WO2022166983A1 - Dérivé d'hétéroaryloxypipéridine, composition pharmaceutique de celui-ci et son utilisation - Google Patents

Dérivé d'hétéroaryloxypipéridine, composition pharmaceutique de celui-ci et son utilisation Download PDF

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Publication number
WO2022166983A1
WO2022166983A1 PCT/CN2022/075490 CN2022075490W WO2022166983A1 WO 2022166983 A1 WO2022166983 A1 WO 2022166983A1 CN 2022075490 W CN2022075490 W CN 2022075490W WO 2022166983 A1 WO2022166983 A1 WO 2022166983A1
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methyl
tetrahydro
fluoropropyl
phenyl
indol
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PCT/CN2022/075490
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English (en)
Chinese (zh)
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祖厚贤
王义乾
杜国龙
陈凯
刘湘永
丁列明
王家炳
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贝达药业股份有限公司
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Priority to CN202280009010.4A priority Critical patent/CN116744920A/zh
Publication of WO2022166983A1 publication Critical patent/WO2022166983A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4355—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having oxygen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4365—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—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
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—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
    • 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
    • C07D471/04—Ortho-condensed systems

Definitions

  • the invention belongs to the field of medicine, and in particular relates to a heteroaryl piperidine derivative and a pharmaceutical composition and application thereof.
  • Estrogen receptor is a transcriptional regulatory protein that mediates ligand-activated activation of multiple biological effects through its interaction with endogenous estrogens.
  • ER contains two isoforms, ER ⁇ and ER ⁇ .
  • ER ⁇ is mainly distributed in the uterus, ovary, testis, pituitary, kidney, epididymis and adrenal gland, while ER ⁇ is mainly distributed in the prostate, ovary, lung, bladder, brain and blood vessels. Because full agonists or full antagonists have serious side effects, the research of selective estrogen receptor modulator SERM came into being.
  • SERM behaves as an agonist in certain tissues such as bone, liver, and ER ⁇ -concentrated areas of the cardiovascular system, and as an antagonist in other tissues such as breast. It can be either an agonist or an antagonist in the uterus (where ERa is more pronounced).
  • SERMs include Tamoxifen, Raloxifene, Bazedoxifene, Toremifene, etc.
  • SESDs Selective estrogen receptor downregulators
  • AF1 and AF2 Drugs (complete antagonists).
  • Fulvestrant is the only SERD drug currently approved for clinical use for the treatment of ER+ breast cancer, but it has poor druggable properties, is rapidly metabolized and must be administered by monthly intramuscular injections, in contrast to what has been seen in in vitro studies This limits the efficient degradation of ER compared to complete ER degradation ( ⁇ 50% ER degradation in clinical samples).
  • Selective estrogen receptor down-regulators have shown some therapeutic advantages, but more orally available selective estrogen receptors still need to be developed, so that drug candidates have more excellent properties, such as better efficacy, lower side effects, oral It has better absorption, good pharmacokinetic properties and blood-brain barrier penetrating ability, etc., so that it can be better used for the prevention or treatment of estrogen receptor-related diseases.
  • the present invention provides an oral selective estrogen receptor compound with good pharmacokinetic properties and blood-brain barrier penetrating ability, and a pharmaceutical composition and application thereof.
