CN117083274A - Fused ring heterocyclic derivative and application thereof in medicine - Google Patents

Fused ring heterocyclic derivative and application thereof in medicine Download PDF

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Publication number
CN117083274A
CN117083274A CN202280013780.6A CN202280013780A CN117083274A CN 117083274 A CN117083274 A CN 117083274A CN 202280013780 A CN202280013780 A CN 202280013780A CN 117083274 A CN117083274 A CN 117083274A
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alkyl
substituted
halogen
cyano
trifluoromethyl
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Inventor
张晨
赵明亮
杨定菊
邓华
刘含波
余彦
叶飞
李瑶
倪佳
严庞科
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Tibet Haisike Pharmaceutical Co ltd
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Sichuan Haisco Pharmaceutical Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5365—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 ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • 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
    • C07D471/12—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 three hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings

Abstract

Provides a compound shown in a general formula (I) or a stereoisomer, a deuterated compound, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a eutectic crystal thereof, an intermediate and a preparation method thereof, and application in preparing medicaments for treating diseases related to PARP7 activity or expression quantity.

Description

Fused ring heterocyclic derivative and application thereof in medicine Technical Field
The invention relates to a compound shown in a general formula (I) or a stereoisomer, a deuterated compound, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a eutectic crystal thereof, an intermediate and a preparation method thereof, and application of the compound or the stereoisomer, the deuterated compound, the solvate, the prodrug, the metabolite, the pharmaceutically acceptable salt or the eutectic crystal in preparation of a medicament for treating diseases related to PARP7 activity or expression quantity.
Background
PARP, which is known as poly-ADP-ribose polymerase, a poly ADP ribose polymerase, is involved in a number of cellular processes including DNA repair, genomic stability, etc. The protein family consists of 17 members, and is divided into polyprps and monoprps. The monoprp protein family plays a role in a variety of stress responses associated with the development of cancer, inflammatory and neurodegenerative diseases, and its member PARP7 has been shown to be overactive in tumors and plays a key role in cancer cell survival.
Many cancer cells have been found to rely on PARP7 to achieve intrinsic cell survival, while PARP7 allows cancer cells to "harbor" outside the immune system. Inhibiting PARP7 is effective in inhibiting the growth of cancer cells and restoring interferon signaling, and in releasing cancer for evading the immune system, inhibiting the "brake" of the innate and adaptive immune mechanisms. In several cancer models, PARP7 inhibitors exhibit durable tumor growth inhibition, potent antiproliferative activity, and interferon signaling recovery, and PARP7 inhibitors are expected to be targets for the development of novel anticancer drugs.
Disclosure of Invention
The invention aims to provide a heterocyclic compound or pharmaceutically acceptable salt thereof, which is applied to PARP7 inhibitors. The compound can effectively inhibit PARP7 and can be used for treating diseases such as tumors and the like.
The present invention provides a compound of formula (I) or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein
In some embodiments, Y is selected from O, S, S (=o), S (=o) 2 、S(＝O) 2 N(R y )、N(R y )、C 1-4 Alkylene, -OC 1-3 Alkylene-, -C 1-3 Alkylene group O-, -C 1-3 Alkylene group S-, -C 1-3 Alkylene S (=o) -, C 1-3 Alkylene group S (=o) 2 -、-N(R y )C 1-3 Alkylene-, -C 1-3 Alkylene N (R) y ) -said alkylene group optionally being further substituted with 0 to 4 (e.g. 0, 1, 2, 3 or 4) groups selected from H, halogen, =o, = S, OH, cyano, C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Substituted cycloalkyl;
in some embodiments, Y is selected from O, N (R y )、C 1-3 Alkylene, -OC 1-2 Alkylene-, -C 1-2 Alkylene group O-, -C 1-2 Alkylene group S-, -C 1-2 Alkylene group S (=o) 2 -、-N(R y )C 1-2 Alkylene-, -C 1-2 Alkylene N (R) y ) -said alkylene group optionally being further substituted with 0 to 4 (e.g. 0, 1, 2, 3 or 4) groups selected from H, halogen, =o, = S, OH, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Substituted cycloalkyl;
in some embodiments, Y is selected from O, N (R y )、-N(R y )C(＝O)-、-C(＝O)N(R y )-、-CH 2 -、-CH 2 CH 2 -、-CH 2 CH 2 CH 2 -、-OCH 2 -、-OCH 2 CH 2 -、-CH 2 O-、-CH 2 CH 2 O-、-CH 2 S-、-CH 2 CH 2 S-、-CH 2 S(＝O) 2 -、-CH 2 CH 2 S(＝O) 2 -、-N(R y )CH 2 -、-N(R y )CH 2 CH 2 -、-CH 2 N(R y )-、-CH 2 CH 2 N(R y )-、-N(R y )C(＝O)CH 2 -、-CH 2 C(＝O)N(R y ) -, the CH 2 Optionally further 0 to 2 (e.g. 0, 1 or 2) are selected from H, =o, = S, OH, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Substituted cycloalkyl;
in some embodiments, Y is selected from O, -NHC (=o) -, -C (=o) NH-, -CH 2 -、-CH 2 CH 2 -、-CH 2 CH 2 CH 2 -、-OCH 2 -、-OCH 2 CH 2 -、-CH 2 O-、-CH 2 CH 2 O-、-NHCH 2 -、-NHCH 2 CH 2 -、-CH 2 NH-、-CH 2 CH 2 NH-、-NHC(＝O)CH 2 -、-CH 2 C(＝O)NH-；
In some embodiments, Y is selected from-NHC (=o) -, -C (=o) NH-, -CH 2 CH 2 CH 2 -、-OCH 2 -、-CH 2 CH 2 -、-CH 2 O-、-CH 2 CH 2 O-、-OCH 2 CH 2 -；
In some embodiments, Y is selected from O, -N (CH) 3 )C(＝O)-、-C(＝O)N(CH 3 )-、-CH 2 C(＝O)NH-、-CH 2 C(＝O)N(CH 3 )-；
In some embodiments, Y is selected from the group consisting of-CH 2 S(＝O) 2 -；
In some embodiments, Y is selected from the group consisting of-N (CH 2 CH 3 )C(＝O)-、-N(CH(CH 3 ) 2 )C(＝O)-、-N(CH 2 CH(CH 3 ) 2 ) C (=o) -, -N (cyclopropyl) C (=o) -, -N (CH) 2 -cyclopropyl) C (=o) -, -C (=o) N (CH) 2 CH 3 )-、-C(＝O)N(CH(CH 3 ) 2 )-、-C(＝O)N(CH 2 CH(CH 3 ) 2 ) -, -C (=O) N (cyclopropyl) -, -C (=O) N (CH) 2 -cyclopropyl) -;
in some embodiments, each Y is independently selected from-C (=o) N (CD 3 )-、-C(＝O)N(CH 2 -oxetanyl) -, -C (=o) N (CH 2 -oxacyclopentyl) -, -C (=o) N (CH 2 -azetidinyl) -, -C (=o) N (CH 2 -pyrrolidinyl) -, -C (=o) N (CH 2 -cyclopentyl) -, -C (=o) N (CH 2 CH 2 CH 3 )-、-C(＝O)N(CH 2 CH(CH 2 CH 3 ) 2 )-、-C(＝O)N(CH 2 CH 2 CH 2 CH 3 )-、-C(＝O)N(CH 2 CH 2 CH(CH 3 ) 2 )-、-C(＝O)N(CH 2 CH(CH 3 )CH 2 CH 3 ) -, -C (=O) N (N-octyl) -, -C (=S) N (CH) 3 )-、-C(＝S)N(CH 2 CH 3 )-、 -C(＝S)N(CH 2 -cyclopropyl) -,
in some embodiments, R y Each independently selected from H, C 1-6 Alkyl or C 3-6 Cycloalkyl, said alkyl or cycloalkyl optionally being further substituted with 0 to 4 (e.g. 0, 1, 2, 3 or 4) groups selected from H, deuterium, halogen, CF 3 OH, cyano, NH 2 、C 1-6 Alkyl, C 1-6 Alkoxy, 3-to 8-membered heterocyclyl or C 3-6 A cycloalkyl substituent substituted, said heterocyclyl containing 1 to 3 heteroatoms selected from O, S, N;
in some embodiments, R y Each independently selected from H, C 1-4 Alkyl or C 3-6 Cycloalkyl, said alkyl or cycloalkyl optionally being further substituted with 0 to 4 (e.g. 0, 1, 2, 3 or 4) groups selected from H, deuterium, halogen, CF 3 OH, cyano, NH 2 、C 1-4 Alkyl, C 1-4 Alkoxy, 3-to 8-membered heterocyclyl or C 3-6 A cycloalkyl substituent substituted, said heterocyclyl containing 1 to 3 heteroatoms selected from O, S, N;
in some embodiments, R y Each independently selected from H, C 1-4 Alkyl, said alkyl or cycloalkyl optionally further being 0 to 4 (e.g. 0, 1, 2, 3 or 4) selected from H, deuterium, halogen, CF 3 OH, cyano, NH 2 、C 1-4 Alkyl, C 1-4 Alkoxy, 3-to 8-membered heterocyclyl or C 3-6 A cycloalkyl substituent substituted, said heterocyclyl containing 1 to 3 heteroatoms selected from O, S, N;
in some embodiments, R y Each independently selected from H, C 1-4 An alkyl group;
in some embodiments, R y Each independently selected from deuterated C 1-4 An alkyl group;
in some embodiments, R y Each independently selected from CD 3 ；
In some embodiments, R y Each independently selected from H, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, sec-butyl, isobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, said methyl, ethyl, propyl, isopropyl, butyl, t-butyl, sec-butyl, isobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl optionally further being 0 to 4 (e.g. 0, 1, 2, 3 or 4) selected from H, deuterium, halogen, CF 3 OH, cyanoRadical, NH 2 、C 1-4 Alkyl, C 1-4 Alkoxy, 3-to 8-membered heterocyclyl or C 3-6 A cycloalkyl substituent substituted, said heterocyclyl containing 1 to 3 heteroatoms selected from O, S, N;
in some embodiments, R y Each independently selected from H, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, sec-butyl, isobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, said methyl, ethyl, propyl, isopropyl, butyl, t-butyl, sec-butyl, isobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl optionally further being 0 to 4 (e.g. 0, 1, 2, 3 or 4) selected from H, deuterium, F, cl, br, CF 3 OH, cyano, NH 2 Substituted with methyl, ethyl, propyl, butyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl;
in some embodiments, R y Each independently selected from H, methyl, ethyl;
in some embodiments, ring a is selected from C 6-10 Aryl, 5-10 membered heteroaryl, or 5-10 membered heterocyclyl, said heteroaryl or heterocyclyl containing 1 to 5 (e.g., 1, 2, 3, 4, or 5) heteroatoms selected from O, S, N;
In some embodiments, ring a is selected from 3 (2H) -pyridazinone or 2 (1H) -pyridinone;
in some embodiments of the present invention, in some embodiments,selected from the group consisting of
In some embodiments of the present invention, in some embodiments,selected from the group consisting of
In some embodiments of the present invention, in some embodiments,selected from the group consisting of
In some embodiments of the present invention, in some embodiments,selected from the group consisting of
In some embodiments of the present invention, in some embodiments,selected from the group consisting of
In some embodiments of the present invention, in some embodiments,selected from the group consisting of
In some embodiments, X 1 、X 2 、X 3 、X 4 Each independently selected from N, CR x ，X 1 、X 2 、X 3 、X 4 Up to 2N;
in some embodiments, X 1 Selected from N, X 2 Selected from CH, X 3 Selected from CH, CF, CCl, CCN or CCF 3 ，X 4 Selected from CH or N;
in some embodiments, ring X is selected from C 6-10 Aryl, 5-10 membered heteroaryl, C 3-10 A carbocycle or 5-10 membered heterocyclyl containing 1 to 5 (e.g. 1, 2, 3, 4 or 5) heteroatoms selected from O, S, N;
in some embodiments, ring X is selected from phenyl, a 5-6 membered heteroaryl, or a 5-6 membered heterocyclyl containing 1 to 5 (e.g., 1, 2, 3, 4, or 5) heteroatoms selected from O, S, N;
in some embodiments, ring X is selected from phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, thienyl, thiazolyl, furanyl, oxazolyl, pyrrolyl, pyrazolyl, or imidazolyl;
In some embodiments, W 1 Selected from N or C (R) a4 )；
In some embodiments, W 1 Selected from N or CH;
in some embodiments, W 1 Selected from N;
in some embodiments, R x 、R a Each of which is a single pieceIndependently selected from H, halogen, cyano, OH, = O, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylthio, -SO 2 -C 1-6 Alkyl, -C (=o) C 1-6 Alkyl, - (CH) 2 ) q -C 3-10 Carbocycle or- (CH) 2 ) q -3 to 12 membered heterocycle, said-CH 2 -, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, carbocycle or heterocycle optionally further being 0 to 4 (e.g. 0, 1, 2, 3 or 4) selected from H, halogen, OH, cyano, = O, NH 2 、NH(C 1-6 Alkyl), N (C) 1-6 Alkyl group 2 、C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or a substituent of a 3 to 10 membered heterocyclic ring containing 1 to 3 (e.g. 1, 2 or 3) heteroatoms selected from O, S, N;
in some embodiments, R a1 、R a2 、R a4 Each independently is selected from R a ；
In some embodiments, R a1 、R a2 、R a4 Each independently selected from H, halogen, cyano, OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylthio, -SO 2 -C 1-6 Alkyl, -C (=o) C 1-6 Alkyl, - (CH) 2 ) q -C 3-10 Carbocycle or- (CH) 2 ) q -3 to 12 membered heterocycle, said-CH 2 -, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, carbocycle or heterocycle optionally further being 0 to 4 (e.g. 0, 1, 2, 3 or 4) selected from H, halogen, OH, cyano, = O, C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 NaphtheneA substituent of a group or a 3 to 10 membered heterocyclic ring containing 1 to 3 (e.g. 1, 2 or 3) heteroatoms selected from O, S, N;
in some embodiments, R a3 Selected from H, C 1-6 Alkyl, - (CH) 2 ) q -C 3-10 Carbocycle or- (CH) 2 ) q -3 to 12 membered heterocycle, said-CH 2 -, alkyl, carbocycle or heterocycle optionally further being 0 to 4 (e.g. 0, 1, 2, 3 or 4) selected from H, halogen, OH, cyano, C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or a substituent of a 3 to 10 membered heterocyclic ring containing 1 to 3 (e.g. 1, 2 or 3) heteroatoms selected from O, S, N;
in some embodiments, R a3 Selected from H, C 1-4 Alkyl, said alkyl optionally being further substituted with 0 to 4 (e.g. 0, 1, 2, 3 or 4) groups selected from H, halogen, OH, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Substituted cycloalkyl;
in some embodiments, R a3 Selected from H, methyl, ethyl, propyl, isopropyl, said methyl, ethyl, propyl or isopropyl optionally being further substituted with 0 to 4 (e.g. 0, 1, 2, 3 or 4) groups selected from H, halogen, OH, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Substituted cycloalkyl;
in some embodiments, R a2 Selected from H, F, cl, br, I, cyano, CF 3 、CHF 2 、CH 2 F. Methyl, methoxy, cyclopropyl;
in some embodiments, R a3 Selected from H or methyl;
in some embodiments, R x 、R a1 、R a2 、R a4 Each independently selected from H, halogen, cyano, OH, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 1-4 Alkylthio, -SO 2 -C 1-4 Alkyl, -C (=o) C 1-4 Alkyl, - (CH) 2 ) q -C 3-6 Carbocycle or- (CH) 2 ) q -3 to 6 membered heterocycle, said-CH 2 -, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, carbocycle or heterocycle optionally further being 0 to 4 (e.g. 0, 1, 2, 3 or 4) selected from H, halogen, OH, cyano, = O, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl or a 3 to 6 membered heterocyclic ring containing 1 to 3 (e.g. 1, 2 or 3) heteroatoms selected from O, S, N;
in some embodiments, R x 、R a1 、R a2 Each independently selected from H, F, cl, br, I, cyano, OH, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, vinyl, ethynyl, methoxy, ethoxy, -SCH 3 、-SCH 2 CH 3 、-SO 2 CH 3 、-SO 2 CH 2 CH 3 、-C(＝O)CH 3 、-C(＝O)CH 2 CH 3 Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, vinyl, ethynyl, methoxy, ethoxy, -SCH 3 、-SCH 2 CH 3 、-SO 2 CH 3 、-SO 2 CH 2 CH 3 、-C(＝O)CH 3 、-C(＝O)CH 2 CH 3 Optionally further 0 to 4 (e.g. 0, 1, 2, 3 or 4) of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl are selected from H, halogen, OH, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Substituted cycloalkyl;
in some embodiments, R x Each independently selected from H, F, cl, br, I, cyano, OH, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, ethynyl, methoxy, ethoxy, -SCH 3 、-SCH 2 CH 3 Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methyl, ethyl, propyl, isopropyl, ethynyl, methoxy, ethoxy, -SCH 3 、-SCH 2 CH 3 Optionally further substituted with 0 to 4 (e.g., 0, 1, 2, 3, or 4) substituents selected from H, F, OH, cyano, methyl, ethyl, methoxy, or ethoxy;
in some embodiments, R x Each independently selected from H, F, cl, cyano, methyl, ethyl, isopropyl, trifluoromethyl, methoxy, ethoxy, -SO 2 CH 3 、-SO 2 CH 2 CH 3 、-C(＝O)CH 3 、-C(＝O)CH 2 CH 3 Cyclopropyl;
in some embodiments, R a1 Selected from H, F, cl, br, I, cyano, CF 3 、CHF 2 、CH 2 F. Methyl, ethyl, propyl, isopropyl, ethynyl, methoxy, ethoxy, -SCH 3 、-SCH 2 CH 3 Cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;
in some embodiments, R a1 Selected from H, F, cl, br, I, cyano, CF 3 Methyl;
in some embodiments, R a2 Selected from H;
in some embodiments, ring B is selected from 4 to 11 membered nitrogen containing heterocycles, C 4-10 A carbocycle;
in some embodiments, ring B is selected from a 4 to 7 membered monocyclic nitrogen-containing heterocycle, a 5-11 membered spiro nitrogen-containing heterocycle, a 5-11 membered fused ring nitrogen-containing heterocycle, a 5-11 membered bridged ring nitrogen-containing heterocycle, or C 4-7 A monocyclic carbocycle;
in some embodiments, ring B is selected from cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl,
In some embodiments of the present invention, in some embodiments,selected from the group consisting of The left side is connected with L;
in some embodiments, R b Each independently selected from H, halogen, cyano, OH, = O, C 1-6 Alkyl, C 1-6 Alkoxy, - (CH) 2 ) q -C 3-6 Cycloalkyl, the-CH 2 -, alkyl, alkoxy or cycloalkyl optionally further being 0 to 4 (e.g. 0, 1, 2, 3 or 4) selected from H, halogen, OH, cyano, NH 2 、C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 Substituted cycloalkyl;
in some embodiments, R b Each independently selected from H, halogen, cyano, OH, = O, C 1-4 Alkyl, C 1-4 Alkoxy, - (CH) 2 ) q -C 3-6 Cycloalkyl, the-CH 2 -, alkyl, alkoxy or cycloalkyl optionally further being 0 to 4 (e.g. 0, 1, 2, 3 or 4) selected from H, halogen, OH, cyano, NH 2 、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, C 1-4 Alkoxy or C 3-6 Substituted cycloalkyl;
in some embodiments, R b Each independently selected from H, F, cl, br, I, cyano, OH, =o, methyl, ethyl, propyl or isopropyl, said methyl, ethyl, propyl or isopropyl optionally being further substituted with 0 to 4 (e.g. 0, 1, 2, 3 or 4) groups selected from H, halogen, OH, cyano, NH 2 、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, C 1-4 Alkoxy or C 3-6 Substituted cycloalkyl;
in some embodiments, R b Each independently selected from H, F, cl, br, I, cyano, OH, =o, methyl, ethyl, propyl or isopropyl;
in some embodiments, W is selected from a bond, C 1-3 Alkylene or Q2, the alkylene group shown optionally being further selected from H, halogen, CF by 0 to 4 (e.g. 0, 1, 2, 3 or 4) 3 OH, cyano, NH 2 、C 1-6 Alkyl or C 1-6 Substituted with alkoxy;
in some embodiments, W is selected from a bond;
in some embodiments, L is selected from L1, L2, or L3;
In some embodiments, L1 is selected from the group consisting of-Q1-Ak 1-Q2-Ak2-Q3-, linked on the right to ring B;
in some embodiments, L1 is selected from the group consisting of-N (R q )-Ak1-O-Ak2-C(＝O)-、-O-Ak1-O-Ak2-C(＝O)-、-O-Ak1-N(R q )-Ak2-C(＝O)-、-N(R q )-Ak1-N(R q )-Ak2-C(＝O)-、-N(R q )-Ak1-O-Ak2-N(R q )C(＝O)-、-O-Ak1-O-Ak2-N(R q )C(＝O)-、-N(R q )-Ak1-Ak2-C(＝O)-、-N(R q )-Ak1-Ak2-N(R q )C(＝O)-、-O-Ak1-N(R q )-Ak2-N(R q )C(＝O)-、-S-Ak1-O-Ak2-C(＝O)-、-O-Ak1-S-Ak2-C(＝O)-、-N(R q )-Ak1-O-Ak2-S(＝O) 2 -、-O-Ak1-O-Ak2-S(＝O) 2 -、-N(R q ) Ak1-O-Ak2-, -O-Ak1-O-Ak2-, the right side being attached to ring B;
in some embodiments, L1 is selected from the group consisting of-N (R q )-Ak1-O-Ak2-C(＝O)N(R q )-、-O-Ak1-N(R q )-Ak2-C(＝O)N(R q )-、-O-Ak1-O-C(＝O)N(R q ) -right side is connected to ring B;
in some embodiments, L1 is selected fromThe right side is connected with the ring B;
in some embodiments, L1 is selected from The right side is connected with the ring B;
in some embodiments, L1 is selected from-NH-Ak 1-O-Ak2-C (=o) -, -O-Ak1-O-Ak2-C (=o) -, -N (CH) 3 )-Ak1-O-Ak2-C(＝O)-、-O-Ak1-NH-Ak2-C(＝O)-、-O-Ak1-N(CH 3 )-Ak2-C(＝O)-、-N(CH 3 )-Ak1-NH-Ak2-C(＝O)-、-NH-Ak1-NH-Ak2-C(＝O)-、-S-Ak1-O-Ak2-C(＝O)-、 -O-Ak1-S-Ak2-C(＝O)-、-NH-Ak1-O-Ak2-S(＝O) 2 -、-O-Ak1-O-Ak2-S(＝O) 2 -, -NH-Ak1-O-Ak 2-; -O-Ak1-O-Ak2-, the right side is connected with the ring B;
in some embodiments, L2 is selected fromThe right side is connected with the ring B;
in some embodiments, L2 is selected fromThe right side is connected with the ring B;
in some embodiments, L2 is selected fromThe right side is connected with the ring B;
in some embodiments, L3 is selected fromThe right side is connected with the ring B;
in some embodiments, L3 is selected from The right side is connected with the ring B;
in some embodiments, L4 is selected from the group consisting of-Ak 3-Q4-Ak4-K1-Q5-K2-Ak5-Q6-, or-Ak 3-Q4-Ak4-K1-Q5-, linked on the right to ring B;
in some embodiments, L4 is selected from-Ak 3-O-K1-C (=o) -, -Ak3-N (R) q )-K1-C(＝O)-、-Ak3-N(R q ) -K1-C (=o) -, right-hand side linked to ring B;
in some embodiments, L4 is selected from-Ak 3-O-K1-C (=o) -, -Ak3-NH-K1-C (=o) -, -Ak3-N (CH) 3 ) -K1-C (=o) -, right-hand side linked to ring B;
in some embodiments, ak1, ak2 are each independently selected from C 1-4 Alkylene, C 2-4 Alkenylene, C 2-4 Alkynylene, the Ak1 is optionally further substituted with 0 to 4 (e.g., 0, 1, 2, 3, or 4) R k1 Substituted, the Ak2 is optionally further substituted with 0 to 4 (e.g., 0, 1, 2, 3, or 4) R k2 Substitution;
in some embodiments, ak1, ak2 are each independently selected from C 1-3 Alkylene, C 2-3 Alkenylene, C 2-3 Alkynylene, the Ak1 is optionally further substituted with 0 to 4 (e.g., 0, 1, 2, 3, or 4) R k1 Substituted, the Ak2 is optionally further substituted with 0 to 4 (e.g., 0, 1, 2, 3, or 4) R k2 Substitution;
in some embodiments, ak1, ak2 are each independently selected from methylene, ethylene, propylene, ethenylene, propenylene, ethynylene, propynylene, said Ak1 optionally being further substituted with 0 to 4 (e.g., 0, 1, 2, 3, or 4) R k1 Substituted, the Ak2 is optionally further substituted with 0 to 4 (e.g., 0, 1, 2, 3, or 4) R k2 Substitution;
in some embodiments, ak3, ak4, ak5 are each independently selected from a bond, C 1-4 Alkylene, C 2-4 Alkenylene, C 2-4 Alkynylene, the Ak3 is optionally further substituted with 0 to 4 (e.g., 0, 1, 2, 3, or 4) R k3 Substituted, the Ak4 is optionally further substituted with 0 to 4 (e.g., 0, 1, 2, 3, or 4) R k4 Substituted, said Ak5 is optionally further substituted with 0 to 4R k5 Substitution;
in some embodiments, ak3, ak4, ak5 are each independently selected from a bond, C 1-3 Alkylene, C 2-3 Alkenylene, C 2-3 Alkynylene radicalsThe Ak3 is optionally further substituted with 0 to 4 (e.g., 0, 1, 2, 3 or 4) R k3 Substituted, the Ak4 is optionally further substituted with 0 to 4 (e.g., 0, 1, 2, 3, or 4) R k4 Substituted, said Ak5 is optionally further substituted with 0 to 4R k5 (e.g., 0, 1, 2, 3, or 4);
in some embodiments, ak3, ak4, ak5 are each independently selected from the group consisting of a bond, methylene, ethylene, propylene, ethenylene, propenylene, ethynylene, propynylene, said Ak3 optionally being further substituted with 0 to 4 (e.g., 0, 1, 2, 3, or 4) R k3 Substituted, the Ak4 is optionally further substituted with 0 to 4 (e.g., 0, 1, 2, 3, or 4) R k4 Substituted, said Ak5 is optionally further substituted with 0 to 4R k5 Substitution;
in some embodiments, K1 or K2 is selected from C 1-2 Alkylene, C 3-10 Carbocycle or 3-to 12-membered heterocycle, said alkylene optionally being further substituted with 0 to 4 (e.g. 0, 1, 2, 3 or 4) R k6 Substituted, said carbocycle or heterocycle optionally being further substituted with 0 to 4 (e.g. 0, 1, 2, 3 or 4) groups selected from H, halogen, OH, cyano, NH 2 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen substituted C 1-6 Alkyl, C 1-6 Alkoxy, -C 1-6 alkyl-OC 1-6 Alkyl, -O-C 1-6 alkyl-OC 1-6 Alkyl, -O-C 3-8 Carbocycle, C 3-8 A carbocycle, substituted with a substituent of a 4 to 10 membered heterocyclic ring containing 1 to 3 (e.g. 1, 2 or 3) heteroatoms selected from O, S, N;
in some embodiments, K1 or K2 is selected from C 1-2 Alkylene, C 3-6 Carbocycle or 3-to 7-membered heterocycle, said alkylene optionally being further substituted with 0 to 4 (e.g. 0, 1, 2, 3 or 4) R k6 Substituted, said carbocycle or heterocycle optionally being further substituted with 0 to 4 (e.g. 0, 1, 2, 3 or 4) groups selected from H, halogen, OH, cyano, NH 2 、C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, halogen substituted C 1-4 Alkyl, C 1-4 Alkoxy, -C 1-4 alkyl-OC 1-4 Alkyl, -O-C 1-4 alkyl-OC 1-4 Alkyl, -O-C 3-6 Carbocycle, C 3-6 A carbocycle, substituted with a substituent of a 4 to 7 membered heterocyclic ring containing 1 to 3 (e.g. 1, 2 or 3) heteroatoms selected from O, S, N;
in some embodiments, K1 or K2 is selected from the group consisting of methylene, ethylene, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, piperazine, morpholine, oxetanyl, oxolanyl, oxepinyl, benzene ring, pyridine, pyrazine, pyrimidine, pyridazine, said methylene, ethylene optionally being further substituted with 0 to 4 (e.g., 0, 1, 2, 3 or 4) R k6 Substituted, said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, piperazine, morpholine, oxetanyl, oxcyclohexyl, benzene ring, pyridine, pyrazine, pyrimidine, pyridazine optionally further substituted with 0 to 4 (e.g. 0, 1, 2, 3 or 4) groups selected from H, halogen, OH, cyano, NH 2 、C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, halogen substituted C 1-4 Alkyl, C 1-4 Alkoxy, -C 1-4 alkyl-OC 1-4 Alkyl, -O-C 1-4 alkyl-OC 1-4 Alkyl, -O-C 3-6 Carbocycle, C 3-6 A carbocycle, substituted with a substituent of a 4 to 7 membered heterocyclic ring containing 1 to 3 (e.g. 1, 2 or 3) heteroatoms selected from O, S, N;
in some embodiments, R k1 、R k2 、R k3 、R k4 、R k5 、R k6 、R L1 、R L2 Each independently selected from H, halogen, cyano, OH, = O, NH 2 、NHC 1-6 Alkyl, N (C) 1-6 Alkyl group 2 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, -OC 3-6 Carbocycle, C 3-6 Carbocycle or 4-to 7-membered heterocycle, said alkyl, alkenyl, alkynyl, alkoxy, carbocycle or heterocycle optionally being further substituted with 0 to 4 (e.g. 0, 1, 2, 3 or 4) groups selected from H, halogen, OH, cyano, NH 2 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen substituted C 1-6 Alkyl, C 1-6 Alkoxy, -O-C 3-8 Carbocycle, C 3-8 A carbocycle, substituted with a substituent of a 4 to 10 membered heterocyclic ring containing 1 to 3 (e.g. 1, 2 or 3) heteroatoms selected from O, S, N;
In some embodiments, R k1 、R k2 、R k3 、R k4 、R k5 、R k6 、R L1 、R L2 Each independently selected from H, halogen, cyano, OH, = O, NH 2 、NHC 1-4 Alkyl, N (C) 1-4 Alkyl group 2 、C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Carbocycle or 4-to 7-membered heterocycle, said alkyl, alkoxy, carbocycle or heterocycle optionally being further substituted with 0 to 4 (e.g. 0, 1, 2, 3 or 4) groups selected from H, halogen, OH, cyano, NH 2 、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Carbocycles (e.g. C 3 、C 4 、C 5 Or C 6 ) A 4 to 6 membered (e.g., 4, 5 or 6 membered) heterocyclic ring containing 1 to 3 (e.g., 1, 2 or 3) heteroatoms selected from O, S, N;
in some embodiments, R k1 、R k2 、R k3 、R k4 、R k5 、R k6 、R L1 、R L2 Each independently selected from H, F, cl, br, I, cyano,OH、＝O、NH 2 、NH(CH 3 )、N(CH 3 ) 2 Methyl, ethyl, propyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azacyclohexyl, oxetanyl, oxolanyl, pyridine, phenyl, said methyl, ethyl, propyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azacyclopentyl, azacyclohexyl, oxetanyl, oxolanyl, pyridine, phenyl optionally further being 0 to 4 (e.g. 0, 1, 2, 3 or 4) selected from H, halogen, OH, cyano, NH 2 、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Carbocycles (e.g. C 3 、C 4 、C 5 Or C 6 ) A 4 to 6 membered (e.g., 4, 5 or 6 membered) heterocyclic ring containing 1 to 3 (e.g., 1, 2 or 3) heteroatoms selected from O, S, N;
in some embodiments, R k1 And R is R k1 、R k2 And R is R k2 、R k1 And R is R k2 、R k3 And R is R k3 、R k4 And R is R k4 、R k5 And R is R k5 、R k6 And R is R k6 Directly connected to form C 3-6 Carbocycles (e.g. C 3 、C 4 、C 5 Or C 6 ) Or a 4 to 7 membered (e.g. 4, 5, 6 or 7 membered) heterocycle, said carbocycle or heterocycle optionally being further substituted with 0 to 4 (e.g. 0, 1, 2, 3 or 4) groups selected from H, halogen, = O, OH, cyano, C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 A cycloalkyl substituent, said heterocycle containing from 1 to 3 (e.g., 1, 2 or 3) heteroatoms selected from O, S, N;
in some embodiments, R k1 And R is R k1 、R k2 And R is R k2 、R k1 And R is R k2 、R k3 And R is R k3 、R k4 And R is R k4 、R k5 And R is R k5 、R k6 And R is R k6 Directly connected to form C 3-6 Carbocycles (e.g. C 3 、C 4 、C 5 Or C 6 ) Or a 4 to 7 membered (e.g. 4, 5, 6 or 7 membered) heterocycle, said carbocycle or heterocycle optionally being further substituted with 0 to 4 (e.g. 0, 1, 2, 3 or 4) groups selected from H, halogen, = O, OH, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 A cycloalkyl substituent, said heterocycle containing from 1 to 3 (e.g., 1, 2 or 3) heteroatoms selected from O, S, N;
In some embodiments, Q1, Q5 are each independently selected from O, S, N (R q )、C(＝O)、C(＝O)N(R q )、N(R q )C(＝O)、C(＝O)O、OC(＝O)、S(＝O)、S(＝O) 2 、S(＝O) 2 N(R q )、N(R q )S(＝O) 2 、N(R q )C(＝O)N(R q )、N(R q )C(＝O)N(R q )；
In some embodiments, Q1, Q5 are each independently selected from O, S, N (R q )、C(＝O)、C(＝O)N(R q )、N(R q )C(＝O)、S(＝O) 2 ；
In some embodiments, Q2, Q3, Q4, Q6 are each independently selected from a bond or Q1;
in some embodiments, ring E is selected from C 3-6 A carbocycle or a 4 to 7 membered heterocycle containing 1 to 3 (e.g. 1, 2 or 3) heteroatoms selected from O, S, N;
in some embodiments, ring E is selected from C 3-6 Carbocycle or 4-to 6-membered heterocycle containing 1 to 3 (e.g. 1, 2 or 3) selected from O,A heteroatom of S, N;
in some embodiments, ring E is selected from phenyl or a 5-6 membered heteroaryl containing 1 to 3 (e.g., 1, 2, or 3) heteroatoms selected from O, S, N;
in some embodiments, ring E is selected from a benzene ring or pyridine;
in some embodiments, R q Each independently selected from H, C 1-6 Alkyl or C 3-6 Cycloalkyl, said alkyl or cycloalkyl optionally being further substituted with 0 to 4 (e.g. 0, 1, 2, 3 or 4) groups selected from H, halogen, CF 3 OH, cyano, NH 2 、C 1-6 Alkyl or C 1-6 Substituted with alkoxy;
in some embodiments, R q Each independently selected from H, C 1-4 Alkyl, said alkyl optionally being further substituted with 0 to 4 (e.g. 0, 1, 2, 3 or 4) groups selected from H, halogen, CF 3 OH, cyano, NH 2 、C 1-4 Alkyl or C 1-4 Substituted with alkoxy;
in some embodiments, R q Each independently selected from H, methyl, ethyl;
in some embodiments, R q And R is R k1 Or R is k2 Directly linked to form a 4 to 7 membered heterocyclic ring, said heterocyclic ring optionally being further substituted with 0 to 4 (e.g. 0, 1, 2, 3 or 4) groups selected from H, halogen, = O, OH, cyano, C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 A cycloalkyl substituent, said heterocycle containing from 1 to 3 (e.g., 1, 2 or 3) heteroatoms selected from O, S, N;
in some embodiments, R q And R is R k1 、R q And R is R k2 Directly linked to form a 4 to 7 membered heterocyclic ring, said heterocyclic ring optionally being further substituted with 0 to 4 (e.g. 0, 1, 2, 3 or 4) groups selected from H, halogen, = O, OH, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 A cycloalkyl substituent, said heterocycle containing from 1 to 3 (e.g., 1, 2 or 3) heteroatoms selected from O, S, N;
in some embodiments, R q And R is R k1 、R q And R is R k2 Directly linked to form a 4 to 7 membered heterocyclic ring, said heterocyclic ring optionally being further substituted with 0 to 4 (e.g. 0, 1, 2, 3 or 4) substituents selected from H, halogen, = O, OH, cyano, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, said heterocyclic ring containing 1 to 3 (e.g. 1, 2 or 3) heteroatoms selected from O, S, N;
In some embodiments, L1 is selected from
The right side is connected with the ring B;
in some embodiments, L1 is selected fromThe right side is connected with the ring B;
in some embodiments, L1 is selected from or L1 is selected from The right side is connected with the ring B;
in some embodiments, L is selected fromOr alternativelyOr Y is selected from-CH 2 S(＝O) 2 -；
In some embodiments, L is selected from The right side is connected with the ring B;
in some embodiments, L is selected from The right side is connected with the ring B;
in some embodiments, L2 is selected from The right side is connected with the ring B;
in some embodiments, L3 is selected fromThe right side is connected with the ring B;
in some embodiments, q is each independently selected from 0, 1, 2, 3, or 4;
in some embodiments, a is selected from 0, 1, 2, 3, or 4;
in some embodiments, b is selected from 0, 1, 2, 3, or 4;
in some embodiments, x is selected from 0, 1, 2, 3, or 4;
in some embodiments, s1 is selected from 0, 1, 2, 3, or 4;
in some embodiments, s2 is selected from 0, 1, 2, 3, or 4;
in some embodiments, s3 is selected from 0, 1, 2, 3, or 4.
As a first embodiment of the present invention, the compound represented by the above general formula (I) or a stereoisomer, deuterated, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof,
Y is selected from O, S, S (=O), S (=O) 2 、S(＝O) 2 N(R y )、N(R y )、C 1-4 Alkylene, -OC 1-3 Alkylene-, -C 1-3 Alkylene group O-, -C 1-3 Alkylene group S-, -C 1-3 Alkylene S (=o) -, C 1-3 Alkylene group S (=o) 2 -、-N(R y )C 1-3 Alkylene-, -C 1-3 Alkylene N (R) y ) -said alkylene group optionally being further substituted with 0 to 4 (e.g. 0, 1, 2, 3 or 4) groups selected from H, halogen, =o, = S, OH, cyano, C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Substituted cycloalkyl;
R y each independently selected from H, C 1-6 Alkyl or C 3-6 Cycloalkyl, said alkyl or cycloalkyl optionally being further substituted with 0 to 4 (e.g. 0, 1, 2, 3 or 4) groups selected from H, deuterium, halogen, CF 3 OH, cyano, NH 2 、C 1-6 Alkyl, C 1-6 Alkoxy, 3-to 8-membered heterocyclyl or C 3-6 A cycloalkyl substituent substituted, said heterocyclyl containing 1 to 3 heteroatoms selected from O, S, N;
ring A is selected from C 6-10 Aryl, 5-10 membered heteroaryl or 5-10 membered heterocyclyl, said heteroaryl or heterocyclyl containing 1 to 5 heteroatoms selected from O, S, N;
ring X is selected from C 6-10 Aryl, 5-10 membered heteroaryl, C 3-10 A carbocycle or 5-10 membered heterocyclyl, said heteroaryl or heterocyclyl containing 1 to 5 heteroatoms selected from O, S, N;
R x 、R a each independently selected from H, halogen, cyano, OH, = O, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylthio, -SO 2 -C 1-6 Alkyl, -C (=o) C 1-6 Alkyl, - (CH) 2 ) q -C 3-10 Carbocycle or- (CH) 2 ) q -3 to 12Meta-heterocycle, said-CH 2 -, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, carbocycle or heterocycle optionally further being 0 to 4 (e.g. 0, 1, 2, 3 or 4) selected from H, halogen, OH, cyano, = O, NH 2 、NH(C 1-6 Alkyl), N (C) 1-6 Alkyl group 2 、C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or a substituent of a 3 to 10 membered heterocyclic ring containing 1 to 3 (e.g. 1, 2 or 3) heteroatoms selected from O, S, N;
ring B is selected from 4-11 membered nitrogen-containing heterocycles, C 4-10 A carbocycle;
R b each independently selected from H, halogen, cyano, OH, = O, C 1-6 Alkyl, C 1-6 Alkoxy, - (CH) 2 ) q -C 3-6 Cycloalkyl, the-CH 2 -, alkyl, alkoxy or cycloalkyl optionally further being 0 to 4 (e.g. 0, 1, 2, 3 or 4) selected from H, halogen, OH, cyano, NH 2 、C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 Substituted cycloalkyl;
w is selected from bond, C 1-3 Alkylene or Q2, the alkylene group shown optionally being further selected from H, halogen, CF by 0 to 4 (e.g. 0, 1, 2, 3 or 4) 3 OH, cyano, NH 2 、C 1-6 Alkyl or C 1-6 Substituted with alkoxy;
l is selected from L1, L2 or L3;
l1 is selected from-Q1-Ak 1-Q2-Ak2-Q3-, the right side is connected with a ring B;
l2 is selected fromThe right side is connected with the ring B;
l3 is selected fromThe right side is connected with the ring B;
l4 is selected from-Ak 3-Q4-Ak4-K1-Q5-K2-Ak 5-Q6-or-Ak 3-Q4-Ak4-K1-Q5-, the right side is connected with the ring B;
ak1 and Ak2 are each independently selected from C 1-4 Alkylene, C 2-4 Alkenylene, C 2-4 Alkynylene, said Ak1 optionally being further substituted with 0 to 4R k1 Substituted, said Ak2 is optionally further substituted with 0 to 4R k2 Substitution;
ak3, ak4, ak5 are each independently selected from the group consisting of bond, C 1-4 Alkylene, C 2-4 Alkenylene, C 2-4 Alkynylene, the Ak3 is optionally further substituted with 0 to 4 (e.g., 0, 1, 2, 3, or 4) R k3 Substituted, the Ak4 is optionally further substituted with 0 to 4 (e.g., 0, 1, 2, 3, or 4) R k4 Substituted, the Ak5 is optionally further substituted with 0 to 4 (e.g., 0, 1, 2, 3, or 4) R k5 Substitution;
k1 or K2 is selected from C 1-2 Alkylene, C 3-10 Carbocycle or 3-to 12-membered heterocycle, said alkylene optionally being further substituted with 0 to 4 (e.g. 0, 1, 2, 3 or 4) R k6 Substituted, said carbocycle or heterocycle optionally being further substituted with 0 to 4 (e.g. 0, 1, 2, 3 or 4) groups selected from H, halogen, OH, cyano, NH 2 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen substituted C 1-6 Alkyl, C 1-6 Alkoxy, -C 1-6 alkyl-OC 1-6 Alkyl, -O-C 1-6 alkyl-OC 1-6 Alkyl, -O-C 3-8 Carbocycle, C 3-8 A carbocycle, substituted with a substituent of a 4 to 10 membered heterocyclic ring containing 1 to 3 (e.g. 1, 2 or 3) heteroatoms selected from O, S, N;
R k1 、R k2 、R k3 、R k4 、R k5 、R k6 、R L1 、R L2 each independently selected from H, halogen, cyano, OH, = O, NH 2 、NHC 1-6 Alkyl, N (C) 1-6 Alkyl group 2 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, -OC 3-6 Carbocycle, C 3-6 Carbocycle or 4-to 7-membered heterocycle, said alkyl, alkenyl, alkynyl, alkoxy, carbocycle or heterocycle optionally being further substituted with 0 to 4 (e.g. 0, 1, 2, 3 or 4) groups selected from H, halogen, OH, cyano, NH 2 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen substituted C 1-6 Alkyl, C 1-6 Alkoxy, -O-C 3-8 Carbocycle, C 3-8 A carbocycle, substituted with a substituent of a 4 to 10 membered heterocyclic ring containing 1 to 3 (e.g. 1, 2 or 3) heteroatoms selected from O, S, N;
alternatively, R k1 And R is R k1 、R k2 And R is R k2 、R k1 And R is R k2 、R k3 And R is R k3 、R k4 And R is R k4 、R k5 And R is R k5 、R k6 And R is R k6 Directly connected to form C 3-6 Carbocycle or 4 to 7 membered heterocycle optionally further substituted with 0 to 4 (e.g. 0, 1, 2, 3 or 4) selected from H, halogen, = O, OH, cyano, C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 A cycloalkyl substituent, said heterocycle containing from 1 to 3 (e.g., 1, 2 or 3) heteroatoms selected from O, S, N;
Q1, Q5 are each independently selected from O, S, N (R q )、C(＝O)、C(＝O)N(R q )、N(R q )C(＝O)、C(＝O)O、OC(＝O)、S(＝O)、S(＝O) 2 、S(＝O) 2 N(R q )、N(R q )S(＝O) 2 、N(R q )C(＝O)N(R q )、N(R q )C(＝O)N(R q )；
Q2, Q3, Q4, Q6 are each independently selected from a bond or Q1;
ring E is selected from C 3-6 A carbocycle or a 4 to 7 membered heterocycle containing 1 to 3 (e.g. 1, 2 or 3) heteroatoms selected from O, S, N;
R q each independently selected from H, C 1-6 Alkyl or C 3-6 Cycloalkyl, said alkyl or cycloalkyl optionally being further substituted with 0 to 4 (e.g. 0, 1, 2, 3 or 4) groups selected from H, halogen, CF 3 OH, cyano, NH 2 、C 1-6 Alkyl or C 1- 6 Substituted with alkoxy;
alternatively, R q And R is R k1 Or R is k2 Directly linked to form a 4 to 7 membered heterocyclic ring, said heterocyclic ring optionally being further substituted with 0 to 4 (e.g. 0, 1, 2, 3 or 4) groups selected from H, halogen, = O, OH, cyano, C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 A cycloalkyl substituent, said heterocycle containing from 1 to 3 (e.g., 1, 2 or 3) heteroatoms selected from O, S, N;
q is each independently selected from 0, 1, 2, 3 or 4;
a is selected from 0, 1, 2, 3 or 4;
b is selected from 0, 1, 2, 3 or 4;
x is selected from 0, 1, 2, 3 or 4;
s1 is selected from 0, 1, 2, 3 or 4;
s2 is selected from 0, 1, 2, 3 or 4;
s3 is selected from 0, 1, 2, 3 or 4.
As a second embodiment of the present invention, a compound represented by the following general formula (II) or a stereoisomer, a deuterate, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof,
W 1 Selected from N or C (R) a4 )；
Ring X is selected from phenyl, 5-6 membered heteroaryl or 5-6 membered heterocyclyl, said heteroaryl or heterocyclyl containing 1 to 5 heteroatoms selected from O, S, N;
R a1 、R a2 、R a4 each independently selected from H, halogen, cyano, OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylthio, -SO 2 -C 1-6 Alkyl, -C (=o) C 1-6 Alkyl, - (CH) 2 ) q -C 3-10 Carbocycle or- (CH) 2 ) q -3 to 12 membered heterocycle, said-CH 2 -, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, carbocycle or heterocycle optionally further being 0 to 4 (e.g. 0, 1, 2, 3 or 4) selected from H, halogen, OH, cyano, = O, C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or a substituent of a 3 to 10 membered heterocyclic ring containing 1 to 3 (e.g. 1, 2 or 3) heteroatoms selected from O, S, N;
R a3 selected from H, C 1-6 Alkyl, - (CH) 2 ) q -C 3-10 Carbocycle or- (CH) 2 ) q -3 to 12 membered heterocycle, said-CH 2 -, alkyl, carbocycle or heterocycle optionally further being 0 to 4 (e.g. 0, 1, 2, 3 or 4) selected from H, halogen, OH, cyano, C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or a substituent of a 3 to 10 membered heterocyclic ring containing 1 to 3 (e.g. 1, 2 or 3) heteroatoms selected from O, S, N;
The remaining groups are as defined in the first embodiment of the invention.
As a third embodiment of the present invention, the compound represented by the aforementioned general formula (II) or a stereoisomer, deuterated, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof,
y is selected from O, N (R) y )、C 1-3 Alkylene, -OC 1-2 Alkylene-, -C 1-2 Alkylene group O-, -C 1-2 Alkylene group S-, -C 1-2 Alkylene group S (=o) 2 -、-N(R y )C 1-2 Alkylene-, -C 1-2 Alkylene N (R) y ) -said alkylene group optionally being further substituted with 0 to 4 (e.g. 0, 1, 2, 3 or 4) groups selected from H, halogen, =o, = S, OH, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Substituted cycloalkyl;
R y each independently selected from H, C 1-4 Alkyl or C 3-6 Cycloalkyl, said alkyl or cycloalkyl optionally being further substituted with 0 to 4 (e.g. 0, 1, 2, 3 or 4) groups selected from H, deuterium, halogen, CF 3 OH, cyano, NH 2 、C 1-4 Alkyl, C 1-4 Alkoxy, 3-to 8-membered heterocyclyl or C 3-6 A cycloalkyl substituent substituted, said heterocyclyl containing 1 to 3 heteroatoms selected from O, S, N;
R x 、R a1 、R a2 、R a4 each independently selected from H, halogen, cyano, OH, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 1-4 Alkylthio, -SO 2 -C 1-4 Alkyl, -C (=o) C 1-4 Alkyl, - (CH) 2 ) q -C 3-6 Carbocycle or- (CH) 2 ) q -3 to 6 membered heterocyclessaid-CH 2 -, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, carbocycle or heterocycle optionally further being 0 to 4 (e.g. 0, 1, 2, 3 or 4) selected from H, halogen, OH, cyano, = O, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl or a 3 to 6 membered heterocyclic ring containing 1 to 3 (e.g. 1, 2 or 3) heteroatoms selected from O, S, N;
R a3 selected from H, C 1-4 Alkyl, said alkyl optionally being further substituted with 0 to 4 (e.g. 0, 1, 2, 3 or 4) groups selected from H, halogen, OH, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Substituted cycloalkyl;
ring B is selected from 4-7 membered monocyclic nitrogen-containing heterocycle, 5-11 membered spiro nitrogen-containing heterocycle, 5-11 membered fused ring nitrogen-containing heterocycle, 5-11 membered bridged ring nitrogen-containing heterocycle or C 4-7 A monocyclic carbocycle;
R b each independently selected from H, halogen, cyano, OH, = O, C 1-4 Alkyl, C 1-4 Alkoxy, - (CH) 2 ) q -C 3-6 Cycloalkyl, the-CH 2 -, alkyl, alkoxy or cycloalkyl optionally further being 0 to 4 (e.g. 0, 1, 2, 3 or 4) selected from H, halogen, OH, cyano, NH 2 、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, C 1-4 Alkoxy or C 3-6 Substituted cycloalkyl;
ak1 and Ak2 are each independently selected from C 1-3 Alkylene, C 2-3 Alkenylene, C 2-3 Alkynylene, the Ak1 is optionally further substituted with 0 to 4 (e.g., 0, 1, 2, 3, or 4) R k1 Substituted, the Ak2 is optionally further substituted with 0 to 4 (e.g., 0, 1, 2, 3, or 4) R k2 Substitution;
ak3, ak4, ak5 are each independently selected from the group consisting of bond, C 1-3 Alkylene, C 2-3 Alkenylene, C 2-3 Alkynylene, the Ak3 is optionally further substituted with 0 to 4 (e.g., 0, 1, 2, 3, or 4) R k3 Substituted, the Ak4 is optionally further substituted with 0 to 4 (e.g., 0, 1, 2, 3, or 4) R k4 Substituted, the Ak5 is optionally further substituted with 0 to 4 (e.g., 0, 1, 2, 3, or 4) R k5 Substitution;
k1 or K2 is selected from C 1-2 Alkylene, C 3-6 Carbocycle or 3-to 7-membered heterocycle, said alkylene optionally being further substituted with 0 to 4 (e.g. 0, 1, 2, 3 or 4) R k6 Substituted, said carbocycle or heterocycle optionally being further substituted with 0 to 4 (e.g. 0, 1, 2, 3 or 4) groups selected from H, halogen, OH, cyano, NH 2 、C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, halogen substituted C 1-4 Alkyl, C 1-4 Alkoxy, -C 1-4 alkyl-OC 1-4 Alkyl, -O-C 1-4 alkyl-OC 1-4 Alkyl, -O-C 3-6 Carbocycle, C 3-6 A carbocycle, substituted with a substituent of a 4 to 7 membered heterocyclic ring containing 1 to 3 (e.g. 1, 2 or 3) heteroatoms selected from O, S, N;
R k1 、R k2 、R k3 、R k4 、R k5 、R k6 、R L1 、R L2 Each independently selected from H, halogen, cyano, OH, = O, NH 2 、NHC 1-4 Alkyl, N (C) 1-4 Alkyl group 2 、C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Carbocycle or 4-to 7-membered heterocycle, said alkyl, alkoxy, carbocycle or heterocycle optionally being further substituted with 0 to 4 (e.g. 0, 1, 2, 3 or 4) groups selected from H, halogen, OH, cyano, NH 2 、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Carbocycles (e.g. C 3 、C 4 、C 5 Or C 6 ) A 4 to 6 membered (e.g., 4, 5 or 6 membered) heterocyclic ring containing 1 to 3 (e.g., 1, 2 or 3) heteroatoms selected from O, S, N;
alternatively, R k1 And R is R k1 、R k2 And R is R k2 、R k1 And R is R k2 、R k3 And R is R k3 、R k4 And R is R k4 、R k5 And R is R k5 、R k6 And R is R k6 Directly connected to form C 3-6 Carbocycles (e.g. C 3 、C 4 、C 5 Or C 6 ) Or a 4 to 7 membered (e.g. 4, 5, 6 or 7 membered) heterocycle, said carbocycle or heterocycle optionally being further substituted with 0 to 4 (e.g. 0, 1, 2, 3 or 4) groups selected from H, halogen, = O, OH, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 A cycloalkyl substituent, said heterocycle containing from 1 to 3 (e.g., 1, 2 or 3) heteroatoms selected from O, S, N;
q1, Q5 are each independently selected from O, S, N (R q )、C(＝O)、C(＝O)N(R q )、N(R q )C(＝O)、S(＝O) 2 ；
Q2, Q3, Q4, Q6 are each independently selected from a bond or Q1;
ring E is selected from C 3-6 A carbocycle or a 4 to 6 membered heterocycle containing 1 to 3 (e.g. 1, 2 or 3) heteroatoms selected from O, S, N;
R q Each independently selected from H, C 1-4 Alkyl, said alkyl optionally being further substituted with 0 to 4 (e.g. 0, 1, 2, 3 or 4) groups selected from H, halogen, CF 3 OH, cyano, NH 2 、C 1-4 Alkyl or C 1-4 Substituted with alkoxy;
alternatively, R q And R is R k1 、R q And R is R k2 Directly connected to form a heterocyclic ring with 4 to 7 membered atoms,the heterocyclic ring is optionally further substituted with 0 to 4 (e.g. 0, 1, 2, 3 or 4) groups selected from H, halogen, = O, OH, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 A cycloalkyl substituent, said heterocycle containing from 1 to 3 (e.g., 1, 2 or 3) heteroatoms selected from O, S, N;
the remaining groups are as defined in the second embodiment of the invention.
