CN117957231A - Fused ring compound, preparation method and application thereof - Google Patents

Fused ring compound, preparation method and application thereof Download PDF

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CN117957231A
CN117957231A CN202280060464.4A CN202280060464A CN117957231A CN 117957231 A CN117957231 A CN 117957231A CN 202280060464 A CN202280060464 A CN 202280060464A CN 117957231 A CN117957231 A CN 117957231A
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alkyl
substituted
independently
membered heterocyclyl
compound
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罗会兵
周华勇
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Shanghai Allist Medicine Polytron Technologies Inc
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Shanghai Allist Medicine Polytron Technologies Inc
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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Abstract

The invention discloses a fused ring compound, a preparation method and application thereof. The invention provides a fused ring compound shown in a formula I, a tautomer thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of the pharmaceutically acceptable salt thereof. The fused ring compound shown in the formula I has better inhibition activity on SOS 1; is expected to treat and/or prevent diseases related to SOS1 activity or expression level; (I) .

Description

Fused ring compound, preparation method and application thereof
The present application claims priority from chinese patent application 2021111465322, 9 and 28, of application date 2021. The present application incorporates the entirety of the above-mentioned chinese patent application.
Technical Field
The invention relates to a fused ring compound, a preparation method and application thereof.
Background
The RAS protein is a Guanine Trinucleotide Phosphate (GTP) binding protein with molecular weight of 21kDa, which is positioned on cell membrane and consists of 188 or 189 amino acids. The activity of the RAS protein is regulated by binding to GTP or Guanine Dinucleotide Phosphate (GDP), and is in an "inactive" state when bound to GDP and in an "active" state when bound to GTP. RAS proteins themselves have a relatively weak GTPase hydrolysis function and a relatively slow nucleotide exchange rate, and binding to GTPase activating proteins (GTPASE ACTIVATING proteins, GAPs) can enhance the GTP hydrolysis function of RAS proteins, while guanine nucleotide exchange factors (GEFs) can catalyze nucleotide exchanges (GTP exchange GDP). SOS1 (Son of Sevenless 1) is a RAS-specific GEF, and the combination of SOS1 with RAS can promote RAS to release GDP and combine with GTP, thereby activating RAS. After RAS is activated, a plurality of downstream signal paths including MAPK signal paths and PI3K signal paths can be activated, and the signal paths play an important role in promoting cell differentiation, proliferation and survival. RAS mutations are the gene driver of many cancers, with RAS mutations present in 20% -30% of human tumors, such as lung, colorectal and pancreatic cancers.
The RAS gene family includes KRAS, NRAS and HRAS. KRAS mutations are present in a variety of tumors, such as lung adenocarcinoma (32%), colorectal carcinoma (41%), pancreatic carcinoma (86%), with KRAS mutations most common with the G12 mutation at codon 12, e.g., in KRAS mutated lung adenocarcinoma, colorectal carcinoma and pancreatic carcinoma, G12 mutations account for 85%, 68% and 91%, respectively; HRAS mutations and NRAS mutations are relatively low in frequency, and occur mainly in cancer species such as melanoma, leukemia, and thyroid cancer. In addition, abnormal activation (such as gene mutation, amplification, overexpression and the like) of RAS proteins and the drug resistance of some antitumor drugs are also closely related, such as EGFR monoclonal antibodies, EGFR small molecule inhibitors and the like. Thus, the RAS-associated signal pathway becomes an important anti-tumor target.
The guanine nucleotide exchange factor of the RAS family involved in cancer-related signaling pathway is mainly SOS1, and decreasing the expression of SOS1 can significantly inhibit proliferation and survival of KRAS mutated cancer cells. Since SOS1 is a common node of multiple activation RAS signaling pathways, almost all growth factor receptors are responsible for the initiation of RAS signaling pathways through SOS1, SOS1 inhibitors have the potential to be broad-spectrum anticancer drugs. SOS1 is involved in activating signaling pathways that play an important role in other types of mutated cancers as well. SOS1 can interact with the adaptor protein Grb2 to form a SOS1/Grb2 complex that binds to activated receptor tyrosine kinases (e.g., EGFR, HER2, erbb4, TRKA, TRKB, TRKC, RET, AXL, etc.). SOS1 may also be recruited to phosphorylated cell surface receptors, such as T cell receptors, B cell receptors, and monocyte colony stimulating factor receptors, among others. The localization of SOS1 on the cell membrane allows SOS1 to better promote RAS family protein activation, activating downstream signaling pathways. SOS1 is also involved in the activation of other GTP hydrolases, such as RAC1, etc., RAC1 also being involved in the pathogenesis of a variety of human cancers and other diseases. In addition, SOS1 mutations were found in lung adenocarcinoma, embryonal rhabdomyosarcoma, and skin granulosa cell tumors, and SOS1 overexpression was found in bladder and prostate cancers. In addition to cancer, inherited SOS1 mutations are also associated with the pathogenesis of RAS lesions, including noonan's syndrome, heart-face-skin syndrome, hereditary gum fibromatosis type one, and the like.
Currently, no SOS1 inhibitors are approved for sale, and therefore, there is a need to develop new and therapeutically effective SOS1 inhibitors to meet clinical demands.
Disclosure of Invention
The invention aims to solve the technical problems that the existing SOS1 inhibitor has a single structure and the like, and provides a fused ring compound, a preparation method and application thereof. The compound has better inhibition activity on SOS 1.
The invention provides a fused ring compound shown in a formula I, a tautomer thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of the pharmaceutically acceptable salt thereof;
Wherein:
X and Y are each independently-O-, -S-, -NH-or-CH 2 -;
Z is-CR 10 or N;
L is a single bond, -C (=O) -, -C (=O) O-, -C (=O) NR 8-、-NR 8-、-S-、-O-、-S(O)-、-S(O) 2 -, or- (CH 2) p -;
Ring a is C 6-12 aryl, 5-10 membered heteroaryl, C 3-7 cycloalkyl, C 3-7 cycloalkenyl, or 3-7 membered heterocyclyl;
each R is independently deuterium, hydroxy, halogen, -N (R, cyano, oxo (= O), nitro, C alkyl-O-, C alkenyl, C alkynyl, C alkyl substituted with one or more R, C alkyl-O-, C alkenyl substituted with one or more R, C alkynyl substituted with one or more R, C cycloalkyl C cycloalkyl substituted with one or more R, 3-7 membered heterocyclyl substituted with one or more R, C aryl substituted with one or more R, 5-10 membered heteroaryl substituted with one or more R, C cycloalkenyl substituted with one or more R or-NR, or two R together with the ring atoms to which they are attached form a C cycloalkyl group, a C cycloalkyl group substituted with one or more R, a 3-7 membered heterocyclic group substituted with one or more R, a C cycloalkenyl group, or a C cycloalkenyl group substituted with one or more R;
each of R 1a、R 1b、R 1c、R 1d、R 1e、R 1f、R 1g、R 1h and R 1i is independently deuterium, hydroxy, halogen, -N (R 7) 2、-SR 9, nitro, cyano, C 1-6 alkyl-O-, C 1-6 alkenyl, C 1-6 alkynyl, C 1-6 alkyl substituted with one or more R 1-6, C 1-6 alkyl-O-, substituted with one or more R 1-6, C 1-6 alkenyl substituted with one or more R 1-6, C 1-6 alkynyl substituted with one or more R 1-6, C 1-6 cycloalkyl-O-, 3-7 membered heterocyclyl-O-, C 1-6 cycloalkyl substituted with one or more R 1-6 or C 1-6 cycloalkyl-O-, 3-7 membered heterocyclyl-O-, C 1-6 aryl substituted with one or more R 1-6, C 1-6 aryl, C 1-6 heteroaryl substituted with one or more R 1-6, C 1-6 alkenyl substituted with one or more R 1-6, C 1-6 cycloalkenyl, C 1-6 -2 or C 1-6 cycloalkenyl;
Each R 1-a、R 1-b、R 1-c、R 1-d、R 1-e、R 1-f、R 1-g、R 1-h and R 1-i is independently deuterium, hydroxy, halogen, -N (R 7) 2、-SR 9, nitro, cyano, C 1-6 alkyl, C 1-6 alkyl-O-, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 3-7 cycloalkenyl, or 3-7 membered heterocyclyl;
Ring D is C 6-12 aryl, 5-6 membered heteroaryl, C 3-7 cycloalkyl, C 3-7 cycloalkenyl, or 3-7 membered heterocyclyl;
R 2 is absent, hydrogen, deuterium, hydroxy, halogen, amino, cyano, oxo, nitro, C 1-6 alkyl, C 1-6 alkyl-O-, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 3-7 cycloalkenyl, or 3-7 membered heterocyclyl;
R 3 is hydrogen, deuterium, C 1-6 alkyl, C 1-6 alkyl substituted by one or more R 3a, C 2-6 alkenyl, C 2-6 alkenyl substituted by one or more R 3b, C 2-6 alkynyl, C 2-6 alkynyl substituted by one or more R 3c, C 3-7 cycloalkyl, C 3-7 cycloalkyl substituted by one or more R 3d, 3-7 membered heterocyclyl substituted by one or more R 3e, C 6-12 aryl, C 6-12 aryl substituted by one or more R 3f, 5-10 membered heteroaryl substituted by one or more R 3g, C 3-7 cycloalkenyl or C 3-7 cycloalkenyl substituted by one or more R 3h;
Each R and R is independently deuterium, hydroxy, halogen, -N (R, cyano, nitro, C alkyl substituted with one or more R-, C alkyl-O-, C alkenyl, C alkynyl, C alkenyl substituted with one or more R, C alkynyl substituted with one or more R, C cycloalkyl substituted with one or more R, 3-7 membered heterocyclyl substituted with one or more R, C aryl substituted with one or more R, 5-10 membered heteroaryl, C cycloalkenyl substituted with one or more R, or-NR, or two R, two R or two R together with the ring atoms to which they are attached form a C cycloalkyl group, a C cycloalkyl group substituted with one or more R, a 3-7 membered heterocyclyl group substituted with one or more R, a C cycloalkenyl group or a C cycloalkenyl group substituted with one or more R;
each R 3-a、R 3-b、R 3-c、R 3-d、R 3-e、R 3-f、R 3-g、R 3-h and R 3-i is independently deuterium, hydroxy, halogen, -N (R 7) 2, nitro, cyano, C 1-6 alkyl, C 1-6 alkyl-O-, C 3-7 cycloalkyl, C 3-7 cycloalkenyl, 3-7 membered heterocyclyl 、-SR 9、-C(＝O)-O-R 9、-O-C(＝O)-R 9、-C(＝O)-N(R 7) 2、-S(O) 2-R 9、-NR 8-S(O) 2-R 9、-NR 8-S(O) 2-N(R 7) 2、-S(O) 2-N(R 7) 2、-C(＝O)-R 9、-NR 8C(＝O)-R 9, or-NR 8C(＝O)-O-R 9;
each R 4 is independently deuterium, hydroxy, halogen, -N (R 7) 2, cyano, oxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C 1-4 alkylene-N (R 7) 2, C 1-6 alkyl substituted with one or more R 4a, C 1-6 alkyl-O-, C 1-6 alkyl-O substituted with one or more R 4b -, C 3-7 cycloalkyl, C 3-7 cycloalkyl substituted with one or more R 4c, 3-7 membered heterocyclyl substituted with one or more R 4d, C 3-7 cycloalkenyl, or C 3-7 cycloalkenyl substituted with one or more R 4e, or two R 3-7 groups together with the attached atoms form a C 3-7 cycloalkyl group, a C 3-7 cycloalkyl substituted with one or more R 3-7, a 3-7 membered heterocyclyl, a 3933-7 membered heterocyclyl substituted with one or more R 3-7, a C 3-7 cycloalkenyl, or a C 3-7 cycloalkenyl substituted with one or more R 3-7;
(R 4 may be attached to the ring To ring atoms allowed by any valency of (2), e.g. attached to the ringX, Y or any methylene group);
Each R 4a、R 4b、R 4c and R 4d is independently deuterium, hydroxy, halogen, amino, cyano, C 1-6 alkyl, C 1-6 alkyl-O-, C 2-6 alkenyl, or C 2-6 alkynyl;
R 5 is absent, oxo, hydrogen, deuterium, hydroxy, halo, amino, cyano, nitro, C 1-6 alkyl, C 1-6 alkyl substituted with one or more R 5a, C 1-6 alkyl-O-, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl substituted with one or more R 5b, 3-7 membered heterocyclyl substituted with one or more R 5c, C 3-7 cycloalkenyl, or C 3-7 cycloalkenyl substituted with one or more R 5d;
Each R 5a、R 5b and R 5c is independently deuterium, C 1-6 alkyl, hydroxy, halogen, amino or cyano;
R 6 is hydrogen, deuterium, hydroxy, halogen, amino, cyano, oxo, C 1-6 alkyl, C 1-6 alkyl-O-, C 2-6 alkenyl, C 2-6 alkynyl or absent;
each R 7 is independently hydrogen, C 1-6 alkyl, C 3-7 cycloalkyl, or C 3-7 cycloalkenyl, or two R 7 together with the nitrogen atom to which they are attached form a 3-7 membered heterocyclyl or a 3-7 membered heterocyclyl substituted with one or more R 7a;
Each R 7a is independently deuterium, C 1-6 alkyl, halogen, hydroxy, amino, cyano, C 1-6 alkyl-O-, C 2-6 alkenyl, or C 2-6 alkynyl;
each R 8 and R 9 is independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 3-7 cycloalkenyl, or a 3-7 membered heterocyclyl;
R 10 is hydrogen, deuterium, hydroxy, halogen, amino, cyano, C 1-6 alkyl, C 1-6 alkyl-O-, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 3-7 cycloalkenyl, or 3-7 membered heterocyclyl;
R 11 is hydrogen, deuterium, cyano, C 1-6 alkyl or C 1-6 alkyl substituted with one or more R 11a;
each R 11a is independently deuterium, halogen, or hydroxy;
m is 0, 1,2,3, 4 or 5;
n is 0, 1,2,3, 4, 5 or 6;
p is 1,2,3, 4, 5 or 6;
the 3-7 membered heterocyclic groups are each independently a 3-7 membered heterocyclic group having a heteroatom type independently selected from N, O and S, the 3-7 membered heterocyclic group having 1, 2 or 3 heteroatoms (the 3-7 membered heterocyclic group is a 3-7 membered heterocyclic group, a 3-7 membered heterocyclic group-O-, a 3-7 membered heterocyclic group substituted with a substituent, and a 3-7 membered heterocyclic group-O-, i.e., the 3-7 membered heterocyclic group in the 3-7 membered heterocyclic group substituted with a substituent in the "ring A、R 1、R 1a、R 1b、R 1c、R 1d、R 1e、R 1f、R 1g、R 1h、R 1i、R 1-a、R 1-b、R 1-c、R 1-d、R 1-e、R 1-f、R 1-g、R 1-h、R 1-i、 ring D、R 2、R 3、R 3a、R 3b、 R 3c、R 3d、R 3e、R 3f、R 3g、R 3h、R 3-a、R 3-b、R 3-c、R 3-d、R 3-e、R 3-f、R 3-g、R 3-h、R 3-i、R 4、R 5、R 8、R 9 and R 10, namely, a 3-7 membered heterocyclic group in the 3-7 membered heterocyclic group substituted with a substituent in the" ring A、R 1、R 1a、R 1b、R 1c、R 1d、R 1e、R 1f、R 1g、R 1h、R 1i、R 1-a、R 1-b、R 1-c、R 1-d、R 1-e、R 1-f、R 1-g、R 1-h、R 1-i、 ring D、R 2、R 3、R 3a、R 3b、 R 3c、R 3d、R 3e、R 3f、R 3g、R 3h、R 3-a、R 3-b、R 3-c、R 3-d、R 3-e、R 3-f、R 3-g、R 3-h、R 3-i、R 4、R 5、R 8、R 9 and R 10, a 3-7 membered heterocyclic group formed by two R 1 together with the attached ring atom, a 3-7 membered heterocyclic group in the 3-7 membered heterocyclic group substituted with one or more R 1f, a 3-7 membered heterocyclic group, two R 3d, two R 3e, two R3995, two R 3g or two R2 together with the attached ring atom form a 3-7 membered heterocyclic group, a 3-7 membered heterocyclic group formed by one or more R3495-7 membered heterocyclic group formed by two or more R3495, a 3-7 membered heterocyclic group which is substituted with one or more R3495-7 membered heterocyclic group, 3-7 membered heterocyclyl; 3-7 membered heterocyclyl in 3-7 membered heterocyclyl-O-substituted with one or more R 1-f, 3-7 membered heterocyclyl in 3-7 membered heterocyclyl-O-in R 1a、R 1b、R 1c、R 1d、R 1e、R 1f、R 1g、R 1h and R 1i ");
The 5-10 membered heteroaryl groups are each independently a 5-10 membered heteroaryl group having a heteroatom of 1,2 or 3, the heteroatom species being independently selected from N, O and S (the 5-10 membered heteroaryl group being a 5-10 membered heteroaryl group of a 5-10 membered heteroaryl group and a 5-10 membered heteroaryl group of a 5-10 membered heteroaryl group substituted with a substituent, namely a 5-10 membered heteroaryl group, a 5-10 membered heteroaryl group of a 5-10 membered heteroaryl group substituted with a substituent in the "ring A、R 1、R 1a、R 1b、R 1c、R 1d、R 1e、R 1f、R 1g、R 1h、R 1i、R 3、R 3a、R 3b、R 3c、R 3d、R 3e、R 3f、R 3g and R 3h");
The 5-6 membered heteroaryl is a 5-6 membered heteroaryl with heteroatom types independently selected from N, O and S and heteroatom numbers of 1,2 or 3;
When the carbon atom has chirality, the condensed-cyclic compound shown as formula I is Or a mixture thereof.
In one embodiment, certain groups in the fused ring compound as shown in formula I, its tautomer, its stereoisomer, its pharmaceutically acceptable salt, its solvate, or a solvate of its pharmaceutically acceptable salt have the following definitions, and the non-mentioned groups are defined as in any one embodiment of the invention (hereinafter referred to as "in one embodiment"): x and Y are each independently-O-, -NH-or-CH 2 -; for example, X and Y are each independently-O-or-CH 2 -.
In one embodiment, Z is N.
In one embodiment, L is a single bond.
In one embodiment, ring A is a C 6-12 aryl or a 5-10 membered heteroaryl; for example, ring A is C 6-12 aryl.
In one embodiment, each R 1 is independently hydroxy, halo, -N (R 7) 2, cyano, C 1-6 alkyl, C 1-6 alkyl-O-, C 1-6 alkyl substituted with one or more R 1a -, C 1-6 alkyl-O-, substituted with one or more R 1b -, or two R 1 together with the attached ring atoms form a C 3-7 cycloalkyl, C 3-7 cycloalkyl substituted with one or more R 1e, 3-7 membered heterocyclyl substituted with one or more R 1f, C 3-7 cycloalkenyl, or C 3-7 cycloalkenyl substituted with one or more R 1i, e.g., each R 1 is independently halo, C 1-6 alkyl, or C 1-6 alkyl substituted with one or more R 1a.
In one embodiment, each R 1a、R 1b、R 1e、R 1f and R 1i is independently hydroxy, halogen, -N (R 7) 2、C 1-6 alkyl or C 1-6 alkyl substituted with one or more R 1-a; e.g., each R 1a is independently halogen.
In one embodiment, each R 1-a is independently C 1-6 alkyl or halogen.
In one embodiment, ring D is a 3-7 membered heterocyclyl; for example, ring D is a six-membered heterocyclic group having a heteroatom of N, 1 or 2 in number, further for example, 1, 2-dihydropyridinyl, further for example"C" means that the atom is meta to the Z atom of the B ring.
In one embodiment, R 2 is hydrogen.
In one embodiment, R 3 is hydrogen, C 3-7 cycloalkyl, C 3-7 cycloalkyl substituted with one or more R 3d, 3-7 membered heterocyclyl or 3-7 membered heterocyclyl substituted with one or more R 3e, C 3-7 cycloalkenyl, or C 3-7 cycloalkenyl substituted with one or more R 3h; for example, R 3 is a 3-7 membered heterocyclyl or a 3-7 membered heterocyclyl substituted with one or more R 3e.
In one embodiment, each R and R is independently hydroxy, halogen, -N (R, cyano, C alkyl substituted with one or more R, C alkyl-O-, C alkenyl, C alkynyl substituted with one or more R, C alkenyl substituted with one or more R, -C (=o) -R, or two R, two R or two R together with the attached ring atom form a C cycloalkyl, C cycloalkyl substituted with one or more R, 3-7 membered heterocyclyl substituted with one or more R, C cycloalkenyl, or C cycloalkenyl substituted with one or more R, e.g., each R is independently hydroxy, halogen, -N (R, cyano, C alkyl-O-, C alkynyl or-C (=o) -R, e.g., each R is independently hydroxy, C alkyl-O-, or-C (=o) -R.
In one embodiment, each R 3-a、R 3-b、R 3-c、R 3-d、R 3-e、R 3-f and R 3-i is independently hydroxy, halogen, -N (R 7) 2, nitro, cyano, C 1-6 alkyl, or C 1-6 alkyl-O-; e.g., each R 3-b is independently hydroxy or halogen.
In one embodiment, each R 4 is independently C 1-6 alkyl, -C 1-4 alkylene-N (R 7) 2, C 1-6 alkyl substituted with one or more R 4a, 3-7 membered heterocyclyl, or 3-7 membered heterocyclyl substituted with one or more R 4d; e.g., each R 4 is independently C 1-6 alkyl, -C 1-4 alkylene-N (R 7) 2, 3-7 membered heterocyclyl, or 3-7 membered heterocyclyl substituted with one or more R 4d).
In one embodiment, each R 4a and R 4d is independently C 1-6 alkyl or halogen; for example, each R 4d is independently C 1-6 alkyl or halogen.
In one embodiment, R 5 is hydrogen or C 1-6 alkyl.
In one embodiment, R 6 is oxo.
In a certain embodiment, each R 7 is independently hydrogen, C 1-6 alkyl, C 3-7 cycloalkyl, or C 3-7 cycloalkenyl; or two R 7 taken together with the attached nitrogen atom form a 3-7 membered heterocyclyl or a 3-7 membered heterocyclyl substituted with one or more R 7a; for example, each R 7 is independently hydrogen or C 1-6 alkyl.
In one embodiment, each R 7a is independently C 1-6 alkyl or halogen.
In one embodiment, each R 8 and R 9 is independently hydrogen or C 1-6 alkyl; for example, each R 9 is independently hydrogen or C 1-6 alkyl.
In one embodiment, R 11 is C 1-6 alkyl.
In one embodiment, m is 0,1,2, or 3; for example m is 1,2 or 3.
In one embodiment, n is 0,1,2, or 3; for example n is 0,1 or 2.
In one embodiment, p is 1,2 or 3.
In one embodiment, the 3-7 membered heterocyclic groups are each independently a 3-7 membered heterocyclic group having a heteroatom selected from N, O and S, the 3-7 membered heterocyclic group having 1,2 or 3 heteroatoms (the 3-7 membered heterocyclic group is a 3-7 membered heterocyclic group of a 3-7 membered heterocyclic group substituted with a substituent; i.e., the 3-7 membered heterocyclic group of a 3-7 membered heterocyclic group substituted with a substituent of R 3 and R 4; a 3-7 membered heterocyclic group of a 3-7 membered heterocyclic group; a 3-7 membered heterocyclic group of a ring D; a 3-7 membered heterocyclic group of a 3-7 membered heterocyclic group substituted with one or more R 1f; a 3-7 membered heterocyclic group of a 3-7 membered heterocyclic group formed by two R 1f together with the attached ring atom; a 3-7 membered heterocyclic group formed by two R 3d, two R 3e or two R 3h together with the attached ring atom; a 3-7 membered heterocyclic group formed by one or more R 3-f; a 3-7 membered heterocyclic group formed by two R537 together with the attached ring atom).
In one embodiment, the 5-10 membered heteroaryl is a 5-10 membered heteroaryl having a heteroatom number of 1,2 or 3, and is independently selected from N, O and S.
In one embodiment, in the fused ring compound represented by formula I,
X and Y are each independently-O-, -NH-or-CH 2 -;
z is N;
L is a single bond;
Ring a is C 6-12 aryl or 5-10 membered heteroaryl;
Each R 1 is independently hydroxy, halogen, -N (R 7) 2, cyano, C 1-6 alkyl, C 1-6 alkyl-O-, C 1-6 alkyl substituted with one or more R 1a, C 1-6 alkyl-O-substituted with one or more R 1b, or, together with the ring atoms attached, two R 1 form a C 3-7 cycloalkyl, a C 3-7 cycloalkyl substituted with one or more R 1e, a 3-7 membered heterocyclyl substituted with one or more R 1f, a C 3- 7 cycloalkenyl, or a C 3-7 cycloalkenyl substituted with one or more R 1i;
Each R 1a、R 1b、R 1e、R 1f and R 1i is independently hydroxy, halogen, -N (R 7) 2、C 1-6 alkyl or C 1-6 alkyl substituted with one or more R 1-a;
Each R 1-a is independently C 1-6 alkyl or halogen;
Ring D is a 3-7 membered heterocyclyl;
r 2 is hydrogen;
R 3 is hydrogen, C 3-7 cycloalkyl, C 3-7 cycloalkyl substituted with one or more R 3d, 3-7 membered heterocyclyl substituted with one or more R 3e, C 3-7 cycloalkenyl, or C 3-7 cycloalkenyl substituted with one or more R 3h;
Each R 3d、R 3e and R 3h is independently hydroxy, halogen, -N (R 7) 2, cyano, C 1-6 alkyl, C 1-6 alkyl substituted with one or more R 3-a, C 1-6 alkyl-O-, C 1-6 alkyl-O substituted with one or more R 3-b, C 2-6 alkenyl, C 2-6 alkynyl, C 2-6 alkenyl substituted with one or more R 3-c, C 2-6 alkynyl substituted with one or more R 3-d, -C (=o) -R 9、-NR 8C(＝O)-R 9, or two R 3d, two R 3e, or two R 3h together with the attached ring atoms form C 3-7 cycloalkyl, C 3-7 cycloalkyl substituted with one or more R 3-e, 3-7 membered heterocyclyl, or 3-7 membered heterocyclyl substituted with one or more R 3-f, C 3-7 cycloalkenyl, or C 3- 7 cycloalkenyl substituted with one or more R 3-i;
Each R 3-a、R 3-b、R 3-c、R 3-d、R 3-e、R 3-f and R 3-i is independently hydroxy, halogen, -N (R 7) 2, nitro, cyano, C 1- 6 alkyl or C 1-6 alkyl-O-;
Each R 4 is independently C 1-6 alkyl, -C 1-4 alkylene-N (R 7) 2, C 1-6 alkyl substituted with one or more R 4a, 3-7 membered heterocyclyl or 3-7 membered heterocyclyl substituted with one or more R 4d;
Each R 4a and R 4d is independently C 1-6 alkyl or halogen;
R 5 is hydrogen or C 1-6 alkyl;
r 6 is oxo;
Each R 7 is independently hydrogen, C 1-6 alkyl, C 3-7 cycloalkyl, or C 3-7 cycloalkenyl; or two R 7 taken together with the attached nitrogen atom form a 3-7 membered heterocyclyl or a 3-7 membered heterocyclyl substituted with one or more R 7a;
Each R 7a is independently C 1-6 alkyl or halogen;
Each R 8 and R 9 is independently hydrogen or C 1-6 alkyl;
R 11 is C 1-6 alkyl;
m is 0, 1,2 or 3;
n is 0, 1,2 or 3;
p is 1,2 or 3;
the 3-7 membered heterocyclic groups are each independently a 3-7 membered heterocyclic group having a heteroatom type independently selected from N, O and S, the heteroatom number being 1,2 or 3 (the 3-7 membered heterocyclic group being a 3-7 membered heterocyclic group of 3-7 membered heterocyclic groups and 3-7 membered heterocyclic groups substituted with substituents; i.e., a 3-7 membered heterocyclic group of 3-7 membered heterocyclic groups substituted with substituents in R 3 and R 4; a 3-7 membered heterocyclic group of 3-7 membered heterocyclic group in ring D; a 3-7 membered heterocyclic group of 3-7 membered heterocyclic group formed by two R 1 together with the attached ring atom, a 3-7 membered heterocyclic group of 3-7 membered heterocyclic group substituted with one or more R 1f; a 3-7 membered heterocyclic group formed by two R 3d, two R 3e or two R 3h together with the attached ring atom; a 3-7 membered heterocyclic group formed by one or more R 3-f; a 3-7 membered heterocyclic group formed by two R5384 together with the attached ring atom, a 3-7 membered heterocyclic group formed by two R 3-f);
The 5-10 membered heteroaryl is a 5-10 membered heteroaryl with heteroatom types independently selected from N, O and S and heteroatom numbers of 1,2 or 3.