  • the present invention provides a compound represented by formula (I), its stereoisomer, tautomer or pharmaceutically acceptable salt:
  • W is selected from O, NH or S
  • D is CR 9 or N
  • E is CR 10 or N
  • L 1 is selected from -O- or -NH-;
  • L 2 is selected from -NH- or C 3 -C 8 heterocyclyl; the C 3 -C 8 heterocyclyl is optionally substituted with one or more R 7 ;
  • R 1 , R 1 ' are independently selected from H, halogen, C 1 -C 3 alkyl, -OR c , -N(R c ) 2 , -SR c , -COR d , -NO 2 , -S ( O) 2 R d , C 3 -C 6 cycloalkyl, 3-6 membered heterocyclyl, C 6 -C 10 aryl, 5-10 membered heteroaryl; wherein, the C 1 -C 3 alkyl , C 3 -C 6 cycloalkyl, 3-6 membered heterocyclyl, C 6 -C 10 membered aryl, 5-10 membered heteroaryl optionally replaced by one or more H, halogen, -OH, -OC 1 -C 3 alkyl, -SO 2 C 1 -C 3 alkyl, -NH 2 , -NHSO 2 C 1 -C 3 alkyl, -NHC 1 -C 3
  • R c is selected from H, C 1 -C 5 alkyl, -COC 1 -C 5 alkyl, -S(O) 2 C 1 -C 5 alkyl, C 3 -C 6 cycloalkyl, 3-6 membered Heterocyclic group; wherein, the C 1 -C 5 alkyl group, C 3 -C 6 cycloalkyl group, 3-6 membered heterocyclic group are optionally replaced by one or more H, C 1 -C 3 alkyl group, -CONH 2 , -S(O) 2 C 1 -C 3 alkyl, -OC 1 -C 3 alkyl, -OH, -N(C 1 -C 3 alkyl) 2 , -P(O)(OH ) 2 replace;
  • R d is selected from H, C 1 -C 5 alkyl, -NH 2 , -OH, -NHC 1 -C 5 alkyl, -N(C 1 -C 5 alkyl) 2 , -OC 1 -C 5 alkane base, -NHC 3 -C 6 cycloalkyl, 3-6 membered heterocyclyloxy; wherein, the C 1 -C 5 alkyl, C 3 -C 6 cycloalkyl, 3-6 membered heterocyclyl optionally substituted with H, -OH, C 1 -C 3 alkyl, -OC 1 -C 3 alkyl;
  • R 2 is selected from C 1 -C 9 alkyl, C 3 -C 9 cycloalkyl, C 3 -C 9 heterocyclyl, C 6 -C 10 aryl, C 5 -C 10 heteroaryl, -(C 1 -C 6 alkylene)-(C 3 -C 9 cycloalkyl), -(C 1 -C 6 alkylene)-(C 3 -C 9 heterocyclyl), -C(O)R b , -C(O)N(R a ) 2 , -SO 2 R a and -SO 2 N(R a ) 2 , wherein the C 1 -C 9 alkyl, C 3 -C 9 cycloalkyl, C 3 -C 9 heterocyclyl, C 6 -C 10 aryl, C 5 -C 10 heteroaryl, -(C 1 -C 6 alkylene)-(C 3 -C 9 cycloalkyl), - (C 1 -
  • Each R 5 is the same or different and each is independently selected from H, F, Cl, Br, I, C 1 -C 6 alkyl, -OC 1 -C 6 alkyl, -CN, -NH 2 , - NO 2 , -COOH, -CHO, -OH, C 3 -C 6 cycloalkyl, 3-6-membered heterocyclyl, 6-10-membered aryl and 5-10-membered heteroaryl; wherein, the C 1 -C 6 alkyl, -OC 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 3-6 membered heterocyclyl, 6-10 membered aryl and 5-10 membered heteroaryl are each independently any C 1 -C 3 alkyl substituted by C 1 -C 3 alkyl, F, Cl, Br, I, -CN, -NH 2 , -NO 2 , -OH, hydroxyl, -OC 1 -C One of 3
  • R7 is H, F, Cl, Br, I, OH or NH2 ;
  • R8 is H, F or CN
  • D is selected from CR 9 or N
  • E is selected from CR 10
  • R 9 is selected from H, halogen, C 1 -C 3 alkyl, halogenated C 1 -C 6 alkoxy
  • R 10 is selected from halo of C 1 -C 6 alkoxy
  • E is selected from CR 10 or N
  • D is selected from CR 9
  • R 9 is selected from halogenated C 1 -C 6 alkoxy
  • R 10 is selected from H, halogen, C 1 -C 3 alkyl, halogenated of C 1 -C 6 alkoxy;
  • R a is selected from H, C 1 -C 6 alkyl, C 2 -C 8 alkenyl, propargyl, C 3 -C 6 cycloalkyl and 3-6 membered heterocyclyl, said C 1 -C 6 Alkyl, C 2 -C 8 alkenyl, propargyl, C 3 -C 6 cycloalkyl, and 3-6 membered heterocyclyl are optionally selected by one or more groups independently selected from the following: F, CI , Br, I, CN, OH, OCH 3 and SO 2 CH 3 substituted;
  • R b is independently selected from H, OH, -O(C 1 -C 3 alkyl), C 1 -C 6 alkyl, C 2 -C 8 alkenyl, propargyl, -(C 1 -C 6 alkylene base)-(C 3 -C 6 cycloalkyl), C 3 -C 6 cycloalkyl and 3-6 membered heterocyclyl, wherein the C 1 -C 3 alkyl, C 1 -C 6 alkyl , C 2 -C 8 alkenyl, propargyl, -(C 1 -C 6 alkylene)-(C 3 -C 6 cycloalkyl), C 3 -C 6 cycloalkyl and 3-6 membered heteroalkyl
  • the cyclyl group is optionally by one or more groups independently selected from: F, Cl , Br, I, CN, -CH2F , -CHF2 , -CF3 , -CH2CF3 ,
  • n 0, 1, 2, 3 or 4;
  • r 0, 1, 2 or 3;
  • s is 1, 2 or 3.