As a fourth embodiment of the present invention, the compound represented by the aforementioned general formula (II) or stereoisomers, deuterates, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals thereof,
W 1 selected from N or CH;
ring X is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thienyl, thiazolyl, furanyl, oxazolyl, pyrrolyl, pyrazolyl or imidazolyl;
R x 、R a1 、R a2 each independently selected from H, F, cl, br, I, cyano, OH, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, vinyl, ethynyl, methoxy, ethoxy, -SCH 3 、-SCH 2 CH 3 、-SO 2 CH 3 、-S O 2 CH 2 CH 3 、-C(＝O)CH 3 、-C(＝O)CH 2 CH 3 Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, vinyl, ethynyl, methoxy, ethoxy, -SCH 3 、-SCH 2 CH 3 、-SO 2 CH 3 、-SO 2 CH 2 CH 3 、-C(＝O)CH 3 、-C(＝O)CH 2 CH 3 Optionally further 0 to 4 (e.g. 0, 1, 2, 3 or 4) of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl are selected from H, halogen, OH, cyano, C 1-4 Alkyl, halogenElement substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Substituted cycloalkyl;
R a3 selected from H, methyl, ethyl, propyl, isopropyl, said methyl, ethyl, propyl or isopropyl optionally being further substituted with 0 to 4 (e.g. 0, 1, 2, 3 or 4) groups selected from H, halogen, OH, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Substituted cycloalkyl;
y is selected from O, N (R) y )、-N(R y )C(＝O)-、-C(＝O)N(R y )-、-CH 2 -、-CH 2 CH 2 -、-CH 2 CH 2 CH 2 -、-OCH 2 -、-OCH 2 CH 2 -、-CH 2 O-、-CH 2 CH 2 O-、-CH 2 S-、-CH 2 CH 2 S-、-CH 2 S(＝O) 2 -、-CH 2 CH 2 S(＝O) 2 -、-N(R y )CH 2 -、-N(R y )CH 2 CH 2 -、-CH 2 N(R y )-、-CH 2 CH 2 N(R y )-、-N(R y )C(＝O)CH 2 -、-CH 2 C(＝O)N(R y ) -, the CH 2 Optionally further 0 to 2 (e.g. 0, 1 or 2) are selected from H, =o, = S, OH, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Substituted cycloalkyl;
R y each independently selected from H, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, sec-butyl, isobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, sec-butyl, iso-butyl Butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl optionally further substituted with 0 to 4 (e.g. 0, 1, 2, 3 or 4) groups selected from H, deuterium, halogen, CF 3 OH, cyano, NH 2 、C 1-4 Alkyl, C 1-4 Alkoxy, 3-to 8-membered heterocyclyl or C 3-6 A cycloalkyl substituent substituted, said heterocyclyl containing 1 to 3 heteroatoms selected from O, S, N;
ring B is selected from cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, and,
R b Each independently selected from H, F, cl, br, I, cyano, OH, =o, methyl, ethyl, propyl or isopropyl, said methyl, ethyl, propyl or isopropyl optionally being further substituted with 0 to 4 (e.g. 0, 1, 2, 3 or 4) groups selected from H, halogen, OH, cyano, NH 2 、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, C 1-4 Alkoxy or C 3-6 Substituted cycloalkyl;
ak1, ak2 are each independently selected from methylene, ethylene, propylene, vinylene, propenylene, ethynylene, propynylene, said Ak1 optionally being further substituted with 0 to 4 (e.g. 0, 1, 2, 3 or 4) R k1 Substituted, said Ak2 is optionally further substituted with 0 to 4R k2 Substitution;
ak3, ak4, ak5 are each independently selected from the group consisting of a bond, methylene, ethylene, propylene, ethenylene, propenylene, ethynylene, propynylene, said Ak3 optionally being further substituted with 0 to 4 (e.g., 0, 1, 2, 3, or 4) R k3 Substituted, the Ak4 is optionally further substituted with 0 to 4 (e.g., 0, 1, 2, 3, or 4) R k4 Substituted, the Ak5 is optionally further substituted with 0 to 4 (e.g., 0, 1, 2, 3, or 4) R k5 Substitution;
k1 or K2 is selected from methylene, ethylene, cyclopropyl, cyclobutylCyclopentyl, cyclohexyl, azetidinyl, piperazine, morpholine, oxetanyl, oxolanyl, oxcyclohexyl, benzene ring, pyridine, pyrazine, pyrimidine, pyridazine, said methylene, ethylene optionally being further substituted with 0 to 4 (e.g., 0, 1, 2, 3 or 4) R k6 Substituted, said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, piperazine, morpholine, oxetanyl, oxcyclohexyl, benzene ring, pyridine, pyrazine, pyrimidine, pyridazine optionally further substituted with 0 to 4 (e.g. 0, 1, 2, 3 or 4) groups selected from H, halogen, OH, cyano, NH 2 、C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, halogen substituted C 1-4 Alkyl, C 1-4 Alkoxy, -C 1-4 alkyl-OC 1-4 Alkyl, -O-C 1-4 alkyl-OC 1-4 Alkyl, -O-C 3-6 Carbocycle, C 3-6 A carbocycle, substituted with a substituent of a 4 to 7 membered heterocyclic ring containing 1 to 3 (e.g. 1, 2 or 3) heteroatoms selected from O, S, N;
R k1 、R k2 、R k3 、R k4 、R k5 、R k6 、R L1 、R L2 Each independently selected from H, F, cl, br, I, cyano, OH, = O, NH 2 、NH(CH 3 )、N(CH 3 ) 2 Methyl, ethyl, propyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azacyclohexyl, oxetanyl, oxolanyl, pyridine, phenyl, said methyl, ethyl, propyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azacyclopentyl, azacyclohexyl, oxetanyl, oxolanyl, pyridine, phenyl optionally further being 0 to 4 (e.g. 0, 1, 2, 3 or 4) selected from H, halogen, OH, cyano, NH 2 、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 A carbocycle, substituted with a substituent of a 4 to 6 membered heterocyclic ring containing 1 to 3 (e.g. 1, 2 or 3) heteroatoms selected from O, S, N;
alternatively, R k1 And R is R k1 、R k2 And R is R k2 、R k1 And R is R k2 、R k3 And R is R k3 、R k4 And R is R k4 、R k5 And R is R k5 、R k6 And R is R k6 Directly connected to form C 3-6 Carbocycles (e.g. C 3 、C 4 、C 5 Or C 6 ) Or a 4 to 7 membered (e.g. 0, 1, 2, 3 or 4) heterocycle, said carbocycle or heterocycle optionally being further substituted with 0 to 4 (e.g. 0, 1, 2, 3 or 4) groups selected from H, halogen, = O, OH, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 A cycloalkyl substituent, said heterocycle containing from 1 to 3 (e.g., 1, 2 or 3) heteroatoms selected from O, S, N;
q1, Q5 are each independently selected from O, S, N (R q )、C(＝O)、C(＝O)N(R q )、N(R q )C(＝O)、S(＝O) 2 ；
Q2, Q3, Q4, Q6 are each independently selected from a bond or Q1;
ring E is selected from phenyl or a 5-6 membered heteroaryl group containing 1 to 3 (e.g. 1, 2 or 3) heteroatoms selected from O, S, N;
R q each independently selected from H, methyl, ethyl;
alternatively, R q And R is R k1 、R q And R is R k2 Directly linked to form a 4 to 7 membered heterocyclic ring, said heterocyclic ring optionally being further substituted with 0 to 4 (e.g. 0, 1, 2, 3 or 4) groups selected from H, halogen, = O, OH, cyano, C 1-4 Alkyl, halogen extractionSubstituted C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 A cycloalkyl substituent, said heterocycle containing from 1 to 3 (e.g., 1, 2 or 3) heteroatoms selected from O, S, N;
the remaining groups are as defined in any of the second or third embodiments of the invention.
As a fifth embodiment of the present invention, the compound represented by the aforementioned general formula (II) or stereoisomers, deuterates, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals thereof,
Selected from the group consisting of The left side is connected with L;
l1 is selected from the group consisting of-N (R) q )-Ak1-O-Ak2-C(＝O)-、-O-Ak1-O-Ak2-C(＝O)-、-O-Ak1-N(R q )-Ak2-C(＝O)-、-N(R q )-Ak1-N(R q )-Ak2-C(＝O)-、-N(R q )-Ak1-O-Ak2-N(R q )C(＝O)-、-O-Ak1-O-Ak2-N(R q )C(＝O)-、-N(R q )-Ak1-Ak2-C(＝O)-、-N(R q )-Ak1-Ak2-N(R q )C(＝O)-、-O-Ak1-N(R q )-Ak2-N(R q )C(＝O)-、-S-Ak1-O-Ak2-C(＝O)-、-O-Ak1-S-Ak2-C(＝O)-、-N(R q )-Ak1-O-Ak2-S(＝O) 2 -、-O-Ak1-O-Ak2-S(＝O) 2 -、-N(R q ) Ak1-O-Ak2-, -O-Ak1-O-Ak2-, the right side being attached to ring B;
or L1 is selected from-N (R) q )-Ak1-O-Ak2-C(＝O)N(R q )-、-O-Ak1-N(R q )-Ak2-C(＝O)N(R q )-、-O-Ak1-O-C(＝O)N(R q ) -right side is connected to ring B;
l4 is selected from the group consisting of-Ak 3-O-K1-C (=O) -, -Ak3-N (R) q )-K1-C(＝O)-、-Ak3-N(R q ) -K1-C (=o) -, right-hand side linked to ring B;
ring E is selected from benzene ring or pyridine;
y is selected from-NHC (=O) -, -C (=O) NH-, -CH 2 -、-CH 2 CH 2 -、-CH 2 CH 2 CH 2 -、-OCH 2 -、-OCH 2 CH 2 -、-CH 2 O-、-CH 2 CH 2 O-、-NHCH 2 -、-NHCH 2 CH 2 -、-CH 2 NH-、-CH 2 CH 2 NH-、-NHC(＝O)CH 2 -、-CH 2 C(＝O)NH-；
Or Y is selected from O, -N (CH) 3 )C(＝O)-、-C(＝O)N(CH 3 )-、-CH 2 C(＝O)NH-、-CH 2 C(＝O)N(CH 3 )-；
Or Y is selected from-N (CH) 2 CH 3 )C(＝O)-、-N(CH(CH 3 ) 2 )C(＝O)-、-N(CH 2 CH(CH 3 ) 2 ) C (=o) -, -N (cyclopropyl) C (=o) -, -N (CH) 2 -cyclopropyl) C (=o) -, -C (=o) N (CH) 2 CH 3 )-、-C(＝O)N(CH(CH 3 ) 2 )-、-C(＝O)N(CH 2 CH(CH 3 ) 2 ) -, -C (=O) N (cyclopropyl) -, -C (=O) N (CH) 2 -cyclopropyl) -;
or Y is each independently selected from-C (=O) N (CD) 3 )-、-C(＝O)N(CH 2 -oxetanyl) -, -C (=o) N (CH 2 -oxacyclopentyl) -, -C (=o) N (CH 2 -azetidinyl) -, -C (=o) N (CH 2 -pyrrolidinyl) -, -C (=o) N (CH 2 -cyclopentyl) -, -C (=O)N(CH 2 CH 2 CH 3 )-、-C(＝O)N(CH 2 CH(CH 2 CH 3 ) 2 )-、-C(＝O)N(CH 2 CH 2 CH 2 CH 3 )-、-C(＝O)N(CH 2 CH 2 CH(CH 3 ) 2 )-、-C(＝O)N(CH 2 CH(CH 3 )CH 2 CH 3 ) -, -C (=O) N (N-octyl) -, -C (=S) N (CH) 3 )-、-C(＝S)N(CH 2 CH 3 )-、-C(＝S)N(CH 2 -cyclopropyl) -,
or Y is selected from-CH 2 S(＝O) 2 -；
R a2 Selected from H;
W 1 selected from N;
the remaining groups are as defined in any of the second, third or fourth embodiments of the invention.
As a sixth embodiment of the present invention, the compound represented by the aforementioned general formula (II) or stereoisomers, deuterates, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals thereof,
L1 is selected from
The right side is connected with the ring B;
or L1 is selected from The right side is connected with the ring B;
l2 is selected from The right side is connected with the ring B;
l3 is selected fromThe right side is connected with the ring B;
R x each independently selected from H, F, cl, br, I, cyano, OH, methyl, ethyl, propyl, isopropyl, butyl, t-butyl,Ethynyl, methoxy, ethoxy, -SCH 3 、-SCH 2 CH 3 Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methyl, ethyl, propyl, isopropyl, ethynyl, methoxy, ethoxy, -SCH 3 、-SCH 2 CH 3 Optionally further substituted with 0 to 4 (e.g., 0, 1, 2, 3, or 4) substituents selected from H, F, OH, cyano, methyl, ethyl, methoxy, or ethoxy;
R a1 selected from H, F, cl, br, I, cyano, CF 3 、CHF 2 、CH 2 F. Methyl, ethyl, propyl, isopropyl, ethynyl, methoxy, ethoxy, -SCH 3 、-SCH 2 CH 3 Cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;
R a3 selected from H or methyl;
R b each independently selected from H, F, cl, br, I, cyano, OH, =o, methyl, ethyl, propyl or isopropyl;
the remaining groups are as defined in any of the second, third, fourth or fifth embodiments of the invention.
As a seventh embodiment of the present invention, a compound represented by the following general formula (II-a), (II-b), (II-c) or a stereoisomer, a deuterate, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof,
Y is selected from-NHC (=O) -, -C (=O) NH-, -CH 2 CH 2 CH 2 -、-OCH 2 -、-CH 2 CH 2 -、-CH 2 O-、-CH 2 CH 2 O-、-OCH 2 CH 2 -；
Or Y is selected from O, -N (CH) 3 )C(＝O)-、-C(＝O)N(CH 3 )-、-CH 2 C(＝O)NH-、-CH 2 C(＝O)N(CH 3 )-；
Or Y is selected from-N (CH) 2 CH 3 )C(＝O)-、-N(CH(CH 3 ) 2 )C(＝O)-、-N(CH 2 CH(CH 3 ) 2 ) C (=o) -, -N (cyclopropyl) C (=o) -, -N (CH) 2 -cyclopropyl) C (=o) -, -C (=o) N (CH) 2 CH 3 )-、-C(＝O)N(CH(CH 3 ) 2 )-、 -C(＝O)N(CH 2 CH(CH 3 ) 2 ) -, -C (=O) N (cyclopropyl) -, -C (=O) N (CH) 2 -cyclopropyl) -;
or Y is each independently selected from-C (=O) N (CD) 3 )-、-C(＝O)N(CH 2 -oxetanyl) -, -C (=o) N (CH 2 -oxacyclopentyl) -, -C (=o) N (CH 2 -azetidinyl) -, -C (=o) N (CH 2 -pyrrolidinyl) -, -C (=o) N (CH 2 -cyclopentyl) -, -C (=o) N (CH 2 CH 2 CH 3 )-、-C(＝O)N(CH 2 CH(CH 2 CH 3 ) 2 )-、-C(＝O)N(CH 2 CH 2 CH 2 CH 3 )-、-C(＝O)N(CH 2 CH 2 CH(CH 3 ) 2 )-、-C(＝O)N(CH 2 CH(CH 3 )CH 2 CH 3 ) -, -C (=O) N (N-octyl) -, -C (=S) N (CH) 3 )-、-C(＝S)N(CH 2 CH 3 )-、-C(＝S)N(CH 2 -cyclopropyl) -,
or Y is selected from-CH 2 S(＝O) 2 -；
X 1 、X 2 、X 3 、X 4 Each independently selected from N, CR x ，X 1 、X 2 、X 3 、X 4 Up to 2N;
R x each independently selected from H, F, cl, cyano, methyl, ethyl, isopropyl, trifluoromethyl, methoxy, ethoxy, -SO 2 CH 3 、-SO 2 CH 2 CH 3 、-C(＝O)CH 3 、-C(＝O)CH 2 CH 3 Cyclopropyl;
the remaining groups are as defined in any of the second, third, fourth, fifth or sixth embodiments of the invention.
As an eighth embodiment of the present invention, the compounds represented by the above general formulae (II-a), (II-b), (II-c) or stereoisomers, deuterates, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals thereof,
l is selected fromOr alternativelyThe right side is connected with the ring B;
or L is selected from The right side is connected with the ring B;
l is selected from The right side is connected with the ring B;
preferably X 1 Selected from N, X 2 Selected from CH, X 3 Selected from CH, CF, CCl, CCN or CCF 3 ，X 4 Selected from CH or N;
the remaining groups are as defined in any of the seventh embodiments of the invention.
The present invention relates to a compound shown below or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein the compound is selected from one of the following structures:
the present invention relates to some embodiments of the general formula (I), (II-a), (II-b) or (II-c), Y being selected from O, S, S (=O), S (=O) 2 、S(＝O) 2 N(R y )、N(R y )、C 1-4 Alkylene, -OC 1-3 Alkylene-, -C 1-3 Alkylene group O-, -C 1-3 Alkylene group S-, -C 1-3 Alkylene S (=o) -, C 1-3 Alkylene group S (=o) 2 -、-N(R y )C 1-3 Alkylene-, -C 1-3 Alkylene N (R) y ) -said alkylene group optionally being further substituted with 0 to 4 (e.g. 0, 1, 2, 3 or 4) groups selected from H, halogen, =o, = S, OH, cyano, C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 The substituents of cycloalkyl groups are substituted.
The present invention relates to some embodiments of the general formula (I), (II-a), (II-b) or (II-c) wherein Y is selected from O, N (R) y )、C 1-3 Alkylene, -OC 1-2 Alkylene-, -C 1-2 Alkylene group O-, -C 1-2 Alkylene group S-, -C 1-2 Alkylene group S (=o) 2 -、-N(R y )C 1-2 Alkylene-, -C 1-2 Alkylene N (R) y ) Optionally further from 0 to 4 (e.g. 0, 1, 2, 3 or 4) of said alkylene groups are selected from H, halogenPlain, =o, = S, OH, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 The substituents of cycloalkyl groups are substituted.
The present invention relates to some embodiments of the general formula (I), (II-a), (II-b) or (II-c) wherein Y is selected from O, N (R) y )、-N(R y )C(＝O)-、-C(＝O)N(R y )-、-CH 2 -、-CH 2 CH 2 -、-CH 2 CH 2 CH 2 -、-OCH 2 -、-OCH 2 CH 2 -、-CH 2 O-、-CH 2 CH 2 O-、-CH 2 S-、-CH 2 CH 2 S-、-CH 2 S(＝O) 2 -、-CH 2 CH 2 S(＝O) 2 -、-N(R y )CH 2 -、-N(R y )CH 2 CH 2 -、-CH 2 N(R y )-、-CH 2 CH 2 N(R y )-、-N(R y )C(＝O)CH 2 -、-CH 2 C(＝O)N(R y ) -, the CH 2 Optionally further 0 to 2 (e.g. 0, 1 or 2) are selected from H, =o, = S, OH, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 The substituents of cycloalkyl groups are substituted.
The present invention relates to some embodiments of formula (I), (II-a), (II-b) or (II-C), wherein Y is selected from the group consisting of O, -NHC (=O) -, -C (=O) NH-, -CH 2 -、-CH 2 CH 2 -、-CH 2 CH 2 CH 2 -、-OCH 2 -、-OCH 2 CH 2 -、-CH 2 O-、-CH 2 CH 2 O-、-NHCH 2 -、-NHCH 2 CH 2 -、-CH 2 NH-、-CH 2 CH 2 NH-、-NHC(＝O)CH 2 -、-CH 2 C(＝O)NH-。
The present invention relates to some embodiments of formula (I), (II-a), (II-b) or (II-C), wherein Y is selected from the group consisting of O, -NHC (=O) -, -C (=O) NH-, -CH 2 CH 2 CH 2 -、-OCH 2 -、-CH 2 CH 2 -、-CH 2 O-、-CH 2 CH 2 O-、-OCH 2 CH 2 -。
The present invention relates to some embodiments of the general formula (I), (II-a), (II-b) or (II-c), Y being selected from O, -N (CH) 3 )C(＝O)-、-C(＝O)N(CH 3 )-、-CH 2 C(＝O)NH-、-CH 2 C(＝O)N(CH 3 )-。
The present invention relates to some embodiments of the general formula (I), (II-a), (II-b) or (II-c), Y being selected from the group consisting of-N (CH) 2 CH 3 )C(＝O)-、-N(CH(CH 3 ) 2 )C(＝O)-、-N(CH 2 CH(CH 3 ) 2 ) C (=o) -, -N (cyclopropyl) C (=o) -, -N (CH) 2 -cyclopropyl) C (=o) -, -C (=o) N (CH) 2 CH 3 )-、-C(＝O)N(CH(CH 3 ) 2 )-、-C(＝O)N(CH 2 CH(CH 3 ) 2 ) -, -C (=O) N (cyclopropyl) -, -C (=O) N (CH) 2 -cyclopropyl) -.
The present invention relates to some embodiments of the general formula (I), (II-a), (II-b) or (II-C), Y is each independently selected from the group consisting of-C (=O) N (CD) 3 )-、-C(＝O)N(CH 2 -oxetanyl) -, -C (=o) N (CH 2 -oxacyclopentyl) -, -C (=o) N (CH 2 -azetidinyl) -, -C (=o) N (CH 2 -pyrrolidinyl) -, -C (=o) N (CH 2 -cyclopentyl) -, -C (=o) N (CH 2 CH 2 CH 3 )-、-C(＝O)N(CH 2 CH(CH 2 CH 3 ) 2 )-、-C(＝O)N(CH 2 CH 2 CH 2 CH 3 )-、-C(＝O)N(CH 2 CH 2 CH(CH 3 ) 2 )-、 -C(＝O)N(CH 2 CH(CH 3 )CH 2 CH 3 ) -, -C (=O) N (N-octyl) -, -C (=S) N (CH) 3 )-、-C(＝S)N(CH 2 CH 3 )-、-C(＝S)N(CH 2 -cyclopropyl) -,
in some embodiments of the general formula (I), (II-a), (II-b) or (II-c), Y is each independently selected from the group consisting of Y is selected from the group consisting of-CH 2 S(＝O) 2 -。
The present invention relates to certain embodiments of the general formula (I), (II-a), (II-b) or (II-c), R y Each independently selected from H, C 1-6 Alkyl or C 3-6 Cycloalkyl, said alkyl or cycloalkyl optionally being further substituted with 0 to 4 (e.g. 0, 1, 2, 3 or 4) groups selected from H, deuterium, halogen, CF 3 OH, cyano, NH 2 、C 1-6 Alkyl, C 1-6 Alkoxy, 3-to 8-membered heterocyclyl or C 3-6 Cycloalkyl is substituted with a substituent, said heterocyclyl containing 1 to 3 heteroatoms selected from O, S, N.
The present invention relates to certain embodiments of the general formula (I), (II-a), (II-b) or (II-c), R y Each independently selected from H, C 1-4 Alkyl or C 3-6 Cycloalkyl, said alkyl or cycloalkyl optionally being further substituted with 0 to 4 (e.g. 0, 1, 2, 3 or 4) groups selected from H, deuterium, halogen, CF 3 OH, cyano, NH 2 、C 1-4 Alkyl, C 1-4 Alkoxy, 3-to 8-membered heterocyclyl or C 3-6 Cycloalkyl is substituted with a substituent, said heterocyclyl containing 1 to 3 heteroatoms selected from O, S, N.
The present invention relates to certain embodiments of the general formula (I), (II-a), (II-b) or (II-c), R y Each independently selected from H, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, sec-butyl, isobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, said methyl, ethyl, propyl, isopropyl, butyl, t-butyl, sec-butyl, isobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl optionally further being 0 to 4 (e.g. 0, 1, 2, 3 or 4) selected from H, deuterium, halogen, CF 3 OH, cyano, NH 2 、C 1-4 Alkyl, C 1-4 Alkoxy, 3-to 8-membered heterocyclyl or C 3-6 Cycloalkyl is substituted with a substituent, said heterocyclyl containing 1 to 3 heteroatoms selected from O, S, N.
The present invention relates to certain embodiments of the general formula (I), (II-a), (II-b) or (II-c), R y Each independently selected from H, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, sec-butyl, isobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, said methyl, ethyl, propyl, isopropyl, butyl, t-butyl, sec-butyl, isobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl optionally further being 0 to 4 (e.g. 0, 1, 2, 3 or 4) selected from H, deuterium, F, cl, br, CF 3 OH, cyano, NH 2 Substituted with methyl, ethyl, propyl, butyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl.
The present invention relates to certain embodiments of the general formula (I), (II-a), (II-b) or (II-c), R y Each independently selected from H, C 1-4 An alkyl group.
The present invention relates to certain embodiments of the general formula (I), (II-a), (II-b) or (II-c), R y Each independently selected from H, methyl, ethyl.
The invention relates to certain embodiments of the general formula (I), (II-a), (II-b) or (II-c)In the scheme, R y Each independently selected from CD 3 ；
In some embodiments of the invention relating to formula (I), ring A is selected from C 6-10 Aryl, 5-10 membered heteroaryl, or 5-10 membered heterocyclyl, said heteroaryl or heterocyclyl containing 1 to 5 (e.g., 1, 2, 3, 4, or 5) heteroatoms selected from O, S, N.
In some embodiments of the present invention, ring A is selected from 3 (2H) -pyridazinone or 2 (1H) -pyridinone.
The present invention relates to some embodiments of formula (I),selected from the group consisting of
The present invention relates to some embodiments of formula (I),selected from the group consisting of
The present invention relates to some embodiments of formula (I),selected from the group consisting of
The present invention relates to some embodiments of formula (I),selected from the group consisting of
The present invention relates to some embodiments of formula (I),selected from the group consisting of
The present invention relates to some embodiments of the general formula (II-a), (II-b) or (II-c), X 1 、X 2 、X 3 、X 4 Each independently selected from N, CR x ，X 1 、X 2 、X 3 、X 4 Containing at most 2N (X) 1 、X 2 、X 3 、X 4 At most 2 of which are N).
In some embodiments of the invention of formula (I), (II), ring X is selected from C 6-10 Aryl, 5-10 membered heteroaryl, C 3-10 Carbocycle or 5-10 membered heterocyclyl, said heteroaryl or heterocyclyl containing 1 to 5 (e.g. 1, 2, 3, 4 or 5) heteroatoms selected from O, S, N.
The present invention relates to some embodiments of the general formula (II-a), (II-b) or (II-c), X 1 Selected from N, X 2 Selected from CH, X 3 Selected from CH, CF,CCl, CCN or CCF 3 ，X 4 Selected from CH or N.
In some embodiments of formulae (I), (II), ring X is selected from phenyl, a 5-6 membered heteroaryl or a 5-6 membered heterocyclyl containing 1 to 5 (e.g., 1, 2, 3, 4 or 5) heteroatoms selected from O, S, N.
The present invention relates to some embodiments of formulae (I), (II), wherein ring X is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thienyl, thiazolyl, furanyl, oxazolyl, pyrrolyl, pyrazolyl or imidazolyl.
In some embodiments of the invention, W of formula (II) 1 Selected from N or C (R) a4 )。
In some embodiments of the invention, W of formula (II) 1 Selected from N or CH.
In some embodiments of the invention, W of formula (II) 1 Selected from N.
The present invention relates to certain embodiments of the general formula (I), (II-a), (II-b) or (II-c), R x 、R a Each independently selected from H, halogen, cyano, OH, = O, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylthio, -SO 2 -C 1-6 Alkyl, -C (=o) C 1-6 Alkyl, - (CH) 2 ) q -C 3-10 Carbocycle or- (CH) 2 ) q -3 to 12 membered heterocycle, said-CH 2 -, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, carbocycle or heterocycle optionally further being 0 to 4 (e.g. 0, 1, 2, 3 or 4) selected from H, halogen, OH, cyano, = O, NH 2 、NH(C 1-6 Alkyl), N (C) 1-6 Alkyl group 2 、C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Substituted by cycloalkyl or by substituents of 3-to 10-membered heterocyclic rings, said substituentsThe heterocycle contains 1 to 3 (e.g., 1, 2 or 3) heteroatoms selected from O, S, N.
The present invention relates to certain embodiments of formula (II), (II-a), (II-b) or (II-c), R a1 、R a2 、R a4 Each independently is selected from R a 。
The present invention relates to certain embodiments of formula (II), (II-a), (II-b) or (II-c), R a1 、R a2 、R a4 Each independently selected from H, halogen, cyano, OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylthio, -SO 2 -C 1-6 Alkyl, -C (=o) C 1-6 Alkyl, - (CH) 2 ) q -C 3-10 Carbocycle or- (CH) 2 ) q -3 to 12 membered heterocycle, said-CH 2 -, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, carbocycle or heterocycle optionally further being 0 to 4 (e.g. 0, 1, 2, 3 or 4) selected from H, halogen, OH, cyano, = O, C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or a 3 to 10 membered heterocyclic ring containing 1 to 3 (e.g. 1, 2 or 3) heteroatoms selected from O, S, N.
In some embodiments of the invention, R is a compound of formula (II) a3 Selected from H, C 1-6 Alkyl, - (CH) 2 ) q -C 3-10 Carbocycle or- (CH) 2 ) q -3 to 12 membered heterocycle, said-CH 2 -, alkyl, carbocycle or heterocycle optionally further being 0 to 4 (e.g. 0, 1, 2, 3 or 4) selected from H, halogen, OH, cyano, C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or a 3 to 10 membered heterocyclic ring containing 1 to 3 (e.g. 1, 2 or 3) heteroatoms selected from O, S, N.
In some embodiments of the invention, R is a compound of formula (II) a3 Selected from H, C 1-4 Alkyl, said alkyl optionally being further substituted with 0 to 4 (e.g. 0, 1, 2, 3 or 4) groups selected from H, halogen, OH, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 The substituents of cycloalkyl groups are substituted.
In some embodiments of the invention, R is a compound of formula (II) a3 Selected from H, methyl, ethyl, propyl, isopropyl, said methyl, ethyl, propyl or isopropyl optionally being further substituted with 0 to 4 (e.g. 0, 1, 2, 3 or 4) groups selected from H, halogen, OH, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 The substituents of cycloalkyl groups are substituted.
In some embodiments of the invention, R is a compound of formula (II) a2 Selected from H, F, cl, br, I, cyano, CF 3 、CHF 2 、CH 2 F. Methyl, methoxy, cyclopropyl.
In some embodiments of the invention, R is a compound of formula (II) a3 Selected from H or methyl.
The present invention relates to certain embodiments of the general formula (I), (II-a), (II-b) or (II-c), R x 、R a1 、R a2 、R a4 Each independently selected from H, halogen, cyano, OH, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 1-4 Alkylthio, -SO 2 -C 1-4 Alkyl, -C (=o) C 1-4 Alkyl, - (CH) 2 ) q -C 3-6 Carbocycle or- (CH) 2 ) q -3 to 6 membered heterocycle, said-CH 2 -, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, carbocycle or heterocycle optionally further being selected from 0 to 4 (e.g. 0, 1, 2, 3 or 4)H. Halogen, OH, cyano, = O, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl or a 3 to 6 membered heterocyclic ring containing 1 to 3 (e.g. 1, 2 or 3) heteroatoms selected from O, S, N.
The present invention relates to certain embodiments of the general formula (I), (II-a), (II-b) or (II-c), R x 、R a1 、R a2 Each independently selected from H, F, cl, br, I, cyano, OH, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, vinyl, ethynyl, methoxy, ethoxy, -SCH 3 、-SCH 2 CH 3 、-SO 2 CH 3 、-SO 2 CH 2 CH 3 、-C(＝O)CH 3 、-C(＝O)CH 2 CH 3 Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, vinyl, ethynyl, methoxy, ethoxy, -SCH 3 、-SCH 2 CH 3 、-SO 2 CH 3 、-SO 2 CH 2 CH 3 、 -C(＝O)CH 3 、-C(＝O)CH 2 CH 3 Optionally further 0 to 4 (e.g. 0, 1, 2, 3 or 4) of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl are selected from H, halogen, OH, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 The substituents of cycloalkyl groups are substituted.
The present invention relates to certain embodiments of the general formula (I), (II-a), (II-b) or (II-c), R x Each independently selected from H, F, cl, br, I, cyano, OH, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, ethynyl, methoxy, ethoxy, -SCH 3 、-SCH 2 CH 3 Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, saidMethyl, ethyl, propyl, isopropyl, ethynyl, methoxy, ethoxy, -SCH 3 、-SCH 2 CH 3 The cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl are optionally further substituted by 0 to 4 (e.g. 0, 1, 2, 3 or 4) substituents selected from H, F, OH, cyano, methyl, ethyl, methoxy or ethoxy.
The present invention relates to certain embodiments of the general formula (I), (II-a), (II-b) or (II-c), R x Each independently selected from H, F, cl, cyano, methyl, ethyl, isopropyl, trifluoromethyl, methoxy, ethoxy, -SO 2 CH 3 、-SO 2 CH 2 CH 3 、-C(＝O)CH 3 、-C(＝O)CH 2 CH 3 Cyclopropyl.
The present invention relates to certain embodiments of formula (II), (II-a), (II-b) or (II-c), R a1 Selected from H, F, cl, br, I, cyano, CF 3 、CHF 2 、CH 2 F. Methyl, ethyl, propyl, isopropyl, ethynyl, methoxy, ethoxy, -SCH 3 、-SCH 2 CH 3 Cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
The present invention relates to certain embodiments of formula (II), (II-a), (II-b) or (II-c), R a1 Selected from H, F, cl, br, I, cyano, CF 3 Methyl.
In some embodiments of the invention, R is a compound of formula (II) a2 Selected from H.
The present invention relates to some embodiments of the general formula (I), (II-a), (II-B) or (II-C), wherein ring B is selected from 4-to 11-membered nitrogen-containing heterocycles, C 4-10 Carbocycles.
The present invention relates to some embodiments of the general formula (I), (II-a), (II-B) or (II-C) wherein ring B is selected from 4 to 7 membered monocyclic nitrogen-containing heterocycle, 5-11 membered spiro nitrogen-containing heterocycle, 5-11 membered fused ring nitrogen-containing heterocycle, 5-11 membered bridged ring nitrogen-containing heterocycle or C 4-7 A monocyclic carbocyclic ring.
In some embodiments of the invention of formula (I), (II), ring B is selected from cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl,
The invention relates to some embodiments of the general formulae (I), (II),selected from the group consisting of The left side is connected with L.
The present invention relates to some embodiments of the general formulae (I), (II), R b Each independently selected from H, halogen, cyano, OH, = O, C 1-6 Alkyl, C 1-6 Alkoxy, - (CH) 2 ) q -C 3-6 Cycloalkyl, the-CH 2 -, alkyl, alkoxy or cycloalkyl optionally further being 0 to 4 (e.g. 0, 1, 2, 3 or 4) selected from H, halogen, OH, cyano, NH 2 、C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 The substituents of cycloalkyl groups are substituted.
The present invention relates to some embodiments of the general formulae (I), (II), R b Each independently selected from H, halogen, cyano, OH, = O, C 1-4 Alkyl, C 1-4 Alkoxy, - (CH) 2 ) q -C 3-6 Cycloalkyl, the-CH 2 -, alkyl, alkoxy or cycloalkyl optionally further being 0 to 4 (e.g. 0, 1, 2, 3 or 4) selected from H, halogen, OH, cyano, NH 2 、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, C 1-4 Alkoxy or C 3-6 The substituents of cycloalkyl groups are substituted.
The present invention relates to some embodiments of the general formulae (I), (II), R b Each independently selected from H, F, cl, br, I, cyano, OH, =o, methyl, ethyl, propyl or isopropyl, said methyl, ethyl, propyl or isopropyl optionally being further substituted with 0 to 4 (e.g. 0, 1, 2, 3 or 4) groups selected from H, halogen, OH, cyano, NH 2 、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, C 1-4 Alkoxy or C 3-6 The substituents of cycloalkyl groups are substituted.
The present invention relates to some embodiments of the general formulae (I), (II), R b Each independently selected from H, F, cl, br, I, cyano, OH, =o, methyl, ethyl, propyl or isopropyl.
In some embodiments of the invention related to formula (I), W is selected from the group consisting of a bond, C 1-3 Alkylene or Q2, the alkylene group shown optionally being further selected from H, halogen, CF by 0 to 4 (e.g. 0, 1, 2, 3 or 4) 3 OH, cyano, NH 2 、C 1-6 Alkyl or C 1-6 The substituent of the alkoxy group is substituted.
In some embodiments of formula (I), W is selected from a bond.
The present invention relates to some embodiments of formula (I), (II-a), (II-b) or (II-c), wherein L is selected from L1, L2 or L3.
The invention relates to some embodiments of the general formula (I), (II-a), (II-B) or (II-c), wherein L1 is selected from the group consisting of-Q1-Ak 1-Q2-Ak2-Q3-, the right side being attached to ring B.
The present invention relates to some embodiments of the general formula (I), (II-a), (II-b) or (II-c), L1 is selected from the group consisting of-N (R) q )-Ak1-O-Ak2-C(＝O)-、-O-Ak1-O-Ak2-C(＝O)-、-O-Ak1-N(R q )-Ak2-C(＝O)-、-N(R q )-Ak1-N(R q )-Ak2-C(＝O)-、-N(R q )-Ak1-O-Ak2-N(R q )C(＝O)-、-O-Ak1-O-Ak2-N(R q )C(＝O)-、-N(R q )-Ak1-Ak2-C(＝O)-、-N(R q )-Ak1-Ak2-N(R q )C(＝O)-、-O-Ak1-N(R q )-Ak2-N(R q )C(＝O)-、-S-Ak1-O-Ak2-C(＝O)-、-O-Ak1-S-Ak2-C(＝O)-、-N(R q )-Ak1-O-Ak2-S(＝O) 2 -、-O-Ak1-O-Ak2-S(＝O) 2 -、-N(R q ) Ak1-O-Ak2-, -O-Ak1-O-Ak2-, the right side being attached to ring B.
The present invention relates to some embodiments of the general formula (I), (II-a), (II-b) or (II-c), or L1 is selected from the group consisting of-N (R) q )-Ak1-O-Ak2-C(＝O)N(R q )-、-O-Ak1-N(R q )-Ak2-C(＝O)N(R q )-、-O-Ak1-O-C(＝O)N(R q ) The right side is connected to ring B.
The present invention relates to some embodiments of the general formula (I), (II-a), (II-b) or (II-c), L1 is selected fromThe right side is connected to ring B.
The present invention relates to certain embodiments of the general formula (I), (II-a), (II-b) or (II-C), L1 is selected from the group consisting of-NH-Ak 1-O Ak2-C (=O) -, -O-Ak1-O-Ak2-C (=o) -, -N (CH) 3 )-Ak1-O-Ak2-C(＝O)-、-O-Ak1-NH-Ak2-C(＝O)-、-O-Ak1-N(CH 3 )-Ak2-C(＝O)-、-N(CH 3 )-Ak1-NH-Ak2-C(＝O)-、-NH-Ak1-NH-Ak2-C(＝O)-、-S-Ak1-O-Ak2-C(＝O)-、-O-Ak1-S-Ak2-C(＝O)-、-NH-Ak1-O-Ak2-S(＝O) 2 -、-O-Ak1-O-Ak2-S(＝O) 2 -, -NH-Ak1-O-Ak 2-; -O-Ak1-O-Ak2-, the right side is connected to ring B.
The present invention relates to some embodiments of the general formula (I), (II-a), (II-b) or (II-c), L2 is selected fromThe right side is connected to ring B.
The present invention relates to some embodiments of the general formula (I), (II-a), (II-b) or (II-c), L2 is selected fromThe right side is connected to ring B.
The present invention relates to some embodiments of the general formula (I), (II-a), (II-b) or (II-c), L2 is selected from The right side is connected to ring B.
The present invention relates to some embodiments of the general formula (I), (II-a), (II-b) or (II-c), L3 is selected fromThe right side is connected to ring B.
The present invention relates to some embodiments of the general formula (I), (II-a), (II-b) or (II-c), L3 is selected from The right side is connected to ring B.
The invention relates to some embodiments of the general formula (I), (II-a), (II-B) or (II-c), wherein L4 is selected from the group consisting of-Ak 3-Q4-Ak4-K1-Q5-K2-Ak 5-Q6-or-Ak 3-Q4-Ak4-K1-Q5-, the right side being attached to ring B.
The present invention relates to some embodiments of the general formula (I), (II-a), (II-b) or (II-C), L4 is selected from the group consisting of-Ak 3-O-K1-C (=O) -, -Ak3-N (R) q )-K1-C(＝O)-、-Ak3-N(R q ) -K1-C (=o) -, right-hand side linked to ring B.
The present invention relates to some embodiments of the general formula (I), (II-a), (II-b) or (II-C), wherein L4 is selected from the group consisting of-Ak 3-O-K1-C (=O) -, -Ak3-NH-K1-C (=O) -, -Ak3-N (CH) 3 ) -K1-C (=o) -, right-hand side linked to ring B.
The present invention relates to some embodiments of the general formula (I), (II-a), (II-b) or (II-C), ak1, ak2 are each independently selected from C 1-4 Alkylene, C 2-4 Alkenylene, C 2-4 Alkynylene, the Ak1 is optionally further substituted with 0 to 4 (e.g., 0, 1, 2, 3, or 4) R k1 Substituted, the Ak2 is optionally further substituted with 0 to 4 (e.g., 0, 1, 2, 3, or 4) R k2 And (3) substitution.
The present invention relates to some embodiments of the general formula (I), (II-a), (II-b) or (II-C), ak1, ak2 are each independently selected from C 1-3 Alkylene, C 2-3 Alkenylene, C 2-3 Alkynylene, the Ak1 is optionally further substituted with 0 to 4 (e.g., 0, 1, 2, 3, or 4) R k1 Substituted, the Ak2 is optionally further substituted with 0 to 4 (e.g., 0, 1, 2, 3, or 4) R k2 And (3) substitution.
The present invention relates to some embodiments of the general formula (I), (II-a), (II-b) or (II-c), wherein each of Ak1, ak2 is independently selected from the group consisting of methylene, ethylene, propylene, ethenylene, propenylene, ethynylene, propynylene, said Ak1 optionally being further substituted with 0 to 4 (e.g. 0, 1, 2, 3 or 4) R k1 Substituted, the Ak2 is optionally further substituted with 0 to 4 (e.g., 0, 1, 2, 3, or 4) R k2 And (3) substitution.
The present invention relates to some embodiments of the general formula (I), (II-a), (II-b) or (II-C), ak3, ak4, ak5 are each independently selected from the group consisting of a bond, C 1-4 Alkylene, C 2-4 Alkenylene, C 2-4 Alkynylene, the Ak3 is optionally further substituted with 0 to 4 (e.g., 0, 1, 2, 3, or 4) R k3 Substituted, the Ak4 is optionally further substituted with 0 to 4 (e.g., 0, 1, 2, 3, or 4) R k4 Substituted, the Ak5 is optionally further substituted with 0 to 4 (e.g., 0, 1, 2, 3, or 4) R k5 And (3) substitution.
The present invention relates to some embodiments of the general formula (I), (II-a), (II-b) or (II-C), ak3, ak4, ak5 are each independently selected from the group consisting of a bond, C 1-3 Alkylene, C 2-3 Alkenylene, C 2-3 Alkynylene, the Ak3 is optionally further substituted with 0 to 4 (e.g., 0, 1, 2, 3, or 4) R k3 Substituted, the Ak4 is optionally further substituted with 0 to 4 (e.g., 0, 1, 2, 3, or 4) R k4 Substituted, the Ak5 is optionally further substituted with 0 to 4 (e.g., 0, 1, 2, 3, or 4) R k5 And (3) substitution.
The present invention relates to some embodiments of the general formula (I), (II-a), (II-b) or (II-c), wherein each of Ak3, ak4, ak5 is independently selected from the group consisting of bond, methylene, ethylene, propylene, vinylene, propenylene, ethynylene, propynylene, said Ak3 optionally being further substituted with 0 to 4 (e.g. 0, 1, 2, 3 or 4) R k3 Substituted, the Ak4 is optionally further substituted with 0 to 4 (e.g., 0, 1, 2, 3, or 4) R k4 Substituted, the Ak5 is optionally further substituted with 0 to 4 (e.g., 0, 1, 2, 3, or 4) R k5 And (3) substitution.
The present invention relates to some embodiments of the general formula (I), (II-a), (II-b) or (II-C), K1 or K2 is selected from C 1-2 Alkylene, C 3-10 Carbocycle or 3-to 12-membered heterocycle, said alkylene optionally being further substituted with 0 to 4 (e.g. 0, 1, 2, 3 or 4) R k6 Substituted, said carbocycle or heterocycle optionally being further substituted with 0 to 4 (e.g. 0, 1, 2, 3 or 4) groups selected from H, halogen, OH, cyano, NH 2 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen substituted C 1-6 Alkyl, C 1-6 Alkoxy, -C 1-6 alkyl-OC 1-6 Alkyl, -O-C 1-6 alkyl-OC 1-6 Alkyl, -O-C 3-8 Carbocycle, C 3-8 Carbocycle, substituted with substituents of 4 to 10 membered heterocycle containing 1 to 3 (e.g. 1, 2 or 3) heteroatoms selected from O, S, N.
The present invention relates to some embodiments of the general formula (I), (II-a), (II-b) or (II-C), K1 or K2 is selected from C 1-2 Alkylene, C 3-6 Carbocycle or 3-to 7-membered heterocycle, said alkylene optionally being further substituted with 0 to 4 (e.g. 0, 1, 2, 3 or 4) R k6 Substituted, said carbocycle or heterocycle optionally being further substituted with 0 to 4 (e.g. 0, 1, 2, 3 or 4) groups selected from H, halogen, OH, cyano, NH 2 、C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, halogen substituted C 1-4 Alkyl, C 1-4 Alkoxy, -C 1-4 alkyl-OC 1-4 Alkyl, -O-C 1-4 alkyl-OC 1-4 Alkyl, -O-C 3-6 Carbocycle, C 3-6 Carbocycle, substituted with substituents of 4 to 7 membered heterocycle containing 1 to 3 (e.g. 1, 2 or 3) heteroatoms selected from O, S, N.
The present invention relates to some embodiments of the general formula (I), (II-a), (II-b) or (II-c), wherein K1 or K2 is selected from methylene, ethylene, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinePentyl, azacyclohexyl, piperazine, morpholine, oxetanyl, oxolanyl, benzene ring, pyridine, pyrazine, pyrimidine, pyridazine, said methylene, ethylene optionally being further substituted with 0 to 4 (e.g. 0, 1, 2, 3 or 4) R k6 Substituted, said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, piperazine, morpholine, oxetanyl, oxcyclohexyl, benzene ring, pyridine, pyrazine, pyrimidine, pyridazine optionally further substituted with 0 to 4 (e.g. 0, 1, 2, 3 or 4) groups selected from H, halogen, OH, cyano, NH 2 、C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, halogen substituted C 1-4 Alkyl, C 1-4 Alkoxy, -C 1-4 alkyl-OC 1-4 Alkyl, -O-C 1-4 alkyl-OC 1-4 Alkyl, -O-C 3-6 Carbocycle, C 3-6 Carbocycle, substituted with substituents of 4 to 7 membered heterocycle containing 1 to 3 (e.g. 1, 2 or 3) heteroatoms selected from O, S, N.
The present invention relates to certain embodiments of the general formula (I), (II-a), (II-b) or (II-c), R k1 、R k2 、R k3 、R k4 、R k5 、R k6 、R L1 、R L2 Each independently selected from H, halogen, cyano, OH, = O, NH 2 、NHC 1-6 Alkyl, N (C) 1-6 Alkyl group 2 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, -OC 3-6 Carbocycle, C 3-6 Carbocycle or 4-to 7-membered heterocycle, said alkyl, alkenyl, alkynyl, alkoxy, carbocycle or heterocycle optionally being further substituted with 0 to 4 (e.g. 0, 1, 2, 3 or 4) groups selected from H, halogen, OH, cyano, NH 2 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen substituted C 1-6 Alkyl, C 1-6 Alkoxy, -O-C 3-8 Carbocycle, C 3-8 Carbocycle, substituted with substituents of 4 to 10 membered heterocycle containing 1 to 3 (e.g. 1, 2 or 3) heteroatoms selected from O, S, N.
The present invention relates to certain embodiments of the general formula (I), (II-a), (II-b) or (II-c), R k1 、R k2 、R k3 、R k4 、R k5 、R k6 、R L1 、R L2 Each independently selected from H, halogen, cyano, OH, = O, NH 2 、NHC 1-4 Alkyl, N (C) 1-4 Alkyl group 2 、C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Carbocycle or 4-to 7-membered heterocycle, said alkyl, alkoxy, carbocycle or heterocycle optionally being further substituted with 0 to 4 (e.g. 0, 1, 2, 3 or 4) groups selected from H, halogen, OH, cyano, NH 2 、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Carbocycle, substituted with substituents of 4-to 6-membered heterocyclic ring containing 1 to 3 (e.g. 1, 2 or 3) heteroatoms selected from O, S, N.
The present invention relates to certain embodiments of the general formula (I), (II-a), (II-b) or (II-c), R k1 、R k2 、R k3 、R k4 、R k5 、R k6 、R L1 、R L2 Each independently selected from H, F, cl, br, I, cyano, OH, = O, NH 2 、NH(CH 3 )、N(CH 3 ) 2 Methyl, ethyl, propyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, cyclohexyl, oxetanyl, oxacyclohexyl, pyridine, phenyl, the methyl, ethyl, propyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl,Optionally further 0 to 4 (e.g. 0, 1, 2, 3 or 4) of an oxacyclopentyl, oxacyclohexyl, pyridine, phenyl group is selected from H, halogen, OH, cyano, NH 2 、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Carbocycle, substituted with substituents of 4-to 6-membered heterocyclic ring containing 1 to 3 (e.g. 1, 2 or 3) heteroatoms selected from O, S, N.
The present invention relates to certain embodiments of the general formula (I), (II-a), (II-b) or (II-c), R k1 And R is R k1 、R k2 And R is R k2 、R k1 And R is R k2 、R k3 And R is R k3 、R k4 And R is R k4 、R k5 And R is R k5 、R k6 And R is R k6 Directly connected to form C 3-6 Carbocycle or 4 to 7 membered heterocycle optionally further substituted with 0 to 4 (e.g. 0, 1, 2, 3 or 4) selected from H, halogen, = O, OH, cyano, C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl groups are substituted with substituents, said heterocyclic ring containing 1 to 3 (e.g. 1, 2 or 3) heteroatoms selected from O, S, N.
The present invention relates to certain embodiments of the general formula (I), (II-a), R k1 And R is R k1 、R k2 And R is R k2 、R k1 And R is R k2 、R k3 And R is R k3 、R k4 And R is R k4 、R k5 And R is R k5 、R k6 And R is R k6 Directly connected to form C 3-6 Carbocycles (e.g. C 3 、C 4 、C 5 Or C 6 ) Or a 4 to 7 membered (e.g. 4, 5, 6 or 7 membered) heterocycle, said carbocycle or heterocycle optionally being further substituted with 0 to 4 (e.g. 0, 1, 2, 3 or 4) groups selected from H, halogen, = O, OH, cyano, C 1-4 Alkyl, halogenSubstituted C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl groups are substituted with substituents, said heterocyclic ring containing 1 to 3 (e.g. 1, 2 or 3) heteroatoms selected from O, S, N.
The present invention relates to some embodiments of the general formula (I), (II-a), (II-b) or (II-c), Q1, Q5 are each independently selected from O, S, N (R) q )、C(＝O)、C(＝O)N(R q )、N(R q )C(＝O)、C(＝O)O、OC(＝O)、S(＝O)、S(＝O) 2 、S(＝O) 2 N(R q )、N(R q )S(＝O) 2 、N(R q )C(＝O)N(R q )、N(R q )C(＝O)N(R q )。
The present invention relates to some embodiments of the general formula (I), (II-a), (II-b) or (II-c), Q1, Q5 are each independently selected from O, S, N (R) q )、C(＝O)、C(＝O)N(R q )、N(R q )C(＝O)、S(＝O) 2 。
The present invention relates to some embodiments of formula (I), (II-a), (II-b) or (II-c), Q2, Q3, Q4, Q6 are each independently selected from a bond or Q1.