In one embodiment, in the fused ring compound represented by formula I,
X and Y are each independently-O-;
Each R 1 is independently halogen, C 1-6 alkyl or C 1-6 alkyl substituted with one or more R 1a;
each R 1a is independently halogen;
Ring a is C 6-12 aryl;
Is that
L is a single bond;
r 2 is hydrogen;
R 3 is a 3-7 membered heterocyclyl or a 3-7 membered heterocyclyl substituted with one or more R 3e;
Each R 3e is independently hydroxy, halogen, -N (R 7) 2, cyano, C 1-6 alkyl, C 1-6 alkyl-O-, C 2-6 alkynyl, or-C (=o) -R 9;
R 5 is hydrogen or C 1-6 alkyl;
Each R 4 is independently C 1-6 alkyl, -C 1-4 alkylene-N (R 7) 2, 3-7 membered heterocyclyl or 3-7 membered heterocyclyl substituted with one or more R 4d;
Each R 4d is independently C 1-6 alkyl or halogen;
Each R 7 is independently hydrogen or C 1-6 alkyl;
Each R 9 is independently hydrogen or C 1-6 alkyl;
R 11 is C 1-6 alkyl;
m is 1, 2 or 3;
n is 0, 1 or 2.
In one embodiment, in the fused ring compound represented by formula I,
X and Y are each independently-O-or-CH 2 -;
Each R 1 is independently halogen, C 1-6 alkyl or C 1-6 alkyl substituted with one or more R 1a;
each R 1a is independently halogen;
Ring a is C 6-12 aryl;
Ring D is a six-membered heterocyclic group having 1 or 2 hetero atoms, e.g. 1, 2-dihydropyridinyl, and further e.g. N "C" means that the atom is meta to the Z atom of ring B; z is N;
L is a single bond;
r 2 is hydrogen;
R 3 is a 3-7 membered heterocyclyl or a 3-7 membered heterocyclyl substituted with one or more R 3e;
Each R 3e is independently hydroxy, halogen, -N (R 7) 2, cyano, C 1-6 alkyl, C 1-6 alkyl-O-, C 1-6 alkyl-O-, C 2-6 alkynyl or-C (=o) -R 9 substituted by one or more R 3-b;
Each R 3-b is independently hydroxy or halogen;
R 5 is hydrogen or C 1-6 alkyl;
r 6 is oxo;
Each R 4 is independently C 1-6 alkyl, -C 1-4 alkylene-N (R 7) 2, 3-7 membered heterocyclyl or 3-7 membered heterocyclyl substituted with one or more R 4d;
Each R 4d is independently C 1-6 alkyl or halogen;
Each R 7 is independently hydrogen or C 1-6 alkyl;
Each R 9 is independently hydrogen or C 1-6 alkyl;
R 11 is C 1-6 alkyl;
m is 1, 2 or 3;
n is 0, 1 or 2.
In one embodiment, in the fused ring compound represented by formula I,
Is that
Is that
L is a single bond;
R 3 is
R 11 is methyl.
In one embodiment, in the fused ring compound represented by formula I,
Is that
Is that
L is a single bond;
R 3 is
R 11 is methyl.
In one embodiment, when ring a is a C 6-12 aryl, the C 6-12 aryl is phenyl or naphthyl, for example phenyl.
In one embodiment, when ring A is a 5-10 membered heteroaryl, the 5-10 membered heteroaryl is a 5-10 membered heteroaryl having a heteroatom of N, 1 or 2 heteroatoms, e.g.
In one embodiment, when R 1 is C 1-6 alkyl substituted with one or more R 1a, the C 1-6 alkyl substituted with one or more R 1a is-CHF 2、-CF 3、-CF 2CH 3、-CF 2CH 2 OH or-CF 2C(CH 3) 2 OH.
In one embodiment, when two R 1 together with the attached ring atoms form a C 3-7 cycloalkenyl or a C 3-7 cycloalkenyl substituted with one or more R 1i, the C 3-7 cycloalkenyl is cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl or cycloheptenyl, e.g., cyclopentenyl.
In one embodiment, when two R 1 together with the attached ring atoms form a 3-7 membered heterocyclyl or a 3-7 membered heterocyclyl substituted with one or more R 1f, the 3-7 membered heterocyclyl is a 3-7 membered heterocyclyl having 1 or 2 heteroatoms, e.g., is selected independently from O, N and S"A" means that the portion is in a loop-by-loop connection with loop A.
In one embodiment, when ring D is a 3-7 membered heterocyclic group, the 3-7 membered heterocyclic group is a six membered heterocyclic group having a heteroatom of N, 1 or 2 heteroatoms, such as 1, 2-dihydropyridinyl, and further such as"C" means that the atom is meta to the Z atom of the B ring.
In one embodiment, when R 3 is a 3-7 membered heterocyclyl or a 3-7 membered heterocyclyl substituted with one or more R 3e, the 3-7 membered heterocyclyl is a 5-7 membered heterocyclyl having 1 or 2 heteroatoms, e.g., is a heteroatom species independently selected from N and O
In one embodiment, when R 3 is C 3-7 cycloalkyl or C 3-7 cycloalkyl substituted with one or more R 3d, said C 3-7 cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or
In one embodiment, when each R 3d and R 3e is independently C 2-6 alkynyl, the C 2-6 alkynyl is ethynyl or propynyl.
In one embodiment, when R 4 is-C 1-4 alkylene-N (R 7) 2, both R 7 together with the nitrogen atom to which they are attached form a 3-7 membered heterocyclyl or a 3-7 membered heterocyclyl substituted with one or more R 7a, e.g., the-C 1-4 alkylene-N (R 7) 2 is
In one embodiment, when R 4 is-C 1-4 alkylene-N (R 7) 2), the R 7 is independently C 1-6 alkyl, e.g., the-C 1-4 alkylene-N (R 7) 2 is
In one embodiment, when R 4 is a 3-7 membered heterocyclic group or a 3-7 membered heterocyclic group substituted with one or more R 4d, the 3-7 membered heterocyclic group is a 5-7 membered heterocyclic group having a heteroatom of N, 1 or 2 heteroatoms, for example
In one embodiment, when two R 7's together with the nitrogen atom to which they are attached form a 3-7 membered heterocyclic group or a 3-7 membered heterocyclic group substituted with one or more R 7a, the 3-7 membered heterocyclic group is a 5-7 membered heterocyclic group having a heteroatom of N, 1 or 2 heteroatoms, e.g.
In one embodiment, when R 1、R 1a、R 1b、R 1e、R 1f、R 1i、R 1-a、R 3d、R 3e、R 3h、R 3-a、R 3-b、R 3-c、R 3-d、R 3- e、R 3-f、R 3-i、R 4、R 4a、R 4d、R 5、R 7、R 7a、R 8、R 9 or R 11 is C 1-6 alkyl or C 1-6 alkyl substituted with a substituent, each of the C 1-6 alkyl groups is independently C 1-4 alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, and further such as methyl, ethyl, or isobutyl.
In one embodiment, when R 1、R 1a、R 1b、R 1e、R 1f、R 1i、R 1-a、R 3d、R 3e、R 3h、R 3-a、R 3-b、R 3-c、R 3-d、R 3- e、R 3-f、R 3-i、R 4a、R 4d or R 7a is halogen, each of the halogens is independently F, cl, br, or I, for example, F or Cl.
In one embodiment, when R 1、R 3d、R 3e、R 3h、R 3-a、R 3-b、R 3-c、R 3-d、R 3-e、R 3-f or R 3-i is C 1-6 alkyl-O-or C 1-6 alkyl-O-substituted with a substituent, each of said C 1-6 alkyl-O-is independently C 1-4 alkyl-O-, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, further such as methoxy, ethoxy or isopropoxy, further such as methoxy or ethoxy.
In one embodiment, ring A is
In one embodiment, R 1 is F、Cl、-CN、-CHF 2、-CF 3、-CH 3、-CF 2CH 2OH、-CF 2CH 3、-NH 2 or-CF 2C(CH 3) 2 OH; or two R 1 together with the ring atoms to which they are attached form"A" means that the portion is in a loop-by-loop connection with loop A.
In one aspect of the present invention,Is that For example, as
In one embodiment, R 3 is For example, as
In one embodiment, R 3 is
In one aspect of the present invention,Is that For example, as
In one embodiment, R 4 is-CH 3,
In one aspect of the present invention,Is thatFor example, as Wherein the b-terminal is attached to the Z atom.
In one aspect of the present invention,Is that For example, as
In one aspect of the present invention,Is that For example, as
In one aspect of the present invention,Is that For example, as
In one aspect of the present invention,Is that For example, as
In one embodiment, the condensed-cyclic compound shown in formula I is
In one embodiment, R 11 is methyl.
In one embodiment, the fused ring compound represented by formula I is selected from any one of the following compounds:
The invention also provides a preparation method of the fused ring compound shown in the formula I, a tautomer thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of the pharmaceutically acceptable salt thereof, which comprises the following steps:
scheme one: when the condensed-ring compound shown in the formula I is a compound Ia, the compound Ia-6 and The compound Ia is obtained through Buchwald-Hartwig coupling reaction;
Scheme II: when the condensed-ring compound shown in the formula I is a compound Ib, the compound Ib-3 and Obtaining a compound Ib through Buchwald-Hartwig coupling reaction;
preferably, in the preparation method, in scheme one or scheme two, the Buchwald-Hartwig coupling reaction is carried out in the presence of a catalyst and a base; the catalyst is conventional in the art, for example RuPhos Pd G (methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropyloxy-1, 1 '-biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (II)), brettPhos Pd G3 (methanesulfonic acid (2-dicyclohexylphosphino) -3, 6-dimethoxy-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) (2 '-amino-1, 1' -biphenyl-2-yl) palladium (II)), XPhos Pd G3 (methanesulfonic acid (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) (2 '-amino-1, 1' -biphenyl-2-yl) palladium (II)), xantPhos Pd G3 (methanesulfonic acid (9, 9-dimethyl-4, 5-diphenylphosphinoxa) (2 '-amino-1, 1' -biphenyl-2-yl) palladium (II)), and RuPhos Pd G (methanesulfonic acid (2-dicyclohexylphosphino-2 ',4, 1' -biphenyl-2-yl) palladium (II), one or more of 6 '-tri-isopropyl-1, 1' -biphenyl) (2 '-amino-1, 1' -biphenyl-2-yl) palladium (II)) and BrettPhos Pd G4 (methanesulfonic acid (2-dicyclohexylphosphine-3, 6-dimethoxy-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) (2 '-methylamino-1, 1' -biphenyl-2-yl) palladium (II)); the base is conventional in the art, for example, is one or more of cesium carbonate, sodium carbonate, potassium phosphate, sodium carbonate, potassium tert-butoxide, and sodium tert-butoxide.
In the preparation method, preferably, the first scheme further includes the following steps:
The compound I-1 and R 5-NH 2 undergo substitution reaction to obtain a compound Ia-1;
The compound Ia-1 and an iodination reagent (such as N-iodinated succinimide and I 2) are subjected to iodination reaction to obtain a compound Ia-2;
The compound Ia-2 and Obtaining a compound Ia-3 through Heck coupling reaction;
The compound Ia-3 is subjected to ring closure reaction under the action of alkali to obtain a compound Ia-4;
The compound Ia-4 and a brominating reagent are subjected to bromination reaction to obtain a compound Ia-5;
Reacting the compound Ia-5 with corresponding substituted ketone, amine and boric acid ester derivatives to obtain a compound Ia-6;
Preferably, in the iodination reaction, the iodination reagent is conventional in the art, such as N-iodosuccinimide and/or I 2.
Preferably, in the ring closure reaction, the base is conventional in the art, for example, is one or more of sodium methyl mercaptide, sodium methoxide and sodium ethoxide;
preferably, in the bromination reaction, the brominating reagent is conventional in the art, such as N-bromosuccinimide and/or Br 2.
In the preparation method, preferably, the second scheme further includes the following steps:
Wherein R 12 is methyl or ethyl;
The compound I-1 undergoes an acylation reaction under the action of strong alkali to obtain a compound Ib-1;
reacting the compound Ib-1 with malonate and decarboxylating to obtain a compound Ib-2;
The compound Ib-2 and H 2N-L-R 3 undergo a ring-closing reaction to obtain a compound Ib-3;
preferably, in the acylation reaction, the strong base is conventional in the art, for example lithium diisopropylamide;
preferably, the malonate is conventional in the art, e.g., methyl malonate, ethyl malonate.
The invention provides a pharmaceutical composition; the pharmaceutical composition comprises:
(1) A substance X which is a fused ring compound as shown in formula I, a tautomer thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof, as described above, and
(2) Pharmaceutically acceptable auxiliary materials.
The invention provides an application of a substance X or a pharmaceutical composition as described above in preparing an SOS1 inhibitor, wherein the substance X is a fused ring compound shown as a formula I, a tautomer thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of the pharmaceutically acceptable salt thereof.
In such applications, preferably, the SOS1 inhibitor is useful in mammalian organisms; it is also useful in vitro, mainly as an experimental use, for example: the kit can be used as a standard sample or a control sample for comparison or prepared according to a conventional method in the field, so as to provide rapid detection for the SOS1 inhibition effect of the compound.
The invention provides an application of a substance X or a pharmaceutical composition as described above in preparing medicines; the substance X is a fused ring compound shown in the formula I, a tautomer thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof as described above; the drug may be a drug for treating and/or preventing a disease associated with SOS1 activity or expression level.
In the application, preferably, the disease associated with SOS1 activity or expression level is selected from the group consisting of non-small cell lung cancer, lung adenocarcinoma, lung squamous carcinoma, pancreatic cancer, colon cancer, thyroid cancer, melanoma, embryonal rhabdomyosarcoma, skin granulocytoma, liver cancer, rectal cancer, bladder cancer, throat cancer, breast cancer, prostate cancer, glioma, ovarian cancer, head and neck squamous carcinoma, cervical cancer, esophageal cancer, renal cancer, skin cancer, lymphoma, stomach cancer, cholangiocarcinoma, uterine cancer, endometrial cancer, urothelial cancer, acute myelogenous leukemia, myelofibrosis, B-cell lymphoma, monocytic leukemia, splenic polycythemia, eosinophilic leukocytosis syndrome, and multiple myeloma, and diseases associated with SOS1 hereditary mutation, including but not limited to neurofibroma type one, nannochi syndrome, multiple-like multiple-pattern south-note syndrome, capillary-to-malformation syndrome, heart-face-skin syndrome, sjogren's syndrome, reg th syndrome, and hereditary fibrous tumor type gingiva.
The invention provides an application of a substance X or a pharmaceutical composition as described above in preparing medicines; the substance X is a fused ring compound shown in the formula I, a tautomer thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof as described above; the medicine is used for treating and/or preventing the following various diseases; the disease is selected from the group consisting of non-small cell lung cancer, lung adenocarcinoma, lung squamous carcinoma, pancreatic cancer, colon cancer, thyroid cancer, melanoma, embryonal rhabdomyosarcoma, skin granulocytic tumors, liver cancer, rectal cancer, bladder cancer, throat cancer, breast cancer, prostate cancer, glioma, ovarian cancer, head and neck squamous carcinoma, cervical cancer, esophageal cancer, renal cancer, skin cancer, lymphoma, gastric cancer, cholangiocarcinoma, uterine cancer, endometrial cancer, urothelial cancer, acute myeloid leukemia, myelofibrosis, B-cell lymphoma, monocytic leukemia, spleen polycythemia, eosinophilic leukocytosis syndrome, and multiple myeloma, as well as neurofibromas of type one, noonan's syndrome, multiple freckle-like noonan's syndrome, capillary malformation-arteriovenous malformation syndrome, heart-face-skin syndrome, ketig syndrome, reg s syndrome, and hereditary gingival fibroma.
The present invention provides a method of inhibiting SOS1 comprising administering to a patient (e.g. a human) a therapeutically effective amount of substance X or a pharmaceutical composition as described above;
The substance X is a fused ring compound shown in the formula I, a tautomer thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof.
The present invention provides a method of treating and/or preventing a disease comprising administering to a patient (e.g. a human) a therapeutically effective amount of substance X or a pharmaceutical composition as described above;
The substance X is a fused ring compound shown in the formula I, a tautomer thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof as described above;
the disease is a disease related to SOS1 activity or expression level.
In the method of treating and/or preventing a disease, preferably, the disease associated with SOS1 activity or expression level is selected from the group consisting of non-small cell lung cancer, lung adenocarcinoma, lung squamous carcinoma, pancreatic cancer, colon cancer, thyroid cancer, melanoma, embryonal rhabdomyosarcoma, skin granulomatous tumor, liver cancer, rectal cancer, bladder cancer, throat cancer, breast cancer, prostate cancer, glioma, ovarian cancer, head and neck squamous carcinoma, cervical cancer, esophageal cancer, kidney cancer, skin cancer, lymphoma, gastric cancer, bile duct cancer, uterine cancer, endometrial cancer, urothelial carcinoma, acute myeloid leukemia, myelofibrosis, B-cell lymphoma, monocytic leukemia, spleen megaly, eosinophilia syndrome, and multiple myeloma, and diseases associated with genetic mutation of SOS1, including but not limited to, neurofibromatosis, noose syndrome, multiple noose's syndrome, capillary blood vessel-malformation, heart-face-skin syndrome, soxhlet syndrome, asperity syndrome, and gliosis of one vein pattern Reg.
Unless otherwise indicated, the terms used in the present invention have the following meanings:
The term "halogen" refers to fluorine, chlorine, bromine or iodine.
The term "alkyl" refers to a straight or branched chain alkyl group having the indicated number of carbon atoms (e.g., C 1-10, preferably C 1-6, more preferably C 1-4). Alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, and the like.
The term "alkylene" means a saturated divalent hydrocarbon group resulting from the removal of two hydrogen atoms from a saturated straight or branched hydrocarbon group; i.e. one hydrogen in the alkyl group is substituted, the definition of alkyl group being as described above. Examples of alkylene groups include methylene (-CH 2 -), ethylene { including-CH 2CH 2 -or-CH (CH 3) - }, isopropylidene { including-CH (CH 3)CH 2 -or-C (CH 3) 2 - }, etc.).
The term "alkenyl" refers to a straight or branched hydrocarbon chain radical having at least one double bond, consisting of only carbon and hydrogen atoms, having the indicated carbon atoms (e.g., C 2-10, preferably C 2-6, more preferably C 2-4), and linked to the remainder of the molecule by a single bond, such as alkenyl including, but not limited to, vinyl, n-propenyl, isopropenyl, n-butenyl, isobutenyl, sec-butenyl, tert-butenyl, n-pentenyl, 2-methylbutenyl, 2-dimethylpropenyl, n-hexenyl, and the like.
The term "alkynyl" refers to a straight or branched hydrocarbon chain radical having at least one triple bond, consisting of only carbon and hydrogen atoms, having the indicated carbon atoms (e.g., C 2-10, preferably C 2-6, more preferably C 2-4), and being attached to the remainder of the molecule by a single bond, e.g., alkynyl groups including, but not limited to, ethynyl, n-propynyl, isopropoxynyl, n-butynyl, isobutynyl, sec-butynyl, tert-butynyl, n-pentynyl, 2-methylbutynyl, 2-dimethylpropynyl, n-hexynyl, and the like.
In the term "C 1-6 alkyl-O-", C 1-6 alkyl is as defined above.
The term "cycloalkyl" means a saturated monocyclic or polycyclic (e.g., bicyclic, tricyclic or more bridged, fused or spiro ring systems) carbocyclic substituent, and which may be attached to the remainder of the molecule by a single bond via any suitable carbon atom; for example having 3 to 15 ring carbon atoms, preferably having 3 to 10 ring carbon atoms, more preferably having 3 to 7 ring carbon atoms; the cycloalkyl group may be further substituted with oxo substituents; for example, C 3-7 cycloalkyl includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, orEtc.
The term "cycloalkenyl" means a monocyclic or polycyclic (e.g., bicyclic, tricyclic or more bridged, fused or spiro ring system) cyclic hydrocarbon group having at least one double bond, such as a carbon-carbon double bond, and which may be attached to the remainder of the molecule by a single bond via any suitable carbon atom; for example having 3 to 15 ring carbon atoms, preferably having 3 to 10 ring carbon atoms, more preferably having 3 to 7 ring carbon atoms; the cycloalkenyl group may be further substituted with oxo substituents; for example, C 3-7 cycloalkenyl includes, but is not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, or cycloheptenyl.
The term "heterocyclyl" refers to a stable 3 to 20 membered (preferably 3 to 10 membered, more preferably 3 to 7 membered, most preferably 5 to 7 membered, still more preferably 6 membered) saturated or partially unsaturated monocyclic or polycyclic (e.g. bicyclic, tricyclic or more bridged, fused or spiro ring system) heterocycloalkyl consisting of 2 to 14 (preferably 2 to 6) carbon atoms and 1 to 6 heteroatoms or heteroatom groups selected from N, O, S, S (=o) and S (=o) 2, which heterocyclyl may be further substituted with oxo substituents; preferably 3-7 membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O and S, such as aziridinyl, oxiranyl, epoxypropyl, thietanyl, tetrahydrothienyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, pyrazolidinyl, piperidinyl, tetrahydropyranyl, piperazinyl, tetrahydropyridinyl, azetidinyl, pyrrolidinyl, morpholinyl, 2-oxa-5-azabicyclo [2.2.1] heptyl, 2H-pyranyl, oxaazepinyl, diazacyclyl, thiazepinyl, azabicycloheptyl, thiazanyl, dihydrofuranyl, imidazolinyl, imidazolidinyl, thiacyclohexyl, triazinidinyl, dithiocyclohexyl, dithiol, dioxacyclohexyl, 2, 6-diazaspiro [3.3] heptyl, 1, 2-dihydropyridinyl, homopiperazinyl, thiomorpholinyl, thiopyranyl, tetrahydrofuranyl, 4H-pyranyl or dihydropyrrolyl, and further such as
The term "aryl" refers to an aromatic group consisting of carbon atoms that satisfies the 4n+2 rule of conjugated hydrocarbon ring systems, each ring having aromaticity. In one embodiment, "aryl" refers to an aromatic group having from 6 to 18 (preferably 6-12) carbon atoms. Examples of aryl groups include, but are not limited to, phenyl or naphthyl, and the like.
The term "heteroaryl" means a 5 to 20 membered (preferably 5 to 12 membered, more preferably 5 to 10 membered) conjugated ring system group having 2 to 15 carbon atoms and 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur in the ring. Unless otherwise specifically indicated in the present specification, heteroaryl groups may be monocyclic, bicyclic, tricyclic or more ring systems, and may also be fused to cycloalkyl or heterocyclyl groups as defined above, provided that heteroaryl groups are attached to the remainder of the molecule via an atom on an aromatic ring by a single bond. In one embodiment, the term "heteroaryl" refers to an aromatic group containing a heteroatom, each ring having aromaticity; preferably, the heteroatom species are independently selected from N, O and S, 5-10 membered heteroaryl or 5-6 membered heteroaryl having 1,2 or 3 heteroatoms. Examples of heteroaryl groups include, but are not limited to, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzimidazolyl (e.g.) A benzopyrazolyl, indolyl, furanyl, pyrrolyl, triazolyl, tetrazolyl, triazinyl, indolizinyl, isoxazolyl, thiadiazolyl, isoindolyl, indazolyl, isoindazolyl, purinyl, quinolinyl, isoquinolinyl, naphthyridinyl, quinoxalinyl, pteridinyl, carbazolyl, carbolinyl, phenanthridinyl, phenanthrolinyl, acridinyl, phenazinyl, isothiazolyl, benzothiazolyl, benzisothiazolyl, benzothienyl, oxazolyl, cinnolinyl, quinazolinyl, indolizinyl, phenanthroline, isoxazolyl, phenoxazinyl, phenothiazinyl, benzoxazolyl, or benzisoxazolyl group.
In the term "cycloalkyl-O-", cycloalkyl is as defined above.
In the term "cycloalkenyl-O-", cycloalkenyl is as defined above.
In the term "heterocyclyl-O-", heterocyclyl is as defined above.
The "-" at the end of a group means that the group is attached to other fragments in the molecule through that site.
As used herein, the singular forms "a", "an", and "the" are understood to include plural referents unless the context clearly dictates otherwise.
The term "one or more" means 1,2,3, 4, 5,6,7,8, 9 or more.
Unless otherwise indicated, the present invention employs conventional methods of mass spectrometry, elemental analysis, and the various steps and conditions are referred to in the art by conventional procedures and conditions.
The present invention employs, unless otherwise indicated, standard nomenclature for analytical chemistry, organic synthetic chemistry and optics, and standard laboratory procedures and techniques. In some cases, standard techniques are used for chemical synthesis, chemical analysis.
In addition, unless explicitly indicated otherwise, the description as used herein "… is to be understood broadly as meaning that each individual described is independent of the other and may be the same or different. In more detail, the description that "… is independently" may mean that specific options expressed between the same symbols in different groups do not affect each other; it may also be expressed that specific options expressed between the same symbols in the same group do not affect each other.
Those skilled in the art will appreciate that, in accordance with the convention used in the art, the present application describes the structural formula of the group usedIt means that the corresponding group R is linked to other fragments, groups in the compound through this site.
Unless otherwise specified, all technical and scientific terms used herein have the standard meaning of the art to which the claimed subject matter belongs. In case there are multiple definitions for a term, the definitions herein control.
As used herein, the fused ring compounds of formula I of the present invention may contain one or more chiral centers and exist in different optically active forms. When a compound contains one chiral center, the compound contains an enantiomer. The invention includes both isomers and mixtures of isomers, such as racemic mixtures. Enantiomers may be resolved by methods known in the art, such as crystallization and chiral chromatography. When the fused ring compound of formula I contains more than one chiral center, diastereomers may be present. The invention includes mixtures of resolved optically pure specific isomers and diastereomers. Diastereomers can be resolved by methods known in the art, such as crystallization and preparative chromatography. The term "stereoisomers" includes conformational isomers and configurational isomers, wherein configurational isomers include predominantly cis-trans isomers and optical isomers. The compounds of the present invention may exist as stereoisomers and thus encompass all possible stereoisomeric forms, including but not limited to cis-trans isomers, enantiomers, diastereomers, atropisomers and the like, as well as any combination or mixture of any of the aforementioned stereoisomers, for example, meso, racemates, equivalent mixtures of atropisomers and the like. For example, a single enantiomer, a single diastereomer or a mixture thereof, or a single atropisomer or a mixture thereof. When the compounds of the present invention contain olefinic double bonds, they include cis-isomers and trans-isomers, as well as any combination thereof, unless specified otherwise. The atropisomers of the present invention are stereoisomers of axial or planar chirality based on limited intramolecular rotation.
As previously mentioned, the present invention provides compounds of the various structures set forth above, or cis-, meso-, racemate-, enantiomer, diastereomer, atropisomer, tautomer, or mixtures thereof, wherein "mixtures thereof" includes any of the stereoisomers (e.g., cis-, trans-, diastereomer-, atropisomer), tautomers, and/or mixtures (meso-, racemate) thereof, such as mixtures of cis-, trans-, and diastereomers, mixtures of enantiomers and mixtures of diastereomers, and the like.
The term "tautomer" refers to a functional group isomer that results from the rapid movement of an atom in a molecule at two positions.
The fused ring compound as shown in formula I, a tautomer thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof is intended to encompass any isotopically-labeled (or "radiolabeled") variant of the fused ring compound as shown in formula I, a tautomer thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof. Such variants may be obtained by replacement of one or more atoms in a fused ring compound as shown in formula I, a tautomer thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof with an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature. The radionuclide used will depend on the particular application of the radiolabeled variant. For example, 3 H or 14 C are often useful for in vitro receptor labeling and competition assays. For radiological imaging applications 11 C or 18 F are often useful.