  • the above-mentioned compound is further a compound represented by formula (Ia):
  • D is CR 9 or N
  • E is CR 10 or N
  • L 1 is selected from -O- or -NH-;
  • L 2 is selected from -NH- or C 3 -C 8 heterocyclyl; the C 3 -C 8 heterocyclyl is optionally substituted by R 7 ;
  • R 1 , R 1 ' are independently selected from H, halogen, C 1 -C 3 alkyl
  • R7 is H, F, Cl, Br, I, OH or NH2 ;
  • R8 is H, F or CN
  • R 9 is selected from H, halogen, C 1 -C 3 alkyl, halogenated C 1 -C 6 alkoxy
  • R 10 is selected from halo C 1 -C 6 alkoxy (eg halogenated C 1 -C 3 alkoxy, halogenated C 1 -C 4 alkoxy, halogenated C 1 -C 5 alkoxy); or
  • E is selected from CR 10 or N
  • D is selected from CR 9 and R 9 is selected from halogenated C 1 -C 6 alkoxy (eg halogenated C 1 -C 3 alkoxy, halogenated C 1 -C 4 alkoxy, halogenated C 1 -C 5 alkoxy), R 10 is selected from H, halogen, C 1 -C 3 alkyl, halogenated C 1 -C 6 alkoxy;
  • R 11 is selected from H, halogen, C 1 -C 3 alkyl; the C 1 -C 3 alkyl is optionally substituted with one or more halogens;
  • R 12 is selected from H, halogen, C 1 -C 3 alkyl; the C 1 -C 3 alkyl is optionally substituted by one or more of -OH, halogen, C 1 -C 3 alkoxy replaced;
  • R 13 is H or halogen
  • R 12 and R 13 together with the carbon atom to which they are attached form C 3 -C 8 cycloalkyl, C 3 -C 8 heterocyclyl;
  • r 0, 1, 2 or 3;
  • s is 1, 2 or 3.
  • the above-mentioned compound is further a compound represented by formula (Ib):
  • Ring A is selected from C 3 -C 8 heterocyclyl
  • D is CR 9 or N
  • E is CR 10 or N
  • L 1 is selected from -O- or -NH-;
  • R 1 , R 1 ' are independently selected from H, halogen, C 1 -C 3 alkyl
  • R7 is H, F, Cl, Br, I, OH or NH2 ;
  • R8 is H, F or CN
  • R 9 is selected from H, halogen, C 1 -C 3 alkyl, halogenated C 1 -C 6 alkoxy
  • R 10 is selected from halo C 1 -C 6 alkoxy (eg halogenated C 1 -C 3 alkoxy, halogenated C 1 -C 4 alkoxy, halogenated C 1 -C 5 alkoxy); or
  • E is selected from CR 10 or N
  • D is selected from CR 9 and R 9 is selected from halogenated C 1 -C 6 alkoxy (eg halogenated C 1 -C 3 alkoxy, halogenated C 1 -C 4 alkoxy, halogenated C 1 -C 5 alkoxy), R 10 is selected from H, halogen, C 1 -C 3 alkyl, halogenated C 1 -C 6 alkoxy;
  • R 11 is selected from H, halogen, C 1 -C 3 alkyl; the C 1 -C 3 alkyl is optionally substituted with one or more halogens;
  • R 12 is selected from H, halogen, C 1 -C 3 alkyl; the C 1 -C 3 alkyl is optionally substituted by one or more of -OH, halogen, C 1 -C 3 alkoxy replaced;
  • R 13 is H or halogen
  • R 12 and R 13 together with the carbon atom to which they are attached form C 3 -C 8 cycloalkyl, C 3 -C 8 heterocyclyl;
  • r 0, 1, 2 or 3;
  • s is 1, 2 or 3.
  • the above-mentioned compound is further a compound represented by formula (Ic):
  • D is CR 9 or N
  • E is CR 10 or N
  • L 1 is selected from -O- or -NH-;
  • R 1 is selected from H, halogen, C 1 -C 3 alkyl
  • R7 is H, F, Cl, Br, I, OH or NH2 ;
  • R8 is H, F or CN
  • R 9 is selected from H, halogen, C 1 -C 3 alkyl, halogenated C 1 -C 6 alkoxy
  • R 10 is selected from halo C 1 -C 6 alkoxy (eg halogenated C 1 -C 3 alkoxy, halogenated C 1 -C 4 alkoxy, halogenated C 1 -C 5 alkoxy); or
  • E is selected from CR 10 or N
  • D is selected from CR 9 and R 9 is selected from halogenated C 1 -C 6 alkoxy (eg halogenated C 1 -C 3 alkoxy, halogenated C 1 -C 4 alkoxy, halogenated C 1 -C 5 alkoxy), R 10 is selected from H, halogen, C 1 -C 3 alkyl, halogenated C 1 -C 6 alkoxy;
  • R 11 is Me, F or CH 2 F
  • R 12 is Me, F, CH 2 F, CHF 2 , CF 3 , CH 2 OMe or CH 2 OH;
  • R 13 is H or F
  • R 12 and R 13 together with the carbon atom to which they are attached form cyclopropyl, cyclobutyl or oxetanyl;
  • p 1, 2 or 3.
