CN112442050A - RET inhibitor, pharmaceutical composition and application thereof - Google Patents

RET inhibitor, pharmaceutical composition and application thereof Download PDF

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CN112442050A
CN112442050A CN202010915991.1A CN202010915991A CN112442050A CN 112442050 A CN112442050 A CN 112442050A CN 202010915991 A CN202010915991 A CN 202010915991A CN 112442050 A CN112442050 A CN 112442050A
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谢洪明
罗明
张英俊
杨桂珍
王凯
何锦
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Sunshine Lake Pharma Co Ltd
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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 invention relates to a institute of formula (I)The invention also relates to pharmaceutical compositions comprising the compounds, and the use of the compounds and pharmaceutical compositions thereof in the manufacture of medicaments, particularly for the treatment and prevention of diseases and conditions associated with 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 medicine, and in particular, the present invention relates to novel compounds exhibiting inhibition of trans-phase Rearrangement (RET) kinases, pharmaceutical compositions comprising said compounds, the use of the compounds or pharmaceutical compositions thereof for the preparation of medicaments, especially 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 (RET) is one of the receptor type tyrosine kinases belonging to the cadherin superfamily, which activates multiple downstream pathways involved in cell proliferation and survival.
It has been reported that the results of the abnormalities in the RET gene (point mutation, chromosomal translocation, chromosomal inversion, gene amplification) are related to canceration. RET fusion proteins are associated with several cancers, including papillary thyroid carcinoma and non-small cell lung cancer. RET fusion proteins have been identified as a driver of certain cancers, driving the use of multi-kinase inhibitors with RET inhibitory activity to treat patients whose tumors express RET fusion proteins. It has been reported that multi-kinase inhibitors such as Sorafenib (Sorafenib), sunitinib, vandetanib, and ponatinib exhibit cell proliferation inhibitory effects on KIF 5B-RET-expressing cell lines (J Clin Oncol 30,2012, suppl; Abstract no: 7510). In addition, the multi-kinase inhibitor cabozantinib was reported to exhibit partial efficacy in two RET fusion gene positive non-small cell lung Cancer patients (Cancer Discov,3(6), Jun 2013, p.630-5). However, these drugs cannot always be administered at levels 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. Reactivation of kinases through mutation is a common mechanism of resistance. When resistance occurs, the treatment options for patients are often very limited, and cancer progression is not inhibited in most cases. WO 2017011776 discloses single-target RET kinase inhibitors with good prophylactic 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 address cancers associated with RET gene abnormalities.
Disclosure of Invention
The invention provides a novel compound showing inhibition of transfection phase Rearrangement (RET) kinase, which has good inhibition effect on RET wild type and RET gene mutants and has better inhibition selectivity on the RET wild type and the RET gene mutants.
The excellent characteristics of some parameters of the compound of the invention, such as half-life period, clearance rate, selectivity, bioavailability, chemical stability, metabolic stability, membrane permeability, solubility and the like, can promote the reduction of side effects, the expansion of therapeutic index or the improvement of tolerance and the like.
In one aspect, the invention provides a compound of formula (I), or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of a compound of formula (I),
Figure BDA0002665034780000011
wherein,
X1、X2、X3、X4and X5Each independently is CR4Or 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 groups selected from D, OH, F, Cl, Br, I, CN, NH2、CF3Alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, heterocyclyl, alkoxy, aryl, heteroaryl, or alkylamino;