Specific isotopic variations of the compounds of the present invention, particularly those in which one or more radioisotopes have been incorporated, can be useful, for example, in examining the mechanism of action or the distribution of active ingredients in the body; compounds labeled with 3 H or 14 C isotopes are particularly suitable for this purpose due to their relatively easy manufacturability and detectability. In addition, inclusion of isotopes such as deuterium may afford particular therapeutic advantages resulting from the compounds having better metabolic stability, for example increased half-life in vivo or reduced effective dosage required; such modifications of the compounds of the invention may therefore also in some cases constitute preferred embodiments of the invention. Isotopic variations of the compounds of the present invention can be prepared by methods known to those skilled in the art, for example, by the methods described below and in the working examples, by using the corresponding isotopically modified specific reagents and/or starting compounds.
In the present application, "pharmaceutical composition" refers to a formulation comprising a compound of the present application and a medium commonly accepted in the art for delivery of biologically active compounds to a mammal (e.g., a human). The medium includes a pharmaceutically acceptable carrier. The purpose of the pharmaceutical composition is to promote the administration of organisms, facilitate the absorption of active ingredients and further exert biological activity.
In the present application, "pharmaceutically acceptable" refers to a substance (e.g., pharmaceutical excipient) that does not affect the biological activity or properties of the compounds of the present application, and is relatively non-toxic, i.e., the substance can be administered to an individual without causing an adverse biological reaction or interacting in an adverse manner with any of the components contained in the composition.
The term "pharmaceutical excipients" or "pharmaceutically acceptable carriers" refers to excipients and additives used in the manufacture of medicaments and formulation prescriptions, and are all substances contained in pharmaceutical preparations except the active ingredient. See the pharmacopoeia of the people's republic of China (2015 Edition), or Handbook of Pharmaceutical Excipients (Raymond C Rowe,2009 sibth Edition). Adjuvants are used primarily to provide a safe, stable and functional pharmaceutical composition, and may also provide means for allowing the subject to dissolve at a desired rate after administration, or for promoting effective absorption of the active ingredient after administration of the composition. The pharmaceutical excipients may be inert fillers or provide a function such as stabilizing the overall pH of the composition or preventing degradation of the active ingredients of the composition. The pharmaceutical excipients can comprise one or more of the following excipients: binders, suspending agents, emulsifiers, diluents, fillers, granulating agents, sizing agents, disintegrants, lubricants, anti-adherents, glidants, wetting agents, gelling agents, absorption retarders, dissolution inhibitors, enhancing agents, adsorbents, buffering agents, chelating agents, preservatives, colorants, flavoring agents, and sweeteners.
The pharmaceutical compositions of the present invention may be prepared in accordance with the disclosure using any method known to those of skill in the art. For example, conventional mixing, dissolving, granulating, emulsifying, levigating, encapsulating, entrapping or lyophilizing processes.
When used as a medicament, the fused ring compound as shown in formula I, a tautomer thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof may be administered in any form of pharmaceutical composition. These compositions may be prepared according to methods well known in the pharmaceutical arts and may be administered by various routes, depending upon the local or systemic treatment and the area to be treated. Administration may be in the form of topical (including epidermal and transdermal, ocular and mucosal, including intranasal, vaginal and rectal delivery), pulmonary (e.g., by powder or aerosol inhalation or insufflation, including by nebulizer; intratracheal or intranasal), oral (solid and liquid formulations) or parenteral administration. Examples of solid oral formulations include, but are not limited to, powders, capsules, caplets, soft capsules, and tablets. Examples of liquid formulations for oral or mucosal administration include, but are not limited to, suspensions, emulsions, elixirs and solutions. Examples of topical formulations include, but are not limited to, emulsions, gels, ointments, creams, patches, pastes, foams, lotions, drops or serum formulations. Examples of formulations for parenteral administration include, but are not limited to, solutions for injection, dry formulations which may be dissolved or suspended in a pharmaceutically acceptable carrier, suspensions for injection, and emulsions for injection. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, emulsions, ointments, gels, drops, suppositories, sprays, liquids and powders. Examples of other suitable formulations of the pharmaceutical composition include, but are not limited to, eye drops and other ophthalmic formulations; aerosol: such as nasal sprays or inhalants. Oral administration may include dosage forms formulated for once-a-day or twice-a-day (BID) administration. Parenteral administration includes intravenous, intra-arterial, subcutaneous, intraperitoneal intramuscular or injection or infusion; or intracranial, such as intrathecal or intraventricular administration. Parenteral administration may be in the form of a single bolus dose or may be by a continuous infusion pump. Conventional pharmaceutical carriers, water, powder or oily bases, thickeners and the like may be necessary or desirable. Pharmaceutical compositions comprising the invention may also be in controlled or delayed release dosage forms (e.g. liposomes or microspheres).
The term "treatment" refers to therapeutic therapy or palliative measures. When specific conditions are involved, treatment refers to: (1) alleviating a disease or one or more biological manifestations of a disorder, (2) interfering with (a) one or more points in a biological cascade that results in or causes a disorder or (b) one or more biological manifestations of a disorder, (3) ameliorating one or more symptoms, effects, or side effects associated with a disorder, or one or more symptoms, effects, or side effects associated with a disorder or treatment thereof, or (4) slowing the progression of a disorder or one or more biological manifestations of a disorder. "treatment" may also refer to an extended survival period compared to the expected survival without treatment.
The term "preventing" refers to a reduced risk of acquiring or developing a disease or disorder.
The term "therapeutically effective amount" refers to an amount of a compound that is sufficient to effectively treat a disease or disorder described herein when administered to a patient. The "therapeutically effective amount" will vary depending on the compound, the condition and severity thereof, and the age of the patient to be treated, but can be adjusted as desired by one of ordinary skill in the art.
The term "patient" refers to any animal, preferably a mammal, most preferably a human, that is about to or has received administration of the compound or composition according to embodiments of the present invention. The term "mammal" includes any mammal. Examples of mammals include, but are not limited to, cattle, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc., with humans being preferred.
The following definitions as used herein should be applied unless otherwise indicated. For the purposes of the present invention, chemical elements are in accordance with CAS version of the periodic Table of the elements, and handbook of chemistry and physics, 75 th edition, 1994. In addition, general principles of organic chemistry may be found in "Organic Chemistry", thomas Sorrell, university Science Books, sausalato 1999, and "March's Advanced Organic Chemistry"by Michael B.Smith and Jerry March,John Wiley&Sons,New York:2007, the entire contents of which are incorporated herein by reference.
The term "pharmaceutically acceptable salt" refers to a salt of a compound that is reacted with a pharmaceutically acceptable (relatively non-toxic, safe, suitable for patient use) acid or base. When the compound contains a relatively acidic functional group, the base addition salt may be obtained by contacting the free form of the compound with a sufficient amount of a pharmaceutically acceptable base in a suitable inert solvent. Pharmaceutically acceptable base addition salts include, but are not limited to, sodium, potassium, calcium, aluminum, magnesium, bismuth, ammonium salts, and the like. When the compound contains a relatively basic functional group, the acid addition salt may be obtained by contacting the free form of the compound with a sufficient amount of a pharmaceutically acceptable acid in a suitable inert solvent. The pharmaceutically acceptable acids include inorganic and organic acids. See, for example, berge et al, "Pharmaceutical Salts", journal of Pharmaceutical Science 66:1-19 (1977), or 、Handbook of Pharmaceutical Salts:Properties,Selection,and Use(P.Heinrich Stahl and Camille G.Wermuth,ed.,Wiley-VCH,2002).
The term "solvate" refers to a material formed upon crystallization of a compound with a solvent (including, but not limited to, water, methanol, ethanol, etc.). The solvates are divided into stoichiometric solvates and non-stoichiometric solvates.
The term "solvate of a pharmaceutically acceptable salt" refers to a compound formed by combining a pharmaceutically acceptable (relatively non-toxic, safe, suitable for patient use) acid or base, solvent (including, but not limited to, water, methanol, ethanol, etc.), wherein the pharmaceutically acceptable salt has the same meaning as the term "pharmaceutically acceptable salt" above.
On the basis of conforming to the common knowledge in the field, the above preferred conditions can be arbitrarily combined to obtain the preferred examples of the invention.
The reagents and materials used in the present invention are commercially available.
The invention has the positive progress effects that: the fused ring compound shown in the formula I has better inhibition activity on SOS 1; it is expected to treat and/or prevent diseases associated with SOS1 activity or expression level.
Detailed Description
The invention is further illustrated by means of the following examples, which are not intended to limit the scope of the invention. The reaction steps in the examples below, for which specific conditions are not noted, may be carried out according to methods and conditions conventional in the art or according to commercial specifications.
The following examples illustrate the invention in more detail, but do not limit the invention in any way.
The structure of the compounds of the present invention is determined by Nuclear Magnetic Resonance (NMR) or/and Mass Spectrometry (MS). The nuclear magnetic resonance chemical shift (δ) is given in parts per million (ppm). Nuclear magnetic resonance was measured using a Bruker (Bruker) AVANCE-400 nuclear magnetic resonance apparatus using deuterated dimethyl sulfoxide (DMSO-d 6) or deuterated chloroform (CDCl 3) as the solvent, and Tetramethylsilane (TMS) as the internal standard. Mass spectrometry was performed using an Agilent 1260-6125B single quadrupole liquid chromatography-mass spectrometer using an electrospray ion source (ESI).
For silica gel column chromatography, a Bayesian (Biotage) Selekt flash preparative chromatograph and a suitably sized BK-SIL silica gel pre-packed column produced by Bayesian or a CLARICEP FLASH silica gel pre-packed column produced by Ai Jieer (Agela) were used.
The thin layer chromatography silica gel plate uses a smoke table yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification adopted is 0.15 mm-0.20 mm, and the specification adopted for preparing the thin layer chromatography silica gel plate is 0.4 mm-0.5 mm.
Preparation high performance liquid chromatography (preparative HPLC) used a AutoPurification LC preparation system with ACQUITy QDa mass spectrometric detector manufactured by Waters corporation. The column was prepared using SunFire C18 μm 19X250mm OBD preparation column. The mobile phase was eluted with different gradients of water (0.1% formic acid) -acetonitrile.
I. Preparation examples of the compounds of the present invention
Example 1 (R) -8- (1-acetyl-4-hydroxypiperidin-4-yl) -6- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -10-methyl-2, 3-dihydro- [1,4] dioxane [2,3-H ] [1,6] naphthyridin-9 (10H) -one (Compound 1)
Step 1: 4-bromo-6-chloro-2-fluoropyridin-3-ol
6-Chloro-2-fluoropyridin-3-ol (80.0 g, 552 mmol) was dissolved in acetonitrile (800 mL), N-bromosuccinimide (106.4 g,596 mmol) was added, and the reaction was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated, diluted with water (600 mL), and extracted with ethyl acetate (2L). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the product as a yellow oil (128 g, crude product) ).ESI-MS m/z：225.9,227.9[M+H] +. 1H NMR(400MHz,DMSO-d 6)δ11.34(s,1H),7.73(s,1H).
Step 2: 4-bromo-6-chloro-2-fluoro-3- ((4-methoxybenzyl) oxy) pyridine
4-Bromo-6-chloro-2-fluoropyridin-3-ol (20 g,88.3 mmol) was dissolved in N, N-dimethylformamide (200 mL), and potassium carbonate (36.6 g,265 mmol) and 4-methoxybenzyl chloride (18.0 g,115 mmol) were added thereto and the reaction was stirred at room temperature for 1 hour. The reaction solution was slowly poured into water (400 mL) and filtered. The filter cake was slurried with absolute ethanol (100 mL) to give the product as a pale yellow solid (25.0 g, yield 83％).ESI-MS m/z：346.0,348.0[M+H] +. 1H NMR(400MHz,DMSO-d 6)δ7.90(s,1H),7.39(d,J＝8.6Hz,2H),6.94(d,J＝8.7Hz,2H),5.16-5.07(m,2H),3.76(s,3H).
Step 3: 4-bromo-2- (2- ((tert-butyldimethylsilyl) oxy) ethoxy) -6-chloro-3- ((4-methoxybenzyl) oxy) pyridine
4-Bromo-6-chloro-2-fluoro-3- ((4-methoxybenzyl) oxy) pyridine (3.48 g,10 mmol) was dissolved in tetrahydrofuran (40 mL), sodium hydride (600 mg,13 mmol) was added at 0deg.C, 2- ((tert-butyldimethylsilyl) oxy) ethanol (3.52 g,20 mmol) was added after stirring for 10 minutes, and the reaction was continued at 0deg.C for 0.5 hours and then at room temperature for 1 hour with stirring. The reaction was quenched by addition of saturated ammonium chloride, diluted with water, extracted with ethyl acetate, the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude product, which was directly used in the next reaction. ESI-MS m/z:502.1, 504.1[ M+H ] +.
Step 4: 4-bromo-6-chloro-2- (2-hydroxyethoxy) pyridin-3-ol
The crude 4-bromo-2- (2- ((tert-butyldimethylsilyl) oxy) ethoxy) -6-chloro-3- ((4-methoxybenzyl) oxy) pyridine obtained in step 3 was dissolved in 4.0M methanolic hydrochloric acid (45 mL), stirred at room temperature for 30min, concentrated under reduced pressure, the residue was neutralized with saturated sodium bicarbonate solution, extracted with ethyl acetate, the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure to give the product as a white solid (5.1 g, crude product) ).ESI-MS m/z：268.0,270.0[M+H] +. 1H NMR(400MHz,CDCl 3)δ＝10.07(s,1H),7.27(s,1H),4.29(t,J＝4.0Hz,2H),3.74(t,J＝4.0Hz,2H).
Step 5: 8-bromo-6-chloro-2, 3-dihydro- [1,4] dioxane [2,3-b ] pyridine
4-Bromo-6-chloro-2- (2-hydroxyethoxy) pyridin-3-ol (5.1 g,19 mmol) was dissolved in tetrahydrofuran (60 mL), triphenylphosphine (6.0 g,28 mmol) was added and diisopropyl azodicarboxylate (5.68 g,28 mmol) was slowly added at 0deg.C and the reaction stirred at room temperature for 1 hour. Ethyl acetate was added for dilution, washed with water and saturated sodium chloride in this order, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=10:1, volume ratio) to give the product as a white solid (3.68g).ESI-MS m/z：249.9,251.9[M+H] +. 1H NMR(400MHz,CDCl 3)δ7.14(s,1H),4.47–4.45(m,2H),4.36–4.34(m,2H).
Step 6: 6-chloro-N-methyl-2, 3-dihydro- [1,4] dioxane [2,3-b ] pyridin-8-amine
8-Bromo-6-chloro-2, 3-dihydro- [1,4] dioxane [2,3-b ] pyridine (1.75 g,7 mmol) was dissolved in ethylene glycol dimethyl ether (20 mL), and aqueous methylamine solution (25 mL) was added, and the mixture was heated to 100℃and stirred for 4 hours. After cooling to room temperature, ethyl acetate is added, and then water and saturated sodium chloride are sequentially used for washing, anhydrous sodium sulfate is dried, and the product crude product is obtained after decompression concentration and is directly used for the next reaction. ESI-MS m/z:201.0[ M+H ] +.
Step 7: 6-chloro-7-iodo-N-methyl-2, 3-dihydro- [1,4] dioxane [2,3-b ] pyridin-8-amine
Crude 6-chloro-N-methyl-2, 3-dihydro- [1,4] dioxane [2,3-b ] pyridin-8-amine product (1.1 g) obtained in step 6 was dissolved in N, N-dimethylformamide (15 mL), N-iodosuccinimide (1.48 g,6.6 mmol) was added, and the mixture was heated to 85℃under argon atmosphere to react for 2 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, washed with water and saturated sodium chloride in this order, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=2:1, volume ratio) to give the product as a white solid (819mg).ESI-MS m/z：326.9,328.9[M+H] +. 1H NMR(400MHz,DMSO-d 6)δ4.36–4.34(m,2H),4.19–4.17(m,2H),3.30(s,1H),3.11(s,3H).
Step 8:3- (6-chloro-8- (methylamino) -2, 3-dihydro- [1,4] dioxo [2,3-b ] pyridin-7-yl) acrylic acid ethyl ester
6-Chloro-7-iodo-N-methyl-2, 3-dihydro- [1,4] dioxane [2,3-b ] pyridin-8-amine (819 mg,2.5 mmol) was dissolved in N, N-dimethylformamide (15 mL), ethyl acrylate (376 mg,3.76 mmol), triethylamine (380 mg,3.76 mmol), palladium acetate (56 mg,0.25 mmol), tris (o-methylphenyl) phosphine (152 mg,0.5 mmol) was added. Under the protection of argon, the temperature is raised to 100 ℃ for reaction for 2 hours. After cooling to room temperature, the reaction was diluted with ethyl acetate, washed with water, saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=2:1, volume ratio) to give the product as a white solid (406 mg). ESI-MS m/z:299.1[ M+H ] +.
Step 9: 6-chloro-10-methyl-2, 3-dihydro- [1,4] dioxane [2,3-H ] [1,6] naphthyridin-9 (10H) -one
Ethyl 3- (6-chloro-8- (methylamino) -2, 3-dihydro- [1,4] dioxo [2,3-b ] pyridin-7-yl) acrylate (406 mg,1.36 mmol) was dissolved in ethanol (8 mL), sodium methyl mercaptide (105 mg,1.5 mmol) was added and reacted at room temperature for 15 min. Concentrated under reduced pressure, and the residue was diluted with water (100 mL) and extracted with ethyl acetate (100 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the product as a white solid (200 mg). ESI-MS m/z:253.0[ M+H ] +.
Step 10: 8-bromo-6-chloro-10-methyl-2, 3-dihydro- [1,4] dioxane [2,3-H ] [1,6] naphthyridin-9 (10H) -one
6-Chloro-10-methyl-2, 3-dihydro- [1,4] dioxane [2,3-H ] [1,6] naphthyridin-9 (10H) -one (1.29 g,5.1 mmol) was dissolved in N, N-dimethylformamide (20 mL), N-bromosuccinimide (2.27 g,12.7 mmol) was added, and the temperature was raised to 70℃for reaction for 2 hours. Saturated aqueous sodium sulfite solution (100 mL) was added for dilution, and extracted with ethyl acetate (200 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure to give the product as a white solid (2.03g).ESI-MS m/z：330.9,332.9[M+H] +. 1H NMR(400MHz,CDCl 3)δ＝8.33(s,1H),4.53–4.51(m,2H),4.37–4.35(m,2H),3.86(s,3H).
Step 11:8- (1-acetyl-4-hydroxypiperidin-4-yl) -6-chloro-10-methyl-2, 3-dihydro- [1,4] dioxane [2,3-H ] [1,6] naphthyridin-9 (10H) -one
8-Bromo-6-chloro-10-methyl-2, 3-dihydro- [1,4] dioxan [2,3-H ] [1,6] naphthyridin-9 (10H) -one (390 mg,1.18 mmol) was dissolved in tetrahydrofuran (20 mL), 1-acetylpiperidin-4-one (284 mg,4.71 mmol) was added, the reaction mixture was cooled to-40℃and samarium iodide (82mL,8.2mmol,0.1M in THF) was slowly added, and the reaction was continued at-40℃with stirring for 2 hours. Saturated aqueous ammonium chloride (60 mL) was added for dilution, followed by extraction with ethyl acetate (200 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was chromatographed on silica gel (dichloromethane/methanol=20:1, volume ratio) to give the product as a brown solid (239 mg). ESI-MS m/z:394.1[ M+H ] +.
Step 12: (R) -8- (1-acetyl-4-hydroxypiperidin-4-yl) -6- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -10-methyl-2, 3-dihydro- [1,4] dioxane [2,3-H ] [1,6] naphthyridin-9 (10H) -one (Compound 1)
8- (1-Acetyl-4-hydroxypiperidin-4-yl) -6-chloro-10-methyl-2, 3-dihydro- [1,4] dioxan [2,3-H ] [1,6] naphthyridin-9 (10H) -one (239 mg,0.61 mmol) was dissolved in toluene (8 mL), and (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethane-1-amine hydrochloride (270 mg,1.21mmol, prepared according to the method described in patent WO2019122129A 1), methanesulfonic acid (2-dicyclohexylphosphine) -3, 6-dimethoxy-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) (2 '-amino-1, 1' -biphenyl-2-yl) palladium (II) (Brettphos Pd G, 55mg,0.06 mmol) and sodium tert-butoxide (175 mg,1.82 mmol) were added. The reaction was stirred at 100℃for 16 hours under nitrogen. After cooling to room temperature, concentration under reduced pressure, the residue was purified by silica gel column chromatography (dichloromethane/methanol=20:1, volume ratio) to give compound 1 as a white solid (209mg).ESI-MS m/z：547.2[M+H] +. 1H NMR(400MHz,DMSO-d 6)δ8.34(s,1H),7.64–7.61(m,1H),7.47(t,J＝4.0Hz,1H),7.26(t,J＝4.0Hz,1H),7.23(s,1H),5.48–5.44(m,1H),4.32-4.30(m,2H),4.12–4.11(m,2H),3.75(s,3H),3.72-3.69(m,1H),3.51–3.43(m,1H),2.95–2.91(m,1H),2.45–2.36(m,2H),2.03(s,3H),1.64–1.61(m,1H),1.56–1.52(m,1H),1.50(d,J＝4.8Hz,3H),1.40–1.37(m,1H),1.34(s,1H),1.30–1.25(m,1H). 13C NMR(400MHz,DMSO-d 6)δ168.30,162.83,150.47,148.30,148.24,137.76,129.82,124.97,118.35,99.14,65.41,63.74,42.40,37.36,35.41,34.64,32.01,31.75,22.12,21.78.
Example 2 (S) -8- (1-acetyl-4-hydroxypiperidin-4-yl) -6- (((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2- ((dimethylamino) methyl) -10-methyl-2, 3-dihydro- [1,4] dioxane [2,3-H ] [1,6] naphthyridin-9 (10H) -one (Compound 2)
Step 1: (S) -4-bromo-6-chloro-2- ((2, 2-dimethyl-1, 3-dioxolan-4-yl) methoxy) -3- ((4-methoxybenzyl) oxy) pyridine
To a 500mL three-necked flask, sodium hydride (2.3 g,57.8 mmol) and anhydrous N, N-dimethylformamide (100 mL) were added, and the mixture was cooled to 0℃and a solution of (S) -glycerolacetonide (5.7 g,43.4 mmol) in 50mL of anhydrous N, N-dimethylformamide was slowly added dropwise. After the completion of the dropwise addition, stirring was continued at 0℃for 1 hour. A solution of 4-bromo-6-chloro-2-fluoro-3- ((4-methoxybenzyl) oxy) pyridine (10.0 g,28.9 mmol) in 50mL anhydrous N, N-dimethylformamide was then slowly added dropwise. After the completion of the dropwise addition, the reaction mixture was stirred at 0℃for 1 hour. To the reaction mixture was added a saturated aqueous ammonium chloride solution (50 mL) to quench the reaction. The reaction mixture was added to ethyl acetate (300 mL) and water (100 mL), the layers were extracted, the organic phase was washed with water (200 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was chromatographed on silica gel (petroleum ether/ethyl acetate=10:1, volume ratio) to give the product as a white solid (12.8 g, yield 97％).ESI-MS m/z：458.0,460.0[M+1] +. 1H NMR(400MHz,DMSO-d 6)δ7.39(d,J＝8.4Hz,2H),7.39(s,1H),6.91(d,J＝8.4Hz,2H),5.03(s,2H),4.46-4.52(m,1H),4.39(dd,J＝4.4Hz,J＝11.2Hz,1H),4.33(dd,J＝5.6Hz,J＝11.2Hz,1H),4.10(dd,J＝6.8Hz,J＝8.4Hz,1H),3.85(dd,J＝6.0Hz,J＝8.4Hz,1H),3.75(s,3H),1.36(s,3H),1.32(s,3H).
Step 2: (R) -3- ((4-bromo-6-chloro-3- ((4-methoxybenzyl) oxy) pyridin-2-yl) oxy) propane-1, 2-diol
(S) -4-bromo-6-chloro-2- ((2, 2-dimethyl-1, 3-dioxolan-4-yl) methoxy) -3- ((4-methoxybenzyl) oxy) pyridine (12.8 g,27.9 mmol) was dissolved in methanol (30 mL), 4.0M methanolic hydrochloride (30 mL) was added at 0deg.C, and the reaction was warmed to room temperature and stirred for 1 hour. Triethylamine was added at 0 ℃ to adjust the pH to neutral, concentrated under reduced pressure, and the residue was chromatographed on silica gel (petroleum ether/ethyl acetate=3:1, volume ratio) to give the product as a yellow solid (10.5 g, yield 90%). ESI-MS m/z:418.0, 420.0[ M+1] +.
Step 3: (S) -3- ((4-bromo-6-chloro-3- ((4-methoxybenzyl) oxy) pyridin-2-yl) oxy) propane-1, 2-diol dimethyl sulfonate
(R) -3- ((4-bromo-6-chloro-3- ((4-methoxybenzyl) oxy) pyridin-2-yl) oxy) propane-1, 2-diol (10.5 g,25.1 mmol) was dissolved in dichloromethane (20 mL), triethylamine (6.3 g,62.6 mmol) and methylsulfonyl chloride (7.2 g,62.6 mmol) were added at 0deg.C and the reaction was stirred at 0deg.C for 0.5h. Water (100 mL) was added for dilution, and ethyl acetate (300 mL) was added for extraction. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the product (14.4 g), the crude product was used directly in the next reaction. ESI-MS m/z:574.0, 576.0[ M+1] +.
Step 4: (S) -3- ((4-bromo-6-chloro-3-hydroxypyridin-2-yl) oxy) propane-1, 2-diol dimethyl sulfonate
The crude product from step 3 (14.4 g) was dissolved in dichloromethane (20 mL), trifluoroacetic acid (20 mL) was added and stirred at room temperature for 0.5 h. The reaction mixture was dried under reduced pressure, diluted with saturated aqueous sodium bicarbonate (300 mL) and extracted with ethyl acetate (500 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was chromatographed on silica gel (dichloromethane/ethyl acetate=8:1, volume ratio) to give the product as a yellow oil (8.2 g, two-step yield 72％).ESI-MS m/z：453.9,455.9[M+1] +. 1H NMR(400MHz,DMSO-d 6)δ10.28(s,1H),7.36(s,1H),5.21(dd,J＝6.4,3.6Hz,1H),4.71(dd,J＝11.5,6.3Hz,1H),4.65-4.46(m,3H),3.30(s,3H),3.26(s,3H).
Step 5: (R) - (8-bromo-6-chloro-2, 3-dihydro- [1,4] dioxane [2,3-b ] pyridin-2-yl) methyl methanesulfonate
(S) -3- ((4-bromo-6-chloro-3-hydroxypyridin-2-yl) oxy) propane-1, 2-diol dimethyl sulfonate (8.2 g,18.0 mmol) in N, N-dimethylformamide (50 mL) was added potassium carbonate (7.5 g,54.1 mmol) and stirred at 60℃for 1 hour. Water (300 mL) was added for dilution, and ethyl acetate (600 mL) was used for extraction. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was chromatographed on silica gel (petroleum ether/ethyl acetate=10:1, volume ratio) to give the product as a yellow oil (6.4 g, yield 98%). ESI-MS m/z:357.9, 359.9[ M+1] +.
Step 6: (S) -6-chloro-N-methyl-2- ((methylamino) methyl) -2, 3-dihydro- [1,4] dioxane [2,3-b ] pyridin-8-amine
(R) - (8-bromo-6-chloro-2, 3-dihydro- [1,4] dioxane [2,3-b ] pyridin-2-yl) methyl methanesulfonate (6.4 g,17.8 mmol) was dissolved in 1, 4-dioxane (50 mL), aqueous methylamine (40 mL) was added, and the reaction was sealed at 100℃and stirred for 16 hours. After cooling to room temperature, the crude product is obtained by concentrating under reduced pressure and is directly used for the next reaction. ESI-MS m/z:244.1[ M+1] +.