  • the above-mentioned compound is further a compound represented by formula (Id):
  • D is CR 9 or N
  • E is CR 10 or N
  • R 1 is selected from H, halogen, C 1 -C 3 alkyl
  • R7 is H, F, Cl, Br, I, OH or NH2 ;
  • R8 is H, F or CN
  • R 9 is selected from H, halogen, C 1 -C 3 alkyl, halogenated C 1 -C 6 alkoxy
  • R 10 is selected from halo C 1 -C 6 alkoxy (eg halogenated C 1 -C 3 alkoxy, halogenated C 1 -C 4 alkoxy, halogenated C 1 -C 5 alkoxy); or
  • E is selected from CR 10 or N
  • D is selected from CR 9 and R 9 is selected from halogenated C 1 -C 6 alkoxy (eg halogenated C 1 -C 3 alkoxy, halogenated C 1 -C 4 alkoxy, halogenated C 1 -C 5 alkoxy), R 10 is selected from H, halogen, C 1 -C 3 alkyl, halogenated C 1 -C 6 alkoxy;
  • R 11 is Me, F or CH 2 F
  • R 12 is Me, F, CH 2 F, CHF 2 , CF 3 , CH 2 OMe or CH 2 OH;
  • R 13 is H or F
  • R 12 and R 13 together with the carbon atom to which they are attached form cyclopropyl, cyclobutyl or oxetanyl;
  • p 1, 2 or 3.
  • the above-mentioned compound is further a compound represented by formula (Ie) or formula (If) or formula (Ig):
  • the above-mentioned compound is further a compound represented by formula (Ih) or formula (Ii) or formula (Ij):
  • R 1 , R 1 ' are the same or different, and are independently selected from H, -CH 3 .
  • D is CR 9
  • E is CR 10
  • R 9 is selected from H, Cl, F, halogenated C 1 -C 6 alkoxy
  • R 10 is selected from halogenated C 1 -C 6 alkoxy oxy
  • R 9 is selected from H, Cl, F, -OCH 2 F, -OCHF 2 or -OCF 3
  • R 10 is selected from -OCH 2 F, -OCHF 2 or -OCF 3 .
  • D is N and E is CR 10 ;
  • R 10 is selected from halogenated C 1 -C 6 alkoxy; further R 10 is selected from -OCH 2 F, -OCHF 2 or -OCF 3 .
  • D is CR 9
  • E is CR 10
  • R 9 is selected from halogenated C 1 -C 6 alkoxy
  • R 10 is selected from H, Cl, F, halogenated C 1 -C 6 alkane oxy
  • R 9 is selected from -OCH 2 F, -OCHF 2 or -OCF 3
  • R 10 is selected from H, Cl, F, -OCH 2 F, -OCHF 2 or -OCF 3 .
  • D is CR 9 and E is N; R 9 is selected from halogenated C 1 -C 6 alkoxy; further, R 9 is selected from -OCH 2 F, -OCHF 2 or -OCF 3 .
  • D is CR9 and E is N; R9 is selected from -OCH2F , -OCHF2 or -OCF3 .
  • D is N and E is CR 10 ; R 10 is selected from -OCH 2 F, -OCHF 2 or -OCF 3 .
  • R 11 is Me, F or CH 2 F.
  • R12 is Me, F, CH2F , CHF2 , CF3 , CH2OMe , or CH2OH .
  • R 13 is H or F.
  • R 12 and R 13 together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, or oxetanyl group.
  • R 11 is F
  • R 12 is F
  • R 13 is F
  • R 11 is F
  • R 12 is CH 2 OH
  • R 13 is F
  • R 11 is F
  • R 12 and R 13 together with the carbon atom to which they are attached form an oxetanyl group.
  • R8 is H.
  • R8 is F.
  • R8 is CN
  • r is 2; s is 2.
  • r is 2; s is 1.
  • Ring A is selected from C4 - C6 heterocyclyl; further, Ring A is azetidinyl, pyrrolidinyl, or piperidinyl.
  • p is 1.
  • p is 2.
  • the compound represented by the formula (I) is selected from:
  • the compound represented by the formula (I) is selected from:
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of at least one compound represented by the formula (I) and at least one pharmaceutically acceptable excipient.
  • the present invention also provides the use of the compound represented by formula (I) in the preparation of a medicament for treating estrogen receptor-related diseases.