The present invention relates to some embodiments of the general formula (I), (II-a), (II-b) or (II-C), wherein ring E is selected from C 3-6 Carbocycle or 4 to 7 membered heterocycle containing 1 to 3 (e.g. 1, 2 or 3) heteroatoms selected from O, S, N.
The present invention relates to some embodiments of the general formula (I), (II-a), (II-b) or (II-C), wherein ring E is selected from C 3-6 Carbocycle or 4 to 6 membered heterocycle containing 1 to 3 (e.g. 1, 2 or 3) heteroatoms selected from O, S, N.
The present invention relates to some embodiments of formula (I), (II-a), (II-b) or (II-c) wherein ring E is selected from phenyl or a 5-6 membered heteroaryl group containing 1 to 3 (e.g., 1, 2 or 3) heteroatoms selected from O, S, N.
The present invention relates to some embodiments of formula (I), (II-a), (II-b) or (II-c), wherein ring E is selected from benzene rings or pyridine.
The present invention relates to certain embodiments of the general formula (I), (II-a), (II-b) or (II-c), R q Each independently selected from H, C 1-6 Alkyl or C 3-6 Cycloalkyl, said alkyl or cycloalkyl optionally being further substituted with 0 to 4 (e.g. 0, 1, 2, 3 or 4) groups selected from H, halogen, CF 3 OH, cyano, NH 2 、C 1-6 Alkyl or C 1-6 The substituent of the alkoxy group is substituted.
The present invention relates to certain embodiments of the general formula (I), (II-a), R q Each independently selected from H, C 1-4 Alkyl, said alkyl optionally being further substituted with 0 to 4 (e.g. 0, 1, 2, 3 or 4) groups selected from H, halogen, CF 3 OH, cyano, NH 2 、C 1-4 Alkyl or C 1-4 The substituent of the alkoxy group is substituted.
The present invention relates to certain embodiments of the general formula (I), (II-a), (II-b) or (II-c), R q Each independently selected from H, methyl, ethyl.
The present invention relates to certain embodiments of the general formula (I), (II-a), (II-b) or (II-c), R q And R is R k1 Or R is k2 Directly linked to form a 4 to 7 membered heterocyclic ring, said heterocyclic ring optionally being further substituted with 0 to 4 (e.g. 0, 1, 2, 3 or 4) groups selected from H, halogen, = O, OH, cyano, C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl groups are substituted with substituents, said heterocyclic ring containing 1 to 3 (e.g. 1, 2 or 3) heteroatoms selected from O, S, N.
The present invention relates to certain embodiments of the general formula (I), (II-a), (II-b) or (II-c), R q And R is R k1 、R q And R is R k2 Directly linked to form a 4 to 7 membered heterocyclic ring, said heterocyclic ring optionally being further substituted with 0 to 4 (e.g. 0, 1, 2, 3 or 4) groups selected from H, halogen, =o,OH, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl groups are substituted with substituents, said heterocyclic ring containing 1 to 3 (e.g. 1, 2 or 3) heteroatoms selected from O, S, N.
The present invention relates to certain embodiments of the general formula (I), (II-a), (II-b) or (II-c), R q And R is R k1 、R q And R is R k2 Direct connection forms a 4 to 7 membered heterocyclic ring, said heterocyclic ring optionally being further substituted with 0 to 4 (e.g. 0, 1, 2, 3 or 4) substituents selected from H, halogen, = O, OH, cyano, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, said heterocyclic ring containing 1 to 3 (e.g. 1, 2 or 3) heteroatoms selected from O, S, N.
The present invention relates to some embodiments of the general formula (I), (II-a), (II-b) or (II-c), L1 is selected from
The right side is connected to ring B.
The present invention relates to some embodiments of the general formula (I), (II-a), (II-b) or (II-c), L1 is selected from The right side is connected to ring B.
The present invention relates to some embodiments of the general formula (I), (II-a), (II-b) or (II-c), L being selected fromOr alternativelyThe right side is connected to ring B.
The present invention relates to some embodiments of the general formula (I), (II-a), (II-b) or (II-c), L being selected from The right side is connected to ring B.
The present invention relates to some embodiments of the general formula (I), (II-a), (II-b) or (II-c), L being selected from The right side is connected to ring B.
The invention relates to the general formula (I), (II-a), (II)In some embodiments of (a) or (b) or (II-c), L2 is selected from The right side is connected to ring B.
The present invention relates to some embodiments of the general formula (I), (II-a), (II-b) or (II-c), L3 is selected fromThe right side is connected to ring B.
In some embodiments of formulae (I), (II), q is each independently selected from 0, 1, 2, 3 or 4.
In some embodiments of formulae (I), (II), a is selected from 0, 1, 2, 3 or 4.
In some embodiments of formulae (I), (II), b is selected from 0, 1, 2, 3 or 4.
In some embodiments of formulae (I), (II), x is selected from 0, 1, 2, 3 or 4.
The present invention relates to some embodiments of formula (I), (II-a), (II-b) or (II-c), wherein s1 is selected from 0, 1, 2, 3 or 4.
The present invention relates to some embodiments of formula (I), (II-a), (II-b) or (II-c), wherein s2 is selected from 0, 1, 2, 3 or 4.
The present invention relates to some embodiments of formula (I), (II-a), (II-b) or (II-c), wherein s3 is selected from 0, 1, 2, 3 or 4.
The present invention relates to a pharmaceutical composition comprising any of the above compounds or stereoisomers, deuterates, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals thereof, and a pharmaceutically acceptable carrier.
The present invention relates to the use of any of the above compounds or stereoisomers, deuterides, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals thereof for the manufacture of a medicament for the treatment of a disease associated with PARP7 activity or expression level, preferably selected from tumors.
Unless stated to the contrary, the terms used in the specification and claims have the following meanings.
The carbon, hydrogen, oxygen, sulfur, nitrogen or F, cl, br, I referred to in the groups and compounds of the invention each include their isotopic condition, and the carbon, hydrogen, oxygen, sulfur or nitrogen referred to in the groups and compounds of the invention are optionally further replaced by one or more of their corresponding isotopes, where the isotopes of carbon include 12 C、 13 C and C 14 Isotopes of C, hydrogen include protium (H), deuterium (D, also known as heavy hydrogen), tritium (T, also known as super heavy hydrogen), isotopes of oxygen include 16 O、 17 O and 18 isotopes of O, sulfur include 32 S、 33 S、 34 S and 36 isotopes of S, nitrogen include 14 N and 15 isotopes of N, fluorine include 17 F and F 19 Isotopes of F, chlorine include 35 Cl and Cl 37 Isotopes of Cl, bromine include 79 Br and 81 Br。
"halogen" means F, cl, br or I.
"halo substituted" means F, cl, br or I substituted, including but not limited to 1 to 10 substituents selected from F, cl, br or I, 1 to 6 substituents selected from F, cl, br or I, and 1 to 4 substituents selected from F, cl, br or I. "halo substituted" is simply referred to as "halo".
"alkyl" refers to a substituted or unsubstituted straight or branched chain saturated aliphatic hydrocarbon group including, but not limited to, alkyl groups of 1 to 20 carbon atoms, alkyl groups of 1 to 8 carbon atoms, alkyl groups of 1 to 6 carbon atoms, alkyl groups of 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl and various branched isomers thereof; alkyl groups appearing herein are defined in accordance with the present definition. The alkyl group may be monovalent, divalent, trivalent, or tetravalent.
"heteroalkyl" refers to a substituted or unsubstituted alkyl in which 1 or more (including but not limited to 2, 3, 4, 5, or 6) carbon atoms are replaced with a heteroatom (including but not limited to N, O or S). Non-limiting examples include-X (CH 2 )v-X(CH 2 )v-X(CH 2 ) v-H (v is an integer from 1 to 5, X is each independently selected from bonds or heteroatoms including, but not limited to N, O or S, and at least 1X is selected from heteroatoms, and N or S in the heteroatoms may be oxidized to various oxidation states). The heteroalkyl group may be monovalent, divalent, trivalent, or tetravalent.
"alkylene" means a substituted or unsubstituted straight and branched chain divalent saturated hydrocarbon radical, including- (CH) 2 ) v - (v is an integer of 1 to 10), alkylene examples include, but are not limited to, methylene, ethylene, propylene, butylene and the like.
"heteroalkylene" means a substituted or unsubstituted alkylene in which 1 or more (including but not limited to 2, 3, 4, 5, or 6) carbon atoms are replaced with a heteroatom (including but not limited to N, O or S). Non-limiting examples include-X (CH 2 )v-X(CH 2 )v-X(CH 2 ) v-, v is an integer from 1 to 5, X is each independently selected from a bond, N, O or S, and at least 1X is selected from N, O or S.
"cycloalkyl" refers to a substituted or unsubstituted saturated carbocyclic hydrocarbon group, typically having 3 to 10 carbon atoms, non-limiting examples of which include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like. Cycloalkyl groups as herein presented are defined as described above. Cycloalkyl groups may be monovalent, divalent, trivalent, or tetravalent.
"heterocycloalkyl" refers to a substituted or unsubstituted saturated heteroatom-containing cyclic hydrocarbon group including, but not limited to, 3 to 10 atoms, 3 to 8 atoms, containing 1 to 3 heteroatoms selected from N, O or S, optionally substituted N, S in the ring of the heterocycloalkyl group being oxidizable to various oxidation states. Heterocycloalkyl groups can be attached to heteroatoms or carbon atoms, heterocycloalkyl groups can be attached to aromatic or non-aromatic rings, and heterocycloalkyl groups can be attached to bridged or spiro rings, non-limiting examples include oxiranyl, aziridinyl, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, dioxolanyl, dioxane, pyrrolidinyl, piperidinyl, imidazolidinyl, oxazolidinyl, oxazinidinyl, morpholinyl, hexahydropyrimidinyl, piperazinyl. Heterocyclylalkyl can be monovalent, divalent, trivalent, or tetravalent
"alkenyl" refers to substituted or unsubstituted straight and branched unsaturated hydrocarbyl groups having at least 1, typically 1, 2 or 3 carbon-carbon double bonds, the backbone including but not limited to 2 to 10, 2 to 6 or 2 to 4 carbon atoms, alkenyl examples including but not limited to vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 1-octenyl, 3-octenyl, 1-nonenyl, 3-nonenyl, 1-decenyl, 4-decenyl, 1, 3-pentadienyl, 1, 4-pentadienyl and the like; alkenyl groups appear herein, the definition of which is consistent with the definition. Alkenyl groups may be monovalent, divalent, trivalent, or tetravalent.
"alkynyl" refers to substituted or unsubstituted straight and branched monovalent unsaturated hydrocarbon radicals having at least 1, typically 1, 2 or 3 carbon-carbon triple bonds, including but not limited to 2 to 10 carbon atoms, 2 to 6 carbon atoms, 2 to 4 carbon atoms in the backbone, alkynyl embodiments including but not limited to ethynyl, propargyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-1-butynyl, 2-methyl-3-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-1-pentynyl, 2-methyl-1-pentynyl, 1-heptynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 1-octynyl, 3-octynyl, 1-nonynyl, 3-decynyl, 4-decynyl, and the like; alkynyl groups may be monovalent, divalent, trivalent or tetravalent.
"alkoxy" refers to a substituted or unsubstituted-O-alkyl group. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, cyclopropoxy and cyclobutoxy.
"carbocyclyl" or "carbocycle" refers to a substituted or unsubstituted saturated or unsaturated aromatic or non-aromatic ring, which may be a 3 to 8 membered monocyclic ring, a 4 to 12 membered bicyclic ring, or a 10 to 15 membered tricyclic ring system, to which carbocyclyl may be attached, optionally in the form of a monocyclic, bridged, or spiro ring. Non-limiting examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl-3-enyl, cyclohexyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexenyl, benzene ring, naphthalene ring,"carbocyclyl" or "carbocycle" may be monovalent, divalent, trivalent, or tetravalent.
"heterocyclyl" or "heterocycle" refers to a substituted or unsubstituted saturated or unsaturated aromatic or non-aromatic ring that may be a 3 to 8 membered monocyclic, 4 to 12 membered bicyclic, or 10 to 15 membered tricyclic ring system and that contains 1 or more (including but not limited to 2, 3, 4, or 5) heteroatoms selected from N, O or S, and N, S optionally substituted in the ring of the heterocyclyl can be oxidized to various oxidation states. The heterocyclic group may be attached to a hetero atom or a carbon atom, the heterocyclic group may be attached to an aromatic ring or a non-aromatic ring, the heterocyclic group may be a single ring, a parallel ring, a bridged ring or a spiro ring, and is not limited Illustrative examples include oxiranyl, aziridinyl, oxetanyl, azetidinyl, 1, 3-dioxolanyl, 1, 4-dioxolanyl, 1, 3-dioxanyl, azepanyl, pyridinyl, furanyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, 1, 3-dithianyl, dihydrofuranyl, dihydropyranyl, dithianyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridyl, pyrrolopyridinyl, benzodihydrofuranyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, pyrazinyl, indazolyl, benzothienyl, benzofuranyl, benzopyrrolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzopyridyl, benzopyrimidinyl, benzopyrazinyl, piperazinyl, diazabicyclo [ 3.1.1.1 ]]Octyl and azabicyclo [5.2.0]Nonylalkyl oxatricyclo [5.3.1.1 ]]Dodecyl, azaadamantyl, oxaspiro [3.3 ]]Heptyl radical, "heterocyclyl" or "heterocycle" may be monovalent, divalent, trivalent, or tetravalent.
"Spiro" or "spirocyclic group" refers to a polycyclic group having one atom (referred to as a spiro atom) shared between substituted or unsubstituted monocyclic rings, the number of ring atoms in the spirocyclic ring system including, but not limited to, 5 to 20, 6 to 14, 6 to 12, 6 to 10, wherein one or more of the rings may contain 0 or more (including, but not limited to, 1, 2, 3, or 4) double bonds, and optionally may contain 0 to 5 members selected from N, O or S (=O) n Is a heteroatom of (2). Non-limiting embodiments include:
"Spiro" or "spirocyclic group" may be monovalent, divalent, trivalent, or tetravalent.
"fused ring" or "fused ring group" refers to a polycyclic group wherein each ring in the system shares an adjacent pair of atoms with the other rings in the system, wherein one or more of the rings may contain 0 or more (including but not limited to 1, 2, 3, or 4) double bonds, and may be substituted or unsubstituted, and each ring in the ring system may contain 0 to 5 heteroatoms or heteroatom-containing groups (including but not limited to those selected from N, S (=o) n Or O, n is 0, 1 or 2). The number of ring atoms in the fused ring system includes, but is not limited to, 5 to 20, 5 to 14, 5 to 12, 5 to 10. Non-limiting examples include: "fused" or "fused-ring" groups may be monovalent, divalent, trivalent, or tetravalent.
"bridged ring" or "bridged ring radical" refers to a substituted or unsubstituted polycyclic group containing any two atoms not directly attached, which may contain 0 or more double bonds, and any ring in the ring system may contain 0 to 5 groups selected from heteroatoms or containing heteroatoms (including but not limited to N, S (=o) n Or O, where n is 0, 1, 2). The number of ring atoms includes, but is not limited to, 5 to 20, 5 to 14, 5 to 12, or 5 to 10. Non-limiting examples include Cubane and adamantane. "bridged ring" or "bridged ring radical" can be monovalent, divalent, trivalent, or tetravalent.
"carbospiro", "spirocarbocyclyl" or "carbospirocyclyl" refers to a "spiro" ring system consisting of only carbon atoms. "carbospiro", "spirocarbocyclyl" or "carbospirocyclyl" as referred to herein are defined in accordance with spirocyclic rings.
"carbon-fused", "fused carbocyclyl" or "carbon-fused cyclic" refers to a "fused ring" in which the ring system has only carbon atoms. "carbo-cyclic", "carbocyclyl" or "carbo-cyclic" as used herein is defined as consistent with a carbo-cyclic group.
"carbon bridged ring", "bridged carbocyclyl" or "carbon bridged cyclyl" refers to a "bridged ring" in which the ring system has only carbon atoms. "carbobridged ring", "bridged ring carbocyclyl", "bridged carbocyclyl" or "carbobridged ring radical" as used herein is defined as being identical to a bridged ring.
"heteromonocyclic", "monocyclic heterocyclyl" or "heteromonocyclic" refers to a "heterocyclyl" or "heterocycle" of a monocyclic system, and the heterocyclic groups, "monocyclic heterocyclyl" or "heteromonocyclic" present herein are defined as identical to heterocycles.
"heterobicyclic", "heterobicyclic group", "fused-to-heterocyclic group" or "heterobicyclic group" refers to a "fused ring" containing a heteroatom. The term "fused ring" as used herein refers to a fused ring, a fused ring heterocyclic group, or a "fused ring group" as defined herein.
"Heterospiro", "spirocyclic heterocyclyl" or "Heterospiro" refers to a "spiro" containing heteroatoms. As used herein, a heterospiro, "spiroheterocyclyl," or "heterospiro" is defined as a spiro.
"heterobridged", "bridged heterocyclyl" or "heterobridged heterocyclyl" refers to a "bridged ring" that contains a heteroatom. The term "heterobridged ring," as used herein, refers to a bridged ring, or a bridged ring.
"aryl" or "aromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group having a single ring or a fused ring, the number of ring atoms in the aromatic ring including, but not limited to, 6 to 18, 6 to 12, or 6 to 10 carbon atoms. The aryl ring may be fused to a saturated or unsaturated carbocyclic or heterocyclic ring in which the ring attached to the parent structure is an aryl ring, non-limiting examples of which include benzene rings, naphthalene rings,The "aryl" or "aromatic ring" may be monovalent, divalent, trivalent, or tetravalent. When divalent, trivalent or tetravalent, the attachment site is located on the aryl ring.
"heteroaryl" or "heteroaryl ring" refers to a substituted or unsubstituted aromatic hydrocarbon group and contains 1 to 5 selected heteroatoms or heteroatom-containing groups (including but not limited to N, O or S (=o) n, n being 0, 1, 2), the number of ring atoms in the heteroaryl ring including but not limited to 5 to 15, 5 to 10, or 5 to 6. Non-limiting examples of heteroaryl groups include, but are not limited to, pyridyl, furyl, thienyl, pyridyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, benzopyrazole, benzimidazole, benzopyridine, pyrrolopyridine, and the like. The heteroaryl ring may be fused to a saturated or unsaturated carbocyclic or heterocyclic ring in which the ring attached to the parent structure is a heteroaryl ring, non-limiting examples of which include Heteroaryl groups as herein appear, the definition of which is consistent with the definition. Heteroaryl groups may be monovalent, divalent, trivalent, or tetravalent. When divalent, trivalent or tetravalent, the attachment sites are located on the heteroaryl ring.
"5 membered ring and 5 membered heteroaryl ring" refers to a fused heteroaryl ring of 5 and 5 members, at least 1 of the 2 rings containing more than 1 heteroatom (including but not limited to O, S or N), the entire group having aromaticity, non-limiting examples including pyrrolopyrrole rings, pyrazolopyrrole rings, pyrazolopyrazole rings, pyrrolofuran rings, pyrazolofuran rings, pyrrolothiene rings, pyrazolothiophene rings.
"5-and 6-membered heteroaromatic ring" refers to a fused heteroaromatic ring of 5 and 6 members, at least 1 of the 2 fused rings containing more than 1 heteroatom (including but not limited to O, S or N), the entire group having aromaticity, non-limiting examples including benzo 5-membered heteroaromatic rings, 6-membered heteroaromatic rings, and 5-membered heteroaromatic rings.
"substituted" or "substituted" means substituted with 1 or more (including but not limited to 2, 3, 4, or 5) substituents including but not limited to H, F, cl, br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclyl, bridged ring, spirocyclic, and cyclic, hydroxyalkyl, =o, carbonyl, aldehyde, carboxylic acid, formate, - (CH) 2 ) m -C(＝O)-R a 、-O-(CH 2 ) m -C(＝O)-R a 、-(CH 2 ) m -C(＝O)-NR b R c 、-(CH 2 ) m S(＝O) n R a 、-(CH 2 ) m -alkenyl-R a 、OR d Or- (CH) 2 ) m -alkynyl-R a (wherein m, n is 0, 1 or 2), arylthio, thiocarbonyl, silane or-NR b R c Etc., wherein R is b And R is R c Independently selected from the group consisting of H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, and optionally R b And R is R c Can form five-membered or six-membered cycloalkyl or heterocyclyl, R a And R is R d Each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged ring, spirocyclic, or fused ring.
"containing 1 to 5 heteroatoms selected from O, S, N" means containing 1, 2, 3, 4 or 5 heteroatoms selected from O, S, N.
"substituted with 0 to X substituents" means substituted with 0, 1, 2, 3 … X substituents, X being selected from any integer between 1 and 10. By "substituted with 0 to 4 substituents" is meant substituted with 0, 1, 2, 3 or 4 substituents. By "substituted with 0 to 5 substituents" is meant substituted with 0, 1, 2, 3, 4 or 5 substituents. By "the hetero-bridge ring is optionally further substituted with 0 to 4 substituents selected from H or F" is meant that the hetero-bridge ring is optionally further substituted with 0, 1, 2, 3 or 4 substituents selected from H or F.
The X-Y membered ring (X is selected from an integer of 3 or less and Y is selected from any integer of 4 to 12) includes X+1, X+2, X+3, X+4 …. The ring includes heterocyclic, carbocyclic, aromatic, aryl, heteroaryl, cycloalkyl, heteromonocyclic, heterobicyclic, heterospiro, or heterobridged rings. For example, "4-7 membered heteromonocyclic ring" means 4-, 5-, 6-or 7-membered heteromonocyclic ring, and "5-10 membered heteromonocyclic ring" means 5-, 6-, 7-, 8-, 9-or 10-membered heteromonocyclic ring.
"optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs or does not. Such as: "alkyl optionally substituted with F" means that the alkyl may be, but is not necessarily, substituted with F, and is intended to include both cases where the alkyl is substituted with F and cases where the alkyl is not substituted with F.
By "pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" is meant a salt of a compound of the invention that retains the biological effectiveness and properties of the free acid or free base, and the free acid is obtained by reaction with a non-toxic inorganic or organic base.
"pharmaceutical composition" refers to one or more compounds of the present invention, or stereoisomers, tautomers, deuterides, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals thereof, and mixtures of other chemical components, wherein "other chemical components" refers to pharmaceutically acceptable carriers, excipients, and/or one or more other therapeutic agents.
The pharmaceutical composition is administered in a manner suitable for the disease to be treated (or prevented). The appropriate dosage and the appropriate duration and frequency of administration will be determined by factors such as the condition of the patient, the type and severity of the disease of the patient, the particular form of the active ingredient, and the method of administration. Experimental models and/or clinical trials may be used to determine the optimal dose.
In some embodiments, the present methods involve administering from about 0.1 μg to about 500mg of at least one compound of the application per kg body weight of the subject. More generally, a dose of the presently disclosed compounds from about 10 μg to about 200mg is used, depending on the physiological response of the subject. For example, the dosage of a compound described herein for use in the treatment and/or prophylaxis of a disease as described herein is from about 0.001 to about 1mg/kg body weight of a subject per day, e.g., about 0.001mg, about 0.002mg, about 0.005mg, about 0.010mg, 0.015mg, about 0.020mg, about 0.025mg, about 0.050mg, about 0.075mg, about 0.1mg, about 0.15mg, about 0.2mg, about 0.25mg, about 0.5mg, about 0.75mg, or about 1mg/kg body weight per day. In some embodiments, the dosage of the compounds described herein for use in the described methods is about 1 to about 1000mg/kg of body weight of the subject being treated per day, about 1mg, about 2mg, about 5mg, about 10mg, about 15mg, about 20mg, about 25mg, about 50mg, about 75mg, about 100mg, about 150mg, about 200mg, about 250mg, about 500mg, about 750mg, or about 1000mg per day.
By "carrier" is meant a material that does not cause significant irritation to the organism and does not abrogate the biological activity and properties of the administered compound.
"excipient" refers to an inert substance that is added to a pharmaceutical composition to facilitate administration of a compound. Non-limiting examples include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binders, and disintegrating agents.
"prodrug" means a compound of the invention which is converted into a biologically active form by in vivo metabolism. Prodrugs of the invention are prepared by modifying amino or carboxyl groups in the compounds of the invention, which modifications may be removed by conventional procedures or in vivo to give the parent compound. When the prodrugs of the invention are administered to a mammalian subject, the prodrugs are cleaved to form the free amino or carboxyl groups.
"co-crystals" refers to crystals of Active Pharmaceutical Ingredient (API) and co-crystal former (CCF) that are bound by hydrogen bonds or other non-covalent bonds, wherein the pure states of the API and CCF are both solid at room temperature and there is a fixed stoichiometric ratio between the components. A co-crystal is a multi-component crystal that includes both binary co-crystals formed between two neutral solids and multi-component co-crystals formed between a neutral solid and a salt or solvate.
"animal" is meant to include mammals, such as humans, companion animals, zoo animals and livestock, preferably humans, horses or dogs.
"stereoisomers" refers to isomers arising from the spatial arrangement of atoms in a molecule, and include cis-trans isomers, enantiomers and conformational isomers.
"tautomer" refers to a functional group isomer produced by rapid movement of an atom in a molecule at two positions, such as keto-enol isomers and amide-imine alcohol isomers.
"optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "a heterocyclic group optionally substituted with an alkyl group" means that the alkyl group may be, but is not necessarily, present, and the description includes cases where the heterocyclic group is substituted with an alkyl group, and cases where the heterocyclic group is not substituted with an alkyl group.
“IC 50 "is the concentration of drug or inhibitor required to inhibit half of a given biological process (or a component of the process such as an enzyme, receptor, cell, etc.).
Detailed Description
The following examples illustrate the technical aspects of the present invention in detail, but the scope of the present invention is not limited thereto.
The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or (sum) Mass Spectrometry (MS). NMR shift (. Delta.) of 10 -6 Units of (ppm) are given. NMR was performed using a (Bruker Avance III and Bruker Avance 300) magnetonuclear apparatus with deuterated dimethyl sulfoxide (DMSO-d) 6 ) Deuterated chloroform (CDCl) 3 ) Deuterated methanol (CD) 3 OD), internal standard Tetramethylsilane (TMS);
MS measurement (Agilent 6120B (ESI) and Agilent 6120B (APCI));
HPLC was performed using an Agilent 1260DAD high performance liquid chromatograph (Zorbax SB-C18X14.6mm, 3.5. Mu.M);
the thin layer chromatography silica gel plate uses a smoke table yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification of the silica gel plate used by the Thin Layer Chromatography (TLC) is 0.15mm-0.20mm, and the specification of the thin layer chromatography separation and purification product is 0.4mm-0.5mm;
column chromatography generally uses 200-300 mesh silica gel of yellow sea of tobacco stand as carrier;
for the purpose of the present invention, organic synthesis techniques known to those skilled in the art are used, starting from commercially available chemicals and/or compounds described in chemical literature, including Shanghai Allatin Biotechnology Co., shanghai Michelin Biotechnology Co., ltd., sigma-Aldrich, alfa Elisa (China) chemical Co., ltd., shanghai chemical industry development Co., an Naiji chemical, shanghai Tetanan technology Co., kelong chemical, balanwei technology Co., etc.
DMSO: dimethylSulfoxide; DMA: dimethylacetamide; solutol: polyethylene glycol-15-hydroxystearate; PEG400: polyethylene glycol 400;20% SBE-beta-CD: sulfobutyl- β -cyclodextrin; saline: physiological saline; MC: a methylcellulose solution; CO 2 : carbon dioxide; meOH: methanol; DEA: diethylamine; DIPEA: n, N-diisopropylethylamine: DMF: n, N-dimethylformamide;
HATU：CAS 148893-10-1；
PyBOP：CAS 128625-52-。
example 1:5- (((S) -1- (3-oxo-3- ((R) -3- (trifluoromethyl) -6a,7,9, 10-tetrahydropyrazino [1,2-d ] pyrido [3,2-b ] [1,4] oxazin-8 (6H) -yl) propoxy) propan-2-yl) amino) -4- (trifluoromethyl) pyridazin-3 (2H) -one (Compound 1)
5-(((S)-1-(3-oxo-3-((R)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyrido[3,2-b][1,4]oxazin-8(6H)-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one
The first step: (3R) -3- (hydroxymethyl) -4- (3-nitro-5- (trifluoromethyl) pyridin-2-yl) piperazine-1-carboxylic acid tert-butyl ester (1 c)
tert-butyl(3R)-3-(hydroxymethyl)-4-(3-nitro-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate
2-chloro-3-nitro-5- (trifluoromethyl) pyridine (1 a) (2.00 g,8.83 mmol) was added to DMF (20 mL) at room temperature, and tert-butyl (3R) -3- (hydroxymethyl) piperazine-1-carboxylate (1.91 g,8.83 mmol) and DIPEA (3.42 g,26.49 mmol) were added. The mixture was stirred at room temperature overnight. The reaction was quenched with water (20 mL), extracted with ethyl acetate (20 mL. Times.2), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give the crude product. The crude product was isolated and purified by column chromatography (petroleum ether: ethyl acetate (v/v) =10:1) to give (3R) -3- (hydroxymethyl) -4- (3-nitro-5- (trifluoromethyl) pyridin-2-yl) piperazine-1-carboxylic acid tert-butyl ester (1 c) (3.50 g, 97%).
LCMS m/z＝351.1[M-55] + 。
And a second step of: (R) -3- (trifluoromethyl) -6a,7,9, 10-Tetrahydropyrazino [1,2-d ] pyrido [3,2-b ] [1,4] oxazine-8 (6H) -carboxylic acid tert-butyl ester (1 d)
tert-butyl(R)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyrido[3,2-b][1,4]oxazine-8(6H)-carboxylate
Tert-butyl (3R) -3- (hydroxymethyl) -4- (3-nitro-5- (trifluoromethyl) pyridin-2-yl) piperazine-1-carboxylate (1 c) (1.0 g,2.46 mmol) was added to a solution of DMF (20 ml) and NaH (0.34 g,8.5 mmol) was added. The mixture was reacted at 40℃for 16 hours. The reaction was quenched with water (10 mL), extracted with ethyl acetate (10 mL. Times.2), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give the crude product. The crude product was purified by column separation (petroleum ether: ethyl acetate (v/v) =10:1) to give (R) -3- (trifluoromethyl) -6a,7,9, 10-tetrahydropyrazino [1,2-d ] pyrido [3,2-b ] [1,4] oxazine-8 (6H) -carboxylic acid tert-butyl ester (1 d) (0.5 g, 56%).
LCMS m/z＝360.2[M+1] + 。
And a third step of: trifluoroacetate salt of (R) -3- (trifluoromethyl) -6,6a,7,8,9, 10-hexahydropyrazino [1,2-d ] pyrido [3,2-b ] [1,4] oxazine (1 e)
(R)-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydropyrazino[1,2-d]pyrido[3,2-b][1,4]oxazinetrifluoroacetate
(R) -3- (trifluoromethyl) -6a,7,9, 10-tetrahydropyrazino [1,2-d ] pyrido [3,2-b ] [1,4] oxazine-8 (6H) -carboxylic acid tert-butyl ester (1 d) (0.37 g,1.03 mmol) was dissolved in DCM (4 mL) and TFA (2 mL) was added and the mixture stirred at room temperature for 2H. The reaction solution was concentrated under reduced pressure to give (R) -3- (trifluoromethyl) -6,6a,7,8,9, 10-hexahydropyrazino [1,2-d ] pyrido [3,2-b ] [1,4] oxazine trifluoroacetate (1 e) (380 mg, 100%) which was used directly in the next step.
LCMS m/z＝260.2[M+1] + 。
Fourth step: (R) -1- (3- (trifluoromethyl) -6a,7,9, 10-tetrahydropyrazino [1,2-d ] pyridinyl [3,2-b ] [1,4] oxazin-8 (6H) -yl) prop-2-en-1-one (1 f)
(R)-1-(3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyrido[3,2-b][1,4]oxazin-8(6H)-yl)prop-2-en-1-one
The trifluoroacetate salt (380 mg,1.02 mmol) of (R) -3- (trifluoromethyl) -6,6a,7,8,9, 10-hexahydropyrazino [1,2-d ] pyrido [3,2-b ] [1,4] oxazine (1 e) was dissolved in dichloromethane (4 mL), then acrylic anhydride (0.15 g,1.22 mmol) and triethylamine (0.31 mg,3.06 mmol) were added, and after reacting the mixture at 20℃for 24H, the reaction mixture was concentrated under reduced pressure to give a crude product which was isolated and purified (petroleum ether: ethyl acetate (v/v) =10:1) via a preparative column to give (R) -1- (3- (trifluoromethyl) -6a,7,9, 10-tetrahydropyrazino [1,2-d ] pyridinyl [3,2-b ] [1,4] oxazin-8 (6H) -yl) prop-2-en-1-one (1 f) (0.3 g, 94%).
LCMS m/z＝314.1[M+1] + 。
Fifth step: (S) -tert-butyl 1- (3-oxo-3- ((R) -3- (trifluoromethyl) -6a,7,9, 10-tetrahydropyrazino [1,2-d ] pyrido [3,2-b ] [1,4] oxazin-8 (6H) -yl) propoxy) propan-2-yl) carbamate (1 g)
tert-butyl((S)-1-(3-oxo-3-((R)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyrido[3,2-b][1,4]oxazin-8(6H)-yl)propoxy)propan-2-yl)carbamate
(R) -1- (3- (trifluoromethyl) -6a,7,9, 10-tetrahydropyrazino [1,2-d ] pyridinyl [3,2-b ] [1,4] oxazin-8 (6H) -yl) prop-2-en-1-one (1 f) (300 mg,0.96 mmol) was dissolved in acetonitrile (1.8 mL), then N-Boc-L-alaninol (0.87 g,5 mmol) and cesium carbonate (0.42 mg,1.29 mmol) were added and the mixture was reacted at 20℃for 48H. The reaction solution was directly filtered, and the filtrate was concentrated under reduced pressure to give a residue, which was separated and purified by preparative column (petroleum ether: ethyl acetate (v/v) =10:1) to give ((S) -1- (3-oxo-3- ((R) -3- (trifluoromethyl) -6a,7,9, 10-tetrahydropyrazino [1,2-d ] pyrido [3,2-b ] [1,4] oxazin-8 (6H) -yl) propoxy) propan-2-yl) carbamate tert-butyl ester (1 g) (0.34 g, 72%).
LCMS m/z＝489.2[M+1] + 。
Sixth step: hydrochloride of 3- ((S) -2-aminopropoxy) -1- ((R) -3- (trifluoromethyl) -6a,7,9, 10-tetrahydropyrazino [1,2-d ] pyridinyl [3,2-b ] [1,4] oxazin-8 (6H) -yl) propan-1-one (1H)
3-((S)-2-aminopropoxy)-1-((R)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyrido[3,2-b][1,4]oxazin-8(6H)-yl)propan-1-one hydrochloride
((S) -tert-butyl 1- (3-oxo-3- ((R) -3- (trifluoromethyl) -6a,7,9, 10-tetrahydropyrazino [1,2-d ] pyrido [3,2-b ] [1,4] oxazin-8 (6H) -yl) propoxy) propan-2-yl) carbamate (1 g) (0.34 g,0.7 mmol) was added to HCl/dioxane (4 mL, 4N) and the mixture stirred at room temperature for 2H. The reaction solution was concentrated directly under reduced pressure to give 3- ((S) -2-aminopropoxy) -1- ((R) -3- (trifluoromethyl) -6a,7,9, 10-tetrahydropyrazino [1,2-d ] pyridinyl [3,2-b ] [1,4] oxazin-8 (6H) -yl) propan-1-one (1H) hydrochloride (230 mg, 77%) which was used directly in the next step.
LCMS m/z＝389.3[M+1] + 。
Seventh step: 2- (4-methoxybenzyl) -5- (((S) -1- (3-oxo-3- ((R) -3- (trifluoromethyl) -6a,7,9, 10-tetrahydropyrazino [1,2-d ] pyrido [3,2-b ] [1,4] oxazin-8 (6H) -yl) propoxy) propan-2-yl) amino) -4- (trifluoromethyl) pyridazin-3 (2H) -one (1 j)
2-(4-methoxybenzyl)-5-(((S)-1-(3-oxo-3-((R)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyrido[3,2-b][1,4]oxazin-8(6H)-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one
Hydrochloride (0.18 g,0.42 mmol) of 3- ((S) -2-aminopropoxy) -1- ((R) -3- (trifluoromethyl) -6a,7,9, 10-tetrahydropyrazino [1,2-d ] pyridinyl [3,2-b ] [1,4] oxazin-8 (6H) -yl) propan-1-one (1H) was dissolved in acetonitrile (3 mL), 5-chloro-2- [ (4-methoxyphenyl) methyl ] -4- (trifluoromethyl) -2, 3-dihydropyridazin-3-one (0.13 g,0.42 mmol) and triethylamine (127.26 mg,1.26 mmol) were added and the mixture was stirred at room temperature for 24H. The reaction solution was concentrated directly under reduced pressure to give crude product, which was prep-TLC (developer: petroleum ether: ethyl acetate=1:2) to give 2- (4-methoxybenzyl) -5- (((S) -1- (3-oxo-3- ((R) -3- (trifluoromethyl) -6a,7,9, 10-tetrahydropyrazino [1,2-d ] pyrido [3,2-b ] [1,4] oxazin-8 (6H) -yl) propoxy) propan-2-yl) amino) -4- (trifluoromethyl) pyridazin-3 (2H) -one (1 j) (130 mg, 46%).
LCMS m/z＝671.3[M+1] + 。
Eighth step: 5- (((S) -1- (3-oxo-3- ((R) -3- (trifluoromethyl) -6a,7,9, 10-tetrahydropyrazino [1,2-d ] pyrido [3,2-b ] [1,4] oxazin-8 (6H) -yl) propoxy) propan-2-yl) amino) -4- (trifluoromethyl) pyridazin-3 (2H) -one (Compound 1)
5-(((S)-1-(3-oxo-3-((R)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyrido[3,2-b][1,4]oxazin-8(6H)-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one
2- (4-methoxybenzyl) -5- (((S) -1- (3-oxo-3- ((R) -3- (trifluoromethyl) -6a,7,9, 10-tetrahydropyrazino [1, 2-d)]Pyrido [3,2-b][1,4]Oxazin-8 (6H) -yl) propoxy) propan-2-yl) amino) -4- (trifluoromethyl) pyridazin-3 (2H) -one (1 j) (0.13 g,0.19 mmol) was dissolved in trifluoroacetic acid (5 mL) and trifluoromethanesulfonic acid (0.14 g,0.95 mmol) was added. The mixture was stirred at room temperature for 1h. The reaction solution is decompressed and concentrated to obtain crude products. Dissolving the crude product with methanol, adding DIPE A dropwise to adjust pH to 8-9, concentrating under reduced pressure, purifying the residue by Pre-HPLC (instrument and preparation column: preparation of liquid phase by Waters 2767, preparation column model XBIdge@PrepC) 18 Inner diameter x length = 19mm x 250 mm). The preparation method comprises the following steps: the crude product was dissolved in DMF and filtered through a 0.45 μm filter to prepare a sample solution. Mobile phase system: acetonitrile/water (0.05% ammonia). The gradient elution method comprises the following steps: acetonitrile was eluted from a 10% gradient to 55% (flow rate: 12mL/min; elution time 17 min) to give 5- (((S) -1- (3-oxo-3- ((R) -3- (trifluoromethyl) -6a,7,9, 10-tetrahydropyrazino [1, 2-d) ]Pyrido [3,2-b][1,4]Oxazin-8 (6H) -yl) propoxy) propan-2-yl) amino) -4- (trifluoromethyl) pyridazin-3 (2H) -one (compound 1) (10 mg, 9.37%).
LCMS m/z＝551.2[M+1] + 。
Example 2:5- (((S) -1- (3-oxo-3- ((S) -3- (trifluoromethyl) -6a,7,9, 10-tetrahydropyrazino [1,2-d ] pyrido [3,2-b ] [1,4] oxazin-8 (6H) -yl) propoxy) propan-2-yl) amino) -4- (trifluoromethyl) pyridazin-3 (2H) -one (Compound 2)
5-(((S)-1-(3-oxo-3-((S)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyrido[3,2-b][1,4]oxazin-8(6H)-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one
The first step: (3S) -3- (hydroxymethyl) -4- (3-nitro-5- (trifluoromethyl) pyridin-2-yl) piperazine-1-carboxylic acid tert-butyl ester (2 c)
tert-butyl(3S)-3-(hydroxymethyl)-4-(3-nitro-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate
2-chloro-3-nitro-5- (trifluoromethyl) pyridine (1 a) (2.00 g,8.83 mmol) was added to DMF (20 mL) at room temperature, and tert-butyl (3S) -3- (hydroxymethyl) piperazine-1-carboxylate (1.91 g,8.83 mmol) and DIPEA (3.42 g,26.49 mmol) were added. The mixture was stirred at room temperature overnight. The reaction was quenched with water (20 mL), extracted with ethyl acetate (20 mL. Times.2), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give the crude product. The crude product was isolated and purified (petroleum ether: ethyl acetate (v/v) =10:1) via a preparative column to give (3S) -3- (hydroxymethyl) -4- (3-nitro-5- (trifluoromethyl) pyridin-2-yl) piperazine-1-carboxylic acid tert-butyl ester (2 c) (3.00 g, 83%).
LCMS m/z＝351.1[M-55] + 。
And a second step of: (S) -3- (trifluoromethyl) -6a,7,9, 10-Tetrahydropyrazino [1,2-d ] pyrido [3,2-b ] [1,4] oxazine-8 (6H) -carboxylic acid tert-butyl ester (2 d)
tert-butyl(S)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyrido[3,2-b][1,4]oxazine-8(6H)-carboxylate
Tert-butyl (3S) -3- (hydroxymethyl) -4- (3-nitro-5- (trifluoromethyl) pyridin-2-yl) piperazine-1-carboxylate (2 c) (1.0 g,2.46 mmol) was added to a solution of DMF (20 ml) and NaH (0.34 g,8.5 mmol) was added. The mixture was reacted at 40℃for 1 6 hours. The reaction was quenched with water (10 mL), extracted with ethyl acetate (10 mL. Times.2), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give the crude product. The crude product was purified by column separation (petroleum ether: ethyl acetate (v/v) =10:1) to give (S) -3- (trifluoromethyl) -6a,7,9, 10-tetrahydropyrazino [1,2-d ] pyrido [3,2-b ] [1,4] oxazine-8 (6H) -carboxylic acid tert-butyl ester (2 d) (0.54 g, 61%).
LCMS m/z＝360.2[M+1] + 。
And a third step of: trifluoroacetate salt of (S) -3- (trifluoromethyl) -6,6a,7,8,9, 10-hexahydropyrazino [1,2-d ] pyrido [3,2-b ] [1,4] oxazine (2 e)
(S)-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydropyrazino[1,2-d]pyrido[3,2-b][1,4]oxazinetrifluoroacetate
(S) -3- (trifluoromethyl) -6a,7,9, 10-tetrahydropyrazino [1,2-d ] pyrido [3,2-b ] [1,4] oxazine-8 (6H) -carboxylic acid tert-butyl ester (2 d) (0.56 g,1.42 mmol) was dissolved in DCM (4 mL) and TFA (2 mL) was added and the mixture stirred at room temperature for 2H. The reaction solution was concentrated under reduced pressure to give (S) -3- (trifluoromethyl) -6,6a,7,8,9, 10-hexahydropyrazino [1,2-d ] pyrido [3,2-b ] [1,4] oxazine trifluoroacetate (2 e) (530 mg, 100%) which was used directly in the next step.
LCMS m/z＝260.1[M+1] + 。
Fourth step: (S) -1- (3- (trifluoromethyl) -6a,7,9, 10-tetrahydropyrazino [1,2-d ] pyridinyl [3,2-b ] [1,4] oxazin-8 (6H) -yl) prop-2-en-1-one (2 f)
(S)-1-(3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyrido[3,2-b][1,4]oxazin-8(6H)-yl)prop-2-en-1-one
The trifluoroacetate salt (530 mg,1.42 mmol) of (S) -3- (trifluoromethyl) -6,6a,7,8,9, 10-hexahydropyrazino [1,2-d ] pyrido [3,2-b ] [1,4] oxazine (2 e) was dissolved in methylene chloride (4 mL), then acrylic anhydride (0.21 g,1.69 mmol) and triethylamine (430 mg,4.26 mmol) were added, the mixture was reacted at 20℃for 24 hours, and then the reaction mixture was concentrated under reduced pressure to give a crude product, which was isolated and purified (petroleum ether: ethyl acetate (v/v) =10:1) by a preparative column to give (S) -1- (3- (trifluoromethyl) -6a,7,9, 10-tetrahydropyrazino [1,2-d ] pyridyl [3,2-b ] [1,4] oxazin-8 (6H) -yl) prop-2-en-1-one (2 f) (0.34 g, 76%).
LCMS m/z＝314.1[M+1] + 。
Fifth step: (S) -tert-butyl 1- (3-oxo-3- ((S) -3- (trifluoromethyl) -6a,7,9, 10-tetrahydropyrazino [1,2-d ] pyrido [3,2-b ] [1,4] oxazin-8 (6H) -yl) propoxy) propan-2-yl) carbamate (2 g)
tert-butyl((S)-1-(3-oxo-3-((S)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyrido[3,2-b][1,4]oxazin-8(6H)-yl)propoxy)propan-2-yl)carbamate
(S) -1- (3- (trifluoromethyl) -6a,7,9, 10-tetrahydropyrazino [1,2-d ] pyridinyl [3,2-b ] [1,4] oxazin-8 (6H) -yl) prop-2-en-1-one (2 f) (278 mg,0.89 mmol) was dissolved in acetonitrile (1.4 mL), then N-Boc-L-alaninol (0.78 g,4.44 mmol) and cesium carbonate (376 mg,1.16 mmol) were added and the mixture was reacted at 20℃for 48H. The reaction solution was directly filtered, and the filtrate was concentrated under reduced pressure to give a residue, which was separated and purified by preparative column (petroleum ether: ethyl acetate (v/v) =10:1) to give ((S) -1- (3-oxo-3- ((S) -3- (trifluoromethyl) -6a,7,9, 10-tetrahydropyrazino [1,2-d ] pyrido [3,2-b ] [1,4] oxazin-8 (6H) -yl) propoxy) propan-2-yl) carbamate tert-butyl ester (2 g) (0.28 g, 64%).
LCMS m/z＝489.3[M+1] + 。
Sixth step: hydrochloride of 3- ((S) -2-aminopropoxy) -1- ((S) -3- (trifluoromethyl) -6a,7,9, 10-tetrahydropyrazino [1,2-d ] pyridinyl [3,2-b ] [1,4] oxazin-8 (6H) -yl) propan-1-one (2H)
3-((S)-2-aminopropoxy)-1-((S)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyrido[3,2-b][1,4]oxazin-8(6H)-yl)propan-1-one hydrochloride
((S) -tert-butyl 1- (3-oxo-3- ((S) -3- (trifluoromethyl) -6a,7,9, 10-tetrahydropyrazino [1,2-d ] pyrido [3,2-b ] [1,4] oxazin-8 (6H) -yl) propoxy) propan-2-yl) carbamate (2 g) (0.28 g,0.57 mmol) was added to HCl/dioxane (4 mL, 4N) and the mixture stirred at room temperature for 2H. The reaction solution was concentrated directly under reduced pressure to give 3- ((S) -2-aminopropoxy) -1- ((S) -3- (trifluoromethyl) -6a,7,9, 10-tetrahydropyrazino [1,2-d ] pyridinyl [3,2-b ] [1,4] oxazin-8 (6H) -yl) propan-1-one (2H) hydrochloride (180 mg, 74%) which was used directly in the next step.
LCMS m/z＝389.1[M+1] + 。
Seventh step: 2- (4-methoxybenzyl) -5- (((S) -1- (3-oxo-3- ((S) -3- (trifluoromethyl) -6a,7,9, 10-tetrahydropyrazino [1,2-d ] pyrido [3,2-b ] [1,4] oxazin-8 (6H) -yl) propoxy) propan-2-yl) amino) -4- (trifluoromethyl) pyridazin-3 (2H) -one (2 j)
2-(4-methoxybenzyl)-5-(((S)-1-(3-oxo-3-((S)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyrido[3,2-b][1,4]oxazin-8(6H)-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one
Hydrochloride (0.14 g,0.36 mmol) of 3- ((S) -2-aminopropoxy) -1- ((S) -3- (trifluoromethyl) -6a,7,9, 10-tetrahydropyrazino [1,2-d ] pyridinyl [3,2-b ] [1,4] oxazin-8 (6H) -yl) propan-1-one (2H) was dissolved in acetonitrile (3 mL), 5-chloro-2- [ (4-methoxyphenyl) methyl ] -4- (trifluoromethyl) -2, 3-dihydropyridazin-3-one (0.12 g,0.36 mmol) and triethylamine (109.08 mg,1.08 mmol) were added and the mixture was stirred at room temperature for 24H. The reaction solution was concentrated directly under reduced pressure to give crude product, which was prep-TLC (developer: petroleum ether: ethyl acetate=1:2) to give 2- (4-methoxybenzyl) -5- (((S) -1- (3-oxo-3- ((S) -3- (trifluoromethyl) -6a,7,9, 10-tetrahydropyrazino [1,2-d ] pyrido [3,2-b ] [1,4] oxazin-8 (6H) -yl) propoxy) propan-2-yl) amino) -4- (trifluoromethyl) pyridazin-3 (2H) -one (2 j) (106 mg, 44%).
LCMS m/z＝671.3[M+1] + 。
Eighth step: 5- (((S) -1- (3-oxo-3- ((S) -3- (trifluoromethyl) -6a,7,9, 10-tetrahydropyrazino [1,2-d ] pyrido [3,2-b ] [1,4] oxazin-8 (6H) -yl) propoxy) propan-2-yl) amino) -4- (trifluoromethyl) pyridazin-3 (2H) -one (Compound 2)
5-(((S)-1-(3-oxo-3-((S)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyrido[3,2-b][1,4]oxazin-8(6H)-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one
2- (4-methoxybenzyl) -5- (((S) -1- (3-oxo-3- ((S) -3- (trifluoromethyl) -6a,7,9, 10-tetrahydropyrazino [1, 2-d)]Pyrido [3,2-b][1,4]Oxazin-8 (6H) -yl) propoxy) propan-2-yl) amino) -4- (trifluoromethyl) pyridazin-3 (2H-one (2 j) (0.11 g,0.16 mmol) was dissolved in trifluoroacetic acid (5 mL) and trifluoromethanesulfonic acid (0.12 g,0.80 mmol) was added. The mixture was stirred at room temperature for 1h. The reaction solution is decompressed and concentrated to obtain crude products. Dissolving the crude product with methanol, adding DIPEA dropwise to adjust pH to 8-9, concentrating under reduced pressure, purifying the residue by Pre-HPLC (instrument and preparation column: preparation of liquid phase by Waters 2767, preparation column model XBIdge@PrepC) 18 Inner diameter x length = 19mm x 250 mm). The preparation method comprises the following steps: the crude product was dissolved in DMF and filtered through a 0.45 μm filter to prepare a sample solution. Mobile phase system: acetonitrile/water (0.05% ammonia). Gradient elutionThe method comprises the following steps: acetonitrile was eluted from a 10% gradient to 55% (flow rate: 12mL/min; elution time 17 min) to give 5- (((S) -1- (3-oxo-3- ((S) -3- (trifluoromethyl) -6a,7,9, 10-tetrahydropyrazino [1, 2-d) ]Pyrido [3,2-b][1,4]Oxazin-8 (6H) -yl) propoxy) propan-2-yl) amino) -4- (trifluoromethyl) pyridazin-3 (2H) -one (compound 2) (12 mg, 13%).
LCMS m/z＝551.2[M+1] + 。
Example 3:5- (((2S) -1- (3-oxo-3- (3- (trifluoromethyl) -6, 7a,8,10, 11-hexahydro-9H-pyrazino [1,2-d ] pyrido [3,2-b ] [1,4] oxazin-9-yl) propoxy) propan-2-yl) amino) -4- (trifluoromethyl) pyridazin-3 (2H) -one (Compound 3)
5-(((2S)-1-(3-oxo-3-(3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydro-9H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxazepin-9-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one
The first step: 3- (2-hydroxyethyl) piperazine-1-carboxylic acid tert-butyl ester (3 b)
tert-butyl 3-(2-hydroxyethyl)piperazine-1-carboxylate
3- (2-methoxy-2-oxoethyl) piperazine-1-carboxylic acid tert-butyl ester (3 a) (1.00 g,3.87 mmol) was added to TMF (10 mL) in ice bath, liAlH was added 4 (0.11 g,2.90 mmol). The mixture was stirred under ice bath for 2h. Quench reaction by adding water (0.11 mL), 2N NaOH (0.11 mL) and water (0.33 mL) in sequence, ethyl acetate (20 mL) and anhydrous MgSO 4 (2g) The mixture was stirred for 1h, filtered, and the filtrate was concentrated under reduced pressure to give tert-butyl 3- (2-hydroxyethyl) piperazine-1-carboxylate (3 b) (1.00 g, 89%) which was used directly in the next step.