ring G is a spiro carbocyclyl or spiro heterocyclyl;
q is 0, 1,2,3 or 4;
Rais D, OH, NH2、F、CF3、Cl、Br、I、CN、NR5R6、OR7、-NR6C(＝O)R7、-S(＝O)2R7、-S(＝O)R7、-C(＝O)R7、-C(＝O)OR7Oxo, alkyl, alkoxy, cycloalkyl, alkoxyalkyl or hydroxyalkyl;
e is a bond, -NR6-, or-O-;
ring A is a bridged, fused or spirocyclic ring group, and A is optionally substituted with 1,2,3 or 4 substituents selected from F, Cl, Br, OH, oxo, NR5R6、R5(C＝O)NR6-, aminoalkyl, alkyl, alkoxy, haloalkyl, hydroxyalkyl, carbocyclyl, heterocyclyl, heterocyclylalkyl, alkoxyalkyl, cycloalkylene, and monoheterocyclylene;
q is a bond, - (CR)2R3)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-NR6(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, CF3、OH、NR5R6、OR7Alkyl, haloalkyl, hydroxyalkyl, haloalkoxy, aryl, alkoxyalkyl, oxo, alkanoyl, heterocyclyl, cycloalkyl;
R1is H, D, CN, F, Cl, Br, alkyl or cycloalkyl, wherein said alkyl and cycloalkyl may independently optionally be substituted with 1,2,3 or 4 substituents selected from F, Cl, Br, CN, NH2OH and NO2Substituted with the substituent(s);
each R2、R3Independently OH, F, CF3、H、D、CN、Cl、Br、NH2Hydroxyalkyl, alkyl, alkylamino, alkoxy, haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl;
or, R2、R3And the same C atom to which it is attached form a carbocyclic or heterocyclic ring;
R4is H, D, F, Cl, Br, alkyl or alkoxy, wherein the alkyl and alkoxy are each independently optionally substituted by 1,2,3 or 4 groups selected from F, Cl, Br, CN, NH2OH and NO2Substituted with the substituent(s);
R5h, D, alkyl,Carbocyclyl, heterocyclyl, aryl or heteroaryl, wherein said alkyl, carbocyclyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with 1,2,3 or 4 substituents selected from F, Cl, Br, OH, NH2Alkylamino, alkyl, alkylsulfonyl, alkoxy, aryl and heteroaryl;
R6is H, D, alkyl or alkoxyalkyl, wherein the alkyl and alkoxyalkyl are each independently optionally substituted with 1,2,3, or 4 substituents selected from F, Cl, Br, CN, NH2OH and NO2Substituted with the substituent(s);
R7OH, alkyl, cycloalkyl, heterocyclic radical, aryl and heteroaryl.
In some embodiments, T is a bond, C1-6Alkylene radical, C1-6alkylene-O-or C1-6alkylene-NH-, and T is optionally substituted by 1,2,3 or 4 groups selected from D, OH, F, Cl, Br, I, CN, CF3、C1-6Alkyl radical, C1-6Hydroxyalkyl radical, C1-6Haloalkyl, C3-7Cycloalkyl, 3-7 membered heterocyclyl, C1-6Alkoxy radical, C6-10Aryl, 5-12 membered heteroaryl or C1-6Substituted by a substituent of 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 said T is optionally substituted by 1,2,3 or 4 groups selected from D, OH, F, Cl, Br, I, CN, CF3Methyl, 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, the substrate is,
g is 6-12 membered spiro carbocyclyl or 6-12 membered spiro heterocyclyl;
Rais D, OH, NH2、F、CF3、Cl、Br、I、CN、NR5R6、OR7、-NR6C(＝O)R7、-S(＝O)2R7、-S(＝O)R7、-C(＝O)R7、-C(＝O)OR7Oxo, C1-6Alkyl radical, C1-6Alkoxy radical, C3-7Cycloalkyl radical, C1-6Alkoxy radical C1-6Alkyl radical, C1-6A hydroxyalkyl group;
R5is H, D, C1-6Alkyl, 3-12 membered carbocyclyl, 3-12 membered heterocyclyl, C6-10Aryl or 5-10 membered heteroaryl, wherein said C1-6Alkyl, 3-12 membered carbocyclyl, 3-12 membered heterocyclyl, C6-10Aryl and 5-10 membered heteroaryl are each independently optionally substituted by 1,2,3 or 4 substituents selected from F, Cl, Br, OH, NH2、C1-6Alkylamino, alkyl, alkylsulfonyl, alkoxy, aryl and heteroaryl;
R6is H, D, C1-6Alkyl or C1-6Alkoxy radical C1-6Alkyl radical, wherein said C1-6Alkyl and C1-6Alkoxy radical C1-6Each alkyl is independently optionally substituted by 1,2,3 or 4 substituents selected from F, Cl, Br, CN, NH2OH and NO2Substituted with the substituent(s);
R7is OH, C1-6Alkyl radical, C3-6Cycloalkyl, 3-12 membered heterocyclyl, C6-10Aryl, 5-10 membered heteroaryl.
In some embodiments, G is the following substructure:
Figure BDA0002665034780000031
wherein each ring T1 is independently a 4-7 membered monocyclic or heteromonocyclic carbon;
Z1and Z2Independently is-CH2-、-O-、-S-、-NH-；
Z3is-O-, -S-, -NH-;
n1 is 0, 1 or 2;
n2 is 1,2 or 3;
n3 is 0 or 1.