  • the estrogen receptor-related disease is a cancer selected from the group consisting of breast cancer, lung cancer, ovarian cancer, endometrial cancer, prostate cancer, and uterine cancer.
  • the present invention also provides a method for treating an estrogen receptor-related disease in a patient, which comprises administering to the patient a therapeutically effective amount of the compound represented by the above formula (I).
  • the estrogen receptor-related disease is a cancer selected from the group consisting of breast cancer, lung cancer, ovarian cancer, endometrial cancer, prostate cancer, and uterine cancer.
  • halo and halogen as used herein refer to fluorine, chlorine, bromine or iodine.
  • Preferred halogen groups include fluorine, chlorine and bromine.
  • alkyl includes linear or branched monovalent saturated hydrocarbon groups. Alkyl groups as used herein may be optionally substituted with one to more substituents. Non-limiting examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3-(2-methyl) ) butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl, 2-methylpentyl and the like. Similarly, “C 1-8 " in "C 1-8 alkyl” refers to a linear or branched arrangement containing 1 , 2, 3, 4, 5, 6, 7 or 8 carbon atoms group.
  • Alkenyl and alkynyl groups include straight or branched chain alkenyl and alkynyl groups.
  • C 2-8 alkenyl and “C 2-8 alkynyl” refer to alkenyl groups containing 2, 3, 4, 5, 6, 7 or 8 carbon atoms arranged in a straight or branched chain or alkynyl.
  • Alkoxy refers to the oxyether form of the aforementioned straight or branched chain alkyl groups, ie, -O-alkyl.
  • Haloalkoxy means the aforementioned "alkoxy” is substituted with one or more halogens; non-limiting examples of halogenated alkoxy groups include, but are not limited to, for example, -OCH2F, - OCHF 2 , -OCF 3 , -OCH 2 CH 2 F, -OCH 2 CHF 2 , -OCH 2 CF 3 , -OCHFCH 3 , -OCF 2 CH 3 , -OCHFCH 2 F and the like.
  • compositions comprising "a” pharmaceutically acceptable excipient can be interpreted to mean that the composition includes “one or more” pharmaceutically acceptable excipients.
  • aromatic ring refers to an unsubstituted or substituted monocyclic, polycyclic or fused-ring aromatic group including carbon atoms, or unsubstituted or substituted including heteroatoms, such as A monocyclic, paracyclic or condensed aromatic group of N, O or S, when it is a polycyclic or condensed ring, at least one ring is aromatic.
  • the aromatic ring is a 5- to 10-membered monocyclic or bicyclic aromatic ring group. Examples of such aromatic rings include, but are not limited to, phenyl, pyridyl, pyrazolyl, pyrimidinyl, chromofuran, indolyl.
  • cycloalkyl refers to monocyclic and polycyclic ring systems containing only carbon atoms in the ring, and which may be optionally substituted with one or more substituents.
  • Cycloalkyl as used herein refers to and includes saturated or unsaturated non-aromatic ring systems.
  • the term cycloalkyl further includes bridged, fused and spiro ring systems.
  • Non-limiting examples of cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, spiro[3.4]octyl, bicyclo[2.2.1]heptane, and the like.
  • heterocyclyl in the present invention, unless otherwise specified, refers to unsubstituted or substituted monocyclic and polycyclic ring systems consisting of carbon atoms and 1-3 heteroatoms selected from N, O or S. , and includes saturated or unsaturated ring systems as well as polycyclic systems having unsaturated and/or aromatic moieties. Wherein nitrogen or sulfur heteroatoms can be selectively oxidized, and nitrogen heteroatoms can be selectively quaternized.
  • the heterocyclyl group can be attached to any heteroatom or carbon atom to form a stable structure. It should be understood that polycyclic heterocycloalkyl groups additionally include fused, bridged, and spiro ring systems.
  • Heterocycloalkyl groups used herein may be optionally substituted with one to more substituents.
  • heterocyclyl groups include, but are not limited to, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidyl, tetrahydrofuranyl, dioxolanyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone and tetrahydro oxadiazolyl.
  • aryl refers to an unsubstituted or substituted monocyclic or polycyclic ring system containing carbon ring atoms, at least one of which is aromatic in nature.
  • Preferred aryl groups are monocyclic or bicyclic 6-10 membered aromatic ring systems. Phenyl and naphthyl are preferred aryl groups. The most preferred aryl group is phenyl.
  • heteroaryl in the present invention, unless otherwise specified, refers to an unsubstituted or substituted stable 5- or 6-membered monocyclic aromatic ring system or an unsubstituted or substituted 9- or 10-membered benzo
  • Heteroaryl groups can be attached to any heteroatom or carbon atom to form a stable structure.
  • heteroaryl groups include, but are not limited to, thienyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridyl Azinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzisoxazolyl, benzothiazolyl, benzothiadiazolyl , benzotriazolyl adenine, quinolinyl or isoquinolinyl.
