酸盐、丙酸盐，水杨酸盐、琥珀酸盐、硫酸盐(如与硫酸形成的)、磺酸盐、酒石酸盐、硫氰酸盐、甲苯磺酸盐如对甲苯磺酸盐、十二烷酸盐等等
本发明的某些化合物可能含有的酸性片段，包括但不限于羧酸，可能会和各种有机或无机碱形成盐。典型的碱形成的盐包括铵盐、碱金属盐如钠、锂、钾盐，碱土金属盐如钙、镁盐，和有机碱形成的盐(如有机胺)，如苄星、二环已基胺、海巴胺(与N,N-二(去氢枞基)乙二胺形成的盐)、N-甲基-D-葡糖胺、N-甲基-D-葡糖酰胺、叔丁基胺，以及和氨基酸如精氨酸、赖氨酸等等形成的盐。碱性含氮基团可以与卤化物季铵盐，如小分子烷基卤化物(如甲基、乙基、丙基和丁基的氯化物、溴化物及碘化物)，二烷基硫酸盐(如，硫酸二甲酯、二乙酯，二丁酯和二戊酯)，长链卤化物(如癸基、十二烷基、十四烷基和 十四烷基的氯化物、溴化物及碘化物)，芳烷基卤化物(如苄基和苯基溴化物)等等。
本发明中化合物的前药及溶剂合物也在涵盖的范围之内。此处术语“前药”是指一种化合物，在治疗相关疾病时，经过代谢或化学过程的化学转化而产生本发明中的化合物、盐、或溶剂合物。本发明的化合物包括溶剂合物，如水合物。
本发明中的化合物、盐或溶剂合物，可能存在的互变异构形式(例如酰胺和亚胺醚)。所有这些互变异构体都是本发明的一部分。
所有化合物的立体异构体(例如，那些由于对各种取代可能存在的不对称碳原子)，包括其对映体形式和非对映形式，都属于本发明的设想范围。本发明中的化合物独立的立体异构体可能不与其他异构体同时存在(例如，作为一个纯的或者实质上是纯的光学异构体具有特殊的活性)，或者也可能是混合物，如消旋体，或与所有其他立体异构体或其中的一部分形成的混合物。本发明的手性中心有S或R两种构型，由理论与应用化学国际联合会(IUPAC)1974年建议定义。外消旋形式可通过物理方法解决，例如分步结晶，或通过衍生为非对映异构体分离结晶，或通过手性柱色谱法分离。单个的光学异构体可通过合适的方法由外消旋体得到，包括但不限于传统的方法，例如与光学活性酸成盐后再结晶。
本发明中的化合物，依次通过制备、分离纯化获得的该化合物其重量含量等于或大于90％，例如，等于或大于95％，等于或大于99％(“非常纯”的化合物)，在正文描述列出。此处这种“非常纯”本发明的化合物也作为本发明的一部分。
本发明的化合物所有的构型异构体都在涵盖的范围之内，无论是混合物、纯的或非常纯的形式。在本发明化合物的定义包含顺式(Z)和返式(E)两种烯烃异构体，以及碳环和杂环的顺式和反式异构体。
在整个说明书中，基团和取代基可以被选择以提供稳定的片段和化合物。
特定官能团和化学术语定义都详细介绍如下。对本发明来说，化学元素与Periodic Table of the Elements,CAS version,Handbook of Chemistry and Physics,75 th Ed.中定义的一致。特定官能团的定义也在其中描述。此外，有机化学的基本原则以及特定官能团和反应性在“Organic Chemistry”,Thomas Sorrell,University Science Books,Sausalito:1999,也有说明，其全部内容纳入参考文献之列。
本发明的某些化合物可能存在于特定的几何或立体异构体形式。本发明涵盖所有的化合物，包括其顺式和反式异构体、R和S对映异构体、非对映体、(D)型异构体、(L)型异构体、外消旋混合物和其它混合物。另外不对称碳原子可表示取代基，如烷基。所有异构体以及它们的混合物，都包涵在本发明中。
按照本发明，同分异构体的混合物含有异构体的比率可以是多样的。例如，在只有两个异构体的混合物可以有以下组合：50:50，60:40，70:30，80:20，90:10，95:5，96:4，97:3，98:2，99:1，或100:0，异构体的所有比率都在本发明范围之内。本专业内一般技术人员容易理解的类似的比率，及为更复杂的异构体的混合物的比率也在本 发明范围之内。
本发明还包括同位素标记的化合物，等同于原始化合物在此公开。不过实际上对一个或更多的原子被与其原子量或质量序数不同的原子取代通常会出现。可以列为本发明的化合物同位素的例子包括氢，碳，氮，氧，磷，硫，氟和氯同位素，分别如 2H、 3H、 13C、 11C、 14C、 15N、 18O、 17O、 31P、 32P、 35S、 18F和 36Cl。本发明中的化合物，或对映体，非对映体，异构体，或药学上可接受的盐或溶剂化物，其中含有上述化合物的同位素或其他同位素原子都在本发明的范围之内。本发明中某些同位素标记化合物，例如 3H和 14C的放射性同位素也在其中，在药物和底物的组织分布实验中是有用的。氚，即 3H和碳-14，即 14C，它们的制备和检测比较容易。是同位素中的首选。此外，较重同位素取代如氘，即 2H，由于其很好的代谢稳定性在某些疗法中有优势，例如在体内增加半衰期或减少用量，因此，在某些情况下可以优先考虑。同位素标记的化合物可以用一般的方法，通过用易得的同位素标记试剂替换为非同位素的试剂，用批露在示例中的方案可以制备。
如果要设计一个本发明的化合物特定的对映体的合成，它可以不对称合成制备，或用手性辅剂衍生化，将所产生的非对映混合物分离，再除去手性辅剂而得到纯的对映体。另外，如果分子中含有一个碱性官能团，如氨基酸，或酸性官能团，如羧基，可以用合适的光学活性的酸或碱的与之形成非对映异构体盐，再通过分离结晶或色谱等常规手段分离，然后就得到了纯的对映体。
如本文所述，本发明中的化合物可与任何数量取代基或官能团而扩大其包涵范围。通常，术语“取代”不论在术语“可选”“任选”前面或后面出现，在本发明配方中包括取代基的通式，是指用指定结构取代基，代替氢自由基。当特定结构中的多个在位置被多个特定的取代基取代时，取代基每一个位置可以是相同或不同。本文中所使用的术语“取代”包括所有允许有机化合物取代。从广义上讲，允许的取代基包括非环状的、环状的、支链的非支链的、碳环的和杂环的，芳环的和非芳环的有机化合物。在本发明中，如杂原子氮可以有氢取代基或任何允许的上文所述的有机化合物来补充其价态。此外，本发明是无意以任何方式限制允许取代有机化合物。本发明认为取代基和可变基团的组合在以稳定化合物形式在疾病的治疗上是很好的，例如传染病或增生性疾病。此处术语“稳定”是指具有稳定的化合物，在足够长的时间内检测足以维持化合物结构的完整性，最好是在足够长的时间内都在效，本文在此用于上述目的。