LCMS m/z＝231.2[M+1] + 。
And a second step of: (3- (2-hydroxyethyl) -4- (3-nitro-5- (trifluoromethyl) pyridin-2-yl) piperazine-1-carboxylic acid tert-butyl ester (3 c)
tert-butyl 3-(2-hydroxyethyl)-4-(3-nitro-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate
2-chloro-3-nitro-5- (trifluoromethyl) pyridine (0.98 g,4.33 mmol) was added to DMF (10 mL) at room temperature, 3- (2-hydroxyethyl) piperazine-1-carboxylic acid tert-butyl ester (3 b) (1.00 g,4.33 mmol) and DIPEA (1.68 g,12.99 mmol) were added. The mixture was stirred at room temperature overnight. The reaction was quenched with water (20 mL), extracted with ethyl acetate (20 mL. Times.2), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give the crude product. The crude product was isolated and purified by column chromatography (petroleum ether: ethyl acetate (v/v) =10:1) to give ((3- (2-hydroxyethyl) -4- (3-nitro-5- (trifluoromethyl) pyridin-2-yl) piperazine-1-carboxylic acid tert-butyl ester (3 c) (0.64 g, 35%).
LCMS m/z＝365.1[M-55] + 。
And a third step of: 3- (trifluoromethyl) -6, 7a,8,10, 11-hexahydro-9H-pyrazino [1,2-d ] pyrido [3,2-b ] [1,4] oxaza-9-carboxylic acid tert-butyl ester (3 d)
tert-butyl 3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydro-9H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxazepine-9-carboxylate
The crude product was isolated and purified (petroleum ether: ethyl acetate (v/v) =10:1) by preparative column (petroleum ether: ethyl acetate (v/v) =10:1) to give 3- (trifluoromethyl) -6, 7a,8,10, 11-hexahydro-9H-pyrazino [1,2-d ] pyrido [3,2-b ] [1,4] oxaza-9-carboxylic acid tert-butyl ester (3 d) (0.5 g, 86%).
LCMS m/z＝374.2[M+1] + 。
Fourth step: trifluoroacetate salt of 3- (trifluoromethyl) -7,7a,8,9,10, 11-hexahydro-6H-pyrazino [1,2-d ] pyrido [3,2-b ] [1,4] oxaza (3 e)
3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydro-6H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxazepine trifluoroacetate
Tert-butyl (3- (trifluoromethyl) -6, 7a,8,10, 11-hexahydro-9H-pyrazino [1,2-d ] pyrido [3,2-b ] [1,4] oxaza-9-carboxylate (3 d) (0.45 g,1.21 mmol) was dissolved in DCM (4 mL), TFA (2 mL) was added, and the mixture was stirred at room temperature for 2H.
LCMS m/z＝274.1[M+1] + 。
Fifth step: 1- (3- (trifluoromethyl) -6, 7a,8,10, 11-hexahydro-9H-pyrazino [1,2-d ] pyrido [3,2-b ] [1,4] oxazepin-9-yl) prop-2-en-1-one (3 f)
1-(3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydro-9H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxazepin-9-yl)prop-2-en-1-one
The trifluoroacetate salt (460 mg,1.19 mmol) of 3- (trifluoromethyl) -7,7a,8,9,10, 11-hexahydro-6H-pyrazino [1,2-d ] pyrido [3,2-b ] [1,4] oxaza (3 e) was dissolved in methylene chloride (4 mL), then acrylic anhydride (0.15 g,1.19 mmol) and triethylamine (601 mg,5.95 mmol) were added, and after the mixture was reacted at 20℃for 24 hours, the reaction mixture was concentrated under reduced pressure to give a crude product, and the crude product was isolated and purified (petroleum ether: ethyl acetate (v/v) =10:1) by preparative column to give 1- (3- (trifluoromethyl) -6, 7a,8,10, 11-hexahydro-9H-pyrazino [1,2-d ] pyrido [3,2-b ] [1,4] oxaza-9-yl) prop-2-en-1-one (3 f) (0.36 g, 92%).
LCMS m/z＝328.1[M+1] + 。
Sixth step: (2S) -tert-butyl 1- (3-oxo-3- (3- (trifluoromethyl) -6, 7a,8,10, 11-hexahydro-9H-pyrazino [1,2-d ] pyrido [3,2-b ] [1,4] oxazepin-9-yl) propoxy) propan-2-yl) carbamate (3 g)
tert-butyl((2S)-1-(3-oxo-3-(3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydro-9H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxazepin-9-yl)propoxy)propan-2-yl)carbamate
1- (3- (trifluoromethyl) -6, 7a,8,10, 11-hexahydro-9H-pyrazino [1,2-d ] pyrido [3,2-b ] [1,4] oxazin-9-yl) prop-2-en-1-one (3 f) (350 mg,1.07 mmol) was dissolved in acetonitrile (1.8 mL), then N-Boc-L-alaninol (0.94 g,5.35 mmol) and cesium carbonate (452 mg,1.39 mmol) were added and the mixture reacted at 20℃for 48H. The reaction solution was directly filtered, and the filtrate was concentrated under reduced pressure to give a residue, which was separated and purified by a preparative column (petroleum ether: ethyl acetate (v/v) =10:1) to give ((2S) -1- (3-oxo-3- (3- (trifluoromethyl) -6, 7a,8,10, 11-hexahydro-9H-pyrazino [1,2-d ] pyrido [3,2-b ] [1,4] oxazin-9-yl) propoxy) propan-2-yl) carbamic acid tert-butyl ester (3 g) (0.33 g, 61%).
LCMS m/z＝503.2[M+1] + 。
Seventh step: hydrochloride of 3- ((S) -2-aminopropoxy) -1- (3- (trifluoromethyl) -6, 7a,8,10, 11-hexahydro-9H-pyrazino [1,2-d ] pyridine [3,2-b ] [1,4] oxazin-9-yl) propan-1-one (3H)
3-((S)-2-aminopropoxy)-1-(3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydro-9H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxazepin-9-yl)propan-1-one hydrochloride
Tert-butyl ((2S) -1- (3-oxo-3- (3- (trifluoromethyl) -6, 7a,8,10, 11-hexahydro-9H-pyrazino [1,2-d ] pyrido [3,2-b ] [1,4] oxazepin-9-yl) propoxy) propan-2-yl) carbamate (3 g) (0.3 g,0.6 mmol) was added to HCl/dioxane (4 mL, 4N) and the mixture stirred at room temperature for 2H. The reaction solution was concentrated directly under reduced pressure to give 3- ((S) -2-aminopropoxy) -1- (3- (trifluoromethyl) -6, 7a,8,10, 11-hexahydro-9H-pyrazino [1,2-d ] pyridin [3,2-b ] [1,4] oxazin-9-yl) propan-1-one (3H) hydrochloride (260 mg, 98%) which was used directly in the next step.
LCMS m/z＝403.1[M+1] + 。
Eighth step: 2- (4-methoxybenzyl) -5- (((2S) -1- (3-oxo-3- (3- (trifluoromethyl) -6, 7a,8,10, 11-hexahydro-9H-pyrazino [1,2-d ] pyrido [3,2-b ] [1,4] oxazin-9-yl) propoxy) propan-2-yl) amino) -4- (trifluoromethyl) pyridazin-3 (2H) -one (3I)
2-(4-methoxybenzyl)-5-(((2S)-1-(3-oxo-3-(3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydro-9H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxazepin-9-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one
Hydrochloride (0.16 g,0.36 mmol) of 3- ((S) -2-aminopropoxy) -1- (3- (trifluoromethyl) -6, 7a,8,10, 11-hexahydro-9H-pyrazino [1,2-d ] pyridin [3,2-b ] [1,4] oxazin-9-yl) propan-1-one (3H) was dissolved in acetonitrile (3 mL), 5-chloro-2- [ (4-methoxyphenyl) methyl ] -4- (trifluoromethyl) -2, 3-dihydropyridazin-3-one (0.11 g,0.36 mmol) and triethylamine (109.08 mg,1.08 mmol) were added and the mixture was stirred at room temperature for 24H. The reaction solution was concentrated directly under reduced pressure to give crude product, which was purified by prep-TLC (developer: petroleum ether: ethyl acetate=1:2) to give 2- (4-methoxybenzyl) -5- (((2S) -1- (3-oxo-3- (3- (trifluoromethyl) -6, 7a,8,10, 11-hexahydro-9H-pyrazino [1,2-d ] pyrido [3,2-b ] [1,4] oxazin-9-yl) propoxy) propan-2-yl) amino) -4- (trifluoromethyl) pyridazin-3 (2H) -one (3I) (100 mg, 41%).
LCMS m/z＝685.2[M+1] + 。
Ninth step: 5- (((2S) -1- (3-oxo-3- (3- (trifluoromethyl) -6, 7a,8,10, 11-hexahydro-9H-pyrazino [1,2-d ] pyrido [3,2-b ] [1,4] oxazin-9-yl) propoxy) propan-2-yl) amino) -4- (trifluoromethyl) pyridazin-3 (2H) -one (Compound 3)
5-(((2S)-1-(3-oxo-3-(3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydro-9H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxazepin-9-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one
2- (4-methoxybenzyl) -5- (((2S) -1- (3-oxo-3- (3- (trifluoromethyl) -6, 7a,8,10, 11-hexahydro-9H-pyrazino [1, 2-d)]Pyrido [3,2-b][1,4]Oxazepin-9-yl) propoxy-propan-2-yl) amino) -4- (trifluoromethyl) pyridazin-3 (2H) -one (3I) (0.1 g,0.15 mmol) was dissolved in trifluoroacetic acid (5 mL) and trifluoromethanesulfonic acid (0.14 g,0.95 mmol) was added. The mixture was stirred at room temperature for 1h. The reaction solution is decompressed and concentrated to obtain crude products. Dissolving the crude product with methanol, adding DIPEA dropwise to adjust pH to 8-9, concentrating under reduced pressure, purifying the residue by Pre-HPLC (instrument and preparation column: preparation of liquid phase by Waters2767, preparation column model XBIdge@PrepC) 18 Inner diameter x length = 19mm x 250 mm). The preparation method comprises the following steps: the crude product was dissolved in DMF and filtered through a 0.45 μm filter to prepare a sample solution. Mobile phase system: acetonitrile/water (0.05% ammonia). The gradient elution method comprises the following steps: acetonitrile was eluted from a 10% gradient to 55% (flow rate: 12mL/min; elution time 17 min) to give 5- (((2S) -1- (3-oxo-3- (3- (tri)) Fluoromethyl) -6, 7a,8,10, 11-hexahydro-9H-pyrazino [1,2-d]Pyrido [3,2-b][1,4]Oxazepin-9-yl) propoxy) propan-2-yl) amino) -4- (trifluoromethyl) pyridazin-3 (2H) -one (compound 3) (10 mg, 11.8%).
LCMS m/z＝565.0[M+1] + 。
1 H NMR(400MHz,DMSO-d 6 )δ12.43(s,1H),8.17-8.12(m,1H),7.93-7.88(m,1H),7.34(s,1H),6.29-6.20(m,1H),4.35-4.19(m,2H),4.18-4.08(m,1H),4.06-3.96(m,1H),3.91-3.76(m,2H),3.75-3.31(m,8H),2.59-2.51(m,2H),2.18-2.00(m,1H),1.95-1.83(m 1H)，1.19-1.10(m，3H)。
Example 4: (R) -8- (3- ((S) -2- ((6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino) propoxy) propanoyl) -3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-pyrazin [1,2-a ] pyridin [3,2-e ] pyrazin-6 (6 aH) -one (Compound 4)
(R)-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one
The first step: 1-tert-butyl 3-methyl (3R) -4- (3-nitro-5- (trifluoromethyl) pyridin-2-yl) piperazine-1, 3-dicarboxylic acid ester (4 c)
1-Tert-butyl-3-methyl-(3R)-4-(3-nitro-5-(trifluoromethyl)pyridin-2-yl)piperazine-1,3-dicarboxylate
2-chloro-3-nitro-5- (trifluoromethyl) pyridine (4 a) (2.00 g,8.83 mmol) was added to DMF (20 mL) followed by (3R) -piperazine-1-carboxylic acid tert-butyl ester-3-carboxylic acid methyl ester (4 b) (2.16 g,8.83 mmol) and DIPEA (3.42 g,26.49 mmol) at room temperature. The mixture was stirred at room temperature overnight. The reaction was quenched with water (40 mL), extracted with ethyl acetate (40 mL. Times.2), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give the crude product. The crude product was isolated and purified (petroleum ether: ethyl acetate (v/v) =10:1) by preparative column to give 1-tert-butyl 3-methyl (3R) -4- (3-nitro-5- (trifluoromethyl) pyridin-2-yl) piperazine-1, 3-dicarboxylic acid ester (4 c) (2.70 g, 70%).
LCMS m/z＝379.1[M-55] + 。
And a second step of: tert-butyl- (R) -6-oxo-3- (trifluoromethyl) -5, 6a,7,9, 10-hexahydro-8H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazine-8-carboxylic acid ester (4 d)
Tert-butyl-(R)-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8-carboxylate
1-tert-butyl 3-methyl (3R) -4- (3-nitro-5- (trifluoromethyl) pyridin-2-yl) piperazine-1, 3-dicarboxylate (4 c) (1.0 g,2.30 mmol) was dissolved in dry methanol (20 mL) at room temperature and then 10% palladium on carbon (200 mg) was added. After three hydrogen substitutions, the reaction was carried out at room temperature for 16 hours. Drying and filtering, and concentrating the filtrate under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate (v/v) =4:1) to give tert-butyl- (R) -6-oxo-3- (trifluoromethyl) -5, 6a,7,9, 10-hexahydro-8H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazine-8-carboxylate (4 d) (380 mg, 44%).
LCMS m/z＝317.1[M-55] + 。
And a third step of: hydrochloride of (R) -3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-pyrazin [1,2-a ] pyridine [3,2-e ] pyrazin-6 (6 aH) -one (4 e)
(R)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one hydrochloride
Tert-butyl- (R) -6-oxo-3- (trifluoromethyl) -5, 6a,7,9, 10-hexahydro-8H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazine-8-carboxylate (4 d) (100 mg,0.27 mmol) was dissolved in 1, 4-dioxane (5 mL) solution at room temperature, and then hydrogen chloride-1, 4-dioxane solution (4.0M, 10mL,40 mmol) was added thereto for reaction at room temperature for 4 hours. After the completion of the reaction, the solvent was removed by concentration under reduced pressure to give (R) -3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-pyrazin [1,2-a ] pyridine [3,2-e ] pyrazin-6 (6 aH) -one (4 e) hydrochloride (83.0 mg, 100%).
LCMS m/z＝273.1[M+1] + 。
Fourth step: 5- { [ (2S) -1-hydroxypropan-2-yl ] amino } -2- [ (4-methoxyphenyl) methyl ] -4- (trifluoromethyl) -2, 3-dihydropyridazin-3-one (4 g)
5-{[(2S)-1-hydroxypropan-2-yl]amino}-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one
5-chloro-2- [ (4-methoxyphenyl) methyl ] -4- (trifluoromethyl) -2, 3-dihydropyridazin-3-one (4 f) (15.0 g,47.07 mmol) and (2S) -2-aminopropane-1-ol (5.40 g,71.9 mmol) were dissolved in anhydrous acetonitrile (100 mL) at room temperature, followed by the addition of DIPEA (30.0 g,233 mmol). The reaction was stirred at room temperature for 4 hours. After the reaction, the reaction solvent was removed by vacuum concentration. Water (50 mL), ethyl acetate extraction (50 mL. Times.3) and the combined organic phases were dried and filtered, and the filtrate was concentrated under reduced pressure to give 5- { [ (2S) -1-hydroxypropan-2-yl ] amino } -2- [ (4-methoxyphenyl) methyl ] -4- (trifluoromethyl) -2, 3-dihydropyridazin-3-one (4 g) (16.5 g, 98%).
LCMS m/z＝358.2[M+1] + 。
Fifth step: methyl-3- [ (2S) -2- [ (1- [ (4-methoxyphenyl) methyl ] -6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino ] propoxy ] propanoate (4 h)
Methyl-3-[(2S)-2-[(1-[(4-methoxyphenyl)methyl]-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino]propoxy]propanoate
5- { [ (2S) -1-hydroxypropan-2-yl ] amino } -2- [ (4-methoxyphenyl) methyl ] -4- (trifluoromethyl) -2, 3-dihydropyridazin-3-one (4 g) (13.5 g,37.82 mmol) and methyl prop-2-enoate (33 g,378.2 mmol) were dissolved in acetonitrile (90 mL) at room temperature, then cesium carbonate (13.6 g,41.60 mmol) was added and the reaction stirred at room temperature for 48 hours. After the completion of the reaction, the solvent was removed by concentration under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V/V) =7:3) to give methyl-3- [ (2S) -2- [ (1- [ (4-methoxyphenyl) methyl ] -6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino ] propoxy ] propanoate (4 h) (6.0 g, 36%).
LCMS m/z＝444.2[M+1] + 。
Sixth step: methyl-3- [ (2S) -2- [ (6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino ] propoxy ] propanoate (4 i)
Methyl-3-[(2S)-2-[(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino]propoxy]propanoate
Methyl-3- [ (2S) -2- [ (1- [ (4-methoxyphenyl) methyl ] -6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino ] propoxy ] propanoate (4 h) (6.0 g,13.5 mmol) was dissolved in trifluoroacetic acid (30 mL) at room temperature, trifluoromethanesulfonic acid (5 mL) was added thereto, and the reaction was stirred at room temperature for 2 hours. After the reaction, the reaction solvent was removed by concentration under reduced pressure to give a crude methyl-3- [ (2S) -2- [ (6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino ] propoxy ] propionate (4 i) which was used directly in the next reaction without purification.
LCMS m/z＝324.1[M+1] + 。
Seventh step: 3- [ (2S) -2- [ (6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino ] propoxy ] propionic acid (4 j)
3-[(2S)-2-[(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino]propoxy]propanoic acid
Crude methyl-3- [ (2S) -2- [ (6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino ] propoxy ] propyl ester (4 i) was dissolved in a mixed solution of methanol (30 mL) and water (30 mL) at room temperature, ph=7 to 8 was adjusted with lithium hydroxide monohydrate, then lithium hydroxide monohydrate (1.14 g,27 mmol) was added, and the reaction was stirred at room temperature for 16 hours. After the completion of the reaction, the pH was adjusted to about 5 with 2M aqueous hydrochloric acid in an ice-water bath, the mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (dichloromethane: methanol (V/V) =15:1) to give 3- [ (2S) -2- [ (6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino ] propoxy ] propionic acid (4 j) (2.5 g, 60%).
LCMS m/z＝310.1[M+1] + 。
Eighth step: (R) -8- (3- ((S) -2- ((6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino) propoxy) propanoyl) -3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-pyrazin [1,2-a ] pyridin [3,2-e ] pyrazin-6 (6 aH) -one (Compound 4)
(R)-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one
3- [ (2S) -2- [ (6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino ] propoxy ] propionic acid (4 j) (50 mg,0.16 mmol) and hydrochloride (49 mg,0.16 mmol) of (R) -3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-pyrazin [1,2-a ] pyridin [3,2-e ] pyrazin-6 (6 aH) -one (4 e) were dissolved in DMF (5 mL) at room temperature, and after addition of DIPEA (83 mg,0.64 mmol) and HATU (46 mg,0.12 mmol), reacted at room temperature for 3 hours. After the reaction was completed, the reaction solution was purified by Pre-HPLC (instrument and preparation column: preparation of liquid phase using WATERS 2767, preparation column model: xselect C18,5 μm, inner diameter×length=19 mm×150 mm). The preparation method comprises the following steps: the reaction solution was filtered through a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: acetonitrile/water (0.05% ammonia). The gradient elution method comprises the following steps: acetonitrile was eluted from 5% gradient to 50% (elution time 15 min). After lyophilization, (R) -8- (3- ((S) -2- ((6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino) propoxy) propanoyl) -3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-pyrazin [1,2-a ] pyridine [3,2-e ] pyrazin-6 (6 aH) -one (compound 4) (10 mg, 11%).
LCMS m/z＝564.2[M+1] + 。
1 H NMR(400MHz,DMSO-d 6 )δ12.42(s,1H),10.93(s,1H),8.12(s,1H),7.90(s,1H),7.16(d,1H),6.31-6.20(m,1H),4.85-4.44(m,2H),4.27-3.96(m,3H),3.74-3.63(m,2H),3.49(d,2H),3.27-3.06(m,1H),2.82-2.59(m,4H),1.16(d,3H)。
Example 5: 5-methyl-8- (3- ((S) -1- (6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) pyrrolidin-2-yl) methoxy) propionyl) -3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-pyrazin [1,2-a ] pyridine [3,2-e ] pyrazin-6 (6 aH) -one (Compound 5)
5-Methyl-8-(3-(((S)-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl)methoxy)propanoyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one
The first step: [ (2S) -pyrrolidin-2-yl ] methanol hydrochloride (5 b)
[(2S)-pyrrolidin-2-yl]methanol hydrochloride
To a solution of tert-butyl (2S) -2- (hydroxymethyl) pyrrolidine-1-carboxylate (5 a) (14.50 g,72.05 mmol) in 1, 4-dioxane (60 mL) was added a solution of hydrogen chloride in 1, 4-dioxane (60 mL, 4N), and the mixture was reacted at room temperature for 16h, followed by concentration under reduced pressure to remove the solvent, thereby obtaining [ (2S) -pyrrolidin-2-yl ] methanol hydrochloride (5 b) (9.91 g, 100%).
LCMS m/z＝101.7[M+1] + 。
And a second step of: 5- [ (2S) -2- (hydroxymethyl) pyrrolidin-1-yl ] -2- [ (4-methoxyphenyl) methyl ] -4- (trifluoromethyl) -2, 3-dihydropyridazin-3-one (5 c)
5-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one
5-chloro-2- [ (4-methoxyphenyl) methyl ] -4- (trifluoromethyl) -2, 3-dihydropyridazin-3-one (17.66 g,55.42 mmol), [ (2S) -pyrrolidin-2-yl ] methanol hydrochloride (5 b) (9.91 g,72.05 mmol), DIPEA (28.65 g,221.68 mmol) were successively added to acetonitrile (150 mL), reacted at room temperature for 2 hours, ethyl acetate (500 mL) was added to dilute the reaction solution after completion of the reaction, then the reaction solution was washed with saturated brine (200 mL. Times.3), dried over anhydrous sodium sulfate, suction filtered, and the filtrate was concentrated under reduced pressure to give 5- [ (2S) -2- (hydroxymethyl) pyrrolidin-1-yl ] -2- [ (4-methoxyphenyl) methyl ] -4- (trifluoromethyl) -2, 3-dihydropyridazin-3-one (5 c) (20.77 g, 98%).
LCMS m/z＝384.2[M+1] + 。
And a third step of: methyl 3- { [ (2S) -1- (1- [ (4-methoxyphenyl) methyl ] -6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) pyrrolidin-2-yl ] methoxy } propanoate (5 d)
Methyl 3-{[(2S)-1-(1-[(4-methoxyphenyl)methyl]-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl]methoxy}propanoate
To a solution of 5- [ (2S) -2- (hydroxymethyl) pyrrolidin-1-yl ] -2- [ (4-methoxyphenyl) methyl ] -4- (trifluoromethyl) -2, 3-dihydropyridazin-3-one (5 c) (16.40 g,42.78 mmol) and methyl acrylate (36.83 g,427.80 mmol) in acetonitrile (100 mL) at room temperature was added cesium carbonate (15.33 g,47.06 mmol). After 48h at room temperature, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica gel (petroleum ether: ethyl acetate (V/V) =1:1) to give methyl 3- { [ (2S) -1- (1- [ (4-methoxyphenyl) methyl ] -6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) pyrrolidin-2-yl ] methoxy } propanoate (5 d) (12.65 g, 63%).
LCMS m/z＝470.2[M+1] + 。
Fourth step: methyl 3- { [ (2S) -1- (6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl ] pyrrolidin-2-yl ] methoxy } propanoate (5 e)
Methyl 3-{[(2S)-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl]methoxy}propanoate
Methyl 3- { [ (2S) -1- (1- [ (4-methoxyphenyl) methyl ] -6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) pyrrolidin-2-yl ] methoxy } propanoate (5 d) (12.65 g,26.95 mmol) was dissolved in trifluoroacetic acid (100 mL) at room temperature, followed by addition of trifluoromethanesulfonic acid (5 mL) and reaction at room temperature for 2h. The reaction solvent was removed by concentration under reduced pressure to give a crude methyl 3- { [ (2S) -1- (6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) pyrrolidin-2-yl ] methoxy } propanoate (5 e) which was used directly in the next reaction without purification.
LCMS m/z＝350.0[M+1] + 。
Fifth step: 3- { [ (2S) -1- (6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) pyrrolidin-2-yl ] methoxy } propanoic acid (5 f)
3-{[(2S)-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl]methoxy}propanoic acid
Methyl 3- { [ (2S) -1- (6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl ] pyrrolidin-2-yl ] methoxy } propanoate (5 e) was dissolved in a mixed solution of methanol (60 mL) and water (60 mL), ph=7 to 8 was adjusted with lithium hydroxide monohydrate, and then lithium hydroxide monohydrate (1.70 g,40.41 mmol) was added and reacted at room temperature for 16 hours. After the completion of the reaction, the pH was adjusted to about 5 with 2M aqueous hydrochloric acid, the mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica gel (methanol: dichloromethane (V/V) =1:15) to give 3- { [ (2S) -1- (6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) pyrrolidin-2-yl ] methoxy } propionic acid (5 f) (4.1 g, 45.39%).
LCMS m/z＝336.2[M+1] + 。
Sixth step: tert-butyl-5-methyl-6-oxo-3- (trifluoromethyl) -5, 6a,7,9, 10-hexahydro-8H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazine-8-carboxylic acid ester (5 g)
Tert-butyl-(R)-5-methyl-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8-carboxylate
Tert-butyl- (R) -6-oxo-3- (trifluoromethyl) -5, 6a,7,9, 10-hexahydro-8H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazine-8-carboxylic acid ester (4 d) (200 mg,0.54 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL) at room temperature, cooled to 0deg.C, and sodium hydride (60%, 93mg,2.32 mmol) was slowly added. After stirring at 0℃for 10 minutes, methyl iodide (232 mg,1.62 mmol) was added, and then the reaction was stirred at room temperature for 16 hours. After the reaction was completed, the reaction was quenched by slowly adding a saturated ammonium chloride solution under an ice-water bath, 10mL of water was added, and extraction was performed with ethyl acetate (15 ml×3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was isolated and purified by preparative column (petroleum ether: ethyl acetate (v/v) =7:3) to give tert-butyl-5-methyl-6-oxo-3- (trifluoromethyl) -5, 6a,7,9, 10-hexahydro-8H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazine-8-carboxylate (5 g) (155 mg, 74%).
LCMS m/z＝331.1[M-55] + 。
Seventh step: hydrochloride of 5-methyl-3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-pyrazin [1,2-a ] pyridine [3,2-e ] pyrazin-6 (6 aH) -one (5H)
5-Methyl-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one hydrochloride
Tert-butyl-5-methyl-6-oxo-3- (trifluoromethyl) -5, 6a,7,9, 10-hexahydro-8H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazine-8-carboxylate (5 g) (155 mg,0.40 mmol) was dissolved in a solution of 1, 4-dioxane (5 mL) at room temperature, and then a solution of hydrogen chloride-1, 4-dioxane (4.0M, 10mL,40 mmol) was added and reacted for 4 hours at room temperature. After the completion of the reaction, the solvent was removed by concentration under reduced pressure to give 5-methyl-3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-pyrazin [1,2-a ] pyridine [3,2-e ] pyrazin-6 (6 aH) -one (5H) hydrochloride (130 mg, 100%).
LCMS m/z＝287.1[M+1] + 。
Eighth step: 5-methyl-8- (3- ((S) -1- (6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) pyrrolidin-2-yl) methoxy) propionyl) -3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-pyrazin [1,2-a ] pyridine [3,2-e ] pyrazin-6 (6 aH) -one (Compound 5)
5-Methyl-8-(3-(((S)-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl)methoxy)propanoyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one
3- { [ (2S) -1- (6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl ] pyrrolidin-2-yl ] methoxy } propanoic acid (5 f) (63 mg,0.19 mmol) and hydrochloride (62 mg,0.19 mmol) of 5-methyl-3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-pyrazin [1,2-a ] pyridin [3,2-e ] pyrazin-6 (6 aH) -one (5H) were dissolved in DMF (5 mL) at room temperature, DIPEA (120 mg,0.95 mmol) and HATU (54 mg,0.14 mmol) were added thereto, respectively, and then the reaction was stirred at room temperature for 3 hours. After the reaction was completed, the reaction solution was purified by Pre-HPLC (instrument and preparation column: preparation of liquid phase using WATERS 2767, preparation column model: xselect C18,5 μm, inner diameter×length=19 mm×150 mm). The preparation method comprises the following steps: the reaction solution was filtered through a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: acetonitrile/water (0.05% ammonia). The gradient elution method comprises the following steps: acetonitrile was eluted from 5% gradient to 50% (elution time 15 min). After lyophilization, 5-methyl-8- (3- ((S) -1- (6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) pyrrolidin-2-yl) methoxy) propionyl) -3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-pyrazin [1,2-a ] pyridine [3,2-e ] pyrazin-6 (6 aH) -one (compound 5) (25 mg, 22%).
LCMS m/z＝604.2[M+1] + 。
Example 6: 5-methyl-8- (3- ((S) -2- ((6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino) propoxy) propanoyl) -3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-pyrazin [1,2-a ] pyridine [3,2-e ] pyrazin-6 (6 aH) -one (Compound 6)
5-Methyl-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one
3- [ (2S) -2- [ (6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino ] propoxy ] propionic acid (4 j) (50 mg,0.16 mmol) and hydrochloride (50 mg,0.16 mmol) of 5-methyl-3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-pyrazin [1,2-a ] pyridin [3,2-e ] pyrazin-6 (6 aH) -one (5H) were dissolved in DMF (5 mL) at room temperature, DIPEA (83 mg,0.64 mmol) and HATU (46 mg,0.12 mmol) were added thereto, respectively, and then the reaction was stirred at room temperature for 3 hours. After the reaction was completed, the reaction solution was purified by Pre-HPLC (instrument and preparation column: preparation of liquid phase using WATERS 2767, preparation column model: xselect C18,5 μm, inner diameter×length=19 mm×150 mm). The preparation method comprises the following steps: the reaction solution was filtered through a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: acetonitrile/water (0.05% ammonia). The gradient elution method comprises the following steps: acetonitrile was eluted from 5% gradient to 50% (elution time 15 min). After lyophilization, 5-methyl-8- (3- ((S) -2- ((6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino) propoxy) propionyl) -3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-pyrazin [1,2-a ] pyridine [3,2-e ] pyrazin-6 (6 aH) -one (compound 6) (15 mg, 17%).
LCMS m/z＝578.2[M+1] + 。
Example 7:5- (((S) -1- (3-oxo-3- ((R) -3- (trifluoromethyl) -6, 7a,8,10, 11-hexahydro-9H-pyrazino [1,2-d ] pyrido [3,2-b ] [1,4] oxazepin-9-yl) propoxy) propan-2-yl) amino) -4- (trifluoromethyl) pyridazin-3 (2H) -one (Compound 7-1)
5-(((S)-1-(3-oxo-3-((R)-3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydro-9H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxazepin-9-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one
5- (((S) -1- (3-oxo-3- ((S) -3- (trifluoromethyl) -6, 7a,8,10, 11-hexahydro-9H-pyrazino [1,2-d ] pyrido [3,2-b ] [1,4] oxazepin-9-yl) propoxy) propan-2-yl) amino) -4- (trifluoromethyl) pyridazin-3 (2H) -one (Compound 7-2)
5-(((S)-1-(3-oxo-3-((S)-3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydro-9H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxazepin-9-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one
Compound 3 was purified by SFC on AD column (apparatus and preparation column: using Waters 150mgm, preparation column model DAICEL CHIRALPAK AD (250 mm. Times.30 mm,10 μm)). The preparation method comprises the following steps: compound 3 was dissolved in ethanol and filtered through a 0.45 μm filter to prepare a sample solution. Mobile phase system: afor CO 2 and B for EtOH(0.1％NH 3 ·H 2 O). The gradient elution method comprises the following steps: 30% phase B (flow rate: 120mL/min; elution time 2.5 min), and Compound 7-1 and Compound 7-2 were obtained after lyophilization.
Analytical method (instrument and preparative column: high performance liquid chromatograph-normal phase chromatograph, preparative column model: CHIRALPAKAD-H (4.6x250 mm,5 um)) mobile phase system: n-hexane-isopropanol (80:20), 1.0ml/min.
Retention time t= 16.489min is example 7-a (example 7-a is one of the structures of compound 7-1 and compound 7-2).
LCMS m/z＝565.3[M+1] + 。
1 H NMR(400MHz,CD 3 OD)δ8.09-8.05(m,1H),7.94-7.90(m,1H),7.28-7.25(m,1H),4.38-4.25(m,2H),4.18-4.02(m,2H),3.97-3.45(m,10H),2.74-2.57(m,2H),2.22-2.08(m,1H),2.03-1.90(m,1H),1.27-1.18(m,3H)。
Retention time t= 19.522min is example 7-B (example 7-B is one of the structures of compound 7-1 and compound 7-2).
LCMS m/z＝565.3[M+1] + 。
1 H NMR(400MHz,CD 3 OD)δ8.10-8.06(m,1H),7.93(s,1H),7.28-7.24(m,1H),4.39-4.25(m,2H),4.20-4.01(m,2H),3.98-3.45(m,10H),2.74-2.58(m,2H),2.22-2.08(m,1H),2.03-1.90(m,1H),1.24(d,3H)。
Example 8:5- ((S) -2- ((3-oxo-3- ((S) -3- (trifluoromethyl) -6a,7,9, 10-tetrahydropyrazin [1,2-d ] pyridine [3,2-b ] [1,4] oxazin-8 (6H) -yl) propoxy) methyl) pyrrolidin-1-yl) -4- (trifluoromethyl) pyrazin-3 (2H) -one (Compound 8)
5-((S)-2-((3-oxo-3-((S)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyrido[3,2-b][1,4]oxazin-8(6H)-yl)propoxy)methyl)pyrrolidin-1-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one
Compound 8 Using (S) -3- (trifluoromethyl) -6a,7,9, 10-tetrahydropyrazino [1,2-d ] pyrido [3,2-b ] [1,4] oxazin-8 (6H) -carboxylic acid tert-butyl ester (2 d) and 3- { [ (2S) -1- (6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) pyrrolidin-2-yl ] methoxy } propanoic acid (5 f) as starting materials, the synthesis procedure of example 4 was followed to give 5- ((S) -2- ((3-oxo-3- ((S) -3- (trifluoromethyl) -6a,7,9, 10-tetrahydropyrazin [1,2-d ] pyridin [3,2-b ] [1,4] oxazin-8 (6H) -yl) propoxy) methyl) pyrrolidin-1-yl) -4- (trifluoromethyl) pyrazin-3 (2H) -one (Compound 8).
LCMS m/z＝577.3[M+1] + 。
1 H NMR(400MHz,DMSO-d 6 )δ12.34(s,1H),8.08-8.06(m,1H),8.00(s,1H),7.28(d,1H),4.58-4.37(m,4H),4.06-3.92(m,2H),3.71-3.58(m,2H),3.56-3.36(m,4H),3.25-3.17(m,1H),3.16-2.38(m,5H),2.14-2.02(m,1H),1.95-1.81(m,1H),1.71-1.56(m,2H)。
Example 9: (R) -8- (3- (((S) -1- (6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) pyrrolidin-2-yl) methoxy) propionyl) -3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-pyridazin [1,2-a ] pyridazin [3,2-e ] pyridazin-6 (6 aH) -one (Compound 9)
(R)-8-(3-(((S)-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl)methoxy)propanoyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one
Compound 9 the synthetic method of example 4 was followed starting from (R) -3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-pyrazin [1,2-a ] pyridin [3,2-e ] pyrazin-6 (6 aH) -one hydrochloride (4 e) and 3- { [ (2S) -1- (6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) pyrrolidin-2-yl ] methoxy } propanoic acid (5 f) to give (R) -8- (3- (((S) -1- (6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) pyrrolidin-2-yl) methoxy) propionyl) -3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-pyridazin [1,2-a ] pyridazin [3,2-e ] pyridazin-6 (6 aH) -one (compound 9).
LCMS m/z＝590.3[M+1] + 。
1 H NMR(400MHz,DMSO-d 6 )δ12.41-12.28(m,1H),11.01-10.86(m,1H),8.13(s,1H),8.01(s,1H),7.16(d,1H),4.86-4.42(m,3H),4.27-3.91(m,2H),3.73-3.58(m,2H),3.56-3.46(m,2H),3.45-3.37(m,1H),3.26-3.02(m,2H),2.83-2.54(m,4H),2.14-2.01(m,1H),1.94-1.82(m,1H),1.72-1.55(m,2H)。
Example 10: (S) -8- (3- ((S) -2- ((6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino) propoxy) propanoyl) -3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazin-6 (6 aH) -one (Compound 10)
(S)-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one
The first step: (S) -4- (3-nitro-5- (trifluoromethyl) pyridin-2-yl) piperazine-1-carboxylic acid tert-butyl ester-3-carboxylic acid methyl ester (10 c)
1-(tert-butyl)3-methyl(S)-4-(3-nitro-5-(trifluoromethyl)pyridin-2-yl)piperazine-1,3-dicarboxylate
2-chloro-3-nitro-5- (trifluoromethyl) pyridine (1 a) (2.00 g,8.83 mmol) was added to DMF (20 mL), methyl (3S) -piperazine-1-carboxylate (10 b) (2.16 g,8.83 mmol) and DIPEA (3.42 g,26.49 mmol) were added at room temperature. The mixture was stirred at room temperature overnight. The reaction was quenched with water (40 mL), extracted with ethyl acetate (40 mL. Times.2), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give the crude product. The crude product was purified by column separation (petroleum ether: ethyl acetate (v/v) =10:1) to give methyl (S) -4- (3-nitro-5- (trifluoromethyl) pyridin-2-yl) piperazine-1-carboxylate (10 c) (3.50 g, 91%).
LCMS m/z＝379.1[M-55] + 。
And a second step of: (S) -6-oxo-3- (trifluoromethyl) -5, 6a,7,9, 10-hexahydro-8H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazine-8-carboxylic acid tert-butyl ester (10 d)
tert-butyl(S)-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8-carboxylate
Methyl (S) -4- (3-nitro-5- (trifluoromethyl) pyridin-2-yl) piperazine-1-carboxylate (10C) (3.5 g,8.06 mmol) was added to a solution of MeOH (50 ml) and Pd/C (0.35 g) was added. The mixture was reacted at room temperature under hydrogen atmosphere for 16 hours. Filtering, and concentrating the filtrate under reduced pressure to obtain crude product. The crude product was isolated and purified by column chromatography (petroleum ether: ethyl acetate (v/v) =10:1) to give (S) -6-oxo-3- (trifluoromethyl) -5, 6a,7,9, 10-hexahydro-8H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazine as tert-butyl-8-carboxylate (10 d) (1.3 g, 43%).
LCMS m/z＝317.1[M-55] + 。
And a third step of: hydrochloride of ((S) -3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazin-6 (6 aH) -one (10 e)
(S)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one hydrochloric acid
(S) -6-oxo-3- (trifluoromethyl) -5, 6a,7,9, 10-hexahydro-8H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazine-8-carboxylic acid tert-butyl ester (10 d) (240 mg,0.64 mmol) was dissolved in HCl/dioxane (5 mL,4M,20 mmol) and the mixture was stirred at room temperature for 2H. The solvent was removed by concentration under reduced pressure to give crude ((S) -3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-pyrazino [1,2-a ] pyrido [3,2-E ] pyrazin-6 (6 aH) -one (10E) hydrochloride (180 mg, 90%) which was used directly in the next step.
LCMS m/z＝273.1[M+1] + 。
Fourth step: (S) -8- (3- ((S) -2- ((6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino) propoxy) propanoyl) -3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazin-6 (6 aH) -one (Compound 10)
(S)-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one
Will (((S) -3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-pyrazino [1, 2-a)]Pyrido [3,2-E]The hydrochloride salt of pyrazin-6 (6 aH) -one (10 e) (49 mg,0.16 mmol) was dissolved in DMF (2 mL) and 3- [ (2S) was added2- [ (6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino group]Propoxy group]Propionic acid (4 j) (50 mg,0.16 mmol), HATU (46 mg,0.12 mmol) and DIPEA (103 mg,0.8 mmol) were reacted at 20℃for 2h, quenched with water (10 mL), extracted with ethyl acetate (10 mL. Times.2), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give the crude product. Purifying the crude product by Pre-HPLC (instrument and preparation column: preparation of liquid phase by Waters 2767, preparation column model XBIdge@Prep C 18 Inner diameter x length = 19mm x 250 mm). The preparation method comprises the following steps: the crude product was dissolved in DMF and filtered through a 0.45 μm filter to prepare a sample solution. Mobile phase system: acetonitrile/water (0.05% ammonia). The gradient elution method comprises the following steps: acetonitrile was eluted from a 10% gradient to 55% (flow rate: 12mL/min; elution time: 17 min) to give (S) -8- (3- ((S) -2- ((6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino) propoxy) propionyl) -3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-pyrazino [1,2-a ]]Pyrido [3,2-e]Pyrazin-6 (6 aH) -one (compound 10) (10 mg, 11%).
LCMS m/z＝564.3[M+1] + 。
1 H NMR(400MHz,DMSO-d 6 )δ12.43(s,1H),10.92(s,1H),8.12(s,1H),7.93-7.86(m,1H),7.16(d,1H),6.31-6.21(m,1H),4.87-4.41(m,2H),4.29-3.93(m,3H),3.76-3.60(m,2H),3.49(d,2H),3.26-3.04(m，1H),2.84-2.57(m,4H),1.16(d,3H)。
Example 11: (S) -5-methyl-8- (3- ((S) -2- ((6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino) propoxy) propanoyl) -3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazin-6 (6 aH) -one (Compound 11)
(S)-5-methyl-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one
The first step: (S) -5-methyl-6-oxo-3- (trifluoromethyl) -5, 6a,7,9, 10-hexahydro-8H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazine-8-carboxylic acid tert-butyl ester (11 a)
tert-butyl(S)-5-methyl-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8-carboxylate
(S) -6-oxo-3- (trifluoromethyl) -5, 6a,7,9, 10-hexahydro-8H-pyrazino [1,2-a ] at room temperature]Pyrido [3,2-e]Pyrazine-8-carboxylic acid tert-butyl ester (10 d) (1.00 g,2.69 mmol) was added to DMF (10 mL) and K was added 2 CO 3 (1.10 g,8.07 mmol) and CH 3 I (1.91 g,13.45 mmol). The mixture was stirred at room temperature overnight. The reaction was quenched with water (40 mL), extracted with ethyl acetate (40 mL. Times.2), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give the crude product. The crude product is separated and purified by a preparation column (petroleum ether: ethyl acetate (v/v) =10:1) to obtain (S) -5-methyl-6-oxo-3- (trifluoromethyl) -5, 6a,7,9, 10-hexahydro-8H-pyrazino [1, 2-a)]Pyrido [3,2-e]Pyrazine-8-carboxylic acid tert-butyl ester (11 a) (0.33 g, 32%).
LCMS m/z＝331.1[M-55] + 。
And a second step of: hydrochloride of (S) -5-methyl-3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazin-6 (6 aH) -one (11 b)
(S)-5-methyl-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one hydrochloric acid
(S) -5-methyl-6-oxo-3- (trifluoromethyl) -5, 6a,7,9, 10-hexahydro-8H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazine-8-carboxylic acid tert-butyl ester (11 a) (120 mg,0.31 mmol) was dissolved in HCl/dioxane (5 mL,4M,20 mmol) and the mixture was stirred at room temperature for 2H. The solvent was removed by concentration under reduced pressure to give the crude (S) -5-methyl-3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazin-6- (6 aH) -one (11 b) hydrochloride (100 mg, 99%) which was used directly in the next step.
LCMS m/z＝287.2[M+1] + 。
And a third step of: (S) -5-methyl-8- (3- ((S) -2- ((6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino) propoxy) propanoyl) -3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazin-6 (6 aH) -one (Compound 11)
(S)-5-methyl-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one
(S) -5-methyl-3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-pyrazino [1,2-a]Pyrido [3,2-e]The hydrochloride salt of pyrazin-6 (6 aH) -one (11 b) (48 mg,0.15 mmol) was dissolved in DMF (2 mL) and 3- [ (2S) -2- [ (6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino was then added]Propoxy group]Propionic acid (4 j) (46 mg,0.15 mmol), HATU (57 mg,0.15 mmol) and DIPEA (58 mg,0.45 mmol) were reacted at 20℃for 2h, quenched with water (10 mL), extracted with ethyl acetate (10 mL. Times.2), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give the crude product. Purifying the crude product by Pre-HPLC (instrument and preparation column: preparation of liquid phase by Waters 2767, preparation column model XBIdge@Prep C 18 Inner diameter x length = 19mm x 250 mm). The preparation method comprises the following steps: the crude product was dissolved in DMF and filtered through a 0.45 μm filter to prepare a sample solution. Mobile phase system: acetonitrile/water (0.05% ammonia). The gradient elution method comprises the following steps: acetonitrile was eluted from 10% gradient to 55% (flow rate: 12mL/min; elution time)17 min) to give ((S) -5-methyl-8- (3- ((S) -2- ((6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino) propoxy) propanoyl) -3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-pyrazino [1, 2-a) ]Pyrido [3,2-e]Pyrazin-6- (6 aH) -one (compound 11) (10 mg, 11%).
LCMS m/z＝578.3[M+1] + 。
Example 12: trifluoroacetate salt of (S) -8- (3- (((S) -1- (6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) pyrrolidin-2-yl) methoxy) propionyl) -3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazin-6 (6 aH) -one (compound 12)
(S)-8-(3-(((S)-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl)methoxy)propanoyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one trifluoroacetate
Will (((S) -3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-pyrazino [1, 2-a)]Pyrido [3,2-e]The hydrochloride salt of pyrazin-6- (6 aH) -one (10 e) (49 mg,0.16 mmol) was dissolved in DMF (2 mL) and then (3- { [ (2S) -1- (6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) pyrrolidin-2-yl was added]Methoxy } propionic acid (5 f) (54 mg,0.16 mmol), HATU (61 mg,0.16 mmol) and DIPEA (103 mg,0.8 mmol), the mixture was reacted at 20℃for 2h, quenched with water (10 mL), extracted with ethyl acetate (10 mL. Times.2), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give the crude product. Purifying the crude product by Pre-HPLC (instrument and preparation column: preparation of liquid phase by Waters 2767, preparation column model is Sunfire@Prep C 18 5 μm, inner diameter x length = 19mm x 250 mm). The preparation method comprises the following steps: the crude product is dissolved by DMFThe solution was filtered through a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: acetonitrile/water (containing 1% trifluoroacetic acid). The gradient elution method comprises the following steps: acetonitrile was eluted from a 5% gradient to 50% (flow rate: 15mL/min; elution time: 15 min), and lyophilized to give (S) -8- (3- (((S) -1- (6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) pyrrolidin-2-yl) methoxy) propionyl) -3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-pyrazino [1, 2-a) ]Pyrido [3,2-e]Trifluoroacetic acid salt of pyrazin-6 (6 aH) -one (compound 12) (10 mg, 9%).
LCMS m/z＝590.3[M+1] + 。
1 H NMR(400MHz,CD 3 OD)δ8.16-8.07(m,2H),7.19(s,1H),5.10-4.50(m,3H),4.46-4.00(m,2H),3.87-3.58(m,4H),3.52-3.40(m,1H),3.39-3.34(m,1H),3.29-3.15(m,1H),2.91-2.60(m,4H),2.28-2.15(m,1H),2.02-1.90(m,1H),1.79-1.60(m,2H)。
Example 13: (S) -5-methyl-8- (3- (((S) -1- (6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) pyrrolidin-2-yl) methoxy) propionyl) -3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazin-6 (6 aH) -one (Compound 13) trifluoroacetate
(S)-5-methyl-8-(3-(((S)-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl)methoxy)propanoyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one trifluoroacetate
(S) -5-methyl-3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-pyrazino [1,2-a]Pyrido [3,2-e]The hydrochloride salt of pyrazin-6- (6 aH) -one (11 b) (48 mg,0.15 mmol) was dissolved in DMF (2 mL) and 3- { [ (2S) -1- (6-oxo-5- (trifluormethyl) was then addedPhenyl) -1, 6-dihydropyridazin-4-yl pyrrolidin-2-yl]Methoxy } propionic acid (5 f) (50 mg,0.15 mmol), HATU (57 mg,0.15 mmol) and DIPEA (58 mg,0.45 mmol) were reacted at 20℃for 2h, quenched with water (10 mL), extracted with ethyl acetate (10 mL. Times.2), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give the crude product. Purifying the crude product by Pre-HPLC (instrument and preparation column: preparation of liquid phase by Waters 2767, preparation column model is Sunfire@Prep C 18 5 μm, inner diameter x length = 19mm x 250 mm). The preparation method comprises the following steps: the crude product was dissolved in DMF and filtered through a 0.45 μm filter to prepare a sample solution. Mobile phase system: acetonitrile/water (containing 1% trifluoroacetic acid). The gradient elution method comprises the following steps: acetonitrile was eluted from a 5% gradient to 50% (flow rate: 15mL/min; elution time: 15 min), and lyophilized to give (S) -5-methyl-8- (3- (((S) -1- (6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) pyrrolidin-2-yl) methoxy) propionyl) -3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-pyrazino [1, 2-a) ]Pyrido [3,2-e]Trifluoroacetic acid salt of pyrazin-6- (6 aH) -one (compound 13) (10 mg, 9%).
LCMS m/z＝604.4[M+1] + 。
Example 14: trifluoroacetate salt of 5- ((S) -2- ((3-oxo-3- ((R) -3- (trifluoromethyl) -6a,7,9, 10-tetrahydropyrazino [1,2-d ] pyrido [3,2-b ] [1,4] oxazin-8 (6H) -yl) propoxy) methyl) pyrrolidin-1-yl) -4- (trifluoromethyl) pyridazin-3 (2H) -one (Compound 14)
5-((S)-2-((3-oxo-3-((R)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyrido[3,2-b][1,4]oxazin-8(6H)-yl)propoxy)methyl)pyrrolidin-1-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one trifluoroacetate
Compound 14 the procedure of example 10 was referenced using (S) -3- (trifluoromethyl) -6a,7,9, 10-tetrahydropyrazino [1,2-d ] pyrido [3,2-b ] [1,4] oxazin-8 (6H) -carboxylic acid tert-butyl ester (1 d) and 3- { [ (2S) -1- (6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) pyrrolidin-2-yl ] methoxy } propanoic acid (5 f) as starting materials to give the trifluoroacetate salt of 5- ((S) -2- ((3-oxo-3- ((R) -3- (trifluoromethyl) -6a,7,9, 10-tetrahydropyrazino [1,2-d ] pyrido [3,2-b ] [1,4] oxazin-8 (6H) -yl) propoxy) methyl) pyrrolidin-1-yl) -4- (trifluoromethyl) pyridazin-3 (2H) -one (compound 14).
LCMS m/z＝577.4[M+1] + 。
1 H NMR(400MHz,CD 3 OD)δ8.11(d,1H),8.00(s,1H),7.18(s,1H),4.65-4.50(m,3H),4.43-4.33(m,1H),4.10-3.97(m,2H),3.82-3.59(m,4H),3.55-3.32(m,3H),3.29-2.51(m,5H),2.29-2.14(m,1H),2.01-1.91(m,1H),1.79-1.59(m,2H)。
Example 15: trifluoroacetate salt of (5- ((2S) -2- ((3-oxo-3- (3- (trifluoromethyl) -6, 7a,8,10,11 hexahydro-9H-pyrazino [1,2-d ] pyrido [3,2-b ] [1,4] oxazepin-9-yl) propoxy) methyl) pyrrolidin-1-yl) -4- (trifluoromethyl) pyridazin-3 (2H) -one (Compound 15)
5-((2S)-2-((3-oxo-3-(3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydro-9H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxazepin-9-yl)propoxy)methyl)pyrrolidin-1-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one trifluoroacetate
Compound 15 the procedure of example 10 was followed starting from 3- (trifluoromethyl) -6, 7a,8,10, 11-hexahydro-9H-pyrazino [1,2-d ] pyrido [3,2-b ] [1,4] oxaza-9-carboxylic acid tert-butyl ester (3 d) and 3- { [ (2S) -1- (6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl ] pyrrolidin-2-yl ] methoxy } propanoic acid (5 f) to give the trifluoroacetate salt of (5- ((2S) -2- ((3-oxo-3- (3- (trifluoromethyl) -6, 7a,8,10, 11-hexahydro-9H-pyrazino [1,2-d ] pyrido [3,2-b ] [1,4] oxaza-9-yl) propoxy) methyl) pyrrolidin-1-yl) -4- (trifluoromethyl) pyridazin-3 (2H) -one (Compound 15).
