CN117279914A - SOS1 inhibitor and preparation method and application thereof - Google Patents

SOS1 inhibitor and preparation method and application thereof Download PDF

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Publication number
CN117279914A
CN117279914A CN202280011875.4A CN202280011875A CN117279914A CN 117279914 A CN117279914 A CN 117279914A CN 202280011875 A CN202280011875 A CN 202280011875A CN 117279914 A CN117279914 A CN 117279914A
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alkyl
cycloalkyl
amino
pharmaceutically acceptable
ethyl
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Inventor
张雁
杨圣伟
庞司林
赵春艳
王峰
唐锋
彭少平
任晋生
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Nanjing Zaiming Pharmaceutical Co ltd
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Nanjing Zaiming Pharmaceutical Co ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Abstract

The invention provides a series of compounds of SOS1 inhibitor, in particular to a compound shown in a formula (I) and pharmaceutically acceptable salts thereof,

Description

SOS1 inhibitor and preparation method and application thereof
This application claims priority from the following five prior applications, which are incorporated by reference in their entirety:
the prior application of the patent application number 202110134521.6, the name of which is SOS1 inhibitor and the preparation method and application thereof, is submitted to the China national intellectual property office on the day 29 of 2021;
the prior application of the patent application No. 202110296210.X, the name of which is SOS1 inhibitor, the preparation method and the application thereof, is submitted to the China national intellectual property office on the 3 rd month 19 th year 2021;
the patent application number is 202110465173.0, and the name is the prior application of SOS1 inhibitor, the preparation method and the application thereof, which are filed to China national intellectual property office on the 4 th month of 2021;
the patent application number is 202110561063.4, and the name is the prior application of SOS1 inhibitor, the preparation method and the application thereof, which are submitted to the China national intellectual property office at the year 2021, month 5 and 21; and
The patent application number is 202111167826.3, and the invention is the prior application of SOS1 inhibitor, the preparation method and the application thereof, which are filed to China national intellectual property office on 9 and 29 days 2021.
Technical Field
The invention belongs to the technical field of medicines, and relates to an SOS1 inhibitor compound or an optical isomer and a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the same and application of the SOS1 inhibitor compound or the optical isomer and the pharmaceutically acceptable salt thereof as an SOS1 inhibitor.
Background
RAS family proteins include KRAS (V-Ki-RAS 2 Kirsten rat sarcoma viral oncogene homolog), NRAS (neuroblastoma RAS viral oncogene homolog), and HRAS (Harvey murine sarcoma viral oncogene), among others, are small GTPases present in the cell in either a GTP-bound or GDP-bound state (McCormick et al, J.mol. Med. (Berl.,) 2016,94 (3): 253-8; nimnal et al, sci. STKE.,2002,2002 (145): pe 36).
RAS family proteins play an important role in human cancers. Tumors caused by RAS protein mutations account for 20-30% of all human tumors and are considered tumorigenic driving factors, particularly in lung, colorectal and pancreatic cancers (Malumbres & Barbacid 2002 Nature Reviews Cancer,Pylayeva-Gupta et al, 2011 Nature Reviews Cancer).
SOS1 (son of sevenless homolog 1) protein is a regulatory protein widely expressed in cells, and plays an important role in regulating RAS and RAC signal transduction pathways in cells as a guanine nucleotide exchange factor of RAS and RAC proteins. SOS1 has two binding sites for RAS family proteins: a catalytic site that binds to a GDP-bound RAS family protein to promote guanine nucleotide exchange; an allosteric site that binds to GTP-bound RAS family proteins, which results in a further increase in catalytic GEF function of SOS1 (Freedman et al, proc. Natl. Acad. Sci. USA.,2006,103 (4) 5): 16692-7; pierre et al, biochem. Pharmacol.,2011,82 (9): 1049-56). Published data indicate that SOS1 is involved in mutant KRAS activation and oncogenic signaling in cancer (Jeng et al, nat. Commun.,2012, 3:1168). Depletion of SOS1 levels reduced proliferation and survival of tumor cells harboring KRAS mutations, which were not observed in KRAS wild-type cell lines. The effect of SOS1 loss cannot be complemented by SOS1 introduced with catalytic site mutations, further demonstrating the important role of SOS1GEF activity in KRAS mutant cancer cells.
Over the last few decades, RAS family protein-SOS 1 protein interactions have been increasingly studied. Small activating molecules have been identified that bind to the lipophilic pocket of SOS1 in close proximity to the RAS binding site (Burns et al, proc. Natl. Acad. Sci.2014,111 (9): 3401-6). However, binding of these molecules appears to result in increased nucleotide exchange, thereby activating the RAS rather than inactivating it.
Although some small-molecule SOS1 inhibitors (such as WO2018/115380A1 and WO2018/172250A 1) are reported in the prior art, a large number of patients still cannot obtain satisfactory clinical treatment effects, so that there is still a need to develop SOS1 inhibitors with good activity, good selectivity and low toxic and side effects.
Disclosure of Invention
The invention provides a compound shown as a formula (I) and pharmaceutically acceptable salts thereof. These compounds can inhibit SOS1 activity, thereby affecting biological function.
The invention provides a compound shown in a formula (I) or pharmaceutically acceptable salt thereof,
wherein,
x is selected from CH or N;
y is selected from CH or N;
z is selected from CH or N;
R 1 selected from H, CN, C 1-6 Alkyl or C 3-6 Cycloalkyl;
ring A is selected from C 6-10 Aryl, benzo 5-7 membered heterocyclyl or benzo 5-7 membered heteroaryl;
l is selected from a bond or O;
R 2 selected from C 3-10 Cycloalkyl, C 6-10 Aryl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl, said C 3-10 Cycloalkyl, C 6- 10 Aryl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl optionally substituted with R 2b And/or R 2c Substitution;
R 2b selected from-OR 2c 、-N(R 2c ) 2 Halogen, hydroxy, cyano, amino, -C (O) R 2c 、-C(O)NHR 2c 、-C(O)NH 2 、-NHR 2c 、-C(O)H、-C(O)OH、-S(O) 2 NHR 2c 、-NHC(O)H、-N(C 1-4 Alkyl) C (O) H, -C (O) N (R) 2c ) 2 、-C(O)OR 2c 、-S(O) 2 R 2c 、-S(O) 2 N(R 2c ) 2 、-NHC(O)R 2c or-N (C) 1-4 Alkyl) C (O) R 2c ；
R 2c Independently selected from C 1-6 Alkyl, C 1-3 Deuterated alkyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl, said C 1-6 Alkyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl optionally substituted with R 2d Substitution;
R 2d selected from halogen, hydroxy, cyano, amino, -C (O) R 2f 、-C(O)N(R 2f ) 2 、-C(O)OR 2f 、-S(O) 2 R 2f 、-S(O) 2 N(R 2f ) 2 、-N(C 1-4 Alkyl) R 2f 、-NHC(O)R 2f or-N (C) 1-4 Alkyl) C (O) R 2f ；
R 2f Independently selected from H or C 1-6 An alkyl group;
R 3 selected from H, halogen, hydroxy, cyano, amino, -NH-C 3-6 Cycloalkyl, C 1-3 Deuterated alkyl, -O-C 1-3 Deuterated alkyl, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclyl, -O-C 1-6 Alkyl, -O-C 3-6 Cycloalkyl, -O- (3-8 membered heterocyclyl), 5-10 membered heteroaryl, -C (O) R 3a 、-C(O)N(R 3a ) 2 、-C(O)OR 3a 、-S(O) 2 R 3a 、-S(O) 2 N(R 3a ) 2 、-NHC(O)R 3a or-N (C) 1-4 Alkyl) C (O) R 3a the-NH-C 3-6 Cycloalkyl, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclyl, -O-C 1-6 Alkyl, -O-C 3-6 Cycloalkyl, -O- (3-8 membered heterocyclyl) or 5-10 membered heteroaryl optionally substituted with R 3b Substitution;
the R is 3a Independently selected from H or C 1-6 An alkyl group;
the R is 3b Independently selected from halogen, hydroxy, cyano, amino, 3-8 membered heterocyclyl or C 1-6 An alkyl group;
R 4 selected from halogen, hydroxy, cyano, amino, C 1-6 Alkyl, C 3-6 Cycloalkyl, -O-C 1-6 Alkyl, -O-C 3-6 Cycloalkyl, -O- (3-8 membered heterocyclyl), 3-8 membered heterocyclyl, 5-10 membered heteroaryl or-S (O) 2 -C 1-4 Alkyl, said C 1-6 Alkyl, C 3-6 Cycloalkyl, -O-C 1-6 Alkyl, -O- C 3-6 Cycloalkyl, -O- (3-8 membered heterocyclyl), 3-8 membered heterocyclyl or 5-10 membered heteroaryl optionally substituted with R 4a Substitution; the R is 4a Selected from halogen, hydroxy, cyano or amino;
R 5 selected from C 1-3 Deuterated alkyl, C 1-6 Alkyl or C 1-6 A haloalkyl group;
R 6 selected from H, deuterium, C 1-3 Deuterated alkyl, C 1-6 Alkyl or C 1-6 A haloalkyl group;
n is selected from 0, 1, 2, 3 or 4;
wherein when X is selected from N and Z is selected from CH, R 1 Selected from CN or C 3-6 Cycloalkyl;
when X, Z is selected from N, R 1 Selected from CN, C 1-6 Alkyl or C 3-6 Cycloalkyl;
when X, Z is selected from CH, R 3 Selected from hydroxy, cyano, amino, C 1-3 Deuterated alkyl, -O-C 1-3 Deuterated alkyl, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclyl, -O-C 1-6 Alkyl, -O-C 3-6 Cycloalkyl, -O- (3-8 membered heterocyclyl), 5-10 membered heteroaryl, -C (O) R 3a 、-C(O)N(R 3a ) 2 、-C(O)OR 3a 、-S(O) 2 R 3a 、-S(O) 2 N(R 3a ) 2 、-NHC(O)R 3a or-N (C) 1-4 Alkyl) C (O) R 3a The C is 1-6 Alkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclyl, -O-C 1-6 Alkyl, -O-C 3-6 Cycloalkyl, -O- (3-8 membered heterocyclyl) or 5-10 membered heteroaryl optionally substituted with R 3b And (3) substitution.
In some embodiments, X, Z is independently selected from N, Y is selected from CH, and R 1 Selected from CN, C 1-6 Alkyl or C 3-6 Cycloalkyl, R 2 Selected from any one ofOptionally by R 2b And/or R 2c The substituted following groups:
in some embodiments, X, Z is independently selected from N, Y is selected from CH, and R 1 Selected from CN, C 1-6 Alkyl or C 3-6 Cycloalkyl, R 2 Selected from optionally by R 2b And/or R 2c The substituted following groups:
in some embodiments, X, Z is independently selected from N, Y is selected from CH, and R 1 Selected from CN, C 1-6 Alkyl or C 3-6 Cycloalkyl, R 2 Selected from the following groups:
in some embodiments, X, Z is independently selected from N, Y is selected from CH, and R 1 Selected from CN, C 1-6 Alkyl or C 3-6 Cycloalkyl, R 2 Selected from optionally by R 2b And/or R 2c The substituted following groups:when R is 3 Selected from the group consisting of-O-CH 2 CHF 2 or-NH-C 3-6 Cycloalkyl groups.
In some embodiments, X, Z is independently selected from N, Y is selected from CH, and R 1 Selected from CN, C 1-6 Alkyl or C 3-6 Cycloalkyl, R 2 Selected from optionally by R 2b And/or R 2c The substituted following groups:when R is 3 Selected from the group consisting of-O-CH 2 CHF 2 。
In some embodiments, X, Z is independently selected from N, Y is selected from CH, and R 1 Selected from CN, C 1-6 Alkyl or C 3-6 Cycloalkyl, R 2 Selected from optionally by R 2b And/or R 2c The substituted following groups:when R is 3 Selected from the group consisting of-O-CH 3 。
In some embodiments, X, Y, Z is independently selected from CH, and R 3 Selected from hydroxy, cyano, amino, C 1-3 Deuterated alkyl, -O-C 1-3 Deuterated alkyl, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclyl, -O-C 1-6 Alkyl, -O-C 3-6 Cycloalkyl, -O- (3-8 membered heterocyclyl), 5-10 membered heteroaryl, -C (O) R 3a 、-C(O)N(R 3a ) 2 、-C(O)OR 3a 、-S(O) 2 R 3a 、-S(O) 2 N(R 3a ) 2 、 -NHC(O)R 3a or-N (C) 1-4 Alkyl) C (O) R 3a The C is 1-6 Alkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclyl, -O-C 1-6 Alkyl, -O-C 3-6 Cycloalkyl, -O- (3-8 membered heterocyclyl) or 5-10 membered heteroaryl optionally substituted with R 3b And (3) substitution. In some embodiments, X, Y, Z is independently selected from CH, and R 3 Selected from-C (O) R 3a 、-C(O)OR 3a 、C 1-6 Alkyl, -O-C 1-6 Alkyl or 5-10 membered heteroaryl, said C 1-6 Alkyl, -O-C 1-6 Alkyl or 5-10 membered heteroaryl optionally substituted with R 3b And (3) substitution.
In some embodiments, ring a is selected from phenyl, indanyl, indenyl, tetrahydronaphthyl, dihydronaphthyl, or naphthyl.
In some embodiments, ring a is selected from phenyl.
In some embodiments, R 1 Selected from H, CN, methyl or cyclopropyl.
In some embodiments, R 1 Selected from C 1-6 An alkyl group.
In some embodiments, R 1 Selected from CH 3 。
In some embodiments, R 2 Selected from C 3-10 Cycloalkyl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl, said C 3-10 Cycloalkyl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl optionally substituted with R 2b And/or R 2c And (3) substitution.
In some embodiments, R 2 Selected from 3-10 membered heterocyclyl or 5-10 membered heteroaryl, said 3-10 membered heterocyclyl or 5-10 membered heteroaryl optionally being substituted with R 2b And/or R 2c And (3) substitution.
In some embodiments, R 2 Selected from 4-8 membered heterocyclyl or 5-6 membered heteroaryl, said 4-8 membered heterocyclyl or 5-6 membered heteroaryl optionally being substituted with R 2b And/or R 2c And (3) substitution.
In some embodiments, R 2 Selected from optionally by R 2b And/or R 2c The substituted following groups:
in some embodiments, R 2 Selected from optionally by R 2b And/or R 2c The substituted following groups:
in some embodiments, R 2 Selected from optionally by R 2b And/or R 2c The substituted following groups:
in some embodiments, R 2 Selected from optionally by R 2b And/or R 2c The substituted following groups:when R is 3 Selected from the group consisting of-O-CH 2 CHF 2 or-NH-C 3-6 Cycloalkyl groups.
In some embodiments, R 2 Selected from optionally by R 2b And/or R 2c The substituted following groups:when R is 3 Selected from the group consisting of-O-CH 2 CHF 2 。
In some embodiments, R 2 Selected from optionally by R 2b And/or R 2c The substituted following groups:when R is 3 Selected from the group consisting of-O-CH 3 。
In some embodiments, R 2b Selected from-OR 2c 、-N(R 2c ) 2 Halogen, hydroxy, cyano, amino, -C (O) R 2c 、-C(O)NHR 2c 、-C(O)N(R 2c ) 2 、-C(O)OR 2c 、-S(O) 2 R 2c 、-S(O) 2 N(R 2c ) 2 、-NHC(O)R 2c or-N (C) 1-4 Alkyl) C (O) R 2c 。
In some embodiments, R 2b Selected from-OR 2c 、-N(R 2c ) 2 Halogen, hydroxy, cyano, amino, -C (O) R 2c 、-C(O)N(R 2c ) 2 、-C(O)OR 2c 、-S(O) 2 R 2c 、-S(O) 2 N(R 2c ) 2 、-NHC(O)R 2c or-N (C) 1-4 Alkyl) C (O) R 2c 。
In some embodiments, R 2b Selected from-OR 2c Halogen, hydroxy, cyano, amino, -C (O) R 2c 、-C(O)OR 2c 、-S(O) 2 R 2c 、-C(O)NHR 2c or-NHC (O) R 2c 。
In some embodiments, R 2b Selected from-OR 2c Halogen, hydroxy, cyano, amino, -C (O) R 2c 、-C(O)OR 2c 、-S(O) 2 R 2c or-C (O) NHR 2c 。
In some embodiments, R 2b Selected from-OR 2c Halogen, hydroxy, cyano, -C (O) R 2c 、-C(O)OR 2c 、-S(O) 2 R 2c or-C (O) NHR 2c 。
In some embodiments, R 2b Selected from-OR 2c Halogen, hydroxy, cyano, -C (O) R 2c 、-C(O)OR 2c or-S (O) 2 R 2c 。
In some embodiments, R 2b Selected from halogen, hydroxy, cyano, amino, -C (O) R 2c 、-S(O) 2 R 2c or-C (O) NHR 2c 。
In some embodiments, R 2b Selected from halogen, hydroxy, cyano, -C (O) R 2c 、-S(O) 2 R 2c or-C (O) NHR 2c 。
In some embodiments, R 2b Selected from halogen, hydroxy, cyano, -C (O) R 2c or-S (O) 2 R 2c 。
In some embodiments, R 2c Independently selected from C 1-6 Alkyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl, said C 1-6 Alkyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl optionally substituted with R 2d And (3) substitution.
In some embodiments, R 2c Selected from C 1-6 Alkyl, C 1-3 Deuterated alkyl, C 3-10 Cycloalkyl or 3-10 membered heterocyclyl, said C 1-6 Alkyl, C 3-10 Cycloalkyl or 3-10 membered heterocyclyl optionally substituted with R 2d And (3) substitution.
In some embodiments, R 2c Selected from C 1-6 Alkyl, C 3-10 Cycloalkyl or 3-10 membered heterocyclyl, said C 1-6 Alkyl, C 3- 10 Cycloalkyl or 3-10 membered heterocyclyl optionally substituted with R 2d And (3) substitution.
In some embodiments, R 2c Selected from C 1-4 Alkyl, C 3-6 Cycloalkyl or 4-6 membered heterocyclyl, said C 1-4 Alkyl, C 3-6 Cycloalkyl or 4-6 membered heterocyclyl optionally being substituted by R 2d And (3) substitution.
In some embodiments, R 2d Selected from halogen, hydroxy, cyano or amino.
In some embodiments, R 4 Selected from halogen, hydroxy, cyano, amino, C 1-6 Alkyl, C 3-6 Cycloalkyl or 3-8 membered heterocyclyl, said C 1-6 Alkyl, C 3-6 Cycloalkyl or 3-8 membered heterocyclyl optionally being substituted by R 4a And (3) substitution.
In some embodiments, R 4 Selected from halogen, hydroxy, cyano, amino or C 1-4 Alkyl, said C 1-4 Alkyl is optionally R 4a And (3) substitution.
In some embodiments, R 4 Selected from halogen, amino or C 1-4 Alkyl, said C 1-4 Alkyl is optionally R 4a And (3) substitution.
In some embodiments, R 3 Selected from H, halogen, hydroxy, cyano, amino, C 1-3 Deuterated alkyl, -O-C 1-3 Deuterated alkyl, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclyl, -O-C 1-6 Alkyl, -O-C 3-6 Cycloalkyl, -O- (3-8 membered heterocyclyl), 5-10 membered heteroaryl, -C (O) R 3a 、-C(O)N(R 3a ) 2 、-C(O)OR 3a 、-S(O) 2 R 3a 、-S(O) 2 N(R 3a ) 2 、-NHC(O)R 3a or-N (C) 1-4 Alkyl) C (O) R 3a The C is 1-6 Alkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclyl, -O-C 1-6 Alkyl, -O-C 3-6 Cycloalkyl, -O- (3-8 membered heterocyclyl) or 5-10 membered heteroaryl optionally substituted with R 3b And (3) substitution.
In some embodiments, R 3 Selected from H, halogen, hydroxy, cyano, amino, -NH-C 3-6 Cycloalkyl, C 1-3 Deuterated alkyl, -O-C 1-3 Deuterated alkyl, C 1-6 Alkyl, C 3-6 Cycloalkyl, -O-C 1-6 Alkyl, -O-C 3-6 Cycloalkyl, -C (O) R 3a 、-C(O)OR 3a 、-S(O) 2 -C 1-4 Alkyl or 5-10 membered heteroaryl, said-NH-C 3-6 Cycloalkyl, C 1-6 Alkyl, C 3-6 Cycloalkyl, -O-C 1-6 Alkyl, -O-C 3-6 Cycloalkyl or 5-to 10-membered heteroaryl optionally substituted with R 3b And (3) substitution.
In some embodiments, R 3 Selected from H, halogen, hydroxy, cyano, amino, C 1-3 Deuterated alkyl, -O-C 1-3 Deuterated alkyl, C 1-6 Alkyl, C 3-6 Cycloalkyl, -O-C 1-6 Alkyl, -O-C 3-6 Cycloalkyl, -S (O) 2 -C 1-4 Alkyl or 5-10 membered heteroaryl, said C 1-6 Alkyl, C 3-6 Cycloalkyl, -O-C 1-6 Alkyl, -O-C 3-6 Cycloalkyl or 5-to 10-membered heteroaryl optionally substituted with R 3b And (3) substitution.
In some embodiments, R 3 Selected from H, halogen, hydroxy, cyano, amino, C 1-3 Deuterated alkyl, -O-C 1-3 Deuterated alkyl, C 1-6 Alkyl, C 3-6 Cycloalkyl, -O-C 1-6 Alkyl, -O-C 3-6 Cycloalkyl or-S (O) 2 -C 1-4 Alkyl, said C 1-6 Alkyl, C 3-6 Cycloalkyl, -O-C 1-6 Alkyl or-O-C 3-6 Cycloalkyl is optionally substituted with R 3b And (3) substitution.
In some embodiments, R 3 Selected from H, halogen, hydroxy, cyano, amino, -NH-C 3-6 Cycloalkyl, C 1-3 Deuterated alkyl, -O-C 1-3 Deuterated alkyl, C 1-6 Alkyl, -O-C 1-6 Alkyl, -C (O) R 3a 、-C(O)OR 3a 、-S(O) 2 -C 1-4 Alkyl or 5-10 membered heteroaryl, said-NH-C 3-6 Cycloalkyl, C 1-6 Alkyl, -O-C 1-6 Alkyl or 5-10 membered heteroaryl optionally substituted with R 3b And (3) substitution.
In some embodiments, R 3 Selected from H, halogen, hydroxy, cyano, amino, C 1-3 Deuterated alkyl, -O-C 1-3 Deuterated alkyl, C 1-6 Alkyl, -O-C 1-6 Alkyl, -S (O) 2 -C 1-4 Alkyl or 5-10 membered heteroaryl, said C 1-6 Alkyl, -O-C 1-6 Alkyl or 5-10 membered heteroaryl optionally substituted with R 3b And (3) substitution.
In some embodiments, R 3 Selected from H, halogen, hydroxy, cyano, amino, C 1-3 Deuterated alkyl, -O-C 1-3 Deuterated alkyl, C 1-6 Alkyl, -O-C 1-6 Alkyl or-S (O) 2 -C 1-4 Alkyl, said C 1-6 Alkyl or-O-C 1-6 Alkyl is optionally R 3b And (3) substitution.
In some embodiments, R 3 Selected from H, C 1-3 Deuterated alkyl, -O-C 1-3 Deuterated alkyl, C 1-6 Alkyl, -O-C 1-6 Alkyl, -S (O) 2 -C 1-4 Alkyl or 5-to 10-memberedHeteroaryl, said C 1-6 Alkyl, -O-C 1-6 Alkyl or 5-10 membered heteroaryl optionally substituted with R 3b And (3) substitution.
In some embodiments, R 3 Selected from H, C 1-3 Deuterated alkyl, -O-C 1-3 Deuterated alkyl, C 1-6 Alkyl, -O-C 1-6 Alkyl or-S (O) 2 -C 1-4 Alkyl, said C 1-6 Alkyl or-O-C 1-6 Alkyl is optionally R 3b And (3) substitution.
In some embodiments, R 3 Selected from H, C 1-3 Deuterated alkyl, -O-C 1-3 Deuterated alkyl, C 1-6 Alkyl or-O-C 1-6 Alkyl, said C 1-6 Alkyl or-O-C 1-6 Alkyl is optionally R 3b And (3) substitution.
In some embodiments, R 3 Selected from H, amino, -NH-C 3-6 Cycloalkyl, -C (O) R 3a 、-C(O)OR 3a 、C 1-6 Alkyl, -O-C 1-6 Alkyl or 5-10 membered heteroaryl, said-NH-C 3-6 Cycloalkyl, C 1-6 Alkyl, -O-C 1-6 Alkyl or 5-10 membered heteroaryl optionally substituted with R 3b And (3) substitution.
In some embodiments, R 3 Selected from H, amino, -NH-cyclobutyl, -C (O) R 3a 、-C(O)OR 3a 、C 1-3 Alkyl, -O-C 1-3 Alkyl or pyrazolyl, said-NH-cyclobutyl, C 1-3 Alkyl, -O-C 1-3 Alkyl or pyrazolyl is optionally substituted with R 3b And (3) substitution.
In some embodiments, R 3 Selected from H, amino, -O-CH 3 、CF 3 、-O-CH 2 CHF 2 、-O-CF 2 H、-C(O)CH 3 、C(O)OH、
In some embodiments, R 3 Selected from H, C 1-6 Alkyl, -O-C 1-6 Alkyl or 5-10 membered heteroaryl, said C 1-6 Alkyl, -O-C 1-6 Alkyl or 5-10 membered heteroaryl optionally substituted with R 3b And (3) substitution.
In some embodiments, R 3 Selected from H, C 1-6 Alkyl or-O-C 1-6 Alkyl, said C 1-6 Alkyl or-O-C 1-6 Alkyl is optionally R 3b And (3) substitution.
In some embodiments, R 3 Selected from-C (O) R 3a 、-C(O)OR 3a 、C 1-6 Alkyl, -O-C 1-6 Alkyl or 5-10 membered heteroaryl, said C 1-6 Alkyl, -O-C 1-6 Alkyl or 5-10 membered heteroaryl optionally substituted with R 3b And (3) substitution.
In some embodiments, R 3 Selected from the group consisting of-O-CH 3 、-O-CH 2 CHF 2 、-O-CF 2 H、-C(O)CH 3 C (O) OH orIn some embodiments, R 3a Selected from H or CH 3 。
In some embodiments, R 3b Independently selected from halogen, hydroxy, cyano, amino, or 3-8 membered heterocyclyl.
In some embodiments, R 3b Independently selected from halogen or C 1-6 An alkyl group.
In some embodiments, R 3b Independently selected from F or CH 3 。
In some embodiments, R 3b Independently selected from halogenElement or C 1-6 An alkyl group.
In some embodiments, R 3b Independently selected from halogen.
In some embodiments, R 2 Selected from the following groups:
in some embodiments, R 5 Selected from C 1-3 Deuterated alkyl, C 1-3 Alkyl or C 1-3 A haloalkyl group.
In some embodiments, R 5 Selected from CH 3 、CD 3 、CF 3 、CHF 2 Or CH (CH) 2 F。
In some embodiments, R 6 Selected from H, deuterium, C 1-3 Deuterated alkyl, C 1-3 Alkyl or C 1-3 A haloalkyl group.
In some embodiments, R 6 Selected from H, deuterium, CH 3 Or CD (compact disc) 3 。
In some embodiments, n is selected from 0, 1, or 2.
In some embodiments, n is 2.