本申请所涉及的化合物及其药学可接受的盐的代谢产物，以及可以在体内转变为本申请所涉及的化合物及其药学可接受的盐的结构的前药，也包含在本申请的权利要求中。
活性成分
如本文所用，术语“本发明化合物”指式F所示的化合物。该术语还包括其药学上可接受的盐、立体异构体、溶剂化物或前药。
其中，术语“药学上可接受的盐”指本发明化合物与酸或碱所形成的适合用作药物的盐。药学上可接受的盐包括无机盐和有机盐。一类优选的盐是本发明化合物与酸形成的盐。适合形成盐的酸包括但并不限于：盐酸、氢溴酸、氢氟酸、硫酸、硝酸、磷酸等无机酸；甲酸、乙酸、三氟乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、苯甲酸、甲磺酸、乙磺酸、对甲苯磺酸、苯磺酸、萘磺酸等有机酸；以及脯氨酸、苯丙氨酸、天冬氨酸、谷氨酸等氨基酸。另一类优选的盐是本发明化合物与碱形成的盐，例如碱金属盐(例如钠盐或钾盐)、碱土金属盐(例如镁盐或钙盐)、铵盐(如低级的烷醇铵盐以及其它药学上可接受的胺盐)，例如甲胺盐、乙胺盐、丙胺盐、二甲基胺盐、三甲基胺盐、二乙基胺盐、三乙基胺盐、叔丁基胺盐、乙二胺盐、羟乙胺盐、二羟乙胺盐、三羟乙胺盐，以及分别由吗啉、哌嗪、赖氨酸形成的胺盐。
术语“溶剂合物”指本发明化合物与溶剂分子配位形成特定比例的配合物。“水合物”是指本发明化合物与水进行配位形成的配合物。
所述的前药包括(但不局限于)所述化合物的羧酸酯、碳酸酯、磷酸酯、硝酸酯、硫酸酯、砜酯、亚砜酯、氨基化合物、氨基甲酸盐、偶氮化合物、磷酰胺、葡萄糖苷、醚、乙缩醛等形式。
制备方法
本发明化合物可以任选将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便地制得，这样的组合可由本发明所属领域的技术人员容易地进行。
优选地，本发明化合物按照如下步骤进行：
S1)在惰性溶剂(如二氧六环)中，催化剂(如Pd(dppf)Cl 2)和碱(如K 2CO 3)存在下，化合物1与化合物2反应，得到化合物3；
S2)在惰性溶剂(如DMF)中，碱(如Cs 2CO 3)存在下，化合物3与化合物4反应，得到化合物F；
Figure PCTCN2020139655-appb-000061
式中，X和X'各自独立地为卤素、OTf或者
Figure PCTCN2020139655-appb-000062
G、K、Ar 1、Ar 2、Q2、E、B、R 5、f的定义如上所述。
药物组合物和施用方法
本发明所述的药物组合物用于预防和/或治疗以下疾病：炎症、癌症、心血管疾病、感染、免疫性疾病、代谢性疾病。
本发明所述化合物可以与已知的治疗或改进相似病状的其他药物联用。联合给药 时，原来药物的给药方式和剂量可以保持不变，而同时或随后服用本发明的化合物。当本发明化合物与其它一种或几种药物同时服用时，可以优选使用同时含有一种或几种已知药物和本发明化合物的药用组合物。药物联用也包括在重叠的时间段服用本发明化合物与其它一种或几种已知药物。当本发明化合物与其它一种或几种药物进行药物联用时，本发明化合物或已知药物的剂量可能比它们单独用药的剂量低。
本发明所述药物组合物的剂型包括(但并不限于)：注射剂、片剂、胶囊剂、气雾剂、栓剂、膜剂、滴丸剂、外用擦剂、控释型或缓释型或纳米制剂。
本发明的药物组合物包含安全有效量范围内的本发明化合物或其药理上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全有效量”指的是：化合物的量足以明显改善病情，而不至于产生严重的副作用。通常，药物组合物含有1-2000mg本发明化合物/剂，更佳地，含有10-1000mg本发明化合物/剂。较佳地，所述的“一剂”为一个胶囊或药片。
“药学上可以接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的化合物以及它们之间相互掺和，而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如
Figure PCTCN2020139655-appb-000063
)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明化合物或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)、和局部给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实 例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂，或必要时可能需要的推进剂一起混合。
本发明治疗方法可以单独施用，或者与其它治疗手段或者治疗药物联用。
使用药物组合物时，是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量，对于60kg体重的人而言，日给药剂量通常为1-2000mg，优选50-1000mg。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。
本发明还提供了一种药物组合物的制备方法，包括步骤：将药学上可接受的载体与本发明所述化合物或其药学上可接受的盐、立体异构体、溶剂化物或前药进行混合，从而形成药物组合物。
本发明还提供了一种治疗方法，它包括步骤：给需要治疗的对象施用本发明中所述化合物，或其药学上可接受的盐、立体异构体、溶剂化物或前药，或施用本发明所述的药物组合物，用于选择性地抑制RET。
本发明具有以下主要优点：
(1)本发明化合物对RET激酶均有很好的抑制能力；
(2)所述化合物具有更好的药效学、药代动力学性能和更低的毒副作用；
(3)研究结果表明，Ar 1和Ar 2均为五元杂芳基的化合物(如化合物C1或C2)比Ar 1和/或Ar 2为六元杂芳基的化合物具有更好的抑制效果。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而 不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件如Sambrook等人，分子克隆：实验室手册(New York:Cold Spring Harbor Laboratory Press,1989)中所述的条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。