In some embodiments, G is the following substructure:
Figure BDA0002665034780000041
Rais D, OH, NH2、F、CF3、Cl、Br、I、CN、NH2、NHCH3、-NHC(＝O)CH3、-S(＝O)2CH3、-S(＝O)CH3、-C(＝O)CH3-C (═ O) OH, oxo, methyl, ethyl, propyl, butyl, methoxy, ethoxy, cyclopropyl, cyclopentyl, methoxymethyl, ethoxymethyl, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 2-hydroxypropyl, 2-hydroxy-2-methylpropyl;
R5h, 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, NH2Methyl, -S (═ O)2CH3Methoxy, ethoxy and phenyl;
R6h, D, methyl, ethyl, n-propyl, n-butyl, methoxymethyl, ethoxymethyl or methoxyethyl, wherein the methyl, ethyl, n-propyl, n-butyl, methoxymethyl, ethoxymethyl and methoxyethyl radicals are each independently optionally substituted by 1,2,3 or 4 radicals selected from the group consisting of F, Cl, Br, CN, NH2OH and NO2Substituted with the substituent(s);
R7is OH, methyl, ethyl, NH2、N(CH3)2N-propyl, isopropyl, tert-butyl, cyclopropyl or phenyl.
In some embodiments, A is 5-12 membered bridged cyclyl, 5-12 membered fused cyclyl, or 5-12 membered spirocyclyl, and A is optionally substituted with 1,2,3, or4 groups selected from F, Cl, Br, OH, oxo, NR5R6、R5(C＝O)NR6-, amino C1-6Alkyl radical, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Haloalkyl, C1-6Hydroxyalkyl, 3-12 membered carbocyclyl, 3-12 membered heterocyclyl C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkyl radical, C3-6Cycloalkylene and 3-6 membered monoheteryl.
In some embodiments, a is the following substructure:
Figure BDA0002665034780000051
wherein Z is1aAnd Z2aEach independently is-CH2-or-NH-;
Z3ais-CH-or-N-;
Z4ais-O-, -S-or-NH-;
each Z5a、Z6aIndependently is-CH2-、-O-、-S-、-S(＝O)-、-S(＝O)2--C (═ O) -, or-NH-;
m and t are each independently 0, 1 or 2;
n and t1 are each independently 0 or 1;
wherein each sub-structural formula of A is independently and optionally substituted by 1,2,3 or 4 selected from F, Cl, Br, OH, oxo, NR5R6、R5(C＝O)NR6-, amino C1-4Alkyl radical, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl, C1-4Hydroxyalkyl, 3-12 membered carbocyclyl, 3-12 membered heterocyclyl C1-4Alkyl radical, C1-4Alkoxy radical C1-4Alkyl radical, C3-6Cycloalkylene and 3-6 membered heterocyclylene.
In some embodiments, a is the following substructure:
Figure BDA0002665034780000052
Figure BDA0002665034780000061
wherein each sub-structural formula of A is independently and optionally substituted by 1,2,3 or 4 selected from F, Cl, Br, OH, oxo, NH2、NHCH3、CH3(C ═ O) NH-, methyl, ethyl, n-propyl, methoxy, ethoxy, isopropoxy, CF3Hydroxymethyl, 2-hydroxyethyl, cyclopropyl, cyclohexyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, cyclopropylene, cyclohexylene and pyrrolidinylidene.
In some embodiments, M is H, D, 5-10 membered heteroaryl, C6-10Aryl radical, C3-7Cycloalkyl or 3-12 membered heterocyclyl; and M is optionally substituted by 1,2,3 or 4 groups selected from D, F, Cl, CN, OH, CF3、NR5R6、OR7、C1-6Alkyl radical, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Haloalkoxy, C6-10Aryl radical, C1-6Alkoxy radical C1-6Alkyl, oxo, C1-6Alkanoyl, 3-7 membered heterocyclic group, C3-7Cycloalkyl substituents.
In some embodiments, M is H, D, pyridinyl, pyrimidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, pyrazinyl, phenyl, cyclopentyl, cyclopropyl, cyclohexyl, cyclobutyl, pyrrolidinyl, piperidinyl, tetrahydrofuryl, tetrahydropyranyl, piperazinyl, morpholinyl, tetrahydrothiopyranyl, oxetanyl, 1, 2-dihydropyridinyl, 7-azabicyclo [2.2.1]Heptalkyl, hexahydrofuro [3,4-c ]]Azolyl, 3-azabicyclo [3.1.0 ]]Hexane radical, octahydropyrrolo [1,2-a ] radical]Pyrazinyl or 5-azaspiro [2.4 ]]A heptalkyl group; and M is optionally substituted by 1,2,3 or 4 groups selected from D, F, Cl, CN, OH, CF3、NH2、NHCH3、N(CH3)2Trifluoromethoxy group, 2,2, 2-trifluoroethoxy group, methoxy group, ethoxy group, isopropoxy group, tert-butoxy group, methyl groupEthyl, n-propyl, isopropyl, phenyl, methoxymethyl, methoxyethyl, oxo, formyl, acetyl, morpholinyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, cyclopropyl and cyclohexyl;
in some embodiments, R1Is H, D, CN, F, Cl, Br, methyl, ethyl or cyclopropyl, wherein said methyl, ethyl and cyclopropyl are independently optionally substituted by 1,2,3 or 4 substituents selected from F, Cl, Br, CN, NH2OH and NO2Substituted with the substituent(s);
R4is H, D, F, Cl, Br, methyl, ethyl, n-propyl, methoxy or ethoxy, wherein the methyl, ethyl, n-propyl, methoxy and ethoxy groups can be independently and optionally substituted by 1,2,3 or 4 groups selected from F, Cl, Br, CN, NH2OH and NO2Substituted with the substituent(s).