Step 7: tert-butyl (S) - (6-chloro-8- (methylamino) -2, 3-dihydro- [1,4] dioxan [2,3-b ] pyridin-2-yl) methyl) (methyl) carbamate
The crude product from step 6 was dissolved in tetrahydrofuran (60 mL), triethylamine (1.8 g,17.8 mmol) and di-tert-butyl dicarbonate (5.8 g,26.7 mmol) were added and stirred at room temperature for 6 hours. Water (150 mL) was added for dilution, and ethyl acetate (300 mL) was added for extraction. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was chromatographed on silica gel (petroleum ether/ethyl acetate=3:1, volume ratio) to give the product as a yellow oil (3.0 g, two-step yield 49％).ESI-MS m/z：344.2[M+1] +. 1H NMR(400MHz,DMSO-d 6)δ6.23(s,1H),6.16(d,J＝20.9Hz,1H),4.40(d,J＝39.2Hz,1H),4.27(d,J＝11.2Hz,1H),4.21-4.03(m,1H),3.59(dd,J＝14.8,8.0Hz,1H),3.44(s,1H),2.91-2.85(m,3H),2.72(d,J＝4.8Hz,3H),1.35(d,J＝43.9Hz,9H).
Step 8: tert-butyl (S) - (6-chloro-7-iodo-8- (methylamino) -2, 3-dihydro- [1,4] dioxan [2,3-b ] pyridin-2-yl) methyl) (methyl) carbamate
Tert-butyl (S) - (6-chloro-8- (methylamino) -2, 3-dihydro- [1,4] dioxan [2,3-b ] pyridin-2-yl) methyl) (methyl) carbamate (3.0 g,8.73 mmol) was dissolved in acetic acid (30 mL), N-iodosuccinimide (2.1 g,9.60 mmol) was added and stirred at room temperature for 1 hour. Saturated aqueous sodium sulfite (100 mL) was added for dilution, saturated aqueous sodium bicarbonate (150 mL) was added for neutralization, and ethyl acetate (300 mL) was added for extraction. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was chromatographed on silica gel (petroleum ether/ethyl acetate=3:1, volume ratio) to give the product as a yellow oil (3.1 g, yield 76%). ESI-MS m/z:470.1[ M+1] +.
Step 9: (S) -3- (2- (tert-Butoxycarbonyl) (methyl) amino) methyl) -6-chloro-8- (methylamino) -2, 3-dihydro- [1,4] dioxan [2,3-b ] pyridin-7-yl) acrylic acid ethyl ester
Tert-butyl (S) - (6-chloro-7-iodo-8- (methylamino) -2, 3-dihydro- [1,4] dioxane [2,3-b ] pyridin-2-yl) methyl) (methyl) carbamate (3.1 g,6.60 mmol), palladium acetate (148 mg,0.660 mmol), tris (o-methylphenyl) phosphine (400 mg,1.32 mmol), triethylamine (1.4 g,13.2 mmol) and ethyl acrylate (2.0 g,19.9 mmol) in N, N-dimethylformamide (40 mL). The reaction was stirred at 100℃for 3 hours under nitrogen. After cooling to room temperature, water (300 mL) was added for dilution, and ethyl acetate (500 mL) was added for extraction. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was chromatographed on silica gel (petroleum ether/ethyl acetate=2:1, vol) to give the product as a yellow oil (2.3 g, yield 79%). ESI-MS m/z:442.2[ M+1] +.
Step 10: tert-butyl (S) - ((6-chloro-10-methyl-9-oxo-2, 3,9, 10-tetrahydro- [1,4] dioxan [2,3-h ] [1,6] naphthyridin-2-yl) methyl) (methyl) carbamate
Ethyl (S) -3- (2- (tert-butoxycarbonyl) (methyl) amino) methyl) -6-chloro-8- (methylamino) -2, 3-dihydro- [1,4] dioxane [2,3-b ] pyridin-7-yl) acrylate (2.3 g,5.20 mmol) was dissolved in ethanol (20 mL), sodium methyl mercaptide (400 mg,5.72 mmol) was added and stirred at room temperature for 0.5 hours. Concentrated under reduced pressure, and the residue was diluted with water (100 mL) and extracted with ethyl acetate (150 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the product as a yellow solid (1.9 g, yield 93%). ESI-MS m/z:396.2[ M+1] +.
Step 11: tert-butyl (S) - ((8-bromo-6-chloro-10-methyl-9-oxo-2, 3,9, 10-tetrahydro- [1,4] dioxane [2,3-h ] [1,6] naphthyridin-2-yl) methyl) (methyl) carbamate
Tert-butyl (S) - ((6-chloro-10-methyl-9-oxo-2, 3,9, 10-tetrahydro- [1,4] dioxan [2,3-h ] [1,6] naphthyridin-2-yl) methyl) (methyl) carbamate (1.9 g,4.80 mmol) was dissolved in N, N-dimethylformamide (30 mL), N-bromosuccinimide (2.5 g,14.4 mmol) was added and the reaction stirred at 70℃for 2 hours. Saturated aqueous sodium sulfite solution (100 mL) was added for dilution, and ethyl acetate (250 mL) was added for extraction. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was chromatographed on silica gel (petroleum ether/ethyl acetate=2:1, volume ratio) to give the product as a yellow solid (1.2 g, yield 53％).ESI-MS m/z：474.1,476.1[M+1] +. 1H NMR(400MHz,DMSO-d 6)δ8.52-8.25(m,1H),4.76-4.51(m,2H),4.43-4.22(m,1H),3.85(s,3H),3.84-3.74(m,1H),3.40-3.25(m,1H),2.96-2.80(m,3H),1.29(m,9H).
Step 12: tert-butyl (S) - ((8- (1-acetyl-4-hydroxypiperidin-4-yl) -6-chloro-10-methyl-9-oxo-2, 3,9, 10-tetrahydro- [1,4] dioxane [2,3-h ] [1,6] naphthyridin-2-yl) methyl) (methyl) carbamate
Tert-butyl (S) - ((8-bromo-6-chloro-10-methyl-9-oxo-2, 3,9, 10-tetrahydro- [1,4] dioxane [2,3-h ] [1,6] naphthyridin-2-yl) methyl) (methyl) carbamate (400 mg,0.842 mmol) and 1-acetylpiperidin-4-one (470 mg,3.37 mmol) were dissolved in tetrahydrofuran (20 mL), nitrogen protected, and samarium iodide (33.7mL,3.37mmol,0.1M in THF) was added dropwise at-30 ℃. The reaction was stirred at-30℃for 0.5 hour. Saturated aqueous ammonium chloride (100 mL) was added at-30℃for dilution, and ethyl acetate (300 mL) was added for extraction. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was chromatographed on silica gel (dichloromethane/methanol=20:1, volume ratio) to give the product as a white solid (230 mg, yield 51%). ESI-MS m/z:481.2[ M-t-Bu ] +.
Step 13: (S) -8- (1-acetyl-4-hydroxypiperidin-4-yl) -6-chloro-10-methyl-2- ((methylamino) methyl) -2, 3-dihydro- [1,4] dioxane [2,3-H ] [1,6] naphthyridin-9 (10H) -one
Tert-butyl (S) - ((8- (1-acetyl-4-hydroxypiperidin-4-yl) -6-chloro-10-methyl-9-oxo-2, 3,9, 10-tetrahydro- [1,4] dioxane [2,3-h ] [1,6] naphthyridin-2-yl) methyl) (methyl) carbamate (230 mg,0.428 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (1 mL) was added and stirred at room temperature for 1 hour. Concentrating under reduced pressure to obtain crude product, which is directly used in the next reaction. ESI-MS m/z:437.2[ M+1] +.
Step 14: (S) -8- (1-acetyl-4-hydroxypiperidin-4-yl) -6-chloro-2- ((dimethylamino) methyl) -10-methyl-2, 3-dihydro- [1,4] dioxane [2,3-H ] [1,6] naphthyridin-9 (10H) -one
The crude product obtained in step 13 was dissolved in tetrahydrofuran (15 mL), 30% aqueous formaldehyde (3 mL) was added, sodium triacetoxyborohydride (227 mg,1.07 mmol) was added, and the mixture was stirred at room temperature for 0.5 hour. Concentration under reduced pressure and column chromatography of the residue on silica gel (dichloromethane/methanol=12:1, volume ratio) gave the product as a white solid (130 mg, 67% yield in two steps). ESI-MS m/z:451.2[ M+1] +.
Step 15: (S) -8- (1-acetyl-4-hydroxypiperidin-4-yl) -6- (((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2- ((dimethylamino) methyl) -10-methyl-2, 3-dihydro- [1,4] dioxane [2,3-H ] [1,6] naphthyridin-9 (10H) -one (Compound 2)
(S) -8- (1-acetyl-4-hydroxypiperidin-4-yl) -6-chloro-2- ((dimethylamino) methyl) -10-methyl-2, 3-dihydro- [1,4] dioxan [2,3-H ] [1,6] naphthyridin-9 (10H) -one (130 mg,0.288 mmol), methanesulfonic acid (2-dicyclohexylphosphine) -3, 6-dimethoxy-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) (2 '-amino-1, 1' -biphenyl-2-yl) palladium (II) (Brettphos Pd G, 39mg,0.029 mmol), (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethane-1-amine hydrochloride (196 mg,0.865mmol, prepared according to the method described in patent WO2019122129A 1) and sodium tert-butoxide (166 mg,1.73 mmol) were dissolved in toluene (6 mL). The reaction was stirred at 100℃for 16 hours under nitrogen. After cooling to room temperature, concentration under reduced pressure, and silica gel column chromatography of the residue (dichloromethane/methanol=20:1, volume ratio) gave compound 2 as a yellow solid (120 mg, yield 69％).ESI-MS m/z：604.3[M+1] +. 1H NMR(400MHz,CDCl 3)δ7.76(d,J＝1.6Hz,1H),7.50(dq,J＝22.0,7.2Hz,2H),7.17(td,J＝7.6,2.4Hz,1H),6.92(t,J＝55.1Hz,1H),5.97(brs,1H),5.89(dd,J＝10.8,7.2Hz,1H),5.64-5.65(m,1H),4.54(d,J＝12.6Hz,1H),4.49(dt,J＝11.2,2.0Hz,1H),4.25-4.18(m,1H),4.14(dd,J＝11.2,7.6Hz,1H),3.92(s,3H),3.66(d,J＝9.6,2H),3.12(td,J＝12.8,2.8Hz,1H),2.68-2.57(m,2H),2.33(s,6H),2.18(td,J＝13.6,2.8Hz,1H),2.07(d,J＝12.8Hz,3H),2.03-1.96(m,1H),1.93-1.77(m,2H),1.58(dd,J＝7.2,3.2Hz,3H).
Example 3 (R) -8- (1-acetyl-4-hydroxypiperidin-4-yl) -6- (((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2- ((dimethylamino) methyl) -10-methyl-2, 3-dihydro- [1,4] dioxane [2,3-H ] [1,6] naphthyridin-9 (10H) -one (Compound 3)
Synthesis of Compound 3 referring to step 1 to step 15 of example 2, except that (S) -glycerolacetonide, which is the raw material in step 1, was replaced with (R) -glycerolacetonide .ESI-MS m/z：604.3[M+1] +. 1H NMR(400MHz,CDCl 3)δ7.65(s,1H),7.42(dt,J＝13.0,7.0Hz,2H),7.09(t,J＝7.1Hz,1H),6.86(dd,J＝74.1,36.0Hz,1H),5.70(s,1H),5.52(d,J＝4.3Hz,1H),4.44(dd,J＝33.3,11.4Hz,2H),4.26(s,1H),4.17–4.06(m,1H),3.84(s,3H),3.60(s,2H),3.06(t,J＝12.7Hz,1H),2.66(s,2H),2.34(d,J＝2.6Hz,6H),2.11(d,J＝12.2Hz,1H),2.00(t,J＝11.6Hz,3H),1.94(d,J＝15.1Hz,1H),1.89–1.71(m,2H),1.58–1.45(m,3H). 13C NMR(101MHz,CDCl 3)δ167.83(s),163.15(s),149.25(s),147.22(s),136.70(s),131.40(d,J＝12.6Hz),129.52(s),126.45(s),124.28(s),123.30(s),116.52(s),109.70(s),98.69(s),69.73(d,J＝14.5Hz),66.68(s),58.12(s),45.02(s),44.76(s),41.47(s),36.49(s),35.67(d,J＝14.5Hz),34.31(d,J＝7.4Hz),33.83(s),28.68(s),25.92(s),20.57(dd,J＝21.5,6.8Hz).
Example 4 (S) -8- (1-acetyl-4-hydroxypiperidin-4-yl) -6- (((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -3- ((dimethylamino) methyl) -10-methyl-2, 3-dihydro- [1,4] dioxane [2,3-H ] [1,6] naphthyridin-9 (10H) -one (Compound 4)
Step 1: (S) -2- ((1-azido-3- ((4-methoxybenzyl) oxy) propan-2-yl) oxy) -4-bromo-6-chloro-3- ((4-methoxybenzyl) oxy) pyridine
Prepared with reference to step 1 of example 2 except that (S) -glycerolacetonide was replaced with (S) -1-azido-3- ((4-methoxybenzyl) oxy) propyl-2-ol. ESI-MS m/z:563.1, 565.1[ m+1] +.
Step 2: (S) -2- ((1-azido-3-hydroxypropan-2-yl) oxy) -4-bromo-6-chloropyridin-3-ol
(S) -2- ((1-azido-3- ((4-methoxybenzyl) oxy) propan-2-yl) oxy) -4-bromo-6-chloro-3- ((4-methoxybenzyl) oxy) pyridine (24.4 g,43.4 mmol), dissolved in dichloromethane (100 mL), and trifluoroacetic acid (50 mL) was added and stirred at room temperature for 1 hour. Concentrated under reduced pressure, the residue was redissolved in ethyl acetate (600 mL), adjusted to pH 8-9 by the addition of saturated sodium bicarbonate solution, and extracted with water (400 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was chromatographed on silica gel (petroleum ether/ethyl acetate=2:1, volume ratio) to give the product as a white solid (12 g, yield 85.7%). ESI-MS m/z:323.0, 325.0[ M+1] +.
Step 3: (S) -N- ((8-bromo-6-chloro-2, 3-dihydro- [1,4] dioxan [2,3-b ] pyridin-3-yl) methyl) -1, 1-triphenylphosphine imine
(S) -2- ((1-azido-3-hydroxypropan-2-yl) oxy) -4-bromo-6-chloropyridin-3-ol (960 mg,3 mmol) was dissolved in tetrahydrofuran (20 mL) and triphenylphosphine (1.57 g,6 mmol) and diisopropyl azodicarboxylate (667 mg,3.3 mmol) were added under nitrogen at 0deg.C. The reaction was warmed to room temperature and stirred for 1 hour. Concentrating under reduced pressure to obtain crude product, which is directly used in the next reaction. ESI-MS m/z:539.0, 541.0[ M+1] +.
Step 4: (S) -3- (aminomethyl) -6-chloro-N-methyl-2, 3-dihydro- [1,4] dioxane [2,3-b ] pyridin-8-amine
The crude (S) -N- ((8-bromo-6-chloro-2, 3-dihydro- [1,4] dioxan [2,3-b ] pyridin-3-yl) methyl) -1, 1-triphenylphosphine imine (3.5 g) obtained in step 3 was dissolved in aqueous methylamine (40 mL), and the mixture was stirred at 100℃for 24 hours in a sealed tube. Concentrating under reduced pressure, dissolving the residue in ethyl acetate (100 mL), adding 4M methanolic hydrochloric acid (10 mL), stirring at room temperature for 5min, extracting with water (100 mL), alkalizing the water phase to pH 10 with concentrated ammonia water, adding ethyl acetate (50 mL,3 times), extracting, drying the organic phase with anhydrous sodium sulfate, concentrating under reduced pressure to obtain crude product, yellow oily substance (960 mg), and directly using for the next reaction. ESI-MS m/z:230.1[ M+1] +.
Step 5: tert-butyl (S) - ((6-chloro-8- (methylamino) -2, 3-dihydro- [1,4] dioxan [2,3-b ] pyridin-3-yl) methyl) carbamate
The crude (S) -3- (aminomethyl) -6-chloro-N-methyl-2, 3-dihydro- [1,4] dioxane [2,3-b ] pyridin-8-amine obtained in step 4 was dissolved in tetrahydrofuran (30 mL), triethylamine (1 mL) was added, di-tert-butyl dicarbonate (972 mg,1.5 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Water (30 mL) was added for dilution, and ethyl acetate (30 mL) was added for extraction. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was chromatographed on silica gel (petroleum ether/ethyl acetate=1:1, volume ratio) to give the product as a white solid (960 mg, total yield of 3 steps 46%). ESI-MS m/z:330.1[ M+1] +.
Step 6: tert-butyl (S) - ((6-chloro-7-iodo-8- (methylamino) -2, 3-dihydro- [1,4] dioxan [2,3-b ] pyridin-3-yl) methyl) carbamate
Preparation with reference to step 8 of example 2 .ESI-MS m/z：456.1[M+1] +. 1H NMR(400MHz,CDCl 3)δ5.09(s,1H),4.39(dd,J＝7.0,4.9Hz,1H),4.30(dd,J＝11.5,2.1Hz,1H),3.83(dd,J＝11.2,8.3Hz,1H),3.55(d,J＝14.3Hz,1H),3.41(d,J＝15.2Hz,1H),3.22(s,3H),1.44(s,9H).
Step 7: (S) -3- (3- (((tert-Butoxycarbonyl) amino) methyl) -6-chloro-8- (methylamino) -2, 3-dihydro- [1,4] dioxan [2,3-b ] pyridin-7-yl) acrylic acid ethyl ester
Preparation with reference to step 9 of example 2 .ESI-MS m/z：428.2[M+1] +. 1H NMR(400MHz,CDCl 3)δ7.71(d,J＝16.3Hz,1H),6.20(t,J＝9.9Hz,1H),4.37(ddd,J＝13.7,7.9,2.2Hz,2H),4.27(q,J＝7.1Hz,2H),3.96–3.83(m,1H),3.54(t,J＝14.9Hz,1H),3.43(dd,J＝13.0,6.9Hz,1H),2.95(d,J＝11.4Hz,3H),1.44(s,11H),1.34(t,J＝7.1Hz,3H).
Step 8: tert-butyl (S) - ((6-chloro-10-methyl-9-oxo-2, 3,9, 10-tetrahydro- [1,4] dioxan [2,3-h ] [1,6] naphthyridin-3-yl) methyl) carbamate
Preparation with reference to step 10 of example 2 .ESI-MS m/z：382.1[M+1] +.1H NMR(400MHz,CDCl 3)δ7.92(t,J＝9.4Hz,1H),6.62(d,J＝9.8Hz,1H),5.16(s,1H),4.58–4.39(m,2H),4.00–3.86(m,4H),3.66–3.44(m,2H),1.47(d,J＝21.6Hz,9H).
Step 9: tert-butyl (S) - ((8-bromo-6-chloro-10-methyl-9-oxo-2, 3,9, 10-tetrahydro- [1,4] dioxane [2,3-h ] [1,6] naphthyridin-3-yl) methyl) carbamate
Prepared with reference to step 11 of example 2. ESI-MS m/z:460.0, 462.0[ M+1] +.
Step 10: tert-butyl (S) - ((8- (1-acetyl-4-hydroxypiperidin-4-yl) -6-chloro-10-methyl-9-oxo-2, 3,9, 10-tetrahydro- [1,4] dioxane [2,3-h ] [1,6] naphthyridin-3-yl) methyl) carbamate
Prepared with reference to step 12 of example 2.ESI-MS m/z:523.2[ M+1] +.
Step 11: (S) -8- (1-acetyl-4-hydroxypiperidin-4-yl) -3- (aminomethyl) -6-chloro-10-methyl-2, 3-dihydro- [1,4] dioxane [2,3-H ] [1,6] naphthyridin-9 (10H) -one
Prepared with reference to step 13 of example 2.ESI-MS m/z:423.1[ M+1] +.
Step 12: (S) -8- (1-acetyl-4-hydroxypiperidin-4-yl) -6-chloro-3- ((dimethylamino) methyl) -10-methyl-2, 3-dihydro- [1,4] dioxane [2,3-H ] [1,6] naphthyridin-9 (10H) -one
Prepared with reference to step 14 of example 2.ESI-MS m/z:451.2[ M+1] +.
Step 13: (S) -8- (1-acetyl-4-hydroxypiperidin-4-yl) -6- (((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -3- ((dimethylamino) methyl) -10-methyl-2, 3-dihydro- [1,4] dioxane [2,3-H ] [1,6] naphthyridin-9 (10H) -one (Compound 4)
Preparation of Compound 4 by reference to step 15 of example 2 .ESI-MS m/z：604.3[M+1] +. 1H NMR(400MHz,MeOD)δ8.19(s,1H),7.60–7.50(m,1H),7.45(t,J＝7.0Hz,1H),7.20(t,J＝7.7Hz,1H),7.00(t,J＝54.9Hz,1H),5.62–5.47(m,1H),4.62(s,1H),4.50(d,J＝12.9Hz,1H),4.22(dt,J＝15.9,8.0Hz,1H),3.95–3.78(m,5H),3.65(td,J＝13.1,2.5Hz,1H),3.10(ddd,J＝21.0,13.5,9.1Hz,2H),2.80(dd,J＝13.4,3.5Hz,1H),2.55(d,J＝7.6Hz,6H),2.37–2.22(m,2H),2.17(s,3H),2.00–1.75(m,2H),1.60(d,J＝7.0Hz,3H). 13C NMR(101MHz,MeOD)δ171.42(s),164.98(s),151.29(s),150.11(s),138.92(s),134.91(d,J＝13.6Hz),132.00(s),130.98(s),130.30(s),126.14(s),125.44(s),119.29(s),100.98(s),73.04(s),72.53(s),66.47(s),59.94(s),46.27(s),45.74(s),43.76(s),38.87(s),36.68(s),35.85(d,J＝6.8Hz),35.20(s),21.85(s),21.22(s).
Example 5 (R) -8- (1-acetyl-4-hydroxypiperidin-4-yl) -6- (((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -10-methyl-2- ((R) -1-methylpyrrolidin-2-yl) -2, 3-dihydro- [1,4] dioxane [2,3-H ] [1,6] naphthyridin-9 (10H) -one (Compound 5)
Step 1: tert-butyl (R) -2- ((S) -2- ((4-bromo-6-chloro-3- ((4-methoxybenzyl) oxy) pyridin-2-yl) oxy) -1-hydroxyethyl) pyrrolidine-1-carboxylic acid ester
(R) -2- ((S) -1, 2-Dihydroxyethyl) pyrrolidine-1-carboxylic acid tert-butyl ester (30.0 g,130 mmol), 4-bromo-6-chloro-2-fluoro-3- ((4-methoxybenzyl) oxy) pyridine (36.0 g,104 mmol) and cesium carbonate (50.7 g,156 mmol) were dissolved in dimethyl sulfoxide (300 mL) and stirred at room temperature for 4 hours. The reaction mixture was diluted with water (1.5L), and extracted with ethyl acetate (1L). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was chromatographed on silica gel (petroleum ether/ethyl acetate=12:1, volume ratio) to give the product as a yellow oil (11.5 g, yield 24％).ESI-MS m/z：579.1,581.1[M+Na] +. 1H NMR(400MHz,CDCl 3)δ7.47(s,2H),7.10-7.03(m,1H),6.94-6.82(m,2H),5.20-5.09(m,1H),5.05(d,J＝10.0Hz,1H),4.49(dd,J＝11.4,2.9Hz,1H),4.36(dd,J＝11.4,4.7Hz,1H),4.13(brs,1H),3.89(brs,1H),3.84-3.77(m,3H),3.51(s,1H),3.42-3.25(m,1H),2.03-1.59(m,4H),1.49(d,J＝3.7Hz,9H).
Step 2: 4-bromo-6-chloro-2- ((S) -2-hydroxy-2- ((R) -pyrrolidin-2-yl) ethoxy) pyridin-3-ol
Tert-butyl (R) -2- ((S) -2- ((4-bromo-6-chloro-3- ((4-methoxybenzyl) oxy) pyridin-2-yl) oxy) -1-hydroxyethyl) pyrrolidine-1-carboxylate (11.5 g,20.6 mmol) was dissolved in dichloromethane (20 mL), trifluoroacetic acid (20 mL) was added and stirred at room temperature for 1 hour. The solvent was dried under reduced pressure to give crude product, which was directly used in the next reaction. ESI-MS m/z:337.0, 339.0[ M+1] +.
Step 3: tert-butyl (R) -2- ((S) -2- ((4-bromo-6-chloro-3-hydroxypyridin-2-yl) oxy) -1-hydroxyethyl) pyrrolidine-1-carboxylic acid ester
The crude product from step 2 was dissolved in tetrahydrofuran (60 mL) and water (20 mL), the pH was adjusted to 8-9 by the addition of triethylamine, and further, di-tert-butyl dicarbonate (8.9 g,41.2 mmol) was added and stirred at room temperature for 16 hours. Water (300 mL) was added for dilution, and ethyl acetate (600 mL) was used for extraction. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was chromatographed on silica gel (petroleum ether/ethyl acetate=9:1, volume ratio) to give the product as a white solid (5.3 g, yield 59％).ESI-MS m/z：459.0,461.0[M+Na] +. 1H NMR(400MHz,DMSO-d 6)δ9.92(s,1H),7.27(s,1H),5.03-4.97(m,1H),4.30(d,J＝8.0Hz,1H),4.04(brs,1H),3.95(brs,1H),3.72-3.60(m,1H),3.40(brs,1H),3.20(brs,1H),1.93(s,3H),1.73(s,1H),1.42(s,9H).
Step 4: tert-butyl (R) -2- ((R) -8-bromo-6-chloro-2, 3-dihydro- [1,4] dioxane [2,3-b ] pyridin-2-yl) pyrrolidine-1-carboxylic acid ester
Tert-butyl (R) -2- ((S) -2- ((4-bromo-6-chloro-3-hydroxypyridin-2-yl) oxy) -1-hydroxyethyl) pyrrolidine-1-carboxylate (5.3 g,12.1 mmol) was dissolved in tetrahydrofuran (50 mL), nitrogen blanketed, and triphenylphosphine (3.8 g,14.6 mmol) and diisopropyl azodicarboxylate (2.9 g,14.6 mmol) were added at 0deg.C. The reaction was warmed to room temperature and stirred for 1 hour. Water (200 mL) was added for dilution, and ethyl acetate (400 mL) was used for extraction. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was chromatographed on silica gel (petroleum ether/ethyl acetate=12:1, volume ratio) to give the product as a white solid (4.0 g, yield 79％).ESI-MS m/z：363.0[M-t-Bu] +. 1H NMR(400MHz,CDCl 3)δ7.13(s,1H),4.54(d,J＝10.8Hz,1H),4.27-4.09(m,2H),4.02(s,1H),3.61-3.30(m,2H),2.21(s,1H),2.08-2.03(m,1H),2.00-1.90(m,2H),1.48(s,9H).
Step 5: tert-butyl (R) -2- ((R) -6-chloro-8- (methylamino) -2, 3-dihydro- [1,4] dioxane [2,3-b ] pyridin-2-yl) pyrrolidine-1-carboxylic acid ester
Tert-butyl (R) -2- ((R) -8-bromo-6-chloro-2, 3-dihydro- [1,4] dioxane [2,3-b ] pyridin-2-yl) pyrrolidine-1-carboxylate (4.0 g,9.55 mmol) was dissolved in dimethyl sulfoxide (40 mL), aqueous methylamine (30 mL) was added, and the mixture was sealed at 100℃and stirred for 24 hours. After cooling to room temperature, water (150 mL) was added for dilution, and ethyl acetate (300 mL) was used for extraction. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the product as a yellow oil (3.5 g, crude yield 100%). ESI-MS m/z:370.2[ M+1] +.
Step 6: tert-butyl (R) -2- ((R) -6-chloro-7-iodo-8- (methylamino) -2, 3-dihydro- [1,4] dioxane [2,3-b ] pyridin-2-yl) pyrrolidine-1-carboxylic acid ester
Tert-butyl (R) -2- ((R) -6-chloro-8- (methylamino) -2, 3-dihydro- [1,4] dioxan [2,3-b ] pyridin-2-yl) pyrrolidine-1-carboxylate (3.5 g,9.55 mmol) was dissolved in acetic acid (20 mL), N-iodosuccinimide (2.3 g,10.5 mmol) was added and stirred at room temperature for 1 hour. Saturated aqueous sodium sulfite (100 mL) was added for dilution, saturated aqueous sodium bicarbonate (150 mL) was added for neutralization, and ethyl acetate (300 mL) was used for extraction. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was chromatographed on silica gel (petroleum ether/ethyl acetate=4:1, volume ratio) to give the product as a white solid (3.5 g, yield 74%). ESI-MS m/z:496.1[ M+1] +.