除非另行定义，文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外，任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅作示范之用。
本发明的化合物结构是通过核磁共振(NMR)和液质联用色谱(LC-MS)来确定的。
实施例
实施例1 化合物C1的合成
合成路线如下：
Figure PCTCN2020139655-appb-000064
(1)中间体C1-9的合成
1、中间体C1-2的合成：
于250mL单口瓶中依次加入C1-1(15.86mmol,3.6g)、DMF(150mL)，将反应降温至-10℃，缓慢滴加POCl 3(47.58mmol,4.43mL)，后-10℃—-5℃反应1h，缓慢升至室温，反应过夜。缓慢加水(150mL)稀释，1N NaOH(350mL)调pH至9～10，过滤，水洗滤饼，乙醚洗滤饼，干燥滤饼，得4.0g中间体C1-2。
2、中间体C1-3的合成：
于50ml单口瓶中依次加入C1-2(15.7mmol,4.0g)、HONH 2·HCl(23.5mmol,1.64g)、EtOH/H 2O(16/8mL)，将反应置于50℃下反应4h。冷却，浓缩反应液，加饱和NaHCO 3水溶液调pH>7，过滤，H 2O/Et 2O洗涤滤饼，干燥得产物3.74g中间体C1-3。
3、中间体C1-4的合成：
于250mL单口瓶中依次加入C1-3(13.8mmol,3.74g)、丙酸酐(80mL)，将反应置于120℃下反应过夜，冷却，旋干，得产物3.43g中间体C1-4。
4、中间体C1-5的合成：
于250mL单口瓶中依次加入C1-4(13.6mmol,3.43g)，C1-14(16.3mmol,3.4g)， Pd(PPh 3) 4(0.54mmol,629mg)，Na 2CO 3(40.8mmol,4.32g)，Dioxane/H 2O(62/27mL)，N 2保护下，将反应置于80℃下反应过夜。LC-MS检测反应完全，加H 2O稀释，EA萃取三次，干燥有机相，减压蒸干，硅胶柱层析，得产物3.05g中间体C1-5。
5、中间体C1-6的合成：
于100mL单口瓶中依次加入C1-5(12.1mmol,3.05g)、DCE(40mL)，AlCl 3(42.2mmol,5.63g)，N 2保护下将反应置于80℃下反应过夜。加DCE稀释，加H 2O淬灭，将反应置于r.t.下搅拌3h。减压蒸干，加甲醇打浆，过滤，浓缩滤液，加水打浆，过滤，干燥滤饼，得产物2.93g中间体C1-6。
6、中间体C1-7的合成：
于100mL单口瓶中依次加入C1-6(11.57mmol,2.93g)、DMA(35mL)，DIPEA(23.14mmol,2.99g)、N-苯基双(三氟甲烷磺酰)亚胺(12.72mmol,4.54g)，N 2保护下，将反应置于r.t.下，反应过夜。加H 2O稀释，将反应置于r.t.下，搅拌30min。过滤，将滤饼溶于DCM中，干燥有机相，浓缩，硅胶柱层析，得产物2.4g中间体C1-7。
7、化合物C1-8的合成：
于25mL单口瓶中依次加入C1-7(0.6mmol,223mg)、C1-16(1.2mmol,374mg)、Pd(dppf)Cl 2(0.06mmol,50mg)、K 2CO 3(0.9mmol,124mg)、Dioxane(10mL)，N 2保护下将反应置于90℃下反应过夜。LCMS检测反应完全，加H 2O稀释，EA萃取三次，干燥有机相，减压蒸干，硅胶柱层析，得产物138mg中间体C1-8。
8、化合物C1-9的合成：
于25mL单口瓶中依次加入C1-8(0.52mmol,210mg)、TFA(4mL)，70℃下反应4h。LCMS检测反应完全，减压蒸干，得180mg黄色固体直接用于下一步反应。
9、中间体C1-13的合成：
于100mL单口瓶中依次加入C1-10(10mmol,1.87g)、DCM(20mL)，DIPEA(30mmol,3.87g)、MsCl(10mmol,1.15g)，r.t.下反应4h。TLC检测反应完全，加DCM稀释，H 2O洗涤三次，干燥有机相，减压蒸干，得2.55g，直接用于下一步反应。
将上述产物溶于10mL DCM中，加入HCl/dioxane(4M,20mL)，室温搅拌反应4h，加DCM稀释，过滤，乙醚洗涤滤饼，干燥，得粗品1.65g白色固体，直接用于下一步反应。
于25mL单口瓶中依次加入C1-12(3.2mmol,642mg)、DMF(10mL)，DIPEA(32mmol,4.13g)、C1-17(3.5mmol,552mg)，r.t.下反应4h。TLC检测反应完全，加H 2O稀释，EA萃取三次，干燥有机相，减压蒸干，硅胶柱层析，得产物126mg。
10、化合物C1的合成：
于25mL单口瓶中依次加入C1-9(0.2mmol,56mg)、C1-13(0.22mmol,64mg)、Cs 2CO 3(0.4mmol,132mg)、DMF(2mL)，将反应置于80℃下反应5h。LC-MS 检测反应完全，加H 2O稀释，EA萃取三次，干燥有机相，减压蒸干，硅胶柱层析，得产物34mg黄色固体，纯度97.7％，[M+H]:480.2，1H NMR(400MHz,DMSO-d6)δ9.19(d,J＝1.5Hz,1H),8.66(s,1H),8.38(s,1H),8.34–8.27(m,1H),8.11(dd,J＝7.9,1.6Hz,2H),7.87(d,J＝0.8Hz,1H),7.83(d,J＝1.5Hz,1H),7.67(dd,J＝8.5,2.4Hz,1H),6.76(d,J＝8.5Hz,1H),4.99(s,1H),3.89(s,3H),3.82(s,3H),3.68–3.53(m,2H),2.89(dt,J＝46.2,8.6Hz,3H),2.57(d,J＝7.3Hz,1H),2.48–2.33(m,1H),2.25–2.11(m,1H).