In some embodiments, each R is2、R3Independently OH, F, CF3、H、D、CN、Cl、Br、NH2、C1-6Hydroxyalkyl radical, C1-6Alkyl radical, C1-6Alkylamino radical, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-7Cycloalkyl radical, C3-7Cycloalkyl radical C1-6Alkyl radical, C6-10Aryl or 5-10 membered heteroaryl;
or, R2、R3And the same C atom to which it is attached form a 3-7 membered carbocyclic or 3-7 membered heterocyclic ring.
In some embodiments, each R is2、R3Independently OH, F, CF3、H、D、CN、Cl、Br、NH2Hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, methyl, ethyl, N (CH)3)2Methoxy, ethoxy, isopropoxy, tert-butoxy, trifluoromethoxy, cyclopropyl, cyclopentyl, cyclopropylmethyl, cyclopentylethyl, cyclopentylmethyl, phenyl, pyridyl, pyrazinyl;
or, R2、R3And the same C atom to which it is attached to cyclopentane, cyclopropane, cyclobutane, tetrahydropyran, cyclopentane, cyclohexane, or mixtures thereof,Tetrahydrofuran, piperidine or pyrrolidine.
In some embodiments, Q is a bond, -O-, - (CH)2)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)CH2-、-(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-、
Figure BDA0002665034780000081
Figure BDA0002665034780000082
In some embodiments, the compounds of the present invention have the structure of formula (I-1), or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt, or prodrug of the structure of formula (I-1),
Figure BDA0002665034780000083
wherein,
ring a1 is of the subformula:
Figure BDA0002665034780000084
wherein Z1aAnd Z2aEach independently is CH2Or NH;
and each sub-formula of A1 is independently optionally substituted by 1,2,3 or 4 substituents selected from F, Cl, Br, OH, oxo, NR5R6、R5(C＝O)NR6-, amino C1-4Alkyl radical, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl, C1-4Hydroxyalkyl, 3-12 membered carbocyclyl, 3-12 membered heterocyclyl C1-4Alkyl radical, C1-4Alkoxy radical C1-4Alkyl radical, C3-6Cycloalkylene and 3-6 membered heterocyclylene.
In some embodiments, a1 is a subformula:
Figure BDA0002665034780000085
wherein each sub-formula of A1 is independently and optionally substituted by 1,2,3 or 4 substituents selected from F, Cl, Br, OH, oxo, NH2、NHCH3、CH3(C ═ O) NH-, methyl, ethyl, n-propyl, methoxy, ethoxy, isopropoxy, CF3Hydroxymethyl, 2-hydroxyethyl, cyclopropyl, cyclohexyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, cyclopropylene, cyclohexylene and pyrrolidinylidene.
In some embodiments, the compounds of the present invention have the structure of formula (I-2) or (I-3), or a stereoisomer, geometric isomer, tautomer, nitroxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the structure of formula (I-2) or (I-3),
Figure BDA0002665034780000091
wherein Z is1、Z2And Z3aEach independently is CH or N;
m and t are each independently 0, 1 or 2;
n and t1 are each independently 0 or 1;
wherein
Figure BDA0002665034780000092
Independently optionally substituted by 1,2,3 or 4 substituents selected from F, Cl, Br, OH, oxo, NR5R6、R5(C＝O)NR6-, amino C1-4Alkyl radical, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl, C1-4Hydroxyalkyl, 3-12 membered carbocyclyl, 3-12 membered heterocyclyl C1-4Alkyl radical, C1-4Alkoxy radical C1-4Alkyl radical, C3-6Cycloalkylene and 3-6 membered heterocyclylene.