LCMS m/z＝591.3[M+1] + 。
1 H NMR(400MHz,CD 3 OD)δ8.14-8.05(m,2H),7.43-7.30(m,1H),4.64-4.51(m,1H),4.44-4.27(m,2H),4.22-4.08(m,1H),3.96-3.75(m,5H),3.74-3.52(m,5H),3.46-3.34(m,2H),2.68-2.49(m,2H),2.28-2.09(m,2H),2.07-1.91(m,2H),1.79-1.58(m,2H)。
Example 16:9- (3- ((S) -2- ((6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino) propoxy) propanoyl) -3- (trifluoromethyl) -7,7a,8,9,10, 11-hexahydropyrazino [1,2-d ] pyrido [3,2-b ] [1,4] diaza-6 (5H) -one (Compound 16)
9-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydropyrazino[1,2-d]pyrido[3,2-b][1,4]diazepin-6(5H)-one
The first step: 3- (2-methoxy-2-oxoethyl) -4- (3-nitro-5- (trifluoromethyl) pyridin-2-yl) piperazine-1-carboxylic acid tert-butyl ester (16 c)
Tert-butyl 3-(2-methoxy-2-oxoethyl)-4-(3-nitro-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate
2-chloro-3-nitro-5- (trifluoromethyl) pyridine (16 a) (1.50 g,6.62 mmol) was added to DMF (20 mL) at room temperature, 3- (2-methoxy-2-oxoethyl) piperazine-1-carboxylic acid tert-butyl ester (3 a) (2.16 g,8.83 mmol) and DIPEA (3.42 g,26.49 mmol) were added. The mixture was stirred at room temperature overnight. The reaction was quenched with water (40 mL), extracted with ethyl acetate (40 mL. Times.2), the organic phases were combined, washed with saturated brine (40 mL. Times.3), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give the crude product. The crude product was isolated and purified by preparative column (petroleum ether: ethyl acetate (v/v) =8:1) to give 3- (2-methoxy-2-oxoethyl) -4- (3-nitro-5- (trifluoromethyl) pyridin-2-yl) piperazine-1-carboxylic acid tert-butyl ester (16 c) (2.4 g, 81%).
LCMS m/z＝393.1[M-55] + 。
And a second step of: 4- (3-amino-5- (trifluoromethyl) pyridin-2-yl) -3- (2-methoxy-2-oxoethyl) piperazine-1-carboxylic acid tert-butyl ester (16 d)
Tert-butyl 4-(3-amino-5-(trifluoromethyl)pyridin-2-yl)-3-(2-methoxy-2-oxoethyl)piperazine-1-carboxylatte
3- (2-methoxy-2-oxoethyl) -4- (3-nitro-5- (trifluoromethyl) pyridin-2-yl) piperazine-1-carboxylic acid tert-butyl ester (16C) (3.2 g,7.14 mmol) was added to a solution of MeOH (50 ml) and Pd/C (0.35 g) was added. The mixture was reacted at room temperature under hydrogen atmosphere for 16 hours. Filtering, and concentrating the filtrate under reduced pressure to obtain crude product. The crude product was isolated and purified by column chromatography (petroleum ether: ethyl acetate (v/v) =5:1) to give tert-butyl 4- (3-amino-5- (trifluoromethyl) pyridin-2-yl) -3- (2-methoxy-2-oxoethyl) piperazine-1-carboxylate (16 d) (2.2 g, 75%).
LCMS m/z＝419.2[M+1] + 。
And a third step of: tert-butyl-6-oxo-3- (trifluoromethyl) -6, 7a,8,10,11 hexahydropyrazino [1,2-d ] pyrido [3,2-b ] [1,4] diaza-9- (5H) -carboxylic acid ester (16 e)
Tert-butyl 6-oxo-3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydropyrazino[1,2-d]pyrido[3,2-b][1,4]diazepine-9(5H)-carboxylate
4- (3-amino-5- (trifluoromethyl) pyridin-2-yl) -3- (2-methoxy-2-oxoethyl) piperazine-1-carboxylic acid tert-butyl ester (16 d) (2.20 g,5.26 mmol) was added to DMF (20 mL) and potassium carbonate (2.20 g,15.94 mmol) was added. The mixture was stirred at room temperature overnight. The reaction was quenched with water (40 mL), extracted with ethyl acetate (40 mL. Times.3), the organic phases were combined, washed with saturated brine (40 mL. Times.3), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give the crude product. The crude product was isolated and purified by preparative column (petroleum ether: ethyl acetate (v/v) =4:1) to give 3- (trifluoromethyl) -7,7a,8,9,10, 11-hexahydropyrazino [1,2-d ] pyrido [3,2-B ] [1,4] diaza-6 (5H) -one (16 e) (1.3 g, 65%).
LCMS m/z＝331.1[M-55] + 。
Fourth step: hydrochloride of 3- (trifluoromethyl) -7,7a,8,9,10, 11-hexahydropyrazino [1,2-d ] pyrido [3,2-B ] [1,4] diaza-6 (5H) -one (16 f)
3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydropyrazino[1,2-d]pyrido[3,2-b][1,4]diazepin-6(5H)-one hydrochloric acid
(3- (trifluoromethyl) -7,7a,8,9,10, 11-hexahydropyrazino [1,2-d ] pyrido [3,2-B ] [1,4] diaza-6 (5H) -one (16 e) (170 mg,0.44 mmol) was dissolved in HCl/dioxane (5 mL,4M,20 mmol), and the mixture was stirred at room temperature for 2H, the solvent was removed by concentration under reduced pressure to give the crude 3- (trifluoromethyl) -7,7a,8,9,10, 11-hexahydropyrazino [1,2-d ] pyrido [3,2-B ] [1,4] diaza-6 (5H) -one (16 f) hydrochloride (130 mg, 92%) which was used directly in the next step.
LCMS m/z＝287.2[M+1] + 。
Fifth step 9- (3- ((S) -2- ((6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino) propoxy) propanoyl) -3- (trifluoromethyl) -7,7a,8,9,10, 11-hexahydropyrazino [1,2-d ] pyrido [3,2-b ] [1,4] diazepin-6 (5H) -one (Compound 16)
9-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydropyrazino[1,2-d]pyrido[3,2-b][1,4]diazepin-6(5H)-one
3- (trifluoromethyl) -7,7a,8,9,10, 11-hexahydropyrazino [1,2-d]Pyrido [3,2-B][1,4]The hydrochloride salt of diaza-6 (5H) -one (16 f) (55 mg,0.17 mmol) was dissolved in DMF (2 mL) and 3- [ (2S) -2- [ (6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino was added]Propoxy group]Propionic acid (4 j) (50 mg,0.16 mmol), HATU (45.6 mg,0.12 mmol) and DIPEA (103.2 mg,0.8 mmol) and the mixture was reacted at 20℃for 2h. Purifying the crude product by Pre-HPLC (instrument and preparation column: preparation of liquid phase by Waters 2767, preparation column model is Sunfire@Prep C 18 5 μm, inner diameter x length = 19mm x 250 mm). The preparation method comprises the following steps: the reaction solution was filtered through a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: acetonitrile/water (0.1% ammonia). The gradient elution method comprises the following steps: acetonitrile was eluted from a 5% gradient to 50% (flow rate: 15mL/min; elution time: 15 min), and after lyophilization 9- (3- ((S) -2- ((6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino) propoxy) propionyl) -3- (trifluoromethyl) -7,7a,8,9,10, 11-hexahydropyrazino [1,2-d]Pyrido [3,2-b][1,4]Diaza-6 (5H) -one (compound 16) (10 mg, 11%).
LCMS m/z＝578.3[M+1] + 。
1 H NMR(400MHz,DMSO-d 6 )δ12.43(s,1H),9.85(s,1H),8.40(s,1H),7.91(s,1H),7.49(d,1H),6.30-6.18(m,1H),4.41-4.30(m,1H),4.18-4.08(m,1H),3.97-3.83(m 2H),3.77-3.58(m,3H),3.49(d,2H),3.28-3.15(m,1H),3.12-2.90(m,2H),2.82-2.54(m,3H),2.46-2.34(m,1H),1.16(d,3H)。
Example 17:9- (3- (((S) -1- (6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) pyrrolidin-2-yl) methoxy) propionyl) -3- (trifluoromethyl) -7,7a,8,9,10, 11-hexahydropyrazino [1,2-d ] pyrido [3,2-b ] [1,4] diaza-6 (5H) -one (Compound 17)
9-(3-(((S)-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl)methoxy)propanoyl)-3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydropyrazino[1,2-d]pyrido[3,2-b][1,4]diazepin-6(5H)-one
Will (((S) -3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-pyrazino [1, 2-a)]Pyrido [3,2-e]The hydrochloride salt of pyrazin-6- (6 aH) -one (16 f) (55 mg,0.17 mmol) was dissolved in DMF (3 mL), then (S) -3- ((1- (6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) pyrrolidin-2-yl) methoxy) propionic acid (5 f) (55 mg,0.17 mmol), HATU (61 mg,0.16 mmol) and DIPEA (105 mg,0.8 mmol) were added and the mixture reacted at 20 ℃ for 2h. The reaction solution was purified by Pre-HPLC (instrument and preparation column: preparation of liquid phase using Waters 2767, preparation column model is Sunfire@Prep C) 1 8 5 μm, inner diameter x length = 19mm x 250 mm). The preparation method comprises the following steps: the reaction solution was filtered through a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: acetonitrile/water (0.1% ammonia). The gradient elution method comprises the following steps: acetonitrile was eluted from a 5% gradient to 50% (flow rate: 15mL/min; elution time: 15 min) and lyophilized to give 9- (3- (((S) -1- (6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) pyrrolidin-2-yl) methoxy) propionyl) -3- (trifluoromethyl) -7,7a,8,9,10, 11-hexahydropyrazino [1, 2-d)]Pyrido [3,2-b][1,4]Diaza-6 (5H) -one (Compound 17) (12 mg, 12%).
LCMS m/z＝604.3[M+1] + 。
1 H NMR(400MHz,DMSO-d 6 )δ12.32(s,1H),9.85(s,1H),8.43-8.39(m,1H),8.00(s,1H),7.49(d,1H),4.59-4.46(m,1H),4.41-4.26(m,1H),3.95-3.84(m,2H),3.76-3.59(m,3H),3.57-3.45(m,2H),3.44-3.35(m,1H),3.25-2.55(m,7H),2.47-2.34 (m,1H),2.14-2.02(m,1H),1.96-1.84(m,1H),1.72-1.57(m,2H)。
Example 18: 5-methyl-9- (3- ((S) -2- ((6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino) propoxy) propanoyl) -3- (trifluoromethyl) -7,7a,8,9,10, 11-hexahydropyrazino [1,2-d ] pyrido [3,2-b ] [1,4] diazepin-6 (5H) -one (Compound 18)
5-methyl-9-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydropyrazino[1,2-d]pyrido[3,2-b][1,4]diazepin-6(5H)-one
The first step: tert-butyl 5-methyl-6-oxo-3- (trifluoromethyl) -6, 7a,8,10, 11-hexahydropyrazino [1,2-d ] pyrido [3,2-B ] [1,4] diaza 9 (5H) -carboxylic acid tert-butyl ester (18 a)
Tert-butyl 5-methyl-6-oxo-3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydropyrazino[1,2-d]pyrido[3,2-b][1,4]diazepine-9(5H)-carboxylate
Tert-butyl-6-oxo-3- (trifluoromethyl) -6, 7a,8,10, 11-hexahydropyrazino [1,2-d ] at room temperature]Pyrido [3,2-B][1,4]Diaza-9- (5H) -carboxylate (16 e) (300 mg,0.78 mmol) was added to DMF (5 mL) and K was added 2 CO 3 (321 mg,2.33 mmol) and CH 3 I (133 gm,0.93 mmol). The mixture was stirred at room temperature overnight. The reaction was quenched with water (15 mL), extracted with ethyl acetate (20 mL. Times.3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give the crude product. The crude product is separated and purified by a preparation column (petroleum ether: ethyl acetate (v/v) =5:1) to obtain tert-butyl 5-methyl-6-oxo-3- (trifluoromethyl) -6, 7a,8,10, 11-hexahydropyrazino [1, 2-d)]Pyrido [3,2-b][1,4]Diaza 9 (5H) -carboxylic acid tert-butyl ester (18 a) (150 mg, 50%).
LCMS m/z＝345.2[M-55] + 。
And a second step of: hydrochloride of 5-methyl-3- (trifluoromethyl) -7,7a,8,9,10, 11-hexahydropyrazino [1,2-d ] pyrido [3,2-B ] [1,4] diaza-6 (5H) -one (18B)
5-methyl-3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydropyrazino[1,2-d]pyrido[3,2-b][1,4]diazepin-6(5H)-one
Tert-butyl 5-methyl-6-oxo-3- (trifluoromethyl) -6, 7a,8,10, 11-hexahydropyrazino [1,2-d ] pyrido [3,2-B ] [1,4] diaza 9 (5H) -carboxylic acid tert-butyl ester (18 a) (150 mg,0.38 mmol) was dissolved in HCl/dioxane (4 ml,4m,16 mmol) and the mixture stirred at room temperature for 2H. The solvent was removed by concentration under reduced pressure to give crude 5-methyl-3- (trifluoromethyl) -7,7a,8,9,10, 11-hexahydropyrazino [1,2-d ] pyrido [3,2-B ] [1,4] diaza-6 (5H) -one hydrochloride (18B) (110 mg, 87%) which was used directly in the next step.
LCMS m/z＝301.2[M+1] + 。
And a third step of: 5-methyl-9- (3- ((S) -2- ((6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino) propoxy) propanoyl) -3- (trifluoromethyl) -7,7a,8,9,10, 11-hexahydropyrazino [1,2-d ] pyrido [3,2-b ] [1,4] diazepin-6 (5H) -one (Compound 18)
5-methyl-9-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydropyrazino[1,2-d]pyrido[3,2-b][1,4]diazepin-6(5H)-one
5-methyl-3- (trifluoromethyl) -7,7a,8,9,10, 11-hexahydropyrazino [1,2-d]Pyrido [3,2-b][1,4]The hydrochloride salt of diaza-6 (5H) -one (18 b) (55 mg,0.15 mmol) was dissolved in DMF (3 mL) and 3- [ (2S) -2- [ (6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino was then added]Propoxy group]Propionic acid (4 j) (50 mg,0.16 mmol), HATU (45.6 mg,0.12 mmol) and DIPEA (103.2 mg,0.8 mmol) and the mixture was reacted at 20℃for 2h. The reaction solution was purified by Pre-HPLC (instrument and preparation column: preparation of liquid phase using Waters 2767, preparation column model is Sunfire@Prep C) 18 5 μm, inner diameter x length = 19mm x 250 mm). The preparation method comprises the following steps: the reaction solution was filtered through a 0.45 μm filter membrane to prepare a sampleAnd (5) preparing a liquid. Mobile phase system: acetonitrile/water (0.1% ammonia). The gradient elution method comprises the following steps: acetonitrile was eluted from a 5% gradient to 50% (flow rate: 15mL/min; elution time: 15 min), and after lyophilization 5-methyl-9- (3- ((S) -2- ((6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino) propoxy) propionyl) -3- (trifluoromethyl) -7,7a,8,9,10, 11-hexahydropyrazino [1,2-d ]Pyrido [3,2-b][1,4]Diaza-6 (5H) -one (Compound 18) (12 mg, 14%).
LCMS m/z＝592.3[M+1] + 。
1 H NMR(400MHz,DMSO-d 6 )δ12.42(s,1H),8.49(s,1H),8.01(d,1H),7.91(s,1H),6.30-6.19(m,1H),4.46-4.29(m,1H),4.21-4.07(m,1H),4.00-3.85(m,1H),3.84-3.44(m,6H),3.24(s,3H),3.11-2.84(m,2H),2.80-2.54(m,4H),2.43-2.32(m,1H),1.16(d,3H)。
Example 19: 5-methyl-9- (3- (((S) -1- (6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) pyrrolidin-2-yl) methoxy) propionyl) -3- (trifluoromethyl) -7,7a,8,9,10, 11-hexahydropyrazino [1,2-d ] pyrido [3,2-b ] [1,4] diazepin-6 (5H) -one (Compound 19)
5-methyl-9-(3-(((S)-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl)methoxy)propanoyl)-3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydropyrazino[1,2-d]pyrido[3,2-b][1,4]diazepin-6(5H)-one
5-methyl-3- (trifluoromethyl) -7,7a,8,9,10, 11-hexahydropyrazino [1,2-d]Pyrido [3,2-B][1,4]The hydrochloride salt of diaza-6 (5H) -one (18 b) (55 mg,0.15 mmol) was dissolved in DMF (3 mL) and then (S) -3- ((1- (6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) pyrrolidin-2-yl) methoxy) propionic acid (5 f) (55 mg,0.17 mmol), HATU (61 mg,0.16 mmol) and DIPEA (105 mg,0.8 mmol) was added and the mixture reacted at 20℃for 2H. The reaction solution was purified by Pre-HPLC (instrument and preparation column: preparation of liquid phase using Waters 2767, preparation column model is Sunfire@Prep C) 18 5 μm, inner diameter XLength = 19mm x 250 mm). The preparation method comprises the following steps: the reaction solution was filtered through a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: acetonitrile/water (0.1% ammonia). The gradient elution method comprises the following steps: acetonitrile was eluted from a 5% gradient to 50% (flow rate: 15mL/min; elution time 15 min), and lyophilized to give (5-methyl-9- (3- (((S) -1- (6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) pyrrolidin-2-yl) methoxy) propionyl) -3- (trifluoromethyl) -7,7a,8,9,10, 11-hexahydropyrazino [1, 2-d) ]Pyrido [3,2-b][1,4]Diaza-6 (5H) -one (Compound 19) (14 mg, 15%).
LCMS m/z＝618.3[M+1] + 。
1 H NMR(400MHz,DMSO-d 6 )δ12.32(s,1H),8.52-8.47(m,1H),8.03-7.99(m,2H),4.57-4.48(m,1H),4.43-4.29(m,1H),3.95-3.85(m,1H),3.83-3.74(m,1H),3.68-3.47(m,5H),3.44-3.38(m,1H),3.26-2.69(m,8H),2.65-2.53(m,2H),2.46-2.35(m,1H),2.13-2.03(m,1H),1.94-1.85(m,1H),1.72-1.59(m,2H)。
Example 20:9- (3- ((S) -2- ((6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino) propoxy) propanoyl) -7,7a,9,10, 11-hexahydro-6H-pyrazino [1,2-d ] pyrido [3,2-b ] [1,4] oxaza-3-carbonitrile (Compound 20)
9-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-7,7a,8,9,10,11-hexahydro-6H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxazepine-3-carbonitrile
The first step: (4- (5-cyano-3-nitropyridin-2-yl) -3- (2-hydroxyethyl) piperazine-1-carboxylic acid tert-butyl ester (20 b)
Tert-butyl 4-(5-cyano-3-nitropyridin-2-yl)-3-(2-hydroxyethyl)piperazine-1-carboxylate
6-chloro-5-nitropyridine-3-carbonitrile (20 a) (1 g,5.45 mmol) was dissolved in DMF (10 mL) at room temperature, and 3- (2-hydroxyethyl) piperazine-1-carboxylic acid tert-butyl ester (3 b) (1.26 g,5.45 mmol) and DIPEA (2.11 g,16.35 mmol) were added. The mixture was stirred at room temperature overnight. The reaction was quenched with water (20 mL), extracted with ethyl acetate (20 mL. Times.2), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give the crude product. The crude product was isolated and purified by column chromatography (petroleum ether: ethyl acetate (v/v) =10:1) to give (4- (5-cyano-3-nitropyridin-2-yl) -3- (2-hydroxyethyl) piperazine-1-carboxylic acid tert-butyl ester (20 b) (1 g, 48%).
LCMS m/z＝322.2[M-55] + 。
And a second step of: 3-cyano-6, 7a,8,10, 11-hexahydro-9H-pyrazino [1,2-d ] pyrido [3,2-b ] [1,4] oxaza-9-carboxylic acid tert-butyl ester (20 c)
Tert-butyl 3-cyano-6,7,7a,8,10,11-hexahydro-9H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxazepine-9-carboxylate
(4- (5-cyano-3-nitropyridin-2-yl) -3- (2-hydroxyethyl) piperazine-1-carboxylic acid tert-butyl ester (20 b) (0.5 g,1.32 mmol) was dissolved in DMF (10 ml) and K was added 2 CO 3 (540 mg,3.97 mmol). The mixture was reacted at 100℃for 16 hours. Cooled to room temperature, quenched with water (10 mL), extracted with ethyl acetate (10 mL. Times.2), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give crude product. The crude product is separated and purified by a preparation column (petroleum ether: ethyl acetate (v/v) =10:1) to obtain 3-cyano-6, 7a,8,10, 11-hexahydro-9H-pyrazino [1,2-d ]]Pyrido [3,2-b][1,4]Tert-butyl oxaza-9-carboxylate (20 c) (0.23 g, 53%).
LCMS m/z＝275.1[M-55] + 。
And a third step of: hydrochloride of 3-cyano-7, 7a,8,9,10, 11-hexahydro-6H-pyrazino [1,2-d ] pyrido [3,2-b ] [1,4] oxaza (20 d)
3-cyano-7,7a,8,9,10,11-hexahydro-6H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxazepinehydrochloric acid
3-cyano-6, 7a,8,10, 11-hexahydro-9H-pyrazino [1,2-d ] pyrido [3,2-b ] [1,4] oxaza-9-carboxylic acid tert-butyl ester (20 c) (120 mg,0.36 mmol) was dissolved in HCl/dioxane (5 mL,4M,20 mmol) and the mixture was stirred at room temperature for 2H. The solvent was removed by concentration under reduced pressure to give 3-cyano-7, 7a,8,9,10, 11-hexahydro-6H-pyrazino [1,2-d ] pyrido [3,2-b ] [1,4] oxaza (20 d) hydrochloride (96 mg, 100%) which was used directly in the next step.
LCMS m/z＝231.2[M+1] + 。
Fourth step: 9- (3- ((S) -2- ((6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino) propoxy) propanoyl) -7,7a,9,10, 11-hexahydro-6H-pyrazino [1,2-d ] pyrido [3,2-b ] [1,4] oxaza-3-carbonitrile (Compound 20)
9-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-7,7a,8,9,10,11-hexahydro-6H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxazepine-3-carbonitrile
(3-cyano-7, 7a,8,9,10, 11-hexahydro-6H-pyrazino [1, 2-d)]Pyrido [3,2-b][1,4]The hydrochloride salt of oxaza (20 d) (48 mg,0.18 mmol) was dissolved in DMF (2 mL) and 3- [ (2S) -2- [ (6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino was added]Propoxy group]Propionic acid (4 j) (46 mg,0.18 mmol), HATU (51 mg,0.14 mmol) and DIPEA (70 mg,0.54 mmol), the mixture was reacted at 20deg.C for 2h, quenched with water (10 mL), extracted with ethyl acetate (10 mL. Times.2), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressureObtaining crude product. Purifying the crude product by Pre-HPLC (instrument and preparation column: preparation of liquid phase by Waters 2767, preparation column model XBIdge@Prep C 18 Inner diameter x length = 19mm x 250 mm). The preparation method comprises the following steps: the crude product was dissolved in DMF and filtered through a 0.45 μm filter to prepare a sample solution. Mobile phase system: acetonitrile/water (0.05% ammonia). The gradient elution method comprises the following steps: acetonitrile was eluted from a 10% gradient to 55% (flow rate: 12mL/min; elution time: 17 min) to give 9- (3- ((S) -2- ((6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino) propoxy) propionyl) -7,7a,9,10, 11-hexahydro-6H-pyrazino [1,2-d]Pyrido [3,2-b][1,4]Oxaza-3-carbonitrile (compound 20) (10 mg, 12%).
LCMS m/z＝522.2[M+1] + 。
1 H NMR(400MHz,CD 3 OD)δ8.14-8.11(m,1H),7.95-7.90(m,1H),7.30-7.27(m,1H),4.39-4.08(m,4H),4.01-3.44(m,10H),2.70-2.59(m,2H),2.22-2.07(m,1H),2.04-1.91(m,1H),1.28-1.18(m,3H)。
Example 21:9- (3- (((S) -1- (6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) pyrrolidin-2-yl) methoxy) propionyl) -7,7a,8,9,10, 11-hexahydro-6H-pyrazino [1,2-d ] pyrido [3,2-b ] [1,4] oxaza-3-carbonitrile (compound 21)
9-(3-(((S)-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl)methoxy)propanoyl)-7,7a,8,9,10,11-hexahydro-6H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxazepine-3-carbonitrile
(3-cyano-7, 7a,8,9,10, 11-hexahydro-6H-pyrazino [1, 2-d)]Pyrido [3,2-b][1,4]Oxaza (20 d) hydrochloride (48 mg,0.18 mmol) was dissolved in DMF (2 mL) and 3- { was added[ (2S) -1- (6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) pyrrolidin-2-yl]Methoxy } propionic acid (5 f) (60 mg,0.18 mmol), HATU (68 mg,0.18 mmol) and DIPEA (70 mg,0.54 mmol), the mixture was reacted at 20℃for 2h, quenched with water (10 mL), extracted with ethyl acetate (10 mL. Times.2), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give the crude product. Purifying the crude product by Pre-HPLC (instrument and preparation column: preparation of liquid phase by Waters 2767, preparation column model XBIdge@Prep C 18 Inner diameter x length = 19mm x 250 mm). The preparation method comprises the following steps: the crude product was dissolved in DMF and filtered through a 0.45 μm filter to prepare a sample solution. Mobile phase system: acetonitrile/water (0.05% ammonia). The gradient elution method comprises the following steps: acetonitrile was eluted from a 10% gradient to 55% (flow: 12mL/min; elution time 17 min) to give 9- (3- (((S) -1- (6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) pyrrolidin-2-yl) methoxy) propionyl) -7,7a,8,9,10, 11-hexahydro-6H-pyrazino [1, 2-d) ]Pyrido [3,2-b][1,4]Oxaza-3-carbonitrile (compound 21) (10 mg, 10%).
LCMS m/z＝548.2[M+1] + 。
1 H NMR(400MHz,CD 3 OD)δ8.15-8.12(m,1H),8.11-8.09(m,1H),7.30(d,1H),4.61-4.50(m,1H),4.41-4.32(m,1H),4.31-4.23(m,1H),4.22-4.13(m,1H),4.02-3.47(m,10H),3.46-3.32(m,2H),2.65-2.49(m,2H),2.26-2.08(m,2H),2.04-1.89(m,2H),1.79-1.59(m,2H)。
Example 22: (R) -5-methyl-8- (3- ((S) -2- ((6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino) propoxy) propanoyl) -3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-pyrazino [1,2-a ] pyridin [3,2-e ] pyrazin-6 (6 aH) -one (Compound 22)
(R)-5-Methyl-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one
The first step: tert-butyl- (R) -5-methyl-6-oxo-3- (trifluoromethyl) -5, 6a,7,9, 10-hexahydro-8H-pyrazino [1,2-a ] pyridine [3,2-e ] pyrazine-8-carboxylic acid ester (22 a)
Tert-butyl-(R)-5-methyl-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8-carboxylate
Tert-butyl- (R) -6-oxo-3- (trifluoromethyl) -5, 6a,7,9, 10-hexahydro-8H-pyrazino [1,2-a ] pyridine [3,2-e ] pyrazine-8-carboxylate (4 d) (16.0 g,43.0 mmol) was dissolved in DMF (150 mL) at room temperature, followed by addition of potassium carbonate (17.82 g,128.9 mmol), methyl iodide (18.43 g,128.9 mmol) and reaction at room temperature for 16 hours. After the reaction was completed, 300mL of water was added and extracted with ethyl acetate (300 mL. Times.3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was purified by column separation (petroleum ether: ethyl acetate (v/v) =7:3) to give tert-butyl- (R) -5-methyl-6-oxo-3- (trifluoromethyl) -5, 6a,7,9, 10-hexahydro-8H-pyrazino [1,2-a ] pyridine [3,2-e ] pyrazine-8-carboxylate (22 a) (12.5 g, 75%).
LCMS m/z＝331.1[M-55] + 。
And a second step of: hydrochloride of (R) -5-methyl-3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-pyrazino [1,2-a ] pyridine [3,2-e ] pyrazin-6 (6 aH) -one (22 b)
(R)-5-Methyl-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one hydrochloride
Tert-butyl- (R) -5-methyl-6-oxo-3- (trifluoromethyl) -5, 6a,7,9, 10-hexahydro-8H-pyrazino [1,2-a ] pyridine [3,2-e ] pyrazine-8-carboxylate (22 a) (12.5 g,32.4 mmol) was dissolved in 1, 4-dioxane (50 mL) and then hydrogen chloride-1, 4-dioxane solution (4.0M, 150mL,600 mmol) was added and reacted at room temperature for 16 hours. After the completion of the reaction, the solvent was removed by concentration under reduced pressure to give (R) -5-methyl-3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-pyrazino [1,2-a ] pyridine [3,2-e ] pyrazin-6 (6 aH) -one (22 b) hydrochloride (10.3 g, 87%).
LCMS m/z＝287.1[M+1] + 。
And a third step of: (R) -5-methyl-8- (3- ((S) -2- ((6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino) propoxy) propanoyl) -3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-pyrazino [1,2-a ] pyridin [3,2-e ] pyrazin-6 (6 aH) -one (Compound 22)
(R)-5-Methyl-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one
3- [ (2S) -2- [ (6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino ] propoxy ] propionic acid (4 j) (8.5 g,27.56 mmol) and hydrochloride (10.0 g,27.84 mmol) of (R) -5-methyl-3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-pyrazino [1,2-a ] pyridin [3,2-e ] pyrazin-6 (6 aH) -one (22 b) were dissolved in DMF (100 mL) at room temperature, and DIPEA (18.0 g,139.2 mmol) and HATU (10.6 g,27.84 mmol) were added thereto, respectively. After the reaction was completed, 200mL of water was added and the mixture was extracted with ethyl acetate (250 mL. Times.3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was isolated and purified by preparative column (dichloromethane: methanol (v/v) =95:5) to give (R) -5-methyl-8- (3- ((S) -2- ((6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino) propoxy) propionyl) -3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-pyrazino [1,2-a ] pyridine [3,2-e ] pyrazin-6 (6 aH) -one (compound 22) (14.0 g, 87%).
LCMS m/z＝578.2[M+1] + 。
Example 23: 5-methyl-8- (3- ((S) -2- ((6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino) propoxy) propanoyl) -3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-bipyrazine [1,2-a:2',3' -e ] pyrazin-6 (6 aH) -one (Compound 23)
5-methyl-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-dipyrazino[1,2-a:2',3'-e]pyrazin-6(6aH)-one
The first step: 1-tert-butyl 3-methyl (3R) -4- (5- (trifluoromethyl) pyrazin-2-yl) piperazine-1, 3-dicarboxylic acid ester (23 b)
1-tert-butyl 3-methyl(3R)-4-(5-(trifluoromethyl)pyrazin-2-yl)piperazine-1,3-dicarboxylate
2-chloro-5- (trifluoromethyl) pyrazine (23 a) (1.00 g,5.48 mmol), 1- (tert-butyl) 3-methyl (R) -piperazine-1, 3-dicarboxylic acid ester (2.01 g,8.22 mmol), DIPEA (2.12 g,16.44 mmol) were added sequentially to dimethyl sulfoxide (15 mL), reacted at 100℃for 16h, after the reaction was completed, cooled to room temperature, the reaction solution was poured into water (150 mL), extracted with ethyl acetate (30 mL. Times.3), the organic phases were combined, backwashed with saturated brine (30 mL. Times.3), dried over anhydrous sodium sulfate, suction filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V/V) =2:1) to give 1-tert-butyl 3-methyl (3R) -4- (5- (trifluoromethyl) pyrazin-2-yl) piperazine-1, 3-dicarboxylic acid ester (23 b) (900 mg, 42%).
LCMS m/z＝335.0[M-55] + 。
And a second step of: 1-tert-butyl 3-methyl (3R) -4- (3-chloro-5- (trifluoromethyl) pyrazin-2-yl) piperazine-1, 3-dicarboxylic acid ester (23 c)
1-tert-butyl 3-methyl(3R)-4-(3-chloro-5-(trifluoromethyl)pyrazin-2-yl)piperazine-1,3-dicarboxylate
To a solution of 1-tert-butyl 3-methyl (3R) -4- (5- (trifluoromethyl) pyrazin-2-yl) piperazine-1, 3-dicarboxylic acid ester (23 b) (500 mg,1.28 mmol) in DMF (5 mL) was added N-chlorosuccinimide (188 mg,1.41 mmol), and after the reaction was completed at room temperature for 16 hours, the reaction solution was poured into water (50 mL), ethyl acetate (20 mL. Times.3) was extracted, the organic phases were combined, the organic phase was backwashed with saturated brine (20 mL. Times.3), dried over anhydrous sodium sulfate, suction-filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V/V) =3:1) to give 1-tert-butyl 3-methyl (3R) -4- (3-chloro-5- (trifluoromethyl) pyrazin-2-yl) piperazine-1, 3-dicarboxylic acid ester (23 c) (3996 mg, 73%).
LCMS m/z＝369.0[M-55] + 。
And a third step of: tert-butyl 5-methyl-6-oxo-3- (trifluoromethyl) -5, 6a,7,9, 10-hexahydro-8H-bipyrazine [1,2-a:2',3' -e ] pyrazine-8-carboxylic acid ester (23 d)
Tert-butyl 5-methyl-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-dipyrazino[1,2-a:2',3'-e]pyrazine-8-carboxylate
To a solution of 1-tert-butyl 3-methyl (3R) -4- (3-chloro-5- (trifluoromethyl) pyrazin-2-yl) piperazine-1, 3-dicarboxylic acid ester (23 c) (348 mg,0.82 mmol) in ethanol (7 mL) was added methylamine hydrochloride (277 mg4.1 mmol), DIPEA (1.06 g,8.2 mmol) in sequence. After the reaction is completed and cooled to room temperature, the reaction solution is concentrated under reduced pressure to obtain a residue, and the residue is separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate (V/V) =5:1) to obtain tert-butyl 5-methyl-6-oxo-3- (trifluoromethyl) -5, 6a,7,9, 10-hexahydro-8H-bipyrazine [1,2-a:2',3' -e ] pyrazine-8-carboxylate (23 d) (265 mg, 83%).
LCMS m/z＝332.1[M-55] + 。
Fourth step: hydrochloride of 5-methyl-3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-bipyrazine [1,2-a:2',3' -e ] pyrazin-6 (6 aH) -one (2 3 e)
5-methyl-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-dipyrazino[1,2-a:2',3'-e]pyrazin-6(6aH)-one hydrochloride
Tert-butyl 5-methyl-6-oxo-3- (trifluoromethyl) -5, 6a,7,9, 10-hexahydro-8H-bipyrazine [1,2-a:2',3' -e ] pyrazine-8-carboxylate (23 d) (150 mg,0.39 mmol) was added to a solution of 1, 4-dioxane (5 mL, 4N) of hydrogen chloride, reacted at room temperature for 1H, and after the reaction was completed, the crude 5-methyl-3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-bipyrazine [1,2-a:2',3' -e ] pyrazin-6 (6 aH) -one (23 e) hydrochloride (130 mg) was concentrated under reduced pressure and used directly in the next step.
Fifth step: 5-methyl-8- (3- ((S) -2- ((6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino) propoxy) propanoyl) -3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-bipyrazine [1,2-a:2',3' -e ] pyrazin-6 (6 aH) -one (Compound 23)
5-methyl-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-dipyrazino[1,2-a:2',3'-e]pyrazin-6(6aH)-one
5-methyl-3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-bipyrazine [1,2-a:2',3' -e]Hydrochloride (60 mg, crude) of pyrazin-6 (6 aH) -one (22 e), 3- [ (2S) -2- [ (6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino]Propoxy group]Propionic acid (4 j) (65 mg,0.21 mmol), HATU (80 mg,0.21 mmol) and DIPEA (140 mg,1.05 mmol) were added sequentially to DMF (2 mL) and reacted at room temperature for 1h. After the reaction, the reaction mixture was purified by Pre-HPLC (instrument and preparation column: preparation of liquid phase by Waters 2767, preparation column model is Sunfire@Prep C 18 5 μm, inner diameter x length = 19mm x 250 mm). The preparation method comprises the following steps: the reaction solution was filtered through a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: acetonitrile/water (0.1% ammonia). The gradient elution method comprises the following steps: acetonitrile was eluted from a 5% gradient to 50% (flow rate: 15mL/min; elution time: 15 min), and after lyophilization 5-methyl-8- (3- ((S) -2- ((6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino) propoxy) propionyl) -3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-bipyrazine [1,2-a:2',3' -e ]Pyrazin-6 (6 aH) -one (compound 23) (30 mg, 25%).
LCMS m/z＝579.1[M+1] + 。
1 H NMR(400MHz,DMSO-d 6 )δ12.42(s,1H),8.18(s,1H),7.90(s,1H),6.30-6.20(m,1H),4.91-4.53(m,1H),4.53-3.98(m,4H),3.75-3.62(m,2H),3.49(d,2H),3.43-3.04(m,4H),2.91-2.81(m,1H),2.77-2.56(m,3H),1.16(d,3H)。
Example 24: 5-methyl-8- (3- (((S) -1- (6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) pyrrolidin-2-yl) methoxy) propionyl) -3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-bipyrazine [1,2-a:2',3' -e ] pyrazin-6 (6 aH) -one (Compound 24)
5-methyl-8-(3-(((S)-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl)methoxy)propanoyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-dipyrazino[1,2-a:2',3'-e]pyrazin-6(6aH)-one
Compound 24 the synthetic method of example 22 was followed using 5-methyl-3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-bipyrazino [1,2-a:2',3' -e ] pyrazin-6 (6 aH) -one (22 e) hydrochloride and 3- { [ (2S) -1- (6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) pyrrolidin-2-yl ] methoxy } propanoic acid (5 f) as starting materials to give 5-methyl-8- (3- (((S) -1- (6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) pyrrolidin-2-yl) methoxy) propionyl) -3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-bipyrazino [1,2-a:2',3' -e ] pyrazin-6 (6 aH) -one (compound 24).
LCMS m/z＝605.2[M+1] + 。
1 H NMR(400MHz,DMSO-d 6 )δ12.32(s,1H),8.19(s,1H),8.01(s,1H),4.93-3.96(m,5H),3.73-3.59(m,2H),3.57-3.46(m,2H),3.46-3.03(m,6H),2.91-2.80(m,1H),2.77-2.53(m,3H),2.15-2.00(m,1H),1.97-1.79(m,1H),1.72-1.55(s,2H)。
Example 25:5- (((S) -1- (3-oxo-3- ((R) -3- (trifluoromethyl) -6a,7,9, 10-tetrahydrodipyrazine [2,3-b:1',2' -d ] [1,4] oxazin-8 (6H) -yl) propoxy) propan-2-yl) amino) -4- (trifluoromethyl) pyridazin-3 (2H) -one (Compound 25)
5-(((S)-1-(3-oxo-3-((R)-3-(trifluoromethyl)-6a,7,9,10-tetrahydrodipyrazino[2,3-b:1',2'-d][1,4]oxazin-8(6H)-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one
The first step: (R) -3- (hydroxymethyl) -4- (5- (trifluoromethyl) pyrazin-2-yl) piperazine-1-carboxylic acid tert-butyl ester (25 b)
tert-butyl(R)-3-(hydroxymethyl)-4-(5-(trifluoromethyl)pyrazin-2-yl)piperazine-1-carboxylate
2-chloro-5- (trifluoromethyl) pyrazine (25 a) (1.00 g,5.48 mmol), (R) -3- (hydroxymethyl) piperazine-1-carboxylic acid tert-butyl ester (1.42 g,6.58 mmol), DIPEA (1.42 g,10.96 mmol) were added sequentially to dimethyl sulfoxide (10 mL), reacted at 100℃for 16h, cooled to room temperature after the reaction was completed, the reaction solution was poured into water (150 mL), extracted with ethyl acetate (30 mL. Times.3), the organic phases were combined, backwashed with saturated brine (30 mL. Times.3), dried over anhydrous sodium sulfate, suction filtered, and the filtrate concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate (V/V) =2:1) to give (R) -3- (hydroxymethyl) -4- (5- (trifluoromethyl) pyrazin-2-yl) piperazine-1-carboxylic acid tert-butyl ester (25 b) (1.77 g, 89%).
LCMS m/z＝363.2[M+1] + 。
And a second step of: (R) -4- (3-chloro-5- (trifluoromethyl) pyrazin-2-yl) -3- (hydroxymethyl) piperazine-1-carboxylic acid tert-butyl ester (25 c)
tert-butyl(R)-4-(3-chloro-5-(trifluoromethyl)pyrazin-2-yl)-3-(hydroxymethyl)piperazine-1-carboxylate
To a solution of tert-butyl (R) -3- (hydroxymethyl) -4- (5- (trifluoromethyl) pyrazin-2-yl) piperazine-1-carboxylate (25 b) (200 mg,0.55 mmol) in DMF (2 mL) was added N-chlorosuccinimide (81 mg,0.61 mmol), and after the reaction was completed at room temperature for 16h, the reaction solution was poured into water (20 mL), ethyl acetate (20 mL. Times.3) was extracted, the organic phases were combined, the organic phases were backwashed with saturated brine (20 mL. Times.3), dried over anhydrous sodium sulfate, suction filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V/V) =3:1) to give (R) -4- (3-chloro-5- (trifluoromethyl) pyrazin-2-yl) -3- (hydroxymethyl) piperazine-1-carboxylic acid tert-butyl ester (25 c) (110 mg, 50%).
LCMS m/z＝341.1[M-55] + 。
And a third step of: (R) -3- (trifluoromethyl) -6a,7,9, 10-tetrahydrodipyrazine [2,3-b:1',2' -d ] [1,4] oxazine-8 (6H) -carboxylic acid tert-butyl ester (25 d)
Tert-butyl(R)-3-(trifluoromethyl)-6a,7,9,10-tetrahydrodipyrazino[2,3-b:1',2'-d][1,4]oxazine-8(6H)-carboxylate
To a solution of (R) -4- (3-chloro-5- (trifluoromethyl) pyrazin-2-yl) -3- (hydroxymethyl) piperazine-1-carboxylic acid tert-butyl ester (25 c) (110 mg,0.28 mmol) in DMF (2 mL) was added potassium carbonate (116 mg,0.84 mmol), the reaction was carried out at 100℃for 16h, after the reaction was completed, cooled to room temperature, the reaction solution was poured into water (20 mL), ethyl acetate (20 mL. Times.3) was extracted, the organic phases were combined, the organic phase was backwashed with saturated brine (20 mL. Times.3), dried over anhydrous sodium sulfate, suction filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V/V) =3:1) to give (R) -3- (trifluoromethyl) -6a,7,9, 10-tetrahydrodipyrazine [2,3-b:1',2' -d ] [1,4] oxazine-8 (6H) -carboxylic acid tert-butyl ester (25 d) (61 mg, 60%).
LCMS m/z＝361.2[M+1] + 。
Fourth step: hydrochloride of (R) -3- (trifluoromethyl) -6,6a,7,8,9, 10-hexahydro-bipyrazine [2,3-b:1',2' -d ] [1,4] oxazine (25 e)
(R)-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydrodipyrazino[2,3-b:1',2'-d][1,4]oxazine hydrochloride
Tert-butyl (R) -3- (trifluoromethyl) -6a,7,9, 10-tetrahydrobipyrazine [2,3-b:1',2' -d ] [1,4] oxazine-8 (6H) -carboxylate (25 d) (61 mg,0.17 mmol) was added to a solution of 1, 4-dioxane (5 mL, 4N) of hydrogen chloride, reacted at room temperature for 1H, and after completion of the reaction, concentrated under reduced pressure to give crude hydrochloride (53 mg) of (R) -3- (trifluoromethyl) -6,6a,7,8,9, 10-hexahydrobipyrazine [2,3-b:1',2' -d ] [1,4] oxazine (25 e) which was directly used in the next reaction.
LCMS m/z＝261.1[M+1] + 。
Fifth step: 5- (((S) -1- (3-oxo-3- ((R) -3- (trifluoromethyl) -6a,7,9, 10-tetrahydrodipyrazine [2,3-b:1',2' -d ] [1,4] oxazin-8 (6H) -yl) propoxy) propan-2-yl) amino) -4- (trifluoromethyl) pyridazin-3 (2H) -one (Compound 25)
5-(((S)-1-(3-oxo-3-((R)-3-(trifluoromethyl)-6a,7,9,10-tetrahydrodipyrazino[2,3-b:1',2'-d][1,4]oxazin-8(6H)-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one
(R) -3- (trifluoromethyl) -6,6a,7,8,9, 10-hexahydro-bipyrazine [2,3-b:1',2' -d][1,4]Hydrochloride (53 mg, crude) of oxazine (25 e), 3- [ (2S) -2- [ (6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino]Propoxy group]Propionic acid (4 j) (56 mg,0.18 mmol), HATU (68 mg,0.18 mmol) and DIPEA (116 mg,0.90 mmol) were added sequentially to DMF (2 mL) and reacted at room temperature for 1h. After the reaction, the reaction mixture was purified by Pre-HPLC (instrument and preparation column: preparation of liquid phase by Waters 2767, preparation column model is Sunfire@Prep C 18 5 μm, inner diameter x length = 19mm x 250 mm). The preparation method comprises the following steps: the reaction solution was filtered through a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: acetonitrile/water (0.1% ammonia). The gradient elution method comprises the following steps: acetonitrile was eluted from a 5% gradient to 50% (flow rate: 15mL/min; elution time: 15 min), and after lyophilization 5- (((S) -1- (3-oxo-3- ((R) -3- (trifluoromethyl) -6a,7,9, 10-tetrahydrodipyrazine [2,3-b:1',2' -d)][1,4]Oxazin-8 (6H) -yl) propoxy) propan-2-yl) amino) -4- (trifluoromethyl) pyridazin-3 (2H) -one (compound 2 5) (30 mg, 30%).
LCMS m/z＝552.2[M+1] + 。
1 H NMR(400MHz,DMSO-d 6 )δ12.43(s,1H),8.16(s,1H),7.90(s,1H),6.32-6.18(m,1H),4.66-4.54(m,1H),4.53-4.33(m,2H),4.24-3.98(m,3H),3.75-3.61(m,3H),3.49(d,2H),3.24-2.73(m,3H),2.66-2.58(m,2H),1.15(d,3H)。
Example 26:5- (((S) -1- (3-oxo-3- ((S) -3- (trifluoromethyl) -6a,7,9, 10-tetrahydrodipyrazine [2,3-b:1',2' -d ] [1,4] oxazin-8 (6H) -yl) propoxy) propan-2-yl) amino) -4- (trifluoromethyl) pyridazin-3 (2H) -one (Compound 26)
5-(((S)-1-(3-oxo-3-((S)-3-(trifluoromethyl)-6a,7,9,10-tetrahydrodipyrazino[2,3-b:1',2'-d][1,4]oxazin-8(6H)-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one
Compound 26 using 2-chloro-5- (trifluoromethyl) pyrazine (25 a) and (S) -3- (hydroxymethyl) piperazine-1-carboxylic acid tert-butyl ester as starting material, the synthesis procedure of example 25 was followed to give 5- (((S) -1- (3-oxo-3- ((S) -3- (trifluoromethyl) -6a,7,9, 10-tetrahydrobipyrazine [2,3-b:1',2' -d ] [1,4] oxazin-8 (6H) -yl) propoxy) propan-2-yl) amino) -4- (trifluoromethyl) pyridazin-3 (2H) -one (compound 26).
LCMS m/z＝552.2[M+1] + 。
1 H NMR(400MHz,DMSO-d 6 )δ12.43(s,1H),8.16(s,1H),7.90(s,1H),6.29-6.21(m,1H),4.67-4.32(m,3H),4.26-3.98(m,3H),3.77-3.61(m,3H),3.49(d,2H),3.22-2.68(m,3H),2.66-2.57(m,2H),1.15(d,3H)。
Example 27: (R) -5-ethyl-8- (3- ((S) -2- ((6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino) propoxy) propanoyl) -3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-pyrazin [1,2-a ] pyridine [3,2-e ] pyrazin-6 (6 aH) -one (Compound 27)
(R)-5-ethyl-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one
The first step: (R) -5-methyl-6-oxo-3- (trifluoromethyl) -5, 6a,7,9, 10-hexahydro-8H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazine-8-carboxylic acid tert-butyl ester (27 b)
Tert-butyl(R)-5-ethyl-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8-carboxylate
(R) -6-oxo-3- (trifluoromethyl) -5, 6a,7,9, 10-hexahydro-8H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazine-8-carboxylic acid tert-butyl ester (4 d) (100 mg,0.27 mmol), potassium carbonate (112 mg,0.81 mmol) was added to DMF (2 mL) followed by iodoethane (84 mg,0.54 mmol) at room temperature. After the reaction was completed at room temperature for 16 hours, the reaction mixture was poured into water (20 mL), extracted with ethyl acetate (20 ml×3), and the organic phases were combined, backwashed with saturated brine (20 ml×3), dried over anhydrous sodium sulfate, suction-filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V/V) =3:1) to give (R) -5-methyl-6-oxo-3- (trifluoromethyl) -5, 6a,7,9, 10-hexahydro-8H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazine-8-carboxylic acid tert-butyl ester (27 b) (120 mg, 100%).
LCMS m/z＝345.1[M-55] + 。
And a second step of: hydrochloride of (R) -5-ethyl-3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-pyrazin [1,2-a ] pyridine [3,2-e ] pyrazin-6 (6 aH) -one (27 c)
(R)-5-ethyl-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one hydrochloride
(R) -5-methyl-6-oxo-3- (trifluoromethyl) -5, 6a,7,9, 10-hexahydro-8H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazine-8-carboxylic acid tert-butyl ester (27 b) (120 mg,0.30 mmol) was added to a solution of 1, 4-dioxane (5 mL, 4N) of hydrogen chloride, reacted at room temperature for 1H, after the reaction was completed, the solvent was removed by concentration under reduced pressure to give crude (R) -5-ethyl-3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-pyrazin [1,2-a ] pyridin [3,2-e ] pyrazin-6 (6 aH) -one (27 c) hydrochloride (100 mg) which was directly used in the next step.
LCMS m/z＝301.1[M+1] + 。
And a third step of: (R) -5-ethyl-8- (3- ((S) -2- ((6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino) propoxy) propanoyl) -3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-pyrazin [1,2-a ] pyridine [3,2-e ] pyrazin-6 (6 aH) -one (Compound 27)
(R)-5-ethyl-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one
(R) -5-ethyl-3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-pyrazine [1,2-a]Pyridine [3,2-e]Hydrochloride (91 mg, crude) of pyrazin-6 (6 aH) -one (27 c), 3- [ (2S) -2- [ (6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino]Propoxy group]Propionic acid (4 j) (84 mg,0.27 mmol), HATU (100 mg,0.27 mmol) and DIPEA (170 mg,1.35 mmol) were added sequentially to DMF (2 mL) and reacted at room temperature for 1h. After the reaction, the reaction mixture was purified by Pre-HPLC (instrument and preparation column: preparation of liquid phase by Waters 2767, preparation column model is Sunfire@Prep C 18 5 μm, inner diameter x length = 19mm x 250 mm). The preparation method comprises the following steps: the reaction solution was filtered through a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: acetonitrile/water (0.1% ammonia). The gradient elution method comprises the following steps: acetonitrile was eluted from 5% gradient to 50% (flow rate: 15mL/min; elution time)15 min), and lyophilizing to give (R) -5-ethyl-8- (3- ((S) -2- ((6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino) propoxy) propionyl) -3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-pyrazine [1, 2-a) ]Pyridine [3,2-e]Pyrazin-6 (6 aH) -one (compound 27) (40 mg, 25%).
LCMS m/z＝592.2[M+1] + 。
1 H NMR(400MHz,CD 3 OD)δ8.14(d,1H),7.92(d,1H),7.43(s,1H),5.15-4.58(m,2H),4.55-3.93(m,5H),3.86-3.72(m,2H),3.64-3.57(m,1H),3.54-3.46(m,1H),3.28-2.62(m,5H),1.29-1.19(m,6H)。
Example 28: (R) -5-cyclopropylmethyl-8- (3- ((S) -2- ((6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino) propoxy) propanoyl) -3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-pyrazin [1,2-a ] pyridine [3,2-e ] pyrazin-6 (6 aH) -one (Compound 28)
(R)-5-(cyclopropylmethyl)-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one
The first step: (R) -5-cyclopropylmethyl-6-oxo-3- (trifluoromethyl) -5, 6a,7,9, 10-hexahydro-8H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazine-8-carboxylic acid tert-butyl ester (28 b)
tert-butyl(R)-5-(cyclopropylmethyl)-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8-carboxylate
(R) -6-oxo-3- (trifluoromethyl) -5, 6a,7,9, 10-hexahydro-8H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazine-8-carboxylic acid tert-butyl ester (4 d) (100 mg,0.27 mmol), potassium carbonate (112 mg,0.81 mmol) was added to DMF (2 mL) followed by (iodomethyl) cyclopropane (74 mg,0.41 mmol) at room temperature. After the reaction was completed at room temperature for 16 hours, the reaction mixture was poured into water (20 mL), extracted with ethyl acetate (20 ml×3), and the organic phases were combined, backwashed with saturated brine (20 ml×3), dried over anhydrous sodium sulfate, suction-filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V/V) =3:1) to give (R) -5-cyclopropylmethyl-6-oxo-3- (trifluoromethyl) -5, 6a,7,9, 10-hexahydro-8H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazine-8-carboxylic acid tert-butyl ester (28 b) (120 mg, 100%).