  • substituted refers to the replacement of one or more hydrogen atoms in a group with the same or a different substituent, respectively.
  • the substituents are independently selected from the group consisting of -F, -Cl, -Br, -I, -OH, trifluoromethoxy, ethoxy, propoxy, isopropoxy, n-butoxy group, isobutoxy, tert-butoxy, -SCH 3 , -SC 2 H 5 , carboxaldehyde, -C(OCH 3 ), cyano, nitro, -CF 3 , -OCF 3 , amino, dimethyl amino, methylthio, sulfonyl and acetyl groups.
  • substituted alkyl groups include, but are not limited to, 2-aminoethyl, 2-hydroxyethyl, pentachloroethyl, trifluoromethyl, methoxymethyl, pentafluoroethyl, and piperazinylmethyl.
  • substituted alkoxy groups include, but are not limited to, aminomethoxy, trifluoromethoxy, 2-diethylaminoethoxy, 2-ethoxycarbonylethoxy, 3-hydroxypropoxy.
  • pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids.
  • acids When the compounds provided herein are acids, their corresponding salts can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic and organic bases.
  • the compound represented by formula (I) will be used as a medicine, it is preferable to use a certain purity, for example, at least 60% pure, more suitably at least 75% pure, particularly suitably at least 98% pure (% by weight) Compare).
  • Prodrugs of the compounds of the present invention are included within the scope of the present invention.
  • the prodrugs refer to functional derivatives that are readily converted into the desired compound in vivo.
  • any pharmaceutically acceptable salt, ester, salt of ester or other derivative of a compound of the present application which, upon administration to a recipient, is capable of providing, directly or indirectly, a compound of the present application or a pharmaceutically active metabolite thereof or Residues.
  • Particularly preferred derivatives or prodrugs are those compounds that, when administered to a patient, increase the bioavailability of the compounds of the present application (eg, make orally administered compounds more readily absorbed into the blood), or promote the delivery of the parent compound to biological organs or Those compounds that are delivered to the site of action (eg, the brain or lymphatic system). Therefore, the term "administration" in the treatment methods provided by the present invention refers to the administration of the compounds disclosed in the present invention that can treat different diseases, or, although not explicitly disclosed, can be transformed into the disclosure in vivo after administration to a subject compound of. Conventional methods for the selection and preparation of suitable prodrug derivatives are described in, for example, Design of Prodrugs (Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985).
  • the compounds of the present invention may contain one or more asymmetric centers and may thereby give rise to diastereomers and optical isomers.
  • the present invention includes all possible diastereomers and racemic mixtures thereof, substantially pure resolved enantiomers thereof, all possible geometric isomers and pharmaceutically acceptable salts thereof.
  • the above formula (I) does not exactly define the stereoscopic structure of the compound at a certain position.
  • the present invention includes all stereoisomers of the compounds represented by formula (I) and pharmaceutically acceptable salts thereof. Further, mixtures of stereoisomers and specific isolated stereoisomers are also included in the present invention. During synthetic procedures to prepare such compounds, or using racemization or epimerization procedures well known to those skilled in the art, the resulting product may be a mixture of stereoisomers.
  • the present invention includes any possible tautomer and pharmaceutically acceptable salts thereof, and mixtures thereof.
  • the present invention includes any possible solvates and polymorphs.
  • the type of solvent that forms the solvate is not particularly limited as long as the solvent is pharmaceutically acceptable.
  • composition refers to a product comprising a specified amount of each of the specified ingredients, as well as any product produced directly or indirectly from a combination of the specified amounts of each of the specified ingredients. Accordingly, pharmaceutical compositions containing the compounds of the present invention as active ingredients and methods of preparing the compounds of the present invention are also part of the present invention.
  • some of the crystalline forms of the compounds may exist as polymorphs, and such polymorphs are included in the present invention.
  • some of the compounds may form solvates with water (ie, hydrates) or common organic solvents, and such solvates are also within the scope of this invention.
  • the pharmaceutical composition provided by the present invention comprises a compound represented by formula (I) (or a pharmaceutically acceptable salt thereof) as an active component, a pharmaceutically acceptable excipient and other optional therapeutic components or Accessories.
  • the pharmaceutical compositions of the present invention include oral, rectal, topical and Pharmaceutical compositions for parenteral (including subcutaneous, intramuscular, intravenous) administration.
  • the pharmaceutical compositions of the present invention may conveniently be presented in unit dosage form and prepared by any of the methods of preparation well known in the art of pharmacy.
  • the pharmaceutical composition of the present invention can be prepared by any pharmaceutical method.
  • such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more essential ingredients.