In some embodiments of the present invention, the substrate is,
Figure BDA0002665034780000093
is of the sub-structure:
Figure BDA0002665034780000094
Figure BDA0002665034780000101
Figure BDA0002665034780000102
is of the sub-structure:
Figure BDA0002665034780000103
wherein
Figure BDA0002665034780000104
Each of the sub-formulae of (1) is independently optionally substituted by 1,2,3 or 4 substituents selected from F, Cl, Br, OH, oxo, NH2、NHCH3、CH3(C ═ O) NH-, methyl, ethyl, n-propyl, methoxy, ethoxy, isopropoxy, CF3Hydroxymethyl, 2-hydroxyethyl, cyclopropyl, cyclohexyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, cyclopropylene, cyclohexylene and pyrrolidinylidene.
In another aspect, the invention provides a pharmaceutical composition comprising a compound of the invention, and a pharmaceutically acceptable adjuvant.
In another aspect, the present invention also provides a use of the compound of the present invention or the pharmaceutical composition of the present invention for the preparation of a medicament for preventing or treating a RET-related disease.
In some embodiments, the RET-associated disease includes cancer, irritable bowel syndrome, and/or pain associated with irritable bowel syndrome.
In another aspect, the present invention also provides a compound according to the present invention or a pharmaceutical composition according to the present invention for use in preventing or treating RET-related diseases.
In some embodiments, the RET-associated disease includes cancer, irritable bowel syndrome, and/or pain associated with irritable bowel syndrome.
In another aspect, the present invention also provides a method for preventing or treating a RET-associated disease, the method comprising administering to a patient a therapeutically effective amount of a compound of the present invention or a pharmaceutical composition thereof.
In some embodiments, the RET-associated disease includes cancer, irritable bowel syndrome, and/or pain associated with irritable bowel syndrome.
In another aspect, the invention relates to intermediates for the preparation of compounds of formula (I), (I-1), (I-2) or (I-3).
In another aspect, the 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 present invention provides a pharmaceutical composition comprising a compound of the present invention and pharmaceutically acceptable adjuvants thereof. In some embodiments, adjuvants of the present invention 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 dosage 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 present invention.
In particular, the salts are pharmaceutically acceptable salts. The term "pharmaceutically acceptable" includes substances or compositions which must be compatible with chemical or toxicological considerations, in connection with the other components which make up the formulation and the mammal being treated.
The salts of the compounds of the present invention also include salts of intermediates used in the preparation or purification of the compounds represented by formula (I), (I-1), (I-2) or (I-3) or isolated enantiomers of the compounds represented by 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 invention, examples of which are illustrated by the accompanying structural and chemical formulas. The invention is intended to cover alternatives, modifications and equivalents, which may be included within the scope of the invention 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 invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the incorporated documents, patents, and similar materials differ or contradict this application (including but not limited to defined terminology, application of terminology, described techniques, and the like), this application controls.
It will be further 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 subcombination.
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. Subjects, e.g., also primates (e.g., humans, males or females), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In certain embodiments, the subject is a primate. In other embodiments, the subject is a human.
The term "patient" as used herein refers to humans (including adults and children) or other animals. In some embodiments, "patient" refers to a human.
The term "comprising" is open-ended, i.e. includes the elements indicated in the present invention, but does not exclude other elements.
"stereoisomers" refers to compounds having the same chemical structure but differing in the arrangement of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis/trans), atropisomers, and the like.
The stereochemical definitions and rules used in the present invention generally follow the general definitions of 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.
Any resulting mixture of stereoisomers may be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, depending on differences in the physicochemical properties of the components, for example, by chromatography and/or fractional crystallization.
The term "tautomer" or "tautomeric form" refers to structural isomers having different energies that can interconvert by a low energy barrier (low energy barrier). If tautomerism is possible (e.g., in solution), then the chemical equilibrium of the tautomer can be reached. For example, proton tautomers (also known as proton transfer tautomers) include interconversions by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers (valenctautomers) include interconversion by recombination of some of the bonding electrons. A specific example of keto-enol tautomerism is the tautomerism of the pentan-2, 4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerism is phenol-ketone tautomerism. One specific example of phenol-ketone tautomerism is the tautomerism 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 depicted herein include all isomeric forms (e.g., enantiomeric, diastereomeric, and geometric (or conformational) isomers): such as the R, S configuration containing an asymmetric center, the (Z), (E) isomers of the double bond, and the conformational isomers of (Z), (E). Thus, individual stereochemical isomers of the compounds of the present invention or mixtures of enantiomers, diastereomers, or geometric isomers (or conformers) thereof are within the scope of the present invention.