Step 7: tert-butyl (R) -2- ((R) -6-chloro-7- (3-ethoxy-3-oxoprop-1-en-1-yl) -8- (methylamino) -2, 3-dihydro- [1,4] dioxo [2,3-b ] pyridin-2-yl) pyrrolidine-1-carboxylic acid ester
Tert-butyl (R) -2- ((R) -6-chloro-7-iodo-8- (methylamino) -2, 3-dihydro- [1,4] dioxan [2,3-b ] pyridin-2-yl) pyrrolidine-1-carboxylate (3.5 g,7.06 mmol), palladium acetate (159 mg,0.706 mmol), tris (o-methylphenyl) phosphine (430 mg,1.41 mmol), triethylamine (1.4 g,14.1 mmol) and ethyl acrylate (1.8 g,1.16 mmol) in N, N-dimethylformamide (40 mL). The reaction was stirred at 100℃for 3 hours under nitrogen. After cooling to room temperature, water (300 mL) was added for dilution, and ethyl acetate (500 mL) was added for extraction. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was chromatographed on silica gel (petroleum ether/ethyl acetate=4:1, volume ratio) to give the product as a yellow oil (2.3 g, yield 70％).ESI-MS m/z：468.2[M+1] +. 1H NMR(400MHz,CDCl3)δ7.71(d,J＝16.4Hz,1H),6.20(d,J＝16.4Hz,1H),4.46(d,J＝10.4Hz,1H),4.27(q,J＝7.2Hz,2H),4.17-4.07(m,2H),4.00(brs,1H),3.57-3.43(m,1H),3.40-3.28(m,1H),3.00(s,3H),2.12-1.93(m,4H),1.48(s,9H),1.34(t,J＝7.2Hz,3H).
Step 8: tert-butyl (R) -2- ((R) -6-chloro-10-methyl-9-oxo-2, 3,9, 10-tetrahydro- [1,4] dioxane [2,3-h ] [1,6] naphthyridin-2-yl) pyrrolidine-1-carboxylate
Tert-butyl (R) -2- ((R) -6-chloro-7- (3-ethoxy-3-oxoprop-1-en-1-yl) -8- (methylamino) -2, 3-dihydro- [1,4] dioxo [2,3-b ] pyridin-2-yl) pyrrolidine-1-carboxylate (2.3 g,4.91 mmol) was dissolved in ethanol (30 mL), sodium methyl mercaptide (378 mg,5.41 mmol) was added and stirred at room temperature for 0.5h. The solvent was evaporated under reduced pressure, diluted with water (100 mL) and extracted with ethyl acetate (150 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the product as a yellow solid (2.2 g, yield 100%). ESI-MS m/z:422.2[ [ M+1] +.
Step 9: tert-butyl (R) -2- ((R) -8-bromo-6-chloro-10-methyl-9-oxo-2, 3,9, 10-tetrahydro- [1,4] dioxane [2,3-h ] [1,6] naphthyridin-2-yl) pyrrolidine-1-carboxylic acid ester
Tert-butyl (R) -2- ((R) -6-chloro-10-methyl-9-oxo-2, 3,9, 10-tetrahydro- [1,4] dioxane [2,3-h ] [1,6] naphthyridin-2-yl) pyrrolidine-1-carboxylate (2.2 g,4.91 mmol) was dissolved in N, N-dimethylformamide (30 mL), N-bromosuccinimide (2.6 g,14.7 mmol) was added and the reaction stirred at 70℃for 2 hours. Saturated aqueous sodium sulfite (100 mL) was added for dilution, and ethyl acetate (150 mL) was used for extraction. The organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the product as a white solid (535 mg, yield 90％).ESI-MS m/z：500.1,502.1[M+1] +. 1H NMR(400MHz,DMSO-d 6)δ8.36(s,1H),4.56(d,J＝11.6Hz,1H),4.37-4.26(m,1H),4.24(dd,J＝11.6,8.8Hz,1H),4.00(s,1H),3.86(s,3H),3.40(s,1H),3.23(brs,1H),2.03-1.90(m,3H),1.85-1.78(m,1H),1.41(s,9H).
Step 10: tert-butyl (R) -2- ((R) -8- (1-acetyl-4-hydroxypiperidin-4-yl) -6-chloro-10-methyl-9-oxo-2, 3,9, 10-tetrahydro- [1,4] dioxy [2,3-h ] [1,6] naphthyridin-2-yl) pyrrolidine-1-carboxylate
Tert-butyl (R) -2- ((R) -8-bromo-6-chloro-10-methyl-9-oxo-2, 3,9, 10-tetrahydro- [1,4] dioxane [2,3-h ] [1,6] naphthyridin-2-yl) pyrrolidine-1-carboxylate (500 mg,1.00 mmol) and 1-acetylpiperidin-4-one (564 mg,4.00 mmol) were dissolved in tetrahydrofuran (25 mL), nitrogen blanketed, and samarium iodide (40.0mL,4.00mmol,0.1M in THF) was added dropwise at-30 ℃. The reaction was stirred at-30℃for 0.5 hour. Saturated aqueous ammonium chloride (100 mL) was added at-30℃for dilution, and ethyl acetate (300 mL) was added for extraction. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was chromatographed on silica gel (dichloromethane/methanol=30:1, volume ratio) to give the product as a yellow solid (380 mg, yield 68%). ESI-MS m/z:507.2[ M-t-Bu ] +.
Step 11: (R) -8- (1-acetyl-4-hydroxypiperidin-4-yl) -6-chloro-10-methyl-2- ((R) -pyrrolidin-2-yl) -2, 3-dihydro- [1,4] dioxane [2,3-H ] [1,6] naphthyridin-9 (10H) -one
Tert-butyl (R) -2- ((R) -8- (1-acetyl-4-hydroxypiperidin-4-yl) -6-chloro-10-methyl-9-oxo-2, 3,9, 10-tetrahydro- [1,4] dioxy [2,3-h ] [1,6] naphthyridin-2-yl) pyrrolidine-1-carboxylate (380 mg,0.676 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (1 mL) was added and stirred at room temperature for 1 hour. The solvent was evaporated to dryness under reduced pressure to give crude product, which was directly used in the next reaction. ESI-MS m/z:463.2[ [ M+1] +.
Step 12: (R) -8- (1-acetyl-4-hydroxypiperidin-4-yl) -6-chloro-10-methyl-2- ((R) -1-methylpyrrolidin-2-yl) -2, 3-dihydro- [1,4] dioxane [2,3-H ] [1,6] naphthyridin-9 (10H) -one
The crude product obtained in step 11 was dissolved in tetrahydrofuran (20 mL), and aqueous formaldehyde (3 mL) and sodium triacetoxyborohydride (356 mg,1.69 mmol) were added thereto, and the reaction was stirred at room temperature for 0.5 hours. Concentration under reduced pressure, column chromatography of the residue on silica gel (dichloromethane/methanol=8:1, volume ratio) gave the product as a white solid (280 mg, yield 88％).ESI-MS m/z：477.2[M+1] +. 1H NMR(400MHz,DMSO-d 6)δ8.27(s,1H),4.77(s,1H),4.68(d,J＝11.3Hz,1H),4.35-4.22(m,2H),3.83-3.80(m,1H),3.81(s,3H),3.70(d,J＝12.0Hz,1H),3.59(brs,2H),3.22-3.14(m,1H),2.95(s,3H),2.91-2.85(m,2H),2.64-2.54(m,1H),2.46-2.40(m,1H),2.26-2.05(m,3H),2.03(s,3H),2.00-1.86(m,2H),1.42-1.22(m,2H).
Step 13: (R) -8- (1-acetyl-4-hydroxypiperidin-4-yl) -6- (((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -10-methyl-2- ((R) -1-methylpyrrolidin-2-yl) -2, 3-dihydro- [1,4] dioxane [2,3-H ] [1,6] naphthyridin-9 (10H) -one (Compound 5)
(R) -8- (1-acetyl-4-hydroxypiperidin-4-yl) -6-chloro-10-methyl-2- ((R) -1-methylpyrrolidin-2-yl) -2, 3-dihydro- [1,4] dioxan [2,3-H ] [1,6] naphthyridin-9 (10H) -one (200 mg,0.42 mmol), methanesulfonic acid (2-dicyclohexylphosphine) -3, 6-dimethoxy-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) (2 '-amino-1, 1' -biphenyl-2-yl) palladium (II) (Brettphos Pd G, 39mg,0.042 mmol), (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethane-1-amine hydrochloride (284 mg,1.26mmol, prepared according to the method described in patent WO2019122129A 1) and sodium tert-butoxide (242 mg,2.56 mmol) were dissolved in 1, 4-dioxane (15 mL), nitrogen-protected, stirred at 100℃for 16 hours. After cooling to room temperature, concentration under reduced pressure, silica gel column chromatography of the residue (dichloromethane/methanol=20:1, volume ratio) gave a crude product, which was purified by preparative HPLC to give compound 5 as a yellow solid (43 mg, yield 16.3％).ESI-MS m/z：630.3[M+1] +. 1H NMR(400MHz,CDCl 3)δ8.09(s,1H),7.49(d,J＝9.2Hz,3H),7.18(t,J＝7.6Hz,1H),6.91(m,1H),5.75(brs,1H),5.57(s,1H),5.26(s,1H),4.60(d,J＝13.2Hz,1H),4.50(d,J＝11.8Hz,1H),4.36(t,J＝9.3Hz,1H),4.19(s,1H),3.92(s,3H),3.76-3.63(m,2H),3.29(s,1H),3.16(t,J＝12.8Hz,1H),2.89(s,1H),2.57(d,J＝5.2Hz,2H),2.51(s,1H),2.21(d,J＝10.8Hz,2H),2.12(d,J＝6.1Hz,3H),2.05-2.00(m,2H),1.97-1.84(m,4H),1.83-1.69(m,2H),1.62(d,J＝7.2Hz,3H).
Example 6 (S) -8- (1-acetyl-4-hydroxypiperidin-4-yl) -6- (((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -10-methyl-2- ((R) -1-methylpyrrolidin-2-yl) -2, 3-dihydro- [1,4] dioxane [2,3-H ] [1,6] naphthyridin-9 (10H) -one (Compound 6)
Synthesis of Compound 6 referring to Steps 1-13 of example 5, except that in step 1 the raw material (R) -2- ((S) -1, 2-dihydroxyethyl) pyrrolidine-1-carboxylic acid tert-butyl ester was replaced with (R) -2- ((R) -1, 2-dihydroxyethyl) pyrrolidine-1-carboxylic acid tert-butyl ester .ESI-MS m/z：630.3[M+1] +. 1H NMR(400MHz,CDCl 3)δ7.55-7.47(m,3H),7.20(td,J＝7.6,2.0Hz,1H),6.92(t,J＝55.0Hz,1H),5.75(s,1H),5.58(p,J＝6.8Hz,1H),5.45-5.27(m,1H),4.58(d,J＝13.6Hz,1H),4.50-4.37(m,2H),4.21(dd,J＝11.6,6.8Hz,1H),3.93(s,3H),3.73-3.63(m,2H),3.34(s,1H),3.15(td,J＝12.8,3.2Hz,1H),2.90(s,1H),2.64-2.42(m,3H),2.28-2.16(m,2H),2.11(d,J＝4.4Hz,3H),2.07-1.97(m,2H),1.96-1.85(m,4H),1.83-1.72(m,2H),1.61(d,J＝6.8Hz,3H).
Example 7 (R) -8- (1-acetyl-4-hydroxypiperidin-4-yl) -6- (((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -10-methyl-2- ((S) -1-methylpyrrolidin-2-yl) -2, 3-dihydro- [1,4] dioxane [2,3-H ] [1,6] naphthyridin-9 (10H) -one (Compound 7)
Synthesis of Compound 7 referring to Steps 1-13 of example 5, except that in step 1 the raw material (R) -2- ((S) -1, 2-dihydroxyethyl) pyrrolidine-1-carboxylic acid tert-butyl ester was replaced with (S) -2- ((S) -1, 2-dihydroxyethyl) pyrrolidine-1-carboxylic acid tert-butyl ester .ESI-MS m/z：630.3[M+1] +. 1H NMR(400MHz,CDCl 3)δ7.81(s,1H),7.49(dt,J＝15.2,7.3Hz,2H),7.16(td,J＝7.6,2.1Hz,1H),7.07–6.74(m,1H),5.95(dd,J＝18.8,10.0Hz,1H),5.61(dd,J＝12.0,6.9Hz,1H),4.62–4.51(m,1H),4.47(d,J＝9.7Hz,1H),4.23–4.09(m,2H),3.93(s,3H),3.67(t,J＝6.5Hz,2H),3.22–3.06(m, 2H),2.78(s,1H),2.41(t,J＝10.6Hz,3H),2.38–2.13(m,3H),2.07(d,J＝18.4Hz,3H),2.02–1.88(m,3H),1.58(dd,J＝6.8,3.0Hz,3H). 13C NMR(101MHz,CDCl 3)δ168.77(d,J＝4.1Hz),164.25(s),157.11(s),150.60(s),148.17(s),137.58(s),132.51(d,J＝12.8Hz),130.43(s),130.18(s),127.78(d,J＝4.5Hz),125.20(s),124.22(s),118.14(s),110.77(s),99.62(d,J＝6.0Hz),74.71(s),70.81(d,J＝3.2Hz),66.23(s),65.07(d,J＝6.5Hz),57.64(s),45.78(s),42.42(d,J＝10.7Hz),37.51(s),36.79(s),36.56(s),35.37(d,J＝16.2Hz),34.92(d,J＝5.4Hz),29.69(s),27.00(s),23.38(s),21.57(dd,J＝14.1,8.4Hz).
Example 8 (S) -8- (1-acetyl-4-hydroxypiperidin-4-yl) -6- (((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -10-methyl-2- ((S) -1-methylpyrrolidin-2-yl) -2, 3-dihydro- [1,4] dioxane [2,3-H ] [1,6] naphthyridin-9 (10H) -one (Compound 8)
Synthesis of Compound 8 referring to Steps 1-13 of example 5, except that in step 1 the raw material (R) -2- ((S) -1, 2-dihydroxyethyl) pyrrolidine-1-carboxylic acid tert-butyl ester was replaced with (S) -2- ((R) -1, 2-dihydroxyethyl) pyrrolidine-1-carboxylic acid tert-butyl ester .ESI-MS m/z：630.3[M+1] +. 1H NMR(400MHz,CDCl 3)δ7.71(d,J＝2.5Hz,1H),7.57–7.42(m,2H),7.16(t,J＝7.3Hz,1H),6.90(t,J＝55.1Hz,1H),5.77(dd,J＝13.7,6.5Hz,1H),5.58(d,J＝2.9Hz,1H),4.54(d,J＝12.5Hz,1H),4.47(d,J＝11.4Hz,1H),4.30–4.20(m,1H),3.98(s,1H),3.91(s,3H),3.66(d,J＝8.4Hz,2H),3.13(dd,J＝20.6,9.4Hz,2H),2.68(s,1H),2.43(s,3H),2.35(d,J＝5.8Hz,1H),2.24–2.12(m,2H),2.07(d,J＝10.7Hz,3H),1.99(d,J＝9.3Hz,2H),1.82(d,J＝18.4Hz,4H),1.57(d,J＝5.2Hz,3H).
Example 9 (S) -8- (1-acetyl-4-hydroxypiperidin-4-yl) -6- (((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -10-methyl-2- (pyrrolidin-1-ylmethyl) -2, 3-dihydro- [1,4] dioxane [2,3-H ] [1,6] naphthyridin-9 (10H) -one (Compound 9)
The synthesis of compound 9 is described in example 2.ESI-MS m/z:630.3[ M+1] +.
Example 10 (R) -8- (1-acetyl-4-hydroxypiperidin-4-yl) -6- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -4, 10-dimethyl-3, 4-dihydro- [1,4] oxazin [3,2-H ] [1,6] naphthyridin-9 (10H) -one (Compound 10)
Synthesis of Compound 10 with reference to example 1, except that starting material 2- ((tert-butyldimethylsilyl) oxy) ethanol in step 3 was replaced with N- [2- (tert-butyldimethylsilyloxy) ethyl ] methylamine. ESI-MS m/z:560.2[ M+1] +.
Example 11 (S) -8- (1-acetyl-4-methoxypiperidin-4-yl) -6- (((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2- ((dimethylamino) methyl) -10-methyl-2, 3-dihydro- [1,4] dioxane [2,3-H ] [1,6] naphthyridin-9 (10H) -one (Compound 11)
Step 1:
(S) -8- (1-acetyl-4-hydroxypiperidin-4-yl) -6- ((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2- ((dimethylamino) methyl) -10-methyl-2, 3-dihydro- [1,4] dioxan [2,3-H ] [1,6] naphthyridin-9 (10H) -one (Compound 2, 80mg,0.132 mmol) was dissolved in dichloromethane (3 mL), nitrogen protected, and diethylaminosulfur trifluoride (DAST, 42mg,0.265 mmol) was added at 0deg.C. The reaction was then stirred at room temperature for 2 hours. Water (20 mL) was added for dilution, and ethyl acetate (50 mL) was added for extraction. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was used directly in the next reaction. ESI-MS m/z:606.3[ M+1] +.
Step 2:
The crude product from step 1 was dissolved in anhydrous methanol (10 mL) and sodium methoxide in methanol (238mg,1.32mmol,30%w.t.in MeOH) was added. The reaction was stirred at room temperature for 16 hours. Water (40 mL) was added for dilution, and ethyl acetate (80 mL) was added for extraction. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, cooled to room temperature, and concentrated under reduced pressure, and the residue was purified by preparative HPLC to give compound 11 as a yellow solid (6 mg, yield 15％).ESI-MS m/z：618.4[M+1] +. 1H NMR(400MHz,CDCl 3)δ7.66(s,1H),7.60-7.39(m,3H),7.19(t,J＝7.6Hz,1H),6.90(t,J＝55.2Hz,1H),5.58(s,1H),5.30(s,1H),4.52(dd,J＝23.6,12.0Hz,2H),4.34-4.11(m,3H),3.99-3.75(m,5H),3.69-3.62(m,1H),3.56-3.39(m,1H),3.24(s,3H),3.00-2.85(m,1H),2.82-2.59(m,3H),2.57-2.42(m,2H),2.39(s,6H),2.21-1.98(m,4H),1.95-1.82(m,1H),1.62(d,J＝6.8Hz,3H).
Example 12 (R) -8- (1-acetyl-4-methoxypiperidin-4-yl) -6- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -10-methyl-2, 3-dihydro- [1,4] dioxane [2,3-H ] [1,6] naphthyridin-9 (10H) -one (Compound 12)
Compound 12 was prepared according to example 11 starting from Compound 1 .ESI-MS m/z：561.2[M+1] +. 1H NMR(400MHz,DMSO-d 6)δ＝7.64–7.61(m,1H),7.42-7.34(m,2H),7.24(t,J＝4.0Hz,1H),6.90(t,J＝4.0Hz,1H),5.26–5.34(m,1H),4.32-4.23(m,2H),3.55(s,2H),3.51-3.43(m,2H),3.35(s,3H),3.17–3.15(m,1H),3.09–3.08(m,2H),2.20–2.09(m,1H),2.03–2.01(m,1H),1.99(s,3H),1.55–1.46(m,1H),1.42–1.34(m,2H),1.30–1.26(m,2H),1.24(s,3H).
Example 13 (R) -8- (1-acetyl-4-methoxypiperidin-4-yl) -6- (((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2- ((dimethylamino) methyl) -10-methyl-2, 3-dihydro- [1,4] dioxane [2,3-H ] [1,6] naphthyridin-9 (10H) -one (Compound 13)
Compound 13 was prepared according to example 11 starting from Compound 3 .ESI-MS m/z：618.3[M+1] +. 1H NMR(400MHz,CDCl 3)δ7.58(s,1H),7.41(dd,J＝17.2,9.8Hz,2H),7.11(t,J＝7.5Hz,1H),6.99–6.66(m,1H),5.49(dd,J＝14.1,7.0Hz,1H),5.12(d,J＝7.6Hz,1H),4.49(d,J＝12.7Hz,1H),4.41(d,J＝10.7Hz,1H),4.20–4.01(m,2H),3.92–3.72(m,3H),3.66–3.55(m,1H),3.40(dd,J＝25.6,13.1Hz,1H),3.14(d,J＝26.1Hz,3H),3.06(s,1H),2.85(dd,J＝25.4,12.8Hz,1H),2.70(s,1H),2.38(t,J＝8.0Hz,3H),2.27–2.14(m,2H),2.05(s,3H),1.81(t,J＝12.1Hz,2H),1.70(s,3H),1.55(d,J＝6.9Hz,3H).
Example 14 (S) -8- (1-acetyl-4-methoxypiperidin-4-yl) -6- (((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -3- ((dimethylamino) methyl) -10-methyl-2, 3-dihydro- [1,4] dioxane [2,3-H ] [1,6] naphthyridin-9 (10H) -one (Compound 14)
Compound 14 was prepared according to example 11 starting from Compound 4 .ESI-MS m/z：618.4[M+1] +. 1H NMR(400MHz,CDCl3)δ7.56(s,1H),7.42(dt,J＝14.1,6.7Hz,2H),7.11(t,J＝7.6Hz,1H),6.99–6.66(m,1H),5.50(dd,J＝14.2,7.0Hz,1H),5.10(d,J＝7.7Hz,1H),4.48(d,J＝11.1Hz,1H),4.39(d,J＝5.9Hz,1H),4.26–4.13(m,1H),3.83(t,J＝5.3Hz,1H),3.79(d,J＝8.7Hz,3H),3.66–3.58(m,1H),3.39(dd,J＝23.3,10.5Hz,1H),3.17(d,J＝1.8Hz,3H),2.85(dd,J＝22.7,10.2Hz,1H),2.61(ddd,J＝20.0,13.0,6.5Hz,2H),2.51–2.38(m,2H),2.29(s,6H),2.03(d,J＝14.5Hz,3H),2.01–1.91(m,1H),1.81(t,J＝12.9Hz,1H), 1.54(d,J＝6.9Hz,3H). 13C NMR(101MHz,CDCl 3)δ167.92(s),161.12(s),149.19(s),146.86(s),137.23(s),131.28(d,J＝11.9Hz),129.87(s),128.15(s),126.61(s),124.41(s),123.42(s),117.38(s),109.70(s),98.09(s),71.60(s),64.84(s),58.24(s),49.23(s),45.85(s),45.08(s),41.34(s),36.33(s),33.52(s),31.90(s),31.14(s),30.78(s),29.94(s),28.67(s),20.92(s),20.42(s).
Example 15 (R) -8- (1-acetyl-4-methoxypiperidin-4-yl) -6- (((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -10-methyl-2- ((R) -1-methylpyrrolidin-2-yl) -2, 3-dihydro- [1,4] dioxane [2,3-H ] [1,6] naphthyridin-9 (10H) -one (Compound 15)
Compound 15 was prepared according to example 11 starting from Compound 5 .ESI-MS m/z：644.4[M+1] +. 1H NMR(400MHz,CDCl3)δ8.14(brs,1H),7.63(s,1H),7.55-7.43(m,2H),7.19(t,J＝7.6Hz,1H),6.89(t,J＝55.2Hz,1H),5.56(s,1H),5.15(s,1H),4.57(d,J＝13.6Hz,1H),4.50(d,J＝11.6Hz,1H),4.36-4.30(m,1H),4.16(s,1H),3.86(s,3H),3.69(d,J＝12.4Hz,1H),3.47(dt,J＝13.6,3.0Hz,1H),3.29(s,1H),3.25(s,2H),3.00-2.84(m,2H),2.58(d,J＝6.4Hz,3H),2.53-2.43(m,3H),2.13(s,3H),2.07-2.02(m,2H),1.96-1.84(m,4H),1.63(d,J＝7.2Hz,3H).
Example 16 (S) -8- (1-acetyl-4-methoxypiperidin-4-yl) -6- (((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -10-methyl-2- ((R) -1-methylpyrrolidin-2-yl) -2, 3-dihydro- [1,4] dioxane [2,3-H ] [1,6] naphthyridin-9 (10H) -one (Compound 16)
Compound 16 was prepared according to reference example 11 starting from compound 6. ESI-MS m/z:644.4[ M+1] +.
Example 17 (R) -8- (1-acetyl-4-methoxypiperidin-4-yl) -6- (((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -10-methyl-2- ((S) -1-methylpyrrolidin-2-yl) -2, 3-dihydro- [1,4] dioxane [2,3-H ] [1,6] naphthyridin-9 (10H) -one (Compound 17)
Compound 17 was prepared according to example 11 starting from compound 7 .ESI-MS m/z：644.4[M+1] +. 1H NMR(400MHz,CDCl 3)δ7.56(s,1H),7.41(dd,J＝14.0,6.6Hz,2H),7.11(t,J＝7.6Hz,1H),6.85(dd,J＝76.5,33.6Hz,1H),5.59–5.38(m,1H),5.07(d,J＝7.7Hz,1H),4.44(dt,J＝14.9,8.6Hz,2H),4.09(dd,J＝6.6,3.3Hz,2H),3.79(s,3H),3.62(d,J＝12.7Hz,1H),3.40(dd,J＝26.7,13.4Hz,1H),3.18(d,J＝1.7Hz,3H),2.85(dd,J＝26.6,13.1Hz,1H),2.66–2.33(m,4H),2.25(s,3H),2.05(s,3H),2.00–1.78(m,6H),1.55(d,J＝6.9Hz,3H). 13C NMR(101MHz,CDCl 3)δ167.94(s),161.16(s),149.30(s),146.65(s),137.43(s),128.14(s),126.68(s),124.47(s),123.44(s),116.93(s),98.20(s),70.07(s),66.92(s),58.41(s),49.24(s),45.98(s),45.14(s),41.35(s),36.36(s),33.63(s),32.09(s),30.93(s),29.79(s),28.68(s),20.95(s),20.41(s).
Example 18 (S) -8- (1-acetyl-4-methoxypiperidin-4-yl) -6- (((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -10-methyl-2- ((S) -1-methylpyrrolidin-2-yl) -2, 3-dihydro- [1,4] dioxane [2,3-H ] [1,6] naphthyridin-9 (10H) -one (Compound 18)
Compound 18 was prepared according to reference example 11 starting from compound 8. ESI-MS m/z:644.4[ M+1] +.
Example 19 (S) -8- (1-acetyl-4-methoxypiperidin-4-yl) -6- (((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -10-methyl-2- (pyrrolidin-1-ylmethyl) -2, 3-dihydro- [1,4] dioxane [2,3-H ] [1,6] naphthyridin-9 (10H) -one (Compound 19)
Compound 19 was prepared according to reference example 11 starting from compound 9. ESI-MS m/z:644.3[ M+1] +.
Example 20 (R) -8- (1-acetyl-4-methoxypiperidin-4-yl) -6- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -4, 10-dimethyl-3, 4-dihydro- [1,4] oxazin [3,2-H ] [1,6] naphthyridin-9 (10H) -one (Compound 20)
Compound 20 was prepared according to reference example 11 starting from compound 10. ESI-MS m/z:574.3[ M+1] +.
Example 21 (S) -8- (1-acetyl-4-methoxypiperidin-4-yl) -6- (((R) -1- (3- (difluoromethyl) -2-methylphenyl) ethyl) amino) -2- ((dimethylamino) methyl) -10-methyl-2, 3-dihydro- [1,4] dioxane [2,3-H ] [1,6] naphthyridin-9 (10H) -one (Compound 21)
Step 1:
Prepared by reaction of intermediate (S) -8- (1-acetyl-4-hydroxypiperidin-4-yl) -6-chloro-2- ((dimethylamino) methyl) -10-methyl-2, 3-dihydro- [1,4] dioxane [2,3-H ] [1,6] naphthyridin-9 (10H) -one and starting material (R) -1- (3- (difluoromethyl) -2-methylphenyl) ethane-1-amine hydrochloride (prepared according to the method described in patent WO2019122129 A1) with reference to the procedure of example 2 step 15. ESI-MS m/z:600.3[ M+1] +.