  • the pharmaceutical compositions are prepared by uniform intimate admixture of the active ingredient with liquid carriers or finely divided solid carriers, or a mixture of both.
  • the product can be easily prepared to the desired appearance.
  • the pharmaceutical composition of the present invention comprises a pharmaceutically acceptable carrier and a compound represented by formula (I) or its stereoisomer, tautomer, polymorph, solvate, pharmaceutically acceptable Salts and their prodrugs.
  • the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, combined with one or more other compounds with therapeutic activity are also included in the pharmaceutical composition of the present invention.
  • the pharmaceutical carrier employed in the present invention can be, for example, a solid carrier, a liquid carrier or a gaseous carrier.
  • NaHCO 3 sodium bicarbonate
  • TosCl p-toluenesulfonyl chloride
  • H 2 hydrogen
  • Pd(OH) 2 /C palladium hydroxide supported on carbon
  • K 2 CO 3 potassium carbonate
  • ACN/CH 3 CN acetonitrile
  • i-PrMgCl isopropyl magnesium chloride (2mol/L tetrahydrofuran solution);
  • TBDPSCl tert-butyldiphenylchlorosilane
  • Tf 2 O trifluoromethanesulfonic anhydride
  • Boc tert-butoxycarbonyl
  • HOAc acetic acid
  • DIEA/DIPEA N,N-diisopropylethylamine
  • 1,4-dioxane 1,4-dioxane
  • Pd 2 (dba) 3 tris(dibenzylideneacetone)dipalladium
  • Xantphos 4,5-bisdiphenylphosphine-9,9-dimethylxanthene
  • TBAF tetrabutylammonium fluoride
  • t-BuONa sodium tert-butoxide
  • ER ⁇ estrogen receptor ⁇
  • LC-MS or LCMS Liquid Chromatography-Mass Spectrometry.
  • the starting materials and reagents used in the Example section can be obtained from commercial sources or prepared by conventional methods in the art.
  • step 2 is the Pictet-Spengler cyclization reaction, which is used to provide the cyclized product mainly as the desired trans isomer (Chem. Rev. 1995, 95 (6). ), 1797-1842.), a small amount of cis diastereomer was removed by subsequent column chromatography purification.
  • intermediate INT12-intermediate INT17, etc. are all obtained through Pictet-Spengler cyclization reaction to obtain cyclization products dominated by trans isomers.
  • hydrochloride salts of compounds INT6, INT7, INT8, INT9, and INT10 can be synthesized according to the synthetic method of the similar compound INT5, using the corresponding raw materials and routes as above.
  • Step 2 Synthesis of compound INT11 (Pictet-Spengler cyclization)
  • step 3 of INT21 replace INT2 with INT15-1 to get INT22.
  • step 2 of INT11 replace INT2 with INT23-1 to get INT23.
  • compound INT24-6 (254mg, 1eq), methanol (10mL), potassium hydroxide (98mg, 3eq) were added, and the temperature was heated to 70°C and stirred for reaction for 3 hours. After the completion of the reaction, the reaction solution was concentrated, the residue was dissolved in ethyl acetate/water, and the layers were separated by stirring. The aqueous phase was extracted once with ethyl acetate, and the organic phases were combined and dried over anhydrous sodium sulfate to obtain 198 mg of compound INT24.
  • step 2 of INT11 replace INT21-2 with INT24 to get INT25.
  • Example 1 Compound A1((S)-N-(3-(difluoromethoxy)-4-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl) yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)-1-(3-fluoropropyl)pyrrolidine-3- amine) preparation
  • Example 2 Compound A2 (N-(3-(difluoromethoxy)-4-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2 ,3,4,9-Tetrahydro-1H-pyridyl[3,4-b]indol-1-yl)phenyl)-1-(3-fluoropropyl)azetidine-3-amine ) preparation
  • Example 1 According to the similar experimental methods of Example 1, Example 2, Example 6, Example 12-13, Example 19-20, Example 32, etc., using the above-mentioned intermediates, and suitable commercially available raw materials and reagents, it can be prepared Examples shown in Table 1.
  • Example 8 Compound A8 (1-(3-fluoropropyl)-N-(4-(((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)- 2,3,4,9-Tetrahydro-1H-pyridyl[3,4-b]indol-1-yl)-3-(trifluoromethoxy)phenyl)azetidine-3- amine) preparation
  • Example 9 Compound A9((S)-1-(3-fluoropropyl)-N-(4-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl) yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3-(trifluoromethoxy)phenyl)pyrrolidine-3- amine) preparation
  • Example 15 Compound A15 (N-(4-((1R,3R)-2-(2,2-difluoroethyl)-3-methyl-2,3,4,9-tetrahydro-1H- Pyridyl[3,4-b]indol-1-yl)-3-(trifluoromethoxy)phenyl)-1-(3-fluoropropyl)azetidine-3-amine) of preparation
  • Example 8 Example 9, Example 15 and Example 27, using the above intermediates and suitable raw materials and reagents, the examples shown in Table 2 were prepared.