Unless otherwise indicated, the structural formulae depicted herein and the compounds depicted herein include all isomeric forms (e.g., enantiomeric, diastereomeric, geometric or conformational isomers), nitroxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts and prodrugs. Thus, compounds that are individual stereochemically isomeric forms, enantiomeric forms, diastereomeric forms, geometric forms, conformational forms, nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts and prodrugs of the compounds of the present invention are also within the scope of the present invention. In addition, unless otherwise indicated, the structural formulae of the compounds described herein include isotopically enriched concentrations of one or more different atoms.
The compounds of the invention may be independently optionally substituted with one or more substituents, as described herein, in the general formula above, or as specified in the examples, subclasses, and classes of compounds encompassed by the invention. It will be appreciated that the term "independently optionally substituted with … …" is used interchangeably with the term "substituted or unsubstituted". In general, the term "substituted" means that one or more hydrogen atoms in a given structure is replaced with a particular substituent. Unless otherwise indicated, an optional substituent group may be substituted at each substitutable position of the group. When more than one position in a given formula can be substituted with one or more substituents selected from a particular group, the substituents may be substituted at each position, identically or differently.
In addition, unless otherwise explicitly indicated, the descriptions of the terms "… independently" and "… independently" and "… independently" used in the present invention are interchangeable and should be understood in a broad sense to mean that the specific items expressed between the same symbols do not affect each other in different groups or that the specific items expressed between the same symbols in the same groups do not affect each other.
In the various parts of this specification, substituents of the disclosed compounds are disclosed in terms of group type or range. It is specifically intended that the invention includes each and every independent subcombination of the various members of these groups and ranges. For example, the term "C1-6Alkyl "means in particular independently disclosed methyl, ethyl, C3Alkyl radical, C4Alkyl radical, C5Alkyl and C6An alkyl group.
In each of the parts of the invention, linking substituents are described. Where the structure clearly requires a linking group, the markush variables listed for that group are understood to be linking groups. For example, if the structure requires a linking group and the markush group definition for the variable recites "alkyl" or "aryl," it is understood that the "alkyl" or "aryl" represents an attached alkylene group or arylene group, respectively.
The term "alkyl" denotes a saturated, straight or branched chain, monovalent hydrocarbon radical containing 1 to 20 carbon atoms, wherein the alkyl radical may be optionally substituted with one or more substituents as described herein. Unless otherwise specified, alkyl groups contain 1-20 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 group (Et, -CH)2CH3) N-propyl (n-Pr, -CH)2CH2CH3) Isopropyl group (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 (C)-CH(CH3)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 the linking group, and "alkyl" is enumerated for this markush group definition, then "alkyl" represents the linked alkylene group.
The term "alkylene" refers to a saturated divalent hydrocarbon radical resulting from the removal of two hydrogen atoms from a saturated straight or branched chain hydrocarbon radical. Examples of alkylene groups include, but are not limited to: -CH2-、-CH2CH2-、-CH(CH3)CH2-, and the like.
The term "alkylene-O-" means an alkylene group attached to the rest of the molecule through an oxygen atom, wherein alkylene has the definition as set forth herein.
The term "alkylene-NH-" means that the alkylene group is attached to the rest of the molecule through NH, wherein alkylene has the definition as described herein.
The term "oxo", i.e., ═ O, denotes the case where two hydrogens on a carbon atom are replaced with ═ O, i.e., -CH2-Substituted by ═ O, to — C (═ O) -.
The term "hydroxyalkyl" denotes an alkyl group substituted with one or more hydroxyl groups. In some embodiments, hydroxyalkyl represents alkyl substituted with 1,2,3, or 4 hydroxy groups. In some embodiments, hydroxyalkyl represents a residue taken from 1 or 2 hydroxy groupsAnd (c) a substituted alkyl group. In some embodiments, hydroxyalkyl represents C1-6Hydroxyalkyl, i.e. C1-6Alkyl in which the alkyl group is substituted by 1 or more hydroxyl groups, preferably, C1-6Hydroxyalkyl represents C1-6Alkyl substituted with 1 hydroxyl. In some embodiments, hydroxyalkyl represents C1-4A hydroxyalkyl group. In some embodiments, hydroxyalkyl represents C1-3A hydroxyalkyl group. Examples of hydroxyalkyl include, but are not limited to, OHCH2-、CH2OHCH2CH2CH2-、CH2OHCH2-、CH2OHCH2CHOHCH2-、CH(CH3)OHCH2CHOHCH2-、(CH3) OHCH-, etc.