Step 2:
Prepared by the method of step 1 of example 11. ESI-MS m/z:602.3[ M+1] +.
Step 3:
Compound 21 was prepared according to the procedure of example 11, step 2. ESI-MS m/z:614.3[ M+1] +.
Referring to the preparation method of example 21, examples 22 to 36 in Table 1, namely, compounds 22 to 36 were prepared using appropriate intermediates and amine derivatives as raw materials.
Table 1 examples 22 to 36
Example 37 (R) -6- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -10-methyl-8- (1-methylcyclopropyl) -2, 3-dihydro- [1,4] dioxan [2,3-H ] [1,6] naphthyridin-9 (10H) -one (Compound 37)
Step 1:
8-bromo-6-chloro-10-methyl-2, 3-dihydro- [1,4] dioxan [2,3-H ] [1,6] naphthyridin-9 (10H) -one (100 mg,0.3 mmol), 4, 5-tetramethyl-2- (1-methylcyclopropyl) -1, 3-dioxolane (109 mg,0.6 mmol), 1-bis (diphenylphosphine) ferrocene palladium dichloride (24 mg,0.03 mmol), potassium carbonate (83 mg,0.6 mmol) were dissolved in dioxane (4 mL) and water (1 mL), nitrogen protected, and the reaction was stirred at 90℃for 16 hours. After cooling to room temperature, the solvent was dried by spinning, the residue was diluted with water, extracted with dichloromethane, the organic phase dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the product 6-chloro-10-methyl-8- (1-methylcyclopropyl) -2, 3-dihydro- [1,4] dioxane [2,3-H ] [1,6] naphthyridin-9 (10H) -one as a yellow solid (25 mg, 27%) by thin layer chromatography (petroleum ether/ethyl acetate=1:1, volume ratio). ESI-MS m/z:307.2[ M+1] +.
Step 2: (R) -6- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -10-methyl-8- (1-methylcyclopropyl) -2, 3-dihydro- [1,4] dioxan [2,3-H ] [1,6] naphthyridin-9 (10H) -one
6-Chloro-10-methyl-8- (1-methylcyclopropyl) -2, 3-dihydro- [1,4] dioxan [2,3-H ] [1,6] naphthyridin-9 (10H) -one (25 mg,0.0847 mmol), methanesulfonic acid (2-dicyclohexylphosphine) -3, 6-dimethoxy-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) (2 '-amino-1, 1' -biphenyl-2-yl) palladium (II) (Brettphos Pd G, 7.7mg,0.00847 mmol), (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethane-1-amine hydrochloride (38 mg,0.17mmol, prepared according to the method described in patent WO2019122129A 1) and sodium t-butoxide (25 mg,0.254 mmol) were dissolved in toluene (3 mL), nitrogen protected, and the reaction was stirred at 100℃for 14 hours. After cooling to room temperature, concentration under reduced pressure, thin layer chromatography (dichloromethane/methanol=20:1, volume ratio) afforded compound 37 (5 mg, yield 12.8%). ESI-MS m/z:460.1[ M+1] +.
With reference to the preparation method of example 37, examples 38 to 43 in Table 2, i.e. compounds 38 to 43, were prepared using the intermediate 8-bromo-6-chloro-10-methyl-2, 3-dihydro- [1,4] dioxan [2,3-H ] [1,6] naphthyridin-9 (10H) -one and the appropriate borate or amine derivative as starting materials.
Table 2 examples 38 to 43
Example 44 (R) -6- (((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -8- (1- (difluoromethyl) cyclopropyl) -2- ((dimethylamino) methyl) -2, 3-dihydro- [1,4] dioxane [2,3-c ] [2,7] naphthyridin-9 (8H) -one (Compound 44)
Step 1: (R) -4-bromo-6-chloro-2- ((2, 2-dimethyl-1, 3-dioxolan-4-yl) methoxy) -3- ((4-methoxybenzyl) oxy) pyridine
A1L three-necked flask was equipped with a low-temperature thermometer, mechanical stirring, and a constant pressure dropping funnel. Sodium hydride (60%, 5.3g,0.1328 mol) and 200mL anhydrous N, N-dimethylformamide were added thereto. The reaction was cooled to 0deg.C and a solution of (R) -glycerolacetonide (13.2 g,0.0996 mol) in 50mL anhydrous N, N-dimethylformamide was slowly added dropwise thereto under argon. After the completion of the dropwise addition, the reaction solution was stirred at 0℃for 1 hour. A solution of 4-bromo-6-chloro-2-fluoro-3- ((4-methoxybenzyl) oxy) pyridine (23 g,0.0664 mol) in 100mL anhydrous N, N-dimethylformamide was then slowly added dropwise thereto. After the completion of the dropwise addition, the reaction solution was stirred at 0℃for 1 hour. The reaction solution was quenched with 100mL of saturated aqueous ammonium chloride at 0deg.C. The reaction mixture was added to ethyl acetate (500 mL) and water (300 mL), the layers were extracted, the organic layer was washed with water (200 mL. Times.3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was chromatographed on silica gel (petroleum ether/ethyl acetate=10:1, volume ratio) to give the product as a white solid (27.8 g, yield 91％).ESI-MS m/z：458.0,460.0[M+1] +. 1H NMR(400MHz,DMSO-d 6)δ7.39(d,J＝8.4Hz,2H),7.39(s,1H),6.91(d,J＝8.4Hz,2H),5.03(s,2H),4.46-4.52(m,1H),4.39(dd,J＝4.4Hz,J＝11.2Hz,1H),4.33(dd,J＝5.6Hz,J＝11.2Hz,1H),4.10(dd,J＝6.8Hz,J＝8.4Hz,1H),3.85(dd,J＝6.0Hz,J＝8.4Hz,1H),3.75(s,3H),1.36(s,3H),1.32(s,3H).
Step 2: (S) -3- ((4-bromo-6-chloro-3- ((4-methoxybenzyl) oxy) pyridin-2-yl) oxy) propane-1, 2-diol
(R) -4-bromo-6-chloro-2- ((2, 2-dimethyl-1, 3-dioxolan-4-yl) methoxy) -3- ((4-methoxybenzyl) oxy) pyridine (27.8 g,0.0606 mol) was dissolved in tetrahydrofuran (100 mL), and water (20 mL) was further added thereto, and dioxane hydrochloride solution (4M, 20mL,0.080 mol) was added. The reaction was stirred at room temperature for 2 hours. Water (100 mL) was added to the reaction mixture, the pH was adjusted to about 8 by adding solid potassium carbonate, the organic solvent was dried by spin-drying, extracted with ethyl acetate (200 mL), and the organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a product, a white solid (22.4 g, yield 88％).ESI-MS m/z：418.0[M+1] +. 1H NMR(400MHz,DMSO-d 6)δ7.40(d,J＝8.8Hz,2H),7.39(s,1H),6.92(d,J＝8.8Hz,2H),5.05(s,2H),4.37(dd,J＝4.0Hz,J＝11.2Hz,1H),4.25(dd,J＝6.0Hz,J＝10.8Hz,1H),3.88-3.93(m,1H),3.75(s,3H),3.73(t,J＝4.4Hz,1H),3.51(d,J＝5.6Hz,2H).
Step 3: (R) -3- ((4-bromo-6-chloro-3- ((4-methoxybenzyl) oxy) pyridin-2-yl) oxy) propane-1, 2-diol dimethyl sulfonate
(S) -3- ((4-bromo-6-chloro-3- ((4-methoxybenzyl) oxy) pyridin-2-yl) oxy) propane-1, 2-diol (22.4 g,0.0535 mol) and triethylamine (32.5 g,0.321 mol) were added to dichloromethane (150 mL) and cooled to 0 ℃. Methanesulfonyl chloride (18.4 g,0.160 mol) was slowly added dropwise to the reaction solution. After the addition was completed, the reaction mixture was stirred at 0℃for 1 hour. The reaction solution was concentrated under reduced pressure, water (100 mL) was added, extraction was performed with ethyl acetate (200 mL), and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a product, a brown liquid (27.9 g, yield 90％).ESI-MS m/z：574.0[M+1] +. 1H NMR(400MHz,DMSO-d 6)δ7.48(s,1H),7.41(d,J＝8.4Hz,2H),6.93(d,J＝8.8Hz,2H),5.33-5.37(m,1H),5.03(s,2H),4.63(dd,J＝3.2Hz,J＝11.6Hz,2H),4.57(dd,J＝6.0Hz,J＝15.2Hz,1H),4.54(dd,J＝6.0Hz,J＝14.8Hz,1H),3.76(s,3H),3.28(s,3H),3.28(s,3H).
Step 4: (R) -3- ((4-bromo-6-chloro-3-hydroxypyridin-2-yl) oxy) propane-1, 2-diol dimethyl sulfonate
(R) -3- ((4-bromo-6-chloro-3- ((4-methoxybenzyl) oxy) pyridin-2-yl) oxy) propane-1, 2-diol disulfonate (27.9 g,0.0485 mol) was dissolved in dichloromethane (50 mL) to which trifluoroacetic acid (44.7 g, 0.399mol) was added. The reaction was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, neutralized with saturated aqueous sodium bicarbonate, extracted with ethyl acetate (150 mL), and the organic phase was dried over anhydrous sodium sulfate, and the residue was chromatographed on silica gel (petroleum ether/ethyl acetate=1:1, volume ratio) to give the product as a white solid (11.5 g, yield 52％).ESI-MS m/z：453.9[M+1] +. 1H NMR(400MHz,DMSO-d 6)δ10.28(s,1H),7.36(s,1H),5.18-5.23(m,1H),6.70(dd,J＝6.4Hz,J＝11.6Hz,1H),4.61(dd,J＝3.2Hz,J＝11.6Hz,1H),4.57(dd,J＝4.4Hz,J＝12.4Hz,1H),4.51(dd,J＝4.8Hz,J＝12.0Hz,1H),3.30(s,3H),3.26(s,3H).
Step 5: (S) - (8-bromo-6-chloro-2, 3-dihydro- [1,4] dioxane [2,3-b ] pyridin-2-yl) methyl methanesulfonate
(R) -3- ((4-bromo-6-chloro-3-hydroxypyridin-2-yl) oxy) propane-1, 2-diol dimethyl sulfonate (11.5 g,0.0253 mol) was dissolved in N, N-dimethylformamide (150 mL), potassium carbonate (7.0 g,0.0506 mol) was added, and the mixture was heated to 60℃and stirred for 2 hours. The reaction was poured into water (300 mL), extracted with ethyl acetate (300 mL), the organic phase was washed with 100mL x 3 water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was chromatographed on silica gel (petroleum ether/ethyl acetate=1:1, volume ratio) to give the product as a white solid (7.5 g, yield 83％).ESI-MS m/z：357.9[M+1] +. 1H NMR(400MHz,DMSO-d 6)δ7.48(s,1H),4.72-4.76(m,1H),4.61(dd,J＝2.8Hz,J＝12.0Hz,1H),4.58(dd,J＝2.0Hz,J＝10.4Hz,1H),4.48(dd,J＝6.0Hz,J＝11.6Hz,1H),4.34(dd,J＝6.8Hz,J＝11.6Hz,1H),3.26(s,3H).
Step 6: (R) -1- (8-bromo-6-chloro-2, 3-dihydro- [1,4] dioxan [2,3-b ] pyridin-2-yl) -N- (2, 4-dimethoxybenzyl) methylamine
(S) - (8-bromo-6-chloro-2, 3-dihydro- [1,4] dioxane [2,3-b ] pyridin-2-yl) methyl methanesulfonate (8.9 g,0.0248 mol), 2, 4-dimethylbenzylamine (10 g,0.0744 mol) and triethylamine (19.4 g,0.192 mol) were dissolved in N, N-dimethylacetamide (150 mL), heated to 100℃and stirred overnight. The reaction solution was poured into water (300 mL), extracted with ethyl acetate (300 mL), the organic phase was washed with water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was chromatographed on silica gel (petroleum ether/ethyl acetate=1:1, volume ratio) to give a product as a colorless liquid (7.4 g, yield 69.4％).ESI-MS m/z：451.1[M+Na] +. 1H NMR(400MHz,DMSO-d 6)δ7.42(s,1H),7.17(d,J＝8.0Hz,1H),6.53(d,J＝2.4Hz,1H),6.47(dd,J＝2.4Hz,J＝8.0Hz,1H),4.55(dd,J＝2.4Hz,J＝11.6Hz,1H),4.28-4.43(m,1H),4.27(dd,J＝7.2Hz,J＝11.6Hz,1H),3.77(s,3H),3.74(s,3H),3.64(dd,J＝13.6 Hz,J＝20.8Hz,2H),2.72-2.80(m,2H),2.14(s,1H).
Step 7: (R) - (8-bromo-6-chloro-2, 3-dihydro- [1,4] dioxan [2,3-b ] pyridin-2-yl) methylamine
(R) -1- (8-bromo-6-chloro-2, 3-dihydro- [1,4] dioxan [2,3-b ] pyridin-2-yl) -N- (2, 4-dimethoxybenzyl) methylamine (7.4 g,0.0172 mol) was mixed with trifluoroacetic acid (148.9 g,1.306 mol) and heated to reflux overnight. The reaction solution was concentrated under reduced pressure to give a product, a bluish-violet liquid (6.8 g, yield 100%) which was used directly in the next reaction .ESI-MS m/z：278.9[M+1] +. 1H NMR(400MHz,DMSO-d 6)δ8.16(s,3H),7.51(s,1H),4.64-4.69(m,1H),4.57(dd,J＝2.8Hz,J＝12.0Hz,1H),4.35(dd,J＝6.0Hz,J＝12.0Hz,1H),3.25-3.31(m,1H),3.13-3.19(m,1H).
Step 8: (R) -1- (8-bromo-6-chloro-2, 3-dihydro- [1,4] dioxane [2,3-b ] pyridin-2-yl) -N, N-dimethylmethylamine
Crude (R) - (8-bromo-6-chloro-2, 3-dihydro- [1,4] dioxane [2,3-b ] pyridin-2-yl) methylamine (6.8 g,0.0172 mol) obtained in step 7 was dissolved in methanol (80 mL), and formaldehyde (40% aqueous solution, 12.8g,0.170 mol) and acetic acid (0.1 g,0.0017 mol) were added. Stirring was carried out at room temperature for 10 minutes, then sodium triacetylborohydride (36.0 g,0.17 mol) was slowly added. The reaction was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, water (80 mL) was added, the pH was adjusted to about 1 with concentrated hydrochloric acid, ethyl acetate (100 mL) was extracted, the organic phase was discarded, the pH was adjusted to about 8 with solid potassium carbonate in the aqueous phase, ethyl acetate (100 mL) was extracted, the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a colorless liquid (4.3 g, yield) 81％).ESI-MS m/z：307.0[M+1] +. 1H NMR(400MHz,DMSO-d 6)δ7.43(s,1H),4.64-4.69(m,1H),4.50(dd,J＝4.8Hz,J＝10.4Hz,1H),4.23(dd,J＝7.6Hz,J＝12.0Hz,1H),2.63(dd,J＝5.2Hz,J＝13.2Hz,1H),2.56(dd,J＝7.2Hz,J＝13.2Hz,1H),2.27(s,6H).
Step 9: (R) -8-bromo-6-chloro-2- ((dimethylamino) methyl) -2, 3-dihydro- [1,4] dioxane [2,3-b ] pyridine-7-carbaldehyde
(R) -1- (8-bromo-6-chloro-2, 3-dihydro- [1,4] dioxane [2,3-b ] pyridin-2-yl) -N, N-dimethylmethylamine (4.5 g,0.0146 mol) was dissolved in anhydrous tetrahydrofuran (63 mL), and the internal temperature was reduced to-40℃under argon atmosphere. Lithium diisopropylamide (2M tetrahydrofuran solution, 23mL,0.046 mol) was slowly added dropwise thereto. After the completion of the dropwise addition, the reaction solution was kept at an internal temperature of-40℃to-50℃and stirring was continued for 2 hours. The internal temperature of the reaction solution was lowered to-70℃and then anhydrous N, N-dimethylformamide (8.8 g,0.120 mol) was slowly added dropwise thereto. After the dripping is finished, the internal temperature is kept at-70 ℃, and stirring is continued for 2 hours. The reaction mixture was kept at an internal temperature of-70℃and quenched with acetic acid (6 mL), followed by the addition of water (5 mL). The reaction mixture was warmed to room temperature, water (50 mL) was added, extraction was performed with ethyl acetate (100 mL), and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Silica gel column chromatography of the residue (petroleum ether/ethyl acetate=1:8, volume ratio) gave the product as a pale yellow solid (1.51 g, yield 31％).ESI-MS m/z：335.0[M+1] +. 1H NMR(400MHz,DMSO-d 6)δ10.15(s,1H),4.61(dd,J＝2.8Hz,J＝12.0Hz,1H),4.55-4.60(m,1H),4.34(dd,J＝7.2Hz,J＝11.6Hz,1H),2.64(dd,J＝5.2Hz,J＝13.6Hz,1H),2.56(dd,J＝7.2Hz,J＝13.2Hz,1H),2.27(s,6H).
Step 10: ethyl (R) -2- (6-chloro-2- ((dimethylamino) methyl) -7-formyl-2, 3-dihydro- [1,4] dioxane [2,3-b ] pyridin-8-yl) acetate ethyl ester
(R) -8-bromo-6-chloro-2- ((dimethylamino) methyl) -2, 3-dihydro- [1,4] dioxane [2,3-b ] pyridine-7-carbaldehyde (330 mg,0.98 mmol), dimethyl malonate (319 mg,1.96 mmol), 2-picolinic acid (24 mg,0.196 mmol), cuprous iodide (19 mg,0.098 mmol) and potassium carbonate (406 mg,2.94 mmol) were added to anhydrous DMSO (15 mL), and the reaction mixture was heated at 90℃for 1 hour under argon. The reaction solution was poured into water (30 mL), extracted with ethyl acetate (30 mL), the organic layer was discarded, the aqueous phase was adjusted to ph=1 with dilute hydrochloric acid, and concentrated under reduced pressure. Ethanol (50 mL) was added to the residue, followed by slow addition of concentrated sulfuric acid (3 mL), and stirring was performed at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to remove ethanol, water (50 mL) was added, the pH was adjusted to 8 with solid potassium carbonate, extraction was performed with ethyl acetate (50 mL), drying was performed over anhydrous sodium sulfate, and concentration was performed under reduced pressure to give a colorless liquid (85 mg, yield 25%). ESI-MS m/z:343.1[ M+1] +.
Step 11: (R) -6-chloro-8- (1- (difluoromethyl) cyclopropane) -2- ((dimethylamino) methyl) -2, 3-dihydro- [1,4] dioxan [2,3-c ] [2,7] naphthyridin-9 (8H) -one
Ethyl (R) -2- (6-chloro-2- ((dimethylamino) methyl) -7-formyl-2, 3-dihydro- [1,4] dioxan [2,3-b ] pyridin-8-yl) acetate (85 mg,0.25 mmol), 1- (difluoromethyl) cyclopropyl-1-amine hydrochloride (72 mg,0.50 mmol), potassium phosphate (53 mg,0.25 mmol), 2-trifluoroethanol (50 mg,0.50 mmol) were added to anhydrous tetrahydrofuran (10 mL), and the reaction mixture was heated in a closed tube at 100℃for 2 hours. The reaction mixture was cooled to room temperature, the solids were removed by filtration, and after concentrating the filtrate under reduced pressure, anhydrous dioxane (10 mL) was added, zirconium tetrachloride (58 mg,0.25 mmol) was added, and the mixture was heated in a sealed tube at 100℃overnight. The reaction mixture was cooled to room temperature, saturated aqueous potassium carbonate (10 mL) was added, extraction was performed with ethyl acetate (50 mL), drying was performed with anhydrous sodium sulfate, and the residue after concentration under reduced pressure was purified by preparative thin layer chromatography to give a product as an orange-yellow solid (22mg,23％).ESI-MS m/z：386.1[M+1] +. 1H NMR(400MHz,DMSO-d 6)δ8.68(s,1H),6.50(s,1H),6.29(t,J＝56.4Hz,1H),4.53-4.70(m,1H),4.52(dd,J＝4.0Hz,J＝11.6Hz,1H),4.22(dd,J＝6.4Hz,J＝11.6Hz,1H),3.08(dd,J＝8.0Hz,J＝16.0Hz,1H),2.74(dd,J＝4.0Hz,J＝12.0Hz,1H),2.50 (s,6H),1.24(m,4H).
Step 12: (R) -6- (((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -8- (1- (difluoromethyl) cyclopropyl) -2- ((dimethylamino) methyl) -2, 3-dihydro- [1,4] dioxane [2,3-c ] [2,7] naphthyridin-9 (8H) -one (compound 44)
(R) -6-chloro-8- (1- (difluoromethyl) cyclopropane) -2- ((dimethylamino) methyl) -2, 3-dihydro- [1,4] dioxane [2,3-c ] [2,7] naphthyridin-9 (8H) -one (13 mg,0.0337 mmol), (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl-1-amine (13 mg,0.0674 mmol), methanesulfonic acid (2-dicyclohexylphosphine) -3, 6-dimethoxy-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) (2 '-amino-1, 1' -biphenyl-2-yl) palladium (II) (Brettphos Pd G, 3mg,0.00337 mmol), sodium t-butoxide (13 mg,0.135 mmol) were added to anhydrous dioxane (3 mL), argon shielded, and heated at 90℃for 2 hours. The reaction solution was quenched with saturated aqueous ammonium chloride (10 mL), extracted with ethyl acetate (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by preparative HPLC to give the product as a yellow solid (3 mg). ESI-MS m/z:539.2[ M+1] +.
With reference to the preparation method of example 44, examples 45 to 70 in Table 3, namely, compounds 45 to 70 were prepared using appropriate raw materials.
Table 3 examples 45 to 70
Example 71 (S) -8- (1-acetyl-4-methoxypiperidin-4-yl) -6- (((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2- ((dimethylamino) methyl) -10-methyl-3, 4-dihydro-2H-pyran [3,2-H ] [1,6] naphthyridin-9 (10H) -one (Compound 71)
Step 1: (R) -4- (6-chloro-3-methoxypyridin-2-yl) -1- ((4-methoxybenzyl) oxy) butanol
Lithium diisopropylamide (106.5mL,213mmol,2.0M in THF) was added to a tetrahydrofuran solution (150 mL) at-70℃and a tetrahydrofuran solution (50 mL) of 6-chloro-3-methoxy-2-methylpyridine (21 g,133 mmol) was added dropwise at-70℃under nitrogen. A solution of (R) -2- ((4-methoxybenzyl) oxy) methyl) oxirane (26 g,133 mmol) in tetrahydrofuran (50 mL) was added dropwise at-70℃after stirring for 1 hour, and the reaction was allowed to warm to room temperature and stirred for 16 hours. The reaction mixture was diluted with saturated ammonium chloride (600 mL) and water (600 mL), and extracted with ethyl acetate (500 mL. Times.2). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was chromatographed on silica gel (petroleum ether/ethyl acetate=2:1, volume ratio) to give the product as a yellow liquid (34.5 g, yield 74％).ESI-MS m/z：352.1[M+H] +. 1H NMR(400MHz,Chloroform-d)δ7.31-7.22(m,2H),7.12(d,J＝8.6Hz,1H),7.08(d,J＝8.6Hz,1H),4.48(s,2H),3.82(s,3H),3.81(s,3H),3.49(dd,J＝9.5,3.7Hz,1H),3.39(dd,J＝9.5,7.3Hz,1H),3.07-2.81(m,2H),2.53(brs,1H),1.97-1.73(m,2H).
Step 2: (R) -6-chloro-2- (3-hydroxy-4- ((4-methoxybenzyl) oxy) butyl) pyridin-3-ol
(R) -4- (6-chloro-3-methoxypyridin-2-yl) -1- ((4-methoxybenzyl) oxy) butanol (34.5 g,98.0 mmol) was dissolved in N, N-dimethylformamide (350 mL), sodium hydroxide (23.5 g,588 mmol) and dodecylmercaptan (59 g, 284 mmol) were added, and the reaction was stirred at 80℃for 6 hours. The reaction mixture was diluted with saturated ammonium chloride (600 mL) and water (600 mL), and extracted with ethyl acetate (500 mL. Times.2). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was chromatographed on silica gel (petroleum ether/ethyl acetate=3:2, volume ratio) to give the product as a colorless liquid (28 g, yield 85％).ESI-MS m/z：352.1[M+H] +. 1H NMR(400MHz,Chloroform-d)δ7.25-7.19(m,2H),7.17(d,J＝8.4Hz,1H),7.06(d,J＝8.4Hz,1H),6.93-6.83(m,2H),4.45(d,J＝1.7Hz,2H),3.81(s,3H),3.74-3.63(m,1H),3.47(dd,J＝9.5,3.0Hz,1H),3.30(dd,J＝9.5,8.2Hz,1H),3.14-3.03(m,1H),2.90-2.81(m,1H),1.96-1.84(m,1H),1.84-1.74(m,1H).
Step 3: (R) -4-bromo-6-chloro-2- (3-hydroxy-4- ((4-methoxybenzyl) oxy) butyl) pyridin-3-ol
(R) -6-chloro-2- (3-hydroxy-4- ((4-methoxybenzyl) oxy) butyl) pyridin-3-ol (12.8 g,27.9 mmol) was dissolved in dichloromethane (300 mL), sodium acetate (15.2 g,186 mmol) and pyridine tribromide (29.7 g,92.7 mmol) were added and the reaction stirred at room temperature for 1 hour. Saturated aqueous sodium sulfite (600 mL) was added for dilution and ethyl acetate (500 mL X2) for extraction. The organic phase was washed with dilute hydrochloric acid (300 mL,1m in H 2 O), aqueous sodium bicarbonate (300 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was chromatographed on silica gel (petroleum ether/ethyl acetate=3:1, volume ratio) to give the product as a yellow liquid (31 g, yield 89％).ESI-MS m/z：337.1[M+1] +. 1H NMR(400MHz,Chloroform-d)δ7.36(s,1H),7.25-7.19(m,2H),6.98-6.84(m,2H),4.54-4.40(m,2H),3.81(s,3H),3.76-3.68(m,1H),3.48(dd,J＝9.5,3.0Hz,1H),3.30(dd,J＝9.5,8.1Hz,1H),3.15-3.03(m,1H),2.96-2.85(m,1H),1.98-1.85(m,1H),1.85-1.74(m,1H).
Step 4: (S) -8-bromo-6-chloro-2- ((4-methoxybenzyl) oxy) methyl) -3, 4-dihydro-2H-pyran [3,2-b ] pyridine
(R) -4-bromo-6-chloro-2- (3-hydroxy-4- ((4-methoxybenzyl) oxy) butyl) pyridin-3-ol (31 g,74.3 mmol) was dissolved in tetrahydrofuran (300 mL) and triphenylphosphine (29 g,111 mmol) and diisopropyl azodicarboxylate (30 g,149 mmol) were added under nitrogen at 0deg.C. The reaction was warmed to room temperature and stirred for 2 hours. Water (500 mL) was added for dilution, and ethyl acetate (500 mL. Times.2) was added for extraction. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was chromatographed on silica gel (petroleum ether/ethyl acetate=5:1, volume ratio) to give the product as a yellow liquid (25.5 g, yield 86%). ESI-MS m/z:397.1[ M+1] +.
Step 5: (S) - (8-bromo-6-chloro-3, 4-dihydro-2H-pyran [3,2-b ] pyridin-2-yl) methanol
(S) -8-bromo-6-chloro-2- ((4-methoxybenzyl) oxy) methyl) -3, 4-dihydro-2H-pyran [3,2-b ] pyridine was dissolved (25.5 g,63.9 mmol) in dichloromethane (70 mL), trifluoroacetic acid (70 mL) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was dried by spinning, diluted with saturated aqueous sodium bicarbonate (300 mL), and extracted with ethyl acetate (500 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was chromatographed on silica gel (dichloromethane/ethyl acetate=3:1, volume ratio) to give the product as a yellow liquid (14.5 g, yield 82%). ESI-MS m/z:278.0[ M+1] +.