LCMS m/z＝427.2[M+1] + 。
And a second step of: hydrochloride of (R) -5-cyclopropylmethyl-3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-pyrazin [1,2-a ] pyridine [3,2-e ] pyrazin-6 (6 aH) -one (28 c)
(R)-5-(cyclopropylmethyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one hydrochloride
(R) -5-cyclopropylmethyl-6-oxo-3- (trifluoromethyl) -5, 6a,7,9, 10-hexahydro-8H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazine-8-carboxylic acid tert-butyl ester (28 b) (120 mg,0.28 mmol) was added to a solution of 1, 4-dioxane (5 mL, 4N) of hydrogen chloride, reacted at room temperature for 1H, after completion of the reaction, the solvent was removed by concentration under reduced pressure to give (R) -5-cyclopropylmethyl-3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-pyrazine [1,2-a ] pyrido [3,2-e ] pyrazin-6 (6 aH) -one (28 c) hydrochloride (100 mg, crude product) which was used directly in the next step.
LCMS m/z＝327.1[M+1] + 。
And a third step of: (R) -5-cyclopropylmethyl-8- (3- ((S) -2- ((6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino) propoxy) propanoyl) -3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-pyrazin [1,2-a ] pyridine [3,2-e ] pyrazin-6 (6 aH) -one (Compound 28)
(R)-5-(cyclopropylmethyl)-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one
(R) -5-cyclopropylmethyl-3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-pyrazine [1,2-a]Pyridine [3,2-e]Hydrochloride (98 mg, crude) of pyrazin-6 (6 aH) -one (28 c), 3- [ (2S) -2- [ (6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino]Propoxy group]Propionic acid (4 j) (84 mg,0.27 mmol), HATU (100 mg,0.27 mmol) and DIPEA (17 0mg,1.35 mmol) were added sequentially to DMF (2 mL) and reacted at room temperature for 1h. After the reaction, the reaction mixture was purified by Pre-HPLC (instrument and preparation column: preparation of liquid phase by Waters 2767, preparation column model is Sunfire@Prep C 18 5 μm, inner diameter x length = 19mm x 250 mm). The preparation method comprises the following steps: the reaction solution was filtered through a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: acetonitrile/water (0.1% ammonia). The gradient elution method comprises the following steps: acetonitrile was eluted from a 5% gradient to 50% (flow rate: 15mL/min; elution time: 15 min), and lyophilized to give (R) -5-cyclopropylmethyl-8- (3- ((S) -2- ((6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino) propoxy) propionyl) -3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-pyrazine [1,2-a ]]Pyridine [3,2-e]Pyrazin-6 (6 aH) -one (compound 28) (40 mg, 24%).
LCMS m/z＝618.2[M+1] + 。
1 H NMR(400MHz,DMSO-d 6 )δ12.42(s,1H),8.21(s,1H),7.90(s,1H),7.63(s,1H),6.30-6.17(m,1H),4.90-4.42(m,2H),4.36-3.86(m,5H),3.75-3.63m,2H),3.49(d,2H),3.25-3.09(m,1H),2.87-2.58(m,4H),1.15(d,3H),1.11-0.99(m,1H),0.53-0.26(m,4H)。
Example 29:5- (((2S) -1- (3-oxo-3- (3- (trifluoromethyl) -5, 6a,7,9, 10-hexahydro-8H-pyrazino [1,2-a ] [1,8] naphthyridin-8-yl) propoxy) propan-2-yl) amino) -4- (trifluoromethyl) pyridazin-3 (2H) -one (Compound 29)
5-(((2S)-1-(3-oxo-3-(3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a][1,8]naphthyridin-8-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one
The first step: 4- (tert-butyl) 2- (hydroxymethyl) piperazine-1, 4-dicarboxylic acid 1-benzyl ester (29 b)
benzyl 4-(tert-butyl)2-(hydroxymethyl)piperazine-1,4-dicarboxylate
1-benzyl 4- (tert-butyl) 2-methyl-piperazine-1, 2, 4-tricarboxylic acid ester (29 a) (5.3 g,14.01 mmol) was dissolved in THF (30 mL) at room temperature, etOH (30 mL), naBH were added 4 (0.79 g,21.02 mmol) and LiCl (0.89 g,21.02 mmol), the mixture was stirred at room temperature overnight, the reaction solution was poured into water (50 mL), ethyl acetate (50 mL. Times.3) was extracted, the organic phases were combined, the organic phases were backwashed with saturated brine (30 mL. Times.3), dried over anhydrous sodium sulfate, suction filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (30% ea in PE) to give: (4- (tert-butyl) 2- (hydroxymethyl) piperazine-1, 4-dicarboxylic acid 1-benzyl ester (29 b) (3 g, 61%).
LCMS m/z＝251.1[M-99] + 。
And a second step of: 1-benzyl 4- (tert-butyl) 2-formylpiperazine-1, 4-dicarboxylic acid ester (29 c)
1-benzyl 4-(tert-butyl)2-formylpiperazine-1,4-dicarboxylate
After completion of the reaction, water was added to quench the reaction for 4 hours under ice bath, ethyl acetate (50 mL. Times.3) was extracted, the organic phases were combined, backwashed with saturated brine (30 mL. Times.3) and dried over anhydrous sodium sulfate, suction filtered, and the filtrate was concentrated under reduced pressure to give the residue which was purified by silica gel column chromatography (20% EA in PE) to give 1-benzyl 4- (tert-butyl) 2-formylpiperazine-1, 4-dicarboxylic acid ester (29 c) (3 g, 77%).
LCMS m/z＝293.1[M-55] + 。
And a third step of: 1-benzyl 4- (tert-butyl) 2-vinylpiperazine-1, 4-dicarboxylic acid ester (29 d)
1-benzyl 4-(tert-butyl)2-vinylpiperazine-1,4-dicarboxylate
Methyl triphenylphosphine bromide (4.61 g,12.91 mmol) was dissolved in THF (60 mL) at room temperature, nitrogen was displaced 3 times, the mixture was cooled to-78deg.C, n-BuLi (6.88 mL,10.33mmol, 1.5M) was added dropwise, stirring was completed at this temperature for 1h, 1-benzyl 4- (tert-butyl) 2-formylpiperazine-1, 4-dicarboxylic acid ester (29 c) (3 g,8.61 mmol) was added, and the reaction was carried out at-78deg.C for 2h. The reaction was quenched with water, extracted with ethyl acetate (50 mL. Times.3), the organic phases were combined, backwashed with saturated brine (30 mL. Times.3), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (15% ea in PE) to give: 1-benzyl 4- (tert-butyl) 2-vinylpiperazine-1, 4-dicarboxylic acid ester (29 d) (1.8 g, 60%).
LCMS m/z＝247.2[M-99] + 。
Fourth step: 1-benzyl 4- (tert-butyl) -2- (2- (2-hydroxy-5- (trifluoromethyl) pyridin-3-yl) vinyl) piperazine-1, 4-dicarboxylic acid ester (compound 29 e)
1-benzyl 4-(tert-butyl)-2-(2-(2-hydroxy-5-(trifluoromethyl)pyridin-3-yl)vinyl)piperazine-1,4-dicarboxylate
1-benzyl 4- (tert-butyl) 2-vinyl piperazine-1, 4-dicarboxylic acid ester (29 d) (200 mg,0.58 mmol) was dissolved in DMF (6 mL) at room temperature, 3-bromo-2-fluoro-5- (trifluoromethyl) pyridine (210 mg,0.87 mmol) was added, K 2 CO 3 (240 mg,1.74 mmol), xphos (110 mg,0.23 mmol) and Pd (OAc) 2 (26 mg,0.12 mmol). The reaction mixture was stirred overnight at 100deg.C, quenched with water, extracted with ethyl acetate (10 mL. Times.3), the organic phases were combined, backwashed with saturated brine (10 mL. Times.3), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (30% ea in PE) to give: 1-benzyl 4- (tert-butyl) -2- (2- (2-hydroxy-5- (trifluoromethyl) pyridin-3-yl) vinyl) piperazine-1, 4-dicarboxylic acid ester (compound 29 e) (38 mg, 13%) was added in parallel to 9 pans to give a total of 340mg.
LCMS m/z＝452.0[M-55] + 。
Fifth step: 3- (2- (2-hydroxy-5- (trifluoromethyl) pyridin-3-yl) ethyl) piperazine-1-carboxylic acid tert-butyl ester (Compound 29 f)
Tert-butyl 3-(2-(2-hydroxy-5-(trifluoromethyl)pyridin-3-yl)ethyl)piperazine-1-carboxylate
1-benzyl 4- (tert-butyl) -2- (2- (2-hydroxy-5- (trifluoromethyl) pyridin-3-yl) vinyl) piperazine-1, 4-dicarboxylate (compound 29 e) (150 mg,0.3 mmol) was dissolved in MeOH (5 mL) at room temperature, pd/C (15 mg) was added, the reaction was stirred at room temperature overnight, filtered, and concentrated to give tert-butyl 3- (2- (2-hydroxy-5- (trifluoromethyl) pyridin-3-yl) ethyl) piperazine-1-carboxylate (compound 29 f) (100 mg, crude product) without further purification, which was directly added to the next step. A total of 200mg was obtained by adding two pots in parallel.
LCMS m/z＝376.2[M+1] + 。
Sixth step: 3- (trifluoromethyl) -5, 6a,7,9, 10-hexahydro-8H-pyrazino [1,2-a ] [1,8] naphthyridine-8-carboxylic acid tert-butyl ester (Compound 29 g)
Tert-butyl 3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a][1,8]naphthyridine-8-carboxylate
3- (2- (2-hydroxy-5- (trifluoromethyl) pyridin-3-yl) ethyl) piperazine-1-carboxylic acid tert-butyl ester (compound 29 f) (110 mg,0.29 mmol) was dissolved in DMSO (5 mL) at room temperature and PyBOP (150 mg,0.29 mmol) and DIPEA (37 mg,0.29 mmol) were added. Stirring overnight at 60deg.C, quenching with water, extracting with ethyl acetate (10mL×3), mixing the organic phases, backwashing the organic phases with saturated saline (10mL×3), drying over anhydrous sodium sulfate, suction filtering, and concentrating the filtrate under reduced pressure to obtain residue. The residue was purified by column chromatography on silica gel (10% ea in PE) to give: 3- (trifluoromethyl) -5, 6a,7,9, 10-hexahydro-8H-pyrazino [1,2-a ] [1,8] naphthyridine-8-carboxylic acid tert-butyl ester (Compound 29 g) (80 mg, 77%).
LCMS m/z＝358.2[M+1] + 。
Seventh step: hydrochloride of 3- (trifluoromethyl) -6,6a,7,8,9, 10-hexahydro-5H-pyrazino [1,2-a ] [1,8] naphthyridine (Compound 29H)
3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a][1,8]naphthyridine hydrochloride
3- (trifluoromethyl) -5, 6a,7,9, 10-hexahydro-8H-pyrazino [1,2-a ] [1,8] naphthyridine-8-carboxylic acid tert-butyl ester (compound 29 g) (80 mg,0.22 mmol) was dissolved in hydrogen chloride/1, 4-dioxane solution (4.0M, 2mL,8 mmol) at room temperature and reacted to completion at room temperature. The solvent was removed by concentration under reduced pressure to give the hydrochloride salt of 3- (trifluoromethyl) -6,6a,7,8,9, 10-hexahydro-5H-pyrazino [1,2-a ] [1,8] naphthyridine (compound 29H) (65.0 mg, crude product) which was used directly in one step without further purification.
LCMS m/z＝258.2[M+1] + 。
Eighth step: 5- (((2S) -1- (3-oxo-3- (3- (trifluoromethyl) -5, 6a,7,9, 10-hexahydro-8H-pyrazino [1,2-a ] [1,8] naphthyridin-8-yl) propoxy) propan-2-yl) amino) -4- (trifluoromethyl) pyridazin-3 (2H) -one (Compound 29)
5-(((2S)-1-(3-oxo-3-(3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a][1,8]naphthyridin-8-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one
Hydrochloride (65 mg, crude) of 3- (trifluoromethyl) -6,6a,7,8,9, 10-hexahydro-5H-pyrazino [1,2-a ] [1,8] naphthyridine (compound 29H) and 3- [ (2S) -2- [ (6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino ] propoxy ] propionic acid (4 j) (68 mg,0.22 mmol) were dissolved in DMF (2 mL), DIPEA (85 mg,0.66 mmol) and HATU (84 mg,0.22 mmol) were added thereto, respectively, and then the reaction was stirred at room temperature for 3 hours. After the reaction was completed, the reaction solution was purified by Pre-HPLC (instrument and preparation column: preparation of liquid phase using WATERS 2767, preparation column model: xselect C18,5 μm, inner diameter×length=19 mm×150 mm). The preparation method comprises the following steps: the reaction solution was filtered through a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: acetonitrile/water (0.05% ammonia). The gradient elution method comprises the following steps: acetonitrile was eluted from 5% gradient to 50% (elution time 15 min). After lyophilization, 5- (((2S) -1- (3-oxo-3- (3- (trifluoromethyl) -5, 6a,7,9, 10-hexahydro-8H-pyrazino [1,2-a ] [1,8] naphthyridin-8-yl) propoxy) propan-2-yl) amino) -4- (trifluoromethyl) pyridazin-3 (2H) -one (Compound 29) (80 mg, 66% yield)
LCMS m/z＝549.2[M+1] + 。
Example 30:5- (((S) -1- (3-oxo-3- ((S) -3- (trifluoromethyl) -5, 6a,7,9, 10-hexahydro-8H-pyrazino [1,2-a ] [1,8] naphthyridin-8-yl) propoxy) propan-2-yl) amino) -4- (trifluoromethyl) pyridazin-3 (2H) -one (Compound 30 a)
5-(((S)-1-(3-oxo-3-((S)-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a][1,8]naphthyridin-8-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one
5- (((S) -1- (3-oxo-3- ((R) -3- (trifluoromethyl) -5, 6a,7,9, 10-hexahydro-8H-pyrazino [1,2-a ] [1,8] naphthyridin-8-yl) propoxy) propan-2-yl) amino) -4- (trifluoromethyl) pyridazin-3 (2H) -one (Compound 30 b)
5-(((S)-1-(3-oxo-3-((R)-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a][1,8]naphthyridin-8-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one
Compound 29 (70 mg,0.13 mmol) was purified by SFC on AD Column (apparatus and preparation Column: using Waters 150mgm, preparation Column model: chiralpak Column). The preparation method comprises the following steps: compound 29 was dissolved in acetonitrile to prepare a sample solution. Mobile phase system: afor CO 2 and B for MeOH(0.1％NH 3 ·H 2 O). The gradient elution method comprises the following steps: 30% phase B (flow rate: 110mL/min; elution time 3.3 min), compound P1 (20 mg) and Compound P2 (33.6 mg) were obtained after lyophilization.
Analytical method (instrument and preparation column: SHIMADZULC-30AD sf, preparation column model: chiralpak AD-3.50X4.6 mm I.D. Mobile phase System: A for CO) 2 and B for MeOH(0.05％DEA)，3.0ml/min。
Retention time t=2.03 min is compound P1 (compound P1 is one of the structures of compound 30a and compound 30 b).
LCMS m/z＝549.2[M+1] + 。
1 H NMR(400MHz,CDCl 3 )δ10.46-10.25(m,1H),8.25(s,1H),7.65(s,1H),7.43-7.32(m,1H),5.88-5.70(m,1H),5.03-4.83(m,1H),4.72-4.55(m,1H),3.99-3.78(m,4H),3.71-3.61(m,1H),3.54-3.45(m,1H),3.44-2.77(m,5H),2.73-2.42(m,3H),2.19-2.04(m,1H),1.81-1.71(m,1H),1.30(d,3H)。
Retention time t= 2.245min is compound P2 (compound P2 is one of the structures of compound 30a and compound 30 b).
LCMS m/z＝549.2[M+1] + 。
1 H NMR(400MHz,CDCl 3 )δ10.34(s,1H),8.25(s,1H),7.66(s,1H),7.44-7.3 2(m,1H),5.90-5.70(m,1H),5.03-4.83(m,1H),4.73-4.54(m,1H),3.99-3.76(m,4H),3.71-3.57(m,1H),3.56-3.45(m,1H),3.44-2.77(m,5H),2.73-2.45(m,3H),2.23-2.04(m,1H),1.81-1.68(m,1H),1.30(d,3H)。
Example 31:5- ((S) -1- (3- ((R) -5-methyl-6-sulfanyl-3- (trifluoromethyl) -5, 6a,7,9, 10-hexahydro-8H-pyrazin [1,2-a ] pyridin [3,2-e ] pyrazin-8-yl) -3-oxypropoxy-2-yl) amino) -4- (trifluoromethyl) pyrazin-3 (2H) -one (Compound 31)
5-(((S)-1-(3-((R)-5-methyl-6-thioxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-8-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one
The first step: (R) -3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-pyrazin [1,2-a ] pyridinyl [3,2-e ] pyrazin-6 (6 aH) -one hydrochloride (31 a)
(R)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one
Tert-butyl (R) -6-oxo-3- (trifluoromethyl) -5, 6a,7,9, 10-hexahydro-8H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazine-8-carboxylate (4 d) (2 g,5.38 mmol) was dissolved in 1, 4-dioxane (30 mL) solution at room temperature, and then hydrogen chloride/1, 4-dioxane solution (4.0M, 30mL,40 mmol) was added to react for 4 hours at room temperature. After the reaction was completed, the solvent was removed by concentration under reduced pressure to give (R) -3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-pyrazin [1,2-a ] pyridinyl [3,2-e ] pyrazin-6 (6 aH) -one (31 a) hydrochloride (1.46 g, crude product) which was used directly in the next step.
LCMS m/z＝273.1[M+1] + 。
And a second step of: 2- (trimethylsilyl) ethyl (R) -6-oxo-3- (trifluoromethyl) -5, 6a,7,9, 10-hexahydro-8H-pyrazin [1,2-a ] pyridine [3,2-e ] pyrazine-8-carboxylic acid ester (31 b)
2-(trimethylsilyl)ethyl(R)-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8-carboxylate
(R) -3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-pyrazin [1,2-a ] pyridinyl [3,2-e ] pyrazin-6 (6 aH) -one (31 a) hydrochloride (1.46 g, crude), N- [2- (trimethylsilyl) ethoxycarbonyloxy ] succinimide (1.4 g,5.38 mmol), triethylamine (1.76 g,16.13 mmol) were dissolved in tetrahydrofuran (50 mL) at room temperature and reacted for one hour. The reaction was quenched with water (50 mL), extracted with ethyl acetate (50 mL. Times.2), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give the crude product. The crude product was purified by preparative column separation (petroleum ether: ethyl acetate (v/v) =8:1) to give 2- (trimethylsilyl) ethyl (R) -6-oxo-3- (trifluoromethyl) -5, 6a,7,9, 10-hexahydro-8H-pyrazine [1,2-a ] pyridine [3,2-e ] pyrazine-8-carboxylate (31 b) (1.9 g, 85%).
LCMS m/z＝415.1[M-1] - 。
And a third step of: 2- (trimethylsilyl) ethyl (R) -6-thio-3- (trifluoromethyl) -5, 6a,7,9, 10-hexahydro-8H-pyrazin [1,2-a ] pyridine [3,2-e ] pyrazine-8-carboxylic acid ester (Compound 31 c)
2-(trimethylsilyl)ethyl(R)-6-thioxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8-carboxylate
2- (trimethylsilyl) ethyl (R) -6-oxo-3- (trifluoromethyl) -5, 6a,7,9, 10-hexahydro-8H-pyrazin [1,2-a ] pyridine [3,2-e ] pyrazine-8-carboxylate (31 b) (3.4 g,8.17 mmol) and Lawson reagent (6.8 g,16.83 mmol) were dissolved in tetrahydrofuran (100 mL) at room temperature and reacted with stirring at 60℃for 3 hours. After the reaction is finished, the crude product is obtained after decompression and concentration. The crude product was purified by column separation (petroleum ether: ethyl acetate (v/v) =8:1) to give 2- (trimethylsilyl) ethyl (R) -6-thio-3- (trifluoromethyl) -5, 6a,7,9, 10-hexahydro-8H-pyrazine [1,2-a ] pyridine [3,2-e ] pyrazine-8-carboxylate (compound 31 c) (1.95 g, 55%).
LCMS m/z＝431.1[M-1] - 。
Fourth step: 2- (trimethylsilyl) ethyl (R) -5-methyl-6-thio-3- (trifluoromethyl) -5, 6a,7,9, 10-hexahydro-8H-pyrazin [1,2-a ] pyridine [3,2-e ] pyrazine-8-carboxylic acid ester (31 d)
2-(trimethylsilyl)ethyl(R)-5-methyl-6-thioxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8-carboxylate
2- (trimethylsilyl) ethyl (R) -6-thio-3- (trifluoromethyl) -5, 6a,7,9, 10-hexahydro-8H-pyrazin [1,2-a ] pyridine [3,2-e ] pyrazine-8-carboxylate (compound 31 c) (300 mg,0.69 mmol) was dissolved in DMF (5 mL) at room temperature, and potassium carbonate (288 mg,2.08 mmol) was added. The reaction was stirred at room temperature for 2 hours. After completion of the reaction, saturated brine (20 mL) was added thereto, and ethyl acetate (20 mL. Times.2) was added thereto for extraction. The organic phases were combined, washed with saturated brine (20 ml x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product. The crude product was isolated and purified by preparative column (petroleum ether: ethyl acetate (v/v) =8:1) to give 2- (trimethylsilyl) ethyl (R) -5-methyl-6-thio-3- (trifluoromethyl) -5, 6a,7,9, 10-hexahydro-8H-pyrazine [1,2-a ] pyridine [3,2-e ] pyrazine-8-carboxylate (31 d) (261 mg, 85%).
LCMS m/z＝447.1[M+1] + 。
Fifth step: (R) -5-methyl-3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-pyrazin [1,2-a ] pyridine [3,2-e ] pyrazin-6 (6 aH) -thione (31 e)
(R)-5-methyl-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-6(6aH)-thione
2- (trimethylsilyl) ethyl (R) -5-methyl-6-thio-3- (trifluoromethyl) -5, 6a,7,9, 10-hexahydro-8H-pyrazin [1,2-a ] pyridine [3,2-e ] pyrazine-8-carboxylate (31 d) (261 mg,0.59 mmol) was dissolved in tetrahydrofuran (3 mL) solution, tetrabutylammonium fluoride-tetrahydrofuran solution (1.0M, 3mL,3.00 mmol) was added and reacted at room temperature for 4 hours. After the reaction, concentrating under reduced pressure to remove the solvent to obtain a crude product, and separating and purifying the crude product by a preparation column (petroleum ether: ethyl acetate (v/v) =1:8) to obtain (R) -5-methyl-3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-pyrazine [1,2-a ] pyridine [3,2-e ] pyrazine-6 (6 aH) -thione (31 e) (87 mg, 49%).
LCMS m/z＝303.1[M+1] + 。
Sixth step: 5- ((S) -1- (3- ((R) -5-methyl-6-sulfanyl-3- (trifluoromethyl) -5, 6a,7,9, 10-hexahydro-8H-pyrazin [1,2-a ] pyridin [3,2-e ] pyrazin-8-yl) -3-oxypropoxy-2-yl) amino) -4- (trifluoromethyl) pyrazin-3 (2H) -one (Compound 31)
5-(((S)-1-(3-((R)-5-methyl-6-thioxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-8-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one
3- [ (2S) -2- [ (6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino ] propoxy ] propionic acid (4 j) (81 mg,0.26 mmol) and (R) -5-methyl-3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-pyrazin [1,2-a ] pyridine [3,2-e ] pyrazine-6 (6 aH) -thione (31 e) (80 mg,0.26 mmol) were dissolved in DMF (3 mL), DIPEA (102 mg,0.79 mmol) and HATU (101 mg,0.26 mmol) were added thereto, respectively, and then reacted by stirring at room temperature for 3 hours. After the reaction was completed, the reaction solution was purified by Pre-HPLC (instrument and preparation column: preparation of liquid phase using WATERS 2767, preparation column model: xselect C18,5 μm, inner diameter×length=19 mm×150 mm). The preparation method comprises the following steps: the reaction solution was filtered through a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: acetonitrile/water (0.05% ammonia). The gradient elution method comprises the following steps: acetonitrile was eluted from 5% gradient to 50% (elution time 15 min). After lyophilization, 5- ((S) -1- (3- ((R) -5-methyl-6-sulfanyl-3- (trifluoromethyl) -5, 6a,7,9, 10-hexahydro-8H-pyrazin [1,2-a ] pyridin [3,2-e ] pyrazin-8-yl) -3-oxypropoxy-2-yl) amino) -4- (trifluoromethyl) pyrazin-3 (2H) -one (compound 31) (20 mg, 12%).
LCMS m/z＝594.3[M+1] + 。
1 H NMR(400MHz,DMSO-d 6 )δ12.43(s,1H),8.21(s,1H),7.90(s,1H),7.52-7.48(m,1H),6.31-6.19(m,1H),4.70-4.58(m,2H),4.50-4.34(m,1H),4.21-4.09(m,1H),4.04-3.87(m,1H),3.73-3.60(m,2H),3.57-3.45(m,2H),3.43-3.05(m,1H),2.93-2.56(m,4H),2.51(s,3H),1.15(d,3H)。
Example 32:5- ((S) -1- (3- ((R) -3-chloro-5-methyl-6-sulfanyl-5, 6a,7,9, 10-hexahydro-8H-pyrazin [1,2-a ] pyrazin [3,2-e ] pyrazin-8-yl) -3-oxypropoxy) propan-2-yl) amino) -4- (trifluoromethyl) pyrazin-3 (2H) -one (Compound 32)
5-(((S)-1-(3-((R)-3-chloro-5-methyl-6-thioxo-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-8-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one
Compound 32 Synthesis of example 31 from 2, 5-dichloro-3-nitropyridine and (3R) -piperazine-1-carboxylic acid tert-butyl ester-3-carboxylic acid methyl ester (4 b) gave 5- ((S) -1- (3- ((R) -3-chloro-5-methyl-6-thio-5, 6a,7,9, 10-hexahydro-8H-pyrazine [1,2-a ] pyridine [3,2-e ] pyrazin-8-yl) -3-oxypropoxy) propan-2-yl) amino) -4- (trifluoromethyl) pyrazin-3 (2H) -one (Compound 32)
LCMS m/z＝560.1[M+1] + 。
1 H NMR(400MHz,DMSO-d 6 )δ12.43(s,1H),7.96-7.85(m,2H),7.40(d,1H),6.34-6.16(m,1H),4.65-4.42(m,2H),4.39-4.24(m,1H),4.20-4.07(m,1H),4.00-3.83(m,1H),3.76-3.60(m,2H),3.54-3.44(m，2H),3.35-3.04(m,1H),2.86-2.55(m,4H),2.49(s,3H),1.15(d,3H)。
Example 33: (R) -5-isobutyl-8- (3- ((S) -2- ((6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino) propoxy) propanoyl) -3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-pyrazino [1,2-a ] pyrido [3,2-E ] pyrazin-6- (6 aH) -one (Compound 33)
(R)-5-isobutyl-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one
The first step: tert-butyl (R) -5-isobutyl-6-oxo-3- (trifluoromethyl) -5, 6a,7,9, 10-hexahydro-8H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazine-8-carboxylic acid ester (33 a)
tert-butyl-(R)-5-isobutyl-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8-carboxylate
Tert-butyl (R) -6-oxo-3- (trifluoromethyl) -5, 6a,7,9, 10-hexahydro-8H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazine-8-carboxylate (4 d) (110 mg,0.30 mmol) and iodoisobutane (83 mg,0.45 mmol) were dissolved in DMF (5 mL) at room temperature, potassium carbonate (210 mg,0.91 mmol) was added. The reaction solution was stirred at room temperature for 16 hours. After completion of the reaction, saturated brine (20 mL) was added thereto, and ethyl acetate (20 mL. Times.2) was added thereto for extraction. The organic phases were combined, washed with saturated brine (20 ml x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product. The crude product was purified by column separation (petroleum ether: ethyl acetate (v/v) =8:2) to give tert-butyl (R) -5-isobutyl-6-oxo-3- (trifluoromethyl) -5, 6a,7,9, 10-hexahydro-8H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazine-8-carboxylate (33 a) (100 mg, 78%).
LCMS m/z＝373.1[M-55] + 。
And a second step of: (R) -5-isobutyl-3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazin-6 (6 aH) -one hydrochloride (33 b)
(R)-5-isobutyl-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one hydrochloride
(R) -5-isobutyl-6-oxo-3- (trifluoromethyl) -5, 6a,7,9, 10-hexahydro-8H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazine-8-carboxylic acid ester (33 a) (100 mg,0.23 mmol) was dissolved in 1, 4-dioxane (3 mL) solution at room temperature, and then hydrogen chloride/1, 4-dioxane solution (4.0M, 3mL,40 mmol) was added thereto for reaction at room temperature for 4 hours. After the reaction, the crude product of (R) -5-isobutyl-3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazin-6 (6 aH) -one hydrochloride (33 b) (80 mg, 96%) is obtained after concentration under reduced pressure.
LCMS m/z＝329.2[M+1] + 。
And a third step of: (R) -5-isobutyl-8- (3- ((S) -2- ((6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino) propoxy) propanoyl) -3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-pyrazino [1,2-a ] pyrido [3,2-E ] pyrazin-6- (6 aH) -one (Compound 33)
(R)-5-isobutyl-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one
3- [ (2S) -2- [ (6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino ] propoxy ] propionic acid (4 j) (66 mg,0.22 mmol) and (R) -5-isobutyl-3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazin-6 (6 aH) -one hydrochloride (33 b) (80 mg,0.22 mmol) were dissolved in DMF (3 mL), and DIPEA (142 mg,1.10 mmol) and HATU (84 mg,0.22 mmol) were added thereto, respectively, and then the reaction was stirred at room temperature for 3 hours. After the reaction was completed, the reaction solution was purified by Pre-HPLC (instrument and preparation column: preparation of liquid phase using WATERS 2767, preparation column model: xselect C18,5 μm, inner diameter×length=19 mm×150 mm). The preparation method comprises the following steps: the reaction solution was filtered through a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: acetonitrile/water (0.05% ammonia). The gradient elution method comprises the following steps: acetonitrile was eluted from 5% gradient to 50% (elution time 15 min). After lyophilization, (R) -5-isobutyl-8- (3- ((S) -2- ((6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino) propoxy) propionyl) -3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-pyrazino [1,2-a ] pyrido [3,2-E ] pyrazin-6- (6 aH) -one (compound 33) (20 mg, 12%).
LCMS m/z＝620.3[M+1] + 。
1 H NMR(400MHz,DMSO-d 6 )δ12.42(s,1H),8.19(s,1H),7.90(s,1H),7.55(s,1H),6.30-6.19(m,1H),4.89-4.45(m,2H),4.31-3.98(m,3H),3.95-3.78(m,2H),3.75-3.62(m,2H),3.49(d,2H),3.28-3.09(m,1H),2.87-2.59(m,4H),1.97-1.85(m,1H),1.15(d,3H),0.98-0.77(m,6H)。
Example 34: (R) -5-isopropyl-8- (3- ((S) -2- ((6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino) propoxy) propanoyl) -3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazin-6 (6 aH) -one (Compound 34)
(R)-5-isopropyl-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one
Compound 34 the synthetic method of reference example 33 was followed starting from tert-butyl- (R) -6-oxo-3- (trifluoromethyl) -5, 6a,7,9, 10-hexahydro-8H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazine-8-carboxylate (4 d) and 3- [ (2S) -2- [ (6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino ] propoxy ] propionic acid (4 j) to give (R) -5-isopropyl-8- (3- ((S) -2- ((6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino) propoxy) -3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazin-6 (6 aH) -one (compound 34).
LCMS m/z＝606.2[M+1] + 。
1 H NMR(400MHz,DMSO-d 6 )δ12.42(s,1H),8.22(s,1H),7.90(s,1H),7.66-7.55(m,1H),6.32-6.18(m,1H),4.86-4.47(m,2H),4.39-4.30(m,1H),4.29-3.85(m,3H),3.77-3.60(m,2H),3.49(d,2H),3.25-3.09(m,1H),2.86-2.54(m,4H),1.63-1.24(m,6H),1.15(d,3H)。
Example 35: (6 aR) -5- (oxetan-2-ylmethyl) -8- (3- ((S) -2- ((6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino) propoxy) propanoyl) -3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazin-6 (6 aH) -one (Compound 35)
(6aR)-5-(oxetan-2-ylmethyl)-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one
The first step: (R) -6-oxo-3- (trifluoromethyl) -5, 6a,7,9, 10-hexahydro-8H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazine-8-carboxylic acid benzyl ester (35 a)
benzyl(R)-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8-carboxylate
(R) -3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-pyrazino [1,2-a ] at room temperature]Pyrido [3,2-e]Pyrazin-6 (6 aH) -one (10 e) (4 g,11.59 mmol) was dissolved in THF (40 mL) and K was added 2 CO 3 (4.81 g,34.77 mmol) and H 2 O (10 mL), the mixture was stirred for 5min, benzyl chloroformate (1.21 g,15.20 mmol) was slowly added under ice-bath, after the reaction was completed, the reaction solution was poured into water (150 mL), extracted with ethyl acetate (50 mL. Times.3), the organic phases were combined, backwashed with saturated brine (30 mL. Times.3), dried over anhydrous sodium sulfate, suction filtered, and the filtrate was concentrated under reduced pressure to give a residue. Purification of the residue by column chromatography on silica gel (petroleum ether: ethyl acetate (V/V) =5:1) gave: (R) -6-oxo-3- (trifluoromethyl) -5, 6a,7,9, 10-hexahydro-8H-pyrazino [1,2-a ]]Pyrido [3,2-e]Pyrazine-8-carboxylic acid benzyl ester (35 a) (4 g, 85%).
LCMS m/z＝407.1[M+1] + 。
And a second step of: (6 aR) -5- (oxetan-2-ylmethyl) -6-oxo-3- (trifluoromethyl) -5, 6a,7,9, 10-hexahydro-8H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazine-8-carboxylic acid benzyl ester (35 b)
Benzyl(6aR)-5-(oxetan-2-ylmethyl)-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8-carboxylate
At room temperature, (35 a) (0.25 g,0.62 mmol) and 2-iodomethyl oxetane (0.25 g,1.24 mmol) were dissolved in DMF (2 mL), and potassium carbonate (0.26 g,1.86 mmol) was added thereto and reacted at room temperature for 36 hours. After completion of the reaction, ethyl acetate (20 ml×2) was added, followed by washing with water (5 ml×3), drying over anhydrous sodium sulfate, suction filtration, and concentration of the filtrate under reduced pressure to obtain a residue. Residue. Purification of the residue by column chromatography on silica gel (petroleum ether: ethyl acetate (V/V) =5:1) gave: (6 aR) -5- (oxetan-2-ylmethyl) -6-oxo-3- (trifluoromethyl) -5, 6a,7,9, 10-hexahydro-8H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazine-8-carboxylic acid benzyl ester (35 b) (0.3 g, 100%).
LCMS m/z＝477.3[M+1] + 。
And a third step of: (6 aR) -5- (oxetan-2-ylmethyl) -3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazin-6 (6 aH) -one (35 c)
(6aR)-5-(oxetan-2-ylmethyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one
(6 aR) -5- (oxetan-2-ylmethyl) -6-oxo-3- (trifluoromethyl) -5, 6a,7,9, 10-hexahydro-8H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazine-8-carboxylic acid benzyl ester (35 b) (0.30 g,0.62 mmol) was dissolved in methanol (8 mL) at room temperature, nitrogen was replaced 3 times, palladium on carbon (45 mg) was added 3 times, hydrogen was replaced 3 times, and the reaction was performed at room temperature for 4 hours. After completion of the reaction, the filtrates were combined and concentrated under reduced pressure to give crude (6 aR) -5- (oxetan-2-ylmethyl) -3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazin-6 (6 aH) -one (35 c) (210 mg, crude) which was used directly in the next step without further purification.
LCMS m/z＝343.1[M+1] + 。
Fourth step: (6 a R) -5- (oxetan-2-ylmethyl) -8- (3- ((S) -2- ((6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino) propoxy) propanoyl) -3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazin-6 (6 aH) -one (Compound 35)
(6aR)-5-(oxetan-2-ylmethyl)-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one
(6 aR) -5- (oxetan-2-ylmethyl) -3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazin-6 (6 aH) -one (35 c) (210 mg,0.61 mmol) and 3- [ (2S) -2- [ (6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino ] propoxy ] propionic acid (4 j) (188 mg,0.61 mmol) were dissolved in DMF (5 mL), DIPEA (240 mg,1.83 mmol) and HATU (230 mg,0.61 mmol) were added thereto, respectively, and then the reaction was stirred at room temperature for 3 hours. After the reaction was completed, the reaction solution was purified by Pre-HPLC (instrument and preparation column: preparation of liquid phase using WATERS 2767, preparation column model: xselect C18,5 μm, inner diameter×length=19 mm×150 mm). The preparation method comprises the following steps: the reaction solution was filtered through a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: acetonitrile/water (0.05% ammonia). The gradient elution method comprises the following steps: acetonitrile was eluted from 5% gradient to 50% (elution time 15 min). After lyophilization, (6 aR) -5- (oxetan-2-ylmethyl) -8- (3- ((S) -2- ((6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino) propoxy) propanoyl) -3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazin-6 (6 aH) -one (Compound 35) (20 mg, 5%)
LCMS m/z＝634.3[M+1] + 。
1 H NMR(400MHz,DMSO-d6)δ12.42(s,1H),8.20(s,1H),7.90(s,1H),7.82(d,1H),6.32-6.19(m,1H),4.97-3.96(m,10H),3.76-3.60(m,2H),3.49(d,2H),3.28-2.59(m,7H),1.15(d,3H)。
Example 36: (R) -5- (methyl-d 3) -8- (3- ((S) -2- ((6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino) propoxy) propanoyl) -3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazin-6 (6 aH) -one (Compound 36)
(R)-5-(methyl-d3)-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one
Compound 34 is prepared from tert-butyl- (R) -6-oxo-3- (trifluoromethyl) -5, 6a,7,9, 10-hexahydro-8H-pyrazino [1,2-a ]]Pyrido [3,2-e]Pyrazine-8-carboxylic acid esters (4 d) and 3- [ (2S) -2- [ (6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino groups]Propoxy group]Propionic acid (4 j) as a starting material was synthesized in accordance with the method of example 33 to give (R) -5- (methyl-d) 3 ) -8- (3- ((S) -2- ((6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino) propoxy) propanoyl) -3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-pyrazino [1,2-a]Pyrido [3,2-e]Pyrazin-6 (6 aH) -one (compound 36).
LCMS m/z＝581.3[M+1] + 。
1H NMR(400MHz,DMSO-d6)δ12.41(s,1H),8.19(s,1H),7.94-7.85(m,1H),7.53-7.40(m,1H),6.31-6.19(m,1H),4.90-4.46(m,2H),4.31-3.99(m,3H),3.77-3.62(m,2H),3.49(d,2H),3.28-3.04(m,1H),2.86-2.58(m,4H),1.15(d,3H)。
Example 37: (R) -5- ((1-methylcyclopropyl) methyl) -8- (3- ((S) -2- ((6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino)) propoxy) propanoyl) -3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazin-6 (6 aH) -one (Compound 37)
(R)-5-((1-methylcyclopropyl)methyl)-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one
The first step: (R) -5- ((1-methylcyclopropyl) methyl) -6-oxo-3- (trifluoromethyl) -5, 6a,7,9, 10-hexahydro-8H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazine-8-carboxylic acid tert-butyl ester (37 a)
Tert-butyl(R)-5-((1-methylcyclopropyl)methyl)-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8-carboxylate
(R) -6-oxo-3- (trifluoromethyl) -5, 6a,7,9, 10-hexahydro-8H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazine-8-carboxylic acid tert-butyl ester (4 d) (150 mg,0.40 mmol) was added to ultra-dry tetrahydrofuran (15 mL) at room temperature, 1-methylcyclopropane methanol (38 mg,0.44 mmol) and triphenylphosphine (115 mg,0.44 mmol) were added, nitrogen was replaced three times, and diethyl azodicarboxylate (77 mg,0.44 mmol) was slowly added. The mixture was stirred at room temperature overnight. The reaction was quenched with water (30 mL), extracted with ethyl acetate (30 mL. Times.2), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give the crude product. The crude product was purified by preparative column separation (petroleum ether: ethyl acetate (v/v) =8:1) to give (R) -5- ((1-methylcyclopropyl) methyl) -6-oxo-3- (trifluoromethyl) -5, 6a,7,9, 10-hexahydro-8H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazine-8-carboxylic acid tert-butyl ester (37 a) (70 mg, 40%).
LCMS m/z＝385.1[M-55] + 。
And a second step of: (R) -5- ((1-methylcyclopropyl) methyl) -3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazin-6 (6 aH) -one (37 b) hydrochloride
(R)-5-((1-methylcyclopropyl)methyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one hydrochloride
(R) -5- ((1-methylcyclopropyl) methyl) -6-oxo-3- (trifluoromethyl) -5, 6a,7,9, 10-hexahydro-8H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazine-8-carboxylic acid tert-butyl ester (37 a) (70 mg,0.16 mmol) was dissolved in a 1, 4-dioxane (3 mL) solution, and a hydrogen chloride/1, 4-dioxane solution (4.0M, 3mL,40 mmol) was added and reacted at room temperature for 4 hours. After the reaction was completed, the solvent was removed by concentration under reduced pressure to give (R) -5- ((1-methylcyclopropyl) methyl) -3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazin-6 (6 aH) -one (37 b) hydrochloride (60 mg, crude product).
LCMS m/z＝341.1[M+1] + 。
And a third step of: (R) -5- ((1-methylcyclopropyl) methyl) -8- (3- ((S) -2- ((6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino)) propoxy) propanoyl) -3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazin-6 (6 aH) -one (Compound 37)
(R)-5-((1-methylcyclopropyl)methyl)-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one
3- [ (2S) -2- [ (6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino ] propoxy ] propionic acid (4 j) (49 mg,0.16 mmol) and (R) -5- ((1-methylcyclopropyl) methyl) -3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazin-6 (6 aH) -one (37 b) hydrochloride (60 mg, crude) were dissolved in DMF (3 mL), DIPEA (103 mg,0.80 mmol) and HATU (61 mg,0.16 mmol) were added thereto, respectively, and then the reaction was stirred at room temperature for 3 hours. After the reaction was completed, the reaction solution was purified by Pre-HPLC (instrument and preparation column: preparation of liquid phase using WATERS 2767, preparation column model: xselect C18,5 μm, inner diameter×length=19 mm×150 mm). The preparation method comprises the following steps: the reaction solution was filtered through a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: acetonitrile/water (0.05% ammonia). The gradient elution method comprises the following steps: acetonitrile was eluted from 5% gradient to 50% (elution time 15 min). After lyophilization, (R) -5- ((1-methylcyclopropyl) methyl) -8- (3- ((S) -2- ((6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino)) propoxy) propionyl) -3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazin-6 (6 aH) -one (compound 37) (20 mg, 15%).
LCMS m/z＝632.2[M+1] + 。
1 H NMR(400MHz,DMSO-d 6 )δ12.42(s,1H),8.21(s,1H),7.90(s,1H),7.69(s,1H),6.31-6.19(m,1H),4.90-4.40(m,2H),4.34-3.94(m,5H),3.76-3.62(m,2H),3.49(d,2H),3.27-3.10(m,1H),2.86-2.59(m,4H),1.15(d,3H),0.91(s,3H),0.55-0.45(m,2H),0.33-0.24(m,2H)。
Example 38:1- (((R) -6-oxo-8- (3- ((S) -2- ((6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino) propoxy) propanoyl) -3- (trifluoromethyl) -6,6a,7,8,9, 10-hexahydro-5H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazin-5-yl) methyl) cyclopropane-1-carbonitrile (Compound 38)
1-(((R)-6-oxo-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a]pyrido[3,2- e]pyrazin-5-yl)methyl)cyclopropane-1-carbonitrile
The first step: 1- (iodomethyl) cyclopropane-1-carbonitrile (38 b)
1-(iodomethyl)cyclopropane-1-carbonitrile
1- (hydroxymethyl) cyclopropanecarbonitrile (38 a) (1.00 g,10.30 mmol), triphenylphosphine (3.24 g,12.36 mmol) and imidazole (0.84 g,12.36 mmol) were added to dichloromethane (30 mL) at room temperature, nitrogen replaced three times, and iodine (2.61 g,10.30 mmol) was slowly added. The mixture was stirred at room temperature overnight. The reaction was quenched with water (30 mL), extracted with dichloromethane (30 mL. Times.2), the organic phases combined, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give the crude product. The crude product was isolated and purified by column chromatography (petroleum ether: ethyl acetate (v/v) =12:1) to give 1- (iodomethyl) cyclopropane-1-carbonitrile (38 b) (1.50 g, 75%).
And a second step of: (R) -5- ((1-cyanocyclopropyl) methyl) -6-oxo-3- (trifluoromethyl) -5, 6a,7,9, 10-hexahydro-8H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazine-8-carboxylic acid tert-butyl ester (38 c)
Tert-butyl(R)-5-((1-cyanocyclopropyl)methyl)-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8-carboxylate
(R) -6-oxo-3- (trifluoromethyl) -5, 6a,7,9, 10-hexahydro-8H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazine-8-carboxylic acid tert-butyl ester (4 d) (110 mg,0.30 mmol) was added to DMF (5 mL) at room temperature, 1- (iodomethyl) cyclopropane-1-carbonitrile (38 b) (93 mg,0.45 mmol) and potassium carbonate (210 mg,0.91 mmol) were added and the mixture stirred at room temperature overnight. The reaction was quenched with saturated brine (30 mL), extracted with ethyl acetate (30 mL. Times.2), the organic phases were combined, washed with saturated brine (30 mL. Times.3), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give the crude product. The crude product was purified by preparative column separation (petroleum ether: ethyl acetate (v/v) =8:1) to give (R) -5- ((1-cyanocyclopropyl) methyl) -6-oxo-3- (trifluoromethyl) -5, 6a,7,9, 10-hexahydro-8H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazine-8-carboxylic acid tert-butyl ester (38 c) (100 mg, 74%).
LCMS m/z＝396.1[M-55] + 。
And a third step of: (R) -1- ((6-oxo-3- (trifluoromethyl) -6,6a,7,8,9, 10-hexahydro-5H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazin-5-yl) methyl) cyclopropane-1-carbonitrile (38 d) hydrochloride
(R)-1-((6-oxo-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-5-yl)methyl)cyclopropane-1-carbonitrile hydrochloride
(R) -5- ((1-cyanocyclopropyl) methyl) -6-oxo-3- (trifluoromethyl) -5, 6a,7,9, 10-hexahydro-8H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazine-8-carboxylic acid tert-butyl ester (38 c) (100 mg,0.22 mmol) was dissolved in 1, 4-dioxane (3 mL) solution and hydrogen chloride/1, 4-dioxane solution (4.0M, 3mL,40 mmol) was added and reacted at room temperature for 4 hours. After the reaction was completed, the solvent was removed by concentration under reduced pressure to give (R) -1- ((6-oxo-3- (trifluoromethyl) -6,6a,7,8,9, 10-hexahydro-5H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazin-5-yl) methyl) cyclopropane-1-carbonitrile (38 d) hydrochloride (85 mg, crude product).
LCMS m/z＝352.1[M+1] + 。
Fourth step: 1- (((R) -6-oxo-8- (3- ((S) -2- ((6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino) propoxy) propanoyl) -3- (trifluoromethyl) -6,6a,7,8,9, 10-hexahydro-5H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazin-5-yl) methyl) cyclopropane-1-carbonitrile (Compound 38)
1-(((R)-6-oxo-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-5-yl)methyl)cyclopropane-1-carbonitrile
3- [ (2S) -2- [ (6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino ] propoxy ] propionic acid (4 j) (68 mg,0.22 mmol) and (R) -1- ((6-oxo-3- (trifluoromethyl) -6,6a,7,8,9, 10-hexahydro-5H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazin-5-yl) methyl) cyclopropane-1-carbonitrile (38 d) hydrochloride (85 mg, crude) were dissolved in DMF (3 mL) at room temperature, DIPEA (142 mg,1.10 mmol) and HATU (84 mg,0.22 mmol) were added thereto, respectively, and the reaction was stirred at room temperature for 3 hours. After the reaction was completed, the reaction solution was purified by Pre-HPLC (instrument and preparation column: preparation of liquid phase using WATERS 2767, preparation column model: xselect C18,5 μm, inner diameter×length=19 mm×150 mm). The preparation method comprises the following steps: the reaction solution was filtered through a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: acetonitrile/water (0.05% ammonia). The gradient elution method comprises the following steps: acetonitrile was eluted from 5% gradient to 50% (elution time 15 min). After lyophilization, 1- (((R) -6-oxo-8- (3- ((S) -2- ((6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino) propoxy) propionyl) -3- (trifluoromethyl) -6,6a,7,8,9, 10-hexahydro-5H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazin-5-yl) methyl) cyclopropane-1-carbonitrile (compound 38) (20 mg, 14%).
LCMS m/z＝643.1[M+1]+。
1 H NMR(400MHz,DMSO-d 6 )δ12.42(s,1H),8.25(s,1H),7.90(s,2H),6.34-6.17(m,1H),4.91-4.42(m,2H),4.37-3.98(m,5H),3.77-3.62(m,2H),3.49(d,2H),3.27-3.10(m,1H),2.90-2.59(m,4H),1.32-1.12(m,7H)。
Example 39:5- (((S) -1- (3- ((R) -5- (cyclopropylmethyl) -3-fluoro-6-thioxo-5, 6a,7,9, 10-hexahydro-8H-pyrazin [1,2-a ] pyrido [3,2-e ] pyrazin-8-yl) -3-oxopropoxy) propan-2-yl) amino) -4- (trifluoromethyl) pyridazin-3 (2H) -one (Compound 39)
5-(((S)-1-(3-((R)-5-(cyclopropylmethyl)-3-fluoro-6-thioxo-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-8-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one
The first step: 1-tert-butyl 3-methyl (3R) -4- (5-fluoro-3-nitropyridin-2-yl) piperazine-1, 3-dicarboxylic acid ester (39 c)
1-tert-butyl 3-methyl(3R)-4-(5-fluoro-3-nitropyridin-2-yl)piperazine-1,3-dicarboxylate
2-chloro-5-fluoro-3-nitropyridine (39 a) (2.00 g,11.33 mmol), 1- (tert-butyl) 3-methyl (R) -piperazine-1, 3-dicarboxylic acid ester (39 b) (3.32 g,13.60 mmol), DIPEA (5.00 g,38.76 mmol) were added sequentially to dimethyl sulfoxide (15 mL), reacted at 100℃for 16h, cooled to room temperature after the reaction was completed, the reaction solution was poured into water (150 mL), extracted with ethyl acetate (30 mL. Times.3), the organic phases were combined, backwashed with saturated brine (30 mL. Times.3), dried over anhydrous sodium sulfate, suction filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. Purification of the residue by column chromatography on silica gel (petroleum ether: ethyl acetate (V/V) =4:1) gave: 1-tert-butyl 3-methyl (3R) -4- (5-fluoro-3-nitropyridin-2-yl) piperazine-1, 3-dicarboxylic acid ester (39 c) (2.13 g, 49%).
LCMS m/z＝329.1[M-55] + 。
And a second step of: (R) -3-fluoro-6-oxo-5, 6a,7,9, 10-hexahydro-8H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazine-8-carboxylic acid tert-butyl ester (39 d)
tert-butyl(R)-3-fluoro-6-oxo-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8-carboxylate
1-tert-butyl 3-methyl (3R) -4- (5-fluoro-3-nitropyridin-2-yl) piperazine-1, 3-dicarboxylic acid ester (39 c) (2.13 g,5.54 mmol) was dissolved in absolute ethanol (30 mL) at room temperature, followed by the addition of zinc powder (3.62 g,55.4 mmol) and ammonium chloride (2.96 g,55.4 mmol). The mixture was stirred at 60℃for 16 hours. The reaction solution was filtered, the filter cake was washed with ethyl acetate (40 mL), the organic phases were combined, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was isolated and purified by column chromatography (petroleum ether: ethyl acetate (v/v) =4:1) to give (R) -3-fluoro-6-oxo-5, 6a,7,9, 10-hexahydro-8H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazine-8-carboxylic acid tert-butyl ester (39 d) (1.30 g, 73%).
LCMS m/z＝321.2[M-1] - 。
And a third step of: (R) -3-fluoro-7, 8,9, 10-tetrahydro-5H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazin-6 (6 aH) -one hydrochloride (39 e)
(R)-3-fluoro-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one
(R) -3-fluoro-6-oxo-5, 6a,7,9, 10-hexahydro-8H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazine-8-carboxylic acid tert-butyl ester (39 d) (1.30 g,4.03 mmol) was dissolved in 1, 4-dioxane (5 mL) solution at room temperature, and hydrogen chloride/1, 4-dioxane solution (4.0M, 10mL,40 mmol) was added thereto for reaction at room temperature for 4 hours. After the reaction was completed, the solvent was removed by concentration under reduced pressure to give (R) -3-fluoro-7, 8,9, 10-tetrahydro-5H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazin-6 (6 aH) -one (39 e) hydrochloride (1.00 g, crude product).