实施例2 化合物C2的合成
合成路线如下：
Figure PCTCN2020139655-appb-000065
1、中间体C2-24的合成：
于100mL单口瓶中依次加入C2-21(10mmol,2.01g)、DCM(20mL)，DIPEA(30mmol,3.87g)、MsCl(15mmol,1.72g)，r.t.下反应4h。TLC检测反应完全，加DCM稀释，H 2O洗涤三次，干燥有机相，减压蒸干，得2.8g褐色油，直接用于下一步反应。
将上述产物溶于10mL DCM中，加入HCl/dioxane(4M,20mL)，室温搅拌反应4h，加DCM稀释，过滤，乙醚洗涤滤饼，干燥得粗品2.0g褐色固体，直接用于下一步反应。
于25mL单口瓶中依次加入C2-23(1mmol,179mg)、DMF(2mL)、DIPEA(3mmol,387mg)、5-氯甲基-2-甲氧基吡啶(1.2mmol,188mg)，r.t.下反应6h。TLC检测反应完全，加H 2O稀释，EA萃取三次，干燥有机相，减压蒸干，硅胶柱层析，得482mg化合物C2-2黄色油。
2、化合物C2的合成
于25mL单口瓶中依次加入C1-9(0.55mmol,106mg)、C2-24(0.6mmol,97mg)、Cs 2CO 3(1.1mmol,239mg)、DMF(5mL)，将反应置于80℃下反应5h。LC-MS检测反应完全，加H 2O稀释，EA萃取三次，干燥有机相，减压蒸干，硅胶柱层析，得产物12mg黄色固体，纯度91.7％，[M+H]:494.2。
实施例3化合物C3的合成
合成路线如下：
Figure PCTCN2020139655-appb-000066
1、中间体C3-7的合成
100mL三口瓶中依次加入C3-11(20mmol,2.9g)和原甲酸三甲酯(30mL)于100℃下氩气保护下反应2小时。将原料C3-1(20mmol,4g)溶于原甲酸三甲酯(30mL)，将上述溶液缓慢滴加到反应中，滴加完毕，反应于100℃下搅拌反应过夜。浓缩反应液，粗品经硅胶柱层析(PE/EA＝10:1-3:1)纯化，得到4.16g中间体C3-2。
于50mL三口瓶中依次加入C3-2(10mmol,4.16g)和二苯醚(30mL)，氩气保护下，于260℃下反应15分钟。冷却至室温，加入30mL石油醚母液过滤，滤饼经硅胶柱层析(先PE/EA＝1:1，后EA/MeOH＝50:1)纯化，得到750mg中间体C3-3。
50mL三口瓶中依次加入C3-3(3mmol,750mg)和DMF(10mL),反应冰浴下，冷却至0℃，氩气保护下滴加PBr 3(2.5mL)，滴加完毕，反应于室温下搅拌2小时。TLC显示反应完毕，加入水(10mL)和乙酸乙酯(20mL)，水相用饱和NaHCO 3调pH＝7-8，水相用乙酸乙酯萃取三次，合并有机相，干燥，浓缩得粗品，粗品经硅胶柱层析(PE/EA＝10:1)，得到约700mg中间体C3-4。
于50mL单口瓶中依次加入C3-4(4mmol,680mg)、氰化锌(4mmol,470mg)、Pd(PPh 3) 4(0.4mmol,450mg)和DMF(10mL)，反应置换氩气后，氩气保护下于90℃下反应过夜。冷却至室温，母液过滤，加入水(10ml)和乙酸乙酯(20mL)水相用乙酸乙酯萃取三次，合并有机相，干燥，浓缩得粗品，粗品经硅胶柱层析(PE/EA＝20:1-10:1)纯化，得到约300mg中间体C3-5。
于10mL反应管瓶依次加入C3-5(0.76mmol,200mg)、AlCl 3(2.3mmol,300mg)和甲苯(10mL)，反应置于110℃下反应48小时。加入10％NaOH调pH＝5-6,水相用乙酸乙酯萃取，合并有机相，用饱和食盐水洗，干燥浓缩，经过硅胶柱层析(PE/EA＝5:1-2:1)纯化，得到100mg中间体C3-6。
于10mL反应管瓶依次加入C3-6(0.4mmol,100mg)，二甲基环氧乙烷(4mmol,300mg)，K 2CO 3(1.21mmol,167mg)和DMF(5mL)，于95℃下封管反应16h。冷却至室温，加入水和乙酸乙酯，水相用乙酸乙酯萃取，合并有机相，用饱和食盐水洗，干燥浓缩，经过硅胶柱层析(PE/EA＝5:1-1:10)纯化，得到80mg中间体C3-7。
2、中间体C3-10的合成
于10mL反应管瓶依次加入C3-8(1.0mmol,290mg)、C3-12(1.1mmol,179mg)、 DIPEA(8mmol,1g)和DMF(5mL)，氩气保护下将反应置于室温下反应16h。加入水和乙酸乙酯，水相用乙酸乙酯萃取，合并有机相，用饱和食盐水洗，干燥浓缩，经过硅胶柱层析(PE/EA＝1:1-1：10)纯化，得到140mg中间体C3-9。
于10mL反应管中依次加入C3-9(0.4mmol,140mg)、联硼酸频那醇酯(0.5mmol,130mg)、KOAc(0.56mmol,55mg)、Pd(dppf)Cl 2(0.04mmol,27mg)和二氧六环(3mL)，反应置换氩气后，氩气保护下于100℃下反应过夜。冷却至室温，母液过滤，滤液干燥浓缩，硅胶柱层析(EA/MeOH＝50:1)纯化，得到120mg中间体C3-10。
3、化合物C3的合成
于10mL反应管中依次加入C3-7(0.3mmol,96mg)、C3-10(0.3mmol,125mg)、K 2CO 3(0.9mmol,100mg)、Pd(dppf)Cl 2(0.03mmol,25mg)和二氧六环(3mL)，反应置换氩气后，氩气保护下于90℃下反应过夜。冷却至室温，母液过滤，滤液浓缩，加入水和乙酸乙酯，水相用乙酸乙酯萃取，合并有机相，有机相用饱和食盐水洗，干燥浓缩，粗品经过液相制备分离，得到30mg化合物C3。
1H NMR(400MHz,Chloroform-d)δ8.94(d,J＝4.4Hz,1H),8.11(d,J＝2.3Hz,1H),7.67–7.58(m,2H),7.55(dd,J＝8.1,2.5Hz,2H),7.32(d,J＝2.7Hz,1H),6.69(dd,J＝19.1,8.6Hz,2H),4.12(q,J＝7.1Hz,2H),4.02(s,3H),3.92(s,2H),3.87-3.79(m,2H),3.67-3.60(m,3H),3.49(s,2H),2.70(m,1H),1.42(s,6H).
实施例4化合物C4的合成
合成路线如下：
Figure PCTCN2020139655-appb-000067
化合物C4的合成:
将化合物C4-1(145mg，0.34mmol)与化合物C4-2(117mg,0.69mmol)溶于10mL DMF中，然后加入0.3mL三乙胺，氩气保护室温搅拌过夜，浓缩，用水稀释，二氯甲烷萃取，合并有机相用饱和食盐水涤，无水硫酸钠干燥，浓缩得粗品，然后用MeOH打浆，过滤得到30mg目标化合物。MS[M+H]520.1.