Step 6: (S) - (8-bromo-6-chloro-3, 4-dihydro-2H-pyran [3,2-b ] pyridin-2-yl) methyl methanesulfonate
(S) - (8-bromo-6-chloro-3, 4-dihydro-2H-pyran [3,2-b ] pyridin-2-yl) methanol (14.5 g,52.0 mmol) was dissolved in dichloromethane (150 mL), triethylamine (7.9 g,78.0 mmol) and methylsulfonyl chloride (7.1 g,62.4 mmol) were added at 0deg.C and stirred at 0deg.C for 0.5 hours. Water (200 mL) was added at 0deg.C for dilution, and ethyl acetate (500 mL) was added for extraction. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the product as a yellow solid (17 g, yield 92%, crude). ESI-MS m/z:356.0[ M+1] +.
Step 7: (S) -6-chloro-N-methyl-2- ((methylamino) methyl) -3, 4-dihydro-2H-pyran [3,2-b ] pyridin-8-amine
(S) - (8-bromo-6-chloro-3, 4-dihydro-2H-pyran [3,2-b ] pyridin-2-yl) methyl methanesulfonate (17 g,47.6 mmol) was dissolved in 1, 4-dioxane (100 mL), aqueous methylamine (200 mL,23% in H 2 O) was added, and the mixture was capped and stirred at 120℃for 20 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure, and the residue was used directly in the next reaction. ESI-MS m/z:242.2[ M+1] +.
Step 8: tert-butyl (S) - (6-chloro-8- (methylamino) -3, 4-dihydro-2H-pyran [3,2-b ] pyridin-2-yl) methyl) (methyl) carbamate
The crude product from step 7 was dissolved in tetrahydrofuran (300 mL), triethylamine (9.6 g,95.2 mmol) and di-tert-butyl dicarbonate (21 g,95.2 mmol) were added and stirred at room temperature for 2 hours. Water (300 mL) was added for dilution, and ethyl acetate (500 mL) was added for extraction. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was chromatographed on silica gel (petroleum ether/ethyl acetate=3:1, volume ratio) to give the product as a colorless liquid (15 g, yield 92%). ESI-MS m/z:342.2[ M+1] +.
Step 9: tert-butyl (S) - (6-chloro-7-iodo-8- (methylamino) -3, 4-dihydro-2H-pyran [3,2-b ] pyridin-2-yl) methyl) (methyl) carbamic acid ester
Tert-butyl (S) - (6-chloro-8- (methylamino) -3, 4-dihydro-2H-pyran [3,2-b ] pyridin-2-yl) methyl) (methyl) carbamate (15.0 g,43.9 mmol) was dissolved in acetic acid (50 mL), N-iodosuccinimide (10.8 g,18.2 mmol) was added and stirred at room temperature for 16 hours. Saturated aqueous sodium sulfite (200 mL) was added for dilution, saturated aqueous sodium bicarbonate (300 mL) was added for neutralization, and ethyl acetate (500 mL. Times.2) was added for extraction. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was chromatographed on silica gel (petroleum ether/ethyl acetate=4:1, volume ratio) to give the product as a colorless liquid (18 g, yield 88％).ESI-MS m/z：468.1[M+1] +. 1H NMR(400MHz,Chloroform-d)δ4.70(brs,1H),4.26-4.14(m,1H),3.76-3.58(m,1H),3.38(dd,J＝14.6,4.5Hz,1H),3.22(s,3H),2.96(s,3H),2.93-2.85(m,2H),2.06(d,J＝10.6Hz,1H),1.88-1.75(m,1H),1.45(d,J＝8.3Hz,9H).
Step 10: tert-butyl (S, E) - (6-chloro-7-iodo-8- (methylamino) -3, 4-dihydro-2H-pyran [3,2-b ] pyridin-2-yl) methyl) (methyl) carbamic acid ester
Tert-butyl (S) - (6-chloro-7-iodo-8- (methylamino) -3, 4-dihydro-2H-pyran [3,2-b ] pyridin-2-yl) methyl) (methyl) carbamate (18 g,38.5 mmol), palladium acetate (860 mg,3.85 mmol), tris (o-methylphenyl) phosphorus (2.3 mg,7.69 mmol), triethylamine (7.7 g,76.9 mmol) and ethyl acrylate (11.5 g,115 mmol) were dissolved in N, N-dimethylformamide (150 mL). The reaction was stirred at 95℃for 6 hours under nitrogen. After cooling to room temperature, water (500 mL) was added for dilution, and ethyl acetate (500 mL X2) was added for extraction. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was chromatographed on silica gel (petroleum ether/ethyl acetate=3:1, volume ratio) to give the product as a yellow liquid (15 g, yield 89%). ESI-MS m/z:440.2[ M+1] +.
Step 11: tert-butyl (S) - (6-chloro-10-methyl-9-oxo-3, 4,9, 10-tetrahydro-2H-pyran [3,2-H ] [1,6] naphthyridin-2-yl) methyl) (methyl) carbamate
Tert-butyl (S, E) - (6-chloro-7-iodo-8- (methylamino) -3, 4-dihydro-2H-pyran [3,2-b ] pyridin-2-yl) methyl) (methyl) carbamate (15 g,34.1 mmol) was dissolved in ethanol (25 mL), sodium methyl mercaptide (2.6 g,37.5 mmol) was added and stirred at room temperature for 0.5H. The solvent was dried under reduced pressure, and the residue was diluted with water (300 mL) and extracted with ethyl acetate (400 mL X2). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure to give the product, and the residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate=3:1, volume ratio) to give the product as a yellow liquid (10 g, yield 75％).ESI-MS m/z：394.2[M+1] +. 1H NMR(400MHz,Chloroform-d)δ8.01(d,J＝9.6Hz,1H),6.74(d,J＝9.6Hz,1H),4.30(d,J＝10.8Hz,1H),3.94(s,3H),3.86-3.68(m,1H),3.41(d,J＝13.6Hz,1H),3.12-3.01(m,2H),2.97(s,3H),2.18(d,J＝13.8Hz,1H),1.98-1.83(m,1H),1.46(s,9H).
Step 12: tert-butyl (S) - (8-bromo-6-chloro-10-methyl-9-oxo-3, 4,9, 10-tetrahydro-2H-pyran [3,2-H ] [1,6] naphthyridin-2-yl) methyl) (methyl) carbamate
Tert-butyl (S) - (6-chloro-10-methyl-9-oxo-3, 4,9, 10-tetrahydro-2H-pyran [3,2-H ] [1,6] naphthyridin-2-yl) methyl) (methyl) carbamate (10 g,25.4 mmol) was dissolved in N, N-dimethylformamide (100 mL), N-bromosuccinimide (13.5 g,76.1 mmol) was added and the reaction stirred at 70℃for 2 hours. Saturated aqueous sodium sulfite solution (200 mL) was added for dilution, and ethyl acetate (300 mL X2) was added for extraction. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was chromatographed on silica gel (petroleum ether/ethyl acetate=2:1, volume ratio) to give the product as a white solid (5.0 g, yield 42％).ESI-MS m/z：472.1[M+1] +. 1H NMR(400MHz,Chloroform-d)δ8.45(s,1H),4.31(brs,1H),4.01(s,3H),3.88-3.62(m,1H),3.49-3.30(m,1H),3.13-3.00(m,2H),2.97(s,3H),2.19(d,J＝14.3Hz,1H),1.99-1.85(m,1H),1.46(s,9H).
Step 13: tert-butyl (S) - (8- (1-acetyl-4-hydroxypiperidin-4-yl) -6-chloro-10-methyl-9-oxo-3, 4,9, 10-tetrahydro-2H-pyran [3,2-H ] [1,6] naphthyridin-2-yl) methyl) (methyl) carbamate
Tert-butyl (S) - (8-bromo-6-chloro-10-methyl-9-oxo-3, 4,9, 10-tetrahydro-2H-pyran [3,2-H ] [1,6] naphthyridin-2-yl) methyl) (methyl) carbamate (500 mg,1.05 mmol) and 1-acetylpiperidin-4-one (596 mg,4.23 mmol) were dissolved in tetrahydrofuran (20 mL), nitrogen protected, and samarium iodide (42mL,4.23mmol,0.1M in THF) was added dropwise at-30 ℃. The reaction was stirred at-30℃for 0.5 hour. Saturated aqueous ammonium chloride (100 mL) was added at-30deg.C for dilution, and ethyl acetate (200 mL X2) was added for extraction. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was chromatographed on silica gel (dichloromethane/methanol=20:1, volume ratio) to give the product as a yellow solid (800 mg, yield 71％).ESI-MS m/z：479.3[M-56] +. 1H NMR(400MHz,Chloroform-d)δ7.92(s,1H),4.61(s,1H),4.30(s,1H),3.97(s,3H),3.92-3.81(m,2H),3.77(t,J＝6.4Hz,1H),3.49-3.32(m,2H),3.09(dd,J＝10.0,6.0Hz,2H),2.97(s,3H),2.49(q,J＝6.8Hz,2H),2.20-2.15(m,7H),1.99-1.79(m,3H),1.45(d,J＝14.7Hz,9H).
Step 14: tert-butyl (((S) -8- (1-acetyl-4-hydroxypiperidin-4-yl) -6- (((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -10-methyl-9-oxo-3, 4,9, 10-tetrahydro-2H-pyran [3,2-H ] [1,6] naphthyridin-2-yl) methyl) (methyl) carbamate
Tert-butyl (S) - (8- (1-acetyl-4-hydroxypiperidin-4-yl) -6-chloro-10-methyl-9-oxo-3, 4,9, 10-tetrahydro-2H-pyran [3,2-H ] [1,6] naphthyridin-2-yl) methyl) (methyl) carbamate (260 mg, 0.481 mmol), methanesulfonic acid (2-dicyclohexylphosphine) -3, 6-dimethoxy-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) (2 '-amino-1, 1' -biphenyl-2-yl) palladium (II) (44 mg,0.049 mmol), (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethane-1-amine (277 mg,1.46 mmol) and sodium tert-butoxide (140 mg,1.46 mmol) were dissolved in toluene (8 mL) and the reaction was stirred at 100 ℃ for 2 hours under nitrogen protection. After cooling to room temperature, concentration under reduced pressure, silica gel column chromatography of the residue (dichloromethane/methanol=20:1, volume ratio) gave the product as a yellow solid (267 mg, yield 80%). ESI-MS m/z:688.3[ M+1] +.
Step 15: (S) -8- (1-acetyl-4-hydroxypiperidin-4-yl) -6- (((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -10-methyl-2- ((methylamino) methyl) -3, 4-dihydro-2H-pyran [3,2-H ] [1,6] naphthyridin-9 (10H) -one
Tert-butyl (((S) -8- (1-acetyl-4-hydroxypiperidin-4-yl) -6- (((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -10-methyl-9-oxo-3, 4,9, 10-tetrahydro-2H-pyran [3,2-H ] [1,6] naphthyridin-2-yl) methyl) (methyl) carbamate (400 mg,0.580 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (1 mL) was added and stirred at room temperature for 1 hour. Concentrated under reduced pressure, and the residue was used directly in the next reaction. ESI-MS m/z:588.3[ M+1] +.
Step 16: (S) -8- (1-acetyl-4-hydroxypiperidin-4-yl) -6- (((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2- ((dimethylamino) methyl) -10-methyl-3, 4-dihydro-2H-pyran [3,2-H ] [1,6] naphthyridin-9 (10H) -one
The crude product from step 15 was dissolved in tetrahydrofuran (15 mL), aqueous formaldehyde (3 mL,30% in H 2 O) was added, sodium triacetoxyborohydride (246 mg,1.16 mmol) was added, and stirred at room temperature for 0.5 hours. Saturated aqueous sodium chloride (100 mL) was added for dilution, and dichloromethane (150 mL X3) was added for extraction. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was chromatographed on silica gel (dichloromethane/methanol=15:1, volume ratio) to give the product as a yellow solid (300 mg, yield 86％).ESI-MS m/z：602.3[M+1] +. 1H NMR(400MHz,Chloroform-d)δ8.21(s,1H),7.55(s,1H),7.53-7.46(m,1H),7.43(t,J＝7.2Hz,1H),7.15(t,J＝7.6Hz,1H),6.91(t,J＝55.2Hz,1H),5.82(s,1H),5.51(p,J＝6.8Hz,1H),5.08(d,J＝6.4Hz,1H),4.58(d,J＝12.8Hz,1H),4.13(brs,1H),3.91(s,3H),3.69(brs,2H),3.15(t,J＝11.4Hz,1H),3.05(dd,J＝12.8,7.2Hz,1H),2.91(dd,J＝12.8,3.6Hz,1H),2.86-2.67(m,2H),2.50(d,J＝3.7Hz,6H), 2.30-2.16(m,2H),2.13(d,J＝2.9Hz,3H),2.10-1.99(m,2H),1.99-1.84(m,2H),1.82-1.69(m,1H),1.62(d,J＝6.8Hz,3H).
Step 17: (S) -8- (1-acetyl-4-fluoropiperidin-4-yl) -6- (((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2- ((dimethylamino) methyl) -10-methyl-3, 4-dihydro-2H-pyran [3,2-H ] [1,6] naphthyridin-9 (10H) -one
(S) -8- (1-acetyl-4-hydroxypiperidin-4-yl) -6- (((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2- ((dimethylamino) methyl) -10-methyl-3, 4-dihydro-2H-pyran [3,2-H ] [1,6] naphthyridin-9 (10H) -one (350 mg,0.581 mmol) was dissolved in dichloromethane (15 mL), nitrogen blanketed, and diethylaminosulfur trifluoride (187 mg,1.16 mmol) was added at 0deg.C. The reaction was stirred at 0deg.C for 2 hours. Water (50 mL) was added for dilution, and methylene chloride (50 mL X3) was added for extraction. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was used directly in the next reaction. ESI-MS m/z:604.3[ M+1] +.
Step 18: (S) -8- (1-acetyl-4-methoxypiperidin-4-yl) -6- (((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2- ((dimethylamino) methyl) -10-methyl-3, 4-dihydro-2H-pyran [3,2-H ] [1,6] naphthyridin-9 (10H) -one
The crude product from step 17 was dissolved in methanol (15 mL) and sodium methoxide in methanol (1.08g,5.81mmol,30%w.t.in MeOH) was added. The reaction solution was stirred at 40℃for 48 hours. After cooling to room temperature, concentration under reduced pressure, the residue was purified by preparative HPLC to give the product as a yellow solid (55 mg, yield 15％).ESI-MS m/z：616.4[M+1] +. 1H NMR(400MHz,Chloroform-d)δ8.21(s,1H),7.68(d,J＝2.0Hz,1H),7.56-7.39(m,2H),7.15(t,J＝7.6Hz,1H),6.90(t,J＝55.2Hz,1H),5.50(s,1H),4.93(s,1H),4.58(d,J＝13.0Hz,1H),4.18(s,1H),3.85(d,J＝1.7Hz,2H),3.70(d,J＝13.5Hz,1H),3.58-3.39(m,1H),3.27(s,3H),2.95(q,J＝14.2Hz,1H),2.87-2.72(m,3H),2.73-2.58(m,1H),2.48(d,J＝3.9Hz,6H),2.19-2.13(m,1H),2.13(s,3H),2.02(t,J＝11.6Hz,1H),1.97-1.80(m,2H), 1.63(d,J＝7.0Hz,3H).
Example 72 (R) -8- (1-acetyl-4-methoxypiperidin-4-yl) -6- (((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2- ((dimethylamino) methyl) -10-methyl-3, 4-dihydro-2H-pyran [3,2-H ] [1,6] naphthyridin-9 (10H) -one (Compound 72)
Synthesis of Compound 72 was prepared by following the procedure of example 71 except that starting material (R) -2- ((4-methoxybenzyl) oxy) methyl) oxirane in step 1 was replaced with (S) -2- ((4-methoxybenzyl) oxy) methyl) oxirane .ESI-MS m/z：616.4[M+1] +. 1H NMR(400MHz,Chloroform-d)δ7.68(s,1H),7.50(q,J＝6.8Hz,1H),7.43(t,J＝7.2Hz,1H),7.15(t,J＝7.6Hz,1H),6.90(t,J＝55.2Hz,1H),5.50(d,J＝7.2Hz,1H),4.93(brs,1H),4.58(d,J＝13.2Hz,1H),4.10(brs,1H),3.87(s,3H),3.70(d,J＝11.2Hz,1H),3.49(t,J＝13.2Hz,1H),3.26(s,3H),2.98-2.82(m,2H),2.74(dd,J＝13.2,6.0Hz,1H),2.70-2.61(m,2H),2.61-2.44(m,5H),2.40(s,6H),2.13(s,4H),2.03(d,J＝13.2Hz,1H),1.88(d,J＝14.0Hz,1H),1.85-1.76(m,1H),1.62(d,J＝7.2Hz,3H).
Example 73 (S) -8- (1-acetyl-4-ethoxypiperidin-4-yl) -6- (((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2- ((dimethylamino) methyl) -10-methyl-3, 4-dihydro-2H-pyran [3,2-H ] [1,6] naphthyridin-9 (10H) -one (Compound 73)
The synthesis of compound 73 was prepared by the procedure of reference example 71 except that sodium methoxide in step 18 was replaced with sodium ethoxide. ESI-MS m/z:630.3[ M+1] +.
Example 74 (S) -8- (1-acetyl-4-isopropoxypiperidin-4-yl) -6- (((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2- ((dimethylamino) methyl) -10-methyl-3, 4-dihydro-2H-pyran [3,2-H ] [1,6] naphthyridin-9 (10H) -one (Compound 74)
The synthesis of compound 74 was prepared by the procedure of reference example 71, except that sodium methoxide in step 18 was replaced with sodium isopropoxide. ESI-MS m/z:644.3[ M+1] +.
Example 75 (S) -8- (1-acetyl-4- (2-hydroxyethoxy) piperidin-4-yl) -6- (((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2- ((dimethylamino) methyl) -10-methyl-3, 4-dihydro-2H-pyran [3,2-H ] [1,6] naphthyridin-9 (10H) -one (Compound 75)
The synthesis of compound 75 was prepared by the procedure of reference example 71 except that sodium methoxide in step 18 was replaced with sodium glycolate. ESI-MS m/z:646.3[ M+1] +.
Example 76 (S) -8- (1-acetyl-4- (2, -trifluoroethoxy) piperidin-4-yl) -6- (((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2- ((dimethylamino) methyl) -10-methyl-3, 4-dihydro-2H-pyran [3,2-H ] [1,6] naphthyridin-9 (10H) -one (Compound 76)
The synthesis of compound 76 was prepared by the procedure of reference example 71 except that sodium methoxide in step 18 was replaced with sodium trifluoroethoxide. ESI-MS m/z:684.3[ M+1] +.
Test examples of Activity of Compounds of the invention
Test example 1: cell growth inhibition of NCI-H358 and MIA PaCa-2 tumor cell lines under 3D culture conditions
Cell source: NCI-H358 was purchased from Shanghai Dijin Biotechnology Co., ltd; MIA PaCa-2 was purchased from Shanghai Diaoko biotechnology Co.
Cells in the logarithmic phase were inoculated into ultra-low adsorption 96-well plates (4000,2000 cells/well, 180. Mu.l/well, respectively) and cultured at 37℃in 5% CO 2 to aggregate the cells into microspheres, and after 1 day, the test compound was added in gradient dilution. The method comprises the following steps: stock solutions of the compounds (10 mM) dissolved in DMSO beforehand were diluted to 10 gradient concentrations at a ratio of 4 times and diluted to 10 times the target concentration with medium in another 96-well plate, and then 20. Mu.l/well of the compound solution was added to the 96-well plate inoculated with cells, i.e., the target concentrations (10000, 2500,625,156,39,10,2.5,0.6,0.15,0.04 nM) were reached. 3 duplicate wells were set for each concentration, and a blank was set. After continuous cultivation for 6 days at 37℃in 5% CO 2, 50. Mu.l of each well was added3D reagent (luciferase ATP bioluminescence detection reagent for detecting 3D cell microsphere, purchased from Promega, cat# G9683), shaking for 10min, incubating at room temperature for 20min, and detecting fluorescence intensity (light receiving time is 100 ms). The activity inhibition ratio of each concentration of the compound to the 3D cell microsphere was calculated, and the cell activity inhibition ratio (%) = [ (light emission intensity 6 control group of cell culture medium -light emission intensity 6 Tian Compound group )/(light emission intensity 6 Tianshen (Chinese character) Cell culture medium control group -light emission intensity 6 Cell-free culture medium control group ) ]×100%. The data were analyzed using GRAPHPAD PRISM 8.3.3 software, a non-linear S-curve regression was used to fit the data to a dose-response curve, and IC 50 values were calculated therefrom. The results are shown in Table 4.
TABLE 4 Table 4
"-" Means not tested;
Among them, BI-3406 is SOS1 inhibitor reported in literature (Cancer Discovery 2021 (11) 142-157).
The compounds of the invention show good cell growth inhibition on NCI-H358 and MIA PaCa-2 tumor cell lines.

Claims (16)

  1. A fused ring compound as shown in formula I, a tautomer thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof; it is characterized in that the method comprises the steps of,
    Wherein:
    X and Y are each independently-O-, -S-, -NH-or-CH 2 -;
    Z is-CR 10 or N;
    L is a single bond, -C (=O) -, -C (=O) O-, -C (=O) NR 8-、-NR 8-、-S-、-O-、-S(O)-、-S(O) 2 -, or- (CH 2) p -;
    Ring a is C 6-12 aryl, 5-10 membered heteroaryl, C 3-7 cycloalkyl, C 3-7 cycloalkenyl, or 3-7 membered heterocyclyl;
    each R is independently deuterium, hydroxy, halogen, -N (R, cyano, oxo (= O), nitro, C alkyl-O-, C alkenyl, C alkynyl, C alkyl substituted with one or more R, C alkyl-O-, C alkenyl substituted with one or more R, C alkynyl substituted with one or more R, C cycloalkyl C cycloalkyl substituted with one or more R, 3-7 membered heterocyclyl substituted with one or more R, C aryl substituted with one or more R, 5-10 membered heteroaryl substituted with one or more R, C cycloalkenyl substituted with one or more R or-NR, or two R together with the ring atoms to which they are attached form a C cycloalkyl group, a C cycloalkyl group substituted with one or more R, a 3-7 membered heterocyclic group substituted with one or more R, a C cycloalkenyl group, or a C cycloalkenyl group substituted with one or more R;
    Each of R 1a、R 1b、R 1c、R 1d、R 1e、R 1f、R 1g、R 1h and R 1i is independently deuterium, hydroxy, halogen, -N (R 7) 2、-SR 9, nitro, cyano, C 1-6 alkyl-O-, C 1-6 alkenyl, C 1-6 alkynyl, C 1-6 alkyl substituted with one or more R 1-6, C 1-6 alkyl-O-, substituted with one or more R 1-6, C 1-6 alkenyl substituted with one or more R 1-6, C 1-6 alkynyl substituted with one or more R 1-6, C 1-6 cycloalkyl-O-, 3-7 membered heterocyclyl-O-, C 1-6 cycloalkyl substituted with one or more R 1-6 or C 1-6 cycloalkyl-O-, 3-7 membered heterocyclyl-O-, C 1-6 aryl substituted with one or more R 1-6, C 1-6 aryl, C 1-6 heteroaryl substituted with one or more R 1-6, C 1-6 alkenyl substituted with one or more R 1-6, C 1-6 cycloalkenyl, C 1-6 -2 or C 1-6 cycloalkenyl;
    Each R 1-a、R 1-b、R 1-c、R 1-d、R 1-e、R 1-f、R 1-g、R 1-h and R 1-i is independently deuterium, hydroxy, halogen, -N (R 7) 2、-SR 9, nitro, cyano, C 1-6 alkyl, C 1-6 alkyl-O-, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 3-7 cycloalkenyl, or 3-7 membered heterocyclyl;
    Ring D is C 6-12 aryl, 5-6 membered heteroaryl, C 3-7 cycloalkyl, C 3-7 cycloalkenyl, or 3-7 membered heterocyclyl;
    R 2 is absent, hydrogen, deuterium, hydroxy, halogen, amino, cyano, oxo, nitro, C 1-6 alkyl, C 1-6 alkyl-O-, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 3-7 cycloalkenyl, or 3-7 membered heterocyclyl;
    R 3 is hydrogen, deuterium, C 1-6 alkyl, C 1-6 alkyl substituted by one or more R 3a, C 2-6 alkenyl, C 2-6 alkenyl substituted by one or more R 3b, C 2-6 alkynyl, C 2-6 alkynyl substituted by one or more R 3c, C 3-7 cycloalkyl, C 3-7 cycloalkyl substituted by one or more R 3d, 3-7 membered heterocyclyl substituted by one or more R 3e, C 6-12 aryl, C 6-12 aryl substituted by one or more R 3f, 5-10 membered heteroaryl substituted by one or more R 3g, C 3-7 cycloalkenyl or C 3-7 cycloalkenyl substituted by one or more R 3h;
    Each R and R is independently deuterium, hydroxy, halogen, -N (R, cyano, nitro, C alkyl substituted with one or more R-, C alkyl-O-, C alkenyl, C alkynyl, C alkenyl substituted with one or more R, C alkynyl substituted with one or more R, C cycloalkyl substituted with one or more R, 3-7 membered heterocyclyl substituted with one or more R, C aryl substituted with one or more R, 5-10 membered heteroaryl, C cycloalkenyl substituted with one or more R, or-NR, or two R, two R or two R together with the ring atoms to which they are attached form a C cycloalkyl group, a C cycloalkyl group substituted with one or more R, a 3-7 membered heterocyclyl group substituted with one or more R, a C cycloalkenyl group or a C cycloalkenyl group substituted with one or more R;
    each R 3-a、R 3-b、R 3-c、R 3-d、R 3-e、R 3-f、R 3-g、R 3-h and R 3-i is independently deuterium, hydroxy, halogen, -N (R 7) 2, nitro, cyano, C 1-6 alkyl, C 1-6 alkyl-O-, C 3-7 cycloalkyl, C 3-7 cycloalkenyl, 3-7 membered heterocyclyl 、-SR 9、-C(＝O)-O-R 9、-O-C(＝O)-R 9、-C(＝O)-N(R 7) 2、-S(O) 2-R 9、-NR 8-S(O) 2-R 9、-NR 8-S(O) 2-N(R 7) 2、-S(O) 2-N(R 7) 2、-C(＝O)-R 9、-NR 8C(＝O)-R 9, or-NR 8C(＝O)-O-R 9;
    each R 4 is independently deuterium, hydroxy, halogen, -N (R 7) 2, cyano, oxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C 1-4 alkylene-N (R 7) 2, C 1-6 alkyl substituted with one or more R 4a, C 1-6 alkyl-O-, C 1-6 alkyl-O substituted with one or more R 4b -, C 3-7 cycloalkyl, C 3-7 cycloalkyl substituted with one or more R 4c, 3-7 membered heterocyclyl substituted with one or more R 4d, C 3-7 cycloalkenyl, or C 3-7 cycloalkenyl substituted with one or more R 4e, or two R 3-7 groups together with the attached atoms form a C 3-7 cycloalkyl group, a C 3-7 cycloalkyl substituted with one or more R 3-7, a 3-7 membered heterocyclyl, a 3933-7 membered heterocyclyl substituted with one or more R 3-7, a C 3-7 cycloalkenyl, or a C 3-7 cycloalkenyl substituted with one or more R 3-7;
    Each R 4a、R 4b、R 4c and R 4d is independently deuterium, hydroxy, halogen, amino, cyano, C 1-6 alkyl, C 1-6 alkyl-O-, C 2-6 alkenyl, or C 2-6 alkynyl;
    R 5 is absent, oxo, hydrogen, deuterium, hydroxy, halo, amino, cyano, nitro, C 1-6 alkyl, C 1-6 alkyl substituted with one or more R 5a, C 1-6 alkyl-O-, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl substituted with one or more R 5b, 3-7 membered heterocyclyl substituted with one or more R 5c, C 3-7 cycloalkenyl, or C 3-7 cycloalkenyl substituted with one or more R 5d;
    Each R 5a、R 5b and R 5c is independently deuterium, C 1-6 alkyl, hydroxy, halogen, amino or cyano;
    R 6 is hydrogen, deuterium, hydroxy, halogen, amino, cyano, oxo, C 1-6 alkyl, C 1-6 alkyl-O-, C 2-6 alkenyl, C 2-6 alkynyl or absent;
    each R 7 is independently hydrogen, C 1-6 alkyl, C 3-7 cycloalkyl, or C 3-7 cycloalkenyl, or two R 7 together with the nitrogen atom to which they are attached form a 3-7 membered heterocyclyl or a 3-7 membered heterocyclyl substituted with one or more R 7a;
    Each R 7a is independently deuterium, C 1-6 alkyl, halogen, hydroxy, amino, cyano, C 1-6 alkyl-O-, C 2-6 alkenyl, or C 2-6 alkynyl;
    each R 8 and R 9 is independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 3-7 cycloalkenyl, or a 3-7 membered heterocyclyl;
    R 10 is hydrogen, deuterium, hydroxy, halogen, amino, cyano, C 1-6 alkyl, C 1-6 alkyl-O-, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 3-7 cycloalkenyl, or 3-7 membered heterocyclyl;
    R 11 is hydrogen, deuterium, cyano, C 1-6 alkyl or C 1-6 alkyl substituted with one or more R 11a;
    each R 11a is independently deuterium, halogen, or hydroxy;
    m is 0, 1,2,3, 4 or 5;
    n is 0, 1,2,3, 4, 5 or 6;
    p is 1,2,3, 4, 5 or 6;
    the 3-7 membered heterocyclic groups are 3-7 membered heterocyclic groups with heteroatom types independently selected from N, O and S and heteroatom numbers of 1,2 or 3;
    The 5-10 membered heteroaryl groups are each independently a 5-10 membered heteroaryl group having 1,2 or 3 heteroatoms and having a heteroatom species independently selected from N, O and S;
    The 5-6 membered heteroaryl is a 5-6 membered heteroaryl with heteroatom types independently selected from N, O and S and heteroatom numbers of 1,2 or 3;
    When the carbon atom has chirality, the condensed-cyclic compound shown as formula I is Or a mixture thereof.