In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from the group consisting of the compound of formula (II) or a pharmaceutically acceptable salt thereof,
therein, A, L, R 1 、R 2 、R 4 、R 5 、R 6 N is as defined above, R 3 Selected from hydroxy, cyano, amino, C 1-3 Deuterated alkyl, -O-C 1-3 Deuterated alkyl, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclyl, -O-C 1-6 Alkyl, -O-C 3-6 Cycloalkyl, -O- (3-8 membered heterocyclyl), 5-10 membered heteroaryl, -C (O) R 3a 、-C(O)N(R 3a ) 2 、-C(O)OR 3a 、-S(O) 2 R 3a 、-S(O) 2 N(R 3a ) 2 、-NHC(O)R 3a or-N (C) 1-4 Alkyl) C (O) R 3a The C is 1-6 Alkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclyl, -O-C 1-6 Alkyl, -O-C 3-6 Cycloalkyl, -O- (3-8 membered heterocyclyl) or 5-10 membered heteroaryl optionally substituted with R 3b Substitution; the R is 3a Independently selected from H or C 1-6 An alkyl group; the R is 3b Selected from halogen, hydroxy, cyano, amino or 3-8 membered heterocyclyl.
In some embodiments, R 3 Selected from hydroxy, cyano, amino, C 1-3 Deuterated alkyl, -O-C 1-3 Deuterated alkyl, C 1-6 Alkyl, -O-C 1-6 Alkyl, -C (O) R 3a 、-C(O)OR 3a 、-S(O) 2 -C 1-4 Alkyl or 5-10 membered heteroaryl, said C 1-6 Alkyl, -O-C 1-6 Alkyl or 5-10 membered heteroaryl optionally substituted with R 3b And (3) substitution.
In some embodiments, R 3 Selected from hydroxy, cyano, amino, C 1-3 Deuterated alkyl, -O-C 1-3 Deuterated alkyl, C 1-6 Alkyl, -O-C 1-6 Alkyl, -S (O) 2 -C 1-4 Alkyl or 5-10 membered heteroaryl, said C 1-6 Alkyl, -O-C 1-6 Alkyl or 5-10 membered heteroaryl optionally substituted with R 3b And (3) substitution.
In some embodiments, R 3 Selected from hydroxy, cyano, amino, C 1-3 Deuterated alkyl, -O-C 1-3 Deuterated alkyl, C 1-6 Alkyl, -O-C 1-6 Alkyl or-S (O) 2 -C 1-4 Alkyl, said C 1-6 Alkyl or-O-C 1-6 Alkyl is optionally R 3b And (3) substitution.
In some embodiments, R 3 Selected from C 1-3 Deuterated alkyl, -O-C 1-3 Deuterated alkyl, C 1-6 Alkyl, -O-C 1-6 Alkyl, -C (O) R 3a 、-C(O)OR 3a 、-S(O) 2 -C 1-4 Alkyl or 5-10 membered heteroaryl, said C 1-6 Alkyl, -O-C 1-6 Alkyl or 5-10 membered heteroaryl optionally substituted with R 3b And (3) substitution.
In some embodiments, R 3 Selected from C 1-3 Deuterated alkyl, -O-C 1-3 Deuterated alkyl, C 1-6 Alkyl, -O-C 1-6 Alkyl, -S (O) 2 -C 1-4 Alkyl or 5-10 membered heteroaryl, said C 1-6 Alkyl, -O-C 1-6 Alkyl or 5-10 membered heteroaryl optionally substituted with R 3b And (3) substitution.
In some embodiments, R 3 Selected from C 1-3 Deuterated alkyl, -O-C 1-3 Deuterated alkyl, C 1-6 Alkyl, -O-C 1-6 Alkyl or-S (O) 2 -C 1-4 Alkyl, said C 1-6 Alkyl or-O-C 1-6 Alkyl is optionally R 3b And (3) substitution.
In some embodiments, R 3 Selected from H, -C (O) R 3a 、-C(O)OR 3a 、C 1-6 Alkyl, -O-C 1-6 Alkyl or 5-10 membered heteroaryl, said C 1-6 Alkyl, -O-C 1-6 Alkyl or 5-to 10-membered heteroarylThe radicals optionally being R 3b And (3) substitution.
In some embodiments, R 3 Selected from-C (O) R 3a 、-C(O)OR 3a 、C 1-6 Alkyl, -O-C 1-6 Alkyl or 5-10 membered heteroaryl, said C 1-6 Alkyl, -O-C 1-6 Alkyl or 5-10 membered heteroaryl optionally substituted with R 3b And (3) substitution.
In some embodiments, R 3 Selected from H, C 1-6 Alkyl, -O-C 1-6 Alkyl or 5-10 membered heteroaryl, said C 1-6 Alkyl, -O-C 1-6 Alkyl or 5-10 membered heteroaryl optionally substituted with R 3b And (3) substitution.
In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from the group consisting of the compound of formula (III) or a pharmaceutically acceptable salt thereof,
Wherein the ring A, L, YR 3 、R 4 、R 5 、R 6 N is as defined above, R 1 Selected from cyano, C 1-6 Alkyl or C 3-6 Cycloalkyl; r is R 2 Selected from optionally by R 2b And/or R 2c The substituted following groups:
in some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from the group consisting of compounds of formula (IV) or a pharmaceutically acceptable salt thereof,
wherein the ring A, L, R 3 、R 4 、R 5 、R 6 N is as defined above, R 1 Selected from cyano, C 1-6 Alkyl or C 3-6 Cycloalkyl, R 2 Selected from optionally by R 2b And/or R 2c The substituted following groups:
in some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from the group consisting of the compound of formula (V) or a pharmaceutically acceptable salt thereof,
wherein the ring A, L, R 3 、R 4 、R 5 、R 6 N is as defined above, R 1 Selected from cyano, C 1-6 Alkyl or C 3-6 Cycloalkyl, R 2 Selected from optionally by R 2b And/or R 2c The substituted following groups:
in some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from the group consisting of the following compounds or pharmaceutically acceptable salts thereof,
further, the invention also provides a pharmaceutical composition, which comprises a compound shown in the formula (I) or pharmaceutically acceptable salt thereof and pharmaceutically acceptable auxiliary materials.
Further, the invention relates to application of a compound shown in the formula (I) or pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof in preparing medicines for preventing or treating SOS 1-related diseases.
Further, the invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the prevention or treatment of SOS 1-related diseases.
Further, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for preventing or treating SOS 1-related diseases.
The invention also relates to a method of preventing or treating SOS 1-related disorders, which comprises administering to a patient a therapeutically effective dose of a pharmaceutical formulation comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein. Further, the SOS 1-related disease is selected from cancer.
In another aspect, the present invention provides the use of a compound of formula (i) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for the prevention or treatment of cancer.
In another aspect, the present invention provides the use of a compound of formula (i), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the prevention or treatment of cancer.
In another aspect, the present invention provides a compound of formula (i), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the prevention or treatment of cancer.
In another aspect, the invention provides a method of preventing or treating cancer comprising therapeutically administering to a patient a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
Definition and description of terms
Unless otherwise indicated, the radical and term definitions recited in the specification and claims of the present invention, including as examples, exemplary definitions, preferred definitions, definitions recited in tables, definitions of specific compounds in the examples, and the like, may be arbitrarily combined and coupled with each other. Such combinations and combinations of radical definitions and structures of compounds should fall within the scope of the present description.
The term "pharmaceutically acceptable salt" refers to pharmaceutically acceptable salts of non-toxic acids or bases, including salts of inorganic acids and bases, organic acids and bases.
The compounds of the invention may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, enantiomers, diastereomers, geometric isomers and individual isomers are all included within the scope of the present invention.
The graphic representation of racemates or enantiomerically pure compounds herein is from Maehr, J.chem. Ed.1985, 62:114-120. Unless otherwise indicated, the absolute configuration of a stereocenter is indicated by the wedge-shaped key and the dashed key. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, they include the E, Z geometric isomers unless specified otherwise. Likewise, all tautomeric forms are included within the scope of the invention.
The compounds of the invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-) -and (+) -enantiomers, (R) -and (S) -enantiomers, diastereomers, (D) -isomers, (L) -isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of the present invention.
The term "stereoisomer" refers to an isomer produced by the spatial arrangement of atoms in a molecule, and includes cis-trans isomers, enantiomers, non-corresponding isomers and conformational isomers.
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 compounds of the present invention may exhibit tautomerism. Tautomeric compounds may exist in two or more interconvertible species. Proton-mobile tautomers result from the migration of a hydrogen atom covalently bonded between two atoms. Tautomers generally exist in equilibrium and attempts to isolate individual tautomers often result in a mixture whose physicochemical properties are consistent with the mixture of compounds. The location of the equilibrium depends on the chemical nature of the molecule. For example, among many aliphatic aldehydes and ketones, such as acetaldehyde, the ketone type predominates; whereas, among phenols, the enol form is dominant. The present invention encompasses all tautomeric forms of the compounds.
The term "pharmaceutical composition" means a mixture of one or more of the compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof with other chemical components, such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate the administration of the compound to the organism.
The term "substituted" means that any one or more hydrogen atoms on a particular atom is substituted with a substituent, provided that the valence of the particular atom is normal and the substituted compound is stable. When the substituent is oxo (i.e., =o), meaning that two hydrogen atoms are replaced, oxo does not occur on the aromatic group.
The term "optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. For example, ethyl "optionally" substituted with halogen means that ethyl may be unsubstituted (CH 2 CH 3 ) Monosubstituted (e.g. CH 2 CH 2 F) Polysubstituted (e.g. CHFCH 2 F、CH 2 CHF 2 Etc.) or fully substituted (CF) 2 CF 3 ). It will be appreciated by those skilled in the art that for any group comprising one or more substituents, no substitution or pattern of substitution is introduced that is sterically impossible and/or synthetic.
The term "C 1-6 Alkyl "is understood to mean a straight-chain or branched saturated monovalent hydrocarbon radical having 1,2, 3, 4, 5 or 6 carbon atoms. The alkyl is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-ethylpropyl, 1, 2-dimethylpropyl, neopentyl, 1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3-dimethylbutyl2, 2-dimethylbutyl, 1-dimethylbutyl, 2, 3-dimethylbutyl, 1, 2-dimethylbutyl, etc. The term "C 1-3 Alkyl "is understood to mean a straight or branched saturated monovalent hydrocarbon radical having 1,2, 3 carbon atoms.
The term "halogen" refers to fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine.
The term "C 3-10 Cycloalkyl "is understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3 to 10 carbon atoms. Examples of cycloalkyl radicals are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, or bicyclic hydrocarbon radicals such as the decalin ring. According to the invention, the bicyclic hydrocarbon ring includes a bridged, spiro or fused ring structure. The term "C 3- 8 Cycloalkyl "is understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3 to 8 atoms. The term "C 3-6 Cycloalkyl "is understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3 to 6 atoms.
The term "C 6-10 Aryl "is understood to mean a monovalent aromatic or partially aromatic, monocyclic, bicyclic or tricyclic hydrocarbon ring having 6, 7, 8, 9, 10 carbon atoms, in particular a ring having 6 carbon atoms (" C 6 Aryl "), such as phenyl; or a ring having 9 carbon atoms ("C) 9 Aryl "), e.g. indanyl or indenyl, or a ring having 10 carbon atoms (" C " 10 Aryl "), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl.
The term "3-10 membered heterocyclyl" is understood to mean a saturated or partially unsaturated monovalent mono-or bicyclic ring having 3 to 10 ring atoms. The bicyclic ring includes bridged, spiro, fused rings. The "hetero" in the heterocyclic group includes, but is not limited to, those independently selected from N, O, S, C (=o), C (=s), S (=o), S (O) 2 And/or groups of atoms. In particular, the heterocyclyl may be monocyclic, including but not limited to: 4-membered rings such as azetidinyl, oxetanyl; 5-membered rings, e.g. tetrahydrofuranyl, dioxolyl, pyri Pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or a 6-membered ring, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, 1-dioxothiomorpholinyl, piperazinyl, trithianyl,Or 7-membered rings, e.g. diazepanyl orOptionally, the heterocyclyl may be bicyclic, such as, but not limited to, a 5,5 membered ring, such as hexahydrocyclopenta [ c ]]Pyrrol-2 (1H) -yl ring, or 5,6 membered bicyclic ring, e.g. hexahydropyrrolo [1,2-a ]]Pyrazin-2 (1H) -yl ring. The ring may be partially unsaturated, i.e. it may contain one or more double bonds, such as but not limited to 2, 5-dihydro-1H-pyrrolyl, 4H- [1,3,4]Thiadiazinyl, 4, 5-dihydrooxazolyl or 4H- [1,4]Thiazinyl orAlternatively, it may be benzo-fused, such as, but not limited to, dihydroisoquinolinyl. The term "3-8 membered heterocyclyl" is understood to mean a saturated or partially unsaturated monovalent mono-or bicyclic ring having 3 to 8 ring atoms. The term "3-6 membered heterocyclyl" is understood to mean a saturated or partially unsaturated monovalent mono-or bicyclic ring having 3 to 6 ring atoms.
The term "benzo 5-7 membered heterocyclyl" is understood to include bicyclic rings formed by a saturated or partially unsaturated heterocyclic ring of 5-7 ring atoms, said bicyclic rings being fused rings, the "hetero" in said benzo 5-7 membered heterocyclyl including, but not limited to, those independently selected from N, O, S, C (=o), C (=s), S (=o), S (O) 2 And/or groups of atoms. In particular, benzo 5-7 membered heterocyclyl groups may include, but are not limited to: benzotetrahydrofuranyl, benzotetrahydropyrrolyl, benzotetrahydropyridinyl, and the like.
The term "5-to 10-membered heteroaryl" shall be taken to meanIs understood to include such monovalent monocyclic, bicyclic or tricyclic aromatic ring systems, in particular 5 or 6 or 9 or 10 ring atoms, and in addition may be benzo-fused in each case. The "hetero" in the heteroaryl group means that the aromatic ring is selected from N, O, S, C (=o), C (=s), S (=o), S (O) independently, but not limited thereto 2 And/or groups of atoms. In particular, heteroaryl is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl and the like, and their benzo derivatives, such as benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazole, indazolyl, indolyl, isoindolyl and the like; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and the like, and their benzo derivatives, such as quinolinyl, quinazolinyl, isoquinolinyl, and the like; or an axcinyl group, an indolizinyl group, a purinyl group, etc., and their benzo derivatives; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, and the like.
The term "benzo 5-7 membered heteroaryl" is understood to include bicyclic rings formed by an unsaturated heterocyclic ring of 5-7 ring atoms, said bicyclic rings being fused rings, the "hetero" in said benzo 5-7 membered heteroaryl representing an aromatic ring including but not limited to those independently selected from N, O, S, C (=o), C (=s), S (=o), S (O) 2 And/or groups of atoms. In particular, benzo 5-7 membered heteroaryl groups may include, but are not limited to: benzothienyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, quinolinyl, quinazolinyl, isoquinolinyl, and the like.
The term "treatment" means administration of a compound or formulation described herein to ameliorate or eliminate a disease or one or more symptoms associated with the disease, and includes:
(i) Inhibiting a disease or disease state, i.e., inhibiting its progression;
(ii) The disease or condition is alleviated, even if the disease or condition subsides.
The term "therapeutically effective amount" means an amount of a compound of the invention that (i) treats a particular disease, condition, or disorder, (ii) reduces, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein. The amount of the compound of the present invention that constitutes a "therapeutically effective amount" will vary depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by one of ordinary skill in the art based on his own knowledge and the present disclosure.
The term "adjuvant" refers to a pharmaceutically acceptable inert ingredient. Examples of the category of the term "excipient" include, without limitation, binders, disintegrants, lubricants, glidants, stabilizers, fillers, diluents, and the like. Excipients can enhance the handling characteristics of the pharmaceutical formulation, i.e., by increasing flowability and/or tackiness, making the formulation more suitable for direct compression. Typical examples of "pharmaceutically acceptable carriers" suitable for use in the above formulations are: saccharides, starches, cellulose and derivatives thereof, and the like.
The term "pharmaceutically acceptable excipients" refers to those excipients which do not significantly stimulate the organism and which do not impair the biological activity and properties of the active compound. Suitable excipients are well known to the person skilled in the art, such as carbohydrates, waxes, water soluble and/or water swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water and the like. The words "comprise", "comprising" or "includes" and variations thereof such as include or comprise are to be interpreted in an open, non-exclusive sense, i.e. "including but not limited to".
The pharmaceutical compositions of the present application may be prepared by combining the compounds of the present application with suitable pharmaceutically acceptable excipients, for example, in solid, semi-solid, liquid or gaseous formulations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres, aerosols, and the like.
Typical routes of administration of the compounds of the present application or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration.
The pharmaceutical compositions of the present application may be manufactured by methods well known in the art, such as conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, freeze-drying, and the like. In some embodiments, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical compositions may be formulated by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present application to be formulated into tablets, pills, troches, dragees, capsules, gels, slurries, suspensions and the like for oral administration to a patient.
The solid oral compositions may be prepared by conventional mixing, filling or tabletting methods. For example, it can be obtained by the following method: the active compound is mixed with solid auxiliary materials, the resulting mixture is optionally milled, if desired with other suitable auxiliary materials, and the mixture is then processed to granules, giving a tablet or dragee core. Suitable excipients include, but are not limited to: binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, and the like.
The pharmaceutical compositions may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in suitable unit dosage forms.
In all methods of administration of the compounds described herein, the daily dose is from 0.01mg/kg body weight to 200mg/kg body weight.
The compounds of the present invention may be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments set forth below, embodiments formed by combining with other chemical synthetic methods, and equivalent alternatives well known to those skilled in the art, preferred embodiments including but not limited to the examples of the present invention.
The chemical reactions of the embodiments of the present invention are accomplished in a suitable solvent that is compatible with the chemical changes of the present invention and the reagents and materials required therefor. In order to obtain the compounds of the present invention, it is sometimes necessary for a person skilled in the art to modify or select the synthesis steps or reaction schemes on the basis of the embodiments already present.
Detailed Description
The following examples illustrate the technical aspects of the invention in detail, but the scope of the invention is not limited thereto.
The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) and/or Mass Spectrometry (MS). The unit of NMR shift is 10 - 6 (ppm). The solvent for NMR measurement is deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard is Tetramethylsilane (TMS); IC (integrated circuit) 50 "means half inhibition concentration" means concentration at which half of the maximum inhibition effect is achieved.
Abbreviations:
Et 3 n and TEA: triethylamine; ACN: acetonitrile; DIPEA and DIEA: n, N-diisopropylethylamine; dioxane:1, 4-dioxane; DMF: n, N-dimethylformamide; acOH: acetic acid; ac (Ac) 2 O: acetic anhydride; cs (cells) 2 CO 3 : cesium carbonate; THF: tetrahydrofuran; DMSO: dimethyl sulfoxide; DCM: dichloromethane; DMAP 4-dimethylaminopyridine; TFA: trifluoroacetic acid; pd (dppf) Cl 2 :1,1' -bis (diphenylphosphino) ferrocene palladium dichloride; pd (Pd) 2 (dba) 3 : tris (benzalacetone) dipalladium; X-Phos: 2-dicyclohexylphosphorus-2 ',4',6' -triisopropylbiphenyl; POCl (Point of care testing) 3 : phosphorus oxychloride; t-Bu-xphos: 2-di-tert-butyl phosphino-2 ',4',6' -triisopropylbiphenyl; brettePhos Pd G3: methanesulfonic acid (2-dicyclohexylphosphine-3, 6-dimethoxy-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) (2 '-amino-1, 1' -biphenyl-2-yl) palladium; brettPhos:2- (dicyclohexylphosphine) 3, 6-dimethoxy-2 ',4',6 '-triisopropyl-1, 1' -biphenyl; t-BuONa: sodium tert-butoxide; : p-toluenesulfonic acid monohydrate; seO (SeO) 2 : selenium dioxide; (CF) 3 CO) 2 O: trifluoro methanesulfonic anhydride; xantphos:4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene; HATU:2- (7-azobenzotriazole) -N, N' -tetramethylurea hexafluorophosphate; meNH 3 Cl: methylamine hydrochloride; BINAP:1,1 '-binaphthyl-2, 2' -bisdiphenylphosphine; DCE:1, 2-dichloroethane; tf (Tf) 2 O: trifluoro methanesulfonic anhydride; NBS, N-bromosuccinimide; pyAOP: (3H-1, 2, 3-triazolo [4, 5-b)]Pyridin-3-yloxy) tris-1-pyrrolidinyl hexafluorophosphate; DBU:1, 8-diazabicyclo [5.4.0]Undec-7-ene; ru-phos: 2-dicyclohexylphosphorus-2 ',6' -diisopropyloxy-1, 1' -biphenyl; DAST: diethylaminosulfur trifluoride; NMP: n-methylpyrrolidone; HCF (HCF) 2 OTf: difluoromethyl triflate; NH (NH) 2 PMB: 4-methoxybenzylamine; tributyl (1-ethoxyvinyl) stannane: tributyl (1-ethoxyethylene) tin; pd (PPh) 3 ) 2 Cl 2 : bis-triphenylphosphine palladium dichloride; me (Me) 3 S (O) I: trimethyl sulfoxide iodide; t-BuOH: t-butanol; t-BuOK: potassium tert-butoxide; PMBCl: p-methoxybenzyl chloride; phNTF (PhNTF) 2 : phenyl bis (trifluoromethanesulfonyl) imide; DPPP:1, 3-bis (diphenylphosphino) propane.
Example 1: (R) -N- (1- (3- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -7-methoxy-6-morpholinoquinolin-4-amine
Step 1: synthesis of (R) -6-bromo-7-methoxy-N- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) quinolin-4-amine
6-bromo-4-chloro-7-methoxyquinoline (150 mg,0.55 mmol), (R) -1- (3-nitro-5- (trifluoromethyl) phenyl) ethan-1-amine (155 mg,0.66 mmol), N, N-diisopropylethylamine (129 mg,1.00 mmol) was added to 3mL of dimethyl sulfoxide, and the reaction was stirred under argon at 130℃for 8 hours. The reaction solution was added to 30mL of saturated aqueous sodium chloride solution, extracted with ethyl acetate, the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the organic layer was concentrated, and the obtained residue was separated by column chromatography (petroleum ether/ethyl acetate gradient elution) to give the title compound.
Step 2: synthesis of (R) -7-methoxy-6-morpholino-N- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) quinolin-4-amine
(R) -6-bromo-7-methoxy-N- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) quinolin-4-amine (100 mg,0.21 mmol), morpholine (18.5 mg,0.21 mmol), tris dibenzylideneacetone dipalladium (12.2 mg,0.01 mmol), 2-dicyclohexylphosphorus-2, 4, 6-triisopropylbiphenyl (20.3 mg,0.04 mmol) and cesium carbonate (138 mg,0.45 mmol) were added to 2mL dioxane and stirred at 100℃under argon, after 3 hours the reaction was complete. 40mL of water was added, extraction was performed with ethyl acetate, the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the organic layer was concentrated, and the resulting residue was separated by column chromatography (gradient elution of petroleum ether/ethyl acetate) to give the title compound.
Step 3: synthesis of (R) -N- (1- (3- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -7-methoxy-6-morpholinoquinolin-4-amine
Iron powder (25.8 mg,0.46 mmol) and ammonium chloride (1.23 mg,0.02 mmol) were dissolved in 2mL of water and heated to 100deg.C for half an hour under reflux; a solution of (R) -7-methoxy-6-morpholino-N- (1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) quinolin-4-amine (55.0 mg,0.11 mmol) in ethanol (2 mL) was added to the reaction system and stirred at 100℃for 4 hours, after which the reaction was completed. 20mL of water was added, extraction was performed with ethyl acetate, the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the organic layer was concentrated, and the resulting residue was separated by column chromatography (gradient elution of petroleum ether/ethyl acetate) to give the title compound.
1 H NMR(400MHz,CDCl 3 )δ8.27(d,J＝5.4Hz,1H),7.35(s,1H),7.06(s,1H),7.00(s,1H),6.81(d,J＝6.81Hz,2H),6.11(d,J＝5.4Hz,1H),5.01-4.97(m,1H),4.68-4.60(m,1H),3.99-3.96(m,7H),3.85(s,2H),3.25-3.18(m,4H),1.69(d,J＝6.7Hz,3H).
LC/MS(m/z,MH + ):447.2.
Example 2: (R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -7-methoxy-6-morpholinoquinolin-4-amine
Step 1: synthesis of (R) -6-bromo-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -7-methoxyquinolin-4-amine
6-bromo-4-chloro-7-methoxyquinoline (200 mg,0.73 mmol), (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethan-1-amine (166 mg,0.88 mmol), N, N-diisopropylethylamine (189 mg,1.47 mmol) was dissolved in 3mL of dimethyl sulfoxide, and the mixture was stirred under argon at 135℃for 14 hours to complete the reaction. The reaction solution was added to 40mL of saturated aqueous sodium chloride solution, extracted with ethyl acetate, the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the organic layer was concentrated, and the obtained residue was separated by column chromatography (gradient elution of petroleum ether/ethyl acetate) to give the title compound.
Step 2: synthesis of (R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -7-methoxy-6-morpholinoquinolin-4-amine
(R) -6-bromo-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -7-methoxyquinolin-4-amine (90.0 mg,0.21 mmol), morpholine (27.7 mg,0.31 mmol), tris (dibenzylideneacetone) dipalladium (19.4 mg,0.02 mmol), 2-dicyclohexylcarbonyl-2 ',4',6' -trisubstituted biphenyl (20.2 mg,0.04 mmol), cesium carbonate (138 mg,0.42 mmol) were dissolved in 2mL dioxane and reacted at 100℃under argon for 3 hours. The reaction solution was added to 30mL of water, extracted with ethyl acetate, the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the organic layer was concentrated, and the obtained residue was separated by column chromatography (gradient elution of petroleum ether/ethyl acetate) to give the title compound.
1 H NMR(400MHz,DMSO-d 6 )δ8.10(d,J＝5.3Hz,1H),7.65(s,1H),7.58(t,J＝7.5Hz,1H),7.51(t,J＝7.1Hz,1H),7.40-7.13(m,4H),6.01(d,J＝5.4Hz,1H),5.07-5.03(m,1H),3.89(s,3H),3.81(t,J＝4.6Hz,4H),3.17-3.07(m,4H),1.66(d,J＝6.8Hz,3H).
LC/MS(m/z,MH + ):432.2.
Example 3: (R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -7-methoxy-6- (1- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) quinolin-4-amine
(R) -6-bromo-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -7-methoxyquinolin-4-amine (60.0 mg,0.14 mmol), 1- (tetrahydro-2H-pyran-4-yl) -4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (58.9 mg,0.21 mmol), 1' -bis (diphenylphosphino) ferrocene palladium dichloride (10.3 mg,0.01 mmol), potassium carbonate (39.0 mg,0.28 mmol) were dissolved in 2mL dioxane/water mixed solution (V: V=10/1), and stirred under argon at 90℃for 2 hours. 20mL of water was added for dilution, ethyl acetate extraction, the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the residue was separated by column chromatography (dichloromethane/methanol gradient elution) after concentration of the organic layer to give the title compound.
1 H NMR(400MHz,DMSO-d 6 )δ8.56(s,1H),8.27(s,1H),8.18-8.16(m,2H),7.62-7.58(m,1H),7.54-7.50(m,1H),7.40-7.13(m,4H),6.04(d,J＝5.5Hz,1H),5.10-5.07(m,1H),4.52-4.48(m,1H),4.02-3.94(m,5H),3.56-3.44(m,2H),2.06-2.01(m,4H),1.68(d,J＝6.8Hz,3H).
LC/MS(m/z,MH + ):497.2.
Example 4: (R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -7-methoxy-6- (1- (oxetan-3-yl) -1H-pyrazol-4-yl) quinolin-4-amine
The procedure used was as described in reference to example 3 except that 1- (tetrahydro-2H-pyran-4-yl) -4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole was replaced with 1- (oxetan-3-yl) -4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole.
1 H NMR(400MHz,DMSO-d 6 )δ8.60(s,1H),8.36(s,1H),8.31(s,1H),8.17(d,J＝5.3Hz,1H),7.62-7.58(m,1H),7.54-7.50(m,1H),7.40-7.13(m,4H),6.04(d,J＝5.5Hz,1H),5.72-5.68(m,1H),5.11-5.07(m,1H),4.98-4.95(m,4H),3.97(s,3H),1.68(d,J＝6.7Hz,3H).
LC/MS(m/z,MH + ):469.2.
Example 5: (R) -1- (4- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -7-methoxyquinolin-6-yl) -1H-pyrazol-1-yl) -2-methylpropan-2-ol
The procedure used was as described in reference to example 3 except that 1- (tetrahydro-2H-pyran-4-yl) -4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole was replaced with 2-methyl-1- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) propan-2-ol.
1 H NMR(400MHz,DMSO-d 6 )δ8.59(s,1H),8.23(s,1H),8.17-8.16(m,2H),7.62-7.58(m,1H),7.54-7.50(m,1H),7.40-7.13(m,4H),6.03(d,J＝5.4Hz,1H),5.10-5.07(m,1H),4.78(s,1H),4.09(s,2H),3.97(s,3H),1.68(d,J＝6.7Hz,3H),1.12(s,6H).
LC/MS(m/z,MH + ):485.2.
Example 6: (R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -7-methoxy-6- (2-oxa-6-aza-spiro [3.3] hept-6-yl) quinolin-4-amine
The title compound was prepared in the same manner as in example 2 except that the morpholine in step 2 was replaced with 2-oxa-6-aza-spiro [3,3] heptane.
1 H NMR(400MHz,DMSO-d 6 )δ8.00(d,J＝5.2Hz,1H),7.58-7.49(m,2H),7.39-7.00(m,5H),5.98(d,J＝5.3Hz,1H),5.06-5.02(m,1H),4.76(s,4H),4.18-4.12(m,4H),3.85(s,3H),1.67(d,J＝6.7Hz,3H).
LC/MS(m/z,MH + ):444.2.
Example 7: (R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -7-methoxy-6- (1-methyl-1H-pyrazol-4-yl) quinolin-4-amine
The title compound was prepared in accordance with the procedure described in example 3 except that 1- (tetrahydro-2H-pyran-4-yl) -4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole was replaced with 1-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole.
1 H NMR(400MHz,DMSO-d 6 )δ8.57(s,1H),8.22(s,1H),8.18-8.14(m,2H),7.60(t,J＝7.5Hz,1H),7.51(t,J＝7.1Hz,1H),7.40-7.13(m,4H),6.03(d,J＝5.4Hz,1H),5.16-5.00(m,1H),3.97(s,3H),3.95(s,3H),1.68(d,J＝6.8Hz,3H).
LC/MS(m/z,MH + ):426.17.
Example 8: (R) -4- (4- (((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -7-methoxyquinolin-6-yl) thiomorpholin-1, 1-dioxide
The title compound was prepared in accordance with the procedure described in example 2, except that the morpholine in step 2 was replaced with thiomorpholine-1, 1-dioxide.
1 H NMR(400MHz,DMSO-d 6 )δ8.12(d,J＝5.2Hz,1H),7.82(s,1H),7.57(t,J＝7.4Hz,1H),7.51(t,J＝6.9Hz,1H),7.40-7.13(m,4H),6.01(d,J＝5.4Hz,1H),5.09-5.02(m,1H),3,91(s,3H),3.62-3.52(m,4H),3.33-3.28(m,4H),1.65(t,J＝6.7Hz,3H).
LC/MS(m/z,MH + ):480.2.
Example 9: (R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methyl-6- (1- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) pyrido [2,3-d ] pyrimidin-4-amine
Step 1: synthesis of 6-bromo-4-chloro-2-methylpyrido [2,3-d ] pyrimidine
6-bromo-2-methyl-3H-pyrido [2,3-d ] pyrimidin-4-one (500 mg,2.08 mmol) was added to the reaction flask, phosphorus oxychloride (5 mL) and N, N-diisopropylethylamine (404 mg,3.12 mmol) were added, and the reaction mixture was heated and stirred at 100℃for 1 hour, followed by completion of the reaction. The reaction solution was concentrated under reduced pressure to remove most of phosphorus oxychloride, then a small amount of methylene chloride was added, the mixture was poured into ice until the ice was completely melted, the pH of the system was adjusted to 7-8 with saturated sodium bicarbonate, then extracted with ethyl acetate (60 ml×3), the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate sufficiently, then filtered, and the filtrate was concentrated under reduced pressure to give the title compound.
Step 2: synthesis of (R) -6-bromo-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methylpyrido [2,3-d ] pyrimidin-4-amine
6-bromo-4-chloro-2-methylpyrido [2,3-d ] pyrimidine (450 mg,1.74 mmol), (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethan-1-amine (362 mg,1.91 mmol) was added to a reaction flask, dimethyl sulfoxide (7 mL) and N, N-diisopropylethylamine (675mg, 5.22 mmol) were added, and the reaction mixture was heated to 90℃for 8 hours to complete the reaction. The reaction solution was cooled and poured into water, followed by extraction with ethyl acetate (50 ml×3), and the organic layers were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the obtained residue was separated and purified by column chromatography (gradient elution of petroleum ether/ethyl acetate) to give the title compound.
Step 3: synthesis of (R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methyl-6- (1- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) pyrido [2,3-d ] pyrimidin-4-amine
(R) -6-bromo-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methylpyrido [2,3-d ] pyrimidin-4-amine (50 mg, 122. Mu. Mol), 1- (tetrahydropyran-4-yl) -1H-pyrazole-4-boronic acid pinacol ester (40.6 mg,0.15 mmol), [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (8.90 mg,0.01 mmol) and potassium carbonate (33.6 mg,0.24 mmol) were added to the reaction flask, and a mixed solvent of dioxane and water (v: v=10:1, 1.6 mL) was added, and the reaction was heated to 100℃under argon for 5 hours. The reaction solution was cooled, concentrated under reduced pressure, and separated by column chromatography (dichloromethane/methanol gradient elution) to obtain the title compound.
DMSO-d6 δ H 9.24-9.23(m,1H),8.97-8.95(m,1H),8.61(d,J＝7.1Hz,1H),8.44(s,1H),8.08(s,1H),7.71(t,J＝7.2Hz,1H),7.52(t,J＝6.8Hz,1H),7.38-7.11(m,2H),5.84-5.77(m,1H),4.52-4.44(m,1H),4.01-3.98(m,2H),3.53-3.47(m,2H),2.38(s,3H),2.07-1.94(m,4H),1.64(d,J＝7.0Hz,3H).
LC/MS(m/z,MH + ):483.2.
Example 10: (R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methyl-6- (1- (oxetan-3-yl) -1H-pyrazol-4-yl) pyrido [2,3-d ] pyrimidin-4-amine
The procedure of example 9 was followed to convert 1- (tetrahydropyran-4-yl) -1H-pyrazole-4-boronic acid pinacol ester to 1- (oxetan-3-yl) -4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole to give the title compound.
DMSO-d6 δ H 9.26-9.25(m,1H),9.01-9.00(m,1H),8.62(d,J＝7.1Hz,1H),8.55(s,1H),8.21(s,1H),7.70(t,J＝7.3Hz,1H),7.52(t,J＝6.9Hz,1H),7.38-7.11(m,2H),5.84-5.77(m,1H),5.71-5.60(m,1H),5.01-4.93(m,4H),2.39(s,3H),1.65(d,J＝7.0Hz,3H).
LC/MS(m/z,MH + ):455.1.
Example 11: (R) -1- (4- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylpyrido [2,3-d ] pyrimidin-6-yl) -1H-pyrazol-1-yl) -2-methylpropan-2-ol
Referring to the preparation of example 9, 1- (tetrahydropyran-4-yl) -1H-pyrazole-4-boronic acid pinacol ester was converted to 2-methyl-1- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) propan-2-ol to give the title compound.
DMSO-d6 δ H 9.25-9.24(m,1H),8.99-8.98(m,1H),8.64(d,J＝7.2Hz,1H),8.29(s,1H),8.08(s,1H),7.70(t,J＝7.4Hz,1H),7.52(t,J＝6.9Hz,1H),7.38-7.11(m,2H),5.84-5.77(m,1H),4.84(s,1H),4.09(s,2H),2.38(s,3H),1.64(d,J＝7.0Hz,3H),1.12(s,6H).
LC/MS(m/z,MH + ):471.1.
Example 12: (R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methyl-6-morpholinylpyrido [2,3-d ] pyrimidin-4-amine
(R) -6-bromo-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methylpyrido [2,3-d ] pyrimidin-4-amine (150 mg,0.37 mmol), morpholine (127 mg,1.46 mmol), cesium carbonate (238 mg, 730. Mu. Mol), 2-dicyclohexylphosphorus-2, 4, 6-triisopropylbiphenyl (34.8 mg, 72.9. Mu. Mol) and tris (dibenzylideneacetone) dipalladium (33.4 mg,0.04 mmol) were added to the reaction flask, and anhydrous 1, 4-dioxane (6 mL) was added and heated to 100deg.C under argon for 8 hours. The reaction solution was cooled and filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (dichloromethane/methanol gradient elution) to give the title compound.
DMSO-d6 δ H 8.88(d,J＝2.9Hz,1H)，8.46(d,J＝7.2Hz,1H),8.05(d,J＝3.0Hz,1H),7.66(t,J＝7.2Hz,1H),7.50(t,J＝6.9Hz,1H),7.38-7.11(m,2H),5.83-5.76(m,1H),3.83-3.81(m,4H),3.31-3.29(m,4H),2.33(s,3H),1.61(d,J＝7.1Hz,3H).
LC/MS(m/z,MH + ):418.1.
Example 13: n- ((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -6- (((2S, 6R) -2, 6-dimethylmorpholinyl) -2-methylpyrido [2,3-d ] pyrimidin-4-amine)
Referring to the preparation of example 12, morpholine was replaced with cis-2, 6-dimethylmorpholine to give the title compound.
DMSO-d6 δ H 8.89(d,J＝2.8Hz,1H),8.44(d,J＝7.2Hz,1H),7.99(d,J＝2.8Hz,1H),7.67(t,J＝7.3Hz,1H),7.50(t,J＝6.9Hz,1H),7.38-7.11(m,2H),5.83-5.76(m,1H),3.79-3.75(m,4H),2.45-2.39(m,2H),2.33(s,3H),1.62(d,J＝7.1Hz,3H),1.21(d,J＝6.1Hz,6H).
LC/MS(m/z,MH + ):446.1.
Example 14: (R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methyl-6- (2-oxa-6-aza-spiro [3.3] hept-6-yl) pyrido [2,3-d ] pyrimidin-4-amine
Referring to the procedure for the preparation of example 12, morpholine was replaced with 2-oxa-6-aza-spiro [3.3] heptane to give the title compound.
DMSO-d6 δ H 8.39-8.35(m,2H),7.69-7.64(m,2H),7.50(t,J＝6.4Hz,1H),7.38-7.10(m,2H),5.81-5.74(m,1H),4.77(s,4H),4.20-4.16(m,4H),2.32(s,3H),1.61(d,J＝7.1Hz,3H).
LC/MS(m/z,MH + ):430.1.
Example 15: (R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methyl-6- (1-methyl-1H-pyrazol-4-yl) pyrido [2,3-d ] pyrimidin-4-amine
The title compound was prepared by substituting 1- (tetrahydropyran-4-yl) -1H-pyrazole-4-boronic acid pinacol ester with 1-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole according to the preparation method of example 9.
DMSO-d6 δ H 9.21(d,J＝2.1Hz,1H),8.97(d,J＝2.1Hz,1H),8.60(d,J＝7.1Hz,1H),8.31(s,1H),8.05(s,1H),7.71(t,J＝7.3Hz,1H),7.52(t,J＝6.9Hz,1H),7.39-7.11(m,2H),5.84-5.77(m,1H),3.93(s,3H),2.39(s,3H),1.65(d,J＝7.0Hz,3H).
LC/MS(m/z,MH + ):413.2.
Example 16: n- ((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -7-methoxy-2-methyl-6- (((S) -tetrahydrofurane-3-yl) oxy) pteridin-4-amine
Step 1: 3-amino-6-chloro-5-methoxypyrazine-2-carboxylic acid methyl ester
Methyl 3-amino-5, 6-dichloropyrazine-2-carboxylate (8.90 g,40.2 mmol), sodium methoxide (2.20 g,40.2 mmol) was added to 90mL of methanol, the reaction was completed at 80℃for 14 hours, cooled, suction filtered, and the filter cake was dried to give the title compound.
Step 2: 3-amino-6-chloro-5-methoxypyrazine-2-carboxylic acid
Methyl 3-amino-6-chloro-5-methoxypyrazine-2-carboxylate (5.50 g,25.2 mmol) was added to 50mL of methanol, and a 15mL aqueous solution of sodium hydroxide (4.00 g,0.10 mmol) was added thereto, and the mixture was heated and stirred at 90℃for 30min to complete the reaction. The reaction solution is concentrated, water is added, the pH is regulated to 3-5, and solid is separated out. Suction filtering, and drying the filter cake to obtain the title compound.
Step 3: 6-chloro-7-methoxy-2-methyl-4H-pyrazino [2,3-d ] [1,3] oxazin-4-one
3-amino-6-chloro-5-methoxypyrazine-2-carboxylic acid (4.50 g,22.1 mmol) was added to 30mL acetic anhydride, heated to 100deg.C, stirred, after 2 hours, and concentrated to give the title compound.
Step 4: 6-chloro-7-methoxy-2-methylprednisoidin-4 (3H) -one
6-chloro-7-methoxy-2-methyl-4H-pyrazino [2,3-d ] [1,3] oxazin-4-one (2.00 g,8.80 mmol) was added to 10mL of methanolic ammonia solution, and the reaction was carried out at 40℃for 5 hours, and the reaction solution was concentrated to obtain the title compound.
Step 5: (S) -7-methoxy-2-methyl-6- ((tetrahydrofuran-3-yl) oxy) pteridin-4 (3H) -one
(S) -tetrahydrofuran-3-ol (290 mg,3.30 mmol) was added to 5mL of tetrahydrofuran, naH (132 mg,3.30 mmol) was added, the mixture was reacted at 20℃for 10 minutes, 6-chloro-7-methoxy-2-methylpterin-4 (3H) -one (500 mg,2.20 mmol) was added, the mixture was stirred at 90℃for 2 hours, and after completion of the reaction, the mixture was concentrated to give the title compound.
Step 6: (S) -7-methoxy-2-methyl-6- ((tetrahydrofuran-3-yl) oxy) pteridin-4-yl-2, 4, 6-triisopropylbenzenesulfonate
((S) -7-methoxy-2-methyl-6- ((tetrahydrofuran-3-yl) oxy) pteridin-4 (3H) -one (600 mg,2.10 mmol), 2,4, 6-triisopropylsulfonyl chloride (760 mg,2.50 mmol), N, N-diisopropylethylamine (541 mg,4.20 mmol), 4-dimethylaminopyridine (25.0 mg,0.20 mmol) were added to 10mL DCM (dichloromethane) and after stirring at 20℃for 1 hour the reaction was completed, the reaction was used directly in the next step.
Step 7: 7-methoxy-2-methyl-N- ((R) -1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) -6- (((S) -tetrahydrofurane-3-yl) oxy) pteridin-4-amine
(S) -7-methoxy-2-methyl-6- ((tetrahydrofuran-3-yl) oxy) pteridin-4-yl-2, 4, 6-triisopropylbenzenesulfonate (544 mg,2.10 mmol), triethylamine (424 mg,4.20 mmol), (R) -1- (3-nitro-5- (trifluoromethyl) phenyl) ethan-1-amine (491 mg,2.10 mmol) were placed in 10mL dimethyl sulfoxide and stirred at 80℃for 20 min. 50mL of water was added, extraction was performed with ethyl acetate, the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated, and the resulting residue was separated by column chromatography (gradient elution of petroleum ether/ethyl acetate) to prepare the title compound.
Step 8: n- ((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -7-methoxy-2-methyl-6- (((S) -tetrahydrofurane-3-yl) oxy) pteridin-4-amine
7-methoxy-2-methyl-N- ((R) -1- (3-nitro-5- (trifluoromethyl) phenyl) ethyl) -6- (((S) -tetrahydrofuranyl-3-yl) oxy) pteridin-4-amine (100 mg,0.20 mmol), iron powder (61.0 mg,1.10 mmol), ammonium chloride (5.40 mg,0.10 mmol) were dissolved in 5mL of ethanol, 2mL of water was added and the reaction was completed after stirring at 90℃for 1 hour. The residue obtained after concentrating the filtrate by filtration while hot was separated by column chromatography (dichloromethane/methanol gradient elution) to give the title compound.
DMSO-d6 δ H 7.86-7.80(m,1H),6.91(s,1H),6.84(s,1H),6.70(s,1H),5.98-5.92(m,1H),5.65-5.40(m,2H),4.12-4.02(m,4H),3.93-3.74(m,4H),2.40-2.31(m,4H),2.11-2.06(m,1H),1.57(d,J＝7.0Hz,3H).
LC/MS(m/z,MH + ):465.2.
Example 17 (R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -7-methoxy-6- (1- (methylsulfonyl) -1H-pyrazol-4-yl) quinolin-4-amine
The procedure used was as described in reference to example 3 except that 1- (tetrahydro-2H-pyran-4-yl) -4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole was replaced with 1- (methylsulfonyl) -4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole.
1 H NMR(400MHz,DMSO-d 6 )δ8.72(s,2H),8.66(s,1H),8.22(d,J＝5.4Hz,1H),7.61(t,J＝7.3Hz,1H),7.53(t,J＝6.9Hz,1H),7.45-7.13(m,4H),6.08(d,J＝5.5Hz,1H),5.16-5.06(m,1H),4.01(s,3H),3.64(s,3H),1.70(d,J＝6.8Hz,3H).
LC/MS(m/z,MH + ):491.2.
Example 18 (R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -7-methoxy-6- (1- (methylsulfonyl) -3, 6-dihydropyridin-1 (2H) -4-yl) quinolin-4-amine
Step 1 Synthesis of tert-butyl (R) -4- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -7-methoxyquinolin-6-yl) -3, 6-dihydropyridine-1 (2H) -carboxylate
(R) -6-bromo-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -7-methoxyquinolin-4-amine (424 mg,1.00 mmol), 4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 6-dihydropyridin-1 (2H) -carboxylic acid tert-butyl ester (463 mg,1.50 mmol), [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (73.1 mg,0.10 mmol), potassium carbonate (276 mg,2.00 mmol) were added to 10mL of 1, 4-dioxane, 1mL of water was added, and the reaction was stirred for 4 hours under argon atmosphere after heating to 100 ℃. The reaction mixture was concentrated, and the residue was separated by column chromatography (gradient elution of petroleum ether/ethyl acetate) to give the title compound.
Step 2 Synthesis of (R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -7-methoxy-6- (1, 2,3, 6-tetrahydropyridin-4-yl) quinolin-4-amine
(R) -4- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -7-methoxyquinolin-6-yl) -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (260 mg,0.50 mmol) was added to 5mL of dichloromethane, 5mL of trifluoroacetic acid, and the reaction was stirred at room temperature for 1 hour. The reaction solution was concentrated, 20mL of ethyl acetate was added, the pH was adjusted to 7-9 with saturated aqueous sodium bicarbonate, the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound.
Step 3 Synthesis of (R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -7-methoxy-6- (1- (methylsulfonyl) -3, 6-dihydropyridin-1 (2H) -4-yl) quinolin-4-amine
(R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -7-methoxy-6- (1, 2,3, 6-tetrahydropyridin-4-yl) quinolin-4-amine (120 mg,0.28 mmol), N, N-diisopropylethylamine (108 mg,0.84 mmol) was added to 10mL of anhydrous dichloromethane, methanesulfonic anhydride (58.7 mg,0.34 mmol) was added, and the mixture was stirred at room temperature for 2 hours, after which the reaction was completed. 30mL of water was added, the extracts were extracted with dichloromethane, the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the organic layer was concentrated, and the resulting residue was separated by column chromatography (dichloromethane/methanol gradient elution) to give the title compound.
1 H NMR(400MHz,DMSO-d 6 )δ H 13.72(s,1H),9.13(d,J＝7.0Hz,1H),8.52(s,1H),8.43(d,J＝7.0Hz,1H),7.68(t,J＝7.3Hz,1H),7.60(t,J＝7.0Hz,1H),7.38-6.97(m,4H),6.59(d,J＝7.2Hz,1H),6.07-5.96(m,1H),5.47-5.37(m,1H),3.95(s,3H),3.92-3.88(m,2H),2.98(s,3H),2.65-2.59(m,2H),1.72(d,J＝6.7Hz,3H).
LC/MS(m/z,MH + ):506.1.
Example 19 (R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -7-methoxy-6- (1- (methylsulfonyl) piperidin-4-yl) quinolin-4-amine
(R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -7-methoxy-6- (1- (methylsulfonyl) -3, 6-dihydropyridin-1 (2H) -4-yl) quinolin-4-amine (60.0 mg,0.12 mmol) and palladium on carbon (10 mg) were added to 5mL of methanol, 0.5mL of acetic acid was added, and after stirring at room temperature for 8 hours under hydrogen, the reaction was completed. Suction filtration, concentration of the filtrate, and separation by column chromatography (dichloromethane/methanol gradient elution) gave the title compound.
1 H NMR(400MHz,DMSO-d 6 )δ H 8.22(s,1H),8.16(d,J＝5.3Hz,1H),7.57(t,J＝7.1Hz,1H),7.51(t,J＝7.0Hz,1H),7.39-7.38(m,1H),7.30-7.12(m,3H),6.02(d,J＝5.5Hz,1H),5.08-5.04(m,1H),3.90(s,3H),3.76-3.73(m,2H),3.19-3.13(m,1H),2.91-2.84(m,5H),2.06-1.88(m,4H),1.66(d,J＝6.7Hz,3H).
LC/MS(m/z,MH + ):508.1.
Example 20 (R) -cyclopropyl (4- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -7-methoxyquinolin-6-yl) piperidin-1-yl) methanone
Referring to the preparation of example 18, except that methanesulfonic anhydride was replaced with cyclopropylcarboxychloride, (R) -cyclopropyl (4- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -7-methoxyquinolin-6-yl) -1,2,3, 6-tetrahydropyridin-1-yl) methanone was prepared in the same manner as in example 19.
1 H NMR(400MHz,DMSO-d 6 )δ8.30-8.22(m,2H),7.85(s,1H),7.59(t,J＝7.1Hz,1H),7.54(t,J＝6.9Hz,1H),7.39-7.12(m,3H),6.15(d,J＝5.6Hz,1H),5.16-5.10(m,1H),4.70-4.0(m,1H),4.50-4.45(m,1H),3.93(s,3H),3.30-3.10(m,2H),2.75-2.55(m,2H),2.12-1.74(m,4H),1.68(d,J＝6.7Hz,3H),0.85-0.65(m,4H).
LC/MS(m/z,MH + ):498.2.
Example 21 (R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -7-methoxy-6- (1- (trifluoroacetyl) piperidin-4-yl) quinolin-4-amine
Referring to the preparation of example 18, except that methanesulfonic anhydride was replaced with trifluoroacetic anhydride, (R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -7-methoxy-6- (1- (trifluoroacetyl) -1,2,3, 6-tetrahydropyridin-4-yl) quinolin-4-amine was prepared in the same manner as in example 19.
1 H NMR(400MHz,DMSO-d 6 )δ.8.22-8.11(m,2H),7.59-7.50(m,2H),7.41-7.12(m,4H),6.03(d,J＝5.0Hz,1H),5.13-4.99(m,1H),4.54(d,J＝12.5Hz,1H),4.04(d,J＝12.4Hz,1H),3.91(s,3H),3.49-3.36(m,2H),3.10-3.07(m,1H),2.08-1.70(m,4H),1.66(d,J＝6.6Hz,3H).
LC/MS(m/z,MH + ):526.2.
Example 22 (R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -6- (4, 4-difluoropiperidin-1-yl) -7-methoxyquinolin-4-amine
The title compound was prepared in the same manner as in example 2 except that the morpholine in step 2 was replaced with 4, 4-difluoropiperidine.
1 H NMR(400MHz,DMSO-d 6 )δ8.11(d,J＝5.3Hz,1H),7.75(s,1H),7.58(t,J＝7.4Hz,1H),7.51(t,J＝7.1Hz,1H),7.43-7.09(m,4H),6.01(d,J＝5.5Hz,1H),5.11-5.01(m,1H),3.91(s,3H),3.28-3.15(m,4H),2.25-2.09(m,4H),1.65(d,J＝6.8Hz,3H).
LC/MS(m/z,MH + ):466.2.
Example 23 (R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -6- (3, 6-dihydro-2H-pyran-4-yl) -7-methoxyquinolin-4-amine
The title compound was prepared with reference to example 3 preparation except that 1- (tetrahydro-2H-pyran-4-yl) -4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole was replaced with 3, 6-dihydro-2H-pyran-4-boronic acid pinacol ester.
1 H NMR(400MHz,CDCl 3 )δ8.34(d,J＝5.4Hz,1H),7.55(s,1H),7.51(t,J＝7.3Hz,1H),7.45(t,J＝7.3Hz,1H),7.33(s,1H),7.19-6.81(m,3H),6.08(d,J＝5.4Hz,1H),5.96-5.93(m,1H),5.10-5.01(m,1H),4.41-4.35(m,2H),3.97(t,J＝5.4Hz,2H),3.94(s,3H),2.63-2.57(m,2H),1.74(d,J＝6.7Hz,3H).
LC/MS(m/z,MH + ):429.2.
Example 24 (R) -1- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -7-methoxyquinolin-6-yl) azetidine-3-carbonitrile
The title compound was prepared in the same manner as in example 2 except that the morpholine in step 2 was replaced with 3-acetonitrile cyclobutylamine hydrochloride.
1 H NMR(400MHz,DMSO-d 6 )δ8.04(d,J＝5.3Hz,1H),7.56(t,J＝7.3Hz,1H),7.51(t,J＝6.8Hz,1H),7.42-7.00(m,5H),6.00(d,J＝5.4Hz,1H),5.10-4.99(m,1H),4.32-4.24(m,2H),4.17-4.06(m,2H),3.86(s,3H),3.85–3.78(m,1H),1.65(d,J＝6.8Hz,3H).
LC/MS(m/z,MH + ):427.2.
Example 25 (R) -N- (1- (3- (1, 1-difluoroethyl) -2-fluorophenyl) ethyl) -7-methoxy-6-morpholino-quinolin-4-amine
The title compound was prepared by the method described in example 2, except that (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethane-1-amine in step 1 was replaced with (R) -1- (3- (1, 1-difluoroethyl) -2-fluorophenyl) ethane-1-amine.
1 H NMR(400MHz,DMSO-d 6 )δ8.10(d,J＝5.0Hz,1H),7.65(s,1H),7.54(t,J＝7.1Hz,1H),7.45(t,J＝7.2Hz,1H),7.23(t,J＝7.6Hz,2H),7.16(s,1H),6.01(d,J＝5.4Hz,1H),5.10-5.00(m,1H),3.89(s,3H),3.81(t,J＝4.3Hz,4H),3.20-3.04(m,4H),2.05(t,J＝19.2Hz,4H),1.66(d,J＝6.7Hz,3H).
LC/MS(m/z,MH + ):446.2.
EXAMPLE 26 (R) -N- (1- (3- (1- (1-, 1-difluoroethyl) -2-fluorophenyl) ethyl) -7-methoxy-6- (2-oxa-6-azaspiro [3.3] hept-6-yl) quinolin-4-amine
The title compound was prepared by the procedure described in example 2, except that (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethane-1-amine in step 1 was replaced with (R) -1- (3- (1, 1-difluoroethyl) -2-fluorophenyl) ethane-1-amine and the morpholine in step 2 was replaced with 2-oxa-6-aza-spiro [3,3] heptane.
1 H NMR(400MHz,DMSO-d 6 )δ8.01(d,J＝5.1Hz,1H),7.52(t,J＝7.3Hz,1H),7.44(t,J＝7.1Hz,1H),7.21(t,J＝7.7Hz,1H),7.10-7.00(m,3H),5.97(d,J＝5.3Hz,1H),5.08-4.99(m,1H),4.76(s,4H),4.15(q,J＝8.5Hz,4H),3.85(s,3H),2.05(t,J＝19.2Hz,3H),1.65(d,J＝6.7Hz,3H).
LC/MS(m/z,MH + ):458.2.
Example 27 (R) -4- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -7-methoxyquinolin-6-yl) -3, 6-dihydro-2H-thiopyran 1, 1-dioxide
The procedure was followed, as described in example 3, except that 1- (tetrahydro-2H-pyran-4-yl) -4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1H-pyrazole was replaced with 4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 6-dihydro-2H-thiopyran 1, 1-dioxide.
1 H NMR(400MHz,DMSO-d 6 )δ8.35(d,J＝5.4Hz,1H),7.59(s,1H),7.52(t,J＝7.0Hz,1H),7.45(t,J＝7.3Hz,1H),7.34(s,1H),7.18(t,J＝7.7Hz,1H),7.09-6.81(m,2H),6.10(d,J＝5.5Hz,1H),5.76-5.74(m,1H),5.12-5.01(m,1H),3.95(s,3H),3.90-3.84(m,2H),3.31-3.28(m,2H),3.22-3.15(m,2H),1.76(d,J＝6.7Hz,3H).
LC/MS(m/z,MH + ):477.2
Example 28N- ((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -7-methoxy-6- ((R-3-methylmorpholino) quinolin-4-amine
The title compound was prepared in the same manner as in example 2 except that the morpholine in step 2 was replaced with 3- (R) -3-methylmorpholine.
1 H NMR(400MHz,DMSO-d 6 )δ8.24(d,J＝6.2Hz,1H),7.95(s,1H),7.64(t,J＝7.2Hz,1H),7.56(t,J＝7.0Hz,1H),7.40-7.13(m,4H),6.27(d,J＝6.4Hz,1H),5.28-5.18(m,1H),3.92(s,3H),3.90-3.70(m,4H),3.49-3.30(m,2H),2.87-2.90(m,1H),1.70(d,J＝6.7Hz,3H),0.90(d,J＝6.3Hz,3H).
LC/MS(m/z,MH + ):446.2
Example 29 (R) -4- (4- (((1- (3- (1, 1-difluoroethyl) -2-fluorophenyl) ethyl) amino) -7-methoxyquinolin-6-yl) thiomorpholin 1, 1-dioxide
Referring to the preparation of example 2, the title compound was prepared by substituting (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethane-1-amine in step 1 with (R) -1- (3- (1, 1-difluoroethyl) -2-fluorophenyl) ethane-1-amine, and substituting the morpholine in step 2 with thiomorpholine-1, 1-dioxide.
1 H NMR(400MHz,DMSO-d 6 )δ8.13(d,J＝4.8Hz,1H),7.85(s,1H),7.52(t,J＝7.2Hz,1H),7.45(t,J＝7.1Hz,1H),7.24-7.18(m,4H),6.01(d,J＝5.3Hz,1H),5.09-5.00(m,1H),3.91(s,3H),3.68-3.49(m,4H),3.34-3.30(m,4H),2.10-2.00(m,3H),1.65(d,J＝6.7Hz,3H).
LC/MS(m/z,MH + ):494.2
Example 30 (R) -4- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -7-methoxy-2-methylquinolin-6-yl) thiomorpholin 1, 1-dioxide
The title compound was prepared in accordance with the procedure described in example 2 except that 6-bromo-4-chloro-7-methoxyquinoline in step 1 was replaced with 6-bromo-4-chloro-7-methoxy-2-methylquinoline and the morpholine in step 2 was replaced with thiomorpholine-1, 1-dioxide.
1 H NMR(400MHz,DMSO-d 6 )δ7.80(s,1H),7.59(t,J＝7.2Hz,1H),7.51(t,J＝6.9Hz,1H),7.40(s,1H),7.33-7.10(m,3H),5.96(s,1H),5.12-5.00(m,1H),3.89(s,3H),3.60-3.50(m,4H),3.30-3.25(m,4H),2.26(s,3H),1.64(d,J＝6.7Hz,3H).
LC/MS(m/z,MH + ):494.2
Example 31 (R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -7-methoxy-2-methyl-6- (2-oxa-6-aza-spiro [3.3] heptan-6-yl) quinolin-4-amine
The title compound was prepared in accordance with the procedure described in example 2, except that 6-bromo-4-chloro-7-methoxyquinoline in step 1 was replaced with 6-bromo-4-chloro-7-methoxy-2-methylquinoline and the morpholine in step 2 was replaced with 2-oxa-6-aza-spiro [3,3] heptane.
1 H NMR(400MHz,DMSO-d 6 )δ7.58(t,J＝7.2Hz,1H),7.50(t,J＝6.8Hz,1H),7.39-6.90(m,5H),5.92(s,1H),5.13-4.96(m,1H),4.75(s,4H),4.12(q,J＝8.5Hz,4H),3.83(s,3H),2.23(s,3H),1.64(d,J＝6.8Hz,3H).
LC/MS(m/z,MH + ):458.2
Example 32 (R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -7-methoxy-2-methyl-6-morpholinoquinolin-4-amine
The title compound was prepared by the same procedures as in example 2 except that 6-bromo-4-chloro-7-methoxyquinoline in step 1 was replaced with 6-bromo-4-chloro-7-methoxy-2-methylquinoline.
1 H NMR(400MHz,DMSO-d 6 )δ7.65-7.58(m,2H),7.51(t,J＝6.8Hz,1H),7.40-7.25(m,2H),7.18-7.01(m,1H),5.95(s,1H),5.10-5.00(m,1H),3.87(s,3H),3.80(t,J＝4.3Hz,4H),3.20-3.04(m,4H),2.26(s,3H),1.65(d,J＝6.7Hz,3H).
LC/MS(m/z,MH + ):446.2
Example 33 (R) -4- (4- (((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -7-methoxyquinolin-6-yl) tetrahydro-2H-thiopyran 1, 1-dioxide
(R) -4- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -7-methoxyquinolin-6-yl) -3, 6-dihydro-2H-thiopyran 1, 1-dioxide (100 mg) was added to 10mL of methanol, palladium on carbon (10 mg) was added, and after stirring at room temperature for 4 hours, the reaction was completed, suction filtration was performed, and the filtrate was concentrated and separated by column chromatography (dichloromethane/methanol gradient elution) to obtain the title compound.
1 H NMR(400MHz,CDCl 3 )δ8.34(d,J＝5.4Hz,1H),7.58(s,1H),7.52(t,J＝7.1Hz,1H),7.46(t,J＝7.2Hz,1H),7.37(s,1H),7.18(t,J＝7.7Hz,1H),7.09-6.81(m,1H),6.11(d,J＝5.5Hz,1H),5.29-5.26(m,1H),5.18-4.97(m,1H),3.97(s,3H),3.45-3.42(m,1H),3.31-3.17(m,4H),2.60-2.41(m,2H),2.33(d,J＝11.4Hz,2H),1.78(d,J＝6.7Hz,3H).
LC/MS(m/z,MH + ):479.2
Example 34 6- (3-oxa-8-azabicyclo [3.2.1] octyl-8-yl) -N- ((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -7-methoxyquinolin-4-amine
The title compound was prepared by the same manner as in example 2 except substituting morpholine in step 2 with 3-oxa-8-azabicyclo [3.2.1] octane hydrochloride.
1 H NMR(400MHz,CDCl 3 )δ8.24(d,J＝4.8Hz,1H),7.50(t,J＝6.6Hz,1H),7.45(t,J＝7.4Hz,1H),7.33(s,1H),7.17(t,J＝7.7Hz,1H),7.08-6.81(m,2H),7.17(t,J＝7.7Hz,1H),6.08(d,J＝5.3Hz,1H),5.05-5.00(m,1H),4.95-4.90(m,1H),4.19-4.17(m,2H),4.05(d,J＝10.6Hz,2H),3.98(s,2H),3.69(d,J＝9.9Hz,2H),2.19–2.02(m,4H),1.73(d,J＝6.7Hz,3H).
LC/MS(m/z,MH + ):458.2
Example 35 (R) -4- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -7-methoxyquinolin-6-yl) thiomorpholin 1-oxide
The title compound was obtained in the same manner as in example 2 except that the morpholine in step 2 was replaced with 1-thiomorpholine oxide.
1 H NMR(400MHz,CDCl 3 )δ8.27(d,J＝5.5Hz,1H),7.54-7.45(m,2H),7.41(s,1H),7.34(s,1H),7.18(t,J＝7.7Hz,1H),7.09-6.82(m,1H),6.12(d,J＝5.6Hz,1H),5.54-5.53(m,1H),5.11-5.06(m,1H),4.00(s,3H),3.87-3.77(m,2H),3.60-3.28(m,2H),3.09-3.07(m,4H),1.76(d,J＝6.7Hz,3H).
LC/MS(m/z,MH + ):464.2
Example 36N- ((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -7-methoxy-6- (((S-tetrahydrofuranyl-3-yl) oxy) quinolin-4-amine
Step 1: synthesis of (R) -4- (((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -7-methoxyquinolin-6-ol
(R) -6-bromo-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -7-methoxyquinolin-4-amine (100 mg), 2-di-t-butyl phosphino-2 ',4',6' -triisopropylbiphenyl (39.9 mg), tris (dibenzylideneacetone) dipalladium (21.5 mg), potassium hydroxide (19.8 mg) were dissolved in 1.5ml of dioxane and 0.5ml of water under argon, and the mixture was stirred at 100℃for 4 hours. After the reaction, ethyl acetate was added for dilution, water washing, saturated brine washing, and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the obtained residue was separated by column chromatography (gradient elution of petroleum ether/ethyl acetate) to give the title compound.
Step 2: synthesis of N- ((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -7-methoxy-6- (((S-tetrahydrofuranyl-3-yl) oxy) quinolin-4-amine
(R) -4- (((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -7-methoxyquinolin-6-ol (61.0 mg), (R) -tetrahydrofuran-3-yl 4-methylbenzenesulfonate (48.9 mg), cesium carbonate (54.8 mg) dissolved in 2ml of N, N-dimethylformamide under the protection of argon, and stirred at 100℃for 16 hours after completion of the reaction, diluted with ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated, and purified by preparative HPLC (Triart C18 ExRS, acetonitrile/water gradient elution) to give the title compound.
1 H NMR(400MHz,DMSO-d 6 )δ8.12(d,J＝5.3Hz,1H),7.74(s,1H),7.57(t,J＝7.5Hz,1H),7.51(t,J＝7.1Hz,1H),7.41-7.08(m,4H),6.04(d,J＝5.4Hz,1H),5.31-5.29(m,1H),5.11-5.01(m,1H),4.04-3.78(m,7H),2.37-2.08(m,1H),2.12–2.03(m,1H),1.66(d,J＝6.8Hz,3H).
LC/MS(m/z,MH + ):433.2
Example 37 (R) -6- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -7-methoxyquinolin-6-yl) -2-thia-6-azaspiro [3.3] heptane 2, 2-dioxide
The title compound was prepared in accordance with the procedure described in example 2, except that the morpholine in step 2 was replaced with 2-thia-6-azaspiro [3.3] heptane, 2-dioxide.
1 H NMR(400MHz,CDCl 3 )δ8.19(d,J＝5.3Hz,1H),7.51(t,J＝6.9Hz,1H),7.45(t,J＝7.4Hz,1H),7.32(s,1H),7.16(t,J＝7.7Hz,1H),7.00-6.80(m,1H),6.53(s,1H),6.11(d,J＝5.5Hz,1H),5.27-5.15(m,1H),5.12-5.01(m,1H),4.38(s,4H),4.34-4.25(m,4H),3.93(s,3H),1.75(d,J＝6.6Hz,3H).
LC/MS(m/z,MH + ):492.2
Example 38 (R) -1- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -7-methoxyquinolin-6-yl) -4-methylpiperidin-4-ol
Step 1: synthesis of (R) -1- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -7-methoxyquinolin-6-yl) piperidin-4-one
(R) -6-bromo-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -7-methoxyquinolin-4-amine (90.0 mg), piperidone (35.0 mg), tris (dibenzylideneacetone) dipalladium (19.4 mg), 2-dicyclohexylcarbonyl-2 ',4',6' -trisubstituted biphenyl (20.2 mg) were dissolved in 2mL of dioxane, and the reaction was completed at 100℃under argon atmosphere for 3 hours. The reaction solution was added to 30mL of water, extracted with ethyl acetate, the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the organic layer was concentrated, and the obtained residue was separated by column chromatography (gradient elution of petroleum ether/ethyl acetate) to give the title compound.
Step 2: synthesis of (R) -1- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -7-methoxyquinolin-6-yl) -4-methylpiperidin-4-ol
(R) -1- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -7-methoxyquinolin-6-yl) piperidin-4-one (44.0 mg) was added to 5mL of anhydrous tetrahydrofuran, cooled to-20℃and 1M/L solution of methylmagnesium bromide (0.1 mL) was added dropwise, the mixture was stirred at room temperature for 2 hours after completion of the addition, quenched by addition to ice water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated, and the resulting residue was purified by preparative HPLC (Triart C18 ExRS, acetonitrile/water gradient elution) to give the title compound.
1 H NMR(400MHz,DMSO-d 6 )δ8.51-8.49(m,1H),8.26(d,J＝6.6Hz,1H),7.88(s,1H),7.65(t,J＝7.5Hz,1H),7.57(t,J＝7.2Hz,1H),7.39-7.12(m,3H),6.39(d,J＝6.7Hz,1H),5.37–5.27(m,1H),4.34(s,1H),3.94(s,3H),3.23-3.04(m,4H),1.72(d,J＝6.7Hz,3H),1.70-1.60(m,4H),1.22(s,3H).
LC/MS(m/z,MH + ):460.2
Example 39 (R) -1- (3- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -7-methoxyquinolin-6-yl) -3-hydroxyazetidin-1-yl) ethan-1-one
Step 1: synthesis of 3- (4-chloro-7-methoxyquinolin-6-yl) -3-hydroxyazetidine-1-carboxylic acid tert-butyl ester
6-bromo-4-chloro-7-methoxyquinoline (200 mg) was dissolved in 5mL of tetrahydrofuran, followed by cooling to-78℃under the protection of inert gas, to which was added dropwise a hexane solution of n-butyllithium (1.6M, 0.64 mL), after completion of the reaction at that temperature for further 1 hour, 3-oxaazetidine-1-carboxylic acid tert-butyl ester (138 mg) was added thereto, and after the reaction was continued at that temperature for 30 minutes, it was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, the organic phase was dried with anhydrous ammonium sulfate, filtered, and concentrated, and the resulting residue was separated by column chromatography (gradient elution with petroleum ether/ethyl acetate) to give the title compound.
Step 2: synthesis of (R) -3- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -7-methoxyquinolin-6-yl) -3-hydroxyazetidine-1-carboxylic acid tert-butyl ester
3- (4-chloro-7-methoxyquinolin-6-yl) -3-hydroxyazetidine-1-carboxylic acid tert-butyl ester (156 mg) and (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethane-1-amine (89 mg) were dissolved in 1mL1, 4-dioxane, followed by BrettePhos Pd G3 (39 mg), 2- (dicyclohexylphosphine) -3, 6-dimethoxy-2 '-4' -6 '-tri-I-propyl-11' -biphenyl (46 mg) and sodium tert-butoxide (82 mg). After reaction for 8 hours at 100 ℃ under the protection of inert gas, the reaction solution is cooled to room temperature, diluted with ethyl acetate, filtered, and the filtrate is concentrated, and the obtained residue is separated by column chromatography (petroleum ether/ethyl acetate gradient elution) to obtain the title compound.
Step 3: synthesis of (R) -3- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -7-methoxyquinolin-6-yl) azetidin-3-ol
(R) -3- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -7-methoxyquinolin-6-yl) -3-hydroxyazetidine-1-carboxylic acid tert-butyl ester (100 mg) was dissolved in 4mL of methylene chloride, 1mL of trifluoroacetic acid was added dropwise thereto under an ice bath, the ice bath was removed after dropping for further 1 hour, and the reaction solution was concentrated to give a crude title compound, which was directly subjected to the next step.
Step 4: synthesis of (R) -1- (3- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -7-methoxyquinolin-6-yl) -3-hydroxyazetidin-1-yl) ethan-1-one
(R) -3- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -7-methoxyquinolin-6-yl) azetidin-3-ol (80 mg) was dissolved in 2mL of methanol, N-diisopropylethylamine (74 mg) was added dropwise thereto with acetic anhydride (22 mg), the ice bath was removed after the addition, and the reaction was continued for 1 hour. The reaction solution was diluted with ethyl acetate, and washed with saturated brine, and the organic phase was dried over anhydrous sodium sulfate, concentrated, and the resulting residue was separated by column chromatography (dichloromethane/methanol gradient elution) to give the title compound.
1 H NMR(400MHz,DMSO-d 6 )δ8.32(d,J＝6.6Hz,1H),8.20(d,J＝5.2Hz,1H),7.65-7.55(m,1H),7.53-7.48(m,2H),7.40-7.12(m,3H),6.09(d,J＝5.6Hz,1H),6.05(t,J＝5.1Hz,1H),5.10-5.04(m,1H),4.71-4.59(m,2H),4.29(d,J＝9.3Hz,1H),3.99(d,J＝10.4Hz,1H),3.89(s,3H),1.84- 1.82(m,3H),1.66(d,J＝6.7Hz,3H).
LC/MS(m/z,MH + ):460.2
Example 40: (R) -4- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -7-methoxyquinolin-6-yl) tetrahydro-2H-pyran-4-ol
Step 1: synthesis of 4- (4-chloro-7-methoxyquinolin-6-yl) tetrahydro-2H-pyran-4-ol
6-bromo-4-chloro-7-methoxyquinoline (200 mg) was dissolved in 4mL of THF, then cooled to-78℃under the protection of inert gas, a hexane solution of n-butyllithium (1.6M, 0.64 mL) was added thereto dropwise, after completion of the reaction at that temperature for further 1 hour, tetrahydropyran-4-one (80.82 mg) was added thereto, the reaction was continued for 30 minutes, then quenched with a saturated ammonium chloride solution, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, concentrated, and the resultant residue was separated by column chromatography (petroleum ether/ethyl acetate gradient elution) to give the title compound.
Step 2: synthesis of (R) -4- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -7-methoxyquinolin-6-yl) tetrahydro-2H-pyran-4-ol
4- (4-chloro-7-methoxyquinolin-6-yl) tetrahydro-2H-pyran-4-ol (70.00 mg,0.24 mmol) and (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethane-1-amine (49.59 mg) were dissolved in 1mL of 1, 4-dioxane, followed by addition of BrettePhos Pd G3 (21.60 mg), 2- (dicyclohexylphosphine) -3, 6-dimethoxy-2 '-4' -6 '-tri-I-propyl-11' -biphenyl (25.58 mg) and sodium t-butoxide (45.80 mg), the reaction mixture was warmed to 100℃under the protection of an inert gas, cooled to room temperature, diluted with ethyl acetate, filtered, and the filtrate was concentrated, and the resulting residue was separated and purified by column chromatography (dichloromethane/methanol gradient elution) to give the title compound.
1 H NMR(400MHz,DMSO-d 6 )δ8.48(s,1H),8.18(d,J＝5.3Hz,1H),7.63(t,J＝7.5Hz,1H),7.52(dd,J＝11.1,4.2Hz,1H),7.46–7.38(m,1H),7.29-7.13(m,3H),6.03(d,J＝5.4Hz,1H),5.08-5.04(m,2H),3.92-3.83(m,5H),3.76-3.72(m,2H),2.67–2.52(m,2H),1.65(d,J＝6.8Hz,3H),1.51(t,J＝10.8Hz,3H).
LC/MS(m/z,MH + ):447.2
Example 41: (R) -2-cyclopropyl-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -7-methoxy-6-morpholinoquinolin-4-amine
Step 1: synthesis of ethyl 3- ((4-bromo-3-methoxyphenyl) imino) -3-cyclopropylpropionate
4-bromo-3-methoxyaniline (10.0 g), p-toluenesulfonic acid monohydrate (85.2 mg), and ethyl cyclopropylcarbonylpropionate (8.5 g) were added to 200mL of cyclohexane, and the reaction was completed at 100℃for 6 hours. The reaction solution was concentrated, and the residue was separated by column chromatography (gradient elution of petroleum ether/ethyl acetate) to give the title compound.
Step 2: synthesis of 6-bromo-2-cyclopropyl-7-methoxyquinolin-4-ol
Ethyl 3- (((4-bromo-3-methoxyphenyl) imino) -3-cyclopropylpropionate (1.60 g) was dissolved in 8mL of diphenyl ether, reacted at 230 ℃ under argon for 20 minutes, the reaction solution was cooled to room temperature, petroleum ether was added, filtration was carried out, the filter cake was washed with petroleum ether, and the filter cake was collected and dried to obtain the title compound.
Step 3: synthesis of 6-bromo-4-chloro-2-cyclopropyl-7-methoxyquinoline
6-bromo-2-cyclopropyl-7-methoxyquinolin-4-ol (0.60 g) was added to 5mL of phosphorus oxychloride, and the reaction was completed at 90℃for 2 hours. The reaction solution was concentrated to dryness, quenched with ice water, and adjusted to pH 9 with saturated sodium bicarbonate solution, extracted with ethyl acetate, the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the resulting residue was separated by column chromatography (petroleum ether/ethyl acetate gradient elution) after the organic layer was concentrated to give the title compound.
Step 4: synthesis of (R) -6-bromo-2-cyclopropyl-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -7-methoxyquinolin-4-amine
6-bromo-4-chloro-2-cyclopropyl-7-methoxyquinoline (0.20 g), (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethan-1-amine (0.145 g), camphorsulfonic acid (59.4 mg) was added to 3mL of dimethyl sulfoxide, and the reaction was completed at 130℃under argon atmosphere for 16 hours. The reaction solution was added to 30mL of saturated aqueous sodium chloride solution, extracted with ethyl acetate, the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the organic layer was concentrated, and the obtained residue was separated by column chromatography (petroleum ether/ethyl acetate gradient elution) to give the title compound.
Step 5: synthesis of (R) -2-cyclopropyl-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -7-methoxy-6-morpholinoquinolin-4-amine
(R) -6-bromo-2-cyclopropyl-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -7-methoxyquinolin-4-amine (130 mg), morpholine (43.8 mg), tris (dibenzylideneacetone) dipalladium (25.6 mg), 2-dicyclohexylcarbonyl-2 ',4',6' -trisubstituted biphenyl (26.6 mg) were dissolved in 2mL of dioxane, and the reaction was completed at 100℃under argon atmosphere for 3 hours. The reaction solution was poured into water, extracted with ethyl acetate, the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the resultant residue was separated by column chromatography (dichloromethane/methanol gradient elution) after concentration of the organic layer to give the title compound.
1 H NMR(400MHz,DMSO-d 6 )δ7.61(t,J＝7.4Hz,1H),7.57(s,1H),7.52(t,J＝6.9Hz,1H),7.40-7.08(m,3H),7.00(s,1H),5.92(s,1H),5.13-5.02(m,1H),3.86(s,3H),3.79(t,J＝4.4Hz,4H),3.19-3.02(m,4H),1.82-1.76(m,1H),1.65(d,J＝6.7Hz,3H),0.85-0.71(m,4H).
LC/MS(m/z,MH + ):472.2
Example 42: (R) -4- (((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -7-methoxy-6-morpholinoquinoline-2-carbonitrile
Step 1: synthesis of 6-bromo-4-chloro-7-methoxyquinoline-2-carbaldehyde
6-bromo-4-chloro-7-methoxy-2-methylquinoline (0.80 g), selenium dioxide (0.62 g) was added to 8mL of dioxane solution, and the reaction was completed at 100℃for 3 hours. The reaction solution was poured into water, extracted with ethyl acetate, the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the resultant residue was separated by column chromatography (gradient elution of petroleum ether/ethyl acetate) after concentration of the organic layer to give the title compound.
Step 2: synthesis of 6-bromo-4-chloro-7-methoxyquinoline-2-formaldoxime
6-bromo-4-chloro-7-methoxyquinoline-2-carbaldehyde (0.25 g), hydroxylamine hydrochloride (0.12 g) and potassium carbonate (0.29 g) were added to a 3mL ethanol/water mixture (V: V=2/1), and the reaction was completed at 80℃for 2 hours. Concentrating to remove part of solvent, diluting with water, filtering, washing filter cake with water, collecting filter cake, and oven drying to obtain the final product.
Step 3: synthesis of 6-bromo-4-chloro-7-methoxyquinoline-2-carbonitrile
6-bromo-4-chloro-7-methoxyquinoline-2-carbaldehyde oxime (0.17 g), trifluoromethanesulfonic anhydride (0.30 g) was added to 3mL of methylene chloride, and triethylamine (0.27 g) was slowly added thereto, followed by reaction at 0℃for 2 hours. The reaction solution was poured into water, extracted with ethyl acetate, the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the resultant residue was separated by column chromatography (gradient elution of petroleum ether/ethyl acetate) after concentration of the organic layer to give the title compound.
Step 4: synthesis of (R) -6-bromo-4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -7-methoxyquinoline-2-carbonitrile
6-bromo-4-chloro-7-methoxyquinoline-2-carbonitrile (0.20 g), (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethane-1-amine (0.145 g), camphorsulfonic acid (59.4 mg) was added to 3mL of dimethyl sulfoxide, and the reaction was completed at 130℃under argon atmosphere for 16 hours. The reaction solution was added to 30mL of saturated aqueous sodium chloride solution, extracted with ethyl acetate, the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the organic layer was concentrated, and the obtained residue was separated by column chromatography (petroleum ether/ethyl acetate gradient elution) to give the title compound.
Step 5: (R) -4- (((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -7-methoxy-6-morpholinoquinoline-2-carbonitrile
(R) -6-bromo-4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -7-methoxyquinoline-2-carbonitrile (130 mg), morpholine (43.8 mg), tris (dibenzylideneacetone) dipalladium (25.6 mg), 2-dicyclohexylcarbonyl-2 ',4',6' -trisubstituted biphenyl (26.6 mg) were dissolved in 2mL of dioxane, and the reaction was completed at 100℃under argon atmosphere for 3 hours. The reaction solution was poured into water, extracted with ethyl acetate, the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the resultant residue was separated by column chromatography (dichloromethane/methanol gradient elution) after concentration of the organic layer to give the title compound.
1 H NMR(400MHz,DMSO-d 6 )δ7.68-7.67(m,2H),7.60(t,J＝7.3Hz,1H),7.55(t,J＝7.0Hz,1H),7.40-7.13(m,3H),6.52(s,1H),5.20-5.15(m,1H),3.92(s,3H),3.81(t,J＝4.4Hz,4H),3.21-3.14(m,4H),1.68(d,J＝6.7Hz,3H).
LC/MS(m/z,MH + ):457.2
Example 43 (R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -7-methoxy-2-methyl-6- (oxetan-3-yloxy) quinolin-4-amine
The title compound was prepared by the method described in example 36, except that (R) -4- (((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -7-methoxyquinolin-6-ol in step 2 was replaced with (R) -4- (((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -7-methoxyquinolin-2-methyl-6-ol and simultaneously (R) -tetrahydrofuran-3-yl 4-methylbenzenesulfonate was replaced with 3-iodooxetane.
1 H NMR(400MHz,DMSO-d 6 )δ8.04(s,1H),7.66(t,J＝7.5Hz,1H),7.62(s,1H),7.56(t,J＝7.1Hz,1H),7.39-7.12(m,3H),6.30(s,1H),5.57-5.52(m,1H),5.28-5.21(m,1H),5.06-5.01(m,2H),4.66-4.59(m,2H),3.93(s,3H),2.41(s,3H),1.71(d,J＝6.7Hz,3H).
LC/MS(m/z,MH + ):433.2
Example 44 (R) -3- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -7-methoxyquinolin-6-yl) oxetan-3-ol
Referring to the synthetic method of example 40, the title compound was prepared by the same procedure except that tetrahydropyran-4-one was replaced with 3-oxetanone in step 1.
1 H NMR(400MHz,DMSO-d 6 )δ8.26(s,1H),8.20(d,J＝5.4Hz,1H),7.59(t,J＝7.4Hz,1H),7.52(t,J＝7.1Hz,1H),7.45(d,J＝7.0Hz,1H),7.40-7.13(m,3H),6.06(d,J＝5.5Hz,1H),5.95(s,1H),5.18(d,J＝6.9Hz,1H),5.13(d,J＝7.0Hz,1H),5.09-5.06(m,1H),4.77(d,J＝6.9Hz,2H),3.86(s,3H),1.66(d,J＝6.8Hz,3H).
LC/MS(m/z,MH + ):419.2
Example 45 (R) -6-cyclopropyl-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -7-methoxy-2-methyl-quinolin-4-amine
Step 1: synthesis of (R) -6-bromo-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -7-methoxy-2-methylquinolin-4-amine
6-bromo-4-chloro-7-methoxy-2-methylquinoline (210 mg), (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethane-1-amine (166 mg), N, N-diisopropylethylamine (189 mg) was dissolved in 3mL of dimethyl sulfoxide, and the mixture was stirred at 130℃under argon atmosphere for 14 hours to complete the reaction. The reaction solution was added to 40mL of saturated aqueous sodium chloride solution, extracted with ethyl acetate, the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the organic layer was concentrated, and the obtained residue was separated by column chromatography (gradient elution of petroleum ether/ethyl acetate) to give the title compound.
Step 2: synthesis of (R) -6-cyclopropyl-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -7-methoxy-2-methylquinolin-4-amine
(R) -6-bromo-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -7-methoxy-2-methylquinolin-4-amine (60.0 mg), cyclopropylboronic acid (20.9 mg), 1' -bis (diphenylphosphino) ferrocene palladium dichloride (10.3 mg,0.01 mmol) and potassium carbonate (39.0 mg,0.28 mmol) were dissolved in 2mL of a dioxane/water mixture (V: V=10/1) and stirred at 90℃for 2 hours under argon atmosphere to complete the reaction. 20mL of water was added for dilution, ethyl acetate extraction, the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the resulting residue was separated by column chromatography (dichloromethane/methanol gradient elution) after concentration of the organic layer to give the title compound.
1 H NMR(400MHz,DMSO-d 6 )δ8.06(s,1H),7.92(s,1H),7.64(t,J＝7.6Hz,1H),7.56(t,J＝6.9Hz,1H),7.39-7.12(m,3H),6.25(s,1H),5.26-5.21(m,1H),3.94(s,3H),2.40(s,3H),2.23-2.16(m,1H),1.68(d,J＝6.8Hz,3H),1.05-0.84(m,4H).
LC/MS(m/z,MH + ):401.2
Example 46 (R) -1- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -7-methoxyquinolin-6-yl) -N, 3-dimethyla-zetidine-3-carboxamide
Step 1: synthesis of methyl (R) -1- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -7-methoxyquinolin-6-yl) -3-methylazetidine-3-carboxylate
(R) -6-bromo-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -7-methoxyquinolin-4-amine (425.24 mg), methyl 3-methylazetidine-3-carboxylate (180 mg) was dissolved in 1, 4-dioxane (3 mL), tris (dibenzylideneacetone) dipalladium (99.5 mg), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (125.7 mg), cesium carbonate (706.5 mg) was added, and the mixture was heated to 100℃under argon atmosphere and stirred, after 6 hours, the reaction was completed. The reaction solution is concentrated and then separated by column chromatography (petroleum ether/ethyl acetate gradient elution) to obtain the target compound.
Step 2: synthesis of (R) -1- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -7-methoxyquinolin-6-yl) -3-methylazetidine-3-carboxylic acid
(R) -1- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -7-methoxyquinolin-6-yl) -3-methylazetidine-3-carboxylic acid methyl ester (100 mg) was dissolved in methanol/tetrahydrofuran/water=4/1/1 (v: v,2 mL), lithium hydroxide (24 mg) was added, and after stirring at 60 ℃ for two hours, the reaction was completed. The pH was adjusted to 7-8 with saturated aqueous ammonium chloride, extracted with ethyl acetate and the organic phase concentrated to give the title compound.
Step 3: synthesis of (R) -1- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -7-methoxyquinolin-6-yl) -N, 3-dimethylazetidine-3-carboxamide
1- (4- ((((R)) -1- (3- (difluoromethyl) -2-fluoro-phenyl) ethyl) amino) -7-methoxy-6-quinolinyl) -3-methyl-azetidine-3-carboxylic acid (14.4 mg), methylamine hydrochloride (3.17 mg) was dissolved in N, N-dimethylformamide (1 mL), N, N-diisopropylethylamine (12.15 mg) was added, and 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (17.74 mg) was stirred at room temperature for two hours to complete the reaction. The organic layer was extracted with 20mL of water and ethyl acetate, the combined organic layers were concentrated and separated by column chromatography (dichloromethane/methanol gradient elution) to afford the title compound.
1 H NMR(400MHz,DMSO-d 6 )δ8.07(d,J＝5.6Hz,1H),785-7.83(m,1H),7.58(t,J＝7.3Hz,1H),7.52(t,J＝6.9Hz,1H),7.47(s,1H),7.39-7.09(m,4H),6.10(d,J＝5.7Hz,1H),5.17-5.06(m,1H),4.20(dd,J＝15.9,8.0Hz,2H),3.86(s,3H),3.79(dd,J＝18.4,7.9Hz,2H),2.63(d,J＝4.4Hz,3H),1.66(d,J＝6.7Hz,3H),1.56(s,3H).
LC/MS(m/z,MH + ):474.2
Example 47: (R) -7- (2, 2-difluoroethoxy) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methyl-6-morpholinylpyrido [2,3-d ] pyrimidin-4-amine
Step 1:6, 7-dichloro-2-methylpyrido [2,3-d ] pyrimidin-4 (3H) -one
Acetamidine hydrochloride (250 mg,2.65 mmol), 2,5, 6-trichloronicotinic acid (500 mg), cuprous iodide (42.0 mg), cesium carbonate (719 mg) were dissolved in 10ml of N, N-dimethylformamide under argon, stirred at 40℃for 16 hours, and at 80℃for 8 hours. After the reaction, ethyl acetate was added for dilution, water washing, saturated brine washing, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated, and the obtained residue was separated by column chromatography (gradient elution of petroleum ether/ethyl acetate) to give the title compound.
Step 2: 6-chloro-7- (2, 2-difluoroethoxy) -2-methylpyrido [2,3-d ] pyrimidin-4 (3H) -one
6, 7-dichloro-2-methylpyrido [2,3-d ] pyrimidin-4 (3H) -one (55.0 mg) was dissolved in 2ml of 2, 2-difluoroethanol, sodium hydride (47.8 mg) was added thereto, and the mixture was stirred at 70℃for 3 hours under argon atmosphere. After the reaction, ethyl acetate was added for dilution, water washing, saturated brine washing, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated, and the obtained residue was separated by column chromatography (gradient elution of petroleum ether/ethyl acetate) to give the title compound.
Step 3:4, 6-dichloro-7- (2, 2-difluoroethoxy) -2-methylpyrido [2,3-d ] pyrimidine
6-chloro-7- (2, 2-difluoroethoxy) -2-methylpyrido [2,3-d ] pyrimidin-4 (3H) -one (65.0 mg) was dissolved in 2ml of acetonitrile, and phosphine oxide (72.3 mg) and N, N-diisopropylethylamine (76.2 mg) were added thereto and stirred at 80℃under argon for 1 hour. After the reaction is finished, the reaction solution is dried by spinning to obtain crude products of the title compounds which are directly used for the next reaction.
Step 4: (R) -6-chloro-7- (2, 2-difluoroethoxy) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methylpyrido [2,3-d ] pyrimidin-4-amine
(R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethane-1-amine (80.5 mg), 4, 6-dichloro-7- (2, 2-difluoroethoxy) -2-methylpyrido [2,3-d ] pyrimidine (70.0 mg) was dissolved in 2ml of dimethyl sulfoxide, N-diisopropylethylamine (123 mg) was added thereto, and the mixture was stirred at 80℃for 1 hour under argon atmosphere. After the reaction, ethyl acetate was added for dilution, water washing, saturated brine washing, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated, and the obtained residue was separated by column chromatography (gradient elution of petroleum ether/ethyl acetate) to give the title compound.
Step 5: (R) -7- (2, 2-difluoroethoxy) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methyl-6-morpholinylpyrido [2,3-d ] pyrimidin-4-amine
(R) -6-chloro-7- (2, 2-difluoroethoxy) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methylpyrido [2,3-d ] pyrimidin-4-amine (34 mg), morpholine (13.2 mg), 2-dicyclohexylphosphorus-2, 4, 6-triisopropylbiphenyl (7.26 mg), tris (dibenzylidene-BASE acetone) dipalladium (6.97 mg), cesium carbonate (49.6 mg) were dissolved in 2ml dioxane under argon and stirred at 100℃for 16 hours. After the reaction, ethyl acetate was added to dilute, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated, and the resulting residue was separated by preparative HPLC (Triart C18 ExRS, acetonitrile/water gradient elution) to give the title compound.
1 H NMR(400MHz,DMSO-d 6 )δ8.37(d,J＝7.2Hz,1H),8.07(s,1H),7.67(t,J＝7.5Hz,1H),7.50(t,J＝7.1Hz,1H),7.38-7.10(m,2H),6.48(tt,J＝54.6,3.3Hz,1H),5.83-5.73(m,1H),4.71(td,J＝15.3,3.3Hz,2H),3.80(t,J＝4.6Hz,4H),3.13-3.12(m,4H),2.32(s,3H),1.60(d,J＝7.1Hz,3H).
LC/MS(m/z,MH + ):498.2
Example 48 (R) -1- (3- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -7-methoxy-2-methylquinolin-6-yl) -3-hydroxyazetidin-1-yl) ethan-1-one
Step 1: synthesis of 3- (4-chloro-7-methoxy-2-methylquinolin-6-yl) -3-hydroxyazetidine-1-carboxylic acid tert-butyl ester
6-bromo-4-chloro-7-methoxy-2-methylquinoline (200 mg) was dissolved in 5mL of tetrahydrofuran, followed by cooling to-78℃under the protection of inert gas, a hexane solution of n-butyllithium (0.64 mL) was added thereto dropwise, after completion of the reaction at that temperature for further 1 hour, tert-butyl 3-oxo-azetidine-1-carboxylate (138 mg) was added thereto, and after the reaction was continued at that temperature for 30 minutes, it was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, the organic phase was dried with anhydrous sodium sulfate, concentrated, and the resulting residue was separated by column chromatography (gradient elution of petroleum ether/ethyl acetate) to give the title compound.
Step 2: synthesis of tert-butyl (R) -3- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -7-methoxy-2-methylquinolin-6-yl) -3-hydroxyazetidine-1-carboxylate
3- (4-chloro-7-methoxy-2-methylquinolin-6-yl) -3-hydroxyazetidine-1-carboxylic acid tert-butyl ester (170 mg) and (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethane-1-amine (89 mg) were dissolved in 1mL1, 4-dioxane, followed by BrettePhos Pd G3 (39 mg), 2- (dicyclohexylphosphine) -3, 6-dimethoxy-2 '-4' -6 '-tri-I-propyl-11' -biphenyl (46 mg) and sodium tert-butoxide (82 mg). After reaction for 8 hours at 100 ℃ under the protection of inert gas, the reaction solution is cooled to room temperature, diluted with ethyl acetate, filtered, and the filtrate is concentrated, and the obtained residue is separated by column chromatography (petroleum ether/ethyl acetate gradient elution) to obtain the title compound.
Step 3: synthesis of (R) -3- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -7-methoxy-2-methylquinolin-6-yl) azetidinol
(R) -3- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -7-methoxy-2-methylquinolin-6-yl) -3-hydroxyazetidine-1-carboxylic acid tert-butyl ester (100 mg) was dissolved in 4mL of methylene chloride, 1mL of trifluoroacetic acid was added dropwise thereto under an ice bath, the ice bath was removed after the completion of the dropwise addition, and the reaction was concentrated to give a crude title compound, which was directly subjected to the next step.
Step 4: synthesis of (R) -1- (3- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -7-methoxy-2-methylquinolin-6-yl) -3-hydroxyazetidin-1-yl) ethan-1-one
(R) -3- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -7-methoxy-2-methylquinolin-6-yl) azetidinol (80 mg) was dissolved in 2mL of methanol, N-diisopropylethylamine (74 mg) was added dropwise thereto with acetic anhydride (22 mg), the ice bath was removed after the addition, and the reaction was continued for 1 hour. The reaction solution was diluted with ethyl acetate, and washed with saturated brine, and the organic phase was dried over anhydrous sodium sulfate, filtered, and the residue obtained after concentration was separated by column chromatography (dichloromethane/methanol gradient elution) to give the title compound.
1 H NMR(400MHz,DMSO-d 6 )δ8.24(d,J＝5.7Hz,1H),7.64-7.59(m,1H),7.52(t,J＝7.1Hz,1H),7.43-7.11(m,4H),6.05(s,1H),6.00(d,J＝5.9Hz,1H),5.11-5.06(m,1H),4.69-4.57(m,2H),4.28(d,J＝9.3Hz,1H),3.97(d,J＝10.3Hz,1H),3.87(s,3H),2.29(d,J＝1.8Hz,3H),1.82(d,J＝1.6Hz,3H),1.65(d,J＝6.7Hz,3H).
LC/MS(m/z,MH + ):474.2.
Example 49 (R) -1- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -7-methoxy-2-methylquinolin-6-yl) -N, 3-dimethyla-zetidine-3-carboxamide
The procedure used for the preparation of reference example 46 was repeated except for replacing (R) -6-bromo-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -7-methoxyquinolin-4-amine in step 1 with (R) -6-bromo-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -7-methoxy-2-methylquinolin-4-amine.
1 H NMR(400MHz,DMSO-d 6 )δ7.84-7.79(m,1H),7.59(t,J＝7.3Hz,1H),7.51(t,J＝6.8Hz,1H),7.40-7.12(m,2H),7.04(s,1H),7.00(s,1H),6.94(d,J＝7.0Hz,1H),5.92(s,1H),5.12-4.97(m,1H),4.18-4.12(m,2H),3.82(s,3H),3.77-3.71(m,2H),2.63(d,J＝4.5Hz,3H),2.24(s,3H),1.63(d,J＝6.7Hz,3H),1.55(s,3H).
LC/MS(m/z,MH + ):487.2.
Example 50 (R) -1- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -7-methoxy-2-methylquinolin-6-yl) -4-methylpiperidin-4-ol
(R) -6-bromo-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -7-methoxy-2-methylquinolin-4-amine (120 mg), 4-methyl-4-hydroxypiperidine (115 mg), tris (dibenzylideneacetone) dipalladium (4.50 mg), 1 '-binaphthyl-2, 2' -bisdiphenylphosphine (6.20 mg), and sodium t-butoxide (144 mg) were added to 5mL of 1, 4-dioxane, followed by stirring at 80℃for 3 hours under argon gas to complete the reaction. 20mL of water was added for dilution, extraction with ethyl acetate was performed, the organic layers were combined, dried over anhydrous sodium sulfate, and after concentration of the organic layers, the title compound was obtained by column chromatography (petroleum ether/ethyl acetate gradient elution).
1 H NMR(400MHz,DMSO-d 6 )δ7.65-7.57(m,2H),7.51(t,J＝6.9Hz,1H),7.41-7.08(m,3H),7.05(s,1H),5.93(s,1H),5.09-4.99(m,1H),4.27(s,1H),3.85(s,3H),3.14-3.05(m,4H),2.25(s,3H),1.70-1.63(m,7H),1.21(s,3H).
LC/MS(m/z,MH + ):474.2.
Example 51: (R) -1- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -7-methoxy-2-methylquinolin-6-yl) -3-methylazetidin-3-ol
(R) -6-bromo-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -7-methoxy-2-methylquinolin-4-amine (120 mg), tris (dibenzylideneacetone) dipalladium (4.50 mg), 3-methyl-3-acrinol (87.0 mg), 1 '-binaphthyl-2, 2' -bisdiphenylphosphine (6.20 mg), sodium t-butoxide (144 mg) was added to 5mL of 1, 4-dioxane, and the mixture was stirred at 80℃under argon for 3 hours to complete the reaction. 20mL of water was added for dilution, ethyl acetate extraction, the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the resulting residue was separated by column chromatography (dichloromethane/methanol gradient elution) after concentration of the organic layer to give the title compound.
1 H NMR(400MHz,DMSO-d 6 )δ7.62-7.56(m,1H),7.51(t,J＝7.1Hz,1H),7.40-7.12(m,2H),7.05(s,1H),7.00(s,1H),6.92(d,J＝7.2Hz,1H),5.93(s,1H),5.41(s,1H),5.09-5.01(m,1H),3.92- 3.87(m,2H),3.82(s,3H),3.80-3.74(m,2H),2.24(s,3H),1.64(d,J＝6.8Hz,3H),1.50(s,3H).
LC/MS(m/z,MH + ):446.2.
Example 52 (R) -1- (7- (2, 2-difluoroethoxy) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylpyrido [2,3-d ] pyrimidin-6-yl) -4-methylpiperidin-4-ol
The title compound was obtained by the method described in referential example 47, except that the morpholine in step 5 was replaced with 4-methylpiperidin-4-ol.
1 H NMR(400MHz,DMSO-d 6 )δ8.34(d,J＝7.3Hz,1H),8.09(s,1H),7.66(t,J＝7.3Hz,1H),7.50(t,J＝6.9Hz,1H),7.38-7.11(m,2H),6.47(tt,J＝54.6,3.4Hz,1H),5.81-5.74(m,1H),4.69(td,J＝15.2,3.1Hz,2H),4.34(s,1H),3.20-3.02(m,4H),2.31(s,3H),1.68-1.65(m,4H),1.59(d,J＝7.1Hz,3H),1.21(s,3H).
LC/MS(m/z,MH + ):526.2.
Example 53 (R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -6- (3, 6-dihydro-2H-pyran-4-yl) -2-methyl-7- (1-methyl-1H-pyrazol-3-yl) quinolin-4-amine
Step 1: synthesis of 6-bromo-4-chloro-2-methylquinolin-7-ol
6-bromo-4-chloro-7-methoxy-2-methylquinoline (5.00 g) was added to the reaction flask, an argon balloon was placed, the atmosphere was replaced three times, anhydrous 1, 2-dichloroethane (100 mL) was added under gas protection, then cooled to 0℃in an ice bath, and then a solution of boron tribromide in dichloromethane (2M, 26.2 mL) was added. The reaction solution was stirred under ice bath for 30 minutes, and then placed in 50 ℃ oil bath for reaction overnight. Cooling to room temperature, adding water to quench the reaction, adding saturated sodium bicarbonate solution to adjust the pH to 7-8, precipitating a large amount of solid, carrying out suction filtration, pulping a filter cake with a small amount of ethyl acetate, filtering, collecting the filter cake, drying, concentrating the filtrate, precipitating solid, filtering, drying the filter cake again, and combining two batches of filter cakes to obtain the title compound.
Step 2: synthesis of 6-bromo-4-chloro-2-methylquinolin-7-yl triflate
6-bromo-4-chloro-2-methylquinolin-7-ol (1.50 g) was added to a reaction flask, dichloromethane (20 mL) and tetrahydrofuran (20 mL) were added, followed by filling with an argon balloon, displacing the gas three times, cooling to-20℃under gas protection, adding anhydrous pyridine (522 mg), and slowly dropwise adding trifluoromethanesulfonic anhydride (3.11 g) with stirring. After the completion of the dropwise addition, the reaction was allowed to proceed to room temperature for 3 hours. The reaction solution was poured into ice water, extracted with ethyl acetate (50 ml×3), the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the obtained residue was separated and purified by column chromatography (gradient elution of petroleum ether/ethyl acetate) to give the title compound.
Step 3: synthesis of 6-bromo-4-chloro-2-methyl-7- (1-methyl-1H-pyrazol-3-yl) quinoline
6-bromo-4-chloro-2-methylquinolin-7-yl trifluoromethanesulfonate (200 mg), 1-methyl-1H-pyrazole-3-boronic acid pinacol ester (108 mg), cesium carbonate (322 mg), [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (36.2 mg) and anhydrous 1, 4-dioxane (3.2 mL) were added to a reaction flask, the flask was filled with an argon balloon, the gas was replaced three times, and the flask was put into an oil bath at 80℃under gas protection to react for 3 hours. The reaction solution was concentrated under reduced pressure and purified by column chromatography (gradient elution with petroleum ether/ethyl acetate) to give the title compound.
Step 4: synthesis of 4-chloro-6- (3, 6-dihydro-2H-pyran-4-yl) -2-methyl-7- (1-methyl-1H-pyrazol-3-yl) quinoline
6-bromo-4-chloro-2-methyl-7- (1-methyl-1H-pyrazol-3-yl) quinoline (150 mg), 3, 6-dihydro-2H-pyran-4-boronic acid pinacol ester (103 mg), [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (32.6 mg), potassium phosphate (189 mg) and 1, 4-dioxane (3.75 mL)/water (0.75 mL) were added to the reaction flask, an argon balloon was charged, the gas was replaced three times, and the mixture was put into an oil bath at 100℃under gas protection for reaction for 2 hours. The reaction solution was concentrated under reduced pressure and purified by column chromatography (gradient elution with petroleum ether/ethyl acetate) to give the title compound.
Step 5: synthesis of (R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -6- (3, 6-dihydro-2H-pyran-4-yl) -2-methyl-7- (1-methyl-1H-pyrazol-3-yl) quinolin-4-amine
4-chloro-6- (3, 6-dihydro-2H-pyran-4-yl) -2-methyl-7- (1-methyl-1H-pyrazol-3-yl) quinoline (52 mg), (1R) -1- [3- (difluoromethyl) -2-fluorophenyl ] ethylamine (31.84 mg), sodium t-butoxide (29.41 mg), brettphos Pd G3 (13.87 mg), brettphos (8.21 mg), 1, 4-dioxane (1.7 mL) was added to the reaction flask, the argon balloon was charged, the gas was replaced three times, and the reaction was allowed to proceed overnight under gas protection at 100 ℃. The reaction was filtered and the filtrate was concentrated under reduced pressure, and the resulting residue was purified by preparative HPLC (triort C18 ExRS, acetonitrile/water gradient elution) to give the title compound.
DMSO-d6 δ H 8.25(s,1H),7.93(s,1H),7.75(d,J＝2.2Hz,1H),7.68-7.57(m,2H),7.57-7.49(m,1H),7.34-7.27(m,1H),7.27(t,J＝67.5Hz,1H),6.54(d,J＝2.2Hz,1H),6.13(s,1H),5.85-5.80(m,1H),5.19-5.06(m,1H),4.30-4.22(m,2H),3.91(s,3H),3.79-3.70(m,2H),2.35(s,3H),2.15-2.07(m,2H),1.67(d,J＝6.7Hz,3H).
LC/MS(m/z,MH + ):493.2.
Example 54: (R) -3- (7- (2, 2-difluoroethoxy) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylquinolin-6-yl) oxetan-3-ol
Step 1: synthesis of 6-bromo-4-chloro-7- (2, 2-difluoroethoxy) -2-methylquinoline
6-bromo-4-chloro-2-methylquinolin-7-ol (700 mg) was dissolved in 5mL of DMF, 1-difluoro-2-iodoethane (493 mg) and potassium carbonate (708 mg) were then added, the reaction system was reacted at 50℃overnight, ethyl acetate was then added to dilute, the solution was separated after washing with saturated brine, and the organic phase was dried over anhydrous sodium sulfate, concentrated, and the obtained residue was separated by column chromatography (gradient elution of petroleum ether/ethyl acetate) to give the title compound.
Step 2: synthesis of 3- (4-chloro-7- (2, 2-difluoroethoxy) -2-methyl-6-quinolinyl) oxetan-3-ol
6-bromo-4-chloro-7- (2, 2-difluoroethoxy) -2-methylquinoline (200 mg) was dissolved in 10mL of ultra-dry tetrahydrofuran, then cooled to-10℃under the protection of argon, and then a tetrahydrofuran solution (1.3M, 1.83 mL) of a lithium chloride complex of isopropyl magnesium chloride was added dropwise thereto, after continuing the reaction at this temperature for 1 hour, 3-oxetanone (171 mg) was added thereto, after continuing the reaction at room temperature for half an hour, it was quenched with a saturated ammonium chloride solution, extracted with ethyl acetate, the combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and the resultant residue was separated and purified by column chromatography (gradient elution of petroleum ether/ethyl acetate) to give the title compound.
Step 3: synthesis of (R) -3- (7- (2, 2-difluoroethoxy) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylquinolin-6-yl) oxetan-3-ol
3- (4-chloro-7- (2, 2-difluoroethoxy) -2-methyl-6-quinolinyl) oxetan-3-ol (100 mg), (1R) -1- (3- (difluoromethyl) -2-fluoro-phenyl) ethanamine (63.1 mmg), brettPhos Pd G3 (27.4 mg), brettPhos (32.5 mg) and sodium t-butoxide (58.2 mg) were dissolved in 1mL of 1, 4-dioxane, and then reacted under argon at 100℃for 3 hours, the reaction solution was cooled to room temperature, diluted with ethyl acetate, filtered, and the filtrate was concentrated to obtain the residue which was separated by column chromatography (dichloromethane/methanol gradient elution) to give the title compound.
DMSO-d6 δ H 8.31(s,1H),7.79(s,1H),7.66-7.61(m,1H),7.54(t,J＝6.6Hz,1H),7.44-7.02(m,3H),6.57-6.28(m,1H),6.18(s,1H),6.02(s,1H),5.18-5.12(m,3H),4.74(d,J＝7.0Hz,2H),4.48-4.36(m,2H),2.36(s,3H),1.67(d,J＝6.8Hz,3H).
LC/MS(m/z,MH + ):483.2.
Example 55 (R) -1- (4- ((1- (3- (1, 1-difluoroethyl) -2-fluorophenyl) ethyl) amino) -7-methoxy-2-methylquinolin-6-yl) -4-methylpiperidin-4-ol
Step 1 (R) -6-bromo-N- (1- (3- (1, 1-difluoroethyl) -2-fluorophenyl) ethyl) -7-methoxy-2-methylquinolin-4-amine
6-bromo-4-chloro-7-methoxy-2-methylquinoline (200 mg) ((R) -1- (3- (1, 1-difluoroethyl) -2-fluorophenyl) ethane-1-amine (166 mg), N, N-diisopropylethylamine (189 mg) was dissolved in 3mL of dimethyl sulfoxide, and the reaction was stirred under argon for 14 hours at 135℃to complete the reaction.
Step 2 Synthesis of (R) -1- (4- ((1- (3- (1, 1-difluoroethyl) -2-fluorophenyl) ethyl) amino) -7-methoxy-2-methylquinolin-6-yl) -4-methylpiperidin-4-ol
(R) -6-bromo-N- (1- (3- (1, 1-difluoroethyl) -2-fluorophenyl) ethyl) -7-methoxy-2-methylquinolin-4-amine (120 mg), 4-methyl-4-hydroxypiperidine (115 mg), tris (dibenzylideneacetone) dipalladium (4.50 mg), 1 '-binaphthyl-2, 2' -bisdiphenylphosphine (6.20 mg), and sodium t-butoxide (144 mg) were added to 5mL of 1, 4-dioxane, followed by stirring at 80℃for 3 hours under argon atmosphere, and the reaction was completed. 20mL of water was added for dilution, ethyl acetate extraction, the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the resulting residue was separated by column chromatography (dichloromethane/methanol gradient elution) after concentration of the organic layer to give the title compound.
1 H NMR(400MHz,DMSO-d 6 )δ7.63(s,1H),7.57(t,J＝7.4Hz,1H),7.44(t,J＝7.4Hz,1H),7.24(t,J＝7.7Hz,1H),7.12(d,J＝7.1Hz,1H),7.05(s,1H),5.93(s,1H),5.08-5.01(m,1H),4.28(s,1H),3.85(s,3H),3.14-3.06(m,4H),2.25(s,3H),2.06(t,J＝19.1Hz,3H),1.71-1.63(m,7H),1.22(s,3H).
LC/MS(m/z,MH + ):488.2.
Example 56: ((R) -1- (4- (7- (2, 2-difluoroethoxy) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylpyrido [2,3-d ] pyrimidin-6-yl) piperidin-1-yl) ethan-1-one
Step 1: synthesis of 2-amino-5-bromo-6-chloropyridine-3-carboxylic acid
2-amino-6-chloropyridine-3-carboxylic acid (25.0 g) was dissolved in 150mL of N, N-dimethylformamide, N-bromosuccinimide (28.4 g) was added in portions, and the mixture was heated to 70℃and stirred for 2 hours, followed by completion of the reaction. The reaction solution was cooled to room temperature, poured into 500ml of an ice-water mixture, suction-filtered, and the cake was washed three times with water, and dried to obtain the title compound.
Step 2: synthesis of 6-bromo-7-chloro-2-methyl-pyrido [2,3-d ] [1,3] oxazin-4-one
2-amino-5-bromo-6-chloropyridine-3-carboxylic acid (36.0 g) was dissolved in 500mL of acetic anhydride, heated to 130℃and stirred for 36 hours, after the reaction was completed, the reaction solution was cooled to room temperature, concentrated and dried, and then directly put into the next step.
Step 3: synthesis of 6-bromo-7-chloro-2-methyl-3H-pyrido [2,3-d ] pyrimidin-4-one
Dissolving the crude product obtained in the step 2 in 1L of tetrahydrofuran, dropwise adding ammonia methanol (7.0 mol/L,415 mL) into the reaction liquid at the temperature of minus 30 ℃, and after the dropwise adding, heating the reaction system to room temperature for reacting for 12 hours, thus finishing the reaction. The reaction solution was poured into 1L of ice water, the pH was adjusted to 8-9 by adding 4N diluted hydrochloric acid, a pale yellow solid was precipitated, filtered, and the cake was dried after washing three times with water, followed by petroleum ether: ethyl acetate = 3:1 (V: V) pulping and purifying to obtain the title compound.
Step 4: 6-bromo-7- (2, 2-difluoroethoxy) -2-methylpyrido [2,3-d ] pyrimidin-4 (3H) -one
6-bromo-7-chloro-2-methyl-3H-pyrido [2,3-d ] pyrimidin-4-one (550 mg) was dissolved in 2ml of 2, 2-difluoroethanol, sodium hydride (90.0 mg) was added thereto, and the mixture was stirred at 70℃for 3 hours under argon atmosphere. After the reaction, ethyl acetate was added for dilution, water washing, saturated brine washing, and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the obtained residue was separated by column chromatography (gradient elution of petroleum ether/ethyl acetate) to give the title compound.
Step 5: synthesis of (R) -6-bromo-7- (2, 2-difluoroethoxy) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methylpyrido [2,3-d ] pyrimidin-4-amine
6-bromo-7- (2, 2-difluoroethoxy) -2-methylpyrido [2,3-d ] pyrimidin-4 (3H) -one (320 mg), (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethan-1-amine (190 mg), (3H-1, 2, 3-triazolo [4,5-b ] pyridin-3-yloxy) tris-1-pyrrolidinyl hexafluorophosphate (780 mg), 1, 8-diazabicyclo [5.4.0] undec-7-ene (300 mg) was added to 5mL of N, N-dimethylformamide, after stirring at room temperature for 1 hour, the reaction was completed, the reaction solution was added to 20mL of water, ethyl acetate was extracted, the organic layers were combined, and after concentration, the resultant residue was separated by column chromatography (petroleum ether/ethyl acetate gradient elution) to prepare the title compound.
Step 6: synthesis of (R) -1- (4- (7- (2, 2-difluoroethoxy) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylpyridin-6-yl) -3, 6-dihydropyridin-1 (2H) -yl) ethan-1-one
(R) -6-bromo-7- (2, 2-difluoroethoxy) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methylpyrido [2,3-d ] pyrimidin-4-amine (240 mg), 1- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 6-dihydropyridin-1 (2H) -yl) ethan-1-one (130 mg), [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (73.1 mg), and potassium carbonate (276 mg) were added to 10mL of 1, 4-dioxane, and the mixture was heated to 100℃under argon atmosphere and stirred for 4 hours. The reaction mixture was concentrated, and the residue was separated by column chromatography (gradient elution of petroleum ether/ethyl acetate) to give the title compound.
Step 7: synthesis of((R) -1- (4- (7- (2, 2-difluoroethoxy) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylpyridino [2,3-d ] pyrimidin-6-yl) piperidin-1-yl) ethan-1-one
(R) -1- (4- (7- (2, 2-difluoroethoxy) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylpyrido [2,3-d ] pyrimidin-6-yl) -3, 6-dihydropyridin-1 (2H) -yl) ethan-1-one (200 mg), palladium on carbon (10 mg) was added to 5mL of methanol, 0.5mL of acetic acid was added, and after stirring at room temperature for 8 hours after the introduction of hydrogen gas, the reaction was completed. The residue was separated by column chromatography (dichloromethane/methanol gradient elution) after suction filtration and concentration of the filtrate to give the title compound.
1 H NMR(400MHz,DMSO-d 6 )δ H 8.57(s,1H),8.47(d,J＝7.2Hz,1H),7.65(t,J＝7.4Hz,1H),7.50(t,J＝6.9Hz,1H),7.37-7.10(m,2H),6.45(tt,J＝54.6,3.4Hz,1H),5.80-5.73(m,1H),4.91-4.53(m,3H),4.00-3.97(m,1H),3.23-3.04(m,2H),2.66-2.60(m,1H),2.33(s,3H),2.05(s,3H).1.95-1.84(m,2H),1.68-1.54(m,5H).
LC/MS(m/z,MH + ):538.2.
Example 57: (R) -1- (7- (2, 2-difluoroethoxy) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylpyrido [2,3-d ] pyrimidin-6-yl) -N, 3-dimethylazetidine-3-carboxamide
Step 1: synthesis of methyl (R) -1- (7- (2, 2-difluoroethoxy) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylpyrido [2,3-d ] pyrimidin-6-yl) -3-methylazetidine-3-carboxylate
(R) -6-bromo-7- (2, 2-difluoroethoxy) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methylpyrido [2,3-d ] pyrimidin-4-amine (200 mg), methyl 3-methylazetidine-3-carboxylate (100 mg) was dissolved in 1, 4-dioxane (3 mL), tris (dibenzylideneacetone) dipalladium (37.3 mg), 2-dicyclohexylphosphine-2 ',4',6' -triisopropylbiphenyl (38.8 mg), cesium carbonate (530.5 mg) and argon were added and heated to 100℃under stirring, after 6 hours the reaction was completed. The reaction mixture was concentrated and separated by column chromatography (gradient elution of petroleum ether/ethyl acetate) to give the title compound.
Step 2: synthesis of (R) -1- (7- (2, 2-difluoroethoxy) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylpyrido [2,3-d ] pyrimidin-6-yl) -N, 3-dimethylazetidine-3-carboxamide
1- (7- (2, 2-difluoroethoxy) -4 ((((R) -1- (3- (difluoromethyl) -2-fluoro-phenyl) ethyl) amino) -2-methyl-pyrido [2,3-d ] pyrimidin-6-yl) -3-methyl-azetidine-3-carboxylic acid methyl ester (60 mg) was dissolved in DMSO/ACN=2/1 (2 mL), aqueous sodium hydroxide solution (88.97 mg, 444.86. Mu. Mol, content 20%) was added, and the reaction was monitored after stirring at room temperature for one hour.
1 H NMR(400MHz,DMSO-d 6 )δ H 8.16(d,J＝7.2Hz,1H),7.85(d,J＝4.5Hz,1H),7.64(t,J＝7.2Hz,1H),7.54(s,1H),7.49(t,J＝7.0Hz,1H),7.37-7.10(m,2H),6.61-6.29(m,1H),5.79-5.72(m,1H),4.66(td,J＝15.2,3.1Hz,2H),4.17(t,J＝7.8Hz,2H),3.76(t,J＝8.6Hz,2H),2.63(d,J＝4.4Hz,3H),2.29(s,3H),1.59(d,J＝7.0Hz,3H),1.56(s,3H).
LC/MS(m/z,MH + ):539.2.
Example 58: (R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methyl-6-morpholino-7- (trifluoromethyl) pyrido [2,3-d ] pyrimidin-4-amine
Step 1: synthesis of 2-amino-5-bromo-6- (trifluoromethyl) nicotinic acid
2-amino-6- (trifluoromethyl) nicotinic acid (500 mg) was dissolved in N, N-dimethylformamide (10 mL), stirred, and N-bromosuccinimide (604 mg) was added to the reaction system as a pale yellow clear solution, and reacted at a temperature of 70℃for half an hour. The reaction solution was slowly added dropwise to 40 ml of water, stirred and dispersed for half an hour, suction-filtered, and the filter cake was dried to obtain the title compound.
Step 2: synthesis of 6-bromo-2-methyl-7- (trifluoromethyl) -pyrido [2,3-d ] [1,3] oxazin-4-one
2-amino-5-bromo-6- (trifluoromethyl) nicotinic acid (640 mg) was placed in a reaction tube; acetic anhydride (10 mL) was added thereto, and the temperature was raised to 130℃with stirring to react for 6 hours. The system was cooled and the solvent was removed under reduced pressure to give the title compound, which was used directly in the next reaction without purification.
Step 3: synthesis of 6-bromo-2-methyl-7- (trifluoromethyl) pyrido [2,3-d ] pyrimidin-4 (3H) -one
6-bromo-2-methyl-7- (trifluoromethyl) -pyrido [2,3-d ] [1,3] oxazin-4-one (700 mg) was dissolved in tetrahydrofuran (20 mL), replaced with argon three times, methanolic ammonia (10 mL) was added dropwise, a white solid precipitated, reacted overnight at room temperature, the solvent was removed under reduced pressure, a portion of the solvent was removed, 4N hydrochloric acid was added to the system to adjust pH.apprxeq.3, then saturated sodium bicarbonate solution was added to adjust pH.apprxeq.7, a large amount of solid precipitated, suction filtration was performed, and the filter cake was washed with water and dried to obtain the title compound.
Step 4: synthesis of (R) -6-bromo-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methyl-7- (trifluoromethyl) pyrido [2,3-d ] pyrimidin-4-amine
6-bromo-2-methyl-7- (trifluoromethyl) pyrido [2,3-d ] pyrimidin-4 (3H) -one (311 mg), (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethane-1-amine hydrochloride (146 mg) was placed in a reaction tube, oxygen was removed by vacuum, 1, 8-diazabicyclo [5.4.0] undec-7-ene (461 mg) was dissolved in N, N-dimethylformamide (2 mL), and the system was added with argon for three times, and after stirring and reacting for 20 minutes, an ice bath was added, and a solution of (3H-1, 2, 3-triazolo [4,5-B ] pyridin-3-yloxy) tris-1-pyrrolidinyl hexafluorophosphate (789.57 mg) in N, N-dimethylformamide (1 mL) was stirred for 10 minutes, and the ice bath was removed and then warmed to room temperature for reaction for 1.5 hours. The system is slowly poured into 15mL of water at the temperature of about 10 ℃ in water bath, a large amount of yellow solid is precipitated, the mixture is stirred and dispersed for half an hour, the mixture is filtered by suction, and a filter cake is purified by column chromatography (petroleum ether/ethyl acetate gradient elution) and separated to obtain the title compound.
Step 5: synthesis of (R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methyl-6-morpholino-7- (trifluoromethyl) pyrido [2,3-d ] pyrimidin-4-amine
6-bromo-N- [ ((1R) -1- [3- (difluoromethyl) -2-fluoro-phenyl ] ethyl ] -2-methyl-7- (trifluoromethyl) pyrido [2,3-d ] pyrimidin-4-amine (100 mg), morpholine (72.7 mg), 2-dicyclohexylphosphorus-2 ',6' -diisopropyloxy-1, 1' -biphenyl (19.5 mg), tris (dibenzylideneacetone) dipalladium (19.1 mg) and cesium carbonate (272 mg) were added to a reaction flask, anhydrous 1, 4-dioxane (4 mL) was added, followed by argon balloon loading, displacement gas three times, and gas protection was placed in an oil bath at 100deg.C for 2 hours.
1 H NMR(400MHz,DMSO-d 6 )δ H 9.09(s,1H),8.91(d,J＝6.9Hz,1H),7.70(t,J＝7.2Hz,1H),7.53(t,J＝7.0Hz,1H),7.39-7.11(m,2H),5.83-5.76(m,1H),3.81-3.72(m,4H),3.02-2.96(m,4H),2.40(s,3H),1.65(d,J＝7.0Hz,3H).
LC/MS(m/z,MH + ):486.2.
Example 59: (R) -6- (4-amino-4-methylpiperidin-1-yl) -7- (2, 2-difluoroethoxy) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methylpyrido [2,3-d ] pyrimidin-4-amine
Step 1: synthesis of tert-butyl (R) - (1- (7- (2, 2-difluoroethoxy) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylpyrido [2,3-d ] pyrimidin-6-yl) -4-methylpiperidin-4-yl) carbamate
6-bromo-7- (2, 2-difluoroethoxy) -N- ((1R) -1- (3- (difluoromethyl) -2-fluoro-phenyl) ethyl) -2-methylpyrido [2,3-d ] pyrimidin-4-amine (80 mg), tert-butyl N- (4-methyl-4-piperidinyl) carbamate (41.9 mg), 2-dicyclohexylphosphine-2 ',4',6' -triisopropylbiphenyl (15.5 mg), tris (dibenzylideneacetone) dipalladium (14.9 mg) and cesium carbonate (159 mg) were added to the reaction flask, anhydrous 1, 4-dioxane (3 mL) was added, the mixture was balloon was filled with argon, the gas was replaced three times, and the mixture was placed in a 100℃oil bath under gas protection to react overnight. The reaction solution was concentrated under reduced pressure and purified by column chromatography (dichloromethane/methanol gradient elution) to give the title compound.
Step 2: synthesis of (R) -6- (4-amino-4-methylpiperidin-1-yl) -7- (2, 2-difluoroethoxy) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methylpyrido [2,3-d ] pyrimidin-4-amine
Tert-butyl (R) - (1- (7- (2, 2-difluoroethoxy) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylpyrido [2,3-d ] pyrimidin-6-yl) -4-methylpiperidin-4-yl) carbamate (79 mg) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (0.5 mL) was added with stirring at room temperature, and then reacted for 2 hours. The reaction solution was concentrated under reduced pressure, then diluted by adding a small amount of dichloromethane and water, adjusting the pH to 8 with saturated sodium bicarbonate solution, extracting with ethyl acetate, combining the organic phases, washing with saturated brine, drying over anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, purifying by prep-HPLC (Triart C18 ExRS, acetonitrile/water gradient elution), and lyophilizing to give the title compound.
1 H NMR(400MHz,DMSO-d 6 )δ H 8.33(d,J＝7.2Hz,1H),8.07(s,1H),7.66(t,J＝7.4Hz,1H),7.50(t,J＝6.9Hz,1H),7.37-7.10(m,2H),6.62-6.31(m,1H),5.80-5.77(m,1H),4.69(td,J＝15.2,3.2Hz,2H),3.18-3.11(m,4H),2.31(s,3H),1.66-1.52(m,7H),1.13(s,3H).
LC/MS(m/z,MH + ):525.2.
Example 60: (R) -1- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -7-methoxy-2-methylquinolin-6-yl) pyridin-2 (1H) -one
(R) -6-bromo-N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -7-methoxy-2-methylquinolin-4-amine (100 mg), cuprous iodide (95.0 mg) and trans- (1R, 2R) -N, N' -dimethyl-1, 2-cyclohexanediamine were added to 10mL of toluene, potassium carbonate (200 mg) was added, 2-pyridone (100 mg) was heated to 110℃under argon atmosphere, and after 16 hours, the reaction mixture was concentrated and separated by column chromatography (dichloromethane/methanol gradient elution) to give the title compound.
1 H NMR(400MHz,DMSO-d 6 )δ H 8.49(s,1H),7.64-7.52(m,5H),7.39-7.12(m,3H),6.51(dd,J＝9.2,2.7Hz,1H),6.34(t,J＝6.6Hz,1H),6.19(s,1H),5.20-5.08(m,1H),3.84(s,3H),2.39(s,3H),1.61(dd,J＝6.6,2.2Hz,3H).
LC/MS(m/z,MH + ):454.2.
Example 61: (R) -1- (3- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -7-methoxy-2-methylquinolin-6-yl) -3-fluoroazetidin-1 yl) ethan-1-one-2, 2-D3
Step 1: synthesis of tert-butyl (R) -3- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -7-methoxy-2-methylquinolin-6-yl) -3-hydroxyazetidine-1-carboxylate
3- (4-chloro-7-methoxy-2-methylquinolin-6-yl) -3-hydroxyazetidine-1-carboxylic acid tert-butyl ester (400.00 mg) was dissolved in 1mL of ultra-dry 1, 4-dioxane, to which was subsequently added (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethane-1-amine (299 mg), brettPhos Pd G3 (113 mg), brettPhos (113 mg) and sodium t-butoxide (202 mmol), and the system was heated to 100℃under the protection of argon to react for 4 hours, and the reaction solution was cooled to room temperature, diluted with ethyl acetate and filtered, and the filtrate was concentrated and separated and purified by column chromatography (petroleum ether/ethyl acetate gradient elution) to obtain the title compound.
Step 2: synthesis of tert-butyl (R) -3- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -7-methoxy-2-methylquinolin-6-yl) -3-fluoroazetidine-1-carboxylate
(R) -3- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -7-methoxy-2-methylquinolin-6-yl) -3-hydroxyazetidine-1-carboxylic acid tert-butyl ester (100 mg) was dissolved in 5mL of ultra-dry dichloromethane, cooled to 0℃and then, diethylaminosulfur trifluoride (36.4 mg) was added dropwise thereto, the reaction mixture was allowed to stand at room temperature for 2 hours, quenched with saturated sodium hydrogencarbonate solution, extracted with ethyl acetate, and the combined organic phases were dried after washing with saturated brine, concentrated and separated by column chromatography (gradient elution with petroleum ether/ethyl acetate) to give the title compound.
Step 3: synthesis of (R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -6- (3-fluoroazetidin-3-yl) -7-methoxy-2-methylquinolin-4-amine
(R) -3- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -7-methoxy-2-methylquinolin-6-yl) -3-fluoroazetidine-1-carboxylic acid tert-butyl ester (100 mg) was dissolved in 5mL of overdry dichloromethane, then 1mL of trifluoroacetic acid was added dropwise thereto, and after reacting the system at room temperature for 1 hour, it was concentrated, and the residue was directly subjected to the next reaction without purification.
Step 4: synthesis of (R) -1- (3- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -7-methoxy-2-methylquinolin-6-yl) -3-fluoroazetidin-1-yl) ethan-1-one-2, 2-D3
(R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -6- (3-fluoroazetidin-3-yl) -7-methoxy-2-methylquinolin-4-amine (80.0 mg) was dissolved in 5mL of methanol, DIEA (119 mg) was then added thereto, acetic anhydride-D6 (29.9 mg) was added thereto dropwise thereto, and the reaction was continued at room temperature for 30 minutes, whereupon the reaction solution was concentrated and separated and purified by preparative HPLC (Triart C18 ExRS, mobile phase: acetonitrile/water) to obtain the title compound.
1 H NMR(400MHz,DMSO-d 6 )δ H 8.40-8.38(m,1H),7.64-7.60(m,1H),7.56-7.53(m,1H),7.47-7.42(m,1H),7.33-7.15(m,3H),6.06(d,J＝4.6Hz,1H),5.15-5.10(m,1H),3.93-4.64(m,3H),4.35-4.26(m,1H),3.93(s,3H),2.33(s,3H),1.68(d,J＝6.7Hz,3H).
LC/MS(m/z,MH + ):479.2.
Example 62: (R) -1- (3- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -7-methoxyquinolin-6-yl) -3-methoxyazetidin-1-yl) ethan-1-one
Step 1: synthesis of 3- (4-chloro-7-methoxyquinolin-6-yl) -3-methoxyazetidine-1-carboxylic acid tert-butyl ester
3- (4-chloro-7-methoxyquinolin-6-yl) -3-hydroxyazetidine-1-carboxylic acid tert-butyl ester (100 mg) was dissolved in 5mL of super-dry DMF, then cooled to 0℃and after the reaction was continued for 30 minutes at this temperature after adding NaH (12.1 mg, 60%) thereto in portions, methyl iodide (38.9 mg) was added thereto dropwise and the reaction was continued for 1 hour at room temperature, the reaction solution was poured into 5mL of ice water, followed by extraction with ethyl acetate, the combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and the resultant residue was separated by column chromatography (gradient elution of petroleum ether/ethyl acetate) to give the title compound.
Step 2: synthesis of (R) -3- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -7-methoxyquinolin-6-yl) -3-methoxyazetidine-1-carboxylic acid tert-butyl ester
3- (4-chloro-7-methoxyquinolin-6-yl) -3-methoxyazetidine-1-carboxylic acid tert-butyl ester (100 mg) was dissolved in 1mL of overdry 1, 4-dioxane, to which was then added (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethan-1-amine (74.9 mg), brettPhos Pd G3 (23.9 mg), brettPhos (28.3 mg) and sodium tert-butoxide (50.7 mg), and after completion of the reaction at a temperature of 100℃under the protection of argon gas for 4 hours, the reaction solution was cooled to room temperature, diluted with ethyl acetate and filtered, and the filtrate was concentrated and separated by column chromatography (gradient elution with petroleum ether/ethyl acetate) to obtain the title compound.
Step 3: synthesis of (R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -7-methoxy-6- (3-methoxyazetidin-3-yl) quinolin-4-amine
(R) -3- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -7-methoxyquinolin-6-yl) -3-methoxyazetidine-1-carboxylic acid tert-butyl ester (120 mg) was dissolved in 5mL of overdry dichloromethane, then 1mL of trifluoroacetic acid was added dropwise thereto, the system was reacted at room temperature for 1 hour and then concentrated, and the residue was directly subjected to the next reaction without purification.
Step 4: synthesis of (R) -1- (3- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -7-methoxyquinolin-6-yl) -3-methoxyazetidin-1-yl) ethan-1-one
(R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -7-methoxy-6- (3-methoxyazetidin-3-yl) quinolin-4-amine (90.0 mg) was dissolved in 5mL of methylene chloride, DIEA (107 mg) was added thereto, acetic anhydride (31.9 mg) was added thereto dropwise thereto, and the reaction was continued at room temperature for 30 minutes, and the reaction solution was concentrated to prepare the title compound by HPLC (Triart C18 ExRS, mobile phase: acetonitrile/water) separation and purification.
1 H NMR(400MHz,DMSO-d 6 )δ8.30(d,J＝7.0Hz,1H),8.22(dd,J＝5.4,1.5Hz,1H),7.61-7.41(m,3H),7.40-7.13(m,3H),6.07-6.06(m,1H),5.10-5.06(m,1H),4.65-4.41(m,3H),4.13-4.09(m,1H),3.88(s,3H),2.98(d,J＝6.7Hz,3H),1.84(d,J＝4.0Hz,3H),1.68(d,J＝6.8Hz,3H).
LC/MS(m/z,MH + ):474.2.
Example 63: (R) -1- (3-amino-3- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -7-methoxyquinolin-6-yl) azetidin-1-yl) ethan-1-one
Step 1: synthesis of (R) -3- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -7-methoxyquinolin-6-yl) -3-hydroxyazetidine-1-carboxylic acid tert-butyl ester
3- (4-chloro-7-methoxyquinolin-6-yl) -3-hydroxyazetidine-1-carboxylic acid tert-butyl ester (150 mg) was dissolved in 1mL of overdry 1, 4-dioxane, to which was then added (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethane-1-amine (116 mg), brettPhos Pd G3 (37.3 mg), brettPhos Pd (44.1 mg) and sodium t-butoxide (79.0 mg), reacted for 4 hours at 100℃under the protection of argon, and the reaction solution was cooled to room temperature, diluted with ethyl acetate, filtered, and the filtrate was concentrated and separated by column chromatography (gradient elution of petroleum ether/ethyl acetate) to obtain the title compound.
Step 2: synthesis of (R) -3- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -7-methoxyquinolin-6-yl) -3-fluoroazetidine-1-carboxylic acid tert-butyl ester
(R) -3- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -7-methoxyquinolin-6-yl) -3-hydroxyazetidine-1-carboxylic acid tert-butyl ester (60.0 mg) was dissolved in 5mL of ultra-dry dichloromethane, followed by cooling to 0℃and then DAST (22.4 mg) was added dropwise thereto, after completion of the dropwise reaction, the reaction was continued at room temperature for 2 hours, quenched with saturated sodium bicarbonate solution, extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated, and the resulting residue was separated by column chromatography (gradient elution of petroleum ether/ethyl acetate) to give the title compound.
Step 3: synthesis of (R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -6- (3-fluoroazetidin-3-yl) -7-methoxyquinolin-4-amine
(R) -3- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -7-methoxyquinolin-6-yl) -3-fluoroazetidine-1-carboxylic acid tert-butyl ester (60.0 mg) was dissolved in 5mL of overdry dichloromethane, then 1mL of trifluoroacetic acid was added dropwise thereto, and after reacting the system at room temperature for 1 hour, it was concentrated, and the residue was directly subjected to the next reaction without purification.
Step 4: synthesis of (R) -1- (3- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -7-methoxyquinolin-6-yl) -3-fluoroazetidin-1-yl) ethan-1-one
(R) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -6- (3-fluoroazetidin-3-yl) -7-methoxyquinolin-4-amine (48.0 mg) was dissolved in 5mL of methylene chloride, DIEA (44.7 mg) was added thereto, acetic anhydride (17.5 mg) was added thereto dropwise thereto, and the reaction was continued at room temperature for 30 minutes, whereupon the reaction solution was concentrated and separated by column chromatography (gradient elution of petroleum ether/ethyl acetate) to obtain the title compound.
Step 5: synthesis of (R) -1- (3-amino-3- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -7-methoxyquinolin-6-yl) azetidin-1-yl) ethan-1-one
(R) -1- (3- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -7-methoxyquinolin-6-yl) -3-fluoroazetidin-1-yl) ethan-1-one (50.0 mg) was dispersed in 3mL of an ammonia-methanol solution, followed by reaction at 100℃for 2 hours under microwaves, the reaction solution was cooled to room temperature, concentrated, and then separated and purified by preparative HPLC (Triart C18 ExRS, mobile phase: acetonitrile/water) to give the title compound. .
1 H NMR(400MHz,DMSO-d 6 )δ8.21-8.19(m,2H),7.61-7.44(m,3H),7.40-7.13(m,3H),6.06(t,J＝5.7Hz,1H),5.12-5.07(m,1H),4.71-4.46(m,2H),4.18(d,J＝8.7Hz,1H),3.92-3.88(m,4H),1.81(d,J＝1.8Hz,3H),1.67(dd,J＝6.9,1.7Hz,3H).
LC/MS(m/z,MH + ):459.2.
Example 64: (R) -1- (7- (difluoromethoxy) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylquinolin-6-yl) -4-methylpiperidin-4-ol
Step 1: synthesis of (R) -6-bromo-4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylquinolin-7-ol
6-bromo-4-chloro-2-methylquinolin-7-ol (500 mg) was dissolved in 5mL of overdry N-methylpyrrolidone, to which (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethane-1-amine hydrochloride (478 mg) and potassium carbonate (976 mg) were then added to react under argon for 4 hours at 150℃under the protection of microwaves, the reaction solution was cooled to room temperature, diluted with ethyl acetate and filtered, the organic phase was washed with saturated brine, the organic phase was dried, and the residue after concentration was slurried with a mixed solvent of ethyl acetate and petroleum ether, v: v=10:1 and filtered, and the cake was dried to obtain the title compound.
Step 2: synthesis of (R) -6-bromo-7- (difluoromethoxy) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methylquinolin-4-amine
(R) -6-bromo-4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylquinolin-7-ol (100 mg) was dissolved in 1mL of acetonitrile, followed by adding thereto 1mL of 6M aqueous potassium hydroxide solution, and finally adding thereto difluoromethyl triflate (51.6 mg), after continuing the reaction at room temperature for 10 minutes, the reaction solution was adjusted to ph=7 with 1M aqueous citric acid solution, extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated, and the resultant residue was separated by column chromatography (petroleum ether/ethyl acetate gradient elution) to obtain the title compound.
Step 3: synthesis of (R) -1- (7- (difluoromethoxy) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylquinolin-6-yl) -4-methylpiperidin-4-ol
(R) -6-bromo-7- (difluoromethoxy) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methylquinolin-4-amine (60.0 mg) was dissolved in 1mL of overdry 1, 4-dioxane, to which was then added 4-methylpiperidin-4-ol (21.8 mg), pd 2 (dba) 3 (11.6 mg), BINAP (15.7 mg) and sodium tert-butoxide (24.3 mg) were reacted at 100℃for 6 hours under the protection of argon, the reaction solution was cooled to room temperature, diluted with ethyl acetate and filtered, and the filtrate was concentrated and purified by preparative HPLC (Triart C18 ExRS, mobile phase: acetonitrile/water) to give the title compound.
Example 65: (R) -1- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -7-methoxy-2-methylpyrido [2,3-d ] pyrimidin-6-yl) -4-methylpiperidin-4-ol
The procedure described above was used to prepare the title compound by the synthetic route of example 56.
1 H NMR(400MHz,DMSO-d 6 )δ8.31(s,1H),8.03(s,1H),7.66(t,J＝7.5Hz,1H),7.50(t,J＝7.1Hz,1H),7.29(t,J＝7.7Hz,1H),7.24(t,J＝54.4Hz,1H),5.78(p,J＝7.0Hz,1H),4.33(s,1H),3.97(s,3H),3.20–2.97(m,4H),2.31(s,3H),1.70-1.58(m,7H),1.21(s,3H).
LC/MS(m/z,MH + ):476.2.
Example 66: (R) -1- (7- (2, 2-difluoroethoxy) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylpyrido [2,3-d ] pyrimidin-6-yl) -N, 4-dimethylpiperidine-4-carboxamide
The title compound was obtained by the synthesis method described in example 57, except that methyl 3-methylazetidine-3-carboxylate in step 1 was replaced with methyl 4-methyl-4-piperidinecarboxylate.
1 H NMR(400MHz,DMSO-d 6 )δ8.41(s,1H),8.04(s,1H),7.67-7.63(m,2H),7.50(t,J＝7.0Hz,1H),7.29(t,J＝7.7Hz,1H),7.24(t,J＝54.4Hz,1H),6.63-6.32(m,1H),5.85-5.69(m,1H),4.69 (td,J＝15.2,2.7Hz,2H),3.33-3.32(m,2H),2.88-2.76(m,2H),2.62(d,J＝4.4Hz,3H),2.31(s,3H),2.21-2.18(m,2H),1.60-1.52(m,5H),1.15(s,3H).
LC/MS(m/z,MH + ):567.2.
Example 67: (R) -N4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methyl-6-morpholinopyrido [2,3-d ] pyrimidine-4, 7-diamine
The procedure described above was followed, using the synthetic method of example 47, to give the title compound.
1 H NMR(400MHz,DMSO-d 6 )δ8.01(s,1H),7.94(d,J＝7.4Hz,1H),7.65(t,J＝7.3Hz,1H),7.48(t,J＝6.8Hz,1H),7.29(t,J＝7.7Hz,1H),7.23(t,J＝54.4Hz,1H),6.58(bs,2H),5.75(p,J＝7.0Hz,1H),3.86-3.77(m,4H),2.91-2.89(m,4H),2.24(s,3H),1.56(d,J＝7.1Hz,3H).
LC/MS(m/z,MH + ):433.2.
Example 68: (R) -1- (3- (7- (2, 2-difluoroethoxy) -4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylpyrido [2,3-d ] pyrimidin-6-yl) -3-hydroxyazetidin-1-yl) ethan-1-one
(R) -6-bromo-7- (2, 2-difluoroethoxy) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methylpyrido [2,3-d ] azoidin-4-amine (200 mg) was dissolved in 10mL of ultra-dry tetrahydrofuran, then cooled to-80℃under the protection of argon, then N-hexane solution (2.00 mL) of N-butyllithium and 1-acetamidobutan-3-one (171 mg) were added dropwise thereto, after the addition was allowed to stand at room temperature for half an hour, the mixture was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, the combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated and separated and purified by column chromatography (gradient elution with petroleum ether/ethyl acetate) to give the title compound.
1 H NMR(400MHz,DMSO-d 6 )δ8.82(s,1H),8.67(d,J＝7.3Hz,1H),7.73-7.63(m,1H),7.51(t,J＝7.1Hz,1H),7.30(t,J＝7.7Hz,1H),7.24(t,J＝54.4Hz,1H),6.45(s,1H),6.39(tt,J＝54.3,3.2Hz,1H),5.82-5.77(m,1H),4.80-4.59(m,3H),4.48(dd,J＝10.3,4.4Hz,1H),4.22-4.20(m,1H),3.94-3.91(m,1H),2.35(d,J＝1.5Hz,3H),1.81(s,3H),1.60(d,J＝7.1Hz,3H).
LC/MS(m/z,MH + ):526.2.
Example 69: (R) -N- (1- (7- (2, 2-difluoroethoxy) -4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylpyrido [2,3-d ] pyrimidin-6-yl) -4-methylpiperidin-4-yl) acetamide
(R) -6- (4-amino-4-methylpiperidin-1-yl) -7- (2, 2-difluoroethoxy) -N- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methylpyrido [2,3-d ] pyrimidin-4-amine (200 mg) was dissolved in 10mL of overdry dichloromethane, DIEPA (200 mg) was added thereto, acetic anhydride (50.0 mg) was added dropwise thereto, and after the dropwise addition was stirred at room temperature for 1 hour, the reaction solution was concentrated and separated by column chromatography (dichloromethane/methanol gradient elution) to obtain the title compound.
1 H NMR(400MHz,DMSO-d 6 )δ8.34(d,J＝7.3Hz,1H),8.04(s,1H),7.66(t,J＝7.5Hz,1H),7.50(t,J＝7.1Hz,1H),7.39(s,1H),7.30(t,J＝7.7Hz,1H),7.24(t,J＝54.4Hz,1H),6.48(tt,J＝54.3,3.1Hz,1H),5.77(p,J＝7.2Hz,1H),4.70(td,J＝15.3,3.4Hz,2H),3.24-3.21(m,2H),3.00-2.85(m,2H),2.33-2.25(m,5H),1.85(s,3H),1.67-1.62(m,2H),1.59(d,J＝7.1Hz,3H),1.34(s,3H).
LC/MS(m/z,MH + ):567.2.
Example 70: (R) -1- (3- (7- (2, 2-difluoroethoxy) -4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylpyrido [2,3-d ] pyrimidin-6-yl) -3-methoxyazetidin-1-yl) ethan-1-one
(R) -1- (3- (7- (2, 2-difluoroethoxy) -4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylpyrido [2,3-d ] pyrimidin-6-yl) -3-hydroxyazetidin-1-yl) ethan-1-one (50.0 mg) was dissolved in 2mL of anhydrous N, N-dimethylformamide, naH (4.0 mg) was added, stirred at room temperature for 30 minutes, methyl iodide was added, stirred at room temperature for 2 hours, and after completion of the reaction, the reaction was concentrated and subjected to preparative HPLC (mobile phase: acetonitrile/water) to prepare the title compound.
1 H NMR(400MHz,DMSO-d 6 )δ8.78(s,1H),8.58(t,J＝6.3Hz,1H),7.67(q,J＝8.1Hz,1H),7.51(t,J＝6.1Hz,1H),7.31(t,J＝7.7Hz,1H),7.24(t,J＝54.4Hz,1H),6.42(tt,J＝54.5,3.3Hz,1H),5.82-5.72(m,1H),4.79–4.64(m,2H),4.62-4.51(m,1H),4.49–4.35(m,2H),4.14-4.01(m,1H),3.02(d,J＝2.1Hz,3H),2.35(d,J＝1.8Hz,3H),1.83(d,J＝4.3Hz,3H),1.62(d,J＝7.1Hz,3H).
LC/MS(m/z,MH + ):540.2.
Example 71: (R) -1- (4- (7- (2, 2-difluoroethoxy) -4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methylpyrido [2,3-d ] pyrimidin-6-yl) piperazin-1-yl) ethan-1-one
The title compound was obtained by the method of referential example 59 except that tert-butyl N- (4-methyl-4-piperidinyl) carbamate was replaced with 1-acetylpiperazine.
1 H NMR(400MHz,DMSO-d 6 )δ8.34(d,J＝7.2Hz,1H),8.09(s,1H),7.66(t,J＝7.1Hz,1H),7.50(t,J＝7.0Hz,1H),7.29(t,J＝7.7Hz,1H),7.24(t,J＝54.4Hz,1H),6.49(tt,J＝54.5,3.3Hz,1H),5.78(p,J＝7.1Hz,1H),4.72(td,J＝15.2,3.2Hz,2H),3.72-3.55(m,4H),3.18-3.03(m,4H),2.32(s,3H),2.07(s,3H),1.60(d,J＝7.1Hz,3H).
LC/MS(m/z,MH + ):539.2.
Example 72: n-7- (3, 3-difluorocyclobutyl) -N-4- ((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methyl-6- (2-methyloxetan-2-yl) pyrido [2,3-d ] pyrimidine-4, 7-diamine
Step 1: synthesis of 6-bromo-7- ((3, 3-difluorocyclobutyl) amino) -2-methyl-pyrido [2,3-d ] pyrimidin-4-ol
6-bromo-7-chloro-2-methylpyrido [2,3-d ] pyrimidin-4-ol (500 mg) was dissolved in 5mL of DMF, 3-difluorocyclobutylamine (234 mg) and N, N-diisopropylethylamine (470 mg) were added thereto, and after reacting at 80℃for 2 hours, the reaction solution was concentrated and separated by column chromatography (petroleum ether/ethyl acetate gradient elution) to give the title compound.
Step 2: synthesis of 6-bromo-N-7- (3, 3-difluorocyclobutyl) -N-4- ((1R) -1- (3- (difluoromethyl) -2-fluoro-phenyl) ethyl) -2-methyl-pyrido [2,3-d ] pyrimidine-4, 7-diamine
6-bromo-7- ((3, 3-difluorocyclobutyl) amino) -2-methyl-pyrido [2,3-d ] pyrimidin-4-ol (500 mg) was dissolved in 10mL of DMF, to which (1R) -1- (3- (difluoromethyl) -2-fluoro-phenyl) ethylamine (392 mg) and (3H-1, 2, 3-triazolo (4, 5-B) pyridin-3-yloxy) tris-1-pyrrolidinyl hexafluorophosphate (1.13 g) were added, and to which DBU (661 mg) was added, the reaction mixture was cooled to room temperature after completion of the reaction at 60℃for 4 hours, diluted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, and concentrated and separated by column chromatography (gradient elution with petroleum ether/ethyl acetate) to give the title compound.
Step 3: synthesis of 1- (7- ((3, 3-difluorocyclobutyl) amino) -4- (((1R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-pyrido [2,3-d ] pyrimidin-6-yl) ethanone
6-bromo-N-7- (3, 3-difluorocyclobutyl) -N-4- ((1R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methyl-pyrido [2,3-d ] pyrimidine-4, 7-diamine (430 mg) and tributyl (1-ethoxyethylene) tin (360 mg) were added to 2mL of ultra-dry 1, 4-dioxane, and then ditriphenylphosphine palladium dichloride (5.85 mg) and triethylamine (168 mg) were added thereto, the reaction solution was allowed to react under the protection of argon for 4 hours at 100℃and then cooled to room temperature, and 1mL of 2M diluted hydrochloric acid was added thereto, after continuing the reaction for 1 hour, 5mL of saturated sodium hydrogencarbonate solution was added, and ethyl acetate was added thereto for dilution, and then the aqueous phase was separated by ethyl acetate extraction, and the title organic phase was combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the obtained residue was separated by column chromatography (petroleum ether/ethyl acetate gradient elution) to give the title compound.
Step 4: synthesis of N-7- (3, 3-difluorocyclobutyl) -N-4- ((R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) -2-methyl-6- (2-methyloxetan-2-yl) pyrido [2,3-d ] pyrimidine-4, 7-diamine
Trimethylsulfoxide iodide (22.9 mg) was dissolved in 1mL of t-butanol, then potassium t-butoxide (11.7 mg) was added thereto, and after reacting at 50 ℃ for 30 minutes, 1- (7- ((3, 3-difluorocyclobutyl) amino) -4- (((1R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -2-methyl-pyrido [2, 3-d) pyrimidin-6-yl) ethanone (10.0 mg) was added thereto, and after continuing the reaction at that temperature for 6 hours, the reaction solution was diluted with ethyl acetate, then filtered, and the filtrate was concentrated and subjected to preparative HPLC (Triart C18 ExRS, mobile phase: acetonitrile/water) to afford the title compound.
1 H NMR(400MHz,DMSO-d 6 )δ7.71-7.58(m,1H),7.51-7.39(m,1H),7.37-7.19(m,2H),7.12-6.98(m,1H),5.70-5.53(m,2H),4.78-4.61(m,1H),3.74-3.61(m,1H),3.60-3.48(m,1H),3.04-2.74(m,4H),3.04-2.74(m,3H),1.74-1.66(m,1H),1.58-1.43(m,3H),1.19(s,3H).
LC/MS(m/z,MH + ):508.2.
Example 73: (R) -1- (3- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -7-methoxy-2-methylquinolin-6-yl) -3-methoxyazetidin-1-yl) ethan-1-one
The title compound was obtained by the method of referential example 62, except that tert-butyl 3- (4-chloro-7-methoxyquinolin-6-yl) -3-hydroxyazetidine-1-carboxylate in step 1 was replaced with tert-butyl 3- (4-chloro-7-methoxy-2-methylquinolin-6-yl) -3-hydroxyazetidine-1-carboxylate.
1 H NMR(400MHz,DMSO-d 6 )δ8.22(d,J＝5.8Hz,1H),7.65-7.56(m,1H),7.52(t,J＝6.9Hz,1H),7.52(t,J＝6.9Hz,1H),6.01(d,J＝3.4Hz,1H),5.13-5.01(m,1H),4.65-4.38(m,3H),4.13-4.06(m,1H),3.86(s,3H),2.96(d,J＝5.7Hz,3H),2.29(d,J＝1.2Hz,3H),1.84(d,J＝3.8Hz,3H),1.67(d,J＝6.8Hz,3H).
LC/MS(m/z,MH + ):488.2.
Example 74: (R) -1- (4- (4- (1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -7-methoxy-2-methylquinolin-6-yl) -4-methoxypiperidin-1-yl) ethan-1-one
Reference example 48 step 1 substituting tert-butyl 3-oxo-azetidine-1-carboxylate with N-t-butoxycarbonyl-4-piperidone gave 4- (4-chloro-7-methoxy-2-methylquinolin-6-yl) -4-hydroxypiperidine-1-carboxylate.
The title compound was obtained by the method of referential example 62, except that tert-butyl 3- (4-chloro-7-methoxyquinolin-6-yl) -3-hydroxyazetidine-1-carboxylate in step 1 was replaced with tert-butyl 4- (4-chloro-7-methoxy-2-methylquinolin-6-yl) -4-hydroxypiperidine-1-carboxylate.
1 H NMR(400MHz,DMSO-d 6 )δ8.05(d,J＝2.6Hz,1H),7.66-7.59(m,1H),7.52(t,J＝7.1Hz,1H),7.33(t,J＝6.4Hz,1H),7.31-7.27(m,1H),7.26(t,J＝54.4Hz,1H),7.15(s,1H),5.98(d,J＝1.6Hz,1H),5.11-5.00(m,1H),4.41-4.30(m,1H),3.86(s,3H),3.77-3.66(m,1H),3.49-3.35(m,1H),2.98(d,J＝4.2Hz,3H),2.94-2.84(m,1H),2.46-2.31(m,2H),2.28(s,3H),2.12-1.94(m,5H),1.65(d,J＝6.7Hz,3H).
LC/MS(m/z,MH + ):516.2.
Example 75: (R) -1- (4- (7-acetyl-4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) quinolin-6-yl) -4-methoxypiperidin-1-yl) ethan-1-one
Step 1: synthesis of 6-bromo-4-chloroquinolin-7-ol
6-bromo-4-chloro-7-methoxyquinoline (3.00 g) was dissolved in dichloroethane (25 mL), replaced with nitrogen, and BBr was added to an ice-water bath 3 (13.8 g), naturally carrying out a reaction at a temperature of ten minutes, heating the yellow turbid liquid to 50 ℃, stirring the reaction solution overnight, pouring the reaction solution into ice water for quenching, adding sodium bicarbonate solid to adjust the pH to 7, carrying out suction filtration, and drying a filter cake to obtain 2.80g of the title compound.
Step 2: synthesis of 6-bromo-4-chloro-7- ((4-methoxybenzyl) oxy) quinoline
6-bromo-4-chloroquinolin-7-ol (2.80 g), p-methoxybenzyl chloride (PMBCl 2.36 g) were placed in a reaction flask, ice-bath, DMF (150 mL), yellow turbidity, nitrogen replacement, naH (557 mg) were added, stirring was performed for half an hour, yellow supernatant, p-methoxybenzyl chloride (PMBCl 2.36 g) was added under ice-bath conditions, and after overnight reaction, the reaction solution was poured into 450 mL of ice water to quench, and suction filtration was performed to obtain the title compound 3.00g.
Step 3: synthesis of tert-butyl 4- (4-chloro-7- ((4-methoxybenzyl) oxy) quinolin-6-yl) -4-hydroxypiperidine-1-carboxylate
6-bromo-4-chloro-7- ((4-methoxybenzyl) oxy) quinoline (3.00 g) was placed in a three-necked flask, dehydrated and deoxygenated, THF (300 mL) was added, n-BuLi (9.51 mmol) was added dropwise at-78deg.C, stirring was completed for half an hour, a THF solution of tert-butyl 4-oxopiperidine-1-carboxylate (3.16 g) was added dropwise at-78deg.C, saturated aqueous ammonium chloride solution was added to the reaction solution after completion of the reaction, pH was adjusted to 7, the solution was separated, the organic phase was washed with water, dried, filtered, and the resultant residue was separated by column chromatography (gradient elution with petroleum ether/ethyl acetate) to give the title compound 1.00g.
Step 4: synthesis of tert-butyl 4- (4-chloro-7- ((4-methoxybenzyl) oxy) quinolin-6-yl) -4-methoxypiperidine-1-carboxylate
Tert-butyl 4- (4-chloro-7- ((4-methoxybenzyl) oxy) quinolin-6-yl) -4-hydroxypiperidine-1-carboxylate (1.00 g) was dissolved in DMF (8 mL), replaced with nitrogen, naH (144 mg) was added under ice-bath conditions, stirred for half an hour, meI (568 mg) was added under ice-bath conditions, the reaction mixture was stirred for one hour, poured into ice-water to quench, extracted with ethyl acetate, the separated liquid, and the organic phase was washed with water, dried, filtered, and concentrated to give a residue which was separated by column chromatography (petroleum ether/ethyl acetate gradient elution) to give 0.50g of the title compound.
Step 5: synthesis of tert-butyl (R) -4- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -7- ((4-methoxybenzyl) oxy) quinolin-6-yl) -4-methoxypiperidine-1-carboxylate
Tert-butyl 4- (4-chloro-7- ((4-methoxybenzyl) oxy) quinolin-6-yl) -4-methoxypiperidine-1-carboxylate (500 mg), (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethan-1-amine (221 mg), brett Phos G3 (176 mg), brett Phos (104 mg), sodium tert-butoxide (280 mg) were all placed in a reaction tube, dehydrated and deoxygenated, replaced with argon, dioxane (8 mL) was added, after stirring and reacting for 4 hours at 100℃the system was cooled to room temperature, concentrated and then separated by column chromatography (gradient elution with petroleum ether/ethyl acetate) to give the title compound 0.30G.
Step 6: synthesis of (R) -4- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -7-hydroxyquinolin-6-yl) -4-methoxypiperidine-1-carboxylic acid tert-butyl ester
The title compound was obtained by dissolving (R) -4- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -7- ((4-methoxybenzyl) oxy) quinolin-6-yl) -4-methoxypiperidine-1-carboxylic acid tert-butyl ester (300 mg) in methanol, adding palladium on carbon (60 mg), displacing hydrogen, reacting for one hour, filtering to remove palladium on carbon, and concentrating.
Step 7: synthesis of (R) -4- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -7- (((((trifluoromethyl) sulfonyl) oxy) quinolin-6-yl) -4-methoxypiperidine-1-carboxylic acid tert-butyl ester
(R) -4- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -7-hydroxyquinolin-6-yl) -4-methoxypiperidine-1-carboxylic acid tert-butyl ester (230 mg), phenylbis (trifluoromethanesulfonyl) imide (PhNTF) 2 237 mg), TEA (85.3 mg) was placed in a reaction tube, dehydrated and deoxygenated, replaced with nitrogen, DCM (7 mL) was added, and after stirring at room temperature and reacting for two hours, water was added to quench the reaction, DCM was extracted, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the resulting residue was separated by column chromatography (gradient elution of petroleum ether/ethyl acetate) to give 0.20g of the title compound.
Step 8: synthesis of (R) -4- (7-acetyl-4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) quinolin-6-yl) -4-methoxypiperidine-1-carboxylic acid tert-butyl ester
(R) -4- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -7- (((((trifluoromethyl) sulfonyl) oxy) quinolin-6-yl) -4-methoxypiperidine-1-carboxylic acid tert-butyl ester (50.0 mg), pd (PPh) 3 ) 2 Cl 2 (15.5 mg) was placed in a reaction tube, water was removed to remove oxygen, nitrogen was replaced, tributyl (1-ethoxyvinyl) tin (53.3 mg), 1, 4-dioxane (5 mL) was added, the reaction was stirred at 100℃for four hours, then water was added to quench the reaction, extraction was performed with ethyl acetate, the organic phases were combined and desolventized, and the mixture was separated by column chromatography (Petroleum ether/ethyl acetate gradient elution) to obtain the title compound.
Step 9: synthesis of (R) -1- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -6- (4-methoxypiperidin-4-yl) quinolin-7-yl) ethan-1-one hydrochloride
(R) -4- (7-acetyl-4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) quinolin-6-yl) -4-methoxypiperidine-1-carboxylic acid tert-butyl ester (20.0 mg) was dissolved in hydrochloric acid-dioxane (5 mL), and after stirring at room temperature for half an hour, the reaction was completed and concentrated to give the title compound.
Step 10: synthesis of (R) -1- (4- (7-acetyl-4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) quinolin-6-yl) -4-methoxypiperidin-1-yl) ethan-1-one
(R) -1- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -6- (4-methoxypiperidin-4-yl) quinolin-7-yl) ethan-1-one hydrochloride (16.5 mg), acetic anhydride (4.64 mg), TEA (7.08 mg) were placed in methanol (1 mL), and after stirring overnight at room temperature, the reaction mixture was concentrated and purified by preparative HPLC (Triart C18 ExRS, mobile phase: acetonitrile: water) to give the title compound.
1 H NMR(400MHz,MeOD)δ8.45-8.41(m,2H),8.07-8.00(m,1H),7.89-7.82(m,1H),7.72(t,J＝7.5Hz,1H),7.59(t,J＝7.3Hz,1H),7.37(t,J＝7.8Hz,1H),7.01(td,J＝54.6,8.8Hz,1H),5.59-5.47(m,1H),4.58-4.35(m,1H),3.95-3.72(m,1H),3.62-3.48(m,1H),3.19(d,J＝2.2Hz,3H),3.15-2.98(m,1H),2.70(s,3H),2.59-2.48(m,1H),2.27-2.17(m,1H),2.14(d,J＝8.7Hz,3H),2.11-1.89(m,2H),1.81-1.74(m,3H).
LC/MS(m/z,MH + ):514.2
Example 76: (R) -6- (1-acetyl-4-methoxypiperidin-4-yl) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) quinoline-7-carboxylic acid
Step 1: synthesis of methyl (R) -6- (1- (tert-butoxycarbonyl) -4-methoxypiperidin-4-yl) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) quinoline-7-carboxylate
(R) -4- (4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -7- (((((trifluoromethyl) sulfonyl) oxy) quinolin-6-yl) -4-methoxypiperidine-1-carboxylic acid tert-butyl ester (130 mg), palladium acetate (8.61 mg, 38.37. Mu. Mol), DPPP (1, 3-bis (diphenylphosphine) propane) 15.8 mg) and TEA (58.2 mg) were placed in a reaction tube, 5mL of DMSO and 0.5mL of water were added, CO gas was introduced and the reaction was stirred at 80℃for 4 hours, and then the reaction mixture was quenched by pouring into water, extracted with ethyl acetate, and the organic phases were combined and dried over anhydrous sodium sulfate to obtain the title compound.
Step 2: synthesis of methyl (R) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -6- (4-methoxypiperidin-4-yl) quinoline-7-carboxylate hydrochloride
(R) -6- (1- (t-Butoxycarbonyl) -4-methoxypiperidin-4-yl) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) quinoline-7-carboxylic acid methyl ester (140 mg) was dissolved in hydrochloric acid-dioxane (3 mL), the reaction was stirred at room temperature for half an hour, and after completion of the reaction, the reaction solution was concentrated to give the title compound.