1H NMR(400MHz,DMSO-d 6)δ10.89(br,1H),9.26(s,1H),8.66(s,1H),8.45-8.33(t,3H),8.12(s,1H),7.94-7.92(t,2H),7.79-7.78(d,1H,J＝1.27Hz),7.11-7.08(d,1H,J＝8.54Hz),6.92-6.90(d,1H,J＝8.84Hz),4.54-4.51(d,2H,J＝14.74Hz),4.36-4.31(q,3H),3.89(s,3H),3.47-3.44(m,2H),3.33(s,3H),3.12-3.09(m,2H),1.35-1.32(t,3H).
实施例5 化合物C5的合成
合成路线如下：
Figure PCTCN2020139655-appb-000068
中间体C5-2的合成：
50mL单口瓶中依次加入C5-1(5mmol,870mg)，联硼酸频那醇酯(5.25mmol,1.33g)，KOAc(7mmol,691mg)，Pd(dppf)Cl 2(0.5mmol,400mg)和二氧六环(10mL)，反应置换氩气后，氩气保护下于90℃下反应过夜。冷却至室温，母液过滤，滤液干燥浓缩，硅胶柱层析(DCM/MeOH＝50:1)得到880mg化合物C5-2。
中间体C5-3的合成：
50mL单口瓶中依次加入C5-2(0.4mmol,88mg)，C1-7(0.2mmol,75mg)，K 2CO 3(0.3mmol,42mg)，Pd(dppf)Cl 2(0.034mmol,25mg)和二氧六环(5mL)，反应置换氩气后，氩气保护下于60℃下反应过夜。冷却至室温，母液过滤，滤液浓缩，加入水和乙酸乙酯，水相用乙酸乙酯萃取，合并有机相，有机相用饱和食盐水洗，干燥浓缩，经硅胶柱层析(DCM/MeOH＝50:1)得到50mg化合物C5-3。
化合物C5的合成：
10mL反应管中依次加入C5-3(0.13mmol,40mg)，C5-4(0.19mmol,54mg)，K 2CO 3(0.21mmol,30mg)和DMF(2mL)，氩气保护下将反应置于90℃下反应过夜。冷却至室温加入水和乙酸乙酯，水相用乙酸乙酯萃取，合并有机相，用饱和食盐水洗，干燥浓缩，经过硅胶柱层析(DCM/MeOH＝20:1)得到10mg化合物C5。
1H NMR(400MHz,Chloroform-d)δ8.71(d,J＝1.5Hz,1H),8.33(d,J＝5.4Hz,1H),8.09(d,J＝2.3Hz,1H),7.80(dd,J＝6.9,0.8Hz,1H),7.72-7.69(m,2H),7.50(dd,J＝5.9,1.5Hz,1H),7.10(dd,J＝5.2,1.5Hz,1H),6.94(d,J＝1.4Hz,1H),6.79-6.58(m,2H),4.20-4.06(m,1H),4.00(s,3H),3.90(s,3H),3.18(s,2H),2.59-2.21(m,2H),2.06(d,J＝8.8Hz,2H),1.80(m,2H).
实施例6 化合物C6的合成
合成路线如下：
Figure PCTCN2020139655-appb-000069
中间体C6-2的合成：
将C6-1(2.5g，18.5mmol)和吡啶(1.6mL)溶于二氯甲烷(15mL)，冰浴下滴加三氟乙酸酐(4.08g，19.42mmol)，自然升温至室温搅拌过夜。反应液加入水中，二氯甲烷萃取，干燥浓缩，柱层析得4.03g化合物C6-2。
中间体C6-3的合成：
将C6-2(3.43g，14.8mmol)溶于浓硫酸(30mL)，在-20℃下缓慢滴加浓硝酸(65％，1.73mL)超过10分钟，并于该温度下搅拌1小时，TLC显示基本反应完全。将反应液倒入冰水浴中，乙酸乙酯萃取，合并有机相，依次用饱和碳酸氢钠溶液、食盐水洗涤，干燥有机相，浓缩，残留物加入石油醚打浆两次，过滤得2.9g化合物C6-3。
中间体C6-4的合成：
将C6-3(2.9g)加入氨水(100mL)，50℃搅拌1小时，TLC显示反应完全。冷却，过滤，固体用水洗涤，干燥得1.63g化合物C6-4。
中间体C6-5的合成：
将C6-4(1.56g，8.68mmol)溶于DMF(30mL)中，在0度下加入NBS(3.4g，19.1mmol)，于室温下搅拌15小时。将反应液倒入水中，用甲基叔丁基醚萃取，干燥，浓缩，柱层析得1.76g化合物C6-5。
中间体C6-6的合成：
将C6-5(1.76g，5.2mmol)加入乙醇(25mL)和浓硫酸(3.22g)中，在60度下加入亚硝酸钠(1.8g，26mmol)，缓慢升温至90度，并于90度搅拌2小时。TLC显示反应完全，冷却，将反应液倒入冰水中，过滤，滤饼用水洗，干燥得1.55g化合物C6-6。
中间体C6-7的合成：
将化合物C6-6(1.5g，0.2mmol)溶于乙酸(23mL)中，于90度下分批加入铁粉(1.56g，6mmol)，在90度反应1小时。TLC显示反应完全，冷却，减压除去溶剂，残留物加入乙酸乙酯，过滤，滤饼用乙酸乙酯洗涤。合并有机相，有机相用饱和碳酸氢钠洗涤，食盐水洗涤，干燥，浓缩柱层析得0.79g化合物C6-7。
化合物C6-8的合成：
将化合物C6-7(293mg)加入盐酸中(6M，3.6mL)，在-10度～0度下滴加亚硝酸钠的水溶液(75.9mg，0.4mL)。加毕，在0度下搅拌1.5小时，自然升至室温搅拌过夜。将反应液于85度搅拌4.5小时，冷却，过滤，滤饼依次用水，乙醚洗涤，真空干燥得153mg化合物C6-8。
1H NMR(400MHz,DMSO-d)δ13.43(br，1H),7.77(d,J＝1.68Hz,1H),7.71-7.70(m,2H).
化合物C6-10的合成：
将C6-8(575mg，1.89mmol)加入氯仿(35mL)，三溴氧磷(10.78g)于70度搅拌过夜。冷却，浓缩，残留物加入冰水，乙酸乙酯萃取2次，合并有机相，并依次用饱和碳酸氢钠、食盐水洗涤，充分干燥，浓缩得534mg粗品C6-9。取粗品512mg化合物C6-9，加入10mL DMSO，氰化亚铜(150mg)在氮气保护下于100度反应5.5小时，TLC检测反应完全。冷却，加入乙酸乙酯(100mL)，过滤，滤饼加入氨水，乙酸乙酯萃取。合并有机相，并用食盐水洗涤，干燥浓缩柱层析得90mg化合物C6-10。
1H NMR(400MHz,DMSO-d)δ9.5999(s，1H),8.88(d,J＝1.92Hz,1H),8.32(d,J＝1.88Hz,1H).