  2. The fused ring compound as set forth in claim 1, a tautomer thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, as set forth in formula I; the fused ring compound shown as the formula I is characterized by meeting one or more of the following conditions:
    (1) X and Y are each independently-O-, -NH-or-CH 2 -;
    (2) Z is N;
    (3) L is a single bond;
    (4) Ring a is C 6-12 aryl or 5-10 membered heteroaryl;
    (5) Each R 1 is independently hydroxy, halogen, -N (R 7) 2, cyano, C 1-6 alkyl, C 1-6 alkyl-O-, C 1-6 alkyl substituted with one or more R 1a, C 1-6 alkyl-O-substituted with one or more R 1b, or two R 1 together with the attached ring atoms form a C 3-7 cycloalkyl, C 3-7 cycloalkyl substituted with one or more R 1e, a 3-7 membered heterocyclyl substituted with one or more R 1f, a C 3-7 cycloalkenyl, or a C 3-7 cycloalkenyl substituted with one or more R 1i;
    (6) Each R 1a、R 1b、R 1e、R 1f and R 1i is independently hydroxy, halogen, -N (R 7) 2、C 1-6 alkyl or C 1-6 alkyl substituted with one or more R 1-a;
    (7) Each R 1-a is independently C 1-6 alkyl or halogen;
    (8) Ring D is a 3-7 membered heterocyclyl;
    (9) R 2 is hydrogen;
    (10) R 3 is hydrogen, C 3-7 cycloalkyl, C 3-7 cycloalkyl substituted with one or more R 3d, 3-7 membered heterocyclyl or 3-7 membered heterocyclyl substituted with one or more R 3e, C 3-7 cycloalkenyl or C 3-7 cycloalkenyl substituted with one or more R 3h;
    (11) Each R 3d、R 3e and R 3h is independently hydroxy, halogen, -N (R 7) 2, cyano, C 1-6 alkyl, C 1-6 alkyl substituted by one or more R 3-a, C 1-6 alkyl-O-, C 1-6 alkyl-O substituted by one or more R 3-b -, C 2-6 alkenyl, C 2-6 alkynyl, C 2-6 alkenyl substituted by one or more R 3-c, C 2-6 alkynyl substituted by one or more R 3-d, -C (=o) -R 9、-NR 8C(＝O)-R 9, or two R 3d, two R 3e, or two R 3h together with the ring atoms to which they are attached form C 3-7 cycloalkyl, C 3-7 cycloalkyl substituted by one or more R 3-e, 3-7 membered heterocyclyl substituted by one or more R 3-f, C 3-7 cycloalkenyl, or C 3-7 cycloalkenyl substituted by one or more R 3-i;
    (12) Each R 3-a、R 3-b、R 3-c、R 3-d、R 3-e、R 3-f and R 3-i is independently hydroxy, halogen, -N (R 7) 2, nitro, cyano, C 1-6 alkyl or C 1-6 alkyl-O-;
    (13) Each R 4 is independently C 1-6 alkyl, -C 1-4 alkylene-N (R 7) 2, C 1-6 alkyl substituted with one or more R 4a, 3-7 membered heterocyclyl or 3-7 membered heterocyclyl substituted with one or more R 4d;
    (14) Each R 4a and R 4d is independently C 1-6 alkyl or halogen;
    (15) R 5 is hydrogen or C 1-6 alkyl;
    (16) R 6 is oxo;
    (17) Each R 7 is independently hydrogen, C 1-6 alkyl, C 3-7 cycloalkyl, or C 3-7 cycloalkenyl; or two R 7 taken together with the attached nitrogen atom form a 3-7 membered heterocyclyl or a 3-7 membered heterocyclyl substituted with one or more R 7a;
    (18) Each R 7a is independently C 1-6 alkyl or halogen;
    (19) Each R 8 and R 9 is independently hydrogen or C 1-6 alkyl;
    (20) R 11 is C 1-6 alkyl;
    (21) m is 0, 1,2 or 3;
    (22) n is 0, 1,2 or 3;
    (23) p is 1,2 or 3;
    (24) The 3-7 membered heterocyclic groups are 3-7 membered heterocyclic groups with heteroatom types independently selected from N, O and S and heteroatom numbers of 1,2 or 3;
    (25) The 5-10 membered heteroaryl is a 5-10 membered heteroaryl with heteroatom types independently selected from N, O and S and heteroatom numbers of 1,2 or 3.
  3. The fused ring compound as shown in formula I, a tautomer thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof as claimed in claim 1 or 2; the method is characterized in that in the condensed-cyclic compound shown in the formula I:
    X and Y are each independently-O-, -NH-or-CH 2 -;
    z is N;
    L is a single bond;
    Ring a is C 6-12 aryl or 5-10 membered heteroaryl;
    Each R 1 is independently hydroxy, halogen, -N (R 7) 2, cyano, C 1-6 alkyl, C 1-6 alkyl-O-, C 1-6 alkyl substituted with one or more R 1a, C 1-6 alkyl-O-substituted with one or more R 1b, or two R 1 together with the attached ring atoms form a C 3-7 cycloalkyl, C 3-7 cycloalkyl substituted with one or more R 1e, a 3-7 membered heterocyclyl substituted with one or more R 1f, a C 3-7 cycloalkenyl, or a C 3-7 cycloalkenyl substituted with one or more R 1i;
    Each R 1a、R 1b、R 1e、R 1f and R 1i is independently hydroxy, halogen, -N (R 7) 2、C 1-6 alkyl or C 1-6 alkyl substituted with one or more R 1-a;
    Each R 1-a is independently C 1-6 alkyl or halogen;
    Ring D is a 3-7 membered heterocyclyl;
    r 2 is hydrogen;
    R 3 is hydrogen, C 3-7 cycloalkyl, C 3-7 cycloalkyl substituted with one or more R 3d, 3-7 membered heterocyclyl substituted with one or more R 3e, C 3-7 cycloalkenyl, or C 3-7 cycloalkenyl substituted with one or more R 3h;
    Each R 3d、R 3e and R 3h is independently hydroxy, halogen, -N (R 7) 2, cyano, C 1-6 alkyl, C 1-6 alkyl substituted with one or more R 3-a, C 1-6 alkyl-O-, C 1-6 alkyl-O substituted with one or more R 3-b, C 2-6 alkenyl, C 2-6 alkynyl, C 2-6 alkenyl substituted with one or more R 3-c, C 2-6 alkynyl substituted with one or more R 3-d, -C (=o) -R 9、-NR 8C(＝O)-R 9, or two R 3d, two R 3e, or two R 3h together with the attached ring atoms form C 3-7 cycloalkyl, C 3-7 cycloalkyl substituted with one or more R 3-e, 3-7 membered heterocyclyl, or 3-7 membered heterocyclyl substituted with one or more R 3-f, C 3-7 cycloalkenyl, or C 3- 7 cycloalkenyl substituted with one or more R 3-i;
    Each R 3-a、R 3-b、R 3-c、R 3-d、R 3-e、R 3-f and R 3-i is independently hydroxy, halogen, -N (R 7) 2, nitro, cyano, C 1- 6 alkyl or C 1-6 alkyl-O-;
    Each R 4 is independently C 1-6 alkyl, -C 1-4 alkylene-N (R 7) 2, C 1-6 alkyl substituted with one or more R 4a, 3-7 membered heterocyclyl or 3-7 membered heterocyclyl substituted with one or more R 4d;
    Each R 4a and R 4d is independently C 1-6 alkyl or halogen;
    R 5 is hydrogen or C 1-6 alkyl;
    r 6 is oxo;
    Each R 7 is independently hydrogen, C 1-6 alkyl, C 3-7 cycloalkyl, or C 3-7 cycloalkenyl; or two R 7 taken together with the attached nitrogen atom form a 3-7 membered heterocyclyl or a 3-7 membered heterocyclyl substituted with one or more R 7a;
    Each R 7a is independently C 1-6 alkyl or halogen;
    Each R 8 and R 9 is independently hydrogen or C 1-6 alkyl;
    R 11 is C 1-6 alkyl;
    m is 0, 1,2 or 3;
    n is 0, 1,2 or 3;
    p is 1,2 or 3;
    the 3-7 membered heterocyclic groups are 3-7 membered heterocyclic groups with heteroatom types independently selected from N, O and S and heteroatom numbers of 1,2 or 3;
    The 5-10 membered heteroaryl is a 5-10 membered heteroaryl with heteroatom types independently selected from N, O and S and heteroatom numbers of 1,2 or 3.
  4. The fused ring compound as shown in formula I, a tautomer thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof as claimed in claim 1 or 2; the fused ring compound shown as the formula I is characterized by meeting one or more of the following conditions:
    (1) X and Y are each independently-O-or-CH 2 -;
    (2) Ring a is C 6-12 aryl;
    (3) Each R 1 is independently halogen, C 1-6 alkyl or C 1-6 alkyl substituted with one or more R 1a;
    (4) Each R 1a is independently halogen;
    (5) Ring D is a six-membered heterocyclic group having 1 or 2 hetero atoms, e.g. 1, 2-dihydropyridinyl, and further e.g. N "C" means that the atom is meta to the Z atom of ring B;
    (6) R 3 is a 3-7 membered heterocyclyl or a 3-7 membered heterocyclyl substituted with one or more R 3e;
    (7) Each R 3e is independently hydroxy, halogen, -N (R 7) 2, cyano, C 1-6 alkyl, C 1-6 alkyl-O-, C 1-6 alkyl-O-, C 2-6 alkynyl or-C (=o) -R 9 substituted with one or more R 3-b; e.g., each R 3e is independently hydroxy, C 1-6 alkyl-O-or-C (=o) -R 9;
    (8) Each R 3-b is independently hydroxy or halogen;
    (9) Each R 4 is independently C 1-6 alkyl, -C 1-4 alkylene-N (R 7) 2, 3-7 membered heterocyclyl or 3-7 membered heterocyclyl substituted with one or more R 4d;
    (10) Each R 4d is independently C 1-6 alkyl or halogen;
    (11) Each R 7 is independently hydrogen or C 1-6 alkyl;
    (12) Each R 9 is independently hydrogen or C 1-6 alkyl;
    (13) m is 1,2 or 3;
    (14) n is 0, 1 or 2.
  5. A fused ring compound as defined in any one of claims 1 to 3, a tautomer thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof, as shown in formula I; the method is characterized in that in the condensed-cyclic compound shown in the formula I:
    X and Y are each independently-O-;
    Each R 1 is independently halogen, C 1-6 alkyl or C 1-6 alkyl substituted with one or more R 1a;
    each R 1a is independently halogen;
    Ring a is C 6-12 aryl;
    Is that
    L is a single bond;
    r 2 is hydrogen;
    R 3 is a 3-7 membered heterocyclyl or a 3-7 membered heterocyclyl substituted with one or more R 3e;
    Each R 3e is independently hydroxy, halogen, -N (R 7) 2, cyano, C 1-6 alkyl, C 1-6 alkyl-O-, C 2-6 alkynyl, or-C (=o) -R 9;
    R 5 is hydrogen or C 1-6 alkyl;
    Each R 4 is independently C 1-6 alkyl, -C 1-4 alkylene-N (R 7) 2, 3-7 membered heterocyclyl or 3-7 membered heterocyclyl substituted with one or more R 4d;
    Each R 4d is independently C 1-6 alkyl or halogen;
    Each R 7 is independently hydrogen or C 1-6 alkyl;
    Each R 9 is independently hydrogen or C 1-6 alkyl;
    R 11 is C 1-6 alkyl;
    m is 1, 2 or 3;
    n is 0, 1 or 2.
  6. A fused ring compound as defined in any one of claims 1 to 4, a tautomer thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof; the method is characterized in that in the condensed-cyclic compound shown in the formula I:
    X and Y are each independently-O-or-CH 2 -;
    Each R 1 is independently halogen, C 1-6 alkyl or C 1-6 alkyl substituted with one or more R 1a;
    each R 1a is independently halogen;
    Ring a is C 6-12 aryl;
    Ring D is a six-membered heterocyclic group having 1 or 2 hetero atoms, e.g. 1, 2-dihydropyridinyl, and further e.g. N "C" means that the atom is meta to the Z atom of ring B;
    z is N;
    L is a single bond;
    r 2 is hydrogen;
    R 3 is a 3-7 membered heterocyclyl or a 3-7 membered heterocyclyl substituted with one or more R 3e;
    Each R 3e is independently hydroxy, halogen, -N (R 7) 2, cyano, C 1-6 alkyl, C 1-6 alkyl-O-, C 1-6 alkyl-O-, C 2-6 alkynyl or-C (=o) -R 9 substituted by one or more R 3-b;
    Each R 3-b is independently hydroxy or halogen;
    R 5 is hydrogen or C 1-6 alkyl;
    r 6 is oxo;
    Each R 4 is independently C 1-6 alkyl, -C 1-4 alkylene-N (R 7) 2, 3-7 membered heterocyclyl or 3-7 membered heterocyclyl substituted with one or more R 4d;
    Each R 4d is independently C 1-6 alkyl or halogen;
    Each R 7 is independently hydrogen or C 1-6 alkyl;
    Each R 9 is independently hydrogen or C 1-6 alkyl;
    R 11 is C 1-6 alkyl;
    m is 1, 2 or 3;
    n is 0, 1 or 2.
  7. A fused ring compound as shown in formula I, a tautomer thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, 5; the method is characterized in that in the condensed-cyclic compound shown in the formula I:
    Is that
    Is that
    L is a single bond;
    R 3 is
    R 11 is methyl.
  8. A fused ring compound as shown in formula I, a tautomer thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, 6; the method is characterized in that in the condensed-cyclic compound shown in the formula I:
    Is that
    Is that
    L is a single bond;
    R 3 is
    R 11 is methyl.
  9. A fused ring compound as defined in any one of claims 1 to 3, a tautomer thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof, as shown in formula I; the fused ring compound shown as the formula I is characterized by meeting one or more of the following conditions:
    (1) When ring a is a C 6-12 aryl group, the C 6-12 aryl group is phenyl or naphthyl, for example phenyl;
    (2) When ring A is a 5-10 membered heteroaryl group, the 5-10 membered heteroaryl group is a 5-10 membered heteroaryl group having a heteroatom of N, 1 or 2 in number, e.g.
    (3) When R 1 is C 1-6 alkyl substituted with one or more R 1a, the C 1-6 alkyl substituted with one or more R 1a is-CHF 2、-CF 3、-CF 2CH 3、-CF 2CH 2 OH or-CF 2C(CH 3) 2 OH;
    (4) When two R 1 taken together with the attached ring atoms form a C 3-7 cycloalkenyl or a C 3-7 cycloalkenyl substituted with one or more R 1i, the C 3-7 cycloalkenyl is cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl or cycloheptenyl, for example cyclopentenyl;
    (5) When two R 1 taken together with the attached ring atoms form a 3-7 membered heterocyclyl or a 3-7 membered heterocyclyl substituted with one or more R 1f, the 3-7 membered heterocyclyl is a heteroatom independently selected from O, N and S, a 3-7 membered heterocyclyl having 1 or 2 heteroatoms, e.g., is "A" means that the moiety is in a position attached to ring A in a ring manner;
    (6) When ring D is a 3-7 membered heterocyclic group, the 3-7 membered heterocyclic group is a six-membered heterocyclic group having a heteroatom of N, 1 or 2 in number, for example, 1, 2-dihydropyridinyl, further for example "C" means that the atom is meta to the Z atom of ring B;
    (7) When R 3 is a 3-7 membered heterocyclic group or a 3-7 membered heterocyclic group substituted with one or more R 3e, the 3-7 membered heterocyclic group is a 5-7 membered heterocyclic group having 1 or 2 hetero atoms, for example, being selected independently from N and O in the heteroatom species
    (8) When R 3 is C 3-7 cycloalkyl or C 3-7 cycloalkyl substituted by one or more R 3d, said C 3-7 cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or
    (9) When each R 3d and R 3e is independently C 2-6 alkynyl, the C 2-6 alkynyl is ethynyl or propynyl;
    (10) When R 4 is-C 1-4 alkylene-N (R 7) 2), the two R 7 groups together with the nitrogen atom to which they are attached form a 3-to 7-membered heterocyclyl or a 3-to 7-membered heterocyclyl substituted with one or more R 7a, e.g., the-C 1-4 alkylene-N (R 7) 2 is
    (11) When R 4 is-C 1-4 alkylene-N (R 7) 2), said R 7 is independently C 1-6 alkyl, e.g., said-C 1-4 alkylene-N (R 7) 2 is
    (12) When R 4 is a 3-7 membered heterocyclic group or a 3-7 membered heterocyclic group substituted with one or more R 4d, the 3-7 membered heterocyclic group is a 5-7 membered heterocyclic group having a heteroatom of 1 or 2, for example, N
    (13) When two R 7's together with the nitrogen atom to which they are attached form a 3-7 membered heterocyclic group or a 3-7 membered heterocyclic group substituted with one or more R 7a, the 3-7 membered heterocyclic group is a 5-7 membered heterocyclic group having a heteroatom of N, 1 or 2 in number, e.g.
    (14) When R 1、R 1a、R 1b、R 1e、R 1f、R 1i、R 1-a、R 3d、R 3e、R 3h、R 3-a、R 3-b、R 3-c、R 3-d、R 3-e、R 3-f、R 3-i、R 4、R 4a、R 4d、R 5、R 7、R 7a、R 8、R 9 or R 11 is C 1-6 alkyl or C 1-6 alkyl substituted with a substituent, each of said C 1-6 alkyl is independently C 1-4 alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, further such as methyl, ethyl or isobutyl;
    (15) When R 1、R 1a、R 1b、R 1e、R 1f、R 1i、R 1-a、R 3d、R 3e、R 3h、R 3-a、R 3-b、R 3-c、R 3-d、R 3-e、R 3-f、R 3-i、R 4a、R 4d or R 7a is halogen, each of the halogens is independently F, cl, br or I, for example F or Cl;
    (16) When R 1、R 3d、R 3e、R 3h、R 3-a、R 3-b、R 3-c、R 3-d、R 3-e、R 3-f or R 3-i is C 1-6 alkyl-O-or C 1-6 alkyl-O-substituted with a substituent, each of said C 1-6 alkyl-O-is independently C 1-4 alkyl-O-, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, further such as methoxy, ethoxy or isopropoxy; and for example methoxy or ethoxy.
  10. A fused ring compound as defined in any one of claims 1 to 3, a tautomer thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof, as shown in formula I; the fused ring compound shown as the formula I is characterized by meeting one or more of the following conditions:
    (1) Ring A is
    (2) R 1 is F、Cl、-CN、-CHF 2、-CF 3、-CH 3、-CF 2CH 2OH、-CF 2CH 3、-NH 2 or-CF 2C(CH 3) 2 OH; or two R 1 together with the ring atoms to which they are attached form"A" means that the moiety is in a position attached to ring A in a ring manner;
    (3) R 3 is For example, as
    (4) Is that For example, as
    (5) R 4 is-CH 3,
    (6) For example, asWherein the b-terminal is attached to the Z atom;
    (7) R 11 is methyl;
    preferably, the fused ring compound shown in formula I meets one or more of the following conditions:
    (1A) Is that For example, as
    (1B) Is that For example, as
    More preferably, the fused ring compound as shown in formula I satisfies one or more of the following conditions:
    (2A) Is that For example, as
    (2B) The condensed-cyclic compound shown as the formula I is
  11. The fused ring compound as set forth in claim 1, a tautomer thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, as set forth in formula I; the fused ring compound shown in the formula I is characterized by being selected from any one of the following compounds:
  12. A process for the preparation of a fused ring compound as defined in any one of claims 1 to 11, as represented by formula I, a tautomer thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof, comprising the steps of:
    scheme one: when the condensed-ring compound shown in the formula I is a compound Ia, the compound Ia-6 and The compound Ia is obtained through Buchwald-Hartwig coupling reaction;
    Scheme II: when the condensed-ring compound shown in the formula I is a compound Ib, the compound Ib-3 and Obtaining a compound Ib through Buchwald-Hartwig coupling reaction;
    preferably, in the preparation method, in scheme one or scheme two, the Buchwald-Hartwig coupling reaction is carried out in the presence of a catalyst and a base; the catalyst is one or more of RuPhos Pd G, brettPhos Pd G3, XPhos Pd G3, xantPhos Pd G3, ruPhos Pd G and BrettPhos Pd G4; the alkali is one or more of cesium carbonate, sodium carbonate, potassium phosphate, sodium carbonate, potassium tert-butoxide and sodium tert-butoxide;
    in the preparation method, preferably, the first scheme further includes the following steps:
    The compound I-1 and R 5-NH 2 undergo substitution reaction to obtain a compound Ia-1;
    The compound Ia-1 and an iodination reagent (such as N-iodinated succinimide and I 2) are subjected to iodination reaction to obtain a compound Ia-2;
    The compound Ia-2 and Obtaining a compound Ia-3 through Heck coupling reaction;
    The compound Ia-3 is subjected to ring closure reaction under the action of alkali to obtain a compound Ia-4;
    The compound Ia-4 and a brominating reagent are subjected to bromination reaction to obtain a compound Ia-5;
    Reacting the compound Ia-5 with corresponding substituted ketone, amine and boric acid ester derivatives to obtain a compound Ia-6;
    More preferably, in the iodination reaction, the iodination reagent is N-iodosuccinimide and/or I 2;
    More preferably, in the ring closure reaction, the base is one or more of sodium methyl mercaptide, sodium methoxide and sodium ethoxide;
    More preferably, in the bromination reaction, the brominating reagent is N-bromosuccinimide and/or Br 2;
    in the preparation method, preferably, the second scheme further includes the following steps:
    Wherein R 12 is methyl or ethyl;
    The compound I-1 undergoes an acylation reaction under the action of strong alkali to obtain a compound Ib-1;
    reacting the compound Ib-1 with malonate and decarboxylating to obtain a compound Ib-2;
    The compound Ib-2 and H 2N-L-R 3 undergo a ring-closing reaction to obtain a compound Ib-3;
    More preferably, in the acylation reaction, the strong base is lithium diisopropylamide;
    more preferably, the malonate is methyl malonate or ethyl malonate.
  13. A pharmaceutical composition; characterized in that the pharmaceutical composition comprises:
    (1) A substance X which is a fused ring compound as shown in the formula I, a tautomer thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 11, and
    (2) Pharmaceutically acceptable auxiliary materials.
  14. Use of a substance X or a pharmaceutical composition according to claim 13 for the preparation of an SOS1 inhibitor, wherein the substance X is a fused ring compound according to any one of claims 1-11, a tautomer thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof, as shown in formula I.
  15. Use of substance X or the pharmaceutical composition of claim 13 for the preparation of a medicament; wherein the substance X is a fused ring compound shown in the formula I, a tautomer thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11; the drug may be a drug for treating and/or preventing a disease associated with SOS1 activity or expression level;
    Preferably, the disease associated with SOS1 activity or expression is selected from the group consisting of non-small cell lung cancer, lung adenocarcinoma, lung squamous carcinoma, pancreatic cancer, colon cancer, thyroid cancer, melanoma, embryonal rhabdomyosarcoma, skin granulosa cell tumor, liver cancer, rectal cancer, bladder cancer, throat cancer, breast cancer, prostate cancer, glioma, ovarian cancer, head and neck squamous carcinoma, cervical cancer, esophageal cancer, renal cancer, skin cancer, lymphoma, gastric cancer, bile duct cancer, uterine cancer, endometrial cancer, urothelial cancer, acute myeloid leukemia, myelofibrosis, B-cell lymphoma, monocytic leukemia, spleen megaloblastic, eosinophilic leukocytosis syndrome, and multiple myeloma, and diseases associated with hereditary mutation of SOS1, such as neurofibroma type, nannon syndrome, multiple-like knoop-Nannon syndrome, vascular malformation-arteriole syndrome, heart-face-skin syndrome, kertus syndrome, reg syndrome, and hereditary gum tumor type.
  16. Use of substance X or the pharmaceutical composition of claim 13 for the preparation of a medicament; wherein the substance X is a fused ring compound shown in the formula I, a tautomer thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11; the medicine is used for treating and/or preventing the following various diseases; the disease is selected from the group consisting of non-small cell lung cancer, lung adenocarcinoma, lung squamous carcinoma, pancreatic cancer, colon cancer, parathyroid carcinoma, melanoma, embryonal rhabdomyosarcoma, skin granulosa tumor, liver cancer, rectal cancer, bladder cancer, throat cancer, breast cancer, prostate cancer, glioma, ovarian cancer, head and neck squamous carcinoma, cervical cancer, esophageal cancer, kidney cancer, skin cancer, lymphoma, gastric cancer, cholangiocarcinoma, uterine cancer, endometrial cancer, urothelial cancer, acute myeloid leukemia, myelofibrosis, B-cell lymphoma, monocytic leukemia, spleen polycythemia, eosinophilic leukocytosis syndrome, and multiple myeloma, as well as neurofibromas of one type, noonan syndrome, multiple freckle-like arteriovenous south syndrome, capillary vessel-vein malformation syndrome, heart-face-skin syndrome, kestosterol syndrome, reg th syndrome, and hereditary gingival fibroma.
CN202280060464.4A 2021-09-28 2022-09-28 Fused ring compound, preparation method and application thereof Pending CN117957231A (en)

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WO2018010142A1 (en) * 2016-07-14 2018-01-18 Shanghai Meton Pharmaceutical Co., Ltd Iso-citrate dehydrogenase (idh) inhibitor
EP3931195A1 (en) * 2019-03-01 2022-01-05 Revolution Medicines, Inc. Bicyclic heteroaryl compounds and uses thereof
JP2022551180A (en) * 2019-10-12 2022-12-07 ジェチアン メトン ファーマシューティカル カンパニー，リミテッド isocitrate dehydrogenase (IDH) inhibitors
US20230101312A1 (en) * 2020-02-24 2023-03-30 Mirati Therapeutics, Inc. Sos1 inhibitors
WO2022156792A1 (en) * 2021-01-25 2022-07-28 Guangdong Newopp Biopharmaceuticals Co., Ltd. Heterocyclic compounds as sos1 inhibitors
CN114835703A (en) * 2021-02-02 2022-08-02 苏州泽璟生物制药股份有限公司 Substituted pyrimidopyridone inhibitor and preparation method and application thereof
WO2022184116A1 (en) * 2021-03-05 2022-09-09 江苏先声药业有限公司 New sos1 inhibitor, preparation method therefor and use thereof
CN115043842A (en) * 2021-03-09 2022-09-13 苏州泽璟生物制药股份有限公司 Amino-substituted bicyclic inhibitor and preparation method and application thereof

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