The term "alkoxy" means an alkyl group attached to the rest of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkoxy group contains 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-pentyloxy (n-pentyloxy, -OCH)2CH2CH2CH2CH3) 2-pentyloxy (-OCH (CH)3)CH2CH2CH3) 3-pentyloxy (-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 so on.
The term "alkoxyalkyl" denotes an alkyl group substituted with one alkoxy group, wherein alkoxy and alkyl have the definitions as described herein. In some embodiments, alkoxyalkyl represents C1-6Alkoxy radical C1-6An alkyl group; in other embodiments, alkoxyalkyl represents C1-4Alkoxy radical C1-4An alkyl group; in other embodiments, alkoxyalkyl represents C1-4Alkoxy radical C1-3An alkyl group; in some embodiments, alkoxyalkyl represents C1-3Alkoxy radical C1-3An alkyl group. Examples of alkoxy groups include, but are not limited to, methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, methoxypropyl, ethoxyethyl, ethoxypropyl, propoxyethyl, propoxypropyl, and the like.
The term "halogen" denotes F (fluorine), Cl (chlorine), Br (bromine) or I (iodine).
The term "haloalkyl" denotes an alkyl group substituted with one or more halogen atoms. In some embodiments, haloalkyl represents C1-6Haloalkyl radicals, i.e. C1-6Alkyl in which the alkyl group is substituted with 1 or more halogens. In some embodiments, haloalkyl represents C1-4A haloalkyl group. In some embodiments, haloalkyl represents C1-3A haloalkyl group. 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" denotesA monovalent saturated monocyclic carbocyclic ring system. In cycloalkyl radicals-CH2-the group may optionally be replaced by-C (═ O) -. In some embodiments, cycloalkyl groups contain 3 to 7 ring carbon atoms, i.e., C3-7A cycloalkyl group. In one embodiment, the cycloalkyl group contains 3 to 6 carbon atoms, i.e., C3-6A cycloalkyl group; in another embodiment, the cycloalkyl group contains 3 to 5 carbon atoms, i.e., C3-5A cycloalkyl group. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. In the carbocyclic ring-CH2Examples of — groups that 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" denotes a divalent saturated monocyclic carbocyclic ring system. In cycloalkylene, -CH2-the group may optionally be replaced by-C (═ O) -. In some embodiments, cycloalkylene groups contain 3-7 ring carbon atoms, i.e., C3-7Cycloalkylene radicals. In one embodiment, the cycloalkylene group contains 3 to 6 carbon atoms, i.e., C3-6A cycloalkylene group; in another embodiment, the cycloalkyl group contains 3 to 5 carbon atoms, i.e., C3-5Cycloalkylene, 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 group may be independently optionally substituted with one or more substituents described herein.
The term "monocyclic" denotes a saturated or unsaturated monocyclic carbocyclic or monocyclic heterocyclic ring system, wherein the carbocyclic and heterocyclic rings have the definitions as described herein. Wherein the monocyclic carbocyclic ring system is a monocyclic carbon ring and the monocyclic heterocyclic ring system is a monocyclic heteroring.
The term "monocyclic group" denotes a monovalent saturated or unsaturated monocyclic carbocyclic or monocyclic heterocyclic ring system, wherein the carbocyclic and heterocyclic rings have the definitions as described herein. In monocyclic radicals-CH2-the group may optionally be replaced by-C (═ O) -. In some embodiments, monocyclic groups contain 3-7 ring atoms, i.e., monocyclic groups are 3-7 membered monocyclic groups; in other embodiments, monocyclic groups contain 3 to 6 ring atoms,i.e. 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, monocyclic groups described herein are monovalent saturated monocyclic carbocyclic or monocyclic heterocyclic ring systems. The monocyclic groups may be independently optionally substituted with one or more substituents described herein.
The term "heteromonocyclic group" denotes a divalent saturated or unsaturated monocyclic carbocyclic or monocyclic heterocyclic ring system, wherein the carbocyclic and heterocyclic rings have the definitions as described herein. In the submonocyclic radical-CH2-the group may optionally be replaced by-C (═ O) -. In some embodiments, the heteromonocyclic group contains 3 to 7 ring atoms, i.e., the heteromonocyclic group is a 3-7 membered heteromonocyclic group; in other embodiments, the heteromonocyclic group contains 3 to 6 ring atoms, i.e., the heteromonocyclic group is a 3-to 6-membered heteromonocyclic group. Preferably, the inventive heteromonocyclic group is a divalent saturated monocyclic carbocyclic or monocyclic heterocyclic ring system. Examples of the heteromonocyclic group include, but are not limited to: cyclopropylene, cyclopentylene, cyclohexylene, 1, 2-cyclopentylene, pyrrolidinylene, and the like. The monocyclic ring may be independently optionally substituted with one or more substituents described herein.