  • compound A39-7 can be obtained by replacing compound INT2 with compound A39-6.
  • Example 39 using the above intermediates and suitable raw materials and reagents, the examples shown in Table 3 can be prepared.
  • reaction solution was diluted with ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by high pressure preparative liquid phase (mobile phase A: 0.1% aqueous formic acid solution, mobile phase B: acetonitrile; 25-55 %B in 20mins; flow rate: 40ml/min; detection wavelength: 254nm; peak: 43%B.), to obtain 27mg of compound A53.
  • mobile phase A 0.1% aqueous formic acid solution
  • mobile phase B acetonitrile
  • Example 55-Example 61 According to the method similar to the above-mentioned embodiment, using the corresponding raw material, can synthesize Example 55-Example 61:
  • Celltiter-glo luminescence viability assay kit (Promega, Cat#G7573) was used to detect compound cell proliferation inhibitory activity on breast cancer cell lines MCF7 and T47D. Cells in logarithmic growth phase were taken, trypsinized, seeded in 96-well cell culture plates at a cell density of 2000/well, and incubated overnight in a humidified incubator at 37°C, 5% CO2 . The next day, the serially diluted compound solution was added to the cell culture medium, so that the final compound concentration was 1 ⁇ M or 8-9 concentrations of 3-fold dilution from 20 nM. The same volume of DMSO was added to control wells as a solvent control.
  • the degradation activity of the compounds on ER proteins in MCF7 and T47D cells was detected by In-Cell Western method.
  • Cells in logarithmic growth phase were taken, trypsinized and collected, inoculated in 384-well plates and incubated overnight at 37°C, 5% CO 2 .
  • the compound was serially diluted with DMSO, and 120nL/well compound solution was added to the well plate (the final concentration of DMSO was 0.5%), so that the final compound concentration was 100, 33, 11, 3.7, 1.2, 0.41, 0.14, 0.046, 0.015, 0.001 nM and incubated overnight.
  • Cells were fixed, washed with PBS, permeabilized and blocked.
  • Mouse PK studies were performed using female BALB/c mice (20-30 g) purchased from Beijing Weitong Lihua Laboratory Animal Technology Co., Ltd. Compound concentrations were 0.5 mg/mL and 1 mg/mL for oral (PO) doses of 5 mg/kg and 10 mg/kg, respectively, as-is formulated. Oral administration was by oral gavage at 5 mg/kg or 10 mL/kg. Blood was drawn through the orbital venous plexus of mice, and 100 ⁇ L of whole blood was loaded into K2 - EDTA tubes per time point. Blood collection time was 15min, 30min, 1h, 2h, 4h, 7h and 24h or 15min, 30min, 1h, 2h, 4h, 7h, 24h, 30h and 48h.
  • the collected whole blood samples were centrifuged and plasma separated, and stored in a -80°C refrigerator for later use.
  • the time points of brain collection were 4h and 24h or 4h and 48h.
  • the collected brain tissue was weighed, diluted and homogenized by adding water at a ratio of 1:4, and stored in a -80°C refrigerator for later use.
  • the brain/plasma drug concentration ratio of the compound of the present invention is higher than that of the control compound, indicating that the compound of the present invention has a good ability to cross the blood-brain barrier; at the same time, other compounds of the present invention
  • brain tissue drug concentrations and brain/plasma drug concentration ratios are also higher than control compounds, eg, Example 20, Example 51, and the like.

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Abstract

La présente invention concerne le domaine de la médecine, et concerne en particulier un dérivé d'hétéroaryloxypipéridine, ainsi qu'une composition pharmaceutique associée et son utilisation. Le dérivé d'hétéroaryloxypipéridine tel que représenté dans la formule (I) fourni par la présente invention peut non seulement être préparé en une préparation orale, mais a également de bonnes propriétés pharmacocinétiques et des capacités de pénétration de barrière hématoencéphalique.
PCT/CN2022/075490 2021-02-08 2022-02-08 Dérivé d'hétéroaryloxypipéridine, composition pharmaceutique de celui-ci et son utilisation WO2022166983A1 (fr)

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WO2024017131A1 (fr) * 2022-07-21 2024-01-25 贝达药业股份有限公司 Dérivé d'hétéroarylopipéridine, et composition pharmaceutique et utilisation s'y rapportant

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WO2024017131A1 (fr) * 2022-07-21 2024-01-25 贝达药业股份有限公司 Dérivé d'hétéroarylopipéridine, et composition pharmaceutique et utilisation s'y rapportant

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