化合物C6-11的合成：
将化合物C6-10(152mg，0.48mmol)化合物C6-12(185mg，0.44mmol)，碳酸钾(132mg，0.96mmol)和[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(26.3mg，0.36mmol)加入DMF(4mL)和水(0.4mL)中，氩气保护下室温反应过夜，反应液加入水，乙酸乙酯萃取，有机相干燥浓缩，柱层析得25mg化合物C6-11。
化合物C6的合成：
将化合物C6-11(15mg)，1-甲基吡唑-4-硼酸频哪醇酯(12mg)，[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(3mg)和碳酸钾(8.28mg)加入二氧六环(1.8mL)和水(0.18mL)，在氩气保护下于室温搅拌过夜。加入乙酸乙酯萃取，干燥浓缩，柱层析得化合物C6。
实施例7 化合物C7的合成
合成路线如下：
Figure PCTCN2020139655-appb-000070
中间体C7-2的合成
于50mL单口瓶加入C7-1(1.79mmol,500mg)和15mL盐酸/二氧六环(4M),反应在室温下过夜，TLC显示反应完全，反应液浓缩后得粗品400mg,直接下一步。
中间体C7-4的合成
于10mL反应管瓶依次加入C7-2(1.08mmol,230mg)，C7-3(1.1mmol,179mg)，DIPEA(8mmol,1g)和DMF(5mL)，氩气保护下将反应置于60度下反应4h。加入水和乙酸乙酯，水相用乙酸乙酯萃取，合并有机相，用饱和食盐水洗，干燥浓缩，经过硅胶柱层析(PE/EA＝10:1)得到棕色油状产品100mg。
化合物C7的合成
于10mL反应管瓶依次加入C7-4(0.175mmol,55mg)，C5-3(0.19mmol,46mg)，K 2CO 3(0.26mmol,36g)和DMF(1mL)，氩气保护下将反应置于80度下反应16h。冷却至室温，加入水和乙酸乙酯，水相用乙酸乙酯萃取，合并有机相，用饱和食盐水洗，干燥浓缩，经过硅胶柱层析(EA/MeOH＝15:1)得到12mg化合物C7。
1H NMR(400MHz,Methanol-d4)δ9.06(d,J＝1.4Hz,1H),8.42(s,1H),8.30(d,J＝5.3Hz,1H),8.25–8.11(m,2H),8.00(s,1H),7.87–7.70(m,2H),7.25(dd,J＝5.2,1.4Hz,1H),7.06(d,J＝1.3Hz,1H),6.80(d,J＝8.5Hz,1H),4.41(d,J＝13.2Hz,1H),3.96(s,3H),3.84(s,3H),3.61(s,2H)3.72–3.51(m,1H),3.28–3.10(m,2H),2.92(q,J＝8.3Hz,1H),2.39–2.12(m,2H),2.00–1.74(m,2H).
实施例8 化合物C8的合成
合成路线如下：
Figure PCTCN2020139655-appb-000071
中间体C8-1的合成
50mL单口瓶中加入C5-3(316mg，1mmol)，N-Boc-4-氯哌啶(263mg，1.2mmol)，N,N-二甲基甲酰胺(6mL)，搅拌下加入碳酸钾(414mg，3mmol)，将反应置于80度下反应过夜，将反应冷至室温，加水(60mL)稀释，乙酸乙酯(3x10mL)萃取，合并有机相，用饱和食盐水(2x10mL)洗涤有机相，无水硫酸钠干燥有机相，过滤，浓缩有机相，柱层析得产品199mg。
中间体C8-2的合成
50ml单口瓶中加入C8-1(100mg，0.2mmol)，1,4-二氧六环(5mL)，滴加HCl/dioxane(3mL)室温反应2小时，有固体析出，过滤，干燥得产品50mg。
化合物C8的合成
50mL单口瓶中加入C8-2(50mg，0.115mmol)，5-(氯甲基)-2-甲氧基吡啶(36mg，0.23mmol)，N,N-二甲基甲酰胺(5mL)，搅拌下加入三乙胺(116mg，1.15mmol)，将反应置于室温下反应过夜，加水(50mL)稀释，乙酸乙酯(3x10mL)萃取，合并有机相，用饱和食盐水(2x10mL)洗涤有机相，无水硫酸钠干燥有机相，过滤，浓缩有机相，柱层析得27.1mg化合物C8，纯度99.2％。
1H NMR(400MHz,CDCl 3)δ8.71(d,J＝1.2Hz,1H),8.31-8.29(m,2H), 7.80-7.71(m,3H),7.50(d,J＝0.88,1H),7.06(dd,J＝5.16,1.28,1H),6.92(s,1H),6.75(d,J＝8.48,1H),5.25(br,1H),4.00(s,3H),3.93(s,3H),3.61(s,2H),2.87(br,2H),2.70-2.30(m,2H),2.20(br,2H),1.98(br,2H).
实施例4生物活性测试实验
下面对本发明化合物进行生物活性测试。
生物活性测试实验过程如下：
使用Kinase activity Assay方法在ATP Km浓度下筛选实施例制备的化合物对野生型RET激酶的活性，并使用星形孢菌素(Staurosporine)做对照品，化合物的生物活性筛选将在10个浓度下重复测定。
1、受试样品
各样品分别配成浓度为10mM的溶液。
2、实验方法
(1)为实验用激酶准备基本缓冲溶液和淬灭缓冲溶液
20mM Hepes(pH 7.5)、10mM MgCl 2、1mM EGTA、0.02％Brij35、0.02mg/ml BSA、0.1mM Na 3VO 4、2mM DTT、1％DMSO。
(2)为实验用激酶准备化合物
测试化合物在100％二甲基亚砜中溶解至特定浓度。用Integra Viaflo Assist辅助DMSO进行(连续)稀释。
(3)反应步骤
将激酶加入新制备的基本反应缓冲液；
向上述底物溶液中加入任何所需的辅因子；
将野生型RET激酶加入到底物溶液中，轻轻混合；
用Acoustic technology(Echo550；nanoliter range)将100％二甲基亚砜中的化合物送入激酶反应混合物中，在室温下培养20分钟；
向反应混合物中加入33P-ATP(Specific activity 10Ci/l)，开始反应；
室温下孵育2小时；
用filter-binding方法检测放射性；
激酶活性数据表示为与媒介(二甲基亚砜)反应相比，试验样品中剩余激酶活性的百分比。使用Prism(GRAPHPAD软件)获得IC50值和曲线拟合。
得到的受试样品对野生型RET的抑制活性IC50(nM)值如表1所示。
表1
Figure PCTCN2020139655-appb-000072
Figure PCTCN2020139655-appb-000073
从上表可知，通过体外生物活性筛选，以星形孢菌素(Staurosporine)为对照品，我们所合成的化合物野生型RET激酶均有很好的抑制能力。此外，本发明研究表明，其他基团相同的情况下Ar 1和Ar 2均为五元杂芳基的化合物(如化合物C1或C2)比Ar 1和/或Ar 2为六元杂芳基的化合物具有更好的抑制效果，有望进一步开发成为用于调节RET激酶活性或治疗RET相关疾病方面的药物。
以上所述仅为本发明的实施例，并非因此限制本发明的专利范围，凡是利用本发明说明书内容所作的等效变换，或直接或间接运用在其他相关的技术领域，均包括在本发明的专利保护范围内。

Claims (15)

  1. 一种式F化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药，
    Figure PCTCN2020139655-appb-100001
    其中，
    G选自：A-Z 1-或D；
    Ar 1为含1～4个N原子的取代或未取代5-6元杂芳基，其中，所述取代是指被选自下组的一个或多个基团取代：H、CN、卤素、甲基、乙基或环丙基；
    Ar 2选自取代或未取代的下组基团：5-6元芳基或5-6元杂芳基，其中，所述取代是指被选自下组的一个或多个基团取代：C1-C6烷基、卤素、羟基、氧代基(＝O)、C1-C6杂烷基、C1-C6烷氧基、C3-C14环烷基、3-14元杂环烷基或氰基；
    K选自：C或N；
    Q 2选自下组：饱和4-7元单环杂环基、饱和7-8元桥连杂环基、饱和7-11元螺杂环基、
    Figure PCTCN2020139655-appb-100002
    其中，所述杂环基中含有1、2或3个作为环骨架的氮杂原子，m、n、m’和n’各自独立地为0、1、2、3；
    且Q 2上的H可以任选地被选自下组的一个或多个取代基取代：氘、羟基、卤素、氰基、酯基、酰胺基、羰基、氧代基(＝O)、氨基、C1-C6烷基、C1-C6卤代烷基、C1-C6硫代烷基、C1-C6烷氧基、C1-C6杂烷基、C1-C6烷胺基、C3-C6环烷基、C3-C8环烷胺基、C6-C14芳基或5-14元杂芳基；R 3为取代或未取代5-6元杂芳基、C1-C6烷基或C1-C6杂烷基，其可任选地被一个或多个C1-C6烷基取代；
    B独立地选自取代或未取代下组基团：3-7元环、C6-C14芳基、5-14元杂芳基、7-20元螺环或桥环，且所述环含有0-3个选自N、O、S的杂原子；所述取代是指被选自下组的一个或多个取代基取代：氘、羟基、卤素、氰基、酯基、酰胺基、羰基、氨基、C1-C6烷基、C1-C6卤代烷基、C1-C6硫代烷基、C1-C6烷氧基、C1-C6杂烷基、C1-C6烷基胺基、C3-C6环烷基、C3-C8环烷基胺基、C6-C14芳基或5-14元杂芳基；
    E独立地选自取代或未取代下组基团：氢、C1-C6烷基、C1-C6烷氧基、C3-C6环烷基、C1-C6杂烷基、3-6元杂环基，其中，所述取代是指被0-5个R a取代；
    各R 5独立地选自取代或未取代下组基团：氢、硝基、氰基、卤素、C1-C6烷基、C2-C6 烯基、C2-C6炔基、C1-C6烷氧基、C1-C6杂烷基、C3-C12环烷基、C6-C14芳基、5-14元杂芳基、C6-C14芳氧基、C6-C14芳基C1-C6烷基、3-12元杂环基、3-12元杂环烷基、-C(O)R 6、-OC(O)R 6、-C(O)OR 6、-(C1-C6亚烷基)-C(O)R 6、-SR 6、-S(O) 2R 6、-S(O) 2-N(R 6)(R 7)、-(C1-C6亚烷基)-S(O) 2R 6、-(C1-C6亚烷基)-S(O) 2-N(R 6)(R 7)、-N(R 6)(R 7)、-C(O)-N(R 6)(R 7)、-N(R 6)-C(O)R 7、-N(R 6)-C(O)OR 7、-(C1-C6亚烷基)-N(R 6)-C(O)R 7、-N(R 6)S(O) 2R 7和-P(O)(R 6)(R 7)；其中，所述取代是指被0、1、2、3、4或5个R a取代；R 6和R 7各自独立地选自下组：C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6烷氧基、C1-C6杂烷基、C3-C6环烷基、C6-C14芳基、5-14元杂芳基、C6-C14芳氧基、C6-C14芳基C1-C6烷基、C3-C6杂环烷基、C1-C6烷胺基、C3-C6环烷基胺基；或R 6和R 7与其相邻的N原子一起构成取代或未取代3-6元杂环基；其中，所述取代是指被0、1、2、3、4或5个R a取代；
    A独立地选自下组：H、取代或未取代C1-C6烷基、取代或未取代4-6元杂环基、(R 1R 2N)C(＝O)-；其中，所述取代选自下组的一个或多个基团：卤素、-OH、C1～C6烷氧基、C1～C6烷基、胺基、5-6元杂芳基、4-6元杂环基、C3-C6环烷基、酰胺基、(R 1R 2N)C(＝O)-、羟基C1-C6烷基、(C1-C6烷基)C(＝O)-、C1-C6烷氧基、氧代基和(C1-C6烷氧基)C(＝O)-；R 1和R 2各自独立的选自：H或C1-C6烷基，其中，烷基可任选地被1-3个氟取代；
    Z 1选自下组：NR b、-S-、-C(R bR c)-或-O-；
    D为5-14元杂芳基，其中，所述杂芳基上的H任选地被一个或多个选自下组的取代基取代：氘、羟基、卤素、氰基、酯基、酰胺基、氧代基、氨基、C1-C6烷基、C1-C6烷氧基、C1-C6杂烷基、C3-C6环烷基、C3-C8环烷基胺基、C6-C14芳基或5-14元杂芳基；所述C1-C6烷基、C1-C6烷氧基、C1-C6杂烷基、C3-C6环烷基、C3-C8环烷基胺基、C6-C14芳基或5-14元杂芳基可进一步被一个或多个选自下组的基团取代：卤素、氰基、羟基；
    f为0、1、2、3、4、5或6；
    R a独立地选自下组：O、C1-C6烷基、卤素、羟基、C1-C6杂烷基、C1-C6烷氧基、C3-C14环烷基、3-14元杂环烷基或氰基；