The term "monoheterocyclylene" denotes a divalent saturated or unsaturated monocyclic heterocyclic ring system, wherein the heterocyclic ring has the meaning as defined in the present invention. In the heteromonocyclic radical-CH2-the group may optionally be replaced by-C (═ O) -. In some embodiments, the heteromonocyclic group contains 3 to 7 ring atoms, i.e., the heteromonocyclic group is a 3-7 membered heteromonocyclic group; in still other embodiments, the heteromonocyclic group contains 3-6 ring atoms, i.e., the heteromonocyclic group is a 3-6 membered heteromonocyclic group. Preferably, the heteromonocyclic group of the present invention is a divalent saturated monocyclic heterocyclic ring system.
The term "heterocyclylalkyl" denotes an alkyl group substituted with a heterocyclyl, wherein heterocyclyl and alkyl have the definitions as described herein. In some embodiments, heterocyclylalkyl is 3-12 membered heterocyclyl C1-6An alkyl group; in other embodiments, heterocyclylalkyl is a 3-6 membered heterocycleRadical C1-6An alkyl group; in some embodiments, heterocyclylalkyl is 3-6 membered heterocyclyl C1-4An alkyl group. 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 definitions as described herein. In some embodiments, haloalkoxy represents C1-6Haloalkoxy, i.e. C1-6Alkyl in which alkoxy is substituted with 1 or more halogens. In some embodiments, haloalkoxy represents C1-4A haloalkoxy group. In some embodiments, haloalkoxy represents C1-3A haloalkoxy group. 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 meaning described herein, and carbonyl represents-C (═ O) -. In some embodiments, alkanoyl represents C1-6An alkyl acyl group; in some other embodiments, alkanoyl represents C1-4An alkyl acyl group. Examples of alkanoyl groups include, but are not limited to: formyl, acetyl, and the like.
The term "cycloalkylalkyl" denotes an alkyl group substituted with one cycloalkyl group. Wherein cycloalkyl and alkyl have the definitions as described herein. In some embodiments, cycloalkylalkyl represents C3-7Cycloalkyl radical C1-6An alkyl group; in some other embodiments, cycloalkylalkyl represents C3-6Cycloalkyl radical C1-6An alkyl group; in some other embodiments, cycloalkylalkyl represents C3-6Cycloalkyl radical C1-4An alkyl group. Examples of cycloalkylalkyl groups include, but are not limited to: cyclopropylmethyl, cyclopentylethyl, cyclohexylmethyl, and the like.
The term "aromatic ring" or "arene" means monocyclic, bicyclic and tricyclic carbon ring systems containing 6 to 14 ring atoms, or 6 to 12 ring atoms, or 6 to 10 ring atoms, wherein at least one ring system is aromatic, wherein each ring system comprises a ring of 3 to 7 atoms. Examples of the aromatic ring may include benzene, naphthalene, and anthracene.
The term "aryl" refers to a monovalent aromatic ring radical formed by the removal of one hydrogen atom from a ring carbon atom of an aromatic ring. Examples of the aryl group may include phenyl, naphthyl and anthracenyl. When aryl is the linking group, and "aryl" is enumerated for this markush group definition, then "aryl" represents the linked arylene group. When M is aryl as defined herein, it means that M is an attached 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 arylene groups represented as attached arylene groups may include phenylene, naphthylene, and anthracenylene. The aryl group may independently be optionally substituted with one or more substituents described herein.
The term "heteroaromatic ring" denotes monocyclic, bicyclic and tricyclic ring systems containing 5 to 12 ring atoms, or 5 to 10 ring atoms, or 5 to 6 ring atoms, wherein at least one ring system is aromatic and at least one ring system contains one or more heteroatoms, wherein each ring system contains a ring of 5 to 7 atoms.
The term "heteroaryl" refers to a monovalent aromatic ring radical formed by the removal of one 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, a 5-10 atom composed heteroaryl or 5-10 membered heteroaryl group comprises 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 5-membered heteroaryl group containing 5 ring atoms, wherein 1,2,3 or 4 heteroatoms independently selected from O, S and N are contained. 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), and the like, 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, 1,2, 3-thiadiazolyl, 1,3, 4-thiadiazolyl, 1,2, 5-thiadiazolyl, pyrazinyl, 1,3, 5-triazinyl; the following bicyclic rings are also included, but are in no way limited to these: benzimidazolyl, benzofuