CN112574236B - RET inhibitor, pharmaceutical composition and application thereof - Google Patents

RET inhibitor, pharmaceutical composition and application thereof Download PDF

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CN112574236B
CN112574236B CN202011034764.4A CN202011034764A CN112574236B CN 112574236 B CN112574236 B CN 112574236B CN 202011034764 A CN202011034764 A CN 202011034764A CN 112574236 B CN112574236 B CN 112574236B
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CN112574236A (en
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谢洪明
罗明
张英俊
寇玉辉
胡扬校
何锦
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Guangdong HEC Pharmaceutical
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • 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
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention belongs to the field of medicines, and relates to a RET inhibitor, a pharmaceutical composition thereof and application thereof. In particular, the present invention relates to a compound of formula (I), or a stereoisomer, a geometric isomer, a tautomer, a nitroxide, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug of a compound of formula (I), to pharmaceutical compositions comprising said compounds, and to the use of said compounds and pharmaceutical compositions thereof in the manufacture of a medicament, in particular for the treatment and prevention of diseases and disorders associated with useful RET, including cancer, irritable bowel syndrome and/or pain associated with irritable bowel syndrome.

Description

RET inhibitor, pharmaceutical composition and application thereof
Technical Field
The present invention is in the field of medicaments, in particular, the present invention relates to novel compounds exhibiting a transfection-phase Rearrangement (RET) kinase inhibition, pharmaceutical compositions comprising said compounds, the use of compounds or pharmaceutical compositions thereof in the manufacture of a medicament, in particular for the treatment and prevention of RET related diseases and disorders, including cancer, irritable bowel syndrome and/or pain associated with irritable bowel syndrome.
Background
Transfection rearrangement (Re-arranged during transfection, RET) is one of the receptor-type tyrosine kinases belonging to the cadherin superfamily that activates a number of downstream pathways involved in cell proliferation and survival.
The consequences of abnormal RET gene production (point mutations, chromosomal translocations, chromosomal inversion, gene amplification) are reported to be related to canceration. RET fusion proteins are associated with several cancers, including papillary thyroid cancers and non-small cell lung cancers. RET fusion proteins are identified as driving factors for certain cancers, which motivates the use of multi-kinase inhibitors with RET inhibiting activity to treat patients whose tumors express RET fusion proteins. Multiple kinase inhibitors such as sorafenib (Sorafenib), sunitinib, vandetanib, and pluratinib have been reported to exhibit cell proliferation inhibition (J Clin Oncol 30,2012,suppl;Abstract no:7510) on cell lines expressing KIF 5B-RET. In addition, the multi-kinase inhibitor cabotinib was reported to exhibit partial efficacy in two patients with non-small cell lung Cancer positive for RET fusion gene (Cancer discover, 3 (6), jun 2013, p.630-5). However, these drugs cannot always be administered at a level sufficient to inhibit RET due to toxicity resulting from inhibition of targets other than RET. Furthermore, one of the biggest challenges in treating cancer is the ability of tumor cells to develop resistance to treatment. Kinase reactivation via mutation is a common drug resistance mechanism. When resistance occurs, the treatment options for patients are often very limited and in most cases cancer progression is not inhibited. WO 2017011776 discloses single-target RET kinase inhibitors having good preventive or therapeutic effects on RET and its mutation-related cancers. There is still a need to further develop compounds that inhibit RET and its resistant mutants to cope with cancers associated with abnormal RET genes.
Disclosure of Invention
The invention provides a novel compound for inhibiting a transfection-phase Rearrangement (RET) kinase, which has good inhibition effect on RET wild type and RET gene mutants and good inhibition selectivity on RET wild type and RET gene mutants.
The excellent properties of certain parameters of the compounds of the present invention, such as half-life, clearance, selectivity, bioavailability, chemical stability, metabolic stability, membrane permeability, solubility, etc., can contribute to a reduction in side effects, an expansion of therapeutic index, or an improvement in tolerability, etc.
In one aspect, the invention provides a compound of formula (I), or a stereoisomer, geometric isomer, tautomer, nitroxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of a compound of formula (I),
Wherein,
X 1、X2、X3、X4 and X 5 are each independently CR 4 or N;
y is O, NH or S;
T is a bond, alkylene-O-or alkylene-NH-, and said T is optionally substituted with 1, 2, 3 or 4 substituents selected from D, OH, F, cl, br, I, CN, NH 2, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, heterocyclyl, alkoxy, aryl, heteroaryl or alkylamino;
Ring G is a carbocyclyl or a heterocyclyl;
q is 0,1, 2, 3 or 4;
R a is D、OH、NH2、F、Cl、Br、I、CN、NR5R6、OR7、-NR6C(＝O)R7、-S(＝O)2R7、-S(＝O)R7、-C(＝O)R7、-C(＝O)OR7、 oxo, alkyl, alkoxy, cycloalkyl, haloalkyl, alkoxyalkyl, hydroxyalkyl, or hydroxyalkoxy;
E is a bond, -NR 6 -, or-O-;
ring a is a bridged, fused or spiro-alkylene group, and ring a is optionally substituted with 1,2,3 or 4 substituents selected from F, cl, br, OH, oxo, NR 5R6、R5(C＝O)NR6 -, aminoalkyl, alkyl, alkoxy, haloalkyl, hydroxyalkyl, carbocyclyl, heterocyclyl, heterocyclylalkyl, alkoxyalkyl, cycloalkylene and heterocyclylalkyl;
q is a bond 、-(CR2R3)tO-、-(CR2R3)f-、-(CR2R3)t-NR6-、-(C＝O)(CR2R3)t-、-(C＝O)(CR2R3)t-(S＝O)2(CR2R3)f-、-(C＝O)(CR2R3)t-NR6(CR2R3)f-、-(C＝O)(CR2R3)t-O(CR2R3)f-、-(C＝O)NR6O(CR2R3)f-、-(S＝O)2-NR6-(CR2R3)t-、-(CR2R3)f-(C＝O)-、-(CR2R3)t-(C＝O)-NR6-(CR2R3)t-、-(S＝O)2(CR2R3)t-、-(CR2R3)f-(S＝O)2(CR2R3)t-、-(S＝O)2O-、-O(C＝O)-、-(C＝O)NR6- or-NR 6 (c=o) -;
each f is independently 1, 2, 3 or 4;
each t is independently 0, 1,2,3 or 4;
M is H, D, heteroaryl, aryl, cycloalkyl or heterocyclyl, and M is optionally substituted with 1,2,3 or 4 substituents selected from D, F, cl, CN, OH, NR 5R6、OR7, alkyl, haloalkyl, hydroxyalkyl, haloalkoxy, aryl, alkoxyalkyl, oxo, alkanoyl, heterocyclyl and cycloalkyl;
R 1 is H, D, CN, F, cl, br, alkyl or cycloalkyl, wherein the alkyl and cycloalkyl groups are independently optionally substituted with 1, 2, 3 or 4 substituents selected from F, cl, br, CN, NH 2, OH and NO 2;
Each R 2 and R 3 is independently OH, F, H, D, CN, cl, br, NH 2, hydroxyalkyl, alkyl, alkylamino, alkoxy, haloalkoxy, cycloalkyl, haloalkyl, cycloalkylalkyl, aryl or heteroaryl;
or R 2、R3 and the same carbon atom to which it is attached form a carbocyclic or heterocyclic ring;
R 4 is H, D, F, cl, br, alkyl or alkoxy, wherein each of said alkyl and alkoxy is independently optionally substituted with 1,2, 3 or 4 substituents selected from F, cl, br, CN, NH 2, OH and NO 2;
R 5 is H, D, alkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl, wherein each of said alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with 1,2, 3, or 4 substituents selected from F, cl, br, OH, NH 2, alkylamino, alkyl, alkylsulfonyl, alkoxy, aryl, and heteroaryl;
R 6 is H, D, alkyl or alkoxyalkyl, wherein each of the alkyl and alkoxyalkyl is independently optionally substituted with 1,2, 3 or 4 substituents selected from F, cl, br, CN, NH 2, OH and NO 2;
R 7 is OH, alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl.
In some embodiments, T is a bond, C 1-6 alkylene, C 1-6 alkylene-O-, or C 1-6 alkylene-NH-, and T is optionally substituted with 1,2,3, or 4 substituents selected from D, OH, F, cl, br, I, CN, NH 2、C1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, C 1-6 alkoxy, C 6-10 aryl, 5-12 membered heteroaryl, and C 1-6 alkylamino.
In some embodiments, T is a bond 、-CH2-、-(CH2)2-、-(CH2)3-、-(CH2)4-、-(CH2)5-、-(CH2)6-、-(CH2)2-O- or- (CH 2)2 -NH-, and the T is optionally substituted with 1,2, 3, or 4 substituents selected from D, OH, F, cl, br, I, CN, NH 2、CF3、CHF2、CHCl2, methyl, ethyl, propyl, 2-hydroxyethyl, 1-hydroxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, oxetanyl, methoxy, ethoxy, propoxy, butoxy, phenyl, methylamino, and dimethylamino.
In some embodiments of the present invention, in some embodiments,
Ring G is 4-12 membered carbocyclyl or 4-12 membered heterocyclo;
r a is D、OH、NH2、F、Cl、Br、I、CN、NR5R6、OR7、-NR6C(＝O)R7、-S(＝O)2R7、-S(＝O)R7、-C(＝O)R7、-C(＝O)OR7、 oxo, C 1-6 alkyl, C 1-6 alkoxy, C 3-7 cycloalkyl, C 1-6 haloalkyl, C 1-6 alkoxy C 1-6 alkyl, C 1-6 hydroxyalkyl or C 1-6 hydroxyalkoxy;
R 5 is H, D, C 1-6 alkyl, 3-12 membered carbocyclyl, 3-12 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl, wherein said C 1-6 alkyl, 3-12 membered carbocyclyl, 3-12 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl are each independently optionally substituted with 1,2,3, or 4 substituents selected from F, cl, br, OH, NH 2、C1-6 alkylamino, C 1-6 alkyl, C 1-6 alkylsulfonyl, C 1-6 alkoxy, C 1-6 aryl, and 5-10 membered heteroaryl;
R 6 is H, D, C 1-6 alkyl or C 1-6 alkoxy C 1-6 alkyl, wherein the C 1-6 alkyl and C 1-6 alkoxy C 1-6 alkyl are each independently optionally substituted with 1,2, 3 or 4 substituents selected from F, cl, br, CN, NH 2, OH and NO 2;
R 7 is OH, C 1-6 alkyl, C 3-6 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl.
In some embodiments, ring G is of the following sub-structural formula:
Wherein,
T 1 is a 3-6 membered carbon monocyclic ring or a 3-6 membered heteromonocyclic ring;
z 4 is CH or N;
Z 1 is NH, O, S or CH 2;
Each Z 2 and Z 3 is independently O, S or NH;
each n1 is independently 0,1 or 2;
n2 is 0, 1, 2 or 3.
In some embodiments, ring G is of the following sub-structural formula:
R a is D、OH、NH2、F、CF3、CHCl2、CHF2、CH2F、CF3CH2、Cl、Br、I、CN、NH2、NHCH3、-NHC(＝O)CH3、-S(＝O)2CH3、-S(＝O)CH3、-C(＝O)CH3、-C(＝O)OH、 oxo, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, methoxy, ethoxy, cyclopropyl, cyclopentyl, methoxymethyl, ethoxymethyl, methoxyethyl, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 2-hydroxypropyl, 2-hydroxy-2-methylpropyl, 2-hydroxyethoxy or 1-hydroxyethoxy;
r 5 is H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, cyclopropyl, cyclopentyl, pyrrolidinyl, phenyl, or pyrazolyl; wherein said methyl, ethyl, n-propyl, cyclopropyl, cyclopentyl, pyrrolidinyl, phenyl, and pyrazolyl are each independently optionally substituted with 1,2, 3, or 4 substituents selected from F, cl, br, OH, NH 2, methyl, -S (=o) 2CH3, methoxy, ethoxy, and phenyl;
r 6 is H, D, methyl, ethyl, n-propyl, n-butyl, methoxymethyl, ethoxymethyl or methoxyethyl, wherein each of the methyl, ethyl, n-propyl, n-butyl, methoxymethyl, ethoxymethyl and methoxyethyl groups is independently optionally substituted with 1,2,3 or 4 substituents selected from F, cl, br, CN, NH 2, OH and NO 2;
R 7 is OH, methyl, ethyl, NH 2、N(CH3)2, methyl, isopropyl, tert-butyl, cyclopropyl or phenyl.
In some embodiments, ring a is a 5-12 membered bridged ring group, a 5-12 membered fused ring group, or a 5-12 membered spiro ring group, and a is optionally substituted with 1, 2, 3, or 4 substituents selected from F, cl, br, OH, oxo, NR 5R6、R5(C＝O)NR6 -, amino C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, 3-12 membered carbocyclyl, 3-12 membered heterocyclyl C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl, C 3-6 cycloalkylene, and 3-6 membered heterocycloalkylene.
In some embodiments, ring a is of the following sub-structural formula:
Wherein Z 1a and Z 2a are each independently CH 2 or NH;
Each Z 3a and Z 7a is independently CH or N;
Z 4a is O, S or NH;
Each Z 5a and Z 6a is independently CH 2、O、S、S(＝O)、S(＝O)2, C (=o) or NH;
Each m and t is independently 0,1 or 2;
each n and t1 is independently 0 or 1;
Wherein each substructure of ring A is independently optionally substituted with 1,2, 3 or 4 substituents selected from F, cl, br, OH, oxo, NR 5R6、R5(C＝O)NR6 -, aminoC 1-4 alkyl, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, 3-12 membered carbocyclyl, 3-12 membered heterocyclyl C 1-4 alkyl, C 1-4 alkoxy C 1-4 alkyl, C 3-6 cycloalkylene and 3-6 membered heterocycloalkylene.
In some embodiments, ring a is of the following sub-structural formula:
Wherein each substructure of ring a is independently optionally substituted with 1, 2, 3 or 4 substituents selected from F, cl, br, OH, oxo, NH 2、NHCH3、CH3 (c=o) NH-, methyl, ethyl, n-propyl, methoxy, ethoxy, isopropoxy, CF 3, hydroxymethyl, 2-hydroxyethyl, cyclopropyl, cyclohexyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, cyclopropylene, cyclohexylene and pyrrolidinylene.
In some embodiments, M is H, D, 5-10 membered heteroaryl, C 6-10 aryl, C 3-7 cycloalkyl, or 3-12 membered heterocyclyl; and M is optionally substituted with 1,2, 3 or 4 substituents selected from F, cl, CN, OH, NR 5R6、OR7、C1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 haloalkoxy, C 6-10 aryl, C 1-6 alkoxy C 1-6 alkyl, oxo, C 1-6 alkanoyl, 3-7 membered heterocyclyl and C 3-7 cycloalkyl.
In some embodiments, M is H, D, pyridinyl, pyrimidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, pyrazinyl, phenyl, cyclopentyl, cyclopropyl, cyclohexyl, cyclobutyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, morpholinyl, tetrahydrothiopyranyl, oxetanyl, 1, 2-dihydropyridinyl, 7-azabicyclo [2.2.1] heptanyl, hexahydrofuro [3,4-c ] pyrrolyl, 3-azabicyclo [3.1.0] hexanyl, octahydropyrrolo [1,2-a ] pyrazinyl, or 5-azaspiro [2.4] heptanyl; and M is optionally substituted with 1,2, 3 or 4 substituents selected from D、F、Cl、CN、OH、CF3、CHCl2、CHF2、CH2F、CF3CH2、NH2、NHCH3、N(CH3)2、 trifluoromethoxy, 2-trifluoroethoxy, methoxy, ethoxy, isopropoxy, tert-butoxy, methyl, ethyl, n-propyl, isopropyl, phenyl, methoxymethyl, methoxyethyl, oxo, formyl, acetyl, morpholinyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, cyclopropyl and cyclohexyl.
In some embodiments, R 1 is H, D, CN, F, cl, br, methyl, ethyl, or cyclopropyl, wherein the methyl, ethyl, and cyclopropyl groups are independently optionally substituted with 1,2,3, or 4 substituents selected from F, cl, br, CN, NH 2, OH, and NO 2;
r 4 is H, D, F, cl, br, methyl, ethyl, n-propyl, methoxy or ethoxy, wherein the methyl, ethyl, n-propyl, methoxy and ethoxy groups are independently optionally substituted with 1, 2, 3 or 4 substituents selected from F, cl, br, CN, NH 2, OH and NO 2.
In some embodiments, each R 2 and R 3 is independently OH, F, H, D, CN, cl, br, NH 2、C1-6 hydroxyalkyl, C 1-6 alkyl, C 1-6 alkylamino, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-7 cycloalkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl C 1-6 alkyl, C 6-10 aryl, or 5-10 membered heteroaryl;
Or R 2、R3 and the same carbon atom to which it is attached form a 3-7 membered carbocyclic ring or a 3-7 membered heterocyclic ring.
In some embodiments, each R 2 and R 3 is independently OH, F, CF 3、CHCl2、CHF2、H、D、CN、Cl、Br、NH2, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, methyl, ethyl, N (CH 3)2, methoxy, ethoxy, isopropoxy, t-butoxy, trifluoromethoxy, cyclopropyl, cyclopentyl, cyclopropylmethyl, cyclopentylethyl, cyclopentylmethyl, phenyl, pyridinyl, or pyrazinyl;
Or R 2、R3 and the same carbon atom to which it is attached form cyclopentane, cyclopropane, cyclobutane, tetrahydropyran, tetrahydrofuran, piperidine or pyrrolidine.
In some embodiments, Q is a bond 、-O-、-(CH2)2O-、-CH2-、-(CH2)2-、-(CH2)3-、-CH2CH(CH3)CH2-、-CH2CH(CH3)CH2NHCH2-、-(C＝O)OC(CH3)2CH2-、-(C＝O)(CH2)2(S＝O)2CH2-、-(C＝O)CH(OH)-、-(C＝O)CH(OH)CH2-、-(C＝O)-、-(S＝O)2-、-(C＝O)CH2CH(OH)-、-(C＝O)CH2-、-(C＝O)CH(CH2OH)-、-(C＝O)C(CH3)2-、-(C＝O)CH2NHC(CH3)2CH2-、-(C＝O)CH2CH(N(CH3)2)-、-(C＝O)(CH2)2N(CH3)CH2-、-(C＝O)C(CH3)2CH2-、-(C＝O)C(OH)(CH3)CH2-、-(C＝O)CH2OCH2-、-(C＝O)(CH2)3-、-(C＝O)CH(NH2)-、-(C＝O)(CH2)3N(CH3)CH2-、-(C＝O)(CH2)2-、-(C＝O)CH2CH(OH)CH2-、-(C＝O)CF2CH2-、-(C＝O)CH(OH)C(CH3)2CH2-、-(C＝O)CH2C(CH3)2CH2-、-(C＝O)CH2C(CH3)(OH)CH2-、-(S＝O)2CH2-、-(S＝O)2CH2C(CH3)2CH2-、-(C＝O)CH(OCH3)-、-(C＝O)NHCH(CH2OH)(CH2)2-、-(C＝O)NH-、-(C＝O)N(CH3)-、-(C＝O)N(CH2CH2CH2CH3)-、-(C＝O)N(CH2CH3)(CH2)2-、-(C＝O)NHC(CH3)2CH2-、-(C＝O)N(CH3)(CH2)2-、-(C＝O)NHCH2CH(CH3)CH2-、-(C＝O)NHCH2-、-(C＝O)NH(CH2)2OCH2-、-(C＝O)N(CH3)(CH2)2OCH2-、-(S＝O)2NHC(CH3)2CH2-、-CH2CH(OH)C(CH3)2CH2-、-CH(CH3)CH(OH)-、-CH2(C＝O)NHCH(CH3)CH2-、-CH2(C＝O)-、-(CH2)2(C＝O)N(CH3)CH2-、-CH2CH(OH)-、-CH2CH(OH)CH2-、-CH2CH(OH)CH(CH3)CH2-、-(C＝O)CH(N(CH3)2)-、-(C＝O)C(CH3)2CH2OCH2-、-(C＝O)C(OCH3)(CF3)-、-(C＝O)N(CH2CH2OCH3)CH2CH(OCH3)-、-CH2CH(OCF3)-、-CH2CH(OCH(CH3)2)-、-CH2CH(OC(CH3)3)-、-CH2CF2-、-CH(CH3)-、-CH2CH(OCH3)C(CH3)2-、-CH2CH(N(CH3)2)-、-NH-、-(C＝O)NHOCH2-、-(C＝O)NHOCH2(CHOH)-、-(S＝O)2(CH2CH3)-、-(S＝O)2O-、-(S＝O)2-NHC(CH3)2-、-(CH2)2(S＝O)2-、
In some embodiments, the compounds of the present invention have the structure of formula (I-1), or stereoisomers, geometric isomers, tautomers, nitroxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs of the structure of formula (I-1),
Wherein,
Ring A1 is of the sub-structural formula:
Wherein each Z 1a and Z 2a is independently CH 2 or NH;
And each sub-structural formula of ring A1 is independently optionally substituted with 1,2,3 or 4 substituents selected from F, cl, br, OH, oxo, NR 5R6、R5(C＝O)NR6 -, aminoC 1-4 alkyl, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, 3-12 membered carbocyclyl, 3-12 membered heterocyclyl C 1-4 alkyl, C 1-4 alkoxy C 1-4 alkyl, C 3-6 cycloalkylene and 3-6 membered heterocycloalkylene.
In some embodiments, ring A1 is of the formula:
Wherein each substructure of ring A1 is independently optionally substituted with 1,2, 3 or 4 substituents selected from F, cl, br, OH, oxo, NH 2、NHCH3、CH3 (c=o) NH-, methyl, ethyl, n-propyl, methoxy, ethoxy, isopropoxy, CF 3, hydroxymethyl, 2-hydroxyethyl, cyclopropyl, cyclohexyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, cyclopropylene, cyclohexylene and pyrrolidinylene.
In some embodiments, the compounds of the present invention have the structure of formula (I-2) or (I-3), or stereoisomers, geometric isomers, tautomers, nitroxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs of the structure of formula (I-2) or (I-3),
Wherein each Z 1、Z2、Z3a and Z 7a is independently CH or N;
Each m and t is independently 0,1 or 2;
each n and t1 is independently 0 or 1;
Each of which is Independently optionally substituted with 1,2, 3 or 4 substituents selected from F, cl, br, OH, oxo, NR 5R6、R5(C＝O)NR6 -, aminoC 1-4 alkyl, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, 3-12 membered carbocyclyl, 3-12 membered heterocyclyl C 1-4 alkyl, C 1-4 alkoxy C 1-4 alkyl, C 3-6 cycloalkylene and 3-6 membered heterocycloalkylene.
In some embodiments of the present invention, in some embodiments,The following sub-structural formula is shown as follows:
the following sub-structural formula is shown as follows:
Wherein the method comprises the steps of Independently optionally substituted with 1,2, 3 or 4 substituents selected from F, cl, br, OH, oxo, NH 2、NHCH3、CH3 (c=o) NH-, methyl, ethyl, n-propyl, methoxy, ethoxy, isopropoxy, CF 3, hydroxymethyl, 2-hydroxyethyl, cyclopropyl, cyclohexyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, cyclopropylene, cyclohexylene and pyrrolidinylene.
In another aspect, the invention provides a pharmaceutical composition comprising a compound of the invention, and a pharmaceutically acceptable adjuvant.
In another aspect, the invention also provides the use of the compound of the invention or the pharmaceutical composition of the invention in the preparation of a medicament for preventing or treating RET-related diseases.
In some embodiments, the RET related disease includes cancer, irritable bowel syndrome and/or pain associated with irritable bowel syndrome.
In another aspect, the invention also provides a compound of the invention or a pharmaceutical composition of the invention for use in the prevention or treatment of RET-related disorders.
In some embodiments, the RET related disease includes cancer, irritable bowel syndrome and/or pain associated with irritable bowel syndrome.
In another aspect, the invention also provides a method of preventing or treating RET-related disorders comprising administering to a patient a therapeutically effective amount of a compound of the invention or a pharmaceutical composition thereof.
In some embodiments, the RET related disease includes cancer, irritable bowel syndrome and/or pain associated with irritable bowel syndrome.
In another aspect, the present invention relates to intermediates for preparing compounds of formula (I), (I-1), (I-2) or (I-3).
In another aspect, the present invention relates to methods for the preparation, isolation and purification of compounds of formula (I), (I-1), (I-2) or (I-3).
In another aspect, the invention provides a pharmaceutical composition comprising a compound of the invention and pharmaceutically acceptable adjuvants thereof. In some embodiments, adjuvants described herein include, but are not limited to, carriers, excipients, diluents, vehicles, or combinations thereof. In some embodiments, the pharmaceutical composition may be in a liquid, solid, semi-solid, gel or spray form.
Unless otherwise indicated, all stereoisomers, geometric isomers, tautomers, nitroxides, hydrates, solvates, metabolites, salts and pharmaceutically acceptable prodrugs of the compounds of the invention are within the scope of the invention.
In particular, salts are pharmaceutically acceptable salts. The term "pharmaceutically acceptable" includes substances or compositions that must be suitable for chemical or toxicological use, in relation to the other components that make up the formulation and the mammal being treated.
Salts of the compounds of the present invention also include salts of the isolated enantiomers of the compounds of formula (I), (I-1), (I-2) or (I-3) or intermediates used in the preparation or purification of the compounds of formula (I), (I-1), (I-2) or (I-3), but are not necessarily pharmaceutically acceptable salts.
Detailed description of the invention
Definitions and general terms
Reference will now be made in detail to certain embodiments of the application, examples of which are illustrated in the accompanying structural and chemical formulas. The application is intended to cover all alternatives, modifications and equivalents, which may be included within the scope of the application as defined by the appended claims. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used in the practice of the present application. The present application is in no way limited to the methods and materials described herein. In the event of one or more of the incorporated references, patents and similar materials differing from or contradictory to the present application (including but not limited to defined terms, term application, described techniques, etc.), the present application controls.
It should further be appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable sub-combination.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference in their entirety.
The term "subject" as used herein refers to an animal. Typically the animal is a mammal. The subject, for example, also refers to a primate (e.g., human, male or female), cow, sheep, goat, horse, dog, cat, rabbit, rat, mouse, fish, bird, and the like. In certain embodiments, the subject is a primate. In other embodiments, the subject is a human.
The term "patient" as used herein refers to a human (including adults and children) or other animals. In some embodiments, "patient" refers to a human.
The term "comprising" is an open-ended expression, i.e., including what is indicated by the invention, but not excluding other aspects.
"Stereoisomers" refer to compounds having the same chemical structure but different arrangements of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis/trans), atropisomers, and the like.
The stereochemical definitions and rules used in the present invention generally follow S.P.Parker,Ed.,McGraw-Hill Dictionary of Chemical Terms(1984)McGraw-Hill Book Company,New York;and Eliel,E.and Wilen,S.,"Stereochemistry of Organic Compounds",John Wiley&Sons,Inc.,New York,1994.
The resulting mixture of any stereoisomers may be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, e.g., by chromatography and/or fractional crystallization, depending on the differences in the physicochemical properties of the components.
The term "tautomer" or "tautomeric form" refers to structural isomers having different energies that can be interconverted by a low energy barrier (low energy barrier). If tautomerism is possible (e.g., in solution), chemical equilibrium of the tautomers can be achieved. For example, proton tautomer (protontautomer) (also known as proton transfer tautomer (prototropic tautomer)) includes interconversions by proton transfer, such as keto-enol isomerisation and imine-enamine isomerisation. Valence tautomers (valence tautomer) include interconversions by recombination of some of the bond-forming electrons. Specific examples of keto-enol tautomerism are tautomerism of pentane-2, 4-dione and 4-hydroxypent-3-en-2-one tautomer. Another example of tautomerism is phenol-ketone tautomerism. One specific example of phenol-ketone tautomerism is the interconversion of pyridin-4-ol and pyridin-4 (1H) -one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
Unless otherwise indicated, the structural formulae described herein include all isomeric forms (e.g., enantiomers, diastereomers, and geometric isomers (or conformational isomers)): for example, R, S configurations containing asymmetric centers, the (Z), (E) isomers of double bonds, and the conformational isomers of (Z), (E). Thus, individual stereochemical isomers of the compounds of the invention, or enantiomers, diastereomers, or mixtures of geometric isomers (or conformational isomers) thereof, are all within the scope of the invention.
Unless otherwise indicated, the structural formulae described herein and the compounds described herein include all isomeric forms (e.g., enantiomers, diastereomers, geometric isomers, or conformational isomers), nitroxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts and prodrugs. Thus, compounds of the individual stereochemical isomers, enantiomers, diastereomers, geometric isomers, conformational isomers, nitroxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts and prodrugs of the compounds of the invention are also within the scope of the invention. In addition, unless otherwise indicated, the structural formulae of the compounds described herein include enriched isotopes of one or more different atoms.
The compounds of the invention, as described herein, may independently be optionally substituted with one or more substituents, such as those of the general formula above, or as exemplified by the specific examples provided herein, subclasses, and classes of compounds encompassed by the invention. It is to be understood that the term "independently optionally substituted with … …" may be used interchangeably with the term "substituted or unsubstituted". In general, the term "substituted" means that one or more hydrogen atoms in a given structure are replaced with a specific substituent. An optional substituent group may be substituted at each substitutable position of the group unless otherwise indicated. When more than one position in a given formula can be substituted with one or more substituents selected from a particular group, then the substituents may be the same or different at each position.
In addition, unless explicitly indicated otherwise, the description used in this disclosure of the manner in which "each … is independently" and "… is independently" and "… is independently" are to be understood in a broad sense as meaning that the particular choices expressed between the same symbols in different groups do not affect each other, or that the particular choices expressed between the same symbols in the same groups do not affect each other.
In the various parts of the present specification, substituents of the presently disclosed compounds are disclosed in terms of the type or scope of groups. It is specifically noted that the present invention includes each individual subcombination of the individual members of these group classes and ranges. For example, the term "C 1-6 alkyl" refers specifically to independently disclosed methyl, ethyl, C 3 alkyl, C 4 alkyl, C 5 alkyl, and C 6 alkyl.
In the various parts of the invention, linking substituents are described. When the structure clearly requires a linking group, the markush variables recited for that group are understood to be linking groups. For example, if the structure requires a linking group and the markush group definition for that variable enumerates an "alkyl" or "aryl" group, it will be understood that the "alkyl" or "aryl" represents a linked alkylene group or arylene group, respectively.
The term "alkyl" denotes a saturated, straight or branched, monovalent hydrocarbon group containing 1 to 20 carbon atoms, wherein the alkyl group may be optionally substituted with one or more substituents described herein. Unless otherwise specified, alkyl groups contain 1 to 20 carbon atoms. In one embodiment, the alkyl group contains 1 to 12 carbon atoms; in another embodiment, the alkyl group contains 1 to 6 carbon atoms; in yet another embodiment, the alkyl group contains 1 to 4 carbon atoms; in yet another embodiment, the alkyl group contains 1 to 3 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me, -CH 3), ethyl (Et, -CH 2CH3), n-propyl (n-Pr, -CH 2CH2CH3), isopropyl (i-Pr, -CH (CH 3)2), n-butyl (n-Bu, -CH 2CH2CH2CH3), isobutyl (i-Bu, -CH 2CH(CH3)2), sec-butyl (s-Bu, -CH (CH 3)CH2CH3), tert-butyl (t-Bu, -C (CH 3)3), N-pentyl (-CH 2CH2CH2CH2CH3), 2-pentyl (-CH (CH 3)CH2CH2CH3), 3-pentyl (-CH (CH 2CH3)2), 2-methyl-2-butyl (-C (CH 3)2CH2CH3)), 3-methyl-2-butyl (-CH (CH 3)CH(CH3)2), 3-methyl-1-butyl (-CH 2CH2CH(CH3)2), 2-methyl-1-butyl (-CH 2CH(CH3)CH2CH3), n-hexyl (-CH 2CH2CH2CH2CH2CH3), 2-hexyl (-CH (CH 3)CH2CH2CH2CH3), 3-hexyl (-CH (CH 2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C (CH 3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH (CH 3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH (CH 3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C (CH 3)(CH2CH3)2), 2-methyl-3-pentyl (-CH (CH 2CH3)CH(CH3)2), 2, 3-dimethyl-2-butyl (-C (CH 3)2CH(CH3)2)), 3, 3-dimethyl-2-butyl (-CH (CH 3)C(CH3)3), n-heptyl, n-octyl, and the like).
When alkyl is a linking group, and "alkyl" is recited for this markush group definition, then "alkyl" represents a linked alkylene group.
The term "alkylene" means a saturated divalent hydrocarbon group resulting from the removal of two hydrogen atoms from a saturated straight or branched hydrocarbon group. Examples of alkylene groups include, but are not limited to: -CH 2-、-CH2CH2-、-CH(CH3)CH2 -, and so on.
The term "alkylene-O-" means an alkylene group attached to the rest of the molecule through an oxygen atom, wherein the alkylene group has the definition as described herein.
The term "alkylene-NH-" means that the alkylene group is attached to the rest of the molecule via NH, wherein the alkylene group has the definition as described herein.
The term "oxo", i.e., =o, means that two hydrogens on the carbon atom are replaced with=o, i.e., -CH 2- is replaced with=o to become-C (=o) -.
The term "hydroxyalkyl" denotes an alkyl group substituted with one or more hydroxy groups. In some embodiments, hydroxyalkyl represents alkyl substituted with 1,2,3, or 4 hydroxy groups. In some embodiments, hydroxyalkyl represents alkyl substituted with 1 or 2 hydroxyl groups. In some embodiments, hydroxyalkyl represents C 1-6 hydroxyalkyl, i.e., C 1-6 alkyl substituted with 1 or more hydroxy groups, preferably C 1-6 hydroxyalkyl represents C 1-6 alkyl substituted with 1 hydroxy group. In some embodiments, hydroxyalkyl represents C 1-4 hydroxyalkyl. In some embodiments, hydroxyalkyl represents C 1-3 hydroxyalkyl. Examples of hydroxyalkyl groups include, but are not limited to ,OHCH2-、CH2OHCH2CH2CH2-、CH2OHCH2-、CH2OHCH2CHOHCH2-、CH(CH3)OHCH2CHOHCH2-, and the like.
The term "alkoxy" means that the alkyl group is attached to the remainder of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkoxy groups contain 1 to 12 carbon atoms. In one embodiment, the alkoxy group contains 1 to 6 carbon atoms; in another embodiment, the alkoxy group contains 1 to 4 carbon atoms; in yet another embodiment, the alkoxy group contains 1 to 3 carbon atoms. The alkoxy group may be optionally substituted with one or more substituents described herein. Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH 3), ethoxy (EtO, -OCH 2CH3), 1-propoxy (n-PrO, n-propoxy, -OCH 2CH2CH3), 2-propoxy (i-PrO, i-propoxy, -OCH (CH 3)2), 1-butoxy (n-BuO, n-butoxy, -OCH 2CH2CH2CH3), 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH 2CH(CH3)2), 2-butoxy (s-BuO, s-butoxy, -OCH (CH 3)CH2CH3), 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC (CH 3)3), 1-pentoxy (n-pentoxy, -OCH 2CH2CH2CH2CH3), 2-pentoxy (-OCH (CH 3)CH2CH2CH3), 3-pentoxy (-OCH (CH 2CH3)2), 2-methyl-2-butoxy (-OC (CH 3)2CH2CH3), 3-methyl-2-butoxy (-OCH (CH 3)CH(CH3)2)), 3-methyl-l-butoxy (-OCH 2CH2CH(CH3)2), 2-methyl-l-butoxy (-OCH 2CH(CH3)CH2CH3), and the like.
The term "hydroxyalkoxy" denotes an alkoxy group substituted with one or more hydroxyl groups. In some embodiments, hydroxyalkoxy represents an alkoxy group substituted with 1, 2, 3, or 4 hydroxyl groups. In some embodiments, hydroxyalkoxy represents an alkoxy group substituted with 1 or 2 hydroxyl groups. In some embodiments, hydroxyalkoxy represents C 1-6 hydroxyalkoxy, i.e., C 1-6 alkoxy substituted with 1 or more hydroxy groups, preferably C 1-6 hydroxyalkyl represents C 1-6 alkyl substituted with 1 hydroxy group. In some embodiments, hydroxyalkyl represents C 1-4 hydroxyalkyl. In some embodiments, hydroxyalkyl represents C 1-3 hydroxyalkyl. Examples of hydroxyalkyl groups include, but are not limited to ,OHCH2O-、CH2OHCH2CH2CH2O-、CH2OHCH2O-、CH2OHCH2CHOHCH2O-、CH(CH3)OHCH2CHOHCH2O-, and the like.
The term "alkoxyalkyl" refers to an alkyl group substituted with one alkoxy group, wherein the alkoxy and alkyl groups have the definitions as described herein. In some embodiments, alkoxyalkyl represents a C 1-6 alkoxy C 1-6 alkyl group; in other embodiments, alkoxyalkyl represents a C 1-4 alkoxy C 1-4 alkyl group; in other embodiments, alkoxyalkyl represents a C 1-4 alkoxy C 1-3 alkyl group; in some embodiments, alkoxyalkyl represents a C 1-3 alkoxy C 1-3 alkyl. Examples of alkoxyalkyl groups include, but are not limited to, methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, methoxypropyl, ethoxyethyl, ethoxypropyl, propoxyethyl, propoxypropyl, and the like.
The term "halogen" means F (fluorine), cl (chlorine), br (bromine) or I (iodine).
The term "haloalkyl" means an alkyl group substituted with one or more halogen atoms. In some embodiments, haloalkyl represents a C 1-6 haloalkyl, i.e., an alkyl group in which the C 1-6 alkyl group is substituted with 1 or more halogens. In some embodiments, haloalkyl represents C 1-4 haloalkyl. In some embodiments, haloalkyl represents C 1-3 haloalkyl. Examples include, but are not limited to, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, 1, 2-difluoroethyl, 1-difluoroethyl, 2-difluoroethyl, monochloromethyl, dichloromethyl, trichloromethyl, monochloroethyl, 1, 2-dichloroethyl, 1-dichloroethyl, 2-dichloroethyl, 1-dibromoethyl, and the like.
The term "cycloalkyl" denotes a monovalent saturated monocyclic carbocyclic ring system. the-CH 2 -group in cycloalkyl groups may optionally be replaced by-C (=O) -. In some embodiments, cycloalkyl contains 3 to 7 ring carbon atoms, i.e., C 3-7 cycloalkyl. In one embodiment, cycloalkyl contains 3 to 6 carbon atoms, i.e., C 3-6 cycloalkyl; in another embodiment, cycloalkyl contains 3 to 5 carbon atoms, i.e., C 3-5 cycloalkyl. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. Examples of carbon rings in which the-CH 2 -group may be replaced by-C (=o) -include, but are not limited to: cyclopentanone, cyclobutanone, and the like. The cycloalkyl groups may independently be optionally substituted with one or more substituents described herein.
The term "cycloalkylene" refers to a divalent saturated monocyclic carbocyclic ring system. the-CH 2 -group in the cycloalkylene group may optionally be replaced by-C (=o) -. In some embodiments, the cycloalkylene group comprises 3-7 ring carbon atoms, i.e., a C 3-7 cycloalkylene group. In one embodiment, the cycloalkylene group comprises 3-6 carbon atoms, i.e., a C 3-6 cycloalkylene group; in another embodiment, the cycloalkyl group contains 3 to 5 carbon atoms, i.e., C 3-5 cycloalkylene, examples of cycloalkylene include, but are not limited to, 1-cyclopropylene, 1, 2-cyclopropylene, 1-cyclopentylene, 1-cyclohexylene, 1, 3-cyclopentylene, and the like. The cycloalkylene groups may be independently optionally substituted with one or more substituents described herein.
The term "monocyclic" means a saturated or unsaturated monocyclic carbocycle or a monocyclic heterocyclic ring system, wherein carbocycles and heterocyclic rings have the definitions as described herein. Wherein the monocyclic carbocyclic ring system is a carbon monocyclic ring and the monocyclic heterocyclic ring system is a heteromonocyclic ring.
The term "monocyclic group" means a monovalent saturated or unsaturated monocyclic carbocycle or monocyclic heterocyclic ring system, wherein carbocycle and heterocyclic ring have the definitions as described herein. the-CH 2 -group in the monocyclic group may optionally be replaced by-C (=o) -. In some embodiments, the monocyclic group contains 3-7 ring atoms, i.e., the monocyclic group is a 3-7 membered monocyclic group; in other embodiments, the monocyclic group contains 3-6 ring atoms, i.e., the monocyclic group is a 3-6 membered monocyclic group. Examples of monocyclic groups include, but are not limited to: cyclopropyl, cyclopentyl, cyclohexyl, 1, 2-cyclopentadienyl, pyrrolidinyl, tetrahydrofuranyl, morpholinyl, furanyl, and the like. Preferably, the monocyclic group according to the present invention is a monovalent saturated monocyclic carbocycle or a monocyclic heterocyclic ring system. The monocyclic groups may independently be optionally substituted with one or more substituents described herein.
The term "monocyclic subunit" means a divalent saturated or unsaturated monocyclic carbocycle or monocyclic heterocycle system wherein carbocycles and heterocycles have the definitions as described herein. the-CH 2 -group in the monocyclic subunit may optionally be replaced by-C (=o) -. In some embodiments, the monocyclic subunit comprises 3 to 7 ring atoms, i.e., the monocyclic subunit is a 3 to 7 membered monocyclic subunit; in other embodiments, the monocyclic subunit contains 3-6 ring atoms, i.e., the monocyclic subunit is a 3-6 membered monocyclic subunit. Preferably, the monocyclic subunit of the present invention is a divalent saturated monocyclic carbocycle or a monocyclic heterocyclic ring system. Examples of monocyclic subunits include, but are not limited to: cyclopropylene, cyclopentylene, cyclohexylene, 1, 2-cyclopentadienyl, pyrrolidinylene, and the like. The monocyclic subunit may independently be optionally substituted with one or more substituents described herein.
The term "subunit" denotes a divalent saturated or unsaturated monocyclic heterocyclic ring system, wherein the heterocyclic ring has the definition as described herein. the-CH 2 -group in the subunit-heterocyclic group may optionally be replaced by-C (=o) -. In some embodiments, the monoene group comprises 3-7 ring atoms, i.e., the monoene group is a 3-7 membered monoene group; in other embodiments, the monoene group comprises 3-6 ring atoms, i.e., the monoene group is a 3-6 membered monoene group. Preferably, the subunit heterocyclyl groups described herein are divalent saturated monocyclic heterocyclic ring systems.
The term "heterocycloalkylene" denotes a divalent saturated monocyclic heterocyclic ring system. the-CH 2 -group in the heterocycloalkylene group may optionally be replaced by-C (=o) -. In some embodiments, the heterocycloalkylene group contains 3-7 ring atoms, i.e., the heterocycloalkylene group is a 3-7 membered heterocycloalkylene group; in other embodiments, the heterocycloalkylene group contains 3-6 ring atoms, i.e., the heterocycloalkylene group is a 3-6 membered heterocycloalkylene group. Examples of heterocycloalkylene groups include, but are not limited to: piperidinyl, morpholinyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, and the like.
The term "heterocyclylalkyl" denotes an alkyl group substituted with a heterocyclyl group, wherein heterocyclyl and alkyl have the definitions as described herein. In some embodiments, the heterocyclylalkyl is a 3-12 membered heterocyclylc 1-6 alkyl; in other embodiments, the heterocyclylalkyl is a 3-6 membered heterocyclylc 1-6 alkyl; in some embodiments, the heterocyclylalkyl is a 3-6 membered heterocyclylc 1-4 alkyl. Examples of heterocyclylalkyl groups include, but are not limited to: pyrrolidinylmethyl, piperidinylmethyl, and the like.
The term "haloalkoxy" denotes an alkoxy group substituted with one or more halogen atoms, wherein halogen and alkoxy have the definition as described herein. In some embodiments, haloalkoxy represents C 1-6 haloalkoxy, i.e., C 1-6 alkoxy substituted with 1 or more halogens. In some embodiments, haloalkoxy represents C 1-4 haloalkoxy. In some embodiments, haloalkoxy represents C 1-3 haloalkoxy. Examples include, but are not limited to, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoroethoxy, 1, 2-difluoroethoxy, monochloroethoxy, and the like.
The term "alkanoyl" means an alkyl group attached to the remainder of the molecule through a carbonyl group, wherein alkyl has the definition as described herein, and carbonyl represents-C (=o) -. In some embodiments, the alkanoyl represents a C 1-6 alkanoyl; in other embodiments, the alkanoyl represents a C 1-4 alkanoyl. Examples of alkyl acyl groups include, but are not limited to: formyl, acetyl, and the like.
The term "cycloalkylalkyl" refers to an alkyl group substituted with a cycloalkyl group. Wherein cycloalkyl and alkyl have the definitions as described herein. In some embodiments, cycloalkylalkyl represents C 3-7 cycloalkyl C 1-6 alkyl; in other embodiments, cycloalkylalkyl represents C 3-6 cycloalkyl C 1-6 alkyl; in other embodiments, cycloalkylalkyl represents C 3-6 cycloalkyl C 1-4 alkyl. Examples of cycloalkylalkyl groups include, but are not limited to: cyclopropylmethyl, cyclopentylethyl, cyclohexylmethyl, and the like.
The term "aryl" refers to a monovalent aromatic ring radical formed by the removal of a hydrogen atom from a ring carbon atom of an aromatic ring. Examples of aryl groups may include phenyl, naphthyl, and anthracene. When aryl is a linking group, and "aryl" is recited for this markush group definition, then "aryl" means a linked arylene group. The term "arylene" refers to a divalent aromatic ring radical formed by the removal of two hydrogen atoms from a ring carbon atom of an aromatic ring. Examples of aryl groups represented as linked arylene groups may include phenylene, naphthylene, and anthracenylene. The aryl groups may independently be optionally substituted with one or more substituents described herein.
The term "heteroaryl" refers to a monovalent aromatic ring radical formed by the removal of a hydrogen atom from a ring atom of a heteroaromatic ring. The heteroaryl group is optionally substituted with one or more substituents described herein. In one embodiment, the 5-10 atom composition heteroaryl or 5-10 membered heteroaryl contains 1,2,3 or 4 heteroatoms independently selected from O, S and N. In some embodiments, the term "heteroaryl" denotes a heteroaryl ring group or a 5 membered heteroaryl group containing 5 ring atoms, which contains 1,2,3 or 4 heteroatoms independently selected from O, S and N. Examples of heteroaryl groups include, but are not limited to, 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g., 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e.g., 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (e.g., 2-pyrazolyl), isothiazolyl, 1,2, 3-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,2, 3-triazolyl, 1, 3-thiotriazinyl, 1, 3-dithio-pyrazinyl, 1, 3-thiotriazinyl; the following bicyclic rings are also included, but are in no way limited to: benzimidazolyl, benzofuranyl, benzothienyl, indolyl (e.g., 2-indolyl), purinyl, quinolinyl (e.g., 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), isoquinolinyl (e.g., 1-isoquinolinyl, 3-isoquinolinyl, or 4-isoquinolinyl), imidazo [1,2-a ] pyridinyl, pyrazolo [1,5-a ] pyrimidinyl, imidazo [1,2-b ] pyridazinyl, [1,2,4] triazolo [4,3-b ] pyridazinyl, [1,2,4] triazolo [1,5-a ] pyrimidinyl, [1,2,4] triazolo [1,5-a ] pyridinyl, and the like. When heteroaryl is a linking group, and heteroaryl is recited for this markush group definition, then heteroaryl represents a linked heteroarylene group. The term "heteroarylene" refers to a divalent heteroaryl ring radical formed by removing two hydrogen atoms from a ring atom of a heteroaryl group. The heteroaryl groups may independently be optionally substituted with one or more substituents described herein.
The term "bridged cyclic group" means a divalent non-aromatic saturated or partially unsaturated bicyclic or polycyclic ring system having two or more non-adjacent ring atoms in common, including bridged carbocyclyl and bridged heterocyclyl. In some embodiments, the bridged ring radical is a 5-12 membered bridged ring radical. The bridged ring systems may be independently optionally substituted with one or more substituents described herein.
The term "acenylene" refers to a divalent non-aromatic, saturated or partially unsaturated, bicyclic or polycyclic ring system sharing two adjacent ring atoms, including an acenylene group and an acenylene group. In some embodiments, the acenylene is a 5-12 membered acenylene. The acenylene groups may independently be optionally substituted with one or more substituents described herein.
The term "spiroylene" means a non-aromatic, saturated or partially unsaturated, bicyclic or polycyclic ring system formed by two rings sharing a single carbon atom, and includes spirocarbocyclic and spiroheterocyclic groups. In some embodiments, the spirosubunit is a 5-12 membered spirosubunit. The spirocyclic subunits may independently be optionally substituted with one or more substituents described herein.
The terms "carbocyclyl" and "carbocyclyl" are used interchangeably to refer to a saturated or partially unsaturated monocyclic, bicyclic or polycyclic ring system having ring atoms that are both carbon atoms, including Shan Tanhuan groups, bridged carbocyclyl groups, and carbocyclyl groups and spiro carbocyclyl groups.
The terms "carbocyclyl" and "carbocyclyl" are used interchangeably to refer to a non-aromatic, saturated or partially unsaturated, bicyclic or polycyclic ring system that shares two adjacent ring carbon atoms, and the ring atoms are carbon atoms. In some embodiments, the carbocyclyl is a 4-12 membered carbocyclyl. In some embodiments, the carbocyclyl is a 5-12 membered carbocyclyl. Examples of carbocyclyl groups include, but are not limited to: bicyclo [2.1.0] pentyl, bicyclo [3.1.0] heptyl, bicyclo [4.1.0] heptyl, bicyclo [3.2.0] heptyl, bicyclo [4.2.0] octyl, octahydro-1H-indenyl, octahydro-cyclopentadienyl, decahydronaphthyl, decahydro-1H-benzo [7] chromene, and the like.
The terms "heterocycle" and "heterocyclo" are used interchangeably and refer to a non-aromatic, saturated or partially unsaturated, bicyclic or polycyclic ring system having two adjacent ring atoms in common, at least one of the ring atoms of the system being a heteroatom selected from O, N, S. In some embodiments, the heterocyclo group is a 4-12 membered heterocyclo group. In some embodiments, the heterocyclo group is a 5-12 membered heterocyclo group. Examples of and heterocyclyl groups include, but are not limited to: 3-azabicyclo [3.1.0] hexy, 2-oxa-5-azabicyclo [2.2.0] hexy, 2, 5-diazabicyclo [2.2.0] hexy, 2-azabicyclo [2.1.0] penty, 2-azabicyclo [3.1.0] hexy, 3-oxabicyclo [3.1.0] hexy, octahydrocyclopenta [ c ] pyrrole, octahydropyrrolo [3,4-c ] pyrrole, hexahydrofuro [3,2-b ] furan, hexahydrofuro [2,3-b ] furan, octahydropyrrolo [3,4-b ] pyrrole, hexahydro-1H-thieno [3,4-c ] pyrrole, hexahydro-1H-furo [3,4-c ] pyrrole, hexahydro-2H- [1,4] dioxino [2,3-c ] pyrrole, octahydro- [1,4] dioxino [2, 4] pyridine, etc.
The terms "bridged carbocycle" and "bridged carbocyclyl" are used interchangeably and refer to a non-aromatic, saturated or partially unsaturated, bicyclic or polycyclic ring system having two or more non-adjacent ring carbon atoms in common, and the ring atoms are carbon atoms. the-CH 2 -group in the bridged carbocycle can optionally be replaced by-C (=O) -. In some embodiments, bridged carbocycles contain 6-12 ring carbon atoms, i.e., represent 6-12 membered bridged carbocycles; in other embodiments, bridged carbocycles contain from 6 to 10 ring carbon atoms, i.e., represent 6-10 membered bridged carbocycles. Examples of bridged carbocycles include, but are not limited to: bicyclo [3.1.1] heptane, bicyclo [3.2.1] octane, bicyclo [2.2.2] octane, bicyclo [2.2.0] hexane, octahydro-1H-indene, and the like. When bridged carbocycle or bridged carbocyclyl is a linking group, and bridged carbocycle or bridged carbocyclyl is recited for this markush group definition, then bridged carbocycle or bridged carbocyclyl represents a linked bridged carbocyclylene group. The term "bridged carbocyclyl" means a divalent bridged carbocyclyl group formed by removing two hydrogen atoms from a ring atom of a bridged carbocycle. The bridged carbocycle or bridged carbocyclyl may independently be optionally substituted with one or more substituents described herein.
The terms "spirocarbocyclyl" and "spirocarbocyclyl" are used interchangeably and refer to a non-aromatic, saturated or partially unsaturated bicyclic or polycyclic ring system formed by two carbocycles sharing one carbon atom. the-CH 2 -group in the spirocarbocyclic ring may optionally be replaced by-C (=o) -. In some embodiments, the spirocarbocycle contains 7-12 ring carbon atoms, i.e., represents a 7-12 membered spirocarbocycle; in other embodiments, the spirocarbocycle contains 7-10 ring carbon atoms, i.e., represents a 7-10 membered spirocarbocycle. Examples of spirocarbocycles include, but are not limited to: spiro [4.4] nonane, spiro [3.4] octane, spiro [4.5] decane, and the like. When a spiro carbocycle or spiro carbocyclyl is a linking group, and spiro carbocycle or spiro carbocyclyl is recited for this markush group definition, then spiro carbocycle or spiro carbocyclyl represents a linked spirocarbocyclylene group. The term "spiroylene" refers to a divalent spirocarbocyclic radical formed by removing two hydrogen atoms from the ring atoms of a spirocarbocyclic ring. The spirocarbocycle or spirocarbocyclyl may independently be optionally substituted with one or more substituents described herein.
The terms "heterocycle" or "heterocyclyl" are used interchangeably and each represents a monovalent, non-aromatic, saturated or partially unsaturated, monocyclic, bicyclic or polycyclic ring system having 3 to 12 ring atoms, and containing at least 1 carbon atom, 1, 2 or 3 heteroatoms selected from O, N, S. Unless otherwise indicated, the heterocyclyl group may be a carbon or nitrogen group, and the-CH 2 -group may optionally be replaced by-C (=o) -. The sulfur atom of the ring may optionally be oxidized to an S-oxide and the nitrogen atom of the ring may optionally be oxidized to an N-oxide. In some embodiments, the heterocyclyl contains 4-7 ring atoms, i.e., represents a 4-7 membered heterocyclyl; examples of heterocyclyl groups include, but are not limited to: oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1, 3-dioxacyclopentyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl, homopiperazinyl, homopiperidinyl, 1-dioxo-1, 3-thiomorpholin, and the like. Examples of the substitution of the-CH 2 -group in the heterocyclyl group by-C (=o) -include, but are not limited to, 2-oxo-pyrrolidinyl, oxo-1, 3-thiazolidinyl, 2-piperidonyl, 3, 5-dioxopiperidyl. Examples of the nitrogen atom in the heterocyclic group being oxidized to an N-oxy compound include, but are not limited to, 1-dioxo-1, 3-thiomorpholine. When a heterocycle or heterocyclyl is the linking group and a heterocycle or heterocyclyl is recited for this markush definition, then the heterocycle or heterocyclyl represents the linked heterocyclylene. The term "heterocyclylene" refers to a divalent heterocyclic group formed by removal of two hydrogen atoms from a ring atom of a heterocycle. The heterocycle or heterocyclyl may independently be optionally substituted with one or more substituents described herein.
The terms "bridged heterocyclic ring" or "bridged heterocyclic group" are used interchangeably and refer to a non-aromatic, saturated or partially unsaturated, bicyclic or polycyclic ring system having two or more non-adjacent ring atoms in common, and having at least 1 carbon atom, including 1, 2, or 3 heteroatoms selected from O, N, S. the-CH 2 -group in the bridged heterocyclic ring can optionally be replaced by-C (=O) -. The sulfur atom of the ring may optionally be oxidized to an S-oxide and the nitrogen atom of the ring may optionally be oxidized to an N-oxide. In some embodiments, bridged heterocycles contain 6-12 ring atoms, i.e., represent 6-12 membered bridged heterocycles; in other embodiments, bridged heterocycles contain 6-10 ring atoms, i.e., represent 6-10 membered bridged heterocycles. Examples of bridged heterocycles include, but are not limited to: 3, 6-diazabicyclo [3.1.1] heptane, 3, 8-diazabicyclo [3.2.1] octane, 2-azabicyclo [2.2.1] heptane, 6-azabicyclo [3.1.1] heptane, 3-azabicyclo [3.1.1] heptane, 8-azabicyclo [3.2.1] octane, 3-azabicyclo [3.2.1] octane, 2-diazabicyclo [2.2.2] octane, and the like. When bridged heterocycle or bridged heterocyclyl is a linking group, and bridged heterocycle or bridged heterocyclyl is recited for this markush definition, then bridged heterocycle or bridged heterocyclyl represents a linked bridged heterocyclyl. The term "bridged heterocyclyl" means a divalent bridged heterocyclic group formed by removing two hydrogen atoms from a ring atom of a bridged heterocyclic ring. The bridged heterocycle or the bridged heterocyclyl may independently be optionally substituted with one or more substituents described herein.
The terms "spiroheterocycle" or "spiroheterocyclyl" are used interchangeably and refer to a non-aromatic, saturated or partially unsaturated ring system formed by two rings sharing one carbon atom, and which contains 1,2 or 3 heteroatoms selected from O, N, S. the-CH 2 -group in the spiroheterocycle may optionally be replaced by-C (=o) -. The sulfur atom of the ring may optionally be oxidized to an S-oxide and the nitrogen atom of the ring may optionally be oxidized to an N-oxide. In some embodiments, the spiroheterocycle contains 7-12 ring atoms, i.e., represents a 7-12 membered spiroheterocycle; in other embodiments, the spiroheterocycle contains 7-10 ring atoms, i.e., represents a 7-10 membered spiroheterocycle. Examples of spiroheterocycles include, but are not limited to: 4, 7-diazaspiro [2.5] octane, 2, 8-diazaspiro [4.5] decane, 2, 7-diazaspiro [3.5] decane, 2, 6-diazaspiro [3.3] heptane, 2, 7-diazaspiro [4.4] nonane, 3-azaspiro [5.5] undecane, 2, 7-diazaspiro [4.4] nonane-1-one, and the like. When a spiroheterocycle or spiroheterocyclyl is a linking group, and a spiroheterocycle or spiroheterocyclyl is recited for this markush group definition, then the spiroheterocycle or spiroheterocyclyl represents a linked spiroheterocyclyl subunit. The term "spiroylene" means a divalent spiroheterocyclic group formed by removing two hydrogen atoms from a ring atom of a spiroheterocyclic ring. The spiroheterocycle or spiroheterocyclyl may independently be optionally substituted with one or more substituents described herein.
The term "aminoalkyl" refers to an alkyl group substituted with one or more amino groups. In some embodiments, the term "aminoalkyl" refers to an alkyl group substituted with one amino group. In some embodiments, the term "aminoalkyl" refers to an amino C 1-6 alkyl group. In other embodiments, the term "aminoalkyl" means an amino C 1-4 alkyl group. In other embodiments, the term "aminoalkyl" means an amino C 1-3 alkyl group. Examples of aminoalkyl groups include, but are not limited to, aminomethyl, aminoethyl, amino-n-propyl, amino-isopropyl, amino-isobutyl, amino-t-butyl, 1, 2-diaminoethyl, and the like.
The term "alkylamino" means an amino group substituted with one or two alkyl groups. In some embodiments, the term "alkylamino" means a C 1-6 alkylamino, i.e., an amino group substituted with one or two C 1-6 alkyl groups. In other embodiments, the term "alkylamino" means a C 1-4 alkylamino. In other embodiments, the term "alkylamino" means a C 1-3 alkylamino. Examples of alkylamino groups include, but are not limited to, methylamino, ethylamino, n-propylamino, isopropylamino, isobutylamino, t-butylamino, dimethylamino, diethylamino, di-n-propylamino, diisopropylamino, diisobutylamino, di-t-butylamino, and the like.
The term "alkylsulfonyl" denotes an alkyl-S (=o) 2 -, i.e. an alkyl group is attached to the remainder of the molecule through-S (=o) 2 -. In some embodiments, alkylsulfonyl represents C 1-6 alkylsulfonyl; in other embodiments, alkylsulfonyl represents C 1-4 alkylsulfonyl; in other embodiments, alkylsulfonyl represents C 1-4 alkylsulfonyl. Examples of alkylsulfonyl groups include, but are not limited to, methylsulfonyl, ethylmethylsulfonyl, n-propylmethylsulfonyl, isopropylmethylsulfonyl, n-butylmethylsulfonyl, and the like.
In the general formula (I) of the compounds of the invention, the left-terminal ring A of Q is linked to the right-terminal ring M of Q, e.g.when Q is- (S=O) 2NR6 -, thenRepresentation ofLikewise, the left end of ring A is connected to E and the right end of ring A is connected to Q.
In the general formula (I) of the compounds according to the invention, when T is alkylene-O-or alkylene-NH-,Representation of
As described herein, unless otherwise specified, a ring substituent may be attached to the remainder of the molecule through any available position on the ring. For example, piperidinyl includes piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, and piperidin-4-yl.
In the present invention, each of the substructures G1, G2 and G3 of ring G represents a union of rings T 1 and T 2a, rings T 1 and T 2b, and rings T 1 and T 2c, respectively, and the attachment points of each of the G1, G2 and G3 rings may be attached to the remainder of the molecule at any of the connectable positions on the G1, G2 and G3 rings, respectively; preferably, the attachment point of each G1, G2 and G3 ring may be attached to the remainder of the molecule at any attachable position of each T 1 ring on the G1, G2 and G3 rings. For example, in the G1 ring, the attachment point may be attached to the remainder of the molecule at any available position on the T 1 ring, or the attachment point may be attached to the remainder of the molecule at any available position on the T 2a ring; preferably, the attachment point is attached to the remainder of the molecule at any available position on the T 1 loop. The sub-formulae G1, G2 and G3 of ring G are shown below.
If two attachment points are attached to the remainder of the molecule on a ring, as described herein, the two attachment points may be attached to the remainder of the molecule at any attachable location on the ring, with the ends of the attachment being interchangeable. For example, the sub-formula a1 of ring a represents that any two possible locations on the ring that may be connected may be used as points of connection (i.e., attachment points), while the two ends of the connection points may be interchanged. Preferably, if there are two attachment points on a ring that are attached to the remainder of the molecule, the two attachment points may be attached to the remainder of the molecule at any attachable position on the ring, and the two attachment points are attached to two different ring atoms on the ring.
Preferably, in the present invention, if one ring is a parallel ring or a spiro ring formed of two sub-rings, and two attachment points on the ring are respectively located on the two sub-rings, the two attachment points are respectively connected with the rest of the molecule at any connectable positions on the two sub-rings, and both ends of the connection may be interchanged. For example, the sub-formula a2 of ring a preferably represents that the two attachment points on the ring are linked to the rest of the molecule on the H1 ring and the H2 ring, respectively, while the two ends of the linkage may be interchanged; the substructures a3 of ring a preferably represent that the two attachment points on the ring are linked to the rest of the molecule on the H1 'ring and the H2' ring, respectively, while the two ends of the linkage may be interchanged.
The term "protecting group" or "PG" refers to a substituent that is commonly used to block or protect a particular functionality when reacted with other functional groups. For example, by "protecting group for an amino group" is meant a substituent attached to the amino group to block or protect the functionality of the amino group in the compound, suitable amino protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC ), benzyloxycarbonyl (CBZ ) and 9-fluorenylmethoxycarbonyl (Fmoc). Similarly, "hydroxy protecting group" refers to the functionality that a substituent of a hydroxy group serves to block or protect the hydroxy group, and suitable protecting groups include acetyl and silyl. "carboxy protecting group" refers to the functionality of a substituent of a carboxy group to block or protect the carboxy group, and typical carboxy protecting groups include-CH 2CH2SO2 Ph, cyanoethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxymethyl, 2- (p-toluenesulfonyl) ethyl, 2- (p-nitrobenzenesulfonyl) ethyl, 2- (diphenylphosphino) ethyl, nitroethyl, and the like. General description of protecting groups can be found in the literature ：T W.Greene,Protective Groups in Organic Synthesis,John Wiley&Sons,New York,1991;and P.J.Kocienski,Protecting Groups,Thieme,Stuttgart,2005.
The term "prodrug" as used herein means a compound that is converted in vivo to a compound of formula (I). Such conversion is effected by hydrolysis of the prodrug in the blood or enzymatic conversion to the parent structure in the blood or tissue. The prodrug of the invention can be esters, and in the prior invention, the esters can be phenyl esters, aliphatic (C 1-24) esters, acyloxymethyl esters, carbonic esters, carbamates and amino acid esters as the prodrugs. For example, one compound of the invention may contain a hydroxyl group, i.e., it may be acylated to provide the compound in a prodrug form. Other prodrug forms include phosphates, such as those obtained by phosphorylation of a hydroxyl group on the parent. For a complete discussion of prodrugs, reference may be made to the following documents ：T.Higuchi and V.Stella,Pro-drugs as Novel Delivery Systems,Vol.14of the A.C.S.Symposium Series,Edward B.Roche,ed.,Bioreversible Carriers in Drug Design,American Pharmaceutical Association and Pergamon Press,1987,J.Rautio et al.,Prodrugs:Design and Clinical Applications,Nature Review Drug Discovery,2008,7,255-270,and S.J.Hecker et al.,Prodrugs of Phosphates and Phosphonates,Journal of Medicinal Chemistry,2008,51,2328-2345.
"Metabolite" refers to a product obtained by metabolizing a specific compound or salt thereof in vivo. The metabolites of a compound may be identified by techniques well known in the art and their activity may be characterized by employing the assay methods as described herein. Such products may be obtained by oxidation, reduction, hydrolysis, amidization, deamination, esterification, degreasing, enzymatic cleavage, etc. of the administered compound. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting a compound of the present invention with a mammal for a period of time sufficient.
As used herein, "pharmaceutically acceptable salts" refers to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as described in document ：S.M.Berge et al.,describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences,1977,66:1-19.. Pharmaceutically acceptable non-toxic acid forming salts include, but are not limited to, inorganic acid salts formed by reaction with amino groups such as hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, and organic acid salts such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, or by other methods described in the literature such as ion exchange. Other pharmaceutically acceptable salts include adipic acid salts, alginates, ascorbates, aspartic acid salts, benzenesulfonates, benzoic acid salts, bisulfate salts, borates, butyric acid salts, camphoric acid salts, cyclopentylpropionates, digluconate, dodecylsulfate, ethanesulfonate, formate salts, fumaric acid salts, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, caproate, hydroiodic acid salts, 2-hydroxy-ethanesulfonate salts, lactobionic aldehyde salts, lactate salts, laurate salts, lauryl sulfate, malate salts, malonate salts, methanesulfonate salts, 2-naphthalenesulfonate salts, nicotinate salts, nitrate salts, oleate salts, palmitate salts, pamoate salts, pectate salts, persulfate salts, 3-phenylpropionate salts, picrate salts, pivalate salts, propionate salts, stearate salts, thiocyanate salts, p-toluenesulfonate salts, undecanoate salts, valerate salts, and the like. Salts obtained with suitable bases include the alkali metal, alkaline earth metal, ammonium and N +(C1-4 alkyl) 4 salts. The present invention also contemplates quaternary ammonium salts formed from any compound containing a group of N. The water-soluble or oil-soluble or dispersible product may be obtained by quaternization. Alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts and counter-ion forming amine cations such as halides, hydroxides, carboxylates, sulphates, phosphates, nitrates, C 1-8 sulphonates and aromatic sulphonates.
Pharmaceutically acceptable salts of the invention can be synthesized from the parent compound, basic or acidic moiety using conventional chemical methods. In general, such salts can be prepared by reacting the free acid forms of these compounds with a stoichiometric amount of a suitable base (e.g., na, ca, mg or K hydroxide, carbonate, bicarbonate, etc.), or by reacting the free base forms of these compounds with a stoichiometric amount of a suitable acid. Such reactions are generally carried out in water or an organic solvent or a mixture of both. Generally, it is desirable to use a non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile where appropriate. In, for example, "Remington's Pharmaceutical Sciences", 20 th edition, mack Publishing Company, easton, pa., (1985); and "manual of pharmaceutically acceptable salts: a list of other suitable salts can be found in the nature, selection and application (Handbook of Pharmaceutical Salts：Properties,Selection,and Use)",Stahl and Wermuth(Wiley-VCH,Weinheim,Germany,2002).
In addition, the compounds disclosed herein, including their salts, may also be obtained in the form of their hydrates or in the form of solvents (e.g., ethanol, DMSO, etc.) containing them, for their crystallization. The disclosed compounds may form solvates inherently or by design with pharmaceutically acceptable solvents (including water); accordingly, the present invention is intended to include solvated and unsolvated forms.
"Solvate" according to the present invention refers to an association of one or more solvent molecules with a compound according to the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethylsulfoxide, ethyl acetate, acetic acid, and aminoethanol. The term "hydrate" refers to an association of solvent molecules that are water.
"Nitroxide" in the present invention means that when a compound contains several amine functions, 1 or more than 1 nitrogen atom can be oxidized to form an N-oxide. Specific examples of N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen atoms of nitrogen-containing heterocycles. The corresponding amine may be treated with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid) to form an N-oxide (see Advanced Organic Chemistry, WILEY INTERSCIENCE, 4 th edition, jerry March, pages). In particular, the N-oxides can be prepared by the method L.W.Deady (Syn.Comm.1977, 7, 509-514) in which an amine compound is reacted with m-chloroperoxybenzoic acid (MCPBA), for example in an inert solvent such as methylene chloride.
The term "treating" as used herein refers in some embodiments to ameliorating a disease or disorder (i.e., slowing or preventing or alleviating the progression of the disease or at least one clinical symptom thereof). In other embodiments, "treating" refers to moderating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, "treating" refers to modulating a disease or disorder physically (e.g., stabilizing a perceived symptom) or physiologically (e.g., stabilizing a parameter of the body) or both. In other embodiments, "treating" refers to preventing or delaying the onset, or exacerbation of a disease or disorder.
The term "RET related cancer" as used herein refers to a cancer associated with or having a deregulation of the expression or activity or level of the RET gene, RET kinase (also referred to herein as RET kinase protein or RET kinase), or any of them. Non-limiting examples of RET related cancers are described herein. The deregulation of the expression or activity or level of the RET gene, RET kinase or any one thereof is one or more point mutations in the RET gene.
The phrase "expression or activity or level of a RET gene, a RET kinase or any of them is deregulated" refers to a mutation in a gene (e.g., a translocation of a RET gene resulting in expression of a fusion protein, a deletion in a RET gene resulting in expression of a RET protein comprising at least one amino acid deletion compared to a wild-type RET protein, or a mutation in a RET gene resulting in expression of a RET protein having one or more point mutations, or an alternatively spliced form of RET mRNA of a RET protein resulting in deletion of at least one amino acid in a RET protein compared to a wild-type RET protein), or an amplification of a RET gene resulting in overexpression of a RET protein or an autocrine activity resulting from overexpression of a RET gene by a cell resulting in an increase in pathogenicity of activity of a kinase domain of a RET protein in a cell (e.g., constitutive activation of a kinase domain of a RET protein). As another example, the expression or activity or level imbalance of a RET gene, a RET kinase, or any of them may be a mutation in a RET gene encoding a RET protein having constitutive activity or having increased activity as compared to a protein encoded by a RET gene that does not include the mutation. For example, the disruption of expression or activity or level of the RET gene, RET kinase or any of them may be the result of a gene or chromosomal translocation that results in the expression of a fusion protein comprising a first RET portion comprising a functional kinase domain and a second portion of chaperone protein (i.e., not RET). In some examples, deregulation of RET genes, RET proteins, or expression or activity can be the result of gene translation of one RET gene with another RET gene.
Deregulation of expression or activity or levels of RET kinase, RET gene, or any (e.g., one or more) thereof, may contribute to tumorigenesis. For example, a RET kinase, a RET gene disorder, or a disorder of expression or activity or level of either of these may be a translocation, overexpression, activation, amplification, or mutation of the RET kinase, RET gene, or RET kinase domain. The translocation may include a translocation involving the RET kinase domain, the mutation may include a mutation involving the RET ligand binding site, and the amplification may be of the RET gene. Other disorders may include RET mRNA splice variants and RET autocrine/paracrine signaling, which may also contribute to tumorigenesis.
In some embodiments, the deregulation of the expression or activity or level of the RET gene, the RET kinase or any of them comprises one or more deletions (e.g., deletion of amino acid 4), insertions or point mutations in the RET kinase. In some embodiments, the deregulation of the expression or activity or level of a RET gene, a RET kinase or any one thereof comprises a deletion of one or more residues of the RET kinase, resulting in constitutive activity of the RET kinase domain.
The term "irritable bowel syndrome" includes diarrhea predominant, constipation predominant or alternating stool patterns, functional bloating, functional constipation, functional diarrhea, nonspecific functional bowel disease, functional abdominal pain syndrome, chronic idiopathic constipation, functional esophageal disease, functional gastroduodenal disease, functional anorectal pain, inflammatory bowel disease, and the like.
Any formulae given herein are also intended to represent non-isotopically enriched forms as well as isotopically enriched forms of such compounds. Isotopically enriched compounds have structures depicted by the formulae given herein except that one or more atoms are replaced by an atom having a selected atomic or mass number. Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2H,3H,11C,13C,14C,15N,17O,18O,18F,31P,32P,35S,36Cl and 125 I.
In another aspect, the compounds of the invention include isotopically enriched compounds defined herein, for example, those in which a radioisotope, such as 3H,14 C and 18 F, is present, or in which a non-radioisotope, such as 2 H and 13 C, is present. Such isotopically enriched compounds are useful in metabolic studies (using 14 C), kinetic studies (using, for example, 2 H or 3 H), detection or imaging techniques, such as Positron Emission Tomography (PET) or Single Photon Emission Computed Tomography (SPECT) including drug or substrate tissue distribution assays, or in radiation therapy of patients. 18 F-enriched compounds are particularly desirable for PET or SPECT studies. Isotopically enriched compounds of formula (I) can be prepared by conventional techniques familiar to those skilled in the art or by describing the examples and processes of preparation of the present invention using a suitable isotopically labelled reagent in place of the one previously used unlabelled reagent.
Furthermore, substitution of heavier isotopes, particularly deuterium (i.e., 2 H or D), may afford certain therapeutic advantages resulting from greater metabolic stability. For example, increased in vivo half-life or reduced dosage requirements or improved therapeutic index. It is to be understood that deuterium in the context of the present invention is considered a substituent for a compound of formula (I), (I-1), (I-2), (I-3) or (I-4). The concentration of such heavier isotopes, particularly deuterium, can be defined by an isotopic enrichment factor. The term "isotopically enriched factor" as used herein refers to the ratio between the isotopic abundance and the natural abundance of a specified isotope. If a substituent of a compound of the invention is designated as deuterium, the compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). Pharmaceutically acceptable solvates of the present invention include those in which the crystallization solvent may be isotopically substituted, e.g. D 2 O, acetone-D 6、DMSO-d6.
Description of the Compounds of the invention
The invention provides a novel compound for inhibiting a transfection-phase Rearrangement (RET) kinase, which has good inhibition effect on RET wild type and RET gene mutants and good inhibition selectivity on RET wild type and RET gene mutants.
In one aspect, the invention provides a compound of formula (I), or a stereoisomer, geometric isomer, tautomer, nitroxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of a compound of formula (I),
Wherein R 1、X1、X2、X3、X4、X5、E、A、Q、M、T、Y、G、Ra, q have the definitions as described in the present invention.
In some embodiments, X 1、X2、X3、X4 and X 5 are each independently CR 4 or N.
In some embodiments, Y is O, NH or S.
In some embodiments, T is a bond, alkylene-O-or alkylene-NH-, and the T is optionally substituted with 1,2,3, or 4 substituents selected from D, OH, F, cl, br, I, CN, NH 2, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, heterocyclyl, alkoxy, aryl, heteroaryl, or alkylamino.
In some embodiments, ring G is a carbocyclyl or a heterocyclyl.
In some embodiments, q is 0, 1, 2, 3, or 4.
In some embodiments, R a is D、OH、NH2、F、Cl、Br、I、CN、NR5R6、OR7、-NR6C(＝O)R7、-S(＝O)2R7、-S(＝O)R7、-C(＝O)R7、-C(＝O)OR7、 oxo, alkyl, alkoxy, cycloalkyl, haloalkyl, alkoxyalkyl, hydroxyalkyl, or hydroxyalkoxy.
In some embodiments, E is a bond, -NR 6 -, or-O-.
In some embodiments, ring a is a bridged, fused or spiro-alkylene group, and ring a is optionally substituted with 1,2,3, or 4 substituents selected from F, cl, br, OH, oxo, NR 5R6、R5(C＝O)NR6 -, aminoalkyl, alkyl, alkoxy, haloalkyl, hydroxyalkyl, carbocyclyl, heterocyclyl, heterocyclylalkyl, alkoxyalkyl, cycloalkylene, and heterocyclylalkyl.
In some embodiments, Q is a bond 、-(CR2R3)tO-、-(CR2R3)f-、-(CR2R3)t-NR6-、-(C＝O)(CR2R3)t-、-(C＝O)(CR2R3)t-(S＝O)2(CR2R3)f-、-(C＝O)(CR2R3)t-NR6(CR2R3)f-、-(C＝O)(CR2R3)t-O(CR2R3)f-、-(C＝O)NR6O(CR2R3)f-、-(S＝O)2-NR6-(CR2R3)t-、-(CR2R3)f-(C＝O)-、-(CR2R3)t-(C＝O)-NR6-(CR2R3)t-、-(S＝O)2(CR2R3)t-、-(CR2R3)f-(S＝O)2(CR2R3)t-、-(S＝O)2O-、-O(C＝O)-、-(C＝O)NR6- or-NR 6 (c=o) -;
each f is independently 1, 2, 3 or 4;
each t is independently 0, 1,2,3 or 4.
In some embodiments, M is H, D, heteroaryl, aryl, cycloalkyl, or heterocyclyl, and M is optionally substituted with 1,2,3, or 4 substituents selected from D, F, cl, CN, OH, NR 5R6、OR7, alkyl, haloalkyl, hydroxyalkyl, haloalkoxy, aryl, alkoxyalkyl, oxo, alkanoyl, heterocyclyl, and cycloalkyl.
In some embodiments, R 1 is H, D, CN, F, cl, br, alkyl, or cycloalkyl, wherein the alkyl and cycloalkyl groups are independently optionally substituted with 1, 2, 3, or 4 substituents selected from F, cl, br, CN, NH 2, OH, and NO 2.
In some embodiments, each R 2 and R 3 is independently OH, F, H, D, CN, cl, br, NH 2, hydroxyalkyl, alkyl, alkylamino, alkoxy, haloalkoxy, cycloalkyl, haloalkyl, cycloalkylalkyl, aryl, or heteroaryl;
or R 2、R3 and the same carbon atom to which it is attached form a carbocyclic or heterocyclic ring;
In some embodiments, R 4 is H, D, F, cl, br, alkyl, or alkoxy, wherein each of the alkyl and alkoxy groups is independently optionally substituted with 1,2,3, or 4 substituents selected from F, cl, br, CN, NH 2, OH, and NO 2.
In some embodiments, R 5 is H, D, alkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl, wherein each of the alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with 1,2,3, or 4 substituents selected from F, cl, br, OH, NH 2, alkylamino, alkyl, alkylsulfonyl, alkoxy, aryl, and heteroaryl.
In some embodiments, R 6 is H, D, alkyl or alkoxyalkyl, wherein each of the alkyl and alkoxyalkyl groups is independently optionally substituted with 1,2, 3, or 4 substituents selected from F, cl, br, CN, NH 2, OH, and NO 2.
In some embodiments, R 7 is OH, alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl.
In some embodiments, T is a bond, C 1-6 alkylene, C 1-6 alkylene-O-, or C 1-6 alkylene-NH-, and T is optionally substituted with 1,2,3, or 4 substituents selected from D, OH, F, cl, br, I, CN, NH 2、C1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, C 1-6 alkoxy, C 6-10 aryl, 5-12 membered heteroaryl, and C 1-6 alkylamino.
In some embodiments, T is a bond 、-CH2-、-(CH2)2-、-(CH2)3-、-(CH2)4-、-(CH2)5-、-(CH2)6-、-(CH2)2-O- or- (CH 2)2 -NH-, and the T is optionally substituted with 1,2, 3, or 4 substituents selected from D, OH, F, cl, br, I, CN, NH 2、CF3、CHF2、CHCl2, methyl, ethyl, propyl, 2-hydroxyethyl, 1-hydroxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, oxetanyl, methoxy, ethoxy, propoxy, butoxy, phenyl, methylamino, and dimethylamino.
In some embodiments, ring G is 4-12 membered and carbocyclyl or 4-12 membered and heterocyclyl.
In some embodiments, R a is D、OH、NH2、F、Cl、Br、I、CN、NR5R6、OR7、-NR6C(＝O)R7、-S(＝O)2R7、-S(＝O)R7、-C(＝O)R7、-C(＝O)OR7、 oxo, C 1-6 alkyl, C 1-6 alkoxy, C 3-7 cycloalkyl, C 1-6 haloalkyl, C 1-6 alkoxyc 1-6 alkyl, C 1-6 hydroxyalkyl, or C 1-6 hydroxyalkoxy.
In some embodiments, R 5 is H, D, C 1-6 alkyl, 3-12 membered carbocyclyl, 3-12 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl, wherein each of said C 1-6 alkyl, 3-12 membered carbocyclyl, 3-12 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl is independently optionally substituted with 1,2, 3, or 4 substituents selected from F, cl, br, OH, NH 2、C1-6 alkylamino, C 1-6 alkyl, C 1-6 alkylsulfonyl, C 1-6 alkoxy, C 6-10 aryl, and 5-10 membered heteroaryl.
In some embodiments, R 6 is H, D, C 1-6 alkyl or C 1-6 alkoxy C 1-6 alkyl, wherein the C 1-6 alkyl and C 1-6 alkoxy C 1-6 alkyl are each independently optionally substituted with 1, 2, 3, or 4 substituents selected from F, cl, br, CN, NH 2, OH, and NO 2.
R 7 is OH, C 1-6 alkyl, C 3-6 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl.
In some embodiments, ring G is of the following sub-structural formula:
Wherein,
T 1 is a 3-6 membered carbon monocyclic ring or a 3-6 membered heteromonocyclic ring;
z 4 is CH or N;
Z 1 is NH, O, S or CH 2;
Each Z 2 and Z 3 is independently O, S or NH;
each n1 is independently 0,1 or 2;
n2 is 0, 1, 2 or 3.
In some embodiments, ring G is of the following sub-structural formula:
In some embodiments, R a is D、OH、NH2、F、CF3、CHCl2、CHF2、CH2F、CF3CH2、Cl、Br、I、CN、NH2、NHCH3、-NHC(＝O)CH3、-S(＝O)2CH3、-S(＝O)CH3、-C(＝O)CH3、-C(＝O)OH、 oxo, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, methoxy, ethoxy, cyclopropyl, cyclopentyl, methoxymethyl, ethoxymethyl, methoxyethyl, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 2-hydroxypropyl, 2-hydroxy-2-methylpropyl, 2-hydroxyethoxy, or 1-hydroxyethoxy.
In some embodiments, R 5 is H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, cyclopropyl, cyclopentyl, pyrrolidinyl, phenyl, or pyrazolyl; wherein the methyl, ethyl, n-propyl, cyclopropyl, cyclopentyl, pyrrolidinyl, phenyl, and pyrazolyl groups are each independently optionally substituted with 1, 2, 3, or 4 substituents selected from F, cl, br, OH, NH 2, methyl, -S (=o) 2CH3, methoxy, ethoxy, and phenyl.
In some embodiments, R 6 is H, D, methyl, ethyl, n-propyl, n-butyl, methoxymethyl, ethoxymethyl, or methoxyethyl, wherein each of the methyl, ethyl, n-propyl, n-butyl, methoxymethyl, ethoxymethyl, and methoxyethyl groups is independently optionally substituted with 1,2, 3, or 4 substituents selected from F, cl, br, CN, NH 2, OH, and NO 2.
In some embodiments, R 7 is OH, methyl, ethyl, NH 2、N(CH3)2, methyl, isopropyl, tert-butyl, cyclopropyl, or phenyl.
In some embodiments, A is a 5-12 membered bridged ring, 5-12 membered fused ring, or 5-12 membered spirocyclic ring, and A is optionally substituted with 1, 2, 3, or 4 substituents selected from F, cl, br, OH, oxo, NR 5R6、R5(C＝O)NR6 -, amino C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, 3-12 membered carbocyclyl, 3-12 membered heterocyclyl C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl, C 3-6 cycloalkylene, and 3-6 membered heterocycloalkylene.
In some embodiments, ring a is of the following sub-structural formula:
Wherein each Z 1a and Z 2a is independently CH 2 or NH;
Each Z 3a and Z 7a is independently CH or N;
Z 4a is O, S or NH;
Each Z 5a and Z 6a is independently CH 2、O、S、S(＝O)、S(＝O)2, C (=o) or NH;
Each m and t is independently 0,1 or 2;
each n and t1 is independently 0 or 1;
Wherein each substructure of ring A is independently optionally substituted with 1,2, 3 or 4 substituents selected from F, cl, br, OH, oxo, NR 5R6、R5(C＝O)NR6 -, aminoC 1-4 alkyl, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, 3-12 membered carbocyclyl, 3-12 membered heterocyclyl C 1-4 alkyl, C 1-4 alkoxy C 1-4 alkyl, C 3-6 cycloalkylene and 3-6 membered heterocycloalkylene.
In some embodiments, ring a is of the following sub-structural formula:
Wherein each substructure of ring a is independently optionally substituted with 1, 2, 3 or 4 substituents selected from F, cl, br, OH, oxo, NH 2、NHCH3、CH3 (c=o) NH-, methyl, ethyl, n-propyl, methoxy, ethoxy, isopropoxy, CF 3, hydroxymethyl, 2-hydroxyethyl, cyclopropyl, cyclohexyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, cyclopropylene, cyclohexylene and pyrrolidinylene.
In some embodiments, M is H, D, 5-10 membered heteroaryl, C 6-10 aryl, C 3-7 cycloalkyl, or 3-12 membered heterocyclyl; and M is optionally substituted with 1,2, 3 or 4 substituents selected from F, cl, CN, OH, NR 5R6、OR7、C1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 haloalkoxy, C 6-10 aryl, C 1-6 alkoxy C 1-6 alkyl, oxo, C 1-6 alkanoyl, 3-7 membered heterocyclyl and C 3-7 cycloalkyl.
In some embodiments, M is H, D, pyridinyl, pyrimidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, pyrazinyl, phenyl, cyclopentyl, cyclopropyl, cyclohexyl, cyclobutyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, morpholinyl, tetrahydrothiopyranyl, oxetanyl, 1, 2-dihydropyridinyl, 7-azabicyclo [2.2.1] heptanyl, hexahydrofuro [3,4-c ] pyrrolyl, 3-azabicyclo [3.1.0] hexanyl, octahydropyrrolo [1,2-a ] pyrazinyl, or 5-azaspiro [2.4] heptanyl; and M is optionally substituted with 1,2,3 or 4 substituents selected from D、F、Cl、CN、OH、CF3、CHCl2、CHF2、CH2F、CF3CH2、NH2、NHCH3、N(CH3)2、 trifluoromethoxy, 2-trifluoroethoxy, methoxy, ethoxy, isopropoxy, tert-butoxy, methyl, ethyl, n-propyl, isopropyl, phenyl, methoxymethyl, methoxyethyl, oxo, formyl, acetyl, morpholinyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, cyclopropyl and cyclohexyl.
In some embodiments, M is phenyl, And M is optionally substituted with 1, 2,3 or 4 substituents selected from D, F, cl, CN, OH, CF 3、NH2、NHCH3、N(CH3)2, trifluoromethoxy, 2-trifluoroethoxy, methoxy, ethoxy, isopropoxy, tert-butoxy, methyl, ethyl, n-propyl, isopropyl, phenyl, methoxymethyl, methoxyethyl, oxo, formyl, acetyl, morpholinyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, cyclopropyl and cyclohexyl.
In some embodiments, M is
In some embodiments, R 1 is H, D, CN, F, cl, br, methyl, ethyl, or cyclopropyl, wherein the methyl, ethyl, and cyclopropyl groups are independently optionally substituted with 1, 2,3, or 4 substituents selected from F, cl, br, CN, NH 2, OH, and NO 2.
In some embodiments, R 4 is H, D, F, cl, br, methyl, ethyl, n-propyl, methoxy, or ethoxy, wherein the methyl, ethyl, n-propyl, methoxy, and ethoxy groups are independently optionally substituted with 1,2,3, or 4 substituents selected from F, cl, br, CN, NH 2, OH, and NO 2.
In some embodiments, each R 2 and R 3 is independently OH, F, H, D, CN, cl, br, NH 2、C1-6 hydroxyalkyl, C 1-6 alkyl, C 1-6 alkylamino, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-7 cycloalkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl C 1-6 alkyl, C 6-10 aryl, or 5-10 membered heteroaryl;
Or R 2 and R 3 form a 3-7 membered carbocyclic ring or a 3-7 membered heterocyclic ring with the same carbon atom to which they are attached.
In some embodiments, each R 2 and R 3 is independently OH, F, CF 3、CHCl2、CHF2、H、D、CN、Cl、Br、NH2, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, methyl, ethyl, N (CH 3)2, methoxy, ethoxy, isopropoxy, t-butoxy, trifluoromethoxy, cyclopropyl, cyclopentyl, cyclopropylmethyl, cyclopentylethyl, cyclopentylmethyl, phenyl, pyridinyl, or pyrazinyl;
Or R 2、R3 and the same carbon atom to which it is attached form cyclopentane, cyclopropane, cyclobutane, tetrahydropyran, tetrahydrofuran, piperidine or pyrrolidine.
In some embodiments, Q is a bond 、-O-、-(CH2)2O-、-CH2-、-(CH2)2-、-(CH2)3-、-CH2CH(CH3)CH2-、-CH2CH(CH3)CH2NHCH2-、-(C＝O)OC(CH3)2CH2-、-(C＝O)(CH2)2(S＝O)2CH2-、-(C＝O)CH(OH)-、-(C＝O)CH(OH)CH2-、-(C＝O)-、-(S＝O)2-、-(C＝O)CH2CH(OH)-、-(C＝O)CH2-、-(C＝O)CH(CH2OH)-、-(C＝O)C(CH3)2-、-(C＝O)CH2NHC(CH3)2CH2-、-(C＝O)CH2CH(N(CH3)2)-、-(C＝O)(CH2)2N(CH3)CH2-、-(C＝O)C(CH3)2CH2-、-(C＝O)C(OH)(CH3)CH2-、-(C＝O)CH2OCH2-、-(C＝O)(CH2)3-、-(C＝O)CH(NH2)-、-(C＝O)(CH2)3N(CH3)CH2-、-(C＝O)(CH2)2-、-(C＝O)CH2CH(OH)CH2-、-(C＝O)CF2CH2-、-(C＝O)CH(OH)C(CH3)2CH2-、-(C＝O)CH2C(CH3)2CH2-、-(C＝O)CH2C(CH3)(OH)CH2-、-(S＝O)2CH2-、-(S＝O)2CH2C(CH3)2CH2-、-(C＝O)CH(OCH3)-、-(C＝O)NHCH(CH2OH)(CH2)2-、-(C＝O)NH-、-(C＝O)N(CH3)-、-(C＝O)N(CH2CH2CH2CH3)-、-(C＝O)N(CH2CH3)(CH2)2-、-(C＝O)NHC(CH3)2CH2-、-(C＝O)N(CH3)(CH2)2-、-(C＝O)NHCH2CH(CH3)CH2-、-(C＝O)NHCH2-、-(C＝O)NH(CH2)2OCH2-、-(C＝O)N(CH3)(CH2)2OCH2-、-(S＝O)2NHC(CH3)2CH2-、-CH2CH(OH)C(CH3)2CH2-、-CH(CH3)CH(OH)-、-CH2(C＝O)NHCH(CH3)CH2-、-CH2(C＝O)-、-(CH2)2(C＝O)N(CH3)CH2-、-CH2CH(OH)-、-CH2CH(OH)CH2-、-CH2CH(OH)CH(CH3)CH2-、-(C＝O)CH(N(CH3)2)-、-(C＝O)C(CH3)2CH2OCH2-、-(C＝O)C(OCH3)(CF3)-、-(C＝O)N(CH2CH2OCH3)CH2CH(OCH3)-、-CH2CH(OCF3)-、-CH2CH(OCH(CH3)2)-、-CH2CH(OC(CH3)3)-、-CH2CF2-、-CH(CH3)-、-CH2CH(OCH3)C(CH3)2-、-CH2CH(N(CH3)2)-、-NH-、-(C＝O)NHOCH2-、-(C＝O)NHOCH2(CHOH)-、-(S＝O)2(CH2CH3)-、-(S＝O)2O-、-(S＝O)2-NHC(CH3)2-、-(CH2)2(S＝O)2-、
In some embodiments, the compounds of the present invention have the structure of formula (IA), or stereoisomers, geometric isomers, tautomers, nitroxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs of the structure of formula (IA),
Wherein R 1、X1、X2、X3、X4、X5、E、A、Q、M、T、G、Ra, q have the definitions as described in the present invention.
In some embodiments, the compounds of the present invention have the structure of formula (I-1), or stereoisomers, geometric isomers, tautomers, nitroxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs of the structure of formula (I-1),
Wherein R 1、X1、X2、X3、X4、X5、E、Q、M、T、G、Ra, q have the definitions as described herein;
Ring A1 is of the sub-structural formula:
Wherein each Z 1a and Z 2a is independently CH 2 or NH;
And each sub-structural formula of ring A1 is independently optionally substituted with 1,2,3 or 4 substituents selected from F, cl, br, OH, oxo, NR 5R6、R5(C＝O)NR6 -, aminoC 1-4 alkyl, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, 3-12 membered carbocyclyl, 3-12 membered heterocyclyl C 1-4 alkyl, C 1-4 alkoxy C 1-4 alkyl, C 3-6 cycloalkylene and 3-6 membered heterocycloalkylene.
In some embodiments, ring A1 is of the formula:
Wherein each substructure of ring A1 is independently optionally substituted with 1,2, 3 or 4 substituents selected from F, cl, br, OH, oxo, NH 2、NHCH3、CH3 (c=o) NH-, methyl, ethyl, n-propyl, methoxy, ethoxy, isopropoxy, CF 3, hydroxymethyl, 2-hydroxyethyl, cyclopropyl, cyclohexyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, cyclopropylene, cyclohexylene and pyrrolidinylene.
In some embodiments, the compounds of the present invention have the structure of formula (IA 1), or stereoisomers, geometric isomers, tautomers, nitroxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs of the structure of formula (IA 1),
Wherein R 1、X1、X2、X3、X4、X5、A、T、G、Ra, q have the definitions as described herein;
Wherein M 1 is heteroaryl, aryl.
In some embodiments, M 1 is a 5-10 membered heteroaryl or C 6-10 aryl; and M is optionally substituted with 1, 2, 3 or 4 substituents selected from D, F, cl, CN, OH, NR 5R6、OR7、C1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 haloalkoxy, C 6-10 aryl, C 1-6 alkoxy C 1-6 alkyl, oxo, C 1-6 alkanoyl, 3-7 membered heterocyclyl and C 3-7 cycloalkyl.
In some embodiments, M 1 is pyridinyl, pyrimidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, pyrazinyl, phenyl; pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, pyrazinyl, phenyl.
In some embodiments, M 1 is
In some embodiments, the compounds of the present invention have the structure of formula (I-1 aa), or stereoisomers, geometric isomers, tautomers, nitroxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs of the structure of formula (I-1 aa),
Wherein R 1、X1、X2、X3、X4、X5、T、G、Ra、q、A1、M1 has the definition as described in the present invention.
In some embodiments, the compounds of the present invention have the structure of formula (I-2) or (I-3), or stereoisomers, geometric isomers, tautomers, nitroxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs of the structure of formula (I-2) or (I-3),
Wherein R 1、X1、X2、X3、X4、X5、E、Q、M、T、G、Ra, q have the definitions as described herein;
Each Z 1、Z2、Z3a and Z 7a is independently CH or N;
Each m and t is independently 0,1 or 2;
each n and t1 is independently 0 or 1;
Each of which is Independently optionally substituted with 1,2, 3 or 4 substituents selected from F, cl, br, OH, oxo, NR 5R6、R5(C＝O)NR6 -, aminoC 1-4 alkyl, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, 3-12 membered carbocyclyl, 3-12 membered heterocyclyl C 1-4 alkyl, C 1-4 alkoxy C 1-4 alkyl, C 3-6 cycloalkylene and 3-6 membered heterocycloalkylene.
In some embodiments of the present invention, in some embodiments,The following sub-structural formula is shown as follows:
the following sub-structural formula is shown as follows:
Wherein the method comprises the steps of Independently optionally substituted with 1,2, 3 or 4 substituents selected from F, cl, br, OH, oxo, NH 2、NHCH3、CH3 (c=o) NH-, methyl, ethyl, n-propyl, methoxy, ethoxy, isopropoxy, CF 3, hydroxymethyl, 2-hydroxyethyl, cyclopropyl, cyclohexyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, cyclopropylene, cyclohexylene and pyrrolidinylene.
In some embodiments, the compounds of the present invention have one of the following structures, or stereoisomers, geometric isomers, tautomers, nitroxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof,
In another aspect, the invention provides a pharmaceutical composition comprising a compound of the invention, and a pharmaceutically acceptable adjuvant.
In another aspect, the invention also provides the use of the compound of the invention or the pharmaceutical composition of the invention in the preparation of a medicament for preventing or treating RET-related diseases.
In some embodiments, the RET related disease includes cancer, irritable bowel syndrome and/or pain associated with irritable bowel syndrome.
In another aspect, the invention also provides a compound of the invention or a pharmaceutical composition of the invention for use in the prevention or treatment of RET-related disorders.
In some embodiments, the RET related disease includes cancer, irritable bowel syndrome and/or pain associated with irritable bowel syndrome.
In another aspect, the invention also provides a method of preventing or treating RET-related disorders comprising administering to a patient a therapeutically effective amount of a compound of the invention or a pharmaceutical composition thereof.
In some embodiments, the RET related disease includes cancer, irritable bowel syndrome and/or pain associated with irritable bowel syndrome.
In another aspect, the present invention relates to intermediates for preparing compounds of formula (I), (I-1), (IA 1), (I-1 aa), (I-2) or (I-3).
In another aspect, the present invention relates to methods for the preparation, isolation and purification of compounds of formula (I), (I-1), (IA 1), (I-1 aa), (I-2) or (I-3).
In another aspect, the invention provides a pharmaceutical composition comprising a compound of the invention and pharmaceutically acceptable adjuvants thereof. In some embodiments, adjuvants described herein include, but are not limited to, carriers, excipients, diluents, vehicles, or combinations thereof. In some embodiments, the pharmaceutical composition may be in a liquid, solid, semi-solid, gel or spray form.
Also provided herein are methods of inhibiting cell proliferation in vitro or in vivo comprising contacting a cell with an effective amount of a compound of the invention or a pharmaceutical composition thereof.
Also provided herein are methods of treating Irritable Bowel Syndrome (IBS) and/or pain associated with IBS in a patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound of the present invention or a pharmaceutical composition thereof.
The invention also provides the use of a compound of the invention or a pharmaceutical composition of the invention in the manufacture of a medicament for the prophylactic or therapeutic treatment of Irritable Bowel Syndrome (IBS) and/or pain associated with IBS.
The invention also provides the use of a compound of the invention or a pharmaceutical composition of the invention for the prophylaxis or treatment of Irritable Bowel Syndrome (IBS) and/or pain associated with IBS.
Unless otherwise indicated, all stereoisomers, geometric isomers, tautomers, nitroxides, hydrates, solvates, metabolites, salts and pharmaceutically acceptable prodrugs of the compounds of the invention are within the scope of the invention.
In particular, salts are pharmaceutically acceptable salts. The term "pharmaceutically acceptable" includes substances or compositions that must be suitable for chemical or toxicological use, in relation to the other components that make up the formulation and the mammal being treated.
Salts of the compounds of the present invention also include salts of enantiomers isolated from intermediates used in the preparation or purification of the compounds of formula (I), (IA 1), (I-1 aa), (I-1), (I-2) or (I-3) or the compounds of formula (I), (I-1), (IA 1), (I-1 aa), (I-2) or (I-3), but are not necessarily pharmaceutically acceptable salts.
In the structures disclosed herein, when the stereochemistry of any particular chiral atom is not indicated, then all stereoisomers of that structure are contemplated as being within the present invention and are included as presently disclosed compounds. When stereochemistry is indicated by the solid wedge (solid wedge) or dashed line representing a particular configuration, then the stereoisomers of that structure are so defined and defined.
Nitrogen oxides of the compounds of the present invention are also included within the scope of the present invention. The nitrogen oxides of the compounds of the invention may be prepared by oxidizing the corresponding nitrogen-containing basic species at elevated temperatures using customary oxidizing agents, such as hydrogen peroxide, in the presence of an acid such as acetic acid, or by reaction with peracetic acid in a suitable solvent, such as dichloromethane, ethyl acetate or methyl acetate, or with 3-chloroperoxybenzoic acid in chloroform or dichloromethane.
If the compounds of the present invention are basic, the desired salts may be prepared by any suitable method provided in the literature, for example, using mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like. Or organic acids such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid and salicylic acid; pyranose acids, such as glucuronic acid and galacturonic acid; alpha-hydroxy acids such as citric acid and tartaric acid; amino acids such as aspartic acid and glutamic acid; aromatic acids such as benzoic acid and cinnamic acid; sulfonic acids such as p-toluenesulfonic acid, ethanesulfonic acid, and the like.
If the compounds of the invention are acidic, the desired salts can be prepared by suitable methods, for example, using inorganic or organic bases, such as ammonia (primary, secondary, tertiary), alkali or alkaline earth metal hydroxides, and the like. Suitable salts include, but are not limited to, organic salts derived from amino acids such as glycine and arginine, ammonia such as primary, secondary and tertiary, and cyclic ammonia such as piperidine, morpholine and piperazine, and the like, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.
Compounds of the present invention and pharmaceutical compositions, formulations and administration thereof
The present invention provides compounds of the invention or pharmaceutical compositions thereof that inhibit wild-type RET and RET mutants, e.g., RET mutants that are resistant to current standard of care treatment ("RET resistant mutants"). In addition, the compounds of the invention or pharmaceutical compositions thereof may be selective for wild-type RET relative to other kinases, resulting in reduced toxicity associated with inhibition of other kinases.
The pharmaceutical composition of the present invention comprises a compound represented by formula (I), (IA 1), (I-1 aa), (I-1), (I-2) or (I-3), a compound listed in the present invention, or a compound of the examples. The amount of the compound in the compositions of the invention is effective to treat or reduce RET-associated diseases or conditions in a patient, including RET-associated cancers, irritable bowel syndrome and/or pain associated with irritable bowel syndrome.
As described herein, the pharmaceutically acceptable compositions of the present invention further comprise pharmaceutically acceptable adjuvants, which as used herein, include any solvent, diluent, or other liquid excipient, dispersant or suspending agent, surfactant, isotonic agent, thickening agent, emulsifying agent, preservative, solid binder or lubricant, and the like, as appropriate for the particular target dosage form. ：In Remington:The Science and Practice of Pharmacy,21st edition,2005,ed.D.B.Troy,Lippincott Williams&Wilkins,Philadelphia,and Encyclopedia of Pharmaceutical Technology,eds.J.Swarbrick and J.C.Boylan,1988-1999,Marcel Dekker,New York,, as described in the following documents, taken together with the content of the documents herein, demonstrate that various adjuvants can be employed in the preparation of pharmaceutically acceptable compositions and their known methods of preparation. In addition to the extent to which any conventional adjuvant is incompatible with the compounds of the present invention, such as any adverse biological effects produced or interactions with any other component of the pharmaceutically acceptable composition in a deleterious manner, their use is also contemplated by the present invention.
In preparing the compositions provided herein, the active ingredient is typically mixed with an excipient, diluted by an excipient or enclosed within such a carrier in the form of, for example, a capsule, pouch, paper or other container. If an excipient is used as a diluent, it may be a solid, semi-solid, or liquid material, which acts as a carrier, vehicle, or medium for the active ingredient. Suitable carriers include, but are not limited to, magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. Thus, the compositions may be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders. In one embodiment, the composition is formulated for oral administration. In one embodiment, the composition is formulated as a tablet or capsule.
When useful in therapy, a therapeutically effective amount of a compound of the present invention, particularly a compound of formula (I), (IA 1), (I-1 aa), (I-1), (I-2), (I-3) or (I-4), and pharmaceutically acceptable salts thereof, may be administered as a raw chemical, and may also be provided as an active ingredient in a pharmaceutical composition. Accordingly, the present disclosure also provides pharmaceutical compositions comprising a therapeutically effective amount of a compound of the present invention, particularly a compound of formula (I), (IA 1), (I-1 aa), (I-1), (I-2), (I-3) or (I-4), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable adjuvants, including, but not limited to, a carrier, diluent or excipient, and the like. The term "therapeutically effective amount" as used herein refers to the total amount of each active ingredient sufficient to exhibit a meaningful patient benefit (e.g., cancer cytopenia). When separate active ingredients are used for separate administration, the term refers only to the ingredient. When applied in combination, the term refers to the combined amounts of the active ingredients that, when administered sequentially or simultaneously, result in a therapeutic effect. The compounds of the present invention, in particular the compounds of formula (I), (IA 1), (I-1 aa), (I-1), (I-2) or (I-3) and their pharmaceutically acceptable salts are as described above. The carrier, diluent or excipient must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. According to a further aspect of the present disclosure there is also provided a process for the preparation of a pharmaceutical formulation, which process comprises homogenizing a compound of the present invention, in particular a compound of formula (I), (IA 1), (I-1 aa), (I-1), (I-2) or (I-3), or a pharmaceutically acceptable salt thereof, with one or more pharmaceutically acceptable carriers, diluents or excipients. The term "pharmaceutically acceptable" as used herein refers to compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio, and are effective for use in the intended use.
The amount of active ingredient combined with one or more adjuvants to prepare a single dosage form will necessarily vary depending upon the host treated and the particular route of administration. The amount of the compound of formula (I), (IA 1), (I-1 aa), (I-1), (I-2) or (I-3) admixed with a carrier material to prepare a single dosage form will vary depending upon the disease to be treated, the severity of the disease, the time of administration, the route of administration, the rate of excretion of the compound employed, the time of treatment and the age, sex, weight and condition of the patient. Preferred unit dosage forms are those containing daily or divided doses or suitable fractions thereof of the active ingredients described herein above. Treatment may be initiated with a small dose that is significantly less than the optimal dose of the compound. Thereafter, the dosage is increased in smaller increments until the optimal effect is reached in this case. In general, the most desirable levels of concentration at which the compound is administered are those that generally provide effective results in terms of anti-tumor efficacy without causing any deleterious or toxic side effects.
Compositions comprising the compounds of the invention may be formulated in unit dosage forms, each dosage comprising from about 5 to about 1,000mg (1 g), more typically from about 100mg to about 500mg, of the active ingredient. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human subjects or other patients, each unit containing a predetermined quantity of active material, i.e., a compound of formula I as provided herein, calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
In some embodiments, the compositions provided herein contain from about 5mg to about 50mg of the active ingredient. Those of ordinary skill in the art will appreciate that this embodies a compound or composition comprising from about 5mg to about 10mg, from about 10mg to about 15mg, from about 15mg to about 20mg, from about 20mg to about 25mg, from about 25mg to about 30mg, from about 30mg to about 35mg, from about 35mg to about 40mg, from about 40mg to about 45mg, or from about 45mg to about 50mg of the active ingredient.
In some embodiments, the compositions provided herein contain from about 50mg to about 500mg of the active ingredient. Those of ordinary skill in the art will appreciate that this embodies a compound or composition comprising from about 50mg to about 100mg, from about 100mg to about 150mg, from about 150mg to about 200mg, from about 200mg to about 250mg, from about 250mg to about 300mg, from about 350mg to about 400mg, or from about 450mg to about 500mg of the active ingredient.
In some embodiments, the compositions provided herein contain from about 500mg to about 1,000mg of the active ingredient. Those of ordinary skill in the art will appreciate that this embodies a compound or composition comprising from about 500mg to about 550mg, from about 550mg to about 600mg, from about 600mg to about 650mg, from about 650mg to about 700mg, from about 700 to about 750mg, from about 750mg to about 800mg, from about 800mg to about 850mg, from about 850mg to about 900mg, from about 900mg to about 950mg, or from about 950mg to about 1,000mg of an active ingredient.
The pharmaceutical composition is suitable for administration by any suitable route, for example by oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intradermal, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intralesional, intravenous or true subcutaneous injection or infusion) route. Such formulations may be prepared by any method known in the pharmaceutical arts, for example, by mixing the active ingredient with carriers or excipients. Oral administration or injection administration is preferred.
The invention also provides methods of treating an individual having RET-associated cancer comprising administering a compound of the invention before, during or after administration of another anti-cancer agent (e.g., not a compound of the invention).
The present invention provides a method for treating cancer in a patient in need thereof, the method comprising: (a) Determining whether the cancer in the patient is a RET related cancer (e.g., a RET related cancer including a RET related cancer having one or more RET inhibitor resistance mutations) (e.g., using regulatory agency approved, e.g., FDA approved, kits to identify a deregulation of the expression or activity or level of a RET gene, RET kinase, or any of them in the patient or in a biopsy sample of the patient, or by performing any non-limiting examples of assays described herein); and (b) administering to the patient a therapeutically effective amount of a compound of formula (I), (IA 1), (I-1 aa), (I-1), (I-2) or (I-3), or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof, if the cancer is determined to be a RET-associated cancer. Some embodiments of these methods further comprise administering to the subject another anti-cancer agent (e.g., another RET inhibitor, e.g., a RET inhibitor that is not a compound of the invention). In some embodiments, the subject is previously treated with a RET inhibitor that is not a compound of formula (I), (IA 1), (I-1 aa), (I-1), (I-2), or (I-3), or a pharmaceutically acceptable salt or solvate thereof, or is previously treated (e.g., after excision of a tumor or radiation therapy) with another anticancer agent.
In some embodiments of any of the methods described herein, a compound of formula (I), (IA 1), (I-1 aa), (I-1), (I-2), or (I-3) (or a pharmaceutically acceptable salt or solvate thereof) is used in combination with a therapeutically effective amount of at least one other therapeutic agent selected from one or more other therapies or therapeutic (e.g., chemotherapeutic) agents.
Non-limiting examples of other therapeutic agents include: other RET targeted therapeutic agents (i.e., other RET kinase inhibitors: RET inhibitors other than the compounds of the present invention), receptor tyrosine kinase targeted therapeutic agents, signal transduction pathway inhibitors, checkpoint inhibitors, apoptosis pathway modulators (e.g., obataclax); cytotoxic chemotherapeutic agents, angiogenesis targeted therapeutic agents, immune targeted agents and radiation therapy.
In some embodiments, the other RET targeted therapeutic agent is a multi-kinase inhibitor that exhibits RET inhibitory activity.
Non-limiting examples of RET targeted therapeutic agents include Alatinib, apatinib, cabatinib (XL-184), multi-vitamin, lenvatinib, mo Taisha Ni, nidanib, pratinib, lei Gela non-Ni, statinib (sitravatinib) (MGCD 516), sunitinib, sorafenib, varatinib, van-Detanib, AUY-922 (5- (2, 4-dihydroxy-5-isopropyl-phenyl) -N-ethyl-4- [4- (morpholinomethyl) phenyl ] isoxazole-3-carboxamide), BLU6864, BLU-667, BLU-2157, NVP-AST487 (1- [4- [ (4-ethylpiperazin-1-yl) methyl ] -3- (trifluoromethyl) phenyl ] -3- [4- [6- (methylamino) pyrimidin-4-yl ] oxyphenyl ] urea), PZ-1 (RPI-1 (1, 3-dihydro-5, 6-dimethoxy-3-hydroxy-phenyl) -4- [ (4-hydroxy-indol-3-yl) isoxazole-3-carboxamide), BLU-667, BLU-2157, NVP-4- [ (4-ethylpiperazin-1-yl) methyl ] -3- (trifluoromethyl) phenyl ] urea, SPP86 (1-isopropyl-3- (phenylethynyl) -1H-pyrazolo [3,4-d ] pyrimidin-4-amine) and TG101209 (N- (1, 1-dimethylethyl) -3- [ [ 5-methyl-2- [ [4- (4-methyl-1-piperazinyl) phenyl ] amino ] -4-pyrimidinyl ] amino ] benzenesulfonamide).
Other therapeutic agents include RET inhibitors, such as those described, for example, in the following: U.S. patent No. 7,504,509;8,299,057;8,399,442;8,067,434;8,937,071;9,006,256; and 9,035,063; U.S. publication No. 2014/0121239;20160176865;2011/0053934;2011/0301157;2010/0324065;2009/0227556;2009/0130229;2009/0099167;2005/0209195; International publication No. WO 2014/184069;WO 2014/072220;WO2012/053606;WO 2009/017838;WO 2008/031551;WO 2007/136103;WO 2007/087245;WO2007/057399;WO 2005/051366;WO 2005/062795; and WO 2005/044835; and j.med.chem.2012,55 (10), 4872-4876, which is incorporated herein by reference in its entirety.
Also provided herein are methods of treating cancer comprising administering to a patient in need thereof a pharmaceutical combination comprising (a) a compound of formula I or a pharmaceutically acceptable salt or solvate thereof, (b) other therapeutic agents, and (c) optionally at least one pharmaceutically acceptable carrier, for simultaneous, separate or sequential use in treating cancer, wherein the amount of the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof and the amount of the other therapeutic agents are co-effective in treating cancer.
The compounds and compositions described herein may be administered alone or in combination with other compounds (including other RET modulating compounds) or other therapeutic agents. In some embodiments, the compounds or compositions of the present invention may be administered in combination with one or more compounds selected from the group consisting of: cabozantinib (COMETRIQ), vandetanib (CALPRESA), sorafenib (NEXAVAR), sunitinib (SUTENT), lei Gela non-ni (STAVARGA), pranoptinib (ICLUSIG), bevacizumab (avastin), crizotinib (XALKORI) or gefitinib (IRESSA). The compounds or compositions of the invention may be administered simultaneously or sequentially with other therapeutic agents by the same or different routes of administration. The compounds of the invention may be included with other therapeutic agents in a single formulation or in separate formulations.
In some embodiments, the compounds of the present invention may be used to treat Irritable Bowel Syndrome (IBS) in combination with one or more other therapeutic agents or therapies that are effective in the treatment of irritable bowel syndrome by acting through the same or different mechanisms of action. The at least one additional therapeutic agent may be administered with the compound of formula I or a pharmaceutically acceptable salt or solvate thereof as part of the same or separate dosage form, via the same or different route of administration, and according to the same or different administration schedule, according to standard pharmaceutical practice known to those skilled in the art. Non-limiting examples of other therapeutic agents for the treatment of Irritable Bowel Syndrome (IBS) include probiotics, fiber supplements (e.g. psyllium, methylcellulose), antidiarrheals (e.g. loperamide), bile acid binders (e.g. cholestyramine, colestipol, colesevelam), anticholinergic and anticonvulsants (e.g. hyoscyamine, dicyclomine), antidepressants (e.g. tricyclic antidepressants such as imipramine or nortriptyline or selective 5-hydroxytryptamine reuptake inhibitors (SSRI) such as fluoxetine or paroxetine), antibiotics (e.g. rifaximin), alosetron and lubiprostone.
Use of the compounds and pharmaceutical compositions of the invention
The invention also provides the use of a compound of the invention or a pharmaceutical composition of the invention in the manufacture of a medicament for the prevention or treatment of a RET related disease or disorder, wherein the RET related disease or disorder comprises RET related cancer, irritable bowel syndrome and/or pain associated with irritable bowel syndrome.
The present invention provides compounds of the invention or pharmaceutical compositions thereof that inhibit wild-type RET and RET mutants, e.g., RET mutants that are resistant to current standard of care treatment ("RET resistant mutants"). In addition, the compounds of the invention or pharmaceutical compositions thereof may be selective for wild-type RET relative to other kinases, resulting in reduced toxicity associated with inhibition of other kinases.
The invention provides application of the compound or the pharmaceutical composition thereof for inhibiting wild RET and RET mutants in preparation of medicines for preventing or treating diseases or symptoms related to the wild RET and RET mutants.
In some embodiments of any of the methods or uses described herein, the cancer (e.g., RET related cancer) is a hematologic cancer. In some embodiments of any of the methods or uses described herein, the cancer (e.g., RET related cancer) is a solid tumor. in some embodiments of any of the methods or uses described herein, the cancer (e.g., RET related cancer) is lung cancer (e.g., small cell lung cancer or non-small cell lung cancer), papillary thyroid cancer, medullary thyroid cancer, differentiated thyroid cancer, recurrent thyroid cancer, refractory differentiated thyroid cancer, lung adenocarcinoma, bronchiolar lung cancer, multiple endocrine tumors of type 2A or 2B (MEN 2A or MEN2B, respectively), pheochromocytoma, parathyroid hyperplasia, breast cancer, colorectal cancer (e.g., metastatic colorectal cancer), papillary renal cell carcinoma, gangliocytomatosis of the gastrointestinal mucosa, inflammatory myofibroblastic tumor, or cervical cancer. In some embodiments of any of the methods or uses described herein, the cancer (e.g., RET related cancer) is selected from the group consisting of: acute Lymphoblastic Leukemia (ALL), acute Myelogenous Leukemia (AML), juvenile cancer, adrenocortical carcinoma, anal carcinoma, appendiceal carcinoma, astrocytoma, atypical teratoma/rhabdoid tumor, basal cell carcinoma, cholangiocarcinoma, bladder carcinoma, bone cancer, brain stem glioma, brain tumor, breast cancer, bronchial tumor, burkitt's lymphoma, carcinoid tumor, unknown primary cancer, cardiac tumor, cervical cancer, childhood cancer, chordoma, chronic Lymphocytic Leukemia (CLL), chronic Myelogenous Leukemia (CML), chronic myeloproliferative neoplasms, colon cancer, colorectal cancer, craniopharyngeal neoplasia, cutaneous T-cell lymphoma, cholangiocarcinoma, ductal carcinoma in situ, embryonal tumors, endometrial carcinoma, ependymoma, esophageal carcinoma, sensorineural cytoma, ewing's sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, extrahepatic cholangiocarcinoma, ocular carcinoma, fallopian tube carcinoma, bone fibrohistiocytoma, gallbladder carcinoma, gastric carcinoma, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell tumor, gestational trophoblastic disease, glioma, hairy cell tumor, hairy cell leukemia, head and neck cancer, heart cancer, hepatocellular carcinoma, histiocytosis, hodgkin's lymphoma, hypopharyngeal carcinoma, intraocular melanoma, islet cell carcinoma, pancreatic neuroendocrine tumor, kaposi's sarcoma, renal carcinoma, langerhans ' histiocytosis, laryngeal carcinoma, leukemia, lip and oral cancer, liver cancer, lung cancer, lymphoma, macroglobulinemia, bone malignant fibrous histiocytoma, bone cancer, melanoma, merkel cell carcinoma, mesothelioma, metastatic squamous neck carcinoma, midline carcinoma, oral carcinoma, multiple endocrine tumor syndrome, multiple myeloma, mycosis granuloma, myelodysplastic syndrome, myelodysplastic/myeloproliferative neoplasm, myelogenous leukemia, multiple myeloma, Myeloproliferative neoplasms, nasal and sinus cancers, nasopharyngeal cancers, neuroblastomas, non-hodgkin lymphomas, non-small cell lung cancers, oral cancers, lip cancers, oropharyngeal cancers, osteosarcoma, ovarian cancers, pancreatic cancers, papillomatosis, paragangliomas, paranasal sinus and nasal cancers, parathyroid cancers, penile cancers, pharyngeal cancers, pheochromocytomas, pituitary cancers, plasmacytomas, pleural-pulmonary blastomas, gestational and breast cancers, primary central nervous system lymphomas, primary peritoneal cancers, prostate cancers, rectal cancers, renal cell carcinomas, retinoblastomas, rhabdomyosarcomas, salivary gland cancers, sarcomas, sezary syndrome, skin cancers, small cell lung cancers, Carcinoma of small intestine, sarcoma of soft tissue, squamous cell carcinoma, squamous neck carcinoma, gastric cancer, T-cell lymphoma, testicular carcinoma, laryngeal carcinoma, thymoma and transitional cell carcinoma of thymus, thyroid carcinoma, transitional cell carcinoma of renal pelvis and ureter, unknown primary carcinoma, carcinoma of urinary tract, carcinoma of uterus, uterine sarcoma, carcinoma of vagina, carcinoma of vulva and wilms' tumor.
In some embodiments, the RET related cancer of the present invention is selected from lung cancer, papillary thyroid cancer, medullary thyroid cancer, differentiated thyroid cancer, recurrent thyroid cancer, refractory differentiated thyroid cancer, multiple endocrine tumors of type 2A or 2B (MEN 2A or MEN2B, respectively), pheochromocytoma, parathyroid hyperplasia, breast cancer, colorectal cancer, papillary renal cell carcinoma, gastrointestinal mucosal gangliocytoma, and cervical cancer. In some embodiments, the RET related cancer is RET fusion lung cancer or medullary thyroid cancer.
In some embodiments, the compounds of formula (I), (IA 1), (I-1 aa), (I-1), (I-2) or (I-3) and pharmaceutically acceptable salts and solvates thereof are useful in treating patients suffering from RET inhibitor resistance mutations that result in increased resistance to compounds or pharmaceutically acceptable salts or solvates that are not of formula (I), (IA 1), (I-1 aa), (I-1), (I-2) or (I-3), e.g., substitutions at amino acid position 804, e.g., V804M, V804L or V804E), by co-administration or as a subsequent treatment of existing drug therapies (e.g., other RET kinase inhibitors that are not compounds of formula (I), (IA 1), (I-1 aa), (I-2) or (I-3) or pharmaceutically acceptable salts or solvates thereof). Described herein are exemplary RET kinase inhibitors (e.g., other RET kinase inhibitors that are not compounds of formula (I), (IA 1), (I-1 aa), (I-1), (I-2), or (I-3), or pharmaceutically acceptable salts or solvates thereof). In some embodiments, the RET kinase inhibitor may be selected from the group consisting of cabotinib, vandetanib, alatinib, sorafenib, lenvatinib, pluratinib, multi-vitamin tinib, sunitinib, fortinib (foretinib), BLU667, and BLU6864.
In some embodiments of any of the methods or uses described herein, the Irritable Bowel Syndrome (IBS) comprises diarrhea predominant, constipation predominant, or alternating, functional abdominal distension, functional constipation, functional diarrhea, unspecific functional bowel disorder, functional abdominal pain syndrome, chronic idiopathic constipation, functional esophageal disease, functional gastroduodenal disease, functional anorectal pain, and inflammatory bowel disease.
The compounds and compositions according to the methods of the invention can be in any amount and by any route effective for treating or lessening the severity of the disease. The exact amount necessary will vary depending on the patient's condition, depending on the race, age, general condition of the patient, severity of the infection, particular factors, mode of administration, and the like. The compounds or compositions may be used in combination with one or more other therapeutic agents, as discussed herein.
General methods for the Synthesis of Compounds of the invention
In general, the compounds of the invention may be prepared by the methods described herein, unless otherwise indicated, wherein the substituents are as defined in formula (I), (IA 1), (I-1 aa), (I-1), (I-2) or (I-3). The following reaction schemes and examples are provided to further illustrate the present invention.
Those skilled in the art will recognize that: the chemical reactions described herein may be used to suitably prepare many other compounds of the present invention, and other methods for preparing the compounds of the present invention are considered to be within the scope of the present invention. For example, the synthesis of those non-exemplified compounds according to the invention can be successfully accomplished by modification methods, such as appropriate protection of interfering groups, by use of other known reagents in addition to those described herein, or by some conventional modification of the reaction conditions, by those skilled in the art. In addition, the reactions disclosed herein or known reaction conditions are also well-known to be applicable to the preparation of other compounds of the present invention.
The examples described below are given unless otherwise indicated that all temperatures are given in degrees celsius. Unless otherwise indicated, reagents were commercially available, e.g., reagents were purchased from commercial suppliers such as Ling Kai medicine, ALDRICH CHEMICAL Company, inc., arco Chemical Company and ALFA CHEMICAL Company, and were used without further purification unless otherwise indicated. The general reagents were purchased from Shandong Chemicals, guangdong Chemicals, guangzhou Chemicals, tianjin Chemie, inc., qingdao Tenglong chemical Co., ltd., and Qingdao ocean chemical works.
The anhydrous tetrahydrofuran is obtained by reflux drying of metallic sodium. The anhydrous methylene chloride and chloroform are obtained by reflux drying of calcium hydride. Ethyl acetate, N-dimethylacetamide and petroleum ether were dried over anhydrous sodium sulfate in advance for use.
The following reaction is typically carried out under nitrogen or argon pressure or with a dry tube (unless otherwise indicated) over anhydrous solvent, the reaction flask is capped with a suitable rubber stopper and the substrate is injected through a syringe. The glassware was all dried.
The chromatographic column is a silica gel column. Silica gel (300-400 mesh) was purchased from Qingdao ocean chemical plant. Nuclear magnetic resonance spectroscopy was performed using CDC1 3 or DMSO-d 6 as a solvent (reported in ppm) and TMS (0 ppm) or chloroform (7.25 ppm) as reference standards. When multiple peaks occur, the following abbreviations will be used: s (singlet ), d (doublet, doublet), t (triplet, doublet), m (multiplet ), br (broadened, broad), dd (doublet of doublets, doublet), dt (doublet of triplets, doublet). Coupling constants are expressed in hertz (Hz).
Low resolution Mass Spectrometry (MS) data were determined by a spectrometer of the Agilent 6320 series LC-MS equipped with a G1312A binary pump and a G a 1316A TCC (column temperature kept at 30 ℃), a G1329A autosampler and a G1315B DAD detector were applied for analysis, and an ESI source was applied to the LC-MS spectrometer.
Low resolution Mass Spectrometry (MS) data were determined by a spectrometer of the Agilent 6120 series LC-MS equipped with a G1311A quaternary pump and a G1316A TCC (column temperature maintained at 30 ℃), a G1329A autosampler and a G1315D DAD detector were applied for analysis, and an ESI source was applied to the LC-MS spectrometer.
Both spectrometers were equipped with Agilent Zorbax SB-C18 columns, 2.1X130 mm,5 μm in size. The injection volume is determined by the sample concentration; the flow rate is 0.6mL/min; the peak of the HPLC was read by recording the UV-Vis wavelengths at 210nm and 254 nm. The mobile phase was a 0.1% acetonitrile formate solution (phase a) and a 0.1% ultrapure formate solution (phase B).
Compound purification was assessed by Agilent 1100 series High Performance Liquid Chromatography (HPLC) with UV detection at 210nm and 254nm on a Zorbax SB-C18 column, 2.1X130 mm,4 μm,10 min, flow rate of 0.6mL/min,5-95% (0.1% aqueous formic acid in acetonitrile) and column temperature maintained at 40 ℃.
The following abbreviations are used throughout the present invention:
DMAC, DMA N, N-2-methylacetamide
PdCl 2(dppf)CH2Cl2 [1,1' -bis (diphenylphosphine) ferrocene ] palladium dichloride dichloromethane complex
H 2 Hydrogen
Pd/C palladium carbon
LiAlH 4 lithium aluminum hydride
CH 3 I methyl iodide
NH 4 Cl ammonium chloride
K 2CO3 Potassium carbonate
KI potassium iodide
MeOH, CH 3 OH methanol
Na 2SO4 sodium sulfate
NaH sodium hydride
Ms methylsulfonyl group
THF tetrahydrofuran
PE Petroleum ether
EA ethyl acetate
HCl hydrochloric acid
DCM dichloromethane
DMF N, N-dimethylformamide
DMAP dimethylaminopyridine
L liter (L)
Mg
G
Mmol millimoles
ML, mL mL
N, mol/L
H hours
Rt room temperature
TLC thin layer chromatography
Ag 2 O silver oxide
Degree centigrade
Rt room temperature
PBr 3 phosphorus tribromide
DCE 1, 2-dichloroethane
NaBH (OAc) 3 sodium triacetoxyborohydride
NaOH sodium hydroxide
CH 3 CN acetonitrile
NaBH 4 sodium borohydride
N 2 Nitrogen
TMSCl trimethylchlorosilane
Et 3 N triethylamine
H 2 O Water
MsCl methanesulfonyl chloride
EtOH ethanol
TBu t-butyl
Ethyl acetate solution of HCl/EA hydrogen chloride
DMSO dimethyl sulfoxide
Ms methylsulfonyl group
The following synthetic schemes describe the steps for preparing the disclosed compounds. R 1、X1、X2、X3、X4、X5、E、A、Q、M、T、G、Ra, q have the definitions as described herein unless otherwise indicated.
Synthesis scheme 1
Synthetic scheme for intermediate (IA-1 a):
intermediate compounds of formula (IA-1 a) may be obtained by reference to the synthetic steps of the above intermediate synthesis scheme. Wherein ring a is of the sub-structural formula: Hal 1 and Hal 2 are each independently F, cl, br, I, preferably Cl, br; pg 1 is an amino protecting group, such as Boc, etc.; pg 2 is a hydroxyl protecting group, such as benzyl, etc. The compound of formula (IA-1 a-1) is coupled with the compound of formula (IA-1 a-2) under suitable coupling agent conditions (e.g., palladium coupling agent, preferably PdCl 2(dppf)CH2Cl2) in a suitable solvent (e.g., dioxane, etc.) to provide the compound of formula (IA-1 a-3); the compound of formula (IA-1 a-3) is coupled with the compound of formula (IA-1 a-4) under suitable coupling agent conditions (e.g., palladium coupling agent, preferably PdCl 2(dppf)CH2Cl2) in a suitable solvent (e.g., toluene, etc.) to provide the compound of formula (IA-1 a-5); reacting a compound of formula (IA-1 a-5) under suitable reaction conditions (e.g., in the presence of sodium hydroxide and hydrogen peroxide in a tetrahydrofuran solvent) to provide a compound of formula (IA-1 a-6); the compound of formula (IA-1 a-6) and the compound of formula (IA-1 a-7) undergo a coupling reaction to obtain the compound of formula (IA-1 a-8); reacting a compound of formula (IA-1 a-8) with a compound of formula (IA-1 a-9) under basic conditions to provide a compound of formula (IA-1 a-10); deamination of the compound of formula (IA-1 a-10) under acidic conditions affords a compound of formula (IA-1 a-11); reacting a compound of formula (IA-1 a-11) with a compound of formula (IA-1 a-12) under basic conditions to provide a compound of formula (IA-1 a-13); the compounds of formula (IA-1 a-13) are reduced under suitable conditions (e.g., H 2, pd/C) to provide compounds of formula (IA-1 a).
Synthesis scheme 1:
The compounds of formula (IA) can be obtained by reference to the synthetic procedure of scheme 1. Wherein Hal is F, cl, br, I, preferably Cl or Br. The compound of formula (IA-1) is reacted with the compound of formula (IA-2) under suitable conditions (e.g., basic conditions, base K 2CO3) in a suitable solvent (e.g., N-dimethylacetamide or N, N-dimethylformamide) to provide the compound of formula (IA).
Synthesis scheme 2:
The compounds of formula (IAa) can be obtained by reference to the synthetic procedure of synthesis scheme 2. Wherein Hal 1 and Hal 2 are each independently F, cl, br, I, preferably Cl, br; represents a nitrogen atom-containing fused ring and is substituted with q R a, wherein q and R a have the meanings as described in the present invention. Reacting a compound of formula (IA-1) with a compound of formula (IAa-2) under suitable conditions (e.g. basic conditions, base K 2CO3) in a suitable solvent (e.g. acetonitrile) to give a compound of formula (IAa-3); the compound of formula (IAa-3) is reacted with the compound of formula (IAa-4) under suitable conditions (e.g., basic conditions, base K 2CO3) in a suitable solvent (e.g., N-dimethylacetamide) to provide the compound of formula (IAa).
Synthesis scheme 3
The compounds of formula (IA) can be obtained by reference to the synthetic procedure of synthesis scheme 3. Wherein Ms is methanesulfonyl. The compound of formula (IA-1) is reacted with the compound of formula (IA-3) under suitable conditions (e.g., basic conditions, base K 2CO3) in a suitable solvent (e.g., N-dimethylformamide) to provide the compound of formula (IA).
Synthesis scheme 4
The compound of formula (IAb) can be obtained by reference to the synthetic procedure of scheme 4. Wherein ring a contains at least one nitrogen atom; hal 2 is F, cl, br, I, preferably Cl, br. Reacting a compound of formula (IA-1) with a compound of formula (IA-3) under suitable conditions (e.g., basic conditions, base K 2CO3) in a suitable solvent (e.g., N-dimethylformamide) to provide a compound of formula (IA-4); the compound of formula (IA-4) and the compound of formula (IA-5) or a salt of the compound of formula (IA-5) are prepared in a suitable solvent (e.g. DMSO) under basic conditions (e.g. K 2CO3 as base) to give compound (IAb).
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
Intermediate 1: 6-hydroxy-4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile
Step 1: 6-bromo-4-hydroxypyrazolo [1,5-a ] pyridine-3-carbonitrile
6-Bromo-4-methoxypyrazolo [1,5-a ] pyridine-3-carbonitrile (50 g,198.36 mmol), water (16.5 mL,916 mmol), sodium hydroxide (16.03 g,396.8 mmol) and DMA (500 mL) were added sequentially to a 1L single-necked flask, stirred at room temperature for 5min, and then dodecyl mercaptan (97 mL,397 mmol) was slowly added at 0℃and after the addition was completed, the reaction was allowed to proceed to 45℃overnight. The reaction solution was poured into 3L of ice water, saturated citric acid water was slowly added to adjust pH=5, stirred for half an hour, then allowed to stand, filtered, and the filter cake was washed with water and petroleum ether several times, and dried at 60℃to obtain 44.1g of a yellow solid as the objective product (yield 93.4%). Rf=0.35 (PE/ea=3:1); LC-MS: m/z=239.05 [ m+h ] +.
Step 2: 3-bromo-3-cyanopyrazolo [1,5-a ] pyridin-4-yl triflate
To a 1L single flask was added 6-bromo-4-hydroxypyrazolo [1,5-a ] pyridine-3-carbonitrile (44.1 g,185 mmol), pyridine (45 mL,559 mmol), DCM (800 mL), and trifluoromethanesulfonic anhydride (50 mL,297.2 mmol) was slowly added at a temperature below-10℃and stirred for 1h before naturally warming to room temperature for reaction overnight. The DCM was dried under reduced pressure, diluted with water (250 mL), extracted with EA (500 mL. Times.3), the organic phase was collected, washed with saturated brine (250 mL), dried over anhydrous sodium sulfate, filtered, dried over silica gel column chromatography (eluent PE/EA=50:1-25:1) to give 61.5g of the yellow-like solid as the target product in 89.7% yield. Rf=0.45 (PE/EA (v/v) =5/1).
Step 3: 6-bromo-4- (6-fluoropyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile
3-Bromo-3-cyanopyrazolo [1,5-a ] pyridin-4-yl trifluoromethanesulfonate (61.5 g,166 mmol), 2-fluoropyridine-5-borate (44.5 g,200 mmol), a [1,1' -bis (diphenylphosphine) ferrocene ] palladium dichloride dichloromethane complex (6.8 g,8.3 mmol), 1, 4-dioxane (850 mL) were added to a 1L three-necked flask under nitrogen, the temperature was lowered to-10℃and potassium acetate solution (115 mL,345mmol,3 mol/L) was slowly added, and after stirring at this temperature for 1h, the reaction was continued at room temperature overnight. Filtering, washing filter cake with EA (500 mL×3), washing with organic phase (500 mL), washing with saturated saline (250 mL), drying with anhydrous sodium sulfate, filtering, spin-drying the filtrate, purifying by silica gel column chromatography (eluent PE/DCM (v/v) =2/1-0/1), collecting target point, spin-drying to obtain 49g white solid as target product, yield 93.0％.Rf＝0.50(PE/EA(v/v)＝1/1).LC-MS：m/z＝318.10[M+H]+.1H NMR(400MHz,DMSO-d6)δ9.49(d,J＝1.2Hz,1H),8.73(s,1H),8.51(d,J＝1.9Hz,1H),8.27(td,J＝8.2,2.5Hz,1H),7.86(d,J＝1.2Hz,1H),7.40(dd,J＝8.4,2.5Hz,1H).
Step 4:4- (6-Fluoropyridin-3-yl) -6- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile
6-Bromo-4- (6-fluoropyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile (8 g,25.23 mmol), pinacol ester (10 g,39.39 mmol), potassium acetate (10 g,101.9 mmol), redistilled toluene (150 mL), bubbling for another 10min after nitrogen substitution, and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex (2.1 g,2.6 mmoles) were sequentially added under nitrogen protection to the flask, and the reaction was heated at 120℃overnight after bubbling for 10min with nitrogen substitution. Filtering with diatomite, washing (50 mL×3) filter cake with EA, washing the organic phase with saturated salt water (250 mL), drying with anhydrous sodium sulfate, filtering, spin-drying, performing silica gel column chromatography (eluent PE/DCM=2:1-0:1), collecting spin-drying to obtain orange solid 8.5g, which is the target product (yield) 93.0％).Rf＝0.15(DCM).1H NMR(400MHz,CDCl3)δ8.99(s,1H),8.43(d,J＝2.1Hz,1H),8.34(s,1H),8.02(td,J＝8.0,2.5Hz,1H),7.66(s,1H),7.13(dd,J＝8.5,2.8Hz,1H),1.40(s,12H).
Step 5:4- (6-fluoropyridin-3-yl) -6-hydroxypyrazolo [1,5-a ] pyridine-3-carbonitrile
To a 250mL single flask, 4- (6-fluoropyridin-3-yl) -6- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile (8.5 g,23 mmol) and tetrahydrofuran (120 mL) were sequentially added, and under ice-bath conditions, sodium hydroxide solution (60 mL,120mmol,2 mol/L) and hydrogen peroxide (14 mL,140mmol,30 mass%) were slowly added and stirred at low temperature. After completion of the reaction, a sodium thiosulfate solution (50 mL,150mmol,3 mol/L) was slowly added, and after returning to room temperature, water (250 mL) was added, EA was extracted (250M L X2), and the combined organic phases were washed with a 0.1M NaOH solution (500 mL X2). All aqueous phases were combined, the pH was adjusted to 4 with dilute hydrochloric acid, stirred at room temperature for 15min, and suction filtered to give a wet cake. The mother liquor was extracted with EA (250 ml×3), all organic phases were combined, dried over anhydrous sodium sulfate, filtered, and spin-dried, and column chromatographed on silica gel (eluent DCM/MeOH (v/v) =100/0-100/1) to give a pale yellow solid. All solids were combined and dried at 50 ℃ to give 5.1g of the desired product as a pale yellow solid (86.0% yield). Rf=0.25 (dcm\meoh (v/v) =100/1). LC-MS: m/z=255.10 [ m+h ] +.
Step 6:3- (5- (3-cyano-6-hydroxypyrazolo [1,5-a ] pyridin-4-yl) pyridin-2-yl) -3, 6-diazabicyclo [3.1.1] heptane-6-tert-butyl carboxylic acid
To a 30mL microwave tube, 4- (6-fluoropyridin-3-yl) -6-hydroxypyrazolo [1,5-a ] pyridine-3-carbonitrile (1.5 g,5.9 mmol), 6- (t-butoxycarbonyl) -3, 6-diazabicyclo [3.1.1] heptane (2.3 g,12 mmol), N, N-diisopropylethylamine (2.0 mL,12 mmol), dimethyl sulfoxide (15 mL) were added sequentially, and the mixture was sealed and reacted at 80℃for 8 hours. Under low temperature conditions, water (50 mL) was added for dilution, EA extraction (100 mL. Times.5), the organic phase saturated brine (250 mL) was combined for washing, dried over anhydrous sodium sulfate, filtered, and the filtrate was purified by spin-drying on a silica gel column (eluent PE/EA (v/v) =5/1-1/1.5), and 1.9g of the yellow product was collected as the target product (yield 74.0%). Rf=0.5 (PE/EA (v/v) =1/1.5). LC-MS: m/z=433.10 [ m+h ] +.
Step 7:3- (5- (6- (benzyloxy) -3-cyanopyrazolo [1,5-a ] pyridin-4-yl) pyridin-2-yl) -3, 6-diazabicyclo [3.1.1] heptane-3-tert-butyl-6-carboxylic acid ethyl ester
To a 25mL single vial was added 3- (5- (3-cyano-6-hydroxypyrazolo [1,5-a ] pyridin-4-yl) pyridin-2-yl) -3, 6-diazabicyclo [3.1.1] heptane-6-tert-butyl carboxylic acid (1 g,2.312 mmol), benzyl bromide (0.302 mL,2.54 mmol), potassium carbonate (0.9683 g,6.936 mmol), N, N-dimethylformamide (10 mL) in sequence and stirred overnight at 80 ℃. Quenching with saturated ammonium chloride (100 mL) at room temperature, extracting with DCM (100 mL. Times.3), mixing the organic phases, drying over anhydrous sodium sulfate, filtering, and purifying the filtrate with spin-drying silica gel column (eluent PE/EA (v/v) =5/1-2/1) to obtain 1.06g of yellow solid as the target product (yield) 87.7％).Rf＝0.7(PE/EA(v/v)＝1/1).LC-MS：m/z＝523.30[M+H].1H NMR(400MHz,CDCl3)δ8.37(s,1H),8.19(s,1H),8.17(d,J＝1.9Hz,1H),7.74(d,J＝8.7Hz,2H),7.42(dt,J＝11.9,7.4Hz,5H),7.18(d,J＝2.0Hz,1H),5.13(s,2H),4.31(d,J＝4.0Hz,2H),4.16(dd,J＝8.7,4.4Hz,2H),3.55(dd,J＝8.1,3.1Hz,2H),2.24–2.20(m,1H),2.01(d,J＝5.5Hz,1H),1.38(s,9H).
Step 8:4- (6- (3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (benzyloxy) pyrazolo [1,5-a ] pyridine-3-carbonitrile hydrochloride
Ethyl 3- (5- (6- (benzyloxy) -3-cyanopyrazolo [1,5-a ] pyridin-4-yl) pyridin-2-yl) -3, 6-diazabicyclo [3.1.1] heptane-3-tert-butyl-6-carboxylate (1.06 g,2.03 mmol), ethyl acetate hydrochloride solution (5 ml,20mmol,4 mol/L) was reacted overnight at room temperature. The reaction solution was spin-dried to give a yellow viscous material, which was dried at 60℃to give 1.0g of a yellow solid as the objective product (yield 100%). LC-MS: m/z=423.30 [ m-2hcl+h ] +.
Step 9: (6-methoxypyridin-3-yl) methanol
To a 25mL single-necked flask at 0deg.C was added 6-methoxy-3-pyridinecarbaldehyde (0.4 g,3 mmol), lithium aluminum hydride (0.06 g,2 mmol) and tetrahydrofuran (10 mL) in this order, and the reaction was carried out overnight at this temperature. EA (50 mL) was added, the reaction mixture was diluted with water (50 mL), the organic layer was washed with a saturated NH 4 Cl (50 mL) solution after separation by extraction, dried over anhydrous sodium sulfate, filtered, and the filtrate was dried by spin-drying, followed by purification on a silica gel column (eluent DCM/EA (v/v) =4/1) to give 0.38g of a pale yellow liquid as the target product (yield 90.0％).LC-MS：m/z＝140.15[M+H]+.1H NMR(400MHz,CDCl3)δ8.12(d,J＝1.8Hz,1H),7.62(dd,J＝8.5,2.4Hz,1H),6.75(d,J＝8.5Hz,1H),4.62(s,2H),3.93(s,3H).
Step 10:5- (bromomethyl) -2-methoxypyridine
In a 25mL single-necked flask, (6-methoxypyridin-3-yl) methanol (0.38 g,2.7 mmol), methylene chloride (8 mL), phosphorus tribromide (0.31 mL,3.3 mmol) were sequentially added, and the mixture was reacted at 0℃for 30min. DCM (25 m l) was added for dilution, saturated K 2CO3 (25 mL) aqueous solution was washed, the organic phase dried over anhydrous sodium sulfate, filtered, and the filtrate was dried by spinning and taken to the next step without further purification.
Step 11:6- (benzyloxy) -4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile
To a 25mL single vial was added 4- (6- (3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (benzyloxy) pyrazolo [1,5-a ] pyridine-3-carbonitrile (400 mg,0.8074 mmol), potassium carbonate (0.3382 g,2.423 mmol), N, N-dimethylformamide (8 mL), followed by slow addition of 5- (bromomethyl) -2-methoxypyridine (0.50 g,2.5 mmol) and stirring overnight at room temperature. The reaction solution was diluted with water (25 mL), extracted with EA (50 ml×3), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and purified by spin-drying silica gel column chromatography (eluent DCM/MeOH (v/v) =1/0-20/1) to give 0.2889g as the target product (yield) 65.82％).LC-MS：m/z＝544.10[M+H].1H NMR(400MHz,CDCl3)δ8.39(s,1H),8.22-8.17(m,2H),8.11(s,1H),8.02(s,1H),7.78(d,J＝8.8Hz,1H),7.42(dd,J＝14.9,7.1Hz,5H),7.19(s,1H),6.70(dd,J＝13.9,8.5Hz,2H),5.13(s,2H),3.92(s,3H),3.80(s,4H),3.59(s,4H),2.22(s,1H),2.01(s,1H).
Step 12: 6-hydroxy-4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile
To a 50mL single vial was added, in sequence, 6- (benzyloxy) -4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile (0.288 g,0.530 mmol), methanol (5 mL), palladium on carbon (0.03 g,10% mass), and after several hydrogen substitutions, stirred overnight at room temperature. Filtering the reaction solution, flushing a filter cake with methanol, and spin-drying the filtrate to obtain 240mg of light yellow solid which is the target product (yield 100.0％).LC-MS：m/z＝454.30[M+H]+.1H NMR(400MHz,CDCl3)δ8.39(d,J＝1.7Hz,1H),8.28(d,J＝2.0Hz,1H),8.21(s,1H),8.17-8.12(m,1H),7.81(dd,J＝8.1,2.2Hz,2H),7.14(s,1H),6.78(d,J＝8.6Hz,1H),6.70(d,J＝8.3Hz,1H),5.37(s,1H),4.00-3.90(m,5H),3.73(s,4H),3.51(s,2H),2.27-2.21(m,1H),2.03(d,J＝6.6Hz,1H).
Intermediate 2:4- (6-fluoropyridin-3-yl) -6-hydroxypyrazolo [1,5-a ] pyridine-3-carbonitrile
Step 1: 6-bromo-4-hydroxypyrazolo [1,5-a ] pyridine-3-carbonitrile
6-Bromo-4-methoxypyrazolo [1,5-a ] pyridine-3-carbonitrile (50 g,198.36 mmol), water (16.5 mL,916 mmol), sodium hydroxide (16.03 g,396.8 mmol) and DMAC (500 mL) were added sequentially to a 1L single-necked flask at room temperature, stirred at room temperature for 5min, and then dodecyl mercaptan (97 mL,397 mmol) was slowly added at 0℃and after the addition was completed, the reaction was allowed to proceed to 45℃overnight. The reaction solution was poured into 3L of ice water, and saturated aqueous citric acid solution was slowly added to adjust pH=5, stirred for half an hour, then allowed to stand, filtered, and the filter cake was washed with water and petroleum ether several times, and dried at 60℃to obtain 44.1g of a yellow solid as the objective product (yield 93.4%). Rf=0.35 (PE/EA (v/v) =3/1). LC-MS: m/z=239.05 [ m+h ] +.
Step 2: 3-bromo-3-cyanopyrazolo [1,5-a ] pyridin-4-yl triflate
To a 1L single flask was added 6-bromo-4-hydroxypyrazolo [1,5-a ] pyridine-3-carbonitrile (44.1 g,185 mmol), pyridine (45 mL,559 mmol), DCM (800 mL), and trifluoromethanesulfonic anhydride (50 mL,297.2 mmol) was slowly added at a temperature below-10℃and stirred for 1h before naturally warming to room temperature for reaction overnight. The DCM was dried under reduced pressure, diluted with water (250 mL), extracted with EA (500 mL. Times.3), the organic phase was collected, washed with saturated brine (250 mL), dried over anhydrous sodium sulfate, filtered, and purified by column chromatography on silica gel (eluent PE/EA (v/v=50/1-25/1) to give 61.5g of the desired product as a yellow-like solid in 89.7% yield, rf=0.45 (PE/EA (v/v=5/1)).
Step 3: 6-bromo-4- (6-fluoropyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile
3-Bromo-3-cyanopyrazolo [1,5-a ] pyridin-4-yl trifluoromethanesulfonate (61.5 g,166 mmol), 2-fluoropyridine-5-borate (44.5 g,200 mmol), a [1,1' -bis (diphenylphosphine) ferrocene ] palladium dichloride dichloromethane complex (6.8 g,8.3 mmol), 1, 4-dioxane (850 mL) were added to a 1L three-necked flask under nitrogen, the temperature was lowered to-10℃and potassium acetate solution (115 mL,345mmol,3 mol/L) was slowly added, and after stirring at this temperature for 1h, the reaction was continued at room temperature overnight. Filtering, washing filter cake with EA (500 mL×3), washing the filtrate with water (500 m l), washing the filtrate with saturated saline (250 mL), drying with anhydrous sodium sulfate, filtering, spin-drying the filtrate, purifying with silica gel column chromatography (eluent PE/DCM=2:1-0:1) to obtain white solid 49g, which is the target product, and obtaining the yield 93.0％.Rf＝0.50(PE/EA(v/v＝1/1).LC-MS：m/z＝318.10[M+H]+.1H NMR(400MHz,DMSO-d6)δ9.49(d,J＝1.2Hz,1H),8.73(s,1H),8.51(d,J＝1.9Hz,1H),8.27(td,J＝8.2,2.5Hz,1H),7.86(d,J＝1.2Hz,1H),7.40(dd,J＝8.4,2.5Hz,1H).
Step 4:4- (6-fluoropyridin-3-yl) -6- (4, 5-tetramethyl-1, 3, 2-dioxapentaborane-2-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile
6-Bromo-4- (6-fluoropyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile (8 g,25.23 mmol), pinacol ester (10 g,39.39 mmol), potassium acetate (10 g,101.9 mmol), redistilled toluene (150 mL), bubbling for another 10min after nitrogen substitution, and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex (2.1 g,2.6 mmoles) were sequentially added under nitrogen protection to the flask, and the reaction was heated at 120℃overnight after bubbling for 10min with nitrogen substitution. Filtering with diatomite, washing (50 ml×3) filter cake with EA, washing the organic phase with saturated salt water (250 mL), drying with anhydrous sodium sulfate, filtering, spin-drying, subjecting to silica gel column chromatography (eluent PE/DCM (v/v) =2/1-0/1), collecting spin-drying to obtain orange solid 8.5g, which is the target product (yield) 93.0％).Rf＝0.15(DCM).1H NMR(400MHz,CDCl3)δ8.99(s,1H),8.43(d,J＝2.1Hz,1H),8.34(s,1H),8.02(td,J＝8.0,2.5Hz,1H),7.66(s,1H),7.13(dd,J＝8.5,2.8Hz,1H),1.40(s,12H).
Step 5:4- (6-fluoropyridin-3-yl) -6-hydroxypyrazolo [1,5-a ] pyridine-3-carbonitrile
To a 250mL single flask, 4- (6-fluoropyridin-3-yl) -6- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile (8.5 g,23 mmol) and tetrahydrofuran (120 mL) were sequentially added, and under ice-bath conditions, sodium hydroxide solution (60 mL,120mmol,2 mol/L) and hydrogen peroxide (14 mL,140mmol,30 mass%) were slowly added and stirred at low temperature. After completion of the TLC monitoring, a sodium thiosulfate solution (50 mL,150mmol,3 mol/L) was slowly added, and after returning to room temperature, water (250 mL), EA extraction (250 mL. Times.2) was performed, and the combined organic phases were washed with a 0.1M NaOH solution (500 mL. Times.2). All aqueous phases were combined, the pH was adjusted to 4 with dilute hydrochloric acid, stirred at room temperature for 15min, and suction filtered to give a wet cake. The mother liquor was extracted with EA (250 ml×3), all organic phases were combined, dried over anhydrous sodium sulfate, filtered, and spin-dried, and column chromatographed on silica gel (eluent DCM/MeOH (v/v) =100/0-100/1) to give a pale yellow solid. Combining all solids, and oven drying at 50deg.C to obtain pale yellow solid 5.1g (yield) 86.0％).Rf＝0.25(DCM\MeOH(v/v)＝100/1).LC-MS：m/z＝255.10[M+H]+.1H NMR(400MHz,DMSO)δ10.44-10.37(m,1H),8.54(s,1H),8.49-8.46(m,1H),8.42-8.40(m,1H),8.26-8.21(m,1H),7.40-7.35(m,1H),7.32-7.30(m,1H).
Example 1: synthesis of 4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (2- (tetrahydro-2H- [1,4] dioxin [2,3-c ] pyrrol-6 (3H) -yl) ethoxy) pyrazolo [1,5-a ] pyridine-3-carbonitrile
Step 1: hexahydro-2H- [1,4] dioxin [2,3-c ] pyrrole hydrochloride
A100 mL single-necked flask was charged with tert-butyl tetrahydro-2H- [1,4] dioxin [2,3-c ] pyrrole-6 (3H) -carboxylate (2230 mg,9.73 mmol), HCl/EA (4N) (18 mL), and stirred at rt for 8H. TLC monitors that the raw materials are completely reacted, and spin-drying is directly carried out for the next reaction. LC-MS (ESI-MS) m/z=130.1 [ M+H ] +.
Step 2:6- (2-chloroethyl) hexahydro-2H- [1,4] dioxadieno [2,3-c ] pyrrole
A100 mL single vial was sequentially charged with hexahydro-2H- [1,4] dioxin [2,3-c ] pyrrole hydrochloride (4.5 mmol,740mg, acetone (15 mL), K 2CO3 (2030 mg,14.7 mmol), rt stirred overnight, the reaction was filtered through celite, EA washed (15 mL. Times.3), concentrated, silica gel column chromatography, PE/EA (v/v) =1/1 eluent to give 37mg of product in yield 4.3％.LC-MS:(ESI-MS):m/z＝192.1[M+H]+.1H NMR(400MHz,CDCl3)δ4.15-4.04(m,2H),3.84-3.77(m,2H),3.62-3.51(m,4H),2.98-2.87(m,6H).
Step 3:4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (2- (tetrahydro-2H- [1,4] dioxin [2,3-c ] pyrrol-6 (3H) -yl) ethoxy) pyrazolo [1,5-a ] pyridine-3-carbonitrile
A50 mL single vial was charged with 6-hydroxy-4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] hept-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile (65 mg,0.143mmol, see synthesis of intermediate 1), 6- (2-chloroethyl) hexahydro-2H- [1,4] dioxadieno [2,3-c ] pyrrole (130 mg,0.678 mmol), DMAC (6 mL), K 2CO3 (102 mg,0.738 mmol) and heated in an 80℃oil bath overnight. After the reaction was cooled, EA was added (30 mL), washed with sodium chloride solution (30 mL. Times.3), aqueous phase EA (10 mL), DCM (10 mL) were extracted, the organic phases were combined, dried, concentrated, and chromatographed on a silica gel column with DCM/MeOH ((v/v) =30/1) as eluent to give 28mg of a pale yellow solid in yield 66％.LC-MS:(ESI-MS):m/z＝609.3[M+H]+;1H NMR(400MHz,CDCl3)δ8.39(d,J＝2.2Hz,1H),8.20(s,1H),8.14(d,J＝1.9Hz,1H),8.10(d,J＝1.7Hz,1H),7.76(dd,J＝8.8,2.4Hz,1H),7.62(dd,J＝8.5,2.2Hz,1H),7.13(d,J＝1.9Hz,1H),6.69(dd,J＝11.3,8.8Hz,2H),4.16-4.09(m,5H),3.91(s,3H),3.87-3.79(m,4H),3.77(d,J＝5.6Hz,2H),3.65-3.52(m,6H),3.04(m,2H),3.02-2.95(m,4H),2.68(dd,J＝13.8,6.2Hz,1H).
Example 2: synthesis of 6- (2- (5-hydroxy-5-methylhexahydrocyclopenta [ c ] pyrrol-2 (1H) -yl) ethoxy) -4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile
Step 1: n-tert-butyl-5-hydroxy-5-methyl hexahydrocyclopentane [ c ] pyrrole
Tert-butyl N-carboxylate-hexahydro-5-oxocyclopenta [ c ] pyrrole (1.00 g,4.44 mmol) was dissolved in anhydrous THF (10 mL), and a solution of methyl magnesium bromide in THF (3 mL,9mmol,3 mol/L) was slowly added and the mixture was allowed to warm to room temperature and stirred for 1h. TLC monitored reaction (PE/EA (v/v) =1/1, rf=0.32) and starting material was complete. Quenching the saturated NH 4 Cl solution, stopping the reaction, filtering, concentrating, performing silica gel column chromatography, eluting with PE/EA (v/v) =10/1-3/1 to obtain yellow brown solid 0.71g, i.e. the target product, yield 66％.1H NMR(400MHz,CDCl3)δ3.58-3.43(m,2H),3.42-3.30(m,2H),2.76-2.62(m,2H),2.01-1.94(m,1H),1.95-1.90(m,1H),1.73-1.68(m,2H),1.46(s,9H),1.34(s,3H)..
Step 2: hexahydro-5-hydroxy-5-methylcyclopenta [ c ] pyrrole
Tert-butyl N-carboxylate-5-hydroxy-5-methyl hexahydrocyclopenta [ c ] pyrrole (0.71 g,2.9 mmol) was dissolved in EA (5 mL), ethyl acetate hydrochloride (5 mL,15mmol,3 mol/L) was slowly added, and the mixture was allowed to warm to room temperature and stirred for 2h. The reaction was stopped and concentrated to give 0.39g of a yellowish-brown viscous liquid with a yield of 94%. LC-MS: m/z=142.2 [ m+h ] +.
Step 3:6- (2-chloroethoxy) -4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile
6-Hydroxy-4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile (60 mg,0.13mmol, see synthesis of intermediate 1) was dissolved in acetonitrile (10 mL), K 2CO3 (55 mg,0.40 mmol) and 1-bromo-2-chloroethane (37 mg,0.26 mmol) were added and the reaction stirred at 80℃for 12h. Cooling to room temperature, stopping reaction, suction filtering, and concentrating. Silica gel column chromatography, eluent DCM/CH 3 OH (v/v) =50/1-20/1, obtaining 50mg of yellowish-brown solid, namely the target product, yield 73％.LC-MS：m/z＝516.3[M+H]+.1H NMR(400MHz,CDCl3)δ8.43(d,J＝2.2Hz,1H),8.25(s,1H),8.18(d,J＝2.0Hz,1H),8.13(d,J＝1.8Hz,1H),7.84-7.77(m,1H),7.70-7.62(m,1H),7.19(d,J＝2.0Hz,1H),6.78-6.66(m,2H),4.33(t,J＝5.6Hz,2H),4.14(q,J＝7.1Hz,1H),3.94(s,3H),3.91(t,J＝5.6Hz,2H),3.86(d,J＝12.0Hz,2H),3.80(d,J＝5.6Hz,2H),3.60(s,4H),2.76-2.67(m,1H).
Step 4:6- (2- (5-hydroxy-5-methyl hexahydrocyclopenta [ c ] pyrrol-2 (1H) -yl) ethoxy) -4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile
6- (2-Chloroethoxy) -4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile (35 mg,0.07 mmol) was dissolved in DMAC (3 mL), K 2CO3 (28 mg,0.20 mmol), hexahydro-5-hydroxy-5-methylcyclopenta [ c ] pyrrole (19 mg,0.13 mmol) and KI (17 mg,0.10 mmol) were added and stirred at 80℃for 12h. Cooling to room temperature, stopping the reaction, extracting with EA (10 mL×3), washing with water, drying with anhydrous sodium sulfate, concentrating, performing silica gel column chromatography to obtain eluent EA/CH3OH=20/1-8/1, and obtaining yellow brown solid 7mg as target product, with yield 17％.LC-MS：m/z＝622.3[M+H]+.1H NMR(400MHz,CDCl3)δ8.42(d,J＝2.1Hz,1H),8.22(d,J＝5.2Hz,1H),8.20-8.07(m,2H),7.84-7.76(m,1H),7.68(d,J＝8.7Hz,1H),7.20-7.13(m,1H),6.77-6.66(m,2H),4.36-4.21(m,1H),4.18(t,J＝5.4Hz,2H),3.94(s,3H),3.85(dd,J＝17.5,8.9Hz,4H),3.66(d,J＝6.8Hz,1H),3.62(s,3H),3.04(d,J＝9.4Hz,2H),2.99(t,J＝5.3Hz,2H),2.94(s,1H),2.86-2.77(m,2H),2.77-2.71(m,1H),2.60(d,J＝13.9Hz,1H),2.40-2.34(m,2H),2.11-2.01(m,2H),1.98-1.92(m,2H),1.78-1.58(m,2H).
Example 3: synthesis of 6- (2- (5-methoxyhexahydrocyclopenta [ c ] pyrrol-2 (1H) -yl) ethoxy) -4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) pyrazole [1,5-a ] pyridine-3-carbonitrile
Step 1: n-tert-butyl-5-hydroxycyclopentan [ c ] pyrrole
LiAlH 4 (0.35 g,9.2 mmol) was slowly added to anhydrous THF (15 mL) in an ice-water bath, stirred at low temperature for 15min, tert-butyl N-carboxylate-hexahydro-5-oxocyclopenta [ c ] pyrrole (1.03 g,4.57 mmol) was slowly added, and the mixture was naturally warmed to room temperature and stirred for 2h. TLC monitored the reaction (PE/EA (v/v) =4/1, iodoform, rf=0.18) and starting material was complete. Quenching the reaction with saturated Na 2SO4 solution, suction filtering and concentrating to obtain brown yellow viscous liquid 0.89g (yield 86％).1H NMR(400MHz,CDCl3)δ4.34-4.23(m,1H),3.54-3.45(m,2H),3.38-3.28(m,2H),2.81-2.64(m,1H),2.62-2.52(m,2H),2.20-2.12(m,2H),1.75-1.57(m,1H),1.45(s,9H).
Step 2: n-tert-butyl formate hexahydro-5-methoxycyclopenta [ c ] pyrrole
Under ice-water bath, tert-butyl N-carboxylate-5-hydroxy hexahydrocyclopenta [ c ] pyrrole (0.89 g,3.9 mmol) was dissolved in anhydrous THF (10 mL), naH (0.47 g,12mmol,60 mass%) was slowly added, stirred at low temperature for 15min, CH 3 I (0.5 mL,8 mmol) was slowly added, and the mixture was naturally warmed to room temperature and stirred for 20h. TLC monitored the reaction (PE/EA (v/v) =4/1, iodoform, rf=0.36) and starting material was complete. Slowly adding water for quenching reaction, filtering, concentrating, and performing silica gel column chromatography (eluting PE/EA (v/v) =10/1-5/1) to obtain colorless viscous liquid 0.64g (yield 68%) as target product .1H NMR(400MHz,CDCl3)δ3.89-3.78(m,1H),3.52(brs,2H),3.35(brs,1H),3.28(s,3H),3.24(brs,1H),2.57(s,2H),2.20-2.07(m,2H),1.57-1.49(m,2H),1.45(s,9H).
Step 3: hexahydro-5-methoxycyclopenta [ c ] pyrrole
N-Boc-hexahydro-5-methoxycyclopenta [ c ] pyrrole (0.30 g,1.2 mmol) was dissolved in EA (5 mL), ethyl acetate hydrochloride (2 mL,6mmol,3 mol/L) was slowly added, and the mixture was allowed to warm to room temperature and stirred. TLC monitoring reaction is complete, reaction is stopped, suction filtration and concentration are carried out, and 0.14g (yield 91%) of yellowish-brown viscous liquid is obtained, namely the target product. LC-MS: m/z=142.2 [ m+h ] +.
Step 4:6- (2-chloroethoxy) -4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile
6-Hydroxy-4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile (20 mg,0.04mmol, see the synthesis of example 1) was dissolved in acetonitrile (15 mL), K 2CO3 (19 mg,0.14 mmol) and 1-bromo-2-chloroethane (10 mg,0.07 mmol) were added and the reaction stirred at 50℃for 12h. Cooling to room temperature, stopping reaction, suction filtering, and concentrating. Silica gel column chromatography (eluent DCM/CH 3 OH (v/v) =50/1-20/1) to obtain 18mg of yellowish-brown solid as target product (yield 68％).LC-MS：m/z＝516.3[M+H]+;1H NMR(400MHz,CDCl3)δ8.43(d,J＝2.2Hz,1H),8.25(s,1H),8.18(d,J＝2.0Hz,1H),8.13(d,J＝1.8Hz,1H),7.84-7.77(m,1H),7.70-7.62(m,1H),7.19(d,J＝2.0Hz,1H),6.78-6.66(m,2H),4.33(t,J＝5.6Hz,2H),4.14(q,J＝7.1Hz,1H),3.94(s,3H),3.91(t,J＝5.6Hz,2H),3.86(d,J＝12.0Hz,2H),3.80(d,J＝5.6Hz,2H),3.60(s,4H),2.76-2.67(m,1H).
Step 5:6- (2- (5-Methoxyhexahydrocyclopenta [ c ] pyrrol-2 (1H) -yl) ethoxy) -4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) pyrazole [1,5-a ] pyridine-3-carbonitrile
6- (2-Chloroethoxy) -4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile (58 mg,0.11 mmol) was dissolved in DMAC (3 mL), K 2CO3 (47 mg,0.34 mmol), hexahydro-5-methoxypentan [ c ] pyrrole (32 mg,0.04 mmol) and KI (28 mg,0.17 mmol) were added and the mixture was stirred at 80℃for 12h. The reaction was stopped after cooling to room temperature, EA (10 mL. Times.3) was extracted, the organic phase was washed with water (10 mL), dried over anhydrous sodium sulfate, and concentrated. Silica gel column chromatography (eluent DCM/CH 3 OH (v/v) =20/1-5/1) to obtain 2mg of yellow brown viscous solid as target product .LC-MS：m/z＝621.1[M+H]+;1H NMR(400MHz,CDCl3)δ8.41(d,J＝2.2Hz,1H),8.23(s,1H),8.20(d,J＝1.9Hz,1H),8.12(d,J＝1.8Hz,1H),7.84-7.77(m,1H),7.69-7.62(m,1H),7.16(d,J＝2.0Hz,1H),6.77-6.65(m,2H),4.32(t,J＝5.2Hz,2H),3.93(s,3H),3.86(d,J＝9.6Hz,2H),3.81(d,J＝5.7Hz,2H),3.60(s,2H),3.50-3.37(m,1H),3.30(s,3H),3.28-3.23(m,2H),3.27-3.21(m,2H),3.22(d,J＝6.5Hz,1H),3.18-3.14(m,2H),3.02(s,1H),2.80(s,2H),2.75-2.70(m,1H),2.70-2.64(m,2H),2.00-1.95(m,1H),1.94-1.88(m,2H).
Example 4: synthesis of 4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- ((octahydrocyclopenta [ c ] pyrrol-5-yl) oxy) pyrazole [1,5-a ] pyridine-3-carbonitrile
Step 1: n-tert-butyl-5-hydroxycyclopentan [ c ] pyrrole
LiAlH 4 (0.35 g,9.2 mmol) was slowly added to anhydrous THF (15 mL) in an ice-water bath, stirred at low temperature for 15min, tert-butyl N-carboxylate-hexahydro-5-oxocyclopenta [ c ] pyrrole (1.03 g,4.57 mmol) was slowly added, and the mixture was naturally warmed to room temperature and stirred for 2h. Quenching reaction with saturated Na 2SO4 solution, suction filtering and concentrating to obtain brown yellow viscous liquid 0.89g, yield 86％.1H NMR(400MHz,CDCl3)δ4.34-4.23(m,1H),3.54-3.45(m,2H),3.38-3.28(m,2H),2.81-2.64(m,1H),2.62-2.52(m,2H),2.20-2.12(m,2H),1.75-1.57(m,1H),1.45(s,9H).
Step 2: tert-butyl N-formate-hexahydro-5- ((methylsulfonyl) oxy) cyclopenta [ c ] pyrrole
In an ice-water bath, tert-butyl N-carboxylate-5-hydroxycyclopenta [ c ] pyrrole (0.50 g,2.2 mmol) was dissolved in DCM (20 mL), naH (0.18 g,4.5mmol,60 mass%) was slowly added, stirred for 10min, methylsulfonyl chloride (0.2 mL,3 mmol) was slowly added, and the mixture was allowed to warm to room temperature and stirred for 3h. The reaction was quenched slowly with water, extracted with DCM (20 ml×3), washed with water, dried over anhydrous sodium sulfate, concentrated, and chromatographed on silica gel to give a colorless viscous liquid, 0.48g, 71% yield, PE/ea=10/1-5/1.
Step 3: tert-butyl N-formate-4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- ((octahydrocyclopenta [ c ] pyrrol-5-yl) oxy) pyrazole [1,5-a ] pyridine-3-carbonitrile
6-Hydroxy-4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] hept-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile (20 mg,0.04mmol, see synthesis of intermediate 1) and tert-butyl N-formate-hexahydro-5- ((methylsulfonyl) oxy) cyclopenta [ c ] pyrrole (20 mg,0.04 mmol) were dissolved in DMF (15 mL), K 2CO3 (19 mg,0.14 mmol) and 1-bromo-2-chloroethane (15 mg,0.05 mmol) were added and stirred at 80℃for 12h. Cooling to room temperature, adding water, extracting with EA (20 mL. Times.3), washing with water, drying over anhydrous sodium sulfate, and concentrating. Silica gel column chromatography (eluent DCM/CH 3 OH (v/v) =50/1-20/1) to obtain 19mg of yellowish-brown solid, which is the target product. LC-MS: m/z=663.3 [ m+h ] +.
Step 4:4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] hept-3-yl) pyridin-3-yl) -6- ((octahydrocyclopenta [ c ] pyrrol-5-yl) oxy) pyrazole [1,5-a ] pyridine-3-carbonitrile
Tert-butyl-4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] hept-3-yl) pyridin-3-yl) -6- ((octahydrocyclopenta [ c ] pyrrol-5-yl) oxy) pyrazolo [1,5-a ] pyridin-3-cyano (19 mg,0.03 mmol) was dissolved in EA (2 mL), ethyl acetate hydrochloride (0.5 mL,2mmol,3 mol/L) was slowly added, and the mixture was naturally warmed to room temperature and stirred for 3h. Filtering and concentrating. The yellowish brown viscous liquid was dissolved in CH 3 OH (5 mL), K 2CO3 (0.3 g) was added, stirred at room temperature for 0.5h, and the pH indicated that the solution was alkaline. Filtering and concentrating. Silica gel column chromatography (eluent DCM/CH 3 oh=40/1-10/1) gives 16mg of yellow-brown solid in two steps yield 22％.LC-MS：m/z＝563.3[M+H]+.1H NMR(400MHz,CDCl3)δ8.41(d,J＝2.1Hz,1H),8.23(s,2H),8.14(s,1H),7.84-7.72(m,2H),7.07(d,J＝1.8Hz,1H),6.80-6.67(m,2H),5.06(s,1H),3.96-3.93(m,3H),3.93(s,2H),3.74-3.64(m,4H),3.45-3.31(m,4H),3.27-3.17(m,2H),2.87-2.80(m,1H),2.44-2.37(m,2H),2.37-2.28(m,1H),2.22-2.15(m,2H),2.08-2.03(m,1H),1.75-1.71(m,1H).
Example 5:6- ((3-methoxybicyclo [3.1.0] hex-6-yl) methoxy) -4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] hept-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile
Step 1: 3-hydroxy-bicyclo [3.1.0] hexane 6-carboxylic acid ethyl ester
50ML of ethyl 3-oxybyclo [3.1.0] hexane 6-carboxylate (370 mg,2.20 mmol), meOH (10 mL), under N 2, were added in this order, stirred at-5℃under low temperature, naBH 4 (105 mg,2.78 mmol) was added, and stirring was maintained at low temperature for 1h. Adding 15mL of ammonium chloride solution into the reaction solution, concentrating, adding 20mL of water, extracting with EA (15 mL×3), mixing the organic phases, drying with sodium sulfate, filtering, separating by column chromatography, and eluting with PE/EA (v/v) =5/1 to obtain 270mg of oily liquid with yield 72％.LC-MS:m/z＝171.2[M+H];1H NMR(400MHz,CDCl3)δ4.38(t,J＝6.4Hz,1H),4.09(q,J＝7.1Hz,2H),2.15(m,2H),1.98(t,J＝2.9Hz,1H),1.88(m,3H),1.84(s,1H),1.25(m,3H).
Step 2: 3-Methoxybicyclo [3.1.0] hexane 6-carboxylic acid ethyl ester
A50 mL single-necked flask was charged with ethyl 3-hydroxy bicyclo [3.1.0] hexane 6-carboxylate (270 mg,1.59 mmol), ag 2O(2230mg,9.62mmol),CH3 I (15 mL,241 mmol) and heated in an oil bath at 45℃overnight. Filtering, washing with EA (10 ml×3), concentrating the filtrate, separating by column chromatography, and eluting with PE/EA (v/v) =3/1 to obtain oily liquid 246mg, yield 80％.LC-MS:m/z＝185.2[M+H]+;1H NMR(400MHz,CDCl3)δ4.11–4.04(m,2H),3.81–3.75(m,1H),3.17(s,3H),1.99(m,4H),1.84(m,2H),1.80(t,J＝2.9Hz,1H),1.23(t,J＝6.2Hz,3H).
Step 3: (3-methoxybicyclo [3.1.0] hex-6-yl) methanol
A50 mL two-necked flask was charged with ethyl 3-methoxybicyclo [3.1.0] hexane 6-carboxylate (246 mg,1.34 mmol), THF (10 mL), N 2 protected, diisobutylaluminum hydride (1N) (4 mL) was slowly injected at-10℃and stirred overnight at rt after 10 min. Slowly injecting 1N HCl and 20mL of water at low temperature, adjusting pH of water phase to be 4-5, extracting EA (20 mL×3), mixing organic phases, drying with sodium sulfate, filtering, concentrating, separating by column chromatography, eluting with PE/EA (v/v) =3/1 to obtain 146mg of compound as oily liquid, and obtaining the final product with yield 76％.LC-MS:m/z＝142.3[M]+;1H NMR(400MHz,CDCl3)δ3.80(t,J＝6.1Hz,1H),3.37(d,J＝7.1Hz,2H),3.18(s,3H),1.99–1.92(m,2H),1.90-1.85(m,2H),1.24(m,1H),1.17(m,2H).
Step4: 6- (bromomethyl) -3-methoxybicyclo [3.1.0] hexane
(3-Methoxybicyclo [3.1.0] hex-6-yl) methanol (93 mg,0.65 mmol), DCM (4.0 mL), PBr 3 (0.15 mL,1.60 mmol) at low temperature of-5℃were added in sequence in a 25mL single-port flask, and the reaction was continued for 1.5h after the addition. 0.5mLH 2 O,3.0% potassium carbonate solution 25mL was added, the organic phase was collected, the aqueous phase was extracted with DCM (10 mL. Times.2), the organic phases were combined, dried over sodium sulfate, filtered, concentrated and directly added to the next reaction.
Step 5:6- ((3-methoxybicyclo [3.1.0] hex-6-yl) methoxy) -4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] hept-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile
10ML of a two-necked flask was charged with 6-hydroxy-4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile (31 mg,0.068mmol, intermediate 1), K 2CO3 (31 mg,0.22 mmol), DMF (3.2 mL), 6- (bromomethyl) -3-methoxybicyclo [3.1.0] hexane (0.250 mmol), N 2 protection, and the reaction was heated and stirred at 50℃for 2h. The reaction mixture was washed with 25mL of EA, 15 (mL. Times.3) water, 10mL of EA aqueous phase extracted 1 time, the organic phases were combined, dried over sodium sulfate, filtered, and concentrated. Column chromatography, DCM/MeOH (v/v) =20/1 as eluent gave 7mg of pale yellow solid in yield 17％.LC-MS：m/z＝578.3[M+H]+;1H NMR(400MHz,CDCl3)δ8.40(d,J＝2.1Hz,1H),8.19(s,1H),8.11(d,J＝1.7Hz,1H),8.08(d,J＝1.9Hz,1H),7.77(dd,J＝8.8,2.4Hz,1H),7.64(dd,J＝8.5,2.0Hz,1H),7.14(d,J＝1.9Hz,1H),6.70(dd,J＝13.5,8.7Hz,2H),3.92(s,3H),3.85(m,3H),3.80(m,4H),3.60(m,4H),3.21(s,3H),2.71(m,1H),2.16(m,1H),2.06(d,J＝13.9Hz,2H),2.00(m,3H),1.66(d,J＝8.7Hz,1H),1.53–1.46(m,1H).
Example 6:4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] hept-3-yl) pyridin-3-yl) -6- ((2-methyl octahydrocyclopenta [ c ] pyrrol-5-yl) oxy) pyrazolo [1,5-a ] pyridine-3-carbonitrile
4- (6- (6- ((6-Methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] hept-3-yl) pyridin-3-yl) -6- ((octahydrocyclopenta [ c ] pyrrol-5-yl) oxy) pyrazolo [1,5-a ] pyridine-3-carbonitrile (30 mg,0.05mmol, example 4) was dissolved in DCE (5 mL), paraformaldehyde (10 mg,0.33 mmol) was added and stirred for 30min. NaBH (OAc) 3 (34 mg,0.16 mmol) was added slowly and the reaction was stirred for 12h at 50 ℃. TLC monitored the reaction (DCM/CH 3 OH (v/v) =20/1, rf=0.22) and starting material was complete. Stopping the reaction, adjusting pH to 8 with 1N NaOH aqueous solution, extracting with DCM (10 mL×3), washing with water, drying with anhydrous sodium sulfate, concentrating, and performing silica gel column chromatography to obtain eluent DCM/CH 3 OH (v/v) =40/1-20/1, which is 12mg of brown yellow solid as target product, with average yield 29％.LC-MS：m/z＝577.3[M+H]+;1H NMR(400MHz,CDCl3)δ8.41(s,1H),8.22(s,1H),8.14(d,J＝16.6Hz,2H),7.80(d,J＝8.6Hz,1H),7.65(d,J＝8.2Hz,1H),7.09(s,1H),6.82–6.63(m,2H),4.90(s,1H),3.94(s,3H),3.91–3.82(m,2H),3.82–3.75(m,2H),3.65–3.61(m,1H),3.59(s,2H),2.93–2.81(m,2H),2.70(s,1H),2.68(d,J＝9.2Hz,2H),2.45–2.41(m,1H),2.39(s,3H),2.30–2.22(m,2H),2.06(brs,3H),1.91–1.83(m,2H),1.69–1.65(m,1H).
Example 7:6- ((2- (2-methoxyethyl) octahydrocyclopenta [ c ] pyrrol-5-yl) oxy) -4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] hept-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile
4- (6- (6- ((6-Methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] hept-3-yl) pyridin-3-yl) -6- ((octahydrocyclopenta [ c ] pyrrol-5-yl) oxy) pyrazolo [1,5-a ] pyridine-3-carbonitrile (20 mg,0.04mmol, example 4) was dissolved in CH 3 CN (5 mL), K 2CO3 (13 mg,0.09 mmol) and KI (8 mg,0.05 mmol) were added, after stirring for 15min, 1-bromo-2-methoxy-ethyl (9 mg,0.06 mmol) was slowly added and the reaction was stirred for 12h at 50 ℃. TLC monitored the reaction (DCM/CH 3 OH (v/v) =20/1, rf=0.25) and starting material was complete. Adding water for quenching reaction, extracting with EA (10 mL×3), washing with water, drying with anhydrous sodium sulfate, concentrating, performing silica gel column chromatography to obtain eluent DCM/CH 3 OH (v/v) =40/1-20/1, and obtaining brown yellow solid 7mg as target product, yield 37.37％.LC-MS：m/z＝621.3[M+H]+;1H NMR(400MHz,CDCl3)δ8.41(d,J＝2.2Hz,1H),8.23(s,1H),8.16(d,J＝1.8Hz,1H),8.13(s,1H),7.83–7.76(m,1H),7.69–7.62(m,1H),7.08(d,J＝1.8Hz,1H),6.77–6.68(m,2H),4.92(s,1H),3.94(s,3H),3.88(s,1H),3.85(s,1H),3.82(d,J＝5.7Hz,2H),3.64(s,2H),3.62(s,2H),3.39(s,3H),2.94(brs,2H),2.85(brs,4H),2.77–2.68(m,4H),2.29–2.22(m,2H),2.08(s,2H),2.02–1.94(m,2H).
Example 8:5- ((3-cyano-4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] hept-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridin-6-yl) oxy) -2, 2-diethyl octahydrocyclopenta [ c ] pyrrole-2-salt
4- (6- (6- ((6-Methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] hept-3-yl) pyridin-3-yl) -6- ((octahydrocyclopenta [ c ] pyrrol-5-yl) oxy) pyrazolo [1,5-a ] pyridine-3-carbonitrile (20 mg,0.04mmol, example 4) was dissolved in CH 3 CN (5 mL), K 2CO3 (13 mg,0.09 mmol) and KI (8 mg,0.05 mmol) were added, after stirring for 15min, bromoethane (10 mg,0.09 mmol) was slowly added and the reaction was stirred for 12h at 50 ℃. TLC monitored the reaction (DCM/CH 3 OH (v/v) =20/1, rf=0.13) and starting material was complete. Stopping the reaction, slowly adding water to quench the reaction, extracting with EA (10 mL×3), washing with water, drying with anhydrous sodium sulfate, concentrating, performing silica gel column chromatography to obtain eluent DCM/CH 3 OH (v/v) =40/1-20/1, and obtaining brown yellow solid 7mg as target product, with yield 37.37％.LC-MS：m/z＝310.3[M]+/2;1H NMR(400MHz,MeOD)δ8.55(d,J＝1.9Hz,1H),8.38(s,1H),8.14(s,1H),7.89–7.84(m,1H),7.79–7.73(m,1H),7.52–7.43(m,1H),7.28(d,J＝1.9Hz,1H),6.91(d,J＝8.8Hz,1H),6.83(d,J＝8.6Hz,1H),5.51(s,2H),5.27–5.22(m,1H),4.60(brs,2H),4.20–4.10(m,2H),3.99(brs,1H),3.93(s,2H),3.92(s,3H),3.77(brs,2H),3.74(brs,1H),3.54–3.49(m,2H),2.78(brs,2H),2.32–2.23(m,2H),2.18–2.05(m,4H),1.77–1.73(m,1H),1.73–1.68(m,1H),1.47(s,6H).
Example 9:6- (((1R, 5S,6 s) -3-oxabicyclo [3.1.0] hex-6-yl) methoxy) -4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] hept-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile
Step 1: (1R, 5S,6 r) -6- (bromomethyl) -3-oxabicyclo [3.1.0] hexane
((1R, 5S,6 s) -3-oxabicyclo [3.1.0] hex-6-yl) methanol (105 mg,0.92 mmol) was dissolved in DCM (5 mL) and PBr 3 (0.39 g,1.4 mmol) was added slowly and the reaction stirred at low temperature for 2h. TLC monitored reaction (PE/EA (v/v) =6/1, rf=0.37) and starting material was complete. The reaction was stopped, quenched with water, adjusted to ph=8 with saturated aqueous NaHCO 3, extracted with dcm (10 ml×3), washed with water, dried over anhydrous sodium sulfate and concentrated at normal temperature to give the product.
Step 2:6- (((1R, 5S,6 s) -3-oxabicyclo [3.1.0] hex-6-yl) methoxy) -4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] hept-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile
6-Hydroxy-4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] hept-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridin-3-cyano (40 mg,0.09mmol, intermediate 1) was dissolved in DMF (6 mL), K 2CO3 (24 mg,0.17 mmol) was added and stirred for 10min. (1R, 5S,6 r) -6- (bromomethyl) -3-oxabicyclo [3.1.0] hexane (31 mg,0.18 mmol) was slowly added thereto, and the reaction was stirred for 12 hours at 50 ℃. TLC monitored the reaction (DCM/CH 3 OH (v/v) =20/1, rf=0.32) and starting material was complete. Cooling to room temperature, adding water, extracting with EA (20 mL. Times.3), washing with water, drying over anhydrous sodium sulfate, and concentrating. Silica gel column chromatography, eluent DCM/CH 3 OH (v/v) =40/1-20/1, obtaining yellow-brown solid 18mg, namely the target product, yield 27％.LC-MS：m/z＝550.3[M+H]+;1H NMR(400MHz,CDCl3)δ8.43(d,J＝2.2Hz,1H),8.23(s,1H),8.16–8.08(m,2H),7.85–7.78(m,1H),7.75–7.65(m,1H),7.16(d,J＝2.0Hz,1H),6.78–6.68(m,2H),3.99(s,1H),3.97(s,2H),3.95(s,1H),3.95(s,3H),3.86(brs,4H),3.77(d,J＝8.3Hz,2H),3.64(brs,4H),2.81–2.72(m,1H),1.74(brs,2H),1.37–1.34(m,1H),0.92–0.86(m,1H).
Example 10:4- (6- (6- (4-methoxybenzyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (2- (tetrahydro-1H-furo [3,4-c ] pyrrol-5 (3H) -yl) ethoxy) pyrazolo [1,5-a ] pyridine-3-carbonitrile
Step 1:5- (2-chloroethyl) hexahydro-1H-furo [3,4-c ] pyrrole
In a 25mL three-necked flask under nitrogen protection was added hexahydro-1H-furo [3,4-c ] pyrrole (2.0 g,18 mmol), potassium carbonate (12.0 g,86.8 mmol), and after purging with acetonitrile (20 mL,383 mmol), 1-bromo-2-chloroethane (13 g,90.649 mmol) was slowly added and stirred overnight at room temperature. After the reaction, the reaction solution is directly spin-dried, and the residue is subjected to silica gel column chromatography (eluent PE/EA (v/v) =100/1-2/1) to obtain 5.1g of yellow clear solution, namely the target product (yield) 97.0％).Rf＝0.35(EA).LC-MS：m/z＝176.50[M+H]+;1H NMR(400MHz,CDCl3)δ3.76(dd,J＝8.7,5.1Hz,2H),3.61-3.53(m,4H),2.86-2.72(m,6H),2.34(d,J＝5.0Hz,2H).
Step 2:4- (6-fluoropyridin-3-yl) -6- (2- (tetrahydro-1H-furan [3,4-c ] pyrrol-5 (3H) -yl) ethoxy) pyrazolo [1,5-a ] pyridine-3-carbonitrile
In a 25mL single vial was added 4- (6-fluoropyridin-3-yl) -6-hydroxypyrazolo [1,5-a ] pyridine-3-carbonitrile (0.5 g,2mmol, intermediate 2), potassium carbonate (0.8 g,6 mmol), 5- (2-chloroethyl) hexahydro-1H-furan [3,4-c ] pyrrole (0.7 g,4 mmol) dissolved in DMF (5 mL) and heated in an oil pot at 85℃overnight. Diluting with water (50 mL), extracting with EA (100 mL. Times.3), mixing the organic phase with saturated saline (50 mL), washing, drying with anhydrous sodium sulfate, filtering, and purifying the filtrate with spin-drying silica gel column (eluent PE/EA (v/v) =4/1-2/1) to obtain 0.43g of yellow solid as target product (yield) 60.0％).LC-MS：m/z＝327.10[M+H]+;1H NMR(400MHz,CDCl3)δ8.38(d,J＝2.1Hz,1H),8.26–8.18(m,2H),8.01(td,J＝8.4,2.5Hz,1H),7.20(d,J＝2.0Hz,1H),7.12(dd,J＝8.4,2.7Hz,1H),4.17(t,J＝5.4Hz,2H),3.76(dd,J＝8.6,6.0Hz,2H),3.63(dd,J＝8.8,1.7Hz,2H),2.93(t,J＝5.0Hz,4H),2.86(s,2H),2.42(dd,J＝8.3,2.7Hz,2H).
Step 3:6- (4-methoxybenzyl) -3, 6-diazabicyclo [3.1.1] heptane-3-carboxylic acid tert-butyl ester
To a 50mL single-necked flask was added tert-butyl 3, 6-diazabicyclo [3.1.1] heptane-3-carboxylate (500 mg,2.52 mmol), 4-methoxybenzaldehyde (401 mg,2.95 mmol), DCE (20 mL) was added to dissolve the tert-butyl 3, acetic acid (0.2 mL,3 mmol), and after stirring for 10min, sodium triethoxyborohydride (2.0 g,9.2 mmol) was added in two portions and reacted at room temperature for 12h. After the reaction is finished, saturated sodium bicarbonate solution (15 mL) is added into the reaction solution, DCM (50 mL multiplied by 2) is added for extraction, an organic phase is washed with water (20 mL multiplied by 2), anhydrous sodium sulfate is dried and filtered, filtrate is concentrated and then silica gel column chromatography is carried out, eluent is EA/MeOH (v/v=100/1), and 800mg of colorless liquid is obtained as a product, and the yield is obtained 99.63％.LC-MS:m/z＝319.20[M+H]+;1H NMR(400MHz,CDCl3)δ7.26(d,J＝8.6Hz,2H),6.85(d,J＝8.6Hz,2H),3.79(s,3H),3.69–3.59(m,3H),3.56(brs,3H),3.38(dd,J＝18.1,6.4Hz,2H),2.58(dd,J＝14.2,6.3Hz,1H),2.41(s,1H),1.51(s,9H).
Step 4:6- (4-methoxybenzyl) -3, 6-diazabicyclo [3.1.1] heptane hydrochloride
To a 25mL single vial was added tert-butyl 6- (4-methoxybenzyl) -3, 6-diazabicyclo [3.1.1] heptane-3-carboxylate (800 mg,2.51 mmol), HCl/EA (8 mL) and stirred at room temperature for 2h. After the reaction is finished, the reaction solution is directly concentrated and dried in vacuum at 60 ℃ to obtain 640mg of white solid which is the product. LC-MS: m/z=219.20 [ m+h ] +.
Step 5:4- (6- (6- (4-methoxybenzyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (2- (tetrahydro-1H-furo [3,4-c ] pyrrol-5 (3H) -yl) ethoxy) pyrazolo [1,5-a ] pyridine-3-carbonitrile
To a 10mL single vial was added 4- (6-fluoropyridin-3-yl) -6- (2- (tetrahydro-1H-furan [3,4-c ] pyrrol-5 (3H) -yl) ethoxy) pyrazolo [1,5-a ] pyridine-3-carbonitrile (25 mg, 0.063555 mmol), 6- (4-methoxybenzyl) -3, 6-diazabicyclo [3.1.1] heptane hydrochloride (32.4 mg,0.127 mmol), potassium carbonate (26.4 mg,0.191 mmol), DMAP (0.8 mg, 0.0071 mmol), DMSO (1.0 mL) and the substrate was dissolved and heated in an oil pot at 90 ℃. After TLC detection reaction is finished, water (25 mL) is added into the reaction solution, EA (50 mL multiplied by 2) is extracted, an organic phase is washed with water (50 mL), saturated sodium chloride is washed (50 mL), anhydrous sodium sulfate is dried and filtered, and filtrate is subjected to spin-dry silica gel column chromatography (eluent DCM/MeOH (v/v) =100/1-20/1) to obtain a white solid, namely 27.1mg of the product .1H NMR(400MHz,CDCl3)δ8.40(d,J＝2.0Hz,1H),8.21(s,1H),8.14(d,J＝1.5Hz,1H),7.78(dd,J＝8.8,2.2Hz,1H),7.29(d,J＝8.4Hz,2H),7.14(d,J＝1.6Hz,1H),6.85(d,J＝8.5Hz,2H),6.68(d,J＝8.7Hz,1H),4.15(t,J＝5.4Hz,2H),3.85(d,J＝10.4Hz,2H),3.78(d,J＝7.5Hz,6H),3.76–3.72(m,2H),3.61(t,J＝13.8Hz,7H),2.92(t,J＝5.4Hz,4H),2.85(d,J＝2.5Hz,2H),2.41(dd,J＝8.5,3.0Hz,2H).
Example 11:5- (2- ((3-cyano-4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] hept-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridin-6-yl) oxy) ethyl) -5-hydroxycyclopenta [ c ] pyrrole-2 (1H) -carboxylic acid tert-butyl ester
Step 1:5- (2-ethoxy-2-oxoethyl) -5-hydroxycyclopenta [ c ] pyrrole-2 (1H) -carboxylic acid tert-butyl ester
Zinc powder (552 mg,8.30 mmol) was added to a 50mL double-necked flask, a reflux condenser was connected, and after replacing nitrogen, anhydrous THF (8 mL), TMSCL (0.1 mL,0.8 mmol) was added and refluxed at 80℃for 40min. Thereafter, tert-butyl 5-oxo-hexahydrocyclopenta [ c ] pyrrole-2 (1H) -carboxylate (1.0 g,4.40 mmol) and ethyl dibromoacetate (920 mg,5.51 mmol) in THF (10 mL) were slowly added and after the addition the oil bath was continued at 80 ℃. After the TLC detection reaction is finished, the reaction solution is filtered out by suction to remove Zn powder, the filtrate is directly concentrated and subjected to silica gel column chromatography, the eluent is PE/EA (v/v) =5/1, and 683mg of colorless liquid is obtained as a product .1H NMR(400MHz,CDCl3)δ4.19(q,J＝7.1Hz,2H),3.69(s,1H),3.55(dd,J＝11.0,8.2Hz,2H),3.36(dd,J＝11.1,3.7Hz,2H),2.74–2.61(m,2H),2.57(s,2H),1.91(dd,J＝13.8,8.1Hz,2H),1.80(dd,J＝13.8,4.6Hz,2H),1.45(s,9H),1.29(t,J＝7.1Hz,3H).
Step 2: 5-hydroxy-5- (2-hydroxyethyl) hexahydrocyclopenta [ c ] pyrrole-2 (1H) -carboxylic acid tert-butyl ester
To a 50mL two-necked flask was added lithium aluminum hydride (71 mg,1.81 mmol), THF (4 mL) was added, and after nitrogen substitution, tert-butyl 5- (2-ethoxy-2-oxoethyl) -5-hydroxycyclopentao [ c ] pyrrole-2 (1H) -carboxylate (230 mg,0.73 mmol) dissolved in THF (6 mL) was added dropwise at-45℃and reacted at this temperature. After TLC detection reaction is finished, adding water for quenching, EA (30 mL multiplied by 2) extraction, washing an organic phase with water (10 mL multiplied by 3), saturated saline water, drying with anhydrous sodium sulfate, filtering, concentrating filtrate, performing silica gel column chromatography, eluting with PE/EA (v/v) =1/1-0/1 to obtain colorless liquid 100mg as a product .1H NMR(400MHz,CDCl3)δ3.92(t,J＝5.5Hz,2H),3.50(dd,J＝11.2,8.1Hz,2H),3.41(dd,J＝11.1,3.1Hz,2H),2.73-2.67(m,2H),2.02(dd,J＝13.7,8.5Hz,2H),1.85–1.81(m,2H),1.76(dd,J＝13.7,3.9Hz,2H),1.47(s,9H).
Step 3: 5-hydroxy-5- (2- ((methylsulfonyl) oxy) ethyl) hexahydrocyclopenta [ c ] pyrrole-2 ((1H) -carboxylic acid tert-butyl ester
To a 10mL single-necked flask was added tert-butyl 5-hydroxy-5- (2-hydroxyethyl) hexahydrocyclopenta [ c ] pyrrole-2 (1H) -carboxylate (140 mg,0.52 mmol), dichloromethane (2 mL) was added to dissolve, triethylamine (0.1 mL,0.7 mmol) was added, and methylsulfonyl chloride (0.08 mL,0.9 mmol) was added while ice-bath and reacted at room temperature. After TLC detection of the end of the reaction of the starting materials, the reaction solution is added with 5mL of water, DCM (15 mL multiplied by 2) is extracted, the organic phase is washed with water (5 mL multiplied by 2), saturated brine is washed with water, dried over anhydrous sodium sulfate and filtered, the filtrate is concentrated and subjected to silica gel column chromatography, the eluent is PE/EA (v/v) =2/1-1/1, and 60mg of light yellow liquid is obtained as a product .1H NMR(400MHz,CDCl3)δ4.44(t,J＝6.7Hz,2H),3.51–3.43(m,2H),3.43–3.35(m,2H),3.02(s,3H),2.81–2.70(m,2H),2.16(s,1H),2.04–1.97(m,4H),1.73(d,J＝11.6Hz,2H),1.45(s,9H).
Step 4:5- (2- ((3-cyano-4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] hept-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridin-6-yl) oxy) ethyl) -5-hydroxycyclopenta [ c ] pyrrole-2 (1H) -carboxylic acid tert-butyl ester
To a 10mL single vial was added 6-hydroxy-4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile (40 mg,0.088mmol, intermediate 1), 5-hydroxy-5- (2- ((methylsulfonyl) oxy) ethyl) hexahydrocyclopenta [ c ] pyrrole-2 ((1H) -carboxylic acid tert-butyl ester (60 mg,0.17 mmol), potassium carbonate (30 mg,0.21 mmol), DMF (1.0 mL), oil bath 60 ℃ after completion of the reaction, the reaction mixture was cooled to room temperature and then quenched with water 5mL, EA (20 mL. Times.2) was extracted, the organic phase was washed with water (5 mL. Times.3), saturated brine (5 mL. Times.2), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated to a column chromatography with DCM/MeOH (v/v) =50/1-20 mg of yellow solid, i.e., the product was obtained .LC-MS：,m/z＝707.30[M+H]+;1H NMR(400MHz,CDCl3)δ8.40(d,J＝2.1Hz,1H),8.21(s,1H),8.18(d,J＝1.9Hz,1H),8.11(s,1H),7.79(dd,J＝8.8,2.4Hz,1H),7.65(d,J＝7.7Hz,1H),7.09(s,1H),6.70(dd,J＝12.8,8.7Hz,2H),4.26(t,J＝6.3Hz,2H),3.92(s,3H),3.89–3.78(m,4H),3.60(s,2H),3.52–3.46(m,2H),3.43–3.39(m,2H),2.78(s,2H),2.13(t,J＝6.3Hz,2H),2.07(dd,J＝13.7,8.2Hz,4H),1.67(d,J＝8.6Hz,2H),1.61(dd,J＝15.0,8.7Hz,2H),1.45(s,9H).
Example 12:6- (2- (3-hydroxy-bicyclo [3.1.0] hex-3-yl) ethoxy) -4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile
Step 1:2- (3-hydroxy-bicyclo [3.1.0] hex-3-yl) ethyl methane sulfonate
A25 mL single vial was charged with 3- (2-hydroxyethyl) bicyclo [3.1.0] hex-3-ol (102 mg,0.72 mmol), DCM (4 mL), et 3 N (0.15 mL,1.1 mmol), msCl (0.09 mL,1 mmol) at low temperature of 5℃was added slowly and the reaction was stirred for 1.5h after the addition. At low temperature, the reaction mixture was added with 20mL of H 2 O, extracted with DCM (15 mL. Times.3), the organic phases were combined, dried over sodium sulfate, filtered and concentrated. Column chromatography, PE/EA (v/v) =2/1 as eluent, gave 108mg of oily liquid, yield 68％.1H NMR(400MHz,CDCl3)δ4.38(t,J＝6.8Hz,2H),3.14(s,1H),3.01(s,3H),2.00(m,4H),1.81(s,1H),1.78(s,1H),1.31(m,2H),0.71(m,1H),0.50(m,1H).
Step2: 6- (2- (3-hydroxy-bicyclo [3.1.0] hex-3-yl) ethoxy) -4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile
10ML of a two-necked flask was charged with 6-hydroxy-4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile (20 mg,0.044mmol, intermediate 1), K 2CO3 (22 mg,0.16 mmol), DMF (2.5 mL) and 2- (3-hydroxycyclo [3.1.0] hex-3-yl) ethylmethanesulfonate (0.10 mmol) and the reaction was heated and stirred at 60℃for 2h. The reaction was washed with 20mL of EA, water (10 mL. Times.3), 10mL of aqueous phase EA was extracted 1 time, the organic phases were combined, dried over sodium sulfate, filtered, and concentrated. Column chromatography, DCM/MeOH (v/v) =20/1 as eluent gave 9mg of pale yellow solid in yield 35％.LC-MS：m/z＝578.5[M+H]+;1H NMR(400MHz,CDCl3)δ8.39(d,J＝2.2Hz,1H),8.21(s,1H),8.15(d,J＝1.9Hz,1H),8.10(d,J＝1.7Hz,1H),7.77(dd,J＝8.8,2.4Hz,1H),7.63(dd,J＝8.5,2.2Hz,1H),7.09(d,J＝2.0Hz,1H),6.69(dd,J＝11.7,8.7Hz,2H),4.21(t,J＝6.4Hz,2H),3.92(s,3H),3.81(m,4H),3.56(m,4H),2.73–2.64(m,1H),2.08(m,4H),1.85(d,J＝13.9Hz,2H),1.65(d,J＝8.7Hz,1H),1.35(m,3H),0.75(m,J＝4.2Hz,1H),0.53(m,1H).
Example 13:6- (2- (bicyclo [3.1.0] hex-2-en-3-yl) ethoxy) -4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] hept-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile
Step 1:2- (3-Hydroxybicyclo [3.1.0] hex-3-yl) acetic acid ethyl ester
Zn powder (930 mg,14.22 mmol) was added sequentially to a 50mL single-port bottle, anhydrous THF (20 mL), TMSCL (0.20 mL,1.6 mmol) was added under N 2 protection, and the reaction was stirred under reflux in an oil bath for 1h. Bicyclo [3.1.0] hex-3-one (760 mg,7.91 mmol) and ethyl bromoacetate (1.10 mL,9.92 mmol) were dissolved in 2mL of THF and added slowly, after which the reflux stirring reaction was maintained for 6-8h. After the reaction solution was cooled, it was filtered, washed with EA (10 mL. Times.5), and concentrated. Column chromatography separation, PE/EA (v/v) =6/1 as eluent gave 830mg of oily liquid, yield 57％.LC-MS:m/z＝185.2[M+H]+;1H NMR(400MHz,CDCl3)δ4.15(q,J＝7.1Hz,2H),3.35(s,1H),2.52(s,2H),1.89(s,4H),1.26(m,5H),0.81(m,1H),0.47(m,1H).
Step 2:3- (2-hydroxyethyl) bicyclo [3.1.0] hex-3-ol
A50 mL single-port bottle is added with LiAlH 4(211mg,5.56mmol),N2 for protection, THF (5 mL) is added, ethyl 2- (3-hydroxy bicyclo [3.1.0] hex-3-yl) acetate (390 mg,2.12 mmol) is dissolved in THF (5 mL) and added slowly at a low temperature of-10 ℃ and stirring is continued for reaction for 1h after the addition. Quenching reaction by slowly adding saturated ammonium chloride solution at low temperature 10mL, extracting with EA (15 mL×3), mixing organic phases, drying with sodium sulfate, filtering, concentrating, separating by column chromatography, and eluting with PE/EA (v/v) =2/1 to obtain oily liquid 75mg in yield 25％.LC-MS:m/z＝165.2[M+Na]+;1H NMR(400MHz,CDCl3)δ3.84(t,J＝5.6Hz,2H),3.05(s,1H),2.93(s,1H),1.94(m,2H),1.83(d,J＝13.8Hz,2H),1.75(t,J＝5.7Hz,2H),1.33–1.21(m,2H),0.71(q,J＝4.0Hz,1H),0.48(m,1H).
Step 3:3- (2-bromoethyl) bicyclo [3.1.0] hex-2-ene
3- (2-Hydroxyethyl) bicyclo [3.1.0] hex-3-ol (59 mg,0.41 mmol), DCM (4.0 mL), PBr 3 (0.06 mL,0.60 mmol) at 15℃were added in sequence in a single-port flask and the reaction was continued for 1h after the addition. 0.5mL of H 2 O, 25mL of saturated sodium bicarbonate solution were added, the organic phase was collected, the aqueous phase was extracted with DCM (15 mL. Times.2), the organic phases were combined, dried over sodium sulfate, filtered, concentrated and taken directly to the next reaction. LC-MS: m/z=187.0, 189.0[ m+h ] +.
Step 4:6- (2- (bicyclo [3.1.0] hex-2-en-3-yl) ethoxy) -4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] hept-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile
10ML of a two-necked flask was charged with 6-hydroxy-4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile (30 mg,0.066mmol, intermediate 1), K 2CO3 (36 mg,0.26 mmol), DMF (3.1 mL), 3- (2-bromoethyl) bicyclo [3.1.0] hex-2-ene (0.250 mmol), N 2 protected, and heated to 40℃with stirring for 4h. The reaction mixture was washed with 25mL of EA, water (10 mL. Times.3), 10mL of aqueous phase EA was extracted 1 time, the organic phases were combined, dried over sodium sulfate, filtered, and concentrated. Column chromatography, DCM/MeOH (v/v) =15/1 as eluent gave 5mg of pale yellow solid in yield 13％.LC-MS：m/z＝560.4[M+H]+;1H NMR(400MHz,CDCl3)δ8.39(d,J＝2.3Hz,1H),8.20(s,1H),8.12–8.07(m,2H),7.78(dd,J＝8.7,2.4Hz,1H),7.64(d,J＝7.6Hz,1H),7.10(d,J＝1.9Hz,1H),6.70(dd,J＝13.1,8.7Hz,2H),5.60(s,1H),4.53(m,2H),3.92(s,3H),3.84(m,5H),3.59(m,5H),2.69(d,J＝13.8Hz,2H),2.37(m,2H),0.87(m,3H),0.52(m,1H).
Example 14:6- (2- (5-hydroxy-octahydrocyclopenta [ c ] pyrrol-5-yl) ethoxy) -4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] hept-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile dihydrochloride
To a 10mL single vial was added 5- (2- ((3-cyano-4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] hept-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridin-6-yl) oxy) ethyl) -5-hydroxycyclopenta [ c ] pyrrole-2 (1H) -carboxylic acid tert-butyl ester (20 mg,0.028mmol, example 11) and HCl/EA (1.5 mL) with stirring. TLC detection of the reaction of the starting material was completed, the solvent was dried by spinning to give 19mg of the product. LC-MS: m/z=607.50 [ m+h-2HCl ] +.
Example 15:4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] hept-3-yl) pyridin-3-yl) -6- (2- (tetrahydro-1H-furo [3,4-c ] pyrrol-5 (3H) -yl) ethoxy) pyrazolo [1,5-a ] pyridine-3-carbonitrile
Step 1:5- (2-chloroethyl) hexahydro-1H-furo [3,4-c ] pyrrole
In a 25mL three-necked flask under nitrogen protection was added hexahydro-1H-furo [3,4-c ] pyrrole (2.0 g,18 mmol), potassium carbonate (12.0 g,86.8 mmol), and after purging with acetonitrile (20 mL,383 mmol), 1-bromo-2-chloroethane (13 g,90.649 mmol) was slowly added and stirred overnight at room temperature. Directly spin-drying silica gel column chromatography (eluent PE/EA (v/v) =100/1-2/1) after reaction, collecting target solution, spin-drying to obtain yellow clear solution 5.1g (yield) 97.0％).Rf＝0.35(EA).LC-MS：m/z＝176.50[M+H];1H NMR(400MHz,CDCl3)δ3.76(dd,J＝8.7,5.1Hz,2H),3.61–3.53(m,4H),2.86–2.72(m,6H),2.34(d,J＝5.0Hz,2H).
Step 2:4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] hept-3-yl) pyridin-3-yl) -6- (2- (tetrahydro-1H-furo [3,4-c ] pyrrol-5 (3H) -yl) ethoxy) pyrazolo [1,5-a ] pyridine-3-carbonitrile
To a 5mL single port flask was added 6-hydroxy-4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile (25 mg, 0.05313 mmol, intermediate 1), 5- (2-chloroethyl) hexahydro-1H-furan [3,4-c ] pyrrole (19.4 mg,0.11 mmol), potassium carbonate (23.09 mg,0.1654 mmol), DMF (0.5 mL) and the oil bath was heated at 85℃overnight. After the reaction, the reaction mixture was diluted with water (10 mL), extracted with EA (25 ml×3), the organic phase was collected, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was purified by spin-drying on a silica gel column, eluent DCM/MeOH (v/v) =100/1 to 15/1, and collected spin-drying to give 25mg of a yellow solid as the target product (yield) 76.51％)(Rf＝0.25,DCM/MeOH(v/v)＝20/1).LC-MS(ES-API):[M/2+H]＝297.30;1H NMR(400MHz,CDCl3)δ8.42(d,J＝2.1Hz,1H),8.23(s,1H),8.17(d,J＝1.7Hz,1H),8.13(s,1H),7.80(dd,J＝8.8,2.3Hz,1H),7.67(d,J＝8.4Hz,1H),7.17(d,J＝1.8Hz,1H),6.72(dd,J＝13.7,8.7Hz,2H),4.19(t,J＝5.4Hz,2H),3.94(s,3H),3.86(d,J＝12.2Hz,2H),3.79(dd,J＝19.1,5.6Hz,4H),3.71–3.54(m,6H),3.06–2.82(m,6H),2.52–2.38(m,2H),1.68(d,J＝8.6Hz,2H).
Example 16:6- (2- (((3R, 3aR,6R,6 aR) -6-methoxyhexahydrofuro [3,2-b ] furan-3-yl) oxy) ethoxy) -4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile
Step 1: (3R, 3aR,6R,6 aR) -6-methoxyhexahydrofuro [3,2-b ] furan-3-ol
To a 250mL single vial was added dehydrated mannitol (11.0 g,75.3 mmol), ag 2O(13.2g,57.0mmol),DCM(120mL)CH3 I (9.20 mL,148 mmol), and the reaction was heated at 40℃with stirring for 20h. After the reaction solution was cooled, it was filtered through celite, washed with EA (10 ml×5), and concentrated. The residue was chromatographed on silica gel with PE/EA (v/v) =1/1 as eluent to give 6.23g of a white solid in yield 52％.1H NMR(400MHz,CDCl3)4.57(t,J＝4.8Hz,1H),4.51(t,J＝5.2Hz,1H),4.28(m,1H),4.08(dd,J＝8.6,6.5Hz,1H),4.02-3.91(m,2H),3.73-3.64(m,2H),3.47(s,3H),2.84(d,J＝8.5Hz,1H).
Step 2:2- ((((3R, 3aR,6R,6 aR) -6-methoxyhexahydrofuro [3,2-b ] furan-3-yl) oxy) acetic acid ethyl ester
To a 50mL single port flask was added NaH (88 mg,2.2 mmol), under N 2 protection, THF (8 mL), at low temperature of-4deg.C, (3R, 3aR,6R,6 aR) -6-methoxyhexahydrofuro [3,2-b ] furan-3-ol (263 mg,1.64 mmol) was added slowly in THF (4 mL) and after addition was stirred at rt for 2-3h. The reaction mixture was slowly added at-4℃with ethyl bromoacetate (0.21 mL,1.9 mmol) and stirred at rt for 3h after addition. The reaction mixture was added with EA (5 mL), ammonium chloride solution (10 mL), the aqueous phase was separated and extracted with EA (15 ml×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was chromatographed on silica gel, with PE/EA (v/v) =1/1 as eluent to give 146mg of oily liquid, yield 36％.LC-MS:m/z＝247.2[M+H]+;1H NMR(400MHz,CDCl3)δ4.58(m,2H),4.25(m,2H),4.21–4.12(m,3H),4.08(m,2H),3.98–3.90(m,1H),3.79(t,J＝8.4Hz,1H),3.70(t,J＝8.5Hz,1H),3.45(s,3H),1.28(t,J＝7.1Hz,3H).
Step 3:2- (((((3R, 3aR,6R,6 aR) -6-methoxyhexahydrofuro [3,2-b ] furan-3-yl) oxy) ethan-1-ol
To a 50mL single port flask, THF (5 mL) was added under the protection of LiAlH 4(53mg,1.40mmol),N2 mL) and ethyl 2- ((((3R, 3aR,6R,6 aR) -6-methoxyhexahydrofuro [3,2-b ] furan-3-yl) oxy) acetate (135 mg,0.55 mmol) was slowly added in THF (5 mL) at-65℃under the protection of LiAlH 4(53mg,1.40mmol),N2, and after the addition, stirring was continued for 1h, 10mL of saturated ammonium chloride solution was slowly added at low temperature to quench the reaction, extracted with EA (15 mL. Times.3), the organic phase was combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was chromatographed on silica gel to give an oily liquid 65mg, PE/EA (v/v) =1/6 as eluent, yield 58％.LC-MS:m/z＝205.1[M+H]+;1H NMR(400MHz,CDCl3)δ4.59(m,2H),4.10–4.02(m,3H),3.98–3.90(m,1H),3.78–3.72(m,2H),3.72–3.63(m,4H),3.46(s,3H),2.84(s,1H).
Step 4:2- ((((3R, 3aR,6R,6 aR) 3- (2-bromoethoxy) -6-methoxyhexahydrofuro [3,2-b ] furan)
To a 25mL single port flask was successively added 2- (((((3R, 3aR,6R,6 aR) -6-methoxyhexahydrofuro [3,2-b ] furan-3-yl) oxy) ethan-1-ol (42 mg,0.21 mmol), DCM (3 mL), et 3 N (0.05 mL,0.40 mmol), -MsCl (0.06 mL,0.8 mmol) at low temperature of 5 ℃ and then stirred for 10H after the addition was completed, H 2 O (15 mL) was added to the reaction solution, extracted (15 mL. Times.3) with DCM, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, the residue was chromatographed on silica gel column with PE/EA (v/v) =1/3 as eluent to give 46mg of oily liquid in yield 79％.1H NMR(400MHz,CDCl3)δ4.55(m,2H),4.36(t,J＝4.5Hz,2H),4.10–4.04(m,1H),4.00(m,2H),3.91(m,2H),3.63-3.76(m,3H),3.43(s,3H),3.04(s,3H).
Step 5:6- (2- (((3R, 3aR,6R,6 aR) -6-methoxyhexahydrofuro [3,2-b ] furan-3-yl) oxy) ethoxy) -4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile
To a 10mL two-port flask was added 6-hydroxy-4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile (31 mg,0.068mmol, intermediate 1), K 2CO3 (36 mg,0.26 mmol), DMF (3.0 mL), 2- ((((3R, 3aR,6R,6 aR) 3- (2-bromoethoxy) -6-methoxyhexahydrofuro [3,2-b ] furan (0.12 mmol), under N 2 protection, the reaction was stirred under heating at 80 ℃ overnight, the reaction mixture was added with EA (25 mL), the aqueous phase was washed with water (15 mL. Times.3), the aqueous phase was extracted with EA (10 mL), the organic phase was combined, dried over anhydrous sodium sulfate, filtered, the concentrated, the residue was chromatographed on silica gel, DCM/(v/v) =15/1 was eluted to give 5mg as a pale yellow solid, yield 14％.LC-MS：m/z＝640.3[M+H]+;1H NMR(400MHz,CDCl3)δ8.40(s,1H),8.20(d,J＝10.3Hz,1H),8.12(s,1H),7.79(m,1H),7.53(d,J＝8.5Hz,1H),7.35(s,1H),7.17–7.13(m,1H),6.72(dd,J＝16.0,8.7Hz,2H),4.61(m,2H),4.17(m,4H),4.07(m,4H),3.92(s,3H),3.81–3.70(m,4H),3.65(m,2H),3.49(s,4H),3.47(s,3H),2.36–2.32(m,2H).
Example 17 6- (bicyclo [3.1.0] hex-3-yloxy) -4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] hept-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile
Step 1: bicyclo [3.1.0] hex-3-ols
To a 50mL two-necked flask was added bicyclo [3.1.0] hex-3-one (418 mg,4.32 mmol), meOH (15 mL), naBH 4 (193 mg,5.10 mmol) in N 2 atmosphere and the mixture was stirred at-5℃for 3h. The reaction was concentrated, water (20 mL) was added, extracted with EA (25 mL. Times.3), the organic phases were combined, dried, filtered, and concentrated. Separating the residue with silica gel column chromatography to obtain oily liquid 225mg and yield with PE/EA (v/v) =5/1 as eluent 53％.1H NMR(400MHz,CDCl3)δ4.36(m,1H),2.13-2.04(m,2H),1.73(s,1H),1.69(s,1H),1.46(s,broad,1H),1.29-1.24(m,2H),0.55-0.43(m,2H).
Step 2: bicyclo [3.1.0] hex-3-yl methanesulfonate
To a 25mL single-necked flask was successively added bicyclo [3.1.0] hex-3-ol (202 mg,2.06 mmol), DCM (6 mL), et 3 N (0.45 mL,3.2 mmol), msCl (0.21 mL,2.70 mmol) at low temperature of-5℃was slowly added, and the reaction was stirred for 3h after the addition. At low temperature, H 2 O (20 mL) was added to the reaction solution, extracted with DCM (15 mL. Times.3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was chromatographed on a silica gel column, with PE/EA (v/v) =5/1 as eluent, to give 300mg of white solid in 82％.1H NMR(400MHz,CDCl3)δ5.18(t,J＝6.6Hz,1H),2.95(s,3H),2.33-2.19(m,2H),2.09(d,J＝15.2Hz,2H),1.39-1.32(m,2H),0.54(m,1H),0.43(m,1H). steps 3:6- (bicyclo [3.1.0] hex-3-yloxy) -4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] hept-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile
To a 10mL two-necked flask was added 6-hydroxy-4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile (26 mg,0.057mmol, intermediate 1), K 2CO3 (27 mg,0.20 mmol), DMF (3.0 mL) and bicyclo [3.1.0] hex-3-ylmethane sulfonate (0.23 mmol) in sequence, and the reaction was stirred at 85deg.C for 8h. The reaction mixture was added with EA (30 mL), washed with water (10 mL. Times.3), the aqueous phase was extracted with EA (10 mL), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was chromatographed on silica gel with DCM/MeOH (v/v) =20/1 as eluent to give 4mg of a pale yellow solid in yield 13％.LC-MS：m/z＝534.2[M+H]+.1H NMR(400MHz,CDCl3)δ8.39(d,J＝2.1Hz,1H),8.20(s,1H),8.13–8.07(m,2H),7.78(dd,J＝8.8,2.4Hz,1H),7.67(s,1H),7.07(d,J＝1.9Hz,1H),6.70(dd,J＝15.7,8.7Hz,2H),4.47–4.36(m,1H),3.92(s,3H),3.87-3.83(m,4H),3.68-3.63(m,5H),2.47–2.40(m,2H),1.65-1.60(m,5H),0.75–0.66(m,1H),0.53(m,1H).
Example 18:4- (6- (5- (3-fluoro-2-methylbenzoyl) hexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) pyridin-3-yl) -6- ((octahydrocyclopenta [ c ] pyrrol-5-yl) oxy) pyrazolo [1,5-a ] pyridine-3-carbonitrile
Step 1: 5-Hydroxyhexahydrocyclopenta [ c ] pyrrole-2 (1H) -carboxylic acid tert-butyl ester
To a 25mL single-necked flask was added tert-butyl 5-oxohexahydrocyclopenta [ c ] pyrrole-2 (1H) -carboxylate (1.0 g,4.4 mmol), etOH (10 mL) was added to dissolve the tert-butyl 5-oxo hexahydrocyclopenta [ c ] pyrrole-2 (1.0 g,4.4 mmol), sodium borohydride (340 mg,8.81 mmol) was added under ice-bath, and the mixture was allowed to spontaneously recover to room temperature for 4H. The reaction solution was directly concentrated on silica gel column chromatography with DCM/MeOH (v/v=50/1) as eluent to give 940mg of colorless liquid as the product in the yield 93.00％.LC-MS：m/z＝172.10[M-tBu+H]+;1H NMR(400MHz,CDCl3)δ4.30(p,J＝6.4Hz,1H),3.50(dd,J＝11.2,8.0Hz,2H),3.34(dd,J＝11.2,3.5Hz,2H),2.66–2.54(m,2H),2.17(dt,J＝20.1,7.2Hz,2H),1.86(s,2H),1.45(s,9H).
Step 2:5- ((methylsulfonyl) oxy) hexahydrocyclopenta [ c ] pyrrole-2 (1H) -carboxylic acid tert-butyl ester
To a 25mL single vial was added 5-hydroxycyclopenta [ c ] pyrrole-2 (1H) -carboxylic acid tert-butyl ester (400 mg,1.76 mmol), dissolved in DCM (5 mL), et 3 N (0.5 mL,4 mmol) was added under ice-bath, and methylsulfonyl chloride (0.2 mL,3 mmol) was then allowed to spontaneously recover to room temperature for 3H. After TLC detection of the reaction of the raw materials, 5mL of water and DCM (20 mL. Times.2) are added to the reaction solution, the organic phase is washed with water (5 mL. Times.2), dried and concentrated with anhydrous sodium sulfate, and subjected to silica gel column chromatography, wherein the eluent is PE/EA (v/v=4/1), 390mg of colorless liquid is obtained as a product, and the yield is improved 72.57％.LC-MS：m/z＝250.10[M-tBu+H]+;1H NMR(400MHz,CDCl3)δ5.18–5.05(m,1H),3.54(s,2H),3.35(s,2H),3.00(s,3H),2.67(s,2H),2.39–2.28(m,2H),1.90–1.83(m,2H),1.46(s,9H).
Step 3:5- ((3-cyano-4- (6-fluoropyridin-3-yl) pyrazolo [1,5-a ] pyridin-6-yl) oxy) hexahydrocyclopenta [ c ] pyrrole-2 (1H) -carboxylic acid tert-butyl ester
To a 25mL single vial was added successively 4- (6-fluoro-pyridin-3-yl) -6-hydroxypyrazolo [1,5-a ] pyridine-3-carbonitrile (250 mg,0.98 mmol), potassium carbonate (410 mg,2.97 mmol), 5- ((methylsulfonyl) oxy) hexahydrocyclopenta [ c ] pyrrole-2 (1H) -carboxylic acid tert-butyl ester (330 mg,1.081 mmol), DMF (2.5 mL) and reacted at 80℃for 3H. After the reaction is stopped, 10mL of water and EA (40 mL multiplied by 2) are added into the reaction solution, the mixture is extracted, an organic phase is washed with water (10 mL multiplied by 5), saturated salt is washed with water (10 mL), anhydrous sodium sulfate is dried and then filtered, a filtrate is subjected to silica gel column chromatography, and an eluent is DCM/MeOH (v/v=50/1), so that 240mg of off-white solid is obtained as a product, and the yield is obtained 52.65％.LC-MS：m/z＝408.30[M-tBu+H]+;1H NMR：(400MHz,CDCl3)δ8.38(d,J＝2.3Hz,1H),8.21(s,1H),8.14(d,J＝1.9Hz,1H),8.01(td,J＝8.2,2.5Hz,1H),7.14(d,J＝2.9Hz,1H),7.12(d,J＝2.1Hz,1H),4.92–4.86(m,1H),3.55(s,2H),3.26(s,2H),2.91(s,2H),2.27(dd,J＝14.6,6.2Hz,2H),1.97–1.88(m,2H),1.47(s,9H).
Step 4:5- (3-fluoro-2-methylbenzoyl) hexahydropyrrolo [3,4-c ] pyrrole-2 (1H) -carboxylic acid tert-butyl ester
To a 100mL single vial was added tert-butyl hexahydropyrrolo [3,4-c ] pyrrole-2 (1H) -carboxylate (500 mg,2.36 mmol), 3-fluoro-2-methylbenzoic acid (550 mg,3.57 mmol), dissolved in DCM, and then 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (803 mg,4.71 mmol), 4-dimethylaminopyridine (580 mg,4.75 mmol) was added and reacted at room temperature for 15H. After stopping the reaction, the reaction solution was directly concentrated, followed by silica gel column chromatography with DCM-DCM/MeOH (v/v=50/1) as eluent to obtain 620mg of colorless viscous liquid as the product in the yield 75.56％.LC-MS:m/z＝293.20[M-tBu+H]+;1H NMR(400MHz,CDCl3)δ7.24–7.17(m,1H),7.05(d,J＝9.0Hz,1H),7.02–6.96(m,1H),3.89(dd,J＝12.2,8.0Hz,1H),3.70–3.50(m,3H),3.41(dd,J＝11.3,7.3Hz,1H),3.32(s,1H),3.23–3.08(m,1H),3.08–3.00(m,1H),2.97(d,J＝6.5Hz,1H),2.90–2.81(m,1H),2.23(d,J＝1.4Hz,3H),1.46(s,9H).
Step 5: (hexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) (3-fluoro-2-methylphenyl) methanone dihydrochloride
To a 25mL single flask was added tert-butyl 5- (3-fluoro-2-methylbenzoyl) hexahydropyrrolo [3,4-c ] pyrrole-2 (1H) -carboxylate (620 mg,1.780 mmol), and EA (5 mL) was added to dissolve, HCl/EA (11 mL,44mmol,4 mol/L) was added, and after the addition was completed, the reaction was performed at room temperature for 2 hours. After the reaction is stopped, the reaction solution is directly concentrated to obtain white solid 410mg which is the product with the yield 71.73％.LC-MS:m/z＝249.20[M+H]+;1H NMR(400MHz,DMSO-d6)δ7.30(dd,J＝13.3,7.8Hz,1H),7.20(t,J＝8.9Hz,1H),7.10(d,J＝7.4Hz,1H),3.73(dd,J＝12.6,7.8Hz,1H),3.55(dd,J＝12.7,4.0Hz,1H),3.44–3.21(m,3H),3.16–3.01(m,3H),3.00–2.87(m,2H),2.15(d,J＝1.6Hz,3H).
Step 6:5- ((3-cyano-4- (6- (5- (3-fluoro-2-methylbenzoyl) hexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridin-6-yl) oxy) hexahydrocyclopenta [ c ] pyrrole-2 (1H) -carboxylic acid tert-butyl ester
To a 10mL single vial was added tert-butyl 5- ((3-cyano-4- (6-fluoropyridin-3-yl) pyrazolo [1,5-a ] pyridin-6-yl) oxy) hexahydrocyclopenta [ c ] pyrrole-2 (1H) -carboxylate (50 mg,0.11 mmol), (hexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) (3-fluoro-2-methylphenyl) methanone dihydrochloride (55 mg,0.1712 mmol), potassium carbonate (92 mg,0.67 mmol), DMSO (1.5 mL), and reacted at 90℃for 18H in an oil bath. After stopping the reaction, cooling the reaction solution to room temperature, adding 5mL of water, extracting with EA (20 mL multiplied by 2), washing the organic phase with water (5 mL multiplied by 3), washing with saturated saline (5 mL multiplied by 2), drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and performing silica gel column chromatography with DCM/MeOH (v/v=20/1) as eluent to obtain 34mg of yellow solid as a product, wherein the yield 45.56％.LC-MS:m/z＝692.40[M+H]+;1H NMR(400MHz,CDCl3)δ8.31(d,J＝2.1Hz,1H),8.19(s,1H),8.06(s,1H),7.70(dd,J＝8.6,2.2Hz,1H),7.23–7.18(m,1H),7.03(dd,J＝12.6,10.5Hz,3H),6.50(d,J＝8.8Hz,1H),4.90–4.84(m,1H),4.00(dd,J＝12.8,7.7Hz,1H),3.90–3.83(m,1H),3.79–3.71(m,2H),3.66(s,1H),3.54–3.48(m,3H),3.41(dd,J＝10.7,3.9Hz,1H),3.24(s,2H),3.19–3.13(m,2H),3.07(s,1H),2.91(s,2H),2.28(d,J＝7.3Hz,2H),2.24(s,3H),1.90(d,J＝13.4Hz,2H),1.47(s,9H).
Step 7:4- (6- (5- (3-fluoro-2-methylbenzoyl) hexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) pyridin-3-yl) -6- ((octahydrocyclopenta [ c ] pyrrol-5-yl) oxy) pyrazolo [1,5-a ] pyridine-3-carbonitrile
To a10 mL single port flask was added 5- ((3-cyano-4- (6- (5- (3-fluoro-2-methylbenzoyl) hexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridin-6-yl) oxy) hexahydrocyclopenta [ c ] pyrrole-2 (1H) -carboxylic acid tert-butyl ester (34 mg,0.04915 mmol), EA (1.5 mL) was added to dissolve it, HCl/EA (0.2 mL,0.8mmol,4 mol/L) was added under ice bath and after the addition was completed, the reaction was carried out at room temperature for 1H. After the reaction was stopped, the reaction mixture was concentrated, then 2mL of MeOH was added to dissolve it, potassium carbonate (130 mg,0.94060 mmol) was added, stirred at room temperature for 40min, the reaction mixture was directly concentrated on silica gel column chromatography with eluent DCM/MeOH (v/v=5/1) to give 12mg of yellow solid as the product in yield 41.26％.LC-MS：m/z＝592.50[M+H]+;1H NMR(400MHz,CDCl3)δ8.30(d,J＝2.2Hz,1H),8.19(s,2H),7.69(dd,J＝8.7,2.3Hz,1H),7.22–7.17(m,1H),7.06–6.99(m,3H),6.49(d,J＝8.8Hz,1H),5.01(s,1H),4.00(dd,J＝12.7,7.7Hz,1H),3.87(dd,J＝10.7,7.8Hz,1H),3.76–3.71(m,2H),3.66(s,2H),3.61(s,1H),3.51(dd,J＝10.7,6.3Hz,2H),3.41(dd,J＝10.8,4.3Hz,1H),3.31(s,2H),3.18–3.14(m,3H),3.06(d,J＝6.6Hz,1H),2.37(d,J＝7.6Hz,2H),2.23(s,3H),2.12(d,J＝13.1Hz,2H).
Example 19:4- (6- (5- (2, 3-dimethylbenzoyl) hexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) pyridin-3-yl) -6- ((octahydrocyclopenta [ c ] pyrrol-5-yl) oxy) pyrazolo [1,5-a ] pyridine-3-carbonitrile
Step 1:5- (2, 3-Dibenzoyl) hexahydropyrrolo [3,4-c ] pyrrole-2 (1H) -carboxylic acid tert-butyl ester
To a 25mL single vial was added tert-butyl hexahydropyrrolo [3,4-c ] pyrrole-2 (1H) -carboxylate (500 mg,2.36 mmol), 2, 3-dimethylbenzoic acid (530 mg,3.53 mmol), dissolved in DCM, and then 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (903 mg,4.71 mmol), 4-dimethylaminopyridine (580 mg,4.75 mmol) was added and reacted at room temperature for 17H. Adding water 10mL into the reaction solution, extracting with water phase DCM (30 mL), mixing the organic phases, washing with water (10 mL×2), drying with anhydrous sodium sulfate, concentrating, performing silica gel column chromatography to obtain colorless viscous liquid 660mg as product, and obtaining yield 81.37％.LC-MS：m/z＝289.25[M-tBu+H]+;1H NMR(400MHz,DMSO-d6)δ7.18(d,J＝7.3Hz,1H),7.12(t,J＝7.5Hz,1H),7.01(d,J＝7.3Hz,1H),3.69(dd,J＝12.3,7.7Hz,1H),3.50(s,1H),3.44–3.36(m,2H),3.31–3.24(m,1H),3.17(dd,J＝11.2,4.8Hz,1H),3.03(dd,J＝11.2,4.5Hz,1H),2.95–2.76(m,3H),2.25(s,3H),2.10(s,3H),1.39(s,9H).
Step 2: (hexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) (2, 3-dimethylphenyl) methanone dihydrochloride
In a 25mL single flask was added tert-butyl 5- (2, 3-dimethylbenzoyl) hexahydropyrrolo [3,4-c ] pyrrole-2 (1H) -carboxylate (330 mg,0.96 mmol), dissolved by the addition of EA (3 mL), HCl/EA (2 mL,8mmol,4 mol/L) and reacted at room temperature for 1H after the addition. White solid is separated out in the reaction process, the reaction liquid is directly concentrated after TLC detection of the raw materials is finished, the white solid is obtained, the white solid is dried in a vacuum drying oven at 60 ℃ to obtain 260mg which is the product, and the yield is obtained 85.54％.LC-MS:m/z＝245.30[M+H]+;1H NMR(400MHz,DMSO d6)δ7.18(d,J＝7.3Hz,1H),7.13(t,J＝7.5Hz,1H),7.03(d,J＝7.3Hz,1H),3.73(dd,J＝12.6,7.9Hz,1H),3.54(dd,J＝12.6,4.1Hz,1H),3.39(dd,J＝10.7,4.8Hz,1H),3.29(dd,J＝10.9,7.3Hz,2H),3.11–2.99(m,3H),3.00–2.86(m,2H),2.25(s,3H),2.12(s,3H).
Step 3:5- ((3-cyano-4- (6- (5- (2, 3-dimethylbenzoyl) hexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridin-6-yl) oxy) hexahydrocyclopenta [ c ] pyrrole-2 (1H) -carboxylic acid tert-butyl ester
To a 10mL single vial was added tert-butyl 5- ((3-cyano-4- (6-fluoropyridin-3-yl) pyrazolo [1,5-a ] pyridin-6-yl) oxy) hexahydrocyclopenta [ c ] pyrrole-2 (1H) -carboxylate (40 mg,0.086mmol, example 18 step 3), hexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) (2, 3-dimethylphenyl) methanone dihydrochloride (50 mg,0.16 mmol), potassium carbonate (80 mg,0.58 mmol), DMSO (1.5 mL) and reacted at 90℃in an oil bath for 15H. Cooling the reaction solution to room temperature, adding water 5mL, extracting with EA (20 mL×2), washing the organic phase with water (5 mL×3), washing with saturated saline (5 mL×2), drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and performing silica gel column chromatography with DCM/MeOH (v/v=20/1) as eluent to obtain a solid 32mg as the product, wherein the yield 53.91％.LC-MS：m/z＝688.40[M+H]+;1H NMR(400MHz,CDCl3)δ8.31(s,1H),8.19(s,1H),8.06(s,1H),7.70(d,J＝8.3Hz,1H),7.14(dd,J＝19.0,7.4Hz,2H),7.04(d,J＝9.0Hz,2H),6.50(d,J＝8.9Hz,1H),4.87(s,1H),4.00(dd,J＝12.8,7.7Hz,1H),3.90–3.84(m,1H),3.80–3.71(m,2H),3.65(s,1H),3.57–3.46(m,4H),3.41(d,J＝7.1Hz,1H),3.24(s,2H),3.19–3.11(m,2H),3.07–3.01(m,1H),2.91(s,2H),2.28(s,3H),2.21(s,3H),2.01(s,1H),1.90(d,J＝14.2Hz,2H),1.46(s,9H).
Step 4:4- (6- (5- (2, 3-dimethylbenzoyl) hexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) pyridin-3-yl) -6- ((octahydrocyclopenta [ c ] pyrrol-5-yl) oxy) pyrazolo [1,5-a ] pyridine-3-carbonitrile
To a 10mL single flask was added tert-butyl 5- ((3-cyano-4- (6- (5- (2, 3-dimethylbenzoyl) hexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridin-6-yl) oxy) hexahydrocyclopentyl [ c ] pyrrole-2 (1H) -carboxylate (32 mg,0.04653 mmol), and EA (2 mL) was added to dissolve it, HCl/EA (0.2 mL,0.8mmol,4 mol/L) was added under ice bath, and a white solid precipitated and reacted at room temperature for 1H. After stopping the reaction, the reaction solution was directly concentrated, 2mLMeOH was added to dissolve it, potassium carbonate (90 mg,0.65118 mmol) was added, stirred at room temperature for 30min, the reaction solution was directly concentrated on silica gel column chromatography, eluent DCM/MeOH (v/v=3/1), and 13mg of yellow solid was obtained as the product, the yield was 47.54％.LC-MS：m/z＝588.35[M+H]+;1H NMR(400MHz,CDCl3)δ8.30(d,J＝2.0Hz,1H),8.19(s,2H),7.69(dd,J＝8.7,2.3Hz,1H),7.17–7.10(m,2H),7.07–7.00(m,2H),6.49(d,J＝8.8Hz,1H),5.01(s,1H),4.00(dd,J＝12.7,7.7Hz,1H),3.89–3.83(m,1H),3.75–3.71(m,2H),3.62–3.59(m,1H),3.52–3.47(m,2H),3.42–3.32(m,4H),3.16(d,J＝6.7Hz,4H),3.04(d,J＝6.4Hz,1H),2.41–2.34(m,2H),2.28(s,3H),2.21(s,3H),2.17–2.11(m,2H).
Example 20:4- (6- (5- (4-methoxybenzoyl) hexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) pyridin-3-yl) -6- ((octahydrocyclopenta [ c ] pyrrol-5-yl) oxy) pyrazolo [1,5-a ] pyridine-3-carbonitrile
Step 1:5- (4-Methoxybenzoyl) hexahydropyrrolo [3,4-c ] pyrrole-2 (1H) -carboxylic acid tert-butyl ester
To a 25mL single vial was added tert-butyl hexahydropyrrolo [3,4-c ] pyrrole-2 (1H) -carboxylate (1.0 g,4.7 mmol), 4-methoxybenzoic acid (1.1 g,7.2 mmol), dissolved in DCM, and then 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.8 g,9.4 mmol), 4-dimethylaminopyridine (1.2 g,9.8 mmol) was added and reacted at room temperature for 20H. After stopping the reaction, 10mL of water was added to the reaction mixture, the aqueous phase was extracted with DCM (30 mL), the organic phases were combined, washed with water (10 mL. Times.2), dried over anhydrous sodium sulfate, concentrated, and chromatographed on silica gel with DCM/MeOH (v/v=50/1) as eluent to give 1.3g of a colorless liquid as the product in the yield 81.25％.LC-MS:m/z＝291.20[M-tBu+H]+;1H NMR(400MHz,DMSO-d6)δ7.51(d,J＝8.7Hz,2H),6.95(d,J＝8.7Hz,2H),3.79(s,3H),3.68(s,2H),3.56–3.33(m,4H),3.20(s,1H),3.05(s,1H),2.85(s,2H),1.39(s,9H).
Step 2: (hexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) (4-methoxyphenyl) methanone dihydrochloride
In a 25mL single flask was added tert-butyl 5- (4-methoxybenzoyl) hexahydropyrrolo [3,4-c ] pyrrole-2 (1H) -carboxylate (600 mg,1.732 mmol), dissolved by the addition of EA (5 mL), HCl/EA (4 mL,16mmol,4 mol/L) and reacted at room temperature for 1H after the addition. After TLC detection reaction is finished, the reaction solution is directly concentrated, and 470mg of solid is obtained after drying, namely the product, the yield is obtained 95.95％.LC-MS:m/z＝247.25[M+H]+;1H NMR(400MHz,DMSO)δ7.50(d,J＝8.7Hz,2H),6.96(d,J＝8.7Hz,2H),3.78(s,3H),3.66(s,2H),3.54(d,J＝3.1Hz,1H),3.52(d,J＝2.6Hz,1H),3.32(s,2H),2.99(s,4H).
Step 3:5- ((3-cyano-4- (6- (5- (4-methoxybenzoyl) hexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridin-6-yl) oxy) hexahydrocyclopenta [ c ] pyrrole-2 (1H) -carboxylic acid tert-butyl ester
To a 10mL single vial was added tert-butyl 5- ((3-cyano-4- (6-fluoropyridin-3-yl) pyrazolo [1,5-a ] pyridin-6-yl) oxy) hexahydrocyclopenta [ c ] pyrrole-2 (1H) -carboxylate (40 mg,0.086mmol, example 18 step 3), hexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) (4-methoxyphenyl) methanone dihydrochloride (55 mg,0.17 mmol), potassium carbonate (85 mg,0.62 mmol), DMSO (1.5 mL) and reacted at 90℃for 8H in an oil bath. After the reaction was stopped, the reaction mixture was cooled to room temperature, 5mL of water was added, EA (20 mL. Times.2) was used for extraction, the organic phase was washed with water (5 mL. Times.3), saturated brine (5 mL. Times.2), dried over anhydrous sodium sulfate, and then filtered, and the filtrate was concentrated under reduced pressure to give a silica gel column chromatography with DCM/MeOH (v/v=20/1) as eluent, giving 21mg as the product in the yield 35.28％.LC-MS：m/z＝690.35[M+H]+;1H NMR(400MHz,CDCl3)δ8.31(s,1H),8.19(s,1H),8.06(s,1H),7.70(d,J＝8.1Hz,1H),7.52(d,J＝8.5Hz,2H),7.03(s,1H),6.91(d,J＝8.4Hz,2H),6.50(d,J＝8.8Hz,1H),4.87(s,1H),3.99(s,1H),3.84(s,3H),3.73(s,2H),3.66(s,2H),3.61(s,1H),3.53(s,4H),3.24(s,2H),3.12(s,2H),2.91(s,2H),2.26(d,J＝8.7Hz,2H),1.90(d,J＝13.6Hz,2H),1.47(s,9H).
Step 4:4- (6- (5- (4-methoxybenzoyl) hexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) pyridin-3-yl) -6- ((octahydrocyclopenta [ c ] pyrrol-5-yl) oxy) pyrazolo [1,5-a ] pyridine-3-carbonitrile
To a 10mL single vial was added 5- ((3-cyano-4- (6- (5- (4-methoxybenzoyl) hexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridin-6-yl) oxy) hexahydrocyclopenta [ c ] pyrrole-2 (1H) -carboxylic acid tert-butyl ester (21 mg,0.03 mmol), EA (1.5 mL) was added to dissolve it, HCl/EA (0.2 mL) was added under ice bath and the reaction was carried out for 1H at room temperature. After the reaction is stopped, the reaction solution is directly concentrated, then 2mL of MeOH is added to dissolve the reaction solution, potassium carbonate (95 mg,0.69 mmol) is added, the reaction solution is stirred at room temperature for 20min, the reaction solution is filtered and then directly concentrated and subjected to silica gel column chromatography, the eluent is DCM/MeOH (v/v=5/1), yellow solid is obtained, and 4mg of white solid is obtained after TLC purification again, namely the product is obtained, the yield 22.28％.LC-MS：m/z＝590.30[M+H]+;1H NMR(400MHz,CDCl3)δ8.30(s,1H),8.19(s,2H),7.69(d,J＝6.9Hz,1H),7.52(d,J＝8.4Hz,2H),7.02(s,1H),6.91(d,J＝8.5Hz,2H),6.49(d,J＝8.6Hz,1H),5.02(s,1H),4.00(s,1H),3.84(s,4H),3.73(s,2H),3.61(d,J＝4.1Hz,2H),3.52(s,2H),3.36(s,2H),3.19(s,2H),3.07(s,2H),2.36(s,2H),2.17(s,2H),2.02(d,J＝7.1Hz,2H).
Example 21:4- (6- (6- (3-fluoro-2-methylbenzoyl) -2, 6-diazaspiro [3.3] heptan-2-yl) pyridin-3-yl) -6- ((octahydrocyclopenta [ c ] pyrrol-5-yl) oxy) pyrazolo [1,5-a ] pyridine-3-carbonitrile
Step 1:6- (3-fluoro-2-methylbenzoyl) -2, 6-diazaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester
To a 50mL single port flask was added tert-butyl 2, 6-diazaspiro [3.3] heptane-2-carboxylate (500 mg,2.52 mmol), 3-fluoro-2-methylbenzoic acid (580 mg,3.76 mmol), 10mL DCM was added followed by 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (980 mg,5.11 mmol), 4-dimethylaminopyridine (636 mg,5.21 mmol) and the reaction was allowed to proceed at room temperature for 15h. After stopping the reaction, adding 5mL of saturated ammonium chloride solution into the reaction solution, extracting with DCM (40 mL×2), washing the organic phase with water (10 mL×2), drying the organic phase with anhydrous sodium sulfate, and performing silica gel column chromatography to obtain 480mg of colorless liquid as the product, wherein the eluent is DCM-DCM/MeOH (v/v=50/1), and the yield is 56.92％.LC-MS：m/z＝335.20[M+H]+;1H NMR(400MHz,CDCl3)δ7.22–7.14(m,1H),7.09–6.98(m,2H),4.29(s,2H),4.11(d,J＝9.3Hz,2H),4.03(d,J＝4.7Hz,4H),2.28(d,J＝2.1Hz,3H),1.43(s,9H).
Step 2: (3-fluoro-2-methylphenyl) (2, 6-diazaspiro [3.3] heptane-2-yl) methanone
To a 25mL single flask was added tert-butyl 6- (3-fluoro-2-methylbenzoyl) -2, 6-diazaspiro [3.3] heptane-2-carboxylate (480 mg,1.43 mmol), DCM (5 mL) was added to dissolve it, trifluoroacetic acid (1.2 mL,16 mmol) was added at 0deg.C and after completion the reaction was carried out at room temperature for 2.5h. After the TLC detection reaction is finished, the reaction liquid is directly concentrated to obtain 330mg of liquid which is the product, and the yield is 98.12%. LC-MS: m/z=235.15 [ m+h ] +. Step 3:5- ((3-cyano-4- (6- (6- (3-fluoro-2-methylbenzoyl) -2, 6-diazaspiro [3.3] heptan-2-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridin-6-yl) oxy) hexahydrocyclopenta [ c ] pyrrole-2 (1H) -carboxylic acid tert-butyl ester
In a10 mL single vial was added 5- ((3-cyano-4- (6-fluoropyridin-3-yl) pyrazolo [1,5-a ] pyridin-6-yl) oxy) hexahydrocyclopenta [ c ] pyrrole-2 (1H) -carboxylic acid tert-butyl ester (40 mg,0.086mmol, example 18 step 3), (3-fluoro-2-methylphenyl) (2, 6-diazaspiro [3.3] heptan-2-yl) methanone (70 mg,0.30 mmol), potassium carbonate (85 mg,0.62 mmol), DMSO (1.5 mL), and reacted at 90℃for 7H in an oil bath. After the reaction was stopped, the reaction mixture was cooled to room temperature, 5mL of water was added, ea (20 ml×2) was extracted, the organic phase was washed with water (5 ml×3), saturated brine (5 ml×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give silica gel column chromatography with eluent DCM/MeOH (v/v=20/1), to give 26mg of a yellow solid as the product in yield 44.45％.LC-MS：m/z＝[M+H]+;1H NMR(400MHz,CDCl3)δ8.28(s,1H),8.18(s,1H),8.07(s,1H),7.68(d,J＝6.7Hz,1H),7.23–7.17(m,1H),7.08(t,J＝7.6Hz,2H),7.02(s,1H),6.42(d,J＝8.6Hz,1H),4.87(s,1H),4.40(s,2H),4.30(d,J＝8.7Hz,2H),4.22(d,J＝8.9Hz,2H),4.14(s,2H),3.54(s,2H),3.24(s,2H),2.90(s,2H),2.32(s,3H),2.26(d,J＝15.3Hz,2H),1.91–1.85(m,2H),1.47(s,9H). step 4:4- (6- (6- (3-fluoro-2-methylbenzoyl) -2, 6-diazaspiro [3.3] heptan-2-yl) pyridin-3-yl) -6- ((octahydrocyclopenta [ c ] pyrrol-5-yl) oxy) pyrazolo [1,5-a ] pyridine-3-carbonitrile
To a 10mL single vial was added 5- ((3-cyano-4- (6- (6- (3-fluoro-2-methylbenzoyl) -2, 6-diazaspiro [3.3] heptan-2-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridin-6-yl) oxy) hexahydrocyclopenta [ c ] pyrrole-2 (1H) -carboxylic acid tert-butyl ester (26 mg,0.038 mmol), EA (1.5 mL) was added to dissolve it, HCl/EA (0.2 mL) was added under ice and the reaction was carried out at room temperature for 1H. Concentrating the reaction solution after stopping the reaction, adding 2mLMeOH to dissolve, adding potassium carbonate (85 mg,0.62 mmol), stirring at room temperature for 20min, filtering the reaction solution, directly concentrating the reaction solution for silica gel column chromatography, eluting with DCM/MeOH (v/v=5/1) to obtain yellow solid (10 mg) as the product, and obtaining the yield 45.13％.LC-MS：m/z＝578.40[M+H]+;1H NMR(400MHz,CDCl3)δ8.26(s,1H),8.18(d,J＝9.6Hz,2H),7.67(d,J＝8.2Hz,1H),7.22–7.16(m,1H),7.07(t,J＝7.5Hz,2H),7.00(s,1H),6.40(d,J＝8.5Hz,1H),5.00(s,1H),4.39(s,2H),4.29(d,J＝8.5Hz,2H),4.20(d,J＝8.6Hz,2H),4.13(s,2H),3.72(s,1H),3.59(s,1H),3.31(s,2H),3.15(s,2H),2.37–2.29(m,5H),2.14(s,2H).
Example 22:4- (6- (6- (2, 3-dimethylbenzoyl) -2, 6-diazaspiro [3.3] heptan-2-yl) pyridin-3-yl) -6- ((octahydrocyclopenta [ c ] pyrrol-5-yl) oxy) pyrazolo [1,5-a ] pyridine-3-carbonitrile
Step 1:6- (2, 3-Didimethylbenzoyl) -2, 6-diazaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester
To a 50mL single vial was added tert-butyl 2, 6-diazaspiro [3.3] heptane-2-carboxylate (500 mg,2.52 mmol), 2, 3-dimethylbenzoic acid (570 mg,3.7957 mmol), 10mL DCM was added followed by 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (962mg, 5.02 mmol), 4-dimethylaminopyridine (620 mg,5.07 mmol) and the reaction was allowed to proceed at room temperature for 23h. After stopping the reaction, 5mL of saturated ammonium chloride solution was added to the reaction mixture, the mixture was extracted with DCM (30 mL. Times.2), the organic phase was washed with water (10 mL. Times.2), dried over anhydrous sodium sulfate, and then chromatographed on silica gel column with DCM as eluent to give 360mg of a colorless liquid as the product in 43.20% yield. LC-MS: m/z=331.30 [ m+h ] +.
Step 2: (2, 3-dimethylphenyl) (2, 6-diazaspiro [3.3] hept-2-yl) methanone
To a 25mL single vial was added tert-butyl 6- (2, 3-dimethylbenzoyl) -2, 6-diazaspiro [3.3] heptane-2-carboxylate (360 mg,1.090 mmol), DCM (4 mL) was added to dissolve it, trifluoroacetic acid (0.8 mL,10 mmol) was added at 0deg.C and after completion the reaction was allowed to proceed at room temperature for 2h. After the reaction is finished, the reaction solution is directly concentrated for the next step. LC-MS: m/z=231.10 [ m+h ] +.
Step 3:5- ((3-cyano-4- (6- (6- (2, 3-dimethylbenzoyl) -2, 6-diazaspiro [3.3] hept-2-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridin-6-yl) oxy) hexahydrocyclopenta [ c ] pyrrole-2 (1H) -carboxylic acid tert-butyl ester
To a 10mL single vial was added 5- ((3-cyano-4- (6-fluoropyridin-3-yl) pyrazolo [1,5-a ] pyridin-6-yl) oxy) hexahydrocyclopenta [ c ] pyrrole-2 (1H) -carboxylic acid tert-butyl ester (40 mg,0.086mmol, example 18 step 3), 2, 6-diazaspiro [3.3] hept-6- (2, 3-dimethylphenyl) methanone (83 mg,0.36 mmol), potassium carbonate (73 mg,0.53 mmol), DMSO (1.5 mL) and the reaction was carried out at 90℃for 15H in an oil bath. After stopping the reaction, cooling the reaction solution to room temperature, adding 5mL of water, extracting with EA (20 mL multiplied by 2), washing the organic phase with water (5 mL multiplied by 3), washing with saturated saline (5 mL multiplied by 2), drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and performing silica gel column chromatography with DCM/MeOH (v/v=10/1) as eluent to obtain 45mg of yellow solid as a product, wherein the yield 77.39％.LC-MS：m/z＝674.45[M+H]+;1H NMR(400MHz,CDCl3)δ8.28(d,J＝2.2Hz,1H),8.18(s,1H),8.06(d,J＝1.9Hz,1H),7.68(dd,J＝8.6,2.4Hz,1H),7.19(d,J＝6.6Hz,1H),7.12(d,J＝7.0Hz,2H),7.01(d,J＝2.0Hz,1H),6.41(d,J＝8.5Hz,1H),4.87(s,1H),4.40(s,2H),4.29(d,J＝8.7Hz,2H),4.20(d,J＝8.7Hz,2H),4.10(s,2H),3.54(s,2H),3.24(s,2H),2.90(s,2H),2.30(s,6H),2.24(dd,J＝11.7,5.0Hz,2H),1.89(d,J＝14.5Hz,2H),1.47(s,9H).
Step 4:4- (6- (6- (2, 3-dimethylbenzoyl) -2, 6-diazaspiro [3.3] heptan-2-yl) pyridin-3-yl) -6- ((octahydrocyclopenta [ c ] pyrrol-5-yl) oxy) pyrazolo [1,5-a ] pyridine-3-carbonitrile
To a 10mL single vial was added tert-butyl 5- ((3-cyano-4- (6- (6- (2, 3-dimethylbenzoyl) -2, 6-diazaspiro [3.3] hept-2-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridin-6-yl) oxy) hexahydrocyclopenta [ c ] pyrrole-2 (1H) -carboxylate (45 mg,0.067 mmol), EA (2 mL) was added to dissolve it, HCl/EA (0.2 mL,0.8mmol,4 mol/L) was added under ice-bath, and the reaction was allowed to warm to room temperature for 30min. The reaction solution was concentrated directly, and then 2mL of methanol was added to dissolve the concentrated solution, followed by addition of potassium carbonate (108 mg,0.78 mmol) and stirring at room temperature for 30min to liberate the base. The reaction solution was filtered and then directly concentrated on silica gel column chromatography, eluent DCM/MeOH (v/v=5/1) to give yellow solid, and TLC purification was performed again to give 4mg of pale yellow solid as product, yield 10.44％.LC-MS：m/z＝574.30[M+H]+;1H NMR(400MHz,CDCl3)δ8.27(s,1H),8.19(s,1H),8.18(s,1H),7.68(d,J＝8.5Hz,1H),7.19(d,J＝6.7Hz,1H),7.13–7.08(m,2H),7.01(s,1H),6.41(d,J＝8.6Hz,1H),5.01(s,1H),4.40(s,2H),4.29(d,J＝8.7Hz,2H),4.21(d,J＝8.7Hz,2H),4.10(s,2H),3.73(s,1H),3.61(s,1H),3.17(d,J＝6.0Hz,2H),2.36(s,2H),2.29(s,6H),2.15(d,J＝11.4Hz,2H),2.06–1.98(m,2H).
The target compounds (23) to (94) of examples 23 to 94, the target compound (96) of example 96, the target compounds (98) to (99) of examples 98 to 99, the target compounds (101) to (131) of examples 101 to 131, the target compounds (134) to (135) of examples 134 to 135, the target compounds (137) of example 137, the target compounds (150) to (160) of examples 150 to 160, the target compounds (163) to (164) of examples 163 to 164, the target compounds (176) to (180) of examples 176 to 180, and the target compounds (182) to (211) of examples 182 to 211 were prepared by using appropriate starting materials with the synthetic route of example 1 or synthetic scheme 1, and the specific structures and characterization data are as described in the following table 1:
TABLE 1
Using the appropriate starting materials, the target compound (95) of example 95, the target compound (97) of example 97, the target compound (100) of example 100, the target compound (102) of example 102, the target compounds (131) to (132) of examples 131 to 132, the target compound (136) of example 136, the target compounds (138) to (149) of examples 138 to 149, the target compounds (161) to (162) of examples 161 to 162, the target compounds (165) to (175) of examples 165 to 175, the target compound (181) of example 181, and the target compounds (212) to (220) of examples 212 to 220 were prepared by the synthetic route of example 18 or synthetic scheme 4, and the specific structures and characterization data are as described in Table 2 below:
TABLE 2
Biological Activity test examples:
Test example 1:
1. The purpose of the experiment is as follows:
The inhibitory activity of the series of compounds on 2 kinases Ret wt, ret V804M was tested by HTRF and IC 50 values were determined.
2. The experimental reagents and consumables used were as follows:
1)HTRF KinEASE-TK kit(Cisbio，62TK0PEC)
2)Ret wt(Invitrogen，PV3082)
3)Ret V804M(Signalchem，R02-12GG-10)
4)MgCl2(Sigma，M1028)
5)ATP(Promega，V910B)
6)DTT(Invitrogen，P2325)
7)DMSO(Sigma，D8418)
8)384-well plate,white,low volume,round-bottom(Greiner，784075)
9)384-Well Polypropylene microplate,Clear,Flatt Bottom,Bar Code(Labcyte，P-05525-BC)
10)96-well polypropylene plate(Nunc，249944)
11)Plate shaker(Thermo，4625-1CECN/THZ Q)
12)Centrifuge(Eppendorf，5810R)
13)Envision 2104multi-label Reader(PerkinElmer，2104-10-1)
14)Echo(Labcyte，550)
3. experimental procedure
3.1 Preparation of 1x kinase reaction buffer:
1 volume of 5X kinase reaction buffer and 4 volumes of water; 5mM MgCl2;1mM DTT;1mM MnCl2.
3.2 Transfer of 10nl of diluted compound per well with an Echo 550 reaction plate (784075, greiner);
3.3 the reaction plate was sealed with a sealing plate membrane and centrifuged at 1000g for 1 min.
3.4 Preparation of 2X kinase with 1X enzyme reaction buffer.
3.5 Mu.l kinase (formulated in step 3) was added to each well in the reaction plate. 1000g of the plate is sealed by a sealing plate membrane and centrifuged for 30 seconds, and the plate is placed at room temperature for 10 minutes.
3.6 Preparation of 4 XTK-substrate-biotin and 4 XATP with 1 Xenzyme reaction buffer, mixing well, and adding 5. Mu. l K-substrate-biotin/ATP mixture to the reaction plate.
3.7 Sealing the plates with sealing plate film 1000g and centrifuging for 30 seconds, reacting for 40 minutes at room temperature.
3.8 4 XSa-XL 665 (250 nM) was formulated in HTRF detection buffer.
3.9 Mu.l of Sa-XL 665 and 5. Mu.l of TK-anti-Cryptate were added per well and centrifuged at 1000g for 30 seconds and reacted at room temperature for 1 hour.
3.10 Fluorescence signals at 615nm (Cryptate) and 665nm (XL 665) were read with Envision 2104.
4. Data analysis
4.1 Calculating the Ratio per well (ratio_665/615 nm)
4.2 Inhibition was calculated as follows:
average of CEP-32496 reads for all positive control wells
Mean value of DMSO well readings for all negative control wells
Wherein, the chemical name of CEP-32496 is: n- [3- [ (6, 7-dimethoxy-4-quinazolinyl) oxy ] phenyl ] -N' - [5- (2, 2-trifluoro-1, 1-dimethylethyl) -3-isoxazolyl ] urea.
4.3 Calculation of IC 50 and plotting inhibition curves for compounds:
IC 50 (half inhibition concentration) of the compound was obtained using the following nonlinear fitting formula: data analysis was performed using Graphpad 6.0 software.
Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*Hill Slope))
Log of compound concentration Y, inhibition (% inhibition)
5. The experimental results are shown in table a:
table A kinase inhibitory Activity of the Compounds of the invention
As can be seen from Table A, the compounds of the present invention have a good inhibitory effect on Ret wt, and in addition, the compounds of the present invention have a good inhibitory effect on Ret V804M.
In addition to the activity of the compounds of the invention in Table A, other compounds of the invention also have good Ret kinase inhibitory activity.
Test example 2:
1. The purpose of the experiment is as follows:
The compounds were tested for 50% inhibition of cell proliferation (IC 50) in a range of tumor cells using CTG method.
2. The experimental reagents and test samples used were as follows:
1)CellTiter-Glo(CTG)(Promega)
2) RPMI medium (Gibco)
3) FBS (fetal bovine serum) (Gibco)
4)DMSO(Sigma)
5) Double antibody (Gibco)
6) 96 Well cell culture plate, white wall and impermeable bottom (Corning)
7) BAF3 (purchased from Shanghai Mingjin organism)
8) BAF3-KIF5B-RET-WT (Steady transfer cell line, constructed by the pharmacology division of the east Guangdong optical pharmaceutical Co., ltd.)
3. The experimental steps are as follows:
1) Cell seeding
Cells in exponential growth phase, BAF3 and BAF3-KIF5B-RET-WT, were collected and viable Cell counted using a Vi-Cell XR cytometer. The cell suspension was adjusted to the corresponding concentration with RPMI complete medium (89% rpmi+10% fbs+1% diabody). mu.L of the cell suspension was added to each well in a 96-well cell culture plate at final cell concentrations of 2000 cells/well and cell cells/well, respectively.
2) Dosing treatment
A, preparing working solution: each test compound was dissolved in DMSO to a final concentration of 10mM stock solution. Serial 3X dilutions were prepared using stock and RPMI complete medium (89% rpmi+10% fbs+1% diabody) for a total of 10 working solutions, each with a final DMSO concentration of 0.1%.
B cell dosing: after the cells are incubated overnight, 10ul of working solution with 10 gradient concentrations are sequentially added, and the cells are placed in a 37 ℃ and 5% CO2 incubator for incubation for 72 hours; negative controls were also set up without compound plus cells.
3) Read plate detection
After 72 hours of drug treatment, 50. Mu.l (1/2 of the culture volume) of CTG solution, which had been previously thawed and equilibrated to room temperature, was added to each well according to the CTG protocol, mixed with a microplate shaker for 2 minutes, and after 10 minutes at room temperature, the fluorescence signal value was measured using a multifunctional microplate reader.
4) Data analysis
Cell viability was expressed as: vsample/Vvehicle control x% calculation. Where Vsample is the reading for the drug-treated group and Vvehicle control is the average value for the solvent control group. The non-linear regression model was used to plot the S-type dose-survival curve and calculate IC 50 values using GRAPHPAD PRISM 5.0.0 software and the experimental results are shown in table B.
TABLE B in vitro cell Activity of the Compounds of the invention
As can be seen from Table B, the compounds of the examples of the present invention also have good inhibitory effects on BAF3 cells transfected with the KIF5B gene.
In the description of the present specification, the descriptions of the terms "one embodiment," "some embodiments," "some implementations," "examples," "particular examples," or "some examples," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, schematic representations of the above terms do not necessarily refer to the same embodiments or examples. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, the features of the different embodiments, implementations or examples and the different embodiments, implementations or examples described in this specification may be combined and combined by persons skilled in the art without contradiction.
Although embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are illustrative and not to be construed as limiting the invention, and that changes, modifications, substitutions and variations may be made therein by those of ordinary skill in the art without departing from the spirit and scope of the invention, which is defined by the appended claims and their equivalents.

Claims (13)

1. A compound which is a compound of formula (I) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof:
Wherein,
X 1、X2、X3、X4 and X 5 are each independently CR 4 or N;
Y is O;
t is a bond, C 1-6 alkylene, C 1-6 alkylene-O-or C 1-6 alkylene-NH-;
ring G is of the sub-structural formula:
Wherein,
T 1 is a 3-6 membered carbon monocyclic ring or a 3-6 membered heteromonocyclic ring;
z 4 is CH or N;
Z 1 is NH, O, S or CH 2;
Each Z 2 and Z 3 is independently O or NH;
each n1 is independently 0,1 or 2;
n2 is 0, 1 or 2;
q is 0,1, 2, 3 or 4;
R a is D、OH、NH2、F、Cl、Br、I、CN、NR5R6、-NR6C(＝O)R7、-S(＝O)2R7、-S(＝O)R7、-C(＝O)R7、-C(＝O)OR7、 oxo, C 1-6 alkyl, C 1-6 alkoxy, C 3-7 cycloalkyl, C 1-6 haloalkyl, C 1-6 alkoxy C 1-6 alkyl, C 1-6 hydroxyalkyl or C 1-6 hydroxyalkoxy;
E is a bond;
ring a is of the sub-structural formula:
Wherein Z 1a and Z 2a are each independently CH 2 or NH;
Each Z 3a and Z 7a is independently CH or N;
Each m and t is independently 0,1 or 2;
each n and t1 is independently 0 or 1;
Wherein each sub-formula of a is independently optionally substituted with 1, 2,3 or 4 substituents selected from F, cl, br, OH, oxo, NR 5R6、R5(C＝O)NR6 -, amino C 1-4 alkyl, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl or C 1-4 hydroxyalkyl;
Q is-CH 2-、-(CH2)2 -or- (c=o) -;
M is a 5-10 membered heteroaryl or C 6-10 aryl; and M is optionally substituted with 1,2, 3 or 4 substituents selected from D, F, cl, CN, OH, NR 5R6、OR7、C1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 haloalkoxy, C 6-10 aryl, C 1-6 alkoxy C 1-6 alkyl and C 3-7 cycloalkyl;
r 1 is H, D, CN, F, cl, br, methyl, ethyl or cyclopropyl;
R 4 is H, D, F, cl, br, methyl, ethyl, n-propyl, methoxy or ethoxy;
r 5 is H, D or C 1-6 alkyl;
R 6 is H, D or C 1-6 alkyl;
R 7 is OH or C 1-6 alkyl.
2. The compound according to claim 1, wherein,
T is a bond 、-CH2-、-(CH2)2-、-(CH2)3-、-(CH2)4-、-(CH2)5-、-(CH2)6-、-(CH2)2-O- or- (CH 2)2 -NH-.
3. The compound according to claim 1, wherein,
Ring G is of the sub-structural formula:
r a is D、OH、NH2、F、CF3、CHCl2、CHF2、CH2F、CF3CH2、Cl、Br、I、CN、NHCH3、-NHC(＝O)CH3、
-S (=o) 2CH3、-S(＝O)CH3、-C(＝O)CH3, -C (=o) OH, oxo, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, methoxy, ethoxy, cyclopropyl, cyclopentyl, methoxymethyl, ethoxymethyl, methoxyethyl, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 2-hydroxypropyl, 2-hydroxy-2-methylpropyl, 2-hydroxyethoxy or 1-hydroxyethoxy;
R 5 is H, D, methyl, ethyl, n-propyl, isopropyl or n-butyl;
r 6 is H, D, methyl, ethyl, n-propyl or n-butyl;
R 7 is OH, methyl, ethyl, isopropyl or tert-butyl.
4. The compound according to claim 1, wherein,
Ring a is of the sub-structural formula:
Wherein each substructure of ring a is independently optionally substituted with 1,2,3, or 4 substituents selected from F, cl, br, OH, oxo, NH 2、NHCH3, methyl, ethyl, n-propyl, methoxy, ethoxy, isopropoxy, CF 3, hydroxymethyl, or 2-hydroxyethyl.
5. The compound according to claim 1, wherein,
M is pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, pyrazinyl or phenyl; and M is optionally substituted with 1,2,3 or 4 substituents selected from D、F、Cl、CN、OH、CF3、CHCl2、CHF2、CH2F、CF3CH2、NH2、NHCH3、N(CH3)2、 trifluoromethoxy, 2-trifluoroethoxy, methoxy, ethoxy, isopropoxy, tert-butoxy, methyl, ethyl, n-propyl, isopropyl, phenyl, methoxymethyl, methoxyethyl, cyclopropyl and cyclohexyl.
6. The compound of claim 1 having the structure of formula (I-1), or a stereoisomer, tautomer, or pharmaceutically acceptable salt of the structure of formula (I-1),
Wherein,
Ring A1 is of the sub-structural formula:
Wherein each Z 1a and Z 2a is independently CH 2 or NH;
And each sub-structural formula of ring A1 is independently optionally substituted with 1, 2,3 or 4 substituents selected from F, cl, br, OH, oxo, NR 5R6、R5(C＝O)NR6 -, amino C 1-4 alkyl, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl or C 1-4 hydroxyalkyl.
7. The compound according to claim 6, wherein,
Ring A1 is of the sub-structural formula:
Wherein each substructure of ring A1 is independently optionally substituted with 1,2, 3 or 4 substituents selected from F, cl, br, OH, oxo, NH 2、NHCH3、CH3 (c=o) NH-, methyl, ethyl, n-propyl, methoxy, ethoxy, isopropoxy, CF 3, hydroxymethyl or 2-hydroxyethyl.
8. The compound of claim 1 having the structure of formula (I-2), or a stereoisomer, tautomer, or pharmaceutically acceptable salt of the structure of formula (I-2),
Wherein each Z 3a and Z 7a is independently CH or N;
Each m and t is independently 0,1 or 2;
each n and t1 is independently 0 or 1;
Wherein the method comprises the steps of Optionally substituted with 1, 2, 3 or 4 substituents selected from F, cl, br, OH, oxo, NR 5R6、R5(C＝O)NR6 -, amino C 1-4 alkyl, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl or C 1-4 hydroxyalkyl.
9. The compound according to claim 8, wherein,
The following sub-structural formula is shown as follows:
Wherein the method comprises the steps of Independently optionally substituted with 1,2,3 or 4 substituents selected from F, cl, br, OH, oxo, NH 2、NHCH3、CH3 (c=o) NH-, methyl, ethyl, n-propyl, methoxy, ethoxy, isopropoxy, CF 3, hydroxymethyl or 2-hydroxyethyl.
10. The compound of claim 1 having one of the following structures, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof,
11. A pharmaceutical composition comprising a compound as claimed in any one of claims 1 to 10, and a pharmaceutically acceptable adjuvant.
12. Use of a compound according to any one of claims 1 to 10 or a pharmaceutical composition according to claim 11 for the manufacture of a medicament for the prevention or treatment of RET related diseases.
13. Use according to claim 12, wherein the RET related disease comprises cancer, irritable bowel syndrome and/or pain associated with irritable bowel syndrome.
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