    R b、R c独立地选自下组：H、C1-C6烷基、卤素、羟基、C1-C6杂烷基、C1-C6烷氧基、C3-C14环烷基、3-14元杂环烷基或氰基；
    限定条件为：
    当
    Figure PCTCN2020139655-appb-100003
    为
    Figure PCTCN2020139655-appb-100004
    时，Ar 2为5-6元杂芳基，且Ar 2通过N与Q 2环和/或
    Figure PCTCN2020139655-appb-100005
    连接；其中，R x选自下组：H、CN、卤素、甲基、乙基或环丙基；Ar 2上的H原子可以被CR a取代。
  2. 如权利要求1所述的化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前 药，其具有式(Ⅰ)、式(Ⅱ)、式(Ⅲ)、式(Ⅳ)、式(V)或式(VI)所示结构，
    Figure PCTCN2020139655-appb-100006
    其中：
    Figure PCTCN2020139655-appb-100007
    为六元杂芳基；
    Figure PCTCN2020139655-appb-100008
    为五元杂芳基；
    X 1、X 2、X 3和X 4各自独立地为CH、N或CR a，且X 1、X 2、X 3和X 4中有0、1、2个为N；
    Y' 1为N；
    Y 1为C或N；
    Y 3、Y 5各自独立地为CH、N或CR a；
    Y 2为N或C；
    Y 4为CH、N或CR a；
    R x独立地选自下组：H、CN、卤素、甲基、乙基或环丙基；
    E、R 5、f、A、Z 1、D、Q 2、B、R a的定义如权利要求1所述；
    限定条件为：在式Ⅰ和式Ⅲ中，当Y 3为N时，Y 4为CH或N时，Y 1和/或Y 2为N。
  3. 如权利要求1所述的化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药，其特征在于，Ar 1为取代或未取代的下组基团：
    Figure PCTCN2020139655-appb-100009
    Figure PCTCN2020139655-appb-100010
    其中，所述取 代是指被选自下组的一个或多个基团取代：H、CN、卤素、甲基、乙基或环丙基。
  4. 如权利要求1所述的化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药，其特征在于，Ar 2中五元或六元杂芳基为
    Figure PCTCN2020139655-appb-100011
    其中，P 1、P 2、P 3和P 4各自独立地选自：N或CH，其中，P 1、P 2、P 3和P 4中有0、1、2个为N，L 1、L 2各自独立地选自：N或C。
  5. 如权利要求1所述的化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药，其特征在于，Q 2为饱和5-6元单环杂环基，其中，所述杂环基中含有一个或两个氮环杂原子，且Q 2上的H可以任选地被选自下组的一个或多个取代基取代：氘、羟基、卤素、氰基、酯基、酰胺基、氧代基、羰基、氨基、C1-C6烷基、C1-C6卤代烷基、C1-C6硫代烷基、C1-C6烷氧基、C1-C6杂烷基、C1-C6烷胺基、C3-C6环烷基、C3-C8环烷胺基、C6-C14芳基或5-14元杂芳基。
  6. 如权利要求2所述的化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药，其特征在于，Y 3为N。
  7. 如权利要求1所述的化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药，其特征在于，B为5-6元杂芳基，且B上H可以任选地被选自下组的一个或多个取代基取代：氘、羟基、卤素、氰基、酯基、酰胺基、羰基、氨基、C1-C6烷基、C1-C6卤代烷基、C1-C6硫代烷基、C1-C6烷氧基、C1-C6杂烷基、C1-C6烷胺基、C3-C6环烷基、C3-C8环烷胺基、C6-C14芳基或5-14元杂芳基。
  8. 如权利要求1所述的化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药，其具有式(VII)、式(VIII)或式(Ⅸ)所示的结构
    Figure PCTCN2020139655-appb-100012
    其中，A、Z 1、D、R x、Q 2、E、B、R 5、f的定义如权利要求1所述，
    Y 3和Y 4各自独立地为CH、N或CR a。
  9. 如权利要求1所述的化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药，其具有式式(Ⅺ)或式(XIII)所示的结构：
    Figure PCTCN2020139655-appb-100013
    其中，A、Z 1、D、R x、Q 2、E、B、R 5、f的定义如权利要求1所述，Y 4和Y 5各自独 立地为CH、N或CR a。
  10. 如权利要求1所述的化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药，其特征在于，其具有式(XIV)所示的结构：
    Figure PCTCN2020139655-appb-100014
    其中，
    各R m独立地选自：C1-C6烷基、卤素、羟基、氧代基(＝O)、C1-C6杂烷基、C1-C6烷氧基、C3-C14环烷基、3-14元杂环烷基或氰基；
    h为0、1或2；
    G、B、Q2、R 5、f的定义如权利要求1所述。
  11. 如权利要求1所述的化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药，所述化合物选自下组：
    Figure PCTCN2020139655-appb-100015
    Figure PCTCN2020139655-appb-100016
    Figure PCTCN2020139655-appb-100017
  12. 一种药物组合物，其包含如权利要求1至11中任一项所述的化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药；和药学上可接受的载体。
  13. 一种如权利要求1至11中任一项所述的化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药或如权利要求12所述的药物组合物在制备用于抑制细胞或受试者中的RET激酶活性的药物中的用途。
  14. 一种如权利要求1至11中任一项所述的化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药或如权利要求12所述的药物组合物在制备用于治疗与RET相关癌症的药物中的用途。
  15. 如权利要求14所述的用途，其特征在于，所述的RET相关癌症选自下组：肺癌、 甲状腺乳头状癌、甲状腺髓样癌、分化型甲状腺癌、复发性甲状腺癌、难治性分化型甲状腺癌、多发性2A或2B型内分泌肿瘤(分别为MEN2A或MEN2B)、嗜铬细胞瘤、甲状旁腺增生、乳腺癌、结肠直肠癌、乳头状肾细胞癌、胃肠粘膜神经节神经瘤病和宫颈癌。
PCT/CN2020/139655 2019-12-27 2020-12-25 用作ret激酶抑制剂的化合物及其应用 Ceased WO2021129841A1 (zh)

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