Step 3: synthesis of methyl (R) -6- (1-acetyl-4-methoxypiperidin-4-yl) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) quinoline-7-carboxylate
(R) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) -6- (4-methoxypiperidin-4-yl) quinoline-7-carboxylic acid methyl ester hydrochloride (116 mg), acetic anhydride (31.6 mg), TEA (48.2 mg) were dissolved in MeOH (3 mL), and after stirring at room temperature for one hour, the reaction was completed. The reaction mixture was concentrated to give the title compound.
Step 4: synthesis of (R) -6- (1-acetyl-4-methoxypiperidin-4-yl) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) quinoline-7-carboxylic acid
(R) -6- (1-acetyl-4-methoxypiperidin-4-yl) -4- ((1- (3- (difluoromethyl) -2-fluorophenyl) ethyl) amino) quinoline-7-carboxylic acid methyl ester (50.0 mg) was dissolved in water (2 mL), meOH (2 mL), naOH (11.3 mg) was added, the reaction was completed after stirring at room temperature for two hours, the reaction mixture was added to 20mL of water, the pH was adjusted to 3-4 with a saturated aqueous ammonium chloride solution, ethyl acetate was extracted, the organic layers were combined, concentrated, and then separated and purified by preparative HPLC (Triart C18 ExRS, mobile phase: acetonitrile/water) to give the title compound.
1 H NMR(400MHz,MeOD)δ8.36(s,1H),8.29(s,1H),8.14-8.06(m,1H),8.00-7.93(m,1H),7.79-7.70(m,1H),7.68-7.59(m,1H),7.45-7.35(m,1H),7.04(td,J＝54.6,6.9Hz,1H),5.84-5.72(m,1H),4.51-4.36(m,1H),3.98-3.76(m,1H),3.67-3.45(m,1H),3.22(d,J＝7.2Hz,3H),3.15-2.99(m,1H),2.56(t,J＝11.9Hz,1H),2.37(dd,J＝29.5,14.0Hz,1H),2.14(d,J＝5.7Hz,3H),2.11-1.90(m,2H),1.84(t,J＝6.0Hz,3H).
LC/MS(m/z,MH + ):516.2.
Biological Activity and related Property testing
Experimental example 1: determination of SOS1 and KRAS G12D binding inhibition Activity in accordance with the examples of the invention
The effect of the compounds of the invention on KRASG12D:: SOS1 BINDING inhibition was evaluated using KRAS-G12D/SOS1 BINDING ASSAY KITS (Cisbio, cat# 63ADK000CB21 PEH).
The experimental method comprises the following steps:
positive control BAY-293 and test compound (10 mM stock solution) were diluted 5-fold to 0.1mM with 100% DMSO and subjected to an equal ratio of 11 concentrations in 384 well dilution plates. Using Echo transfer 0.1. Mu.L of the gradient diluted compound solution into 384 well plates, 2 multiplex wells were made per compound, 1000rpm/min, and centrifuged for 1min. Transfer 5. Mu.L of 4 XKRAS G12D (final concentration 1X) and GTP solution (final concentration 10. Mu.M, sigma, cat. No.: V900868) to 384 reaction plates, centrifuge at 1000rpm/min, incubate at 25℃for 15min. Transfer 5. Mu.L of 4 XSO 1 solution (final concentration 1X) to 384 reaction plates, centrifuge 1min, incubate at 25℃for 45min. The final concentration of BAY-293 compound was 10,3.33,1.11,0.37,0.12,0.04,0.014,0.0046,0.0015,0.0005,0.00017,0uM. The final concentrations of the test compounds were 10,3.33,1.11,0.37,0.12,0.04,0.014,0.0046,0.0015,0.0005,0.00017,0uM. The final concentration of DMSO was 0.5%. Transfer 10. Mu.L of 2 Xdetection reagent solution to 384 reaction plates, centrifuge at 1000rpm/min, incubate at 4℃for 180min. Excitation wavelength 665nm and emission wavelength 615nm were read using an Envision multifunction microplate reader. 665/615Ratio signal intensity was used to characterize the extent of enzyme activity.
The data processing method comprises the following steps: fitting compound IC by Graphpad Prism 8 nonlinear regression equation 50 ：
Negative control: DMSO (DMSO)
Positive control: 10 mu M BAY-293
IC of the compound was obtained using the following nonlinear fitting equation 50 (half inhibition concentration):
Y＝Bottom+(Top-Bottom)/(1+10^((LogIC 50 -X)*HillSlope))
log of compound concentration
Y:665/615 Ratio
Test results: under the experimental conditions, the test compound has good inhibition activity on KRASG12 D:SOS 1 binding. The corresponding activity test results of the test compounds are shown in Table 1.
TABLE 1 test results of inhibitory Activity of the examples of this patent on KRAS G12D:: SOS1 binding
Examples IC 50 (nM)
1 2.08
2 2.79
3 4.92
4 4.50
12 7.68
Experimental example 2: measurement of proliferation inhibitory Activity of H358 cells according to the examples of the present invention
The effect of the compounds of the invention on proliferation of H358 cells was assessed by CellTiter-Glo luminescence cell viability assay kit method.
The experimental method comprises the following steps:
h358 cells (ATCC, CRL-5807) were cultured in RPMI1640 (Hyclone, SH 30256.01) complete medium containing 10% FBS (Gibco, 10100147) and 100U/mL of a mixture of green streptomycin (Gibco, 15140163), when the cells had grown to 80-90%, the cells were digested and blown off and then plated in 96-well plates (Corning, 4515) with 3000 cells per well (180. Mu.l of RPMI1640 complete medium), and then the 96-well plates were placed at 37℃and 5% CO 2 Is cultured overnight in an incubator.
After overnight, 20. Mu.L of diluted compound was added to each well using a row gun, and the 96-well plate was placed at 37℃in 5% CO 2 Incubator relay of (a)And (5) culturing continuously. After 7 days, 100. Mu.L of supernatant was aspirated, discarded, and 50. Mu.L of supernatant was added to each well3D Cell Viability Assay liquid, shaking for 30min at 450rpm at room temperature, and after complete cell lysis, the microplate reader was selected from the "Luminescence" reading plate. In this experiment, the group without cells (replaced with 1640 medium) was taken as the 100% inhibition group, and the group without compounds added to cells was taken as the 0% inhibition group.
The percentage of inhibition of H358 cell proliferation by the compound can be calculated by the following formula:
percent inhibition = 100 (0% inhibition group signal value-signal value at the particular concentration of test compound)/(0% inhibition group signal value-100% inhibition group signal value).
Compound IC 50 The values were calculated from 8 concentration points using XLfit (ID Business Solutions ltd., UK) software by the following formula:
Y＝Bottom+(Top-Bottom)/(1+10^((logIC 50 -X)×slope factor))
wherein Y is the inhibition percentage, X is the logarithmic value of the concentration of the compound to be detected, bottom is the minimum inhibition percentage, top is the maximum inhibition percentage, and slope factor is the curve slope coefficient.
Test results: under the experimental conditions, the embodiment of the invention has good proliferation inhibition activity on H358 cells. The corresponding activity test results of the test compounds are shown in Table 2.
TABLE 2 test results of the proliferation inhibitory Activity of the examples of this patent on H358 cells
Examples IC 50 (nM)
1 30.3
2 24.6
3 48.1
4 126.2
5 85.6
6 10.7
8 6.1
9 61.1
10 79.2
11 140.5
12 29.8
17 154.0
18 70.3
19 374
20 118
21 307
22 119
23 64.1
24 96.6
25 54.5
26 45.1
27 48.4
28 114.0
29 12.8
30 34.6
31 116.8
32 12.3
33 36.2
34 111.4
35 14.6
36 85.7
37 42.1
38 102.1
39 41.3
40 102.7
41 130.7
42 231.8
43 146.3
44 119.6
45 254.7
46 33.1
47 74.2
48 45.1
49 36.4
50 91.6
51 304.1
52 65.9
53 117.6
54 184.9
55 93.5
56 58.4
57 22.9
58 61.9
59 46.2
62 29.5
65 92.8
66 33.4
67 59.2
69 50.2
70 156.1
71 57.3
73 118.4
74 13.0
Experimental example 3 pharmacokinetic Property detection of Compounds of the invention
Test animals
Healthy adult BALB/c mice, females, evenly grouped, 3 per group, 3 intragastric, 3 intravenous, mice purchased from beijing villous laboratory animal technologies ltd, animal production license number: SCXK (Zhe) 2019-0001.
Pharmaceutical formulation
A certain amount of the compound of the present invention was weighed and dissolved in DMSO 5% + PG 20% + absolute ethanol 5% + solutol 10% + water 60% to prepare 10mg/mL for gastric lavage. An amount of the compound of the present invention was weighed, dissolved in DMSO 1% + PG 4% + absolute ethanol 1% + solutol 2% + water 92%, formulated at 3mg/mL or formulated at 2mg/mL, and used for intravenous injection.
Administration mode
Gastric lavage group: BALB/c mice were fed by gastric lavage after overnight fast, at a dose of 10mg/kg and a volume of 1mL/kg.
Vein group: BALB/c mice were dosed intravenously after overnight fast at a dose of 3mg/kg and a dose volume of 1mL/kg.
Method of operation
After the mice were given by gastric lavage or intravenous administration, the blood was collected from the eyebox for 5min,15min,30min,1h,2h,4h,6h, 40. Mu.L, 5. Mu.L EDTA-K2 was anticoagulated, and the plasma was centrifuged at 12000rpm at 4℃for 5min and stored at-20 ℃.
Determination of the content of test compounds in plasma of mice after gastric lavage or intravenous administration of different concentrations of drug: melting the sample at room temperature, and swirling for 1min; quantitatively transferring 15 μl to 2ml 96-well plate, adding 150 μl of internal standard precipitant, and shaking (1200 rpm for 3 min); centrifugation (4000 rpm. Times.15 min), transfer supernatant 100. Mu.L to 1mL 96-well plates; blow-dry with nitrogen, add 100 μl of complex solution (acetonitrile water 1:9), shake well (900 rpm 3 min), and analyze with 20 μl of sample. LC/MS conditions: mobile phase a:0.1% formic acid in water, mobile phase B:0.1% acetonitrile formate, column: ACE C18 μm (3.0 mm. Times.50 mm), column temperature: the flow rate was 0.5mL/min at 35 ℃.
Test results
Under the experimental conditions, the test compounds showed better pharmacokinetic properties, and the results are shown in tables 3 and 4.
Table 3 pharmacokinetic parameters following single intragastric administration of compounds in mice
Examples Cmax(ng/mL) T max (hr) AUClast(hr*ng/mL) T 1/2 (hr)
1 116.9 0.4 344.0 1.5
2 420.3 0.5 1371.1 2.0
3 157.3 0.3 164.7 0.8
4 170.3 0.3 308.6 1.0
12 697.3 0.1 274.4 0.3
47 1293.3 0.3 3177.1 0.9
Table 4 pharmacokinetic parameters following single intravenous administration of compounds in mice
Examples C 0 (ng/mL) T 1/2 (hr) AUClast(hr*ng/mL) Vss(L/Kg)
1* 463.4 1.1 228.2 8.1
2 900.0 1.1 473.3 6.1
3 1064.7 0.9 499.1 3.8
4 1001.1 1.1 449.5 4.4
12 2579.4 0.3 491.3 1.3
47 5251.7 0.5 1509.2 0.7
* The single intravenous dose is 2mg/Kg
Experimental example 4 Effect of the inventive Compounds on the p-ERK pathway of H358 cells
The effect of the compounds of the invention on the p-ERK pathway of H358 cells was assessed by the Advanced phospho-ERK (Thr 202/Tyr 204) cellular kit method.
The experimental procedure is summarized as follows:
h358 cells (ATCC, CRL-5807) were cultured in a complete medium of RPMI1640 (ThermoFisher, A1049101) containing 10% FBS (Gibco, 10100147) and 100U/mL of a mixture of penicillin and streptomycin (Gibco, 15140163), when the coverage of the cells in the culture vessel reached 80-90%, the cells were blown off and then plated in 96-well plates (Corning, 3599), 50000 cells per well (90. Mu.l of RPMI1640 complete medium), and left standing for 5 minutes at 37℃under 5% CO 2 Is cultured in the incubator of (2) for 6 hours, and is replaced with RPMI1640 without serum for overnight starvation.
After overnight, 10. Mu.L of diluted compound was added to each well with a lance, and the 96-well plate was placed at 37℃with 5% CO 2 Is cultured in an incubator for 1 hour. Pouring the supernatant, washing with PBS once, adding 50 μl of lysate (Advanced phospho-ERK (Thr 202/Tyr 204) cell kit,64 AERPEH) into each well, shaking at 450rpm at room temperature for 1h, adding 16uL of supernatant into 384 wells (PE, 6007299) after complete cell lysis, adding mixed antibody (d 2/Eu=1:1), incubating at room temperature for 4h, selecting HTRF reading plate with ratio=Signal 665nm/Signal 620nm x 10 4 . In this experiment, the group without cells (replaced with 1640 medium) was taken as the 100% inhibition group, and the group with cells but without compound was taken as the 0% inhibition group.
The percent inhibition of the p-ERK pathway by the compound on H358 cells can be calculated using the following formula:
percent inhibition = 100 (0% inhibition group signal value-signal value at the particular concentration of test compound)/(0% inhibition group signal value-100% inhibition group signal value).
Compound IC 50 The values were calculated from 8 concentration points using XLfit (IDBusiness Solutions ltd. Uk) software by the following formula:
Y＝Bottom+(Top-Bottom)/(1+10^((logIC 50 -X)×slope factor))
wherein Y is the inhibition percentage, X is the logarithmic value of the concentration of the compound to be detected, bottom is the minimum inhibition percentage, top is the maximum inhibition percentage, and slope factor is the curve slope coefficient. Fitting sigmoid slope using default fitted curve to determine IC 50 Values.
TABLE 5 results of p-ERK inhibition test for this patent example
Examples IC 50 (nM)
38 41.9
39 13.3
40 25.0
43 103.5
44 38.2
45 110.0
46 34.7
47 17.14
48 143.11
49 34.7
50 38.1
51 179.4
52 20.0
53 69.8
54 71.0
56 36.6
57 27.5
58 81.6
59 55.3
61 42.5
62 17.3
64 121.1
65 124.3
66 41.1
67 48.4
68 112.8
69 37.4
70 135.3
71 47.5
73 86.4
74 22.1

Claims (21)

  1. A compound of formula (I) or a pharmaceutically acceptable salt thereof,
    wherein,
    x is selected from CH or N;
    y is selected from CH or N;
    z is selected from CH or N;
    R 1 selected from H, CN, C 1-6 Alkyl or C 3-6 Cycloalkyl;
    ring A is selected from C 6-10 Aryl, benzo 5-7 membered heterocyclyl or benzo 5-7 membered heteroaryl;
    l is selected from a bond or O;
    R 2 selected from C 3-10 Cycloalkyl, C 6-10 Aryl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl, said C 3-10 Cycloalkyl, C 6- 10 Aryl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl optionally substituted with R 2b And/or R 2c Substitution;
    R 2b selected from-OR 2c 、-N(R 2c ) 2 Halogen, hydroxy, cyano, amino, -C (O) R 2c 、-C(O)NHR 2c 、-C(O)NH 2 、-NHR 2c 、-C(O)H、-C(O)OH、-S(O) 2 NHR 2c 、-NHC(O)H、-N(C 1-4 Alkyl) C (O) H, -C (O) N (R) 2c ) 2 、-C(O)OR 2c 、-S(O) 2 R 2c 、-S(O) 2 N(R 2c ) 2 、-NHC(O)R 2c or-N (C) 1-4 Alkyl) C (O) R 2c ；
    R 2c Independently selected from C 1-6 Alkyl, C 1-3 Deuterated alkyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl, said C 1-6 Alkyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl optionally substituted with R 2d Substitution;
    R 2d selected from halogen, hydroxy, cyano, amino, -C (O) R 2f 、-C(O)N(R 2f ) 2 、-C(O)OR 2f 、-S(O) 2 R 2f 、-S(O) 2 N(R 2f ) 2 、-N(C 1-4 Alkyl) R 2f 、-NHC(O)R 2f or-N (C) 1-4 Alkyl) C (O) R 2f ；
    R 2f Independently selected from H or C 1-6 An alkyl group;
    R 3 selected from H, halogen, hydroxy, cyano, amino, -NH-C 3-6 Cycloalkyl, C 1-3 Deuterated alkyl, -O-C 1-3 Deuterated alkyl, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclyl, -O-C 1-6 Alkyl, -O-C 3-6 Cycloalkyl, -O- (3-8 membered heterocyclyl), 5-10 membered heteroaryl, -C (O) R 3a 、-C(O)N(R 3a ) 2 、-C(O)OR 3a 、-S(O) 2 R 3a 、-S(O) 2 N(R 3a ) 2 、-NHC(O)R 3a or-N (C) 1-4 Alkyl) C (O) R 3a the-NH-C 3-6 Cycloalkyl, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclyl, -O-C 1- 6 Alkyl, -O-C 3-6 Cycloalkyl, -O- (3-8 membered heterocyclyl) or 5-10 membered heteroaryl optionally substituted with R 3b Substitution;
    the R is 3a Independently selected from H or C 1-6 An alkyl group;
    the R is 3b Independently selected from halogen, hydroxy, cyano, amino, 3-8 membered heterocyclyl or C 1-6 An alkyl group;
    R 4 selected from halogen, hydroxy, cyano, amino, C 1-6 Alkyl, C 3-6 Cycloalkyl, -O-C 1-6 Alkyl, -O-C 3-6 Cycloalkyl, -O- (3-8 membered heterocyclyl), 3-8 membered heterocyclyl, 5-10 membered heteroaryl or-S (O) 2 -C 1-4 Alkyl, said C 1-6 Alkyl, C 3-6 Cycloalkyl, -O-C 1-6 Alkyl, -O-C 3-6 Cycloalkyl, -O- (3-8 membered heterocyclyl), 3-8 membered heterocyclyl or 5-10 membered heteroaryl optionally substituted with R 4a Substitution; the R is 4a Selected from halogen, hydroxy, cyano or amino;
    R 5 selected from C 1-3 Deuterated alkyl, C 1-6 Alkyl or C 1-6 A haloalkyl group;
    R 6 selected from H, deuterium, C 1-3 Deuterated alkyl, C 1-6 Alkyl or C 1-6 A haloalkyl group;
    n is selected from 0, 1, 2, 3 or 4;
    wherein when X is selected from N and Z is selected from CH, R 1 Selected from CN or C 3-6 Cycloalkyl;
    when X, Z is selected from N, R 1 Selected from CN, C 1-6 Alkyl or C 3-6 Cycloalkyl;
    when X, Z is selected from CH, R 3 Selected from hydroxy, cyano, amino, C 1-3 Deuterated alkyl, -O-C 1-3 Deuterated alkyl, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclyl, -O-C 1-6 Alkyl, -O-C 3-6 Cycloalkyl, -O- (3-8 membered heterocyclyl), 5-10 membered heteroaryl, -C (O) R 3a 、-C(O)N(R 3a ) 2 、-C(O)OR 3a 、-S(O) 2 R 3a 、-S(O) 2 N(R 3a ) 2 、-NHC(O)R 3a or-N (C) 1- 4 Alkyl) C (O) R 3a The C is 1-6 Alkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclyl, -O-C 1-6 Alkyl, -O-C 3-6 Cycloalkyl, -O- (3-8 membered heterocyclyl) or 5-10 membered heteroaryl optionally substituted with R 3b And (3) substitution.
  2. A compound of formula ((I)) or a pharmaceutically acceptable salt thereof according to claim 1, wherein: ring a is selected from phenyl, indanyl, indenyl, tetrahydronaphthyl, dihydronaphthyl or naphthyl.
  3. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein: r is R 2 Selected from C 3-10 Cycloalkyl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl, said C 3-10 Cycloalkyl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl optionally substituted with R 2b And/or R 2c Substitution; or alternatively
    R 2 Selected from 3-10 membered heterocyclyl or 5-10 membered heteroaryl, said 3-10 membered heterocyclyl or 5-10 membered heteroaryl optionally being substituted with R 2b And/or R 2c And (3) substitution.
  4. A compound of formula ((I)) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein: r is R 2 Selected from optionally by R 2b And/or R 2c The substituted following groups:
  5. a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein: r is R 2b Selected from-OR 2c Halogen, hydroxy, cyano, amino, -C (O) R 2c 、-C(O)OR 2c 、-S(O) 2 R 2c 、-C(O)NHR 2c or-NHC (O) R 2c The method comprises the steps of carrying out a first treatment on the surface of the Or R is 2b Selected from halogen, hydroxy, cyano, amino, -C (O)R 2c 、-S(O) 2 R 2c or-C (O) NHR 2c 。
  6. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein:
    R 2c selected from C 1-6 Alkyl, C 1-3 Deuterated alkyl, C 3-10 Cycloalkyl or 3-10 membered heterocyclyl, said C 1-6 Alkyl, C 3-10 Cycloalkyl or 3-10 membered heterocyclyl optionally substituted with R 2d And (3) substitution.
  7. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein: r is R 4 Selected from halogen, hydroxy, cyano, amino, C 1-6 Alkyl, C 3-6 Cycloalkyl or 3-8 membered heterocyclyl, said C 1-6 Alkyl, C 3-6 Cycloalkyl or 3-8 membered heterocyclyl optionally being substituted by R 4a And (3) substitution.
  8. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein: r is R 3 Selected from H, halogen, hydroxy, cyano, amino, -NH-C 3-6 Cycloalkyl, C 1-3 Deuterated alkyl, -O-C 1-3 Deuterated alkyl, C 1-6 Alkyl, C 3-6 Cycloalkyl, -O-C 1-6 Alkyl, -O-C 3-6 Cycloalkyl, -C (O) R 3a 、-C(O)OR 3a 、-S(O) 2 -C 1-4 Alkyl or 5-10 membered heteroaryl, said-NH-C 3-6 Cycloalkyl, C 1-6 Alkyl, C 3-6 Cycloalkyl, -O-C 1-6 Alkyl, -O-C 3-6 Cycloalkyl or 5-to 10-membered heteroaryl optionally substituted with R 3b Substitution; or alternatively
    R 3 Selected from H, halogen, hydroxy, cyano, amino, -NH-C 3-6 Cycloalkyl, C 1-3 Deuterated alkyl, -O-C 1-3 Deuterated alkyl, C 1-6 Alkyl, -O-C 1-6 Alkyl, -C (O) R 3a 、-C(O)OR 3a 、-S(O) 2 -C 1-4 Alkyl or 5-10 membered heteroaryl, said-NH-C 3-6 Cycloalkyl, C 1-6 Alkyl, -O-C 1-6 Alkyl or 5-10 membered heteroaryl optionally substituted with R 3b Substitution; or alternatively
    R 3 Selected from H, amino, -NH-C 3-6 Cycloalkyl, -C (O) R 3a 、-C(O)OR 3a 、C 1-6 Alkyl, -O-C 1-6 Alkyl or 5-10 membered heteroaryl, said-NH-C 3-6 Cycloalkyl, C 1-6 Alkyl, -O-C 1-6 Alkyl or 5-10 membered heteroaryl optionally substituted with R 3b And (3) substitution.
  9. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein: r is R 5 Selected from C 1-3 Deuterated alkyl, C 1-3 Alkyl or C 1-3 A haloalkyl group.
  10. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein: r is R 6 Selected from H, deuterium, C 1-3 Deuterated alkyl, C 1-3 Alkyl or C 1-3 A haloalkyl group; or R is 6 Selected from H, deuterium, CH 3 Or CD (compact disc) 3 。
  11. A compound of formula ((I)) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, wherein: n is selected from 0, 1 or 2; or n is selected from 2.
  12. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7 or 9 to 11, wherein: the compound shown in the formula (I) or the pharmaceutically acceptable salt thereof is selected from the compound shown in the formula (II) or the pharmaceutically acceptable salt thereof,
    wherein the ring A, L, R 1 、R 2 、R 4 、R 5 、R 6 N is as defined in any one of claims 1 to 7 or 9 to 11, R 3 Selected from hydroxy, cyano, amino, C 1-3 Deuterated alkyl, -O-C 1-3 Deuterated alkyl, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclyl, -O-C 1-6 Alkyl, -O-C 3-6 Cycloalkyl, -O- (3-8 membered heterocyclyl), 5-10 membered heteroaryl, -C (O) R 3a 、-C(O)N(R 3a ) 2 、-C(O)OR 3a 、-S(O) 2 R 3a 、-S(O) 2 N(R 3a ) 2 、-NHC(O)R 3a or-N (C) 1-4 Alkyl) C (O) R 3a The C is 1 - 6 Alkyl, C 3- 6 Cycloalkyl, 3-8 membered heterocyclyl, -O-C 1-6 Alkyl, -O-C 3-6 Cycloalkyl, -O- (3-8 membered heterocyclyl) or 5-10 membered heteroaryl optionally substituted with R 3b Substitution; the R is 3a Independently selected from H or C 1-6 An alkyl group; the R is 3b Selected from halogen, hydroxy, cyano, amino or 3-8 membered heterocyclyl.
  13. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 12, wherein: r is R 3 Selected from C 1-3 Deuterated alkyl, -O-C 1-3 Deuterated alkyl, C 1-6 Alkyl, -O-C 1-6 Alkyl, -C (O) R 3a 、-C(O)OR 3a 、-S(O) 2 -C 1-4 Alkyl or 5-10 membered heteroaryl, said C 1-6 Alkyl, -O-C 1-6 Alkyl or 5-10 membered heteroaryl optionally substituted with R 3b And (3) substitution.
  14. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, wherein: the compound shown in the formula (I) or the pharmaceutically acceptable salt thereof is selected from the compound shown in the formula (III) or the pharmaceutically acceptable salt thereof,
    wherein the ring A, L, Y, R 3 、R 4 、R 5 、R 6 N is as defined in any one of claims 1 to 11, R 1 Selected from cyano, C 1-6 Alkyl or C 3-6 Cycloalkyl, R 2 Selected from optionally by R 2b And/or R 2c The substituted following groups:
  15. the compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 14, wherein: the compound shown in the formula (I) or the pharmaceutically acceptable salt thereof is selected from the compound shown in the formula (IV) or the pharmaceutically acceptable salt thereof,
    Wherein the ring A, L, R 3 、R 4 、R 5 、R 6 N is as defined in claim 14, R 1 Selected from cyano, C 1-6 Alkyl or C 3-6 Cycloalkyl, R 2 Selected from optionally by R 2b And/or R 2c The substituted following groups:
  16. the compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 14, wherein: the compound shown in the formula (I) or the pharmaceutically acceptable salt thereof is selected from the compound shown in the formula (V) or the pharmaceutically acceptable salt thereof,
    wherein the ring A, L, R 3 、R 4 、R 5 、R 6 N is as defined in claim 14, R 1 Selected from cyano, C 1-6 Alkyl or C 3-6 Cycloalkyl, R 2 Selected from optionally by R 2b And/or R 2c The substituted following groups:
  17. a compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein: the compound shown in the formula (I) or pharmaceutically acceptable salt thereof is selected from the following compounds or pharmaceutically acceptable salts thereof,
  18. a pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant.
  19. Use of a compound of formula (I) according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 18, for the manufacture of a medicament for the prophylaxis or treatment of a disease associated with SOS 1.
  20. A method of preventing or treating SOS 1-related disorders, which comprises administering to a patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 17, or a pharmaceutical composition as claimed in claim 18.
  21. The use according to claim 19 or the method according to claim 20, characterized in that: the SOS 1-related disease is selected from cancer.
CN202280011875.4A 2021-01-29 2022-01-28 SOS1 inhibitor and preparation method and application thereof Pending CN117279914A (en)

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