LCMS m/z＝223.1[M+1] + 。
Fourth step: 2- (trimethylsilyl) ethyl (R) -3-fluoro-6-oxo-5, 6a,7,9, 10-hexahydro-8H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazine-8-carboxylic acid ester (39 f)
2-(trimethylsilyl)ethyl(R)-3-fluoro-6-oxo-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8-carboxylate
(R) -3-fluoro-7, 8,9, 10-tetrahydro-5H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazin-6 (6 aH) -one hydrochloride (39 e) (0.30 g,1.35 mmol) and triethylamine (0.41 g,4.05 mmol) were dissolved in tetrahydrofuran (10 mL) at room temperature, and N- [2- (trimethylsilyl) ethoxycarbonyloxy ] succinimide (0.35 g,1.35 mmol) was slowly added. The reaction solution was stirred at room temperature for 2 hours. After the reaction is finished, the crude product is obtained after decompression and concentration. The crude product was isolated and purified by preparative column (petroleum ether: ethyl acetate (v/v) =3:1) to give 2- (trimethylsilyl) ethyl (R) -3-fluoro-6-oxo-5, 6a,7,9, 10-hexahydro-8H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazine-8-carboxylate (39 f) (0.35 g, 71%).
LCMS m/z＝365.2[M-1] -
Fifth step: 2- (trimethylsilyl) ethyl (R) -3-fluoro-6-thioxo-5, 6a,7,9, 10-hexahydro-8H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazine-8-carboxylic acid ester (39 g)
2-(trimethylsilyl)ethyl(R)-3-fluoro-6-thioxo-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8-carboxylate
Tert-2- (trimethylsilyl) ethyl (R) -3-fluoro-6-oxo-5, 6a,7,9, 10-hexahydro-8H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazine-8-carboxylate (39 f) (0.35 g,0.96 mmol) was dissolved in tetrahydrofuran (5 mL) at room temperature, and L-Lawson reagent (0.78 g,1.92 mmol) was added and the mixture reacted at 60℃for 16 hours. After the reaction is finished, the crude product is obtained after decompression and concentration. The crude product was isolated and purified by preparative column (petroleum ether: ethyl acetate (v/v) =3:1) to give 2- (trimethylsilyl) ethyl (R) -3-fluoro-6-thio-5, 6a,7,9, 10-hexahydro-8H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazine-8-carboxylate (39 g) (0.20 g, 54%).
Sixth step: 2- (trimethylsilyl) ethyl (R) -5- (cyclopropylmethyl) -3-fluoro-6-thioxo-5, 6a,7,9, 10-hexahydro-8H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazine-8-carboxylic acid ester (39H)
2-(trimethylsilyl)ethyl(R)-5-(cyclopropylmethyl)-3-fluoro-6-thioxo-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8-carboxylate
2- (trimethylsilyl) ethyl (R) -3-fluoro-6-thio-5, 6a,7,9, 10-hexahydro-8H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazine-8-carboxylate (39 g) (110 mg,0.26 mmol), (iodomethyl) cyclopropane (71 mg,0.39 mmol) was dissolved in DMF (5 mL) at room temperature, and potassium carbonate (110 mg,0.78 mmol) was added. The reaction solution was stirred at room temperature for 16 hours. After completion of the reaction, saturated brine (20 mL) was added thereto, and ethyl acetate (20 mL. Times.2) was added thereto for extraction. The organic phases were combined, washed with saturated brine (20 ml x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product. The crude product was isolated and purified by preparative column (petroleum ether: ethyl acetate (v/v) =6:1) to give 2- (trimethylsilyl) ethyl (R) -5- (cyclopropylmethyl) -3-fluoro-6-thio-5, 6a,7,9, 10-hexahydro-8H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazine-8-carboxylate (39H) (70 mg, 62%).
LCMS m/z＝437.2[M+1] + 。
Seventh step: (R) -5- (cyclopropylmethyl) -3-fluoro-7, 8,9, 10-tetrahydro-5H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazine-6 (6 aH) -thione (39 i)
(R)-5-(cyclopropylmethyl)-3-fluoro-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-6(6aH)-thione
2- (trimethylsilyl) ethyl (R) -5- (cyclopropylmethyl) -3-fluoro-6-thioxo-5, 6a,7,9, 10-hexahydro-8H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazine-8-carboxylate (39H) (70 mg,0.16 mmol) was dissolved in tetrahydrofuran (3 mL) at room temperature, and tetrabutylammonium fluoride in tetrahydrofuran (1.0M, 1.5mL,1.5 mmol) was added and reacted at room temperature for 2 hours. After completion of the reaction, saturated brine (20 mL) was added thereto, and ethyl acetate (20 mL. Times.2) was added thereto for extraction. The organic phases were combined, washed with saturated brine (20 ml x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product. The crude product was purified by preparative column separation (petroleum ether: ethyl acetate (v/v) =2:1) to give (R) -5- (cyclopropylmethyl) -3-fluoro-7, 8,9, 10-tetrahydro-5H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazine-6 (6 aH) -thione (39 i) (25 mg, 47%).
LCMS m/z＝293.1[M+1] + 。
Eighth step: 5- (((S) -1- (3- ((R) -5- (cyclopropylmethyl) -3-fluoro-6-thioxo-5, 6a,7,9, 10-hexahydro-8H-pyrazin [1,2-a ] pyrido [3,2-e ] pyrazin-8-yl) -3-oxopropoxy) propan-2-yl) amino) -4- (trifluoromethyl) pyridazin-3 (2H) -one (Compound 39)
5-(((S)-1-(3-((R)-5-(cyclopropylmethyl)-3-fluoro-6-thioxo-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-8-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one
3- [ (2S) -2- [ (6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino ] propoxy ] propionic acid (4 j) (27 mg,0.09 mmol) and (R) -5- (cyclopropylmethyl) -3-fluoro-7, 8,9, 10-tetrahydro-5H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazine-6 (6 aH) -thione (39 i) (25 mg,0.09 mmol) were dissolved in DMF (3 mL), and DIPEA (58 mg,0.45 mmol) and HATU (34 mg,0.09 mmol) were added thereto, respectively, and then reacted at room temperature with stirring for 3 hours. After the reaction was completed, the reaction solution was purified by Pre-HPLC (instrument and preparation column: preparation of liquid phase using WATERS 2767, preparation column model: xselect C18,5 μm, inner diameter×length=19 mm×150 mm). The preparation method comprises the following steps: the reaction solution was filtered through a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: acetonitrile/water (containing 0.05% ammonium acetate). The gradient elution method comprises the following steps: acetonitrile was eluted from 5% gradient to 50% (elution time 15 min). After lyophilization, 5- (((S) -1- (3- ((R) -5- (cyclopropylmethyl) -3-fluoro-6-thioxo-5, 6a,7,9, 10-hexahydro-8H-pyrazin [1,2-a ] pyrido [3,2-e ] pyrazin-8-yl) -3-oxopropoxy) propan-2-yl) amino) -4- (trifluoromethyl) pyridazin-3 (2H) -one (compound 39) (10 mg, 18%).
LCMS m/z＝584.2[M+1] + 。
1 H NMR(400MHz,DMSO-d 6 )δ12.42(s,1H),7.95-7.86(m,2H),7.33(dd,1H),6.33-6.18(m,1H),4.64-4.34(m,2H),4.25-3.82(m,3H),3.75-3.59(m,2H),3.56-3.44(m,2H),3.17-2.53(m,7H),1.25-1.05(m,4H),0.63-0.49(m,2H),0.39-0.25(m,2H)。
Example 40: (R) -8- (3- ((S) -2- ((6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino) propoxy) propanoyl) -5-propyl-3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazin-6 (6 aH) -one (Compound 40)
(R)-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-5-propyl-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one
Compound 40 (R) -8- (3- ((S) -2- ((6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino) propoxy) -5-propyl-3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-pyrazin-1, 2-a ] pyrido [3,2-e ] pyrazin-6 (6 aH) -one (compound 40) was obtained by the synthetic procedure of reference example 29 starting from tert-butyl- (R) -6-oxo-3- (trifluoromethyl) -5, 6a,7,9, 10-hexahydro-8H-pyrazin [1,2-a ] pyrido [3,2-e ] pyrazine-8-carboxylate (4 d), iodopropane and 3- [ (6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino ] propoxy ] propionic acid (4 j).
LCMS m/z＝606.2[M+1] + 。
1 H NMR(400MHz,DMSO-d 6 )δ12.42(s,1H),8.19(s,1H),7.90(s,1H),7.52(s,1H),6.32-6.15(m,1H),4.93-4.39(m,2H),4.31-3.83(m,5H),3.74-3.58(m,2H),3.49(d,2H),3.27-3.04(m,1H),2.88-2.55(m,4H),1.62-1.43(m,2H),1.15(d,3H),0.88(t,3H)。
Example 41: (R) -5-octyl-8- (3- ((S) -2- ((6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino) propoxy) propanoyl) -3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-pyrazino [1,2-a ] pyrido [3,2-E ] pyrazin-6- (6 aH) -one (Compound 41)
(R)-5-octyl-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one
Compound 41 starting from tert-butyl- (R) -6-oxo-3- (trifluoromethyl) -5, 6a,7,9, 10-hexahydro-8H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazine-8-carboxylate (4 d) and 3- [ (2S) -2- [ (6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino ] propoxy ] propionic acid (4 j), the synthetic procedure of reference example 29 gives (R) -5-octyl-8- (3- ((S) -2- ((6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino) propoxy) -3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazin-6- (6 aH) -one (compound 41).
LCMS m/z＝676.3[M+1] + 。
1 H NMR(400MHz,DMSO-d 6 )δ12.42(s,1H),8.19(s,1H),7.90(s,1H),7.49 (s,1H),6.30-6.18(m,1H),4.92-4.40(m,2H),4.34-3.86(m,5H),3.76-3.61(m,2H),3.49(d,2H),3.26-3.05(m,1H),2.85-2.55(m,4H),1.58-1.42(m,2H),1.35-1.12(m,13H),0.89-0.79(m,3H)。
Example 42: (S) -5- (methyl-D3) -8- (3- ((S) -2- ((6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino) propoxy) propanoyl) -3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazin-6 (6 aH) -one (Compound 42)
(S)-5-(methyl-D 3 )-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one
Compound 42 is tert-butyl- (S) -6-oxo-3- (trifluoromethyl) -5, 6a,7,9, 10-hexahydro-8H-pyrazino [1,2-a ]]Pyrido [3,2-e]Pyrazine-8-carboxylic acid esters (10 d) deuterated iodomethane and 3- [ (2S) -2- [ (6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino groups]Propoxy group]Propionic acid (4 j) as a starting material was synthesized in accordance with the method of example 11 to give (S) -5- (methyl-D) 3 ) -8- (3- ((S) -2- ((6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino) propoxy) propanoyl) -3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-pyrazino [1,2-a]Pyrido [3,2-e]Pyrazin-6 (6 aH) -one (compound 42).
LCMS m/z＝581.3[M+1] + 。
1 H NMR(400MHz,CD 3 OD)δ8.14(s,1H),7.91(d,1H),7.40(s,1H),5.15-4.57(m,2H),4.56-3.92(m,3H),3.88-3.68(m,2H),3.65-3.46(m,2H),3.27-3.18(m,1H),2.93-2.60(m,4H),1.25(d,3H)。
Example 43:5- (((S) -1- (3- ((S) -5-methyl-6-sulfanyl-3- (trifluoromethyl) -5, 6a,7,9, 10-hexahydro-8H-pyrazin [1,2-a ] pyrido [3,2-e ] pyrazin-8-yl) -3-oxopropoxy) propan-2-yl) amino) -4- (trifluoromethyl) pyridazin-3 (2H) -one (Compound 43)
5-(((S)-1-(3-((S)-5-methyl-6-thioxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-8-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one
Compound 43 starting from tert-butyl- (S) -6-oxo-3- (trifluoromethyl) -5, 6a,7,9, 10-hexahydro-8H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazine-8-carboxylate (10 d) and 3- [ (2S) -2- [ (6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino ] propoxy ] propionic acid (4 j), the synthetic procedure of reference example 31 gives 5- (((S) -1- (3- ((S) -5-methyl-6-thioxo-3- (trifluoromethyl) -5, 6a,7,9, 10-hexahydro-8H-pyrazin [1,2-a ] pyrido [3,2-e ] pyrazin-8-yl) -3-oxopropoxy) propan-2-yl) amino) -4- (trifluoromethyl) pyridazin-3 (2H) -one (compound 43).
LCMS m/z＝594.2[M+1] + 。
1 H NMR(400MHz,CDCl 3 )δ10.14-9.87(m,1H),8.15(s,1H),7.65(s,1H),7.59-7.51(m,1H),5.83-5.70(m,1H),5.09-4.53(m,2H),4.41-4.23(m,1H),4.15-3.74(m,4H),3.71-3.59(m,1H),3.56-3.43(m,1H),3.39-3.14(m,1H),2.95-2.72(m,2H),2.71-2.48(m,5H),1.30(d,3H)。
Example 44: (R) -5-cyclopentylmethyl-8- (3- ((S) -2- ((6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino) propoxy) propanoyl) -3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-pyrazino [1,2-a ] pyrido [3,2-E ] pyrazin-6- (6 aH) -one (Compound 44)
(R)-5-(cyclopentylmethyl)-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one
Compound 44 starting from tert-butyl- (R) -6-oxo-3- (trifluoromethyl) -5, 6a,7,9, 10-hexahydro-8H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazine-8-carboxylate (4 d), iodomethylcyclopentane and 3- [ (2S) -2- [ (6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino ] propoxy ] propionic acid (4 j), the synthetic procedure of reference example 33 was followed to give (R) -5-cyclopentylmethyl-8- (3- ((S) -2- ((6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino) propoxy) -3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazin-6- (6 aH) -one (compound 44).
LCMS m/z＝646.3[M+1] + 。
1 H NMR(400MHz,DMSO-d 6 )δ12.42(s,1H),8.20(s,1H),7.90(s,1H),7.58(s,1H),6.36-6.15(m,1H),4.99-4.41(m,2H),4.33-3.84(m,5H),3.78-3.60(m,2H),3.49(d,2H),3.27-3.07(m,1H),2.88-2.55(m,4H),2.22-2.07(m,1H),1.71-1.39(m,6H),1.31-1.18(m,2H)，1.15(d,3H)。
Example 45: (R) -5-isopentyl-8- (3- ((S) -2- ((6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino)) propoxy) propanoyl) -3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazin-6 (6 aH) -one (Compound 45)
(R)-5-isopentyl-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one
Compound 45 (R) -5-isopentyl-8- (3- ((S) -2- ((6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino)) propoxy) propionyl) -3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazin-6 (6 aH) -one (compound 45) was obtained by the synthetic method of reference example 33 starting from tert-butyl- (R) -6-oxo-3- (trifluoromethyl) -5, 6a,7,9, 10-hexahydro-8H-pyrazin [1,2-a ] pyrido [3,2-e ] pyrazine-8-carboxylate (4 d), isopentyl iodide and 3- [ (6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino ] propoxy ] propionic acid (4 j).
LCMS m/z＝634.3[M+1] + 。
1 H NMR(400MHz,DMSO-d 6 )δ12.42(s,1H),8.20(s,1H),7.90(s,1H),7.44(s,1H),6.30-6.18(m,1H),4.91-4.40(m,2H),4.36-3.90(m,5H),3.76-3.58(m,2H),3.49(d,2H),3.27-3.04(m,1H),2.87-2.56(m,4H),1.68-1.52(m,1H),1.44-1.33(m,2H),1.15(d,3H),0.97-0.84(m,6H)。
Example 46: (R) -5- (2-ethylbutyl) -8- (3- ((S) -2- ((6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino)) propoxy) propanoyl) -3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazin-6 (6 aH) -one (Compound 46)
(R)-5-(2-ethylbutyl)-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one
Compound 46 was obtained by the synthetic method of reference example 37 starting from tert-butyl- (R) -6-oxo-3- (trifluoromethyl) -5, 6a,7,9, 10-hexahydro-8H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazine-8-carboxylate (4 d), 2-ethyl-1-butanol and 3- [ (2S) -2- [ (6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino ] propoxy ] propionic acid (4 j), by (R) -5- (2-ethylbutyl) -8- (3- ((S) -2- ((6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino)) propoxy) -3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazin-6 (6 aH) -one (compound 46).
LCMS m/z＝648.3[M+1] + 。
1 H NMR(400MHz,DMSO-d 6 )δ12.42(s,1H),8.21(s,1H),7.90(s,1H),7.46(s,1H),6.33-6.17(m,1H),4.94-4.39(m,2H),4.37-3.93(m,4H),3.90-3.79(m,1H),3.78-3.61(m,2H),3.49(d,2H),3.25-3.08(m,1H),2.88-2.55(m,4H),1.62-1.48(m,1H),1.36-1.18(m,4H),1.15(d,3H),0.92-0.76(m,6H)。
Example 47: (R) -5- (2-methylbutyl) -8- (3- ((S) -2- ((6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino)) propoxy) propanoyl) -3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazin-6 (6 aH) -one (Compound 47)
(R)-5-(2-methylbutyl)-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one
Compound 47 starting from tert-butyl- (R) -6-oxo-3- (trifluoromethyl) -5, 6a,7,9, 10-hexahydro-8H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazine-8-carboxylate (4 d), 2-methylbutanol and 3- [ (2S) -2- [ (6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino ] propoxy ] propionic acid (4 j), the synthetic procedure of reference example 37 was followed to give (R) -5- (2-methylbutyl) -8- (3- ((S) -2- ((6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino) propoxy) -3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazin-6 (6 aH) -one (compound 47).
LCMS m/z＝634.3[M+1] + 。
1 H NMR(400MHz,DMSO-d 6 )δ12.42(s,1H),8.20(s,1H),7.90(s,1H),7.51(s,1H),6.31-6.19(m,1H),4.90-4.42(m,2H),4.34-3.78(m,5H),3.76-3.60(m,2H),3.49(d,2H),3.25-3.06(m,1H),2.90-2.58(m,4H),1.80-1.60(m,1H),1.46-1.28(m,1H),1.22-1.05(m,4H),0.91-0.73(m,6H)。
Example 48: (R) -5-butyl-8- (3- ((S) -2- ((6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino)) propoxy) propanoyl) -3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazin-6 (6 aH) -one (Compound 48)
(R)-5-butyl-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one
Compound 48 starting from tert-butyl- (R) -6-oxo-3- (trifluoromethyl) -5, 6a,7,9, 10-hexahydro-8H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazine-8-carboxylate (4 d), 1-iodobutane and 3- [ (6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino ] propoxy ] propionic acid (4 j), the synthetic procedure of reference example 33 gives (R) -5-butyl-8- (3- ((S) -2- ((6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino)) propoxy) propionyl) -3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazin-6 (6 aH) -one (compound 48).
LCMS m/z＝620.3[M+1] + 。
1 H NMR(400MHz,DMSO-d 6 )δ12.42(s,1H),8.19(s,1H),7.90(s,1H),7.51(s,1H),6.37-6.18(m,1H),4.94-4.40(m,2H),4.31-3.91(m,5H),3.81-3.60(m,2H),3.49(d,2H),3.24-3.05(m,1H),2.87-2.60(m,4H),1.58-1.42(m,2H),1.38-1.25(m,2H),1.15(d,3H),0.99-0.84(m,3H)。
Example 49: (R) -5- ((S) -2-methylbutyl) -8- (3- ((S) -2- ((6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino)) propoxy) propanoyl) -3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazin-6 (6 aH) -one (Compound 49)
(R)-5-((S)-2-methylbutyl)-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one
Compound 49 was obtained by the synthetic method of reference example 37 starting from tert-butyl- (R) -6-oxo-3- (trifluoromethyl) -5, 6a,7,9, 10-hexahydro-8H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazine-8-carboxylate (4 d), S- (-) -2-methyl-1-butanol and 3- [ (2S) -2- [ (6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino ] propoxy ] propionic acid (4 j), and (R) -5- ((S) -2-methylbutyl) -8- (3- ((S) -2- ((6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino)) propoxy) propionyl) -3- (trifluoromethyl) -7,8,9, 10-tetrahydro-5H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazin-6-one (49).
LCMS m/z＝634.3[M+1] + 。
1 H NMR(400MHz,DMSO-d 6 )δ12.42(s,1H),8.20(s,1H),7.90(s,1H),7.50(s,1H),6.32-6.16(m,1H),4.95-4.37(m,2H),4.37-3.76(m,5H),3.74-3.59(m,2H),3.49(d,2H),3.28-3.06(m,1H),2.89-2.56(m,4H),1.76-1.60(m,1H),1.47-1.32(m,1H),1.26-1.08(m,4H),0.97-0.75(m,6H)。
Example 50: (R) -5- (cyclopropylmethyl) -8- (3- ((S) -2- ((6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino) propoxy) propanoyl) -6-thio-6, 6a,7,8,9, 10-hexahydro-5H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazine-3-carbonitrile (Compound 50)
(R)-5-(cyclopropylmethyl)-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-6-thioxo-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-3-carbonitrile
Compound 50 was obtained by the synthetic method of reference example 39 from 6-chloro-5-nitronicotinonitrile and 3- [ (2S) -2- [ (6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino ] propoxy ] propionic acid (4 j), (iodomethyl) cyclopropane and tert-butyl- (R) -6-oxo-3- (trifluoromethyl) -5, 6a,7,9, 10-hexahydro-8H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazine-8-carboxylate (4 d) as starting materials, and (R) -5- (cyclopropylmethyl) -8- (3- ((S) -2- ((6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino) propoxy) propionyl) -6-thio-6, 6a,7,8,9, 10-hexahydro-5H-pyrazino [1,2-a ] pyrido [3,2-e ] pyrazine-8-carboxylate (50).
LCMS m/z＝591.2[M+1] + 。
1 H NMR(400MHz,DMSO-d 6 )δ12.43(s,1H),8.29(d,1H),7.90(s,1H),7.59(d,1H),6.33-6.19(m,1H),4.77-4.31(m,3H),4.24-3.88(m,2H),3.77-3.62(m,2H),3.55-3.45(m,2H),3.44-3.01(m,3H),2.94-2.56(m,4H),1.22-1.04(m,4H),0.61-0.50(m,2H),0.37-0.27(m,2H)。
Example 51:5- (((S) -1- (3-oxo-3- ((R) -3- (trifluoromethyl) -5, 6a,7,9, 10-hexahydro-8H-pyridine [1,6-a:2,3-b' ] bipyrazinyl-8-yl) propoxy) propan-2-yl) amino) -4- (trifluoromethyl) pyrazin-3 (2H) -one (Compound 51)
5-(((S)-1-(3-oxo-3-((R)-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrido[1,6-a:2,3-b']dipyrazin-8-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one
The first step: 5- (trifluoromethyl) pyrazin-2-ol (51 b)
5-(trifluoromethyl)pyrazin-2-ol
2-chloro-5- (trifluoromethyl) pyrazine (2.00 g,10.96 mmol) (51 a) was dissolved in tetrahydrofuran (10 mL), a solution of sodium hydroxide (0.88 g,21.92 mmol) in water (4 mL) was added, and the temperature was raised to 70℃for 3h. After the reaction, the pH was adjusted to 6 to 7 with hydrochloric acid solution (2M) in an ice-water bath. Then extracted with ethyl acetate (20 mL. Times.3), the organic phases were combined, backwashed with saturated brine (20 mL. Times.2), dried over anhydrous sodium sulfate, suction filtered, and the filtrate concentrated under reduced pressure to give 5- (trifluoromethyl) pyrazin-2-ol (51 b) (1.60 g, 89%).
LCMS m/z＝165.0[M+1] + 。
And a second step of: 3-bromo-5- (trifluoromethyl) pyrazin-2-ol (51 c)
3-bromo-5-(trifluoromethyl)pyrazin-2-ol
To a solution of 5- (trifluoromethyl) pyrazin-2-ol (51 b) (1.40 g,8.53 mmol) in DMF (15 mL) was slowly added dropwise bromine (7.80 g,48.81 mmol) under an ice-water bath. After the completion of the dropping, the temperature was maintained for reaction for 3 hours. After the reaction was completed, the reaction mixture was slowly added to ice water (100 mL), extracted with ethyl acetate (30 ml×3), and the organic phases were combined, backwashed with saturated brine (20 ml×2), dried over anhydrous sodium sulfate, suction-filtered, and the filtrate was concentrated under reduced pressure to give a residue, which was separated and purified by a preparative column (methanol: dichloromethane (v/v) =1:25) to give 3-bromo-5- (trifluoromethyl) pyrazin-2-ol (51 c) (1.40 g, 68%).
LCMS m/z＝240.9[M-1] -
And a third step of: 1-benzyl 4- (tert-butyl) (R) -2- (2- (3-hydroxy-6- (trifluoromethyl) pyrazin-2-yl) vinyl) piperazine-1, 4-dicarboxylic acid ester (51 d)
1-benzyl 4-(tert-butyl)(R)-2-(2-(3-hydroxy-6-(trifluoromethyl)pyrazin-2-yl)vinyl)piperazine-1,4-dicarboxylate
1-benzyl 4- (tert-butyl) (R) -2-vinylpiperazine-1, 4-dicarboxylic acid ester (200 mg,0.58mmol, prepared with reference to WO2007146066 starting from tert-butyl (S) -3- (hydroxymethyl) piperazine-1-carboxylate) was dissolved in DMF (12 mL), 3-bromo-5- (trifluoromethyl) pyrazin-2-ol (51 c) (211 mg,0.87 mmol), potassium carbonate (240 mg,1.74 mmol), 2-dicyclohexylphosphine-2 ',4',6' -triisopropylbiphenyl (111 mg,0.23 mmol) and palladium acetate (26 mg,0.12 mmol) were added at room temperature. The reaction was carried out at 100℃for 16h with nitrogen substitution 3 times. After the reaction, water (40 mL) and ethyl acetate (40 mL) were added, the mixture was filtered through celite, the filtrate was separated, the aqueous phase was extracted with ethyl acetate (40 ml×2), the organic phases were combined, the organic phase was backwashed with saturated brine (20 ml×2), dried over anhydrous sodium sulfate, filtered with suction, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (tetrahydrofuran: dichloromethane (v/v) =15:85) to give 1-benzyl 4- (tert-butyl) (R) -2- (2- (3-hydroxy-6- (trifluoromethyl) pyrazin-2-yl) vinyl) piperazine-1, 4-dicarboxylic acid ester (51 d) (100 mg, 34%).
LCMS m/z＝453.0[M-55] + 。
Fourth step: (R) -3- (2- (3-hydroxy-6- (trifluoromethyl) pyrazin-2-yl) ethyl) piperazine-1-carboxylic acid tert-butyl ester (51 e)
tert-butyl(R)-3-(2-(3-hydroxy-6-(trifluoromethyl)pyrazin-2-yl)ethyl)piperazine-1-carboxylate
1-benzyl 4- (tert-butyl) (R) -2- (2- (3-hydroxy-6- (trifluoromethyl) pyrazin-2-yl) vinyl) piperazine-1, 4-dicarboxylic acid ester (51 d) (150 mg,0.29 mmol) was dissolved in MeOH (10 mL) at room temperature, aqueous ammonia (mass fraction 25% -28%,0.1 mL) was added, palladium on carbon (20 mg, 10%) was reacted at room temperature under hydrogen atmosphere for 16h after hydrogen substitution, pad celite was filtered after the reaction was completed, and the filtrate was concentrated under reduced pressure to give (R) -3- (2- (3-hydroxy-6- (trifluoromethyl) pyrazin-2-yl) ethyl) piperazine-1-carboxylic acid tert-butyl ester (51 e) (110 mg) crude product which was directly used in the next step.
LCMS m/z＝377.2[M+1] + 。
Fifth step: tert-butyl (R) -3- (trifluoromethyl) -5, 6a,7,9, 10-hexahydro-8H-pyridine [1,6-a:2,3-b' ] bipyrazine-8-carboxylic acid ester (51 f)
tert-butyl(R)-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrido[1,6-a:2,3-b']dipyrazine-8-carboxylate
(R) -3- (2- (3-hydroxy-6- (trifluoromethyl) pyrazin-2-yl) ethyl) piperazine-1-carboxylic acid tert-butyl ester (51 e) (110 mg, crude) was dissolved in dimethyl sulfoxide (5 mL) at room temperature, DIPEA (112 mg,0.87 mmol) and 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate (151 mg,0.29 mmol) were added. The temperature is raised to 60 ℃ to react for 1h. After the reaction, the reaction mixture was poured into water (50 mL), extracted with ethyl acetate (20 ml×3), and the organic phases were combined, backwashed with saturated brine (20 ml×3), dried over anhydrous sodium sulfate, suction filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether (v/v) =15:85) to give tert-butyl (R) -3- (trifluoromethyl) -5, 6a,7,9, 10-hexahydro-8H-pyridine [1,6-a:2,3-b' ] bipyrazine-8-carboxylate (51 f) (52 mg,50%, 2-step yield).
LCMS m/z＝303.1[M-55] + 。
Sixth step: hydrochloride of (R) -3- (trifluoromethyl) -6,6a,7,8,9, 10-hexahydro-5H-pyridine [1,6-a:2,3-b' ] bipyrazine (51 g)
(R)-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrido[1,6-a:2,3-b']dipyrazine
Tert-butyl (R) -3- (trifluoromethyl) -5, 6a,7,9, 10-hexahydro-8H-pyridine [1,6-a:2,3-b' ] bipyrazine-8-carboxylate (51 f) (87 mg,0.24 mmol) was dissolved in hydrogen chloride/1, 4-dioxane solution (10 mL, 4M) at room temperature and reacted for 1H at room temperature. After the completion of the reaction, the crude (R) -3- (trifluoromethyl) -6,6a,7,8,9, 10-hexahydro-5H-pyridine [1,6-a:2,3-b' ] bipyrazine (51 g) hydrochloride (71 mg) was obtained by concentrating under reduced pressure and used directly in the next reaction.
LCMS m/z＝259.2[M+1] + 。
Seventh step: 5- (((S) -1- (3-oxo-3- ((R) -3- (trifluoromethyl) -5, 6a,7,9, 10-hexahydro-8H-pyridine [1,6-a:2,3-b' ] bipyrazinyl-8-yl) propoxy) propan-2-yl) amino) -4- (trifluoromethyl) pyrazin-3 (2H) -one (Compound 51)
5-(((S)-1-(3-oxo-3-((R)-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrido[1,6-a:2,3-b']dipyrazin-8-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one
(R) -3- (trifluoromethyl) -6,6a,7,8,9, 10-hexahydro-5H-pyridine [1,6-a:2,3-b' ] bipyrazine (51 g) hydrochloride (71 mg, crude) and 3- [ (2S) -2- [ (6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino ] propoxy ] propionic acid (4 j) (75 mg,0.24 mmol) were dissolved in DMF (2 mL), DIPEA (93 mg,0.72 mmol) and HATU (91 mg,0.24 mmol) were added thereto, respectively, and then the reaction was stirred at room temperature for 1H. After the reaction was completed, the reaction solution was purified by Pre-HPLC (instrument and preparation column: preparation of liquid phase using WATERS 2767, preparation column model: xselect C18,5 μm, inner diameter×length=19 mm×150 mm). The preparation method comprises the following steps: the reaction solution was filtered through a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: acetonitrile/water (0.05% ammonia). The gradient elution method comprises the following steps: acetonitrile was eluted from 5% gradient to 50% (elution time 15 min). After lyophilization, 5- (((S) -1- (3-oxo-3- ((R) -3- (trifluoromethyl) -5, 6a,7,9, 10-hexahydro-8H-pyridine [1,6-a:2,3-b' ] bipyrazinyl-8-yl) propoxy) propan-2-yl) amino) -4- (trifluoromethyl) pyrazin-3 (2H) -one (compound 51) (55 mg,42%, 2-step yield).
LCMS m/z＝550.1[M+1] + 。
1 H NMR(400MHz,CDCl 3 )δ10.46-10.19(m,1H),8.26-8.17(m,1H),7.65(s,1H),5.90-5.73(m,1H),4.82-4.56(m,2H),4.00-3.79(m,4H),3.69-3.63(m,1H),3.53-3.36(m,2H),3.32-2.48(m,7H),2.29-2.15(m,1H),1.93-1.77(m,1H),1.30(d,3H)。
Example 52:5- (((S) -1- (3-oxo-3- ((S) -3- (trifluoromethyl) -5, 6a,7,9, 10-hexahydro-8H-pyridine [1,6-a:2,3-b' ] bipyrazinyl-8-yl) propoxy) propan-2-yl) amino) -4- (trifluoromethyl) pyrazin-3 (2H) -one (Compound 52)
5-(((S)-1-(3-oxo-3-((S)-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrido[1,6-a:2,3-b']dipyrazin-8-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one
Compound 52 Using 2-chloro-5- (trifluoromethyl) pyrazine and tert-butyl (R) -3- (hydroxymethyl) piperazine-1-carboxylate as raw materials, the synthesis method of example 51 gave 5- (((S) -1- (3-oxo-3- ((S) -3- (trifluoromethyl) -5, 6a,7,9, 10-hexahydro-8H-pyridine [1,6-a:2,3-b' ] bipyrazinyl-8-yl) propoxy) propan-2-yl) amino) -4- (trifluoromethyl) pyrazin-3 (2H) -one (Compound 52)
LCMS m/z＝550.3[M+1] + 。
1 H NMR(400MHz,CDCl 3 )δ10.68-10.45(m,1H),8.25-8.16(m,1H),7.65(s,1H),5.88-5.72(m,1H),4.85-4.53(m,2H),4.01-3.77(m,4H),3.70-3.62(m,1H),3.56-3.35(m,2H),3.32-2.49(m,7H),2.29-2.14(m,1H),1.94-1.76(m,1H),1.31(d,3H)。
Example 53:5- (((S) -1- (3- ((S) -5, 5-Dioxo-3- (trifluoromethyl) -6a,7,9, 10-tetrahydropyrazin [1,2-d ] pyrido [3,2-b ] [1,4] thiazin-8 (6H) -yl) -3-oxopropoxy) propan-2-yl) amino) -4- (trifluoromethyl) pyridazin-3 (2H) -one (Compound 53)
5-(((S)-1-(3-((S)-5,5-dioxido-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyrido[3,2-b][1,4]thiazin-8(6H)-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one
The first step: (S) -4- (3-bromo-5- (trifluoromethyl) pyridin-2-yl) -3- (hydroxymethyl) piperazine-1-carboxylic acid tert-butyl ester (Compound 53 b)
Tert-butyl(S)-4-(3-bromo-5-(trifluoromethyl)pyridin-2-yl)-3-(hydroxymethyl)piperazine-1-carboxylate
(S) -1-BOC-3-hydroxymethylpiperazine (4.48 g,20.73 mmol) and N, N-diisopropylethylamine (5.36 g,41.46 mmol) were added to a solution of 3-bromo-2-chloro-5-trifluoromethylpyridine (53 a) (5.40 g,20.73mmol of N, N-dimethylformamide (30 mL) at room temperature, nitrogen was replaced, the reaction was warmed to 100℃for 16 hours, after completion of the reaction, cooled to room temperature, ethyl acetate (50 mL) was added to the reaction mixture to dilute the reaction mixture, the reaction mixture was washed with clear water (20 mL. Times.3). The organic phase was concentrated under reduced pressure to give a crude product, which was isolated and purified by column chromatography (petroleum ether: ethyl acetate (v/v) =5:3) to give (S) -4- (3-bromo-5- (trifluoromethyl) pyridin-2-yl) -3- (hydroxymethyl) piperazine-1-carboxylic acid tert-butyl ester (53 b) (3.80 g, 42%).
LCMS m/z＝384.1[M-55] + 。
And a second step of: (S) -3- ((Acetylthio) methyl) -4- (3-bromo-5- (trifluoromethyl) pyridin-2-yl) piperazine-1-carboxylic acid tert-butyl ester (Compound 53 c)
Tert-butyl(S)-3-((acetylthio)methyl)-4-(3-bromo-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate
Thioacetic acid (0.79 g,10.36 mmol) was added to a solution of (S) -tert-butyl 4- (3-bromo-5- (trifluoromethyl) pyridin-2-yl) -3- (hydroxymethyl) piperazine-1-carboxylate (53 b) (3.80 g,8.63 mmol), triphenylphosphine (2.72 g,10.36 mmol), DEAD (1.80 g,10.36 mmol) in anhydrous tetrahydrofuran (30 mL) under an ice-water bath. After keeping the ice water bath for 2 hours, the reaction was carried out at room temperature for 16 hours. Silica gel is directly added to the reaction solution for sample mixing, and (petroleum ether: ethyl acetate (v/v) =10:1) is separated and purified by column chromatography to obtain (S) -3- ((acetylthio) methyl) -4- (3-bromo-5- (trifluoromethyl) pyridin-2-yl) piperazine-1-carboxylic acid tert-butyl ester (53 c) (0.20 g, 5%).
LCMS m/z＝442.0[M-55] + 。
And a third step of: sodium salt of (S) - (1- (3-bromo-5- (trifluoromethyl) pyridin-2-yl) -4- (tert-butoxycarbonyl) piperazin-2-yl) methyl mercaptan (Compound 53 d)
sodium(S)-(1-(3-bromo-5-(trifluoromethyl)pyridin-2-yl)-4-(tert-butoxycarbonyl)piperazin-2-yl)methanethiolate
A0.5M sodium ethoxide solution (15 mg,0.64mmol,1.28 mL) was added to a solution of (S) -3- ((acetylthio) methyl) -4- (3-bromo-5- (trifluoromethyl) pyridin-2-yl) piperazine-1-carboxylic acid tert-butyl ester (53 c) (0.32 g,0.64 mmol) in anhydrous tetrahydrofuran (2 mL) under an ice-water bath, and then left to react at room temperature for 0.5 h. After the completion of the reaction, the dry reaction solution was directly concentrated to give the sodium salt (300 mg) of (S) - (1- (3-bromo-5- (trifluoromethyl) pyridin-2-yl) -4- (tert-butoxycarbonyl) piperazin-2-yl) methyl mercaptan (53 d) which was directly used as the next step without purification.
LCMS m/z＝431.9[M-23] + 。
Fourth step: (S) -3- (trifluoromethyl) -6a,7,9, 10-Tetrahydropyrazino [1,2-d ] pyrido [3,2-b ] [1,4] thiazine-8 (6H) -carboxylic acid tert-butyl ester (Compound 53 e)
Tert-butyl(S)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyrido[3,2-b][1,4]thiazine-8(6H)-carboxylate
Tris (dibenzylideneandene acetonide) dipalladium (29 mg,0.032 mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (36 mg,0.063 mmol), N-diisopropylethylamine (163 mg,1.26 mmol) were added to a solution of the sodium salt (300 mg) of (S) - (1- (3-bromo-5- (trifluoromethyl) pyridin-2-yl) -4- (t-butoxycarbonyl) piperazin-2-yl) methyl mercaptan (53 d) in dry dioxane (2 mL) at room temperature under nitrogen. After nitrogen was replaced 3 times, the temperature was raised to 70℃and the reaction was carried out for 2 hours. After the reaction was completed, the reaction was quenched with water (2 mL), extracted with ethyl acetate (5 mLx 3), and the organic layer was dried over anhydrous sodium sulfate, filtered with suction, and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was isolated and purified by prep. plate (PE: EA (v/v) =5:1) to give (S) -3- (trifluoromethyl) -6a,7,9, 10-tetrahydropyrazino [1,2-d ] pyrido [3,2-b ] [1,4] thiazine-8 (6H) -carboxylic acid tert-butyl ester (53 e) (100 mg,41%,2 step yield).
LCMS m/z＝376.1[M+1] + 。
Fifth step: (S) -3- (trifluoromethyl) -6a,7,9, 10-Tetrahydropyrazino [1,2-d ] pyrido [3,2-b ] [1,4] thiazine-8 (6H) -carboxylic acid tert-butyl ester 5, 5-dioxide (Compound 53 f)
Tert-butyl(S)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyrido[3,2-b][1,4]thiazine-8(6H)-carboxylate 5,5-dioxide
M-chloroperoxybenzoic acid (219 mg,1.08 mmol) was added in portions to a solution of (S) -3- (trifluoromethyl) -6a,7,9, 10-tetrahydropyrazino [1,2-d ] pyrido [3,2-b ] [1,4] thiazine-8 (6H) -carboxylic acid tert-butyl ester (53 e) (100 mg,0.27 mmol) in methylene chloride (2 mL) at room temperature, and the reaction was maintained at room temperature for 5 hours. After the reaction, the reaction was quenched with water (2 mL), extracted with dichloromethane (10 mLx 2), the organic phase was dried over anhydrous sodium sulfate, filtered off with suction, and the filtrate was concentrated under reduced pressure to give crude product. The crude product was isolated and purified by prep. plate (petroleum ether: ethyl acetate (v/v) =5:2) to give the desired product (S) -3- (trifluoromethyl) -6a,7,9, 10-tetrahydropyrazino [1,2-d ] pyrido [3,2-b ] [1,4] thiazine-8 (6H) -carboxylic acid tert-butyl ester 5, 5-dioxide (53 f) (60 mg, 55%).
LCMS m/z＝352.1[M-55] + 。
Sixth step: hydrochloride of (S) -3- (trifluoromethyl) -6,6a,7,8,9, 10-hexahydropyrazino [1,2-d ] pyrido [3,2-b ] [1,4] thiazine 5, 5-dioxide (Compound 53 g)
(S)-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydropyrazino[1,2-d]pyrido[3,2-b][1,4]thiazine5,5-dioxide
(S) -3- (trifluoromethyl) -6a,7,9, 10-tetrahydropyrazino [1,2-d ] pyrido [3,2-b ] [1,4] thiazine-8 (6H) -carboxylic acid tert-butyl ester 5, 5-dioxide (53 f) (50 mg,0.12 mmol) was dissolved in 4N dioxane hydrochloride solution (4 mL) at room temperature, and the reaction was stirred at room temperature for 2 hours. After the completion of the reaction, the hydrochloride (40 mg) of (S) -3- (trifluoromethyl) -6,6a,7,8,9, 10-hexahydropyrazino [1,2-d ] pyrido [3,2-b ] [1,4] thiazine 5, 5-dioxide (53 g) was obtained by concentration under reduced pressure, and the reaction was directly carried out without purification.
LCMS m/z＝308.1[M+1] + 。
Seventh step: 5- (((S) -1- (3- ((S) -5, 5-Dioxo-3- (trifluoromethyl) -6a,7,9, 10-tetrahydropyrazin [1,2-d ] pyrido [3,2-b ] [1,4] thiazin-8 (6H) -yl) -3-oxopropoxy) propan-2-yl) amino) -4- (trifluoromethyl) pyridazin-3 (2H) -one (Compound 53)
5-(((S)-1-(3-((S)-5,5-dioxido-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyrido[3,2-b][1,4]thiazin-8(6H)-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one
HATU (49 mg,0.13 mmol) was added to a solution of (S) -3- (trifluoromethyl) -6,6a,7,8,9, 10-hexahydropyrazino [1,2-d ] pyrido [3,2-b ] [1,4] thiazine 5, 5-dioxide (53 g) in hydrochloride (40 mg), 3- [ (2S) -2- [ (6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino ] propoxy ] propionic acid (4 j) (40 mg,0.13 mmol), N-diisopropylethylamine (17 mg,0.13 mmol) in N, N-dimethylformamide (2 mL) at room temperature, followed by stirring at room temperature for 1 hour. After the reaction was completed, the reaction solution was purified by Pre-HPLC (instrument and preparation column: preparation of liquid phase using WATERS 2767, preparation column model: xselect C18,5 μm, inner diameter×length=19 mm×150 mm). The preparation method comprises the following steps: the reaction solution was filtered through a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: acetonitrile/water (0.05% ammonia). The gradient elution method comprises the following steps: acetonitrile was eluted from 5% gradient to 50% (elution time 15 min). After lyophilization, 5- (((S) -1- (3- ((S) -5, 5-dioxo-3- (trifluoromethyl) -6a,7,9, 10-tetrahydropyrazin [1,2-d ] pyrido [3,2-b ] [1,4] thiazin-8 (6H) -yl) -3-oxopropoxy) propan-2-yl) amino) -4- (trifluoromethyl) pyridazin-3 (2H) -one (compound 53) (25 mg,34%,2 step yield).
LCMS m/z＝599.2[M+1] + 。
1 H NMR(400MHz,DMSO-d 6 )δ11.91(s,1H),8.75(d,1H),8.23(d,1H),7.91(s,1H),6.34-6.19(m,1H),4.88-4.66(m,1H),4.61-4.30(m,1H),4.26-3.85(m,4H),3.76-3.61(m,3H),3.50(d,2H),3.29-3.06(m,2H),2.93-2.81(m,1H),2.74-2.56(m,2H),1.17(d,3H)。
Example 54:5- (((S) -1- (3- ((R) -5, 5-Dioxo-3- (trifluoromethyl) -6a,7,9, 10-tetrahydropyrazin [1,2-d ] pyrido [3,2-b ] [1,4] thiazin-8 (6H) -yl) -3-oxopropoxy) propan-2-yl) amino) -4- (trifluoromethyl) pyridazin-3 (2H) -one (Compound 54)
5-(((S)-1-(3-((R)-5,5-dioxido-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyrido[3,2-b][1,4]thiazin-8(6H)-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one
Compound 54 was prepared according to the method of reference example 53 starting from 3-bromo-2-chloro-5-trifluoromethylpyridine, (R) -1-Boc-3-hydroxymethylpiperazine and 3- [ (2S) -2- [ (6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino ] propoxy ] propionic acid (4 j) to give 5- (((S) -1- (3- ((R) -5, 5-dioxo-3- (trifluoromethyl) -6a,7,9, 10-tetrahydropyrazin [1,2-d ] pyrido [3,2-b ] [1,4] thiazin-8 (6H) -yl) -3-oxopropoxy) propan-2-yl) amino) -4- (trifluoromethyl) pyridazin-3 (2H) -one (compound 54).
LCMS m/z＝599.1[M+1] + 。
1 H NMR(400MHz,DMSO-d 6 )δ12.44(s,1H),8.74(s,1H),8.23(s,1H),7.91(s,1H),6.32-6.20(m,1H),4.85-4.67(m,1H),4.59-4.31(m,1H),4.21-3.89(m,4H),3.75-3.63(m,3H),3.49(d,2H),3.29-3.05(m,2H),2.93-2.81(m,1H),2.71-2.57(m,2H),1.16(d,3H)
Example 55:5- (((2S) -1- (2-hydroxy-3-oxo-3- ((R) -3- (trifluoromethyl) -5, 6a,7,9, 10-hexahydro-8H-pyrido [1,6-a:2,3-b' ] bipyrazinyl-8-yl) propoxy) propan-2-yl) amino) -4- (trifluoromethyl) pyridazin-3 (2H) -one (Compound 55)
5-(((2S)-1-(2-hydroxy-3-oxo-3-((R)-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrido[1,6-a:2,3-b']dipyrazin-8-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one
Compound 55 starting from (R) -3- (trifluoromethyl) -6,6a,7,8,9, 10-hexahydro-5H-pyridine [1,6-a:2,3-b '] bipyrazine (51 g) hydrochloride and 2-hydroxy-3- ((S) -2- ((6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino) propoxy) propanoic acid (55 a) (intermediate synthesis prepared according to WO 2021087018), the synthetic method of reference example 51 gives 5- (((2S) -1- (2-hydroxy-3-oxo-3- ((R) -3- (trifluoromethyl) -5, 6a,7,9, 10-hexahydro-8H-pyrido [1,6-a:2,3-b' ] bipyrazin-8-yl) propoxy) propan 2-yl) amino) -4- (trifluoromethyl) pyridazin-3 (2H) -one (compound 55).
LCMS m/z＝566.2[M+1] + 。
1 H NMR(400MHz,CDCl 3 )δ10.47-10.33(m,1H),8.23(s,1H),7.65(s,1H),5.82-5.58(m,1H),4.89-4.50(m,3H),4.00-3.41(m,8H),3.28-2.58(m,5H),2.32-2.13(m,1H),1.95-1.78(m,1H),1.31(d,3H)。
Example 56: trifluoroacetate salt of 5- (((2S) -1- (2-hydroxy-3-oxo-3- ((R) -3- (trifluoromethyl) -5, 6a,7,9, 10-hexahydro-8H-pyrazin [1,2-a ] [1,8] naphthyridin-8-yl) propoxy) propan-2-yl) amino) -4- (trifluoromethyl) pyridazin-3 (2H) -one (Compound 56)
5-(((2S)-1-(2-hydroxy-3-oxo-3-((R)-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a][1,8]naphthyridin-8-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one trifluoroacetate
The first step: 1-benzyl 4- (tert-butyl) (R) -2- (2- (2-hydroxy-5- (trifluoromethyl) pyridin-3-yl) vinyl) piperazine-1, 4-dicarboxylic acid ester (Compound 56 b)
Benzyl 4-(tert-butyl)(R)-2-(2-(2-hydroxy-5-(trifluoromethyl)pyridin-3-yl)vinyl)piperazine-1,4-dicarboxylate
1-benzyl 4- (tert-butyl) (R) -2-vinylpiperazine-1, 4-dicarboxylic acid ester (56 a) (synthesized in reference to WO 2015013835) (2.5 g,7.22 mmol) was dissolved in DMF (20 mL) and 3-bromo-2-hydroxy-5- (trifluoromethyl) pyridine (2.62 g,10.83 mmol), DIPEA (2.80 g,21.66 mmol), xphos (1.38 g,2.89 mmol) and Pd (OAc) were added at room temperature 2 (320 mg,1.44 mmol). The reaction mixture was stirred overnight at 115℃with nitrogen displacement, quenched with water, extracted with ethyl acetate (50 mL. Times.3), the organic phases were combined, backwashed with saturated brine (50 mL. Times.3), dried over anhydrous sodium sulfate, filtered off with suction, and the filtrate concentrated under reduced pressure to give a residue. Purification of the residue by column chromatography on silica gel (DCM in thf=5-10%) gave: 1-benzyl 4- (tert-butyl) (R) -2- (2- (2-hydroxy-5- (trifluoromethyl) pyridin-3-yl) vinyl) piperazine-1, 4-dicarboxylic acid ester (compound 56 b) (530 mg, 14%).
LCMS m/z＝452.2[M-55] + 。
And a second step of: (R) -3- (2- (2-hydroxy-5- (trifluoromethyl) pyridin-3-yl) ethyl) piperazine-1-carboxylic acid tert-butyl ester (Compound 56 c)
Tert-butyl(R)-3-(2-(2-hydroxy-5-(trifluoromethyl)pyridin-3-yl)ethyl)piperazine-1-carboxylate
1-benzyl 4- (tert-butyl) (R) -2- (2- (2-hydroxy-5- (trifluoromethyl) pyridin-3-yl) vinyl) piperazine-1, 4-dicarboxylate (compound 56 b) (1 g,1.97 mmol) was dissolved in MeOH (5 mL), pd/C (100 mg) was added, the reaction stirred at room temperature overnight, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent to give (R) -3- (2- (2-hydroxy-5- (trifluoromethyl) pyridin-3-yl) ethyl) piperazine-1-carboxylate (compound 56C) (700 mg) which was directly added to the next step without further purification.
LCMS m/z＝376.2[M+1] + 。
And a third step of: (R) -3- (trifluoromethyl) -5, 6a,7,9, 10-hexahydro-8H-pyrazino [1,2-a ] [1,8] naphthyridine-8-carboxylic acid tert-butyl ester (Compound 56 d)
Tert-butyl(R)-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a][1,8]naphthyridine-8-carboxylate
(R) -3- (2- (2-hydroxy-5- (trifluoromethyl) pyridin-3-yl) ethyl) piperazine-1-carboxylic acid tert-butyl ester (compound 56 c) (700 mg,1.86 mmol) was dissolved in DMSO (15 mL) at room temperature and PyBOP (970 mg,1.86 mmol) and DIPEA (720 mg,5.58 mmol) were added. The reaction was quenched with water at 60℃overnight, extracted with ethyl acetate (10 mL. Times.3), the organic phases were combined, backwashed with saturated brine (10 mL. Times.3), dried over anhydrous sodium sulfate, filtered off with suction, and the filtrate concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (10% ea in PE) to give tert-butyl (R) -3- (trifluoromethyl) -5, 6a,7,9, 10-hexahydro-8H-pyrazino [1,2-a ] [1,8] naphthyridine-8-carboxylate (compound 56 d) (270 mg,38%,2 steps reaction).
LCMS m/z＝358.2[M+1] + 。
Fourth step: hydrochloride of (R) -3- (trifluoromethyl) -6,6a,7,8,9, 10-hexahydro-5H-pyrazino [1,2-a ] [1,8] naphthyridine (Compound 56 e)
(R)-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a][1,8]naphthyridine
(R) -3- (trifluoromethyl) -5, 6a,7,9, 10-hexahydro-8H-pyrazino [1,2-a ] [1,8] naphthyridine-8-carboxylic acid tert-butyl ester (compound 56 d) (39 mg,0.11 mmol) was dissolved in hydrogen chloride-1, 4-dioxane solution (4.0M, 2mL,8 mmol) at room temperature, and the reaction was completed at room temperature. The solvent was concentrated under reduced pressure to give (R) -3- (trifluoromethyl) -6,6a,7,8,9, 10-hexahydro-5H-pyrazino [1,2-a ] [1,8] naphthyridine (compound 55 e) hydrochloride (36 mg) which was directly taken to the next step without further purification.
LCMS m/z＝258.2[M+1]+
Fifth step: trifluoroacetate salt of 5- (((2S) -1- (2-hydroxy-3-oxo-3- ((R) - (3- (trifluoromethyl) -5, 6a,7,9, 10-hexahydro-8H-pyrazino [1,2-a ] [1,8] naphthyridin-8-yl) propoxy) propan-2-yl) amino) -4- (trifluoromethyl) pyridazin-3 (2H) -one (Compound 56)
5-(((2S)-1-(2-hydroxy-3-oxo-3-((R)-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a][1,8]naphthyridin-8-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one trifluoroacetate
Hydrochloride (36 mg,0.11 mmol) of (R) -3- (trifluoromethyl) -6,6a,7,8,9, 10-hexahydro-5H-pyrazino [1,2-a ] [1,8] naphthyridine (compound 56 e) and 2-hydroxy-3- [ (2S) -2- [ (6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino ] propoxy ] propionic acid (36 mg,0.11 mmol) were dissolved in DMF (2 mL), and DIPEA (43 mg,0.33 mmol) and HATU (42 mg,0.11 mmol) were added thereto, respectively, and then reacted by stirring at room temperature for 3 hours. After the reaction, the reaction mixture was purified by Pre-HPLC (instrument and preparation column: preparation of liquid phase by SHIMADZULC-20AP, preparation column model: phenomenex C18. Preparation method: filtration of the reaction mixture with 0.45 μm filter membrane, preparation of sample liquid. Mobile phase system: acetonitrile/water (containing 0.01% trifluoroacetic acid.) gradient elution method: acetonitrile was eluted with a gradient of 10% -40% (elution time 10 min.) after lyophilization, trifluoroacetate (10 mg, 14%) of 5- (((2S) -1- (2-hydroxy-3-oxo-3- ((R) -3- (trifluoromethyl) -5, 6a,7,9, 10-hexahydro-8H-pyrazin [1,2-a ] [1,8] naphthyridin-8-yl) propoxy) propan-2-yl) amino) -4- (trifluoromethyl) pyridazin-3 (2H) -one (Compound 56) was obtained, 2-step reaction.
LCMS m/z＝565.3[M+1] + 。
1 H NMR(400MHz,CDCl 3 )δ10.94(s,1H),8.26(s,1H),7.76(s,1H),7.50-7.35(m,1H),5.87-5.61(m,1H),5.10-4.83(m,1H),4.76-4.50(m,2H),3.96-2.59(m,13H),2.30-2.01(m,1H),1.88-1.63(m,1H),1.31(d,3H)。
Example 56-1:5- (((S) -1- ((S) -2-hydroxy-3-oxo-3- ((R) -3- (trifluoromethyl) -5, 6a,7,9, 10-hexahydro-8H-pyrazin [1,2-a ] [1,8] naphthyridin-8-yl) propoxy) propan-2-yl) amino) -4- (trifluoromethyl) pyridazin-3 (2H) -one (Compound 56-1)
5-(((S)-1-((S)-2-hydroxy-3-oxo-3-((R)-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a][1,8]naphthyridin-8-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one
5- (((S) -1- ((R) -2-hydroxy-3-oxo-3- ((R) -3- (trifluoromethyl) -5, 6a,7,9, 10-hexahydro-8H-pyrazin [1,2-a ] [1,8] naphthyridin-8-yl) propoxy) propan-2-yl) amino) -4- (trifluoromethyl) pyridazin-3 (2H) -one (Compound 56-2)
5-(((S)-1-((R)-2-hydroxy-3-oxo-3-((R)-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a][1,8]naphthyridin-8-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one
Compound 56 was purified by SFC on AD Column (apparatus and preparation Column: waters 150 SFC, preparation Column model: chiralcel Column (250 mm. Times.30 mm,10 μm)). The preparation method comprises the following steps: compound 56 was dissolved in acetonitrile and filtered through a 0.45 μm filter to prepare a sample solution. Mobile phase system: afor CO 2 and B for MeOH(0.1％NH 3 ·H 2 O). The gradient elution method comprises the following steps: 25% phase B (flow rate: 100mL/min; elution time 2.5 min), and Compound 56-1 and Compound 56-2 were obtained after lyophilization.
Analytical method (instrument and preparative column: high performance liquid chromatograph-normal phase chromatograph, preparative column model: SHIMADZULC-30AD sf (50×4.6mm,3 um)) mobile phase system: afor CO 2 and B for MeOH(0.05％DEA)。
The retention time t=1.341 min (P1) is example 56-a (example 56-a is one of the structures of compound 56-1 and compound 56-2).
LCMS m/z＝565.3[M+1] + 。
1 H NMR(400MHz,CDCl 3 )δ10.05(s,1H),8.24(s,1H),7.65(s,1H),7.35(s,1H),5.81-5.66(m,1H),5.03-4.90(m,1H),4.72-4.50(m,2H),3.98-2.54(m,13H),2.17-2.03(m,1H),1.84-1.69(m,1H),1.31(d,3H).
Retention time t= 1.531min (P2) is example 56-B (example 56-B is one of the structures of compound 56-1 and compound 56-2).
LCMS m/z＝565.3[M+1] +
1 H NMR(400MHz,CDCl 3 )δ9.81(s,1H),8.24(s,1H),7.64(s,1H),7.34(s,1H),5.81-5.59(m,1H),5.03-4.86(m,1H),4.77-4.48(m,2H),3.96-2.63(m,13H),2.15-1.99(m,1H),1.82-1.67(m,1H),1.31(d,3H)。
Example 57: synthesis of Compound 57-A and Compound 57-B
The first step: preparation of Compound 57a
3- (trifluoromethyl) -6, 7a,8,10, 11-hexahydro-9H-pyrazino [1,2-d]Pyrido [3,2-b][1,4]The oxazepine-9-carboxylic acid tert-butyl ester (3 d) was purified by SFC on AD Column (apparatus and preparation Column: waters 150 AP, preparation Column model: chiralpak Column). The preparation method comprises the following steps: compound 3d was dissolved in acetonitrile and filtered through a 0.45 μm filter to prepare a sample solution. Mobile phase system: afor CO 2 and B for MeOH(0.1％NH 3 ·H 2 O). The gradient elution method comprises the following steps: 10% phase B (flow rate: 70mL/min; elution time: 6 min), and lyophilizing to obtain compound 3d-Peak-1 and compound 3d-Peak-2.
Analytical method (apparatus and method)Preparation of the column: SHIMADZU LC-30AD sfc, prepared column model was: chiralpak AD-3.50X4.6 mm I.D.,3 μm) mobile phase system: afor CO 2 and B for MeOH(0.05％DEA)。
Compound 3d-Peak-1 retention time was t=0.587 min, compound 57a.
LCMS m/z＝374.2[M+1] + 。
Compound 3d-Peak-2 retention time was t=0.677 min.
And a second step of: preparation of Compound 57b
Compound 57a (0.29 g,0.77 mmol) was dissolved in HCl/dioxane (10 mL, 4M) and the mixture was stirred at room temperature for 2h. The reaction solution was concentrated under reduced pressure to give hydrochloride (270 mg) of compound 57b, which was used directly in the next step.
LCMS m/z＝274.1[M+1] + 。
And a third step of: preparation of Compound 57-A
HATU (300 mg,0.78 mmol) was added to a solution of compound 57b hydrochloride (270 mg,0.78 mmol), 2-hydroxy-3- ((S) -2- ((6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino) propoxy) propionic acid (55 a) (250 mg,0.78 mmol), DIPEA (300 mg,0.78 mmol) in N, N-dimethylformamide (5 mL) at room temperature and then stirred at room temperature for 1 hour. After the reaction, the reaction mixture was purified by Pre-HPLC (instrument and preparation column: preparation of liquid phase using SHIMADZU LC-20AP, preparation column model: phenomnex C18). The preparation method comprises the following steps: the reaction solution was filtered through a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: a is 10mM NH 4 HCO 3 in H 2 O; b is acetonitrile. The gradient elution method comprises the following steps: acetonitrile from 25% to 50% (elution)Time 10 min). Compound 57-A (compound 57 is one of the structures of compound 57-1 and compound 57-2) is obtained after lyophilization.
LCMS m/z＝581.3[M+1] + 。
1 H NMR(400MHz,DMSO-d 6 )δ12.44(s,1H),8.15(s,1H),7.94-7.87(m,1H),7.38–7.32(m,1H),6.33-6.20(m,1H),5.31-5.18(m,1H),4.49-4.38(m,1H),4.35-4.20(m,2H),4.19-3.58(m,8H),3.58-3.35(m,4H),2.17-2.01(m,1H),1.99-1.85(m,1H),1.19-1.09(m,3H)。
Preparation of Compound 57-B
The compound 57-B can be obtained by taking the compound 3d-Peak-2 as a starting material and referring to a synthesis method of the compound 57-A, wherein the compound 57-B is one of the structures of the compound 57-1 and the compound 57-2.
Biological test case
NCI-H1373 cell proliferation inhibition
NCI-H1373 cells were purchased at ATCC, culture conditions: RPMI-1640+10% FBS+1% diabody, cultured at 37 ℃,5% CO 2 In the incubator. NCI-H1373 cells in exponential growth phase were harvested on the first day as clear bottom white 96-well plates at a density of 500 plates/well at 37℃with 5% CO 2 Culturing overnight in incubator, and plating while spreading T 0 And (3) a hole. The next day before dosing, the medium was aspirated, and 90. Mu.L fresh medium and 10. Mu.L of different concentrations of compound were added to each well to give final DMSO concentration of 0.1% per well at 37℃with 5% CO 2 After culturing in the incubator for 72 hours, the medium was changed and the compound was newly formulated, and the culture was continued for 72 hours. The next day of dosing while detecting T using CellTiter-Glo kit 0 Board, denoted RLU 0 . After the incubation, 50. Mu.L of detection solution (Cell Viability Assay, promega, G7573) was added to each well, mixed for 2 min, incubated at room temperature for 10 min, and chemiluminescent readings were detected by an enzyme-labeled instrument. The result is processed according to the formula (1) to calculate the compoundCell viability at each concentration was calculated for compound concentration GI at 50% proliferation using origin9.2 software 50 Values. RLU (radio link Unit) compound For drug treatment group readings, RLU control Mean value of the solvent control group.
Growth％＝(RLU compound -RLU 0 )/(RLU control -RLU 0 ) X 100% type (1)
Inhibition of cell proliferation of NCI-H1373 cells by the compounds of Table 1
Sequence number Numbering of compounds GI 50 (nM)
1 Compound 1 ＜50nM
2 Compound 2 ＜50nM
3 Compound 3 ＜50nM
4 Compound 5 ＜50nM
5 Compound 6 ＜50nM
6 Example 7-A ＜50nM
7 Compound 10 <100nM
8 Compound 11 <100nM
9 Trifluoroacetate salt of Compound 13 ＜50nM
10 Compound 23 ＜50nM
11 Compound 25 ＜50nM
12 Compound 27 ＜20nM
13 Compound 28 ＜50nM
14 Compound 29 ＜50nM
15 Compound 31 ＜50nM
16 Compound 32 ＜50nM
17 Compound 33 ＜50nM
18 Compound 34 ＜50nM
19 Compound 37 ＜50nM
20 Compound 43 ＜50nM
21 Compound 44 ＜50nM
22 Compound 48 ＜50nM
23 Compound 50 ＜50nM
24 Compound 51 ＜50nM
25 Trifluoroacetate salt of Compound 56 ＜50nM
26 Compound 57-A ＜50nM
Conclusion: the compounds of the invention have cell proliferation inhibiting activity on NCI-H1373 cells. Inhibition of NCI-H1373 cell proliferation 50 < 100nM, e.g., trifluoroacetate salt of Compounds 28, 31, 43, 51, 56, 57-A vs. NCI-H1373 cell proliferation inhibitory Activity GI 50 The values were 5.1nM, 6nM, 8nM, 6nM, 11nM, 13nM, respectively.
PARP7 enzyme Activity test assay
PARP7 chemofluorescence detection kit was purchased from BPS Bioscience. The histone solution in the kit was diluted 5-fold with 1X PBS, 25 μl of the histone dilution was taken into a microplate, and incubated overnight at 4 ℃. After incubation, the plates were washed 3 times with P BST (0.05% Tween-20), 100. Mu.L of blocking solution was added to the microplates and incubated at 25℃for 90 minutes; after incubation, the PBST plates were washed 3 times. 2.5. Mu.L of the compound and 12.5. Mu.L of the substrate mixture (1.25. Mu.L of 10 XPARP test buffer; 1.25. Mu.L of 10 XPARP test mixture; 10. Mu.L of double distilled water) diluted with the test buffer were taken up in the microplate. Diluting PARP7 enzyme to 6 ng/. Mu.L, taking 10. Mu.L to a microplate, and incubating the reaction system at 25 ℃ for 60 minutes;
After incubation, the PBST plates were washed 3 times. Strepitavidin-HRP was diluted 50-fold with blocking solution and 25. Mu.L was then applied to the microplate and incubated at 25℃for 30 min. After incubation, PBST was washed 3 times, ELISA ECL substrate A and substrate B were mixed 1:1 (v/v), 50. Mu.L was taken to microwell plates, and chemiluminescent values were read.
The inhibition ratio was calculated according to formula 1, wherein RLU sample For compound well read values, RLU max For solvent control well read values, RLU min For PARP7 enzyme free control well reads, curve fitting was performed by four parameters (log (inhibitor) vs. response-Variable slope) using GraphPad Prism software and IC was calculated 50 Values.
Inhibition％＝(1-(RLU sample -RLU min )/(RLU max -RLU min ) 100% (formula 1)
TABLE 2 inhibition of PARP7 enzyme by Compounds
Sequence number Compounds of formula (I) PARP7 IC 50 (nM)
1 Compound 1 <100nM
2 Compound 2 <100nM
3 Compound 5 <100nM
4 Compound 6 <100nM
5 Trifluoroacetate salt of Compound 13 <100nM
6 Compound 33 <100nM
7 Compound 51 <100nM
Conclusion: the compounds of the invention have an inhibitory effect on PARP7 enzymes, e.g. compounds 33, 51 have an IC for PARP7 enzymes 50 The values were 0.88nM and 0.78nM, respectively.
MARING test experiment in NCI-H1373 cells
NCI-H1373 cells were purchased at ATCC, culture conditions: RPMI-1640+10% FBS+1% diabody, cultured at 37 ℃,5% CO 2 In the incubator. NCI-H1373 cells in exponential growth phase were collected on the first day as clear bottom white 6-well plates with a plating density of 2X 10 5 Every well, at 37 ℃,5% CO 2 Incubate overnight in incubator. The next day before dosing, the medium was removed by pipetting, 1mL fresh medium and 1mL of compound at different concentrations were added to each well to give final DMSO concentration of 0.1% per well at 37℃with 5% CO 2 Culturing in incubator for 48 hr. After the completion of the culture, the cells were collected. 35. Mu.L of cell lysate was added to each tube and lysed on ice for 15 minutes, during which vortex shaking occurred; centrifuging at 13000rpm at 4deg.C for 10 min, and collecting supernatant. Detection kit using BCA (Biyundian)P0009) protein quantification was performed to calculate the sample protein concentration. Diluting the protein concentration of each tube of sample to 0.8mg/mL with 0.1 Xsample buffer, taking 4 mu L of diluent and 1 mu L of 5 Xmix, and mixing uniformly; the mixture was allowed to stand at 95℃for 5min to denature the protein. The sample was applied according to WES (ProteinSimple), wherein the dilution ratio of Poly/Mono-ADP Ribose (E6F 6A) Rabbit mAb was 1:100, and the dilution ratio of β -action (8H 10D 10) Mouse mAb was 1:400, and the samples were run on a machine. Results MARING was calculated for each concentration of compound by treatment according to formula (2) and IC was fitted using GraphPad Prism 8 software 50 Values. Corr. Area compound Peak area for drug treatment group, corr control Peak area for the solvent control group.
MARylation％＝Average(Corr.Area compound /Corr.Area control ) X 100 type (2)
TABLE 3 MARING inhibitory Activity of Compounds in NCI-H1373 cells
Sequence number Compounds of formula (I) PARP7 IC 50 (nM)
1 Compound 51 <30nM
2 Compound 57-A <30nM
Conclusion: the compounds of the invention have inhibitory effect on MARylation in NCI-H1373 cells.
4. Mouse pharmacokinetic test
1.1 test animals: male BALB/c mice, 18-20 g, 9/compound. Purchased from Chengdu laboratory animals Inc.
1.2 test design: on the day of the trial, 36 BALB/c mice were randomly grouped by body weight. The water is not forbidden for 12-14 h after 1 day of feeding, and the feed is fed for 4h after the feeding.
Administration information
Intravenous administration vehicle: 5% DMA+5% Solutol+90% Saline;
gastric lavage dosing vehicle: 5% DMSO+5% Solutol+30% PEG400+60% (20% SBE-. Beta. -CD)
Before and after administration, 0.06ml of isoflurane was anesthetized and collected via orbit, placed in an EDTAK2 centrifuge tube, centrifuged at 5000rpm at 4℃for 10min, and plasma was collected. The blood sampling time points of vein and stomach irrigation are 0,5,15,30min,1,2,4,6,8 and 24h. All samples were stored at-80 ℃ prior to analytical testing.
TABLE 4 pharmacokinetic parameters of Compounds in mouse plasma
-: is not applicable.
Conclusion: the compounds of the invention have higher exposure in mice.
5. Beagle pharmacokinetic testing
The purpose of the experiment is as follows: the concentration of the test substance in the beagle plasma was measured by administering the test substance to the beagle by intravenous and intragastric administration at a single dose, and the in vivo pharmacokinetic profile of the test substance was evaluated.
Test animals: male beagle, about 8-11 kg, 3 compounds per compound, purchased from Beijing Mas Biotechnology Co.
The test method comprises the following steps: on the day of the trial, 12 beagle dogs were randomly grouped by body weight. The water is not forbidden for 12-14 h after 1 day of feeding, and the feed is fed for 4h after the feeding.
Administration information
Intravenous administration vehicle: 5% DMA+5% Solutol+90% Saline; gastric lavage dosing vehicle: 0.5% MC
Sampling: blood 1ml was taken through the vein of the limb before and after administration and placed in an EDTAK2 centrifuge tube. The plasma was collected by centrifugation at 5000rpm at 4℃for 10 min.
Blood collection time point: 0,5,15,30min,1,2,4,6,8,10,12,24h. All samples were stored at-80 ℃ prior to analytical testing. The samples were quantitatively analyzed by LC-MS/MS.
Table 5 pharmacokinetic parameters of test compounds in beagle plasma
-: is not applicable.
Conclusion: compounds 33, 51 have better PK properties on beagle dogs.
CYP450 enzyme inhibition test
The test adopts the mixed human liver microsomes to be respectively tested with different concentrations After incubation of the compound (0.05-50 mu M) and the corresponding probe, the change of CYP enzyme activity is measured, and IC is calculated 50 The inhibition potential of the test compounds for each CYP enzyme was evaluated.
The test results show that compound 51 has substantially no inhibition of the CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 enzymes, IC 50 The values were all greater than 50. Mu.M.
hERG Potassium ion channel action test
Experiment platform: electrophysiological manual patch clamp system
Cell line: chinese Hamster Ovary (CHO) cell lines stably expressing hERG potassium ion channels
The experimental method comprises the following steps: CHO (Chinese Hamster Ovary) cells stably expressing the hERG potassium channel, hERG potassium channel currents were recorded using whole cell patch clamp technique at room temperature. The glass microelectrode is formed by drawing a glass electrode blank (BF 150-86-10, sutter) through a drawing instrument, the tip resistance after the electrode inner liquid is poured is about 2-5MΩ, and the glass microelectrode can be connected to a patch clamp amplifier after being inserted into an amplifier probe. The clamp voltage and data recording are controlled and recorded by pClamp 10 software through a computer, the sampling frequency is 10kHz, and the filtering frequency is 2kHz. After whole cell recordings were obtained, cells were clamped at-80 mV, and hERG potassium current was induced (I hERG ) From-80 mV gives a depolarization voltage of 2s to +20mV and repolarization to-50 mV for 1s and back to-80 mV. This voltage stimulus was administered every 10s, and the administration was started after the hERG potassium current had stabilized (at least 1 minute). Each test concentration of the compound was administered for at least 1 minute, and at least 2 cells were tested per concentration (n.gtoreq.2).
And (3) data processing: the data analysis was performed using pClamp 10,GraphPad Prism 5 and Excel software. The extent of inhibition of hERG potassium current (-peak hERG tail current induced at 50 mV) by different compound concentrations was calculated using the following formula:
Inhibition％＝[1–(I/Io)]×100％
wherein Inhibition% represents the percent Inhibition of the compound on hERG potassium current, and I and Io represent the magnitude of hERG potassium current after and before dosing, respectively.
Compound IC 50 Calculation was fitted using GraphPad Prism 5 software by the following equation:
Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))
wherein X is the Log value of the detection concentration of the sample, Y is the inhibition percentage under the corresponding concentration, and Bottom and Top are the minimum and maximum inhibition percentages respectively.
Table 6: IC of compounds for hERG potassium channel current inhibition 50 Value of
Compounds of formula (I) IC 50 (μM)
Compound 51 >20μM
8. Liver microsome stability
The test uses canine and human liver microsomes as in vitro models to evaluate the metabolic stability of the compounds. 1. Mu.M of the compound was incubated with the above species liver microsomes, respectively, with the NADPH regeneration system for different times (5,1 0,20,30,60min) at 37℃and the concentration of the compound tested in the resulting samples was measured by the LC-MS/MS method.
Conclusion: the compound of the invention has good liver microsome stability.

Claims (13)

  1. A compound selected from the group consisting of a compound of formula (I) or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein
    Y is selected from O, S, S (=O), S (=O) 2 、S(＝O) 2 N(R y )、N(R y )、C 1-4 Alkylene, -OC 1-3 Alkylene-, -C 1-3 Alkylene group O-, -C 1-3 Alkylene group S-, -C 1-3 Alkylene S (=o) -, C 1-3 Alkylene group S (=o) 2 -、-N(R y )C 1-3 alkylene-or-C 1-3 Alkylene N (R) y ) -said alkylene group optionally being further substituted with 0 to 4 groups selected from H, halogen, =o, = S, OH, cyano, C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 Substituted cycloalkyl;
    R y each independently selected from H, C 1-6 Alkyl or C 3-6 Cycloalkyl, said alkyl or cycloalkyl optionally being further substituted with 0 to 4 groups selected from H, deuterium, halogen, CF 3 OH, cyano, NH 2 、C 1-6 Alkyl, C 1-6 Alkoxy, 3-to 8-membered heterocyclyl or C 3-6 A cycloalkyl substituent substituted, said heterocyclyl containing 1 to 3 heteroatoms selected from O, S or N;
    ring A is selected from C 6-10 Aryl, 5-10 membered heteroaryl or 5-10 membered heterocyclyl, said heteroaryl or heterocyclyl containing 1 to 5 heteroatoms selected from O, S, N;
    ring X is selected from C 6-10 Aryl, 5-10 membered heteroaryl, C 3-10 A carbocycle or 5-10 membered heterocyclyl, said heteroaryl or heterocyclyl containing 1 to 5 heteroatoms selected from O, S or N;
    R x 、R a Each independently selected from H, halogen, cyano, OH, = O, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylthio, -SO 2 -C 1-6 Alkyl, -C (=o) C 1-6 Alkyl, - (CH) 2 ) q -C 3-10 Carbocycle or- (CH) 2 ) q -3 to 12 membered heterocycle, said-CH 2 -, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, carbocycle or heterocycle optionally further substituted with 0 to 4 groups selected from H, halogen, OH, cyano, = O, NH 2 、NH(C 1-6 Alkyl), N (C) 1-6 Alkyl group 2 、C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or a substituent of a 3 to 10 membered heterocyclic ring, said heterocyclic ring containing 1 to 3 heteroatoms selected from O, S or N;
    ring B is selected from 4-11 membered nitrogen-containing heterocycles or C 4-10 A carbocycle;
    R b each independently selected from H, halogen, cyano, OH, = O, C 1-6 Alkyl, C 1-6 Alkoxy or- (CH) 2 ) q -C 3-6 Cycloalkyl, the-CH 2 -, alkyl, alkoxy or cycloalkyl optionally further substituted with 0 to 4 groups selected from H, halogen, OH, cyano, NH 2 、C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 Substituted cycloalkyl;
    w is selected from bond, C 1-3 Alkylene or Q2, the alkylene radicals indicated optionally being further substituted by 0 to 4 radicals selected from H, halogen, CF 3 OH, cyano, NH 2 、C 1-6 Alkyl or C 1-6 Substituted with alkoxy;
    l is selected from L1, L2 or L3;
    L1 is selected from-Q1-Ak 1-Q2-Ak2-Q3-, the right side is connected with a ring B;
    l2 is selected fromThe right side is connected with the ring B;
    l3 is selected fromThe right side is connected with the ring B;
    l4 is selected from-Ak 3-Q4-Ak4-K1-Q5-K2-Ak 5-Q6-or-Ak 3-Q4-Ak4-K1-Q5-, the right side is connected with the ring B;
    ak1 and Ak2 are each independently selected from C 1-4 Alkylene, C 2-4 Alkenylene or C 2-4 Alkynylene, said Ak1 optionally being further substituted with 0 to 4R k1 Substituted, said Ak2 is optionally further substituted with 0 to 4R k2 Substitution;
    ak3, ak4, ak5 are each independently selected from the group consisting of bond, C 1-4 Alkylene, C 2-4 Alkenylene or C 2-4 Alkynylene, said Ak3 optionally being further substituted with 0 to 4R k3 Substituted, said Ak4 is optionally further substituted with 0 to 4R k4 Substituted, said Ak5 is optionally further substituted with 0 to 4R k5 Substitution;
    k1 or K2 is selected from C 1-2 Alkylene, C 3-10 Carbocycle or 3-to 12-membered heterocycle, said alkylene optionally being further substituted with 0 to 4R k6 Substituted, said carbocycle or heterocycle optionally being further substituted with 0 to 4 groups selected from H, halogen, OH, cyano, NH 2 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen substituted C 1-6 Alkyl, C 1-6 Alkoxy, -C 1-6 alkyl-OC 1-6 Alkyl, -O-C 1-6 alkyl-OC 1-6 Alkyl, -O-C 3-8 Carbocycle, C 3-8 A carbocycle, substituted with a substituent of a 4 to 10 membered heterocyclic ring, said heterocyclic ring containing 1 to 3 heteroatoms selected from O, S or N;
    R k1 、R k2 、R k3 、R k4 、R k5 、R k6 、R L1 、R L2 Each independently selected from H, halogen, cyano, OH, = O, NH 2 、NHC 1-6 Alkyl, N (C) 1-6 Alkyl group 2 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, -OC 3-6 Carbocycle, C 3-6 Carbocycle or 4-to 7-membered heterocycle, said alkyl, alkenyl, alkynyl, alkoxy, carbocycle or heterocycle optionally being further substituted with 0 to 4 groups selected from H, halogen, OH, cyano, NH 2 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen substituted C 1-6 Alkyl, C 1-6 Alkoxy, -O-C 3-8 Carbocycle, C 3-8 A carbocycle or a substituent of a 4 to 10 membered heterocyclic ring, said heterocyclic ring containing 1 to 3 heteroatoms selected from O, S or N;
    alternatively, R k1 And R is R k1 、R k2 And R is R k2 、R k1 And R is R k2 、R k3 And R is R k3 、R k4 And R is R k4 、R k5 And R is R k5 、R k 6 And R is R k6 Directly connected to form C 3-6 Carbocycles or 4-to 7-membered heterocycles, said carbocycles or heterocycles optionally being further substituted with 0 to 4 groups selected from H, halogen, = O, OH, cyano, C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 Substituted by substituents of cycloalkyl, said heterocycle containing 1 to 3 substituents selected from O, S orA heteroatom of N;
    q1, Q5 are each independently selected from O, S, N (R q )、C(＝O)、C(＝O)N(R q )、N(R q )C(＝O)、C(＝O)O、OC(＝O)、S(＝O)、S(＝O) 2 、S(＝O) 2 N(R q )、N(R q )S(＝O) 2 、N(R q )C(＝O)N(R q ) Or N (R) q )C(＝O)N(R q )；
    Q2, Q3, Q4, Q6 are each independently selected from a bond or Q1;
    ring E is selected from C 3-6 A carbocycle or a 4 to 7 membered heterocycle containing 1 to 3 heteroatoms selected from O, S or N;
    R q Each independently selected from H, C 1-6 Alkyl or C 3-6 Cycloalkyl, said alkyl or cycloalkyl optionally being further substituted with 0 to 4 groups selected from H, halogen, CF 3 OH, cyano, NH 2 、C 1-6 Alkyl or C 1-6 Substituted with alkoxy;
    alternatively, R q And R is R k1 Or R is k2 Directly linked to form a 4 to 7 membered heterocyclic ring, said heterocyclic ring optionally being further substituted with 0 to 4 groups selected from H, halogen, = O, OH, cyano, C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 A cycloalkyl substituent substituted, said heterocycle containing 1 to 3 heteroatoms selected from O, S or N;
    q is each independently selected from 0, 1, 2, 3 or 4;
    a is selected from 0, 1, 2, 3 or 4;
    b is selected from 0, 1, 2, 3 or 4;
    x is selected from 0, 1, 2, 3 or 4;
    s1 is selected from 0, 1, 2, 3 or 4;
    s2 is selected from 0, 1, 2, 3 or 4;
    s3 is selected from 0, 1, 2, 3 or 4.
  2. The compound according to claim 1, or a stereoisomer, a deuteride, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof, wherein the compound is selected from the group consisting of compounds represented by the general formula (II),
    W 1 selected from N or C (R) a4 )；
    Ring X is selected from phenyl, 5-6 membered heteroaryl or 5-6 membered heterocyclyl, said heteroaryl or heterocyclyl containing 1 to 5 heteroatoms selected from O, S or N;
    R a1 、R a2 、R a4 Each independently selected from H, halogen, cyano, OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylthio, -SO 2 -C 1-6 Alkyl, -C (=o) C 1-6 Alkyl, - (CH) 2 ) q -C 3-10 Carbocycle or- (CH) 2 ) q -3 to 12 membered heterocycle, said-CH 2 -, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, carbocycle or heterocycle optionally further substituted with 0 to 4 groups selected from H, halogen, OH, cyano, = O, C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or a substituent of a 3 to 10 membered heterocyclic ring, said heterocyclic ring containing 1 to 3 heteroatoms selected from O, S or N;
    R a3 selected from H, C 1-6 Alkyl, - (CH) 2 ) q -C 3-10 Carbocycle or- (CH) 2 ) q -3 to 12 membered heterocycle, said-CH 2 -, alkyl, carbocyclic or heterocyclic optionallyOne step is substituted with 0 to 4 groups selected from H, halogen, OH, cyano, C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or a substituent of a 3 to 10 membered heterocyclic ring, said heterocyclic ring containing 1 to 3 heteroatoms selected from O, S or N;
    the remaining groups are as defined in claim 1.
  3. The compound according to claim 2, or a stereoisomer, a deuterate, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof,
    y is selected from O, N (R) y )、C 1-3 Alkylene, -OC 1-2 Alkylene-, -C 1-2 Alkylene group O-, -C 1-2 Alkylene group S-, -C 1-2 Alkylene group S (=o) 2 -、-N(R y )C 1-2 alkylene-or-C 1-2 Alkylene N (R) y ) -said alkylene group optionally being further substituted with 0 to 4 groups selected from H, halogen, =o, = S, OH, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, C 1-4 Alkoxy or C 3-6 Substituted cycloalkyl;
    R y each independently selected from H, C 1-4 Alkyl or C 3-6 Cycloalkyl, said alkyl or cycloalkyl optionally being further substituted with 0 to 4 groups selected from H, deuterium, halogen, CF 3 OH, cyano, NH 2 、C 1-4 Alkyl, C 1-4 Alkoxy, 3-to 8-membered heterocyclyl or C 3-6 A cycloalkyl substituent substituted, said heterocyclyl containing 1 to 3 heteroatoms selected from O, S or N;
    R x 、R a1 、R a2 、R a4 each independently selected from H, halogen, cyano, OH, C 1-4 Alkyl, C 2-4 Alkenyl, C 2- 4 Alkynyl, C 1-4 Alkoxy, C 1-4 Alkylthio, -SO 2 -C 1-4 Alkyl, -C (=o) C 1-4 Alkyl, - (CH) 2 ) q -C 3-6 Carbocycle or- (CH) 2 ) q -3 to 6 membered heterocycle, said-CH 2 -, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, carbocycle or heterocycle optionally further substituted with 0 to 4 groups selected from H, halogen, OH, cyano, = O, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl or a substituent of a 3 to 6 membered heterocyclic ring, said heterocyclic ring containing 1 to 3 heteroatoms selected from O, S or N;
    R a3 Selected from H or C 1-4 Alkyl, said alkyl optionally being further substituted with 0 to 4 groups selected from H, halogen, OH, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, C 1-4 Alkoxy or C 3-6 Substituted cycloalkyl;
    ring B is selected from 4-7 membered monocyclic nitrogen-containing heterocycle, 5-11 membered spiro nitrogen-containing heterocycle, 5-11 membered fused ring nitrogen-containing heterocycle, 5-11 membered bridged ring nitrogen-containing heterocycle or C 4-7 A monocyclic carbocycle;
    R b each independently selected from H, halogen, cyano, OH, = O, C 1-4 Alkyl, C 1-4 Alkoxy or- (CH) 2 ) q -C 3-6 Cycloalkyl, the-CH 2 -, alkyl, alkoxy or cycloalkyl optionally further substituted with 0 to 4 groups selected from H, halogen, OH, cyano, NH 2 、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, C 1-4 Alkoxy or C 3-6 Substituted cycloalkyl;
    ak1 and Ak2 are each independently selected from C 1-3 Alkylene, C 2-3 Alkenylene or C 2-3 Alkynylene radicalsThe Ak1 is optionally further substituted with 0 to 4R k1 Substituted, said Ak2 is optionally further substituted with 0 to 4R k2 Substitution;
    ak3, ak4, ak5 are each independently selected from the group consisting of bond, C 1-3 Alkylene, C 2-3 Alkenylene or C 2-3 Alkynylene, said Ak3 optionally being further substituted with 0 to 4R k3 Substituted, said Ak4 is optionally further substituted with 0 to 4R k4 Substituted, said Ak5 is optionally further substituted with 0 to 4R k5 Substitution;
    k1 or K2 is selected from C 1-2 Alkylene, C 3-6 Carbocycle or 3-to 7-membered heterocycle, said alkylene optionally being further substituted with 0 to 4R k6 Substituted, said carbocycle or heterocycle optionally being further substituted with 0 to 4 groups selected from H, halogen, OH, cyano, NH 2 、C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, halogen substituted C 1-4 Alkyl, C 1-4 Alkoxy, -C 1-4 alkyl-OC 1-4 Alkyl, -O-C 1-4 alkyl-OC 1-4 Alkyl, -O-C 3-6 Carbocycle, C 3-6 A carbocycle or a substituent of a 4 to 7 membered heterocyclic ring, said heterocyclic ring containing 1 to 3 heteroatoms selected from O, S or N;
    R k1 、R k2 、R k3 、R k4 、R k5 、R k6 、R L1 、R L2 each independently selected from H, halogen, cyano, OH, = O, NH 2 、NHC 1-4 Alkyl, N (C) 1-4 Alkyl group 2 、C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Carbocycle or 4-to 7-membered heterocycle, said alkyl, alkoxy, carbocycle or heterocycle optionally being further substituted with 0 to 4 groups selected from H, halogen, OH, cyano, NH 2 、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 A carbocycle or a substituent of a 4 to 6 membered heterocyclic ring, said heterocyclic ring containing 1 to 3 heteroatoms selected from O, S or N;
    alternatively, R k1 And R is R k1 、R k2 And R is R k2 、R k1 And R is R k2 、R k3 And R is R k3 、R k4 And R is R k4 、R k5 And R is R k5 、R k 6 And R is R k6 Directly connected to form C 3-6 Carbocycles (e.g. C 3 、C 4 、C 5 Or C 6 ) Or a 4 to 7 membered (e.g. 4, 5, 6 or 7 membered) heterocycle, optionally further substituted with 0 to 4 groups selected from H, halogen, = O, OH, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, C 1-4 Alkoxy or C 3-6 A cycloalkyl substituent substituted, said heterocycle containing 1 to 3 heteroatoms selected from O, S or N;
    q1, Q5 are each independently selected from O, S, N (R q )、C(＝O)、C(＝O)N(R q )、N(R q ) C (=o) or S (=o) 2 ；
    Q2, Q3, Q4, Q6 are each independently selected from a bond or Q1;
    ring E is selected from C 3-6 A carbocycle or a 4 to 6 membered heterocycle containing 1 to 3 heteroatoms selected from O, S or N;
    R q each independently selected from H or C 1-4 Alkyl, said alkyl optionally being further substituted with 0 to 4 groups selected from H, halogen, CF 3 OH, cyano, NH 2 、C 1-4 Alkyl or C 1-4 Substituted with alkoxy;
    alternatively, R q And R is R k1 、R q And R is R k2 Directly linked to form 4 to 7 membersOptionally further substituted with 0 to 4 heterocyclic rings selected from H, halogen, = O, OH, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, C 1-4 Alkoxy or C 3-6 Cycloalkyl substituents are substituted and the heterocycle contains 1 to 3 heteroatoms selected from O, S or N.
  4. The compound of claim 3, or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein,
    W 1 selected from N or CH;
    ring X is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thienyl, thiazolyl, furanyl, oxazolyl, pyrrolyl, pyrazolyl or imidazolyl;
    R x 、R a1 、R a2 Each independently selected from H, F, cl, br, I, cyano, OH, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, vinyl, ethynyl, methoxy, ethoxy, -SCH 3 、-SCH 2 CH 3 、-SO 2 CH 3 、-SO 2 CH 2 CH 3 、-C(＝O)CH 3 、-C(＝O)CH 2 CH 3 Cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, said methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, vinyl, ethynyl, methoxy, ethoxy, -SCH 3 、-SCH 2 CH 3 、-SO 2 CH 3 、-SO 2 CH 2 CH 3 、-C(＝O)CH 3 、-C(＝O)CH 2 CH 3 Optionally further 0 to 4 members selected from H, halogen, OH, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, C 1-4 Alkoxy groupOr C 3-6 Substituted cycloalkyl;
    R a3 selected from H, methyl, ethyl, propyl or isopropyl, said methyl, ethyl, propyl or isopropyl optionally being further substituted with 0 to 4 groups selected from H, halogen, OH, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, C 1-4 Alkoxy or C 3-6 Substituted cycloalkyl;
    y is selected from O, N (R) y )、-N(R y )C(＝O)-、-C(＝O)N(R y )-、-CH 2 -、-CH 2 CH 2 -、-CH 2 CH 2 CH 2 -、-OCH 2 -、-OCH 2 CH 2 -、-CH 2 O-、-CH 2 CH 2 O-、-CH 2 S-、-CH 2 CH 2 S-、-CH 2 S(＝O) 2 -、-CH 2 CH 2 S(＝O) 2 -、-N(R y )CH 2 -、-N(R y )CH 2 CH 2 -、-CH 2 N(R y )-、-CH 2 CH 2 N(R y )-、-N(R y )C(＝O)CH 2 -or-CH 2 C(＝O)N(R y ) -, the CH 2 Optionally further 0 to 2 are selected from H, =o, = S, OH, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, C 1-4 Alkoxy or C 3-6 Substituted cycloalkyl;
    R y each independently selected from H, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, sec-butyl, isobutyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, said methyl, ethyl, propyl, isopropyl, butyl, t-butyl, sec-butyl, isobutyl, cyclopropyl Optionally further 0 to 4 groups selected from H, deuterium, halogen, CF, cyclobutyl, cyclopentyl, cyclohexyl 3 OH, cyano, NH 2 、C 1-4 Alkyl, C 1-4 Alkoxy, 3-to 8-membered heterocyclyl or C 3-6 A cycloalkyl substituent substituted, said heterocyclyl containing 1 to 3 heteroatoms selected from O, S or N;
    ring B is selected from cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, and,
    R b Each independently selected from H, F, cl, br, I, cyano, OH, =o, methyl, ethyl, propyl or isopropyl, said methyl, ethyl, propyl or isopropyl optionally being further substituted with 0 to 4 groups selected from H, halogen, OH, cyano, NH 2 、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, C 1-4 Alkoxy or C 3-6 Substituted cycloalkyl;
    ak1, ak2 are each independently selected from methylene, ethylene, propylene, vinylene, propenylene, ethynylene or propynylene, said Ak1 optionally being further substituted with 0 to 4R k1 Substituted, said Ak2 is optionally further substituted with 0 to 4R k2 Substitution;
    ak3, ak4, ak5 are each independently selected from the group consisting of a bond, methylene, ethylene, propylene, ethenylene, propenylene, ethynylene, or propynylene, said Ak3 optionally being further substituted with 0 to 4R k3 Substituted, said Ak4 is optionally further substituted with 0 to 4R k4 Substituted, said Ak5 is optionally further substituted with 0 to 4R k5 Substitution;
    k1 or K2 is selected from methylene, ethylene, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, piperazine,Morpholine, oxetanyl, benzene ring, pyridine, pyrazine, pyrimidine or pyridazine, said methylene, ethylene optionally being further substituted with 0 to 4R k6 Substituted, said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, piperazine, morpholine, oxetanyl, oxcyclohexyl, benzene ring, pyridine, pyrazine, pyrimidine, pyridazine optionally further substituted with 0 to 4 groups selected from H, halogen, OH, cyano, NH 2 、C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, halogen substituted C 1-4 Alkyl, C 1-4 Alkoxy, -C 1-4 alkyl-OC 1-4 Alkyl, -O-C 1-4 alkyl-OC 1-4 Alkyl, -O-C 3-6 Carbocycle, C 3-6 A carbocycle or a substituent of a 4 to 7 membered heterocyclic ring, said heterocyclic ring containing 1 to 3 heteroatoms selected from O, S or N;
    R k1 、R k2 、R k3 、R k4 、R k5 、R k6 、R L1 、R L2 each independently selected from H, F, cl, br, I, cyano, OH, = O, NH 2 、NH(CH 3 )、N(CH 3 ) 2 Methyl, ethyl, propyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azacyclohexyl, oxetanyl, oxacyclopentyl, oxacyclohexyl, pyridine or phenyl, said methyl, ethyl, propyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azacyclohexyl, oxetanyl, oxacyclopentyl, oxacyclohexyl, pyridine or phenyl optionally being further substituted with 0 to 4 groups selected from H, halogen, OH, cyano, NH 2 、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 A carbocycle or a substituent of a 4 to 6 membered heterocyclic ring, said heterocyclic ring containing 1 to 3 heteroatoms selected from O, S or N;
    alternatively, R k1 And R is R k1 、R k2 And R is R k2 、R k1 And R is R k2 、R k3 And R is R k3 、R k4 And R is R k4 、R k5 And R is R k5 、R k 6 And R is R k6 Directly connected to form C 3-6 Carbocycles (e.g. C 3 、C 4 、C 5 Or C 6 ) Or a 4 to 7 membered (e.g. 4, 5, 6 or 7 membered) heterocycle, optionally further substituted with 0 to 4 groups selected from H, halogen, = O, OH, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, C 1-4 Alkoxy or C 3-6 A cycloalkyl substituent substituted, said heterocycle containing 1 to 3 heteroatoms selected from O, S or N;
    q1, Q5 are each independently selected from O, S, N (R q )、C(＝O)、C(＝O)N(R q )、N(R q ) C (=o) or S (=o) 2 ；
    Q2, Q3, Q4, Q6 are each independently selected from a bond or Q1;
    ring E is selected from phenyl or a 5-6 membered heteroaryl group containing 1 to 3 heteroatoms selected from O, S or N;
    R q each independently selected from H, methyl or ethyl;
    alternatively, R q And R is R k1 、R q And R is R k2 Directly linked to form a 4 to 7 membered heterocyclic ring, said heterocyclic ring optionally being further substituted with 0 to 4 groups selected from H, halogen, = O, OH, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, C 1-4 Alkoxy or C 3-6 Substituted by substituents of cycloalkyl groups, said heterocyclic ring containing 1 to 3 selected groups A heteroatom from O, S or N.
  5. The compound of claim 4, or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, wherein
    Selected from the group consisting of The left side is connected with L;
    l1 is selected from the group consisting of-N (R) q )-Ak1-O-Ak2-C(＝O)-、-O-Ak1-O-Ak2-C(＝O)-、-O-Ak1-N(R q )-Ak2-C(＝O)-、-N(R q )-Ak1-N(R q )-Ak2-C(＝O)-、-N(R q )-Ak1-O-Ak2-N(R q )C(＝O)-、-O-Ak1-O-Ak2-N(R q )C(＝O)-、-N(R q )-Ak1-Ak2-C(＝O)-、-N(R q )-Ak1-Ak2-N(R q )C(＝O)-、-O-Ak1-N(R q )-Ak2-N(R q )C(＝O)-、-S-Ak1-O-Ak2-C(＝O)-、-O-Ak1-S-Ak2-C(＝O)-、-N(R q )-Ak1-O-Ak2-S(＝O) 2 -、- O-Ak1-O-Ak2-S(＝O) 2 -、-N(R q ) Ak1-O-Ak 2-or-O-Ak 1-O-Ak2-, the right side being connected to ring B;
    or L1 is selected from-N (R) q )-Ak1-O-Ak2-C(＝O)N(R q )-、-O-Ak1-N(R q )-Ak2-C(＝O)N(R q ) -or-O-Ak 1-O-C (=o) N (R q ) -right side is connected to ring B;
    l4 is selected from the group consisting of-Ak 3-O-K1-C (=O) -, -Ak3-N (R) q ) -K1-C (=O) -or-Ak 3-N (R) q ) -K1-C (=o) -, right-hand side linked to ring B;
    ring E is selected from benzene ring or pyridine;
    y is selected from-NHC (=O) -, -C (=O) NH-, -CH 2 -、-CH 2 CH 2 -、-CH 2 CH 2 CH 2 -、-OCH 2 -、-OCH 2 CH 2 -、-CH 2 O-、-CH 2 CH 2 O-、-NHCH 2 -、-NHCH 2 CH 2 -、-CH 2 NH-、-CH 2 CH 2 NH-、-NHC(＝O)CH 2 -or-CH 2 C(＝O)NH-；
    Or Y is selected from O, -N (CH) 3 )C(＝O)-、-C(＝O)N(CH 3 )-、-CH 2 C (=O) NH-or-CH 2 C(＝O)N(CH 3 )-；
    Or Y is selected from-N (CH) 2 CH 3 )C(＝O)-、-N(CH(CH 3 ) 2 )C(＝O)-、-N(CH 2 CH(CH 3 ) 2 ) C (=o) -, -N (cyclopropyl) C (=o) -, -N (CH) 2 -cyclopropyl) C (=o) -, -C (=o) N (CH) 2 CH 3 )-、-C(＝O)N(CH(CH 3 ) 2 )-、-C(＝O)N(CH 2 CH(CH 3 ) 2 ) -, -C (=O) N (cyclopropyl) -or-C (=O) N (CH) 2 -cyclopropyl) -;
    or Y is each independently selected from-C (=O) N (CD) 3 )-、-C(＝O)N(CH 2 -oxetanyl) -, -C (=o) N (CH 2 -oxacyclopentyl) -, -C (=o) N (CH 2 -azetidinyl) -, -C (=o) N (CH 2 -pyrrolidinyl) -, -C (=o) N (CH 2 -cyclopentyl) -, -C (=o) N (CH 2 CH 2 CH 3 )-、-C(＝O)N(CH 2 CH(CH 2 CH 3 ) 2 )-、-C(＝O)N(CH 2 CH 2 CH 2 CH 3 )-、-C(＝O)N(CH 2 CH 2 CH(CH 3 ) 2 )-、-C(＝O)N(CH 2 CH(CH 3 )CH 2 CH 3 ) -, -C (=O) N (N-octyl) -, -C (=S) N (CH) 3 )-、-C(＝S)N(CH 2 CH 3 )-、-C(＝S)N(CH 2 -cyclopropyl) -,
    or Y is selected from-CH 2 S(＝O) 2 -；
    R a2 Selected from H;
    W 1 selected from N.
  6. The compound according to claim 5, or a stereoisomer, a deuterate, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof,
    L1 is selected from
    The right side is connected with the ring B;
    or L1 is selected from The right side is connected with the ring B;
    l2 is selected from The right side is connected with the ring B;
    l3 is selected fromThe right side is connected with the ring B;
    R x each independently selected from H, F, cl, br, I, cyano, OH, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, ethynyl, methoxy, ethoxy, -SCH 3 、-SCH 2 CH 3 Cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, the nailGroup, ethyl, propyl, isopropyl, ethynyl, methoxy, ethoxy, -SCH 3 、-SCH 2 CH 3 Optionally further substituted with 0 to 4 substituents selected from H, F, OH, cyano, methyl, ethyl, methoxy or ethoxy;
    R a1 selected from H, F, cl, br, I, cyano, CF 3 、CHF 2 、CH 2 F. Methyl, ethyl, propyl, isopropyl, ethynyl, methoxy, ethoxy, -SCH 3 、-SCH 2 CH 3 Cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;
    R a3 selected from H or methyl;
    R b each independently selected from H, F, cl, br, I, cyano, OH, =o, methyl, ethyl, propyl or isopropyl.
  7. The compound according to claim 6, or a stereoisomer, a deuterate, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof, wherein the compound is selected from the group consisting of compounds represented by the general formulae (II-a), (II-b) and (II-c),
    Y is selected from-NHC (=O) -, -C (=O) NH-, -CH 2 CH 2 CH 2 -、-OCH 2 -、-CH 2 CH 2 -、-CH 2 O-、-CH 2 CH 2 O-or-OCH 2 CH 2 -；
    Or Y is selected from O, -N (CH) 3 )C(＝O)-、-C(＝O)N(CH 3 )-、-CH 2 C (=O) NH-or-CH 2 C(＝O)N(CH 3 )-；
    Or Y is selected from-N (CH) 2 CH 3 )C(＝O)-、-N(CH(CH 3 ) 2 )C(＝O)-、-N(CH 2 CH(CH 3 ) 2 ) C (=o) -, -N (cyclopropyl) C (=o) -, -N (CH) 2 -cyclopropyl) C (=o) -, -C (=o) N (CH) 2 CH 3 )-、-C(＝O)N(CH(CH 3 ) 2 )-、-C(＝O)N(CH 2 CH(CH 3 ) 2 ) -, -C (=O) N (cyclopropyl) -or-C (=O) N (CH) 2 -cyclopropyl) -;
    or Y is each independently selected from-C (=O) N (CD) 3 )-、-C(＝O)N(CH 2 -oxetanyl) -, -C (=o) N (CH 2 -oxacyclopentyl) -, -C (=o) N (CH 2 -azetidinyl) -, -C (=o) N (CH 2 -pyrrolidinyl) -, -C (=o) N (CH 2 -cyclopentyl) -, -C (=o) N (CH 2 CH 2 CH 3 )-、-C(＝O)N(CH 2 CH(CH 2 CH 3 ) 2 )-、-C(＝O)N(CH 2 CH 2 CH 2 CH 3 )-、-C(＝O)N(CH 2 CH 2 CH(CH 3 ) 2 )-、-C(＝O)N(CH 2 CH(CH 3 )CH 2 CH 3 ) -, -C (=O) N (N-octyl) -, -C (=S) N (CH) 3 )-、-C(＝S)N(CH 2 CH 3 )-、-C(＝S)N(CH 2 -cyclopropyl) -,
    or Y is selected from-CH 2 S(＝O) 2 -；
    X 1 、X 2 、X 3 、X 4 Each independently selected from N or CR x ，X 1 、X 2 、X 3 、X 4 Up to 2N;
    R x each independently selected from H, F, cl, cyano, methyl, ethyl, isopropyl, trifluoromethyl, methoxy, ethoxy, -SO 2 CH 3 、-SO 2 CH 2 CH 3 、-C(＝O)CH 3 、-C(＝O)CH 2 CH 3 Or cyclopropyl;
    the remaining groups are as defined in weight 6.
  8. The compound of claim 7, or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof,
    l is selected fromOr alternativelyThe right side is connected with the ring B;
    or L is selected from The right side is connected with the ring B;
    or L is selected from The right side is connected with the ring B;
    X 1 selected from N, X 2 Selected from CH, X 3 Selected from CH, CF, CCl, CCN or CCF 3 ，X 4 Selected from CH or N.
  9. The compound of claim 1, or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, wherein the compound is selected from one of the following structures:
  10. a pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of claims 1-9, or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, and a pharmaceutically acceptable carrier, optionally comprising one or more other chemotherapeutic agents.
  11. The pharmaceutical composition according to claim 10, wherein said therapeutically effective amount means that the pharmaceutical composition is administered in a dosage suitable for the disease to be treated (or prevented), e.g. about 0.1 μg to about 50mg of at least one compound per kg body weight of the subject, preferably about 10 μg to about 200mg per kg body weight per day.
  12. Use of a compound according to any one of claims 1-9, or a stereoisomer, deuterated, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, for the manufacture of a medicament for the treatment of a disease associated with PARP7 activity or expression level.
  13. The use according to claim 12, wherein the disease is selected from the group consisting of tumors.
CN202280013780.6A 2021-04-23 2022-04-22 Fused ring heterocyclic derivative and application thereof in medicine Pending CN117083274A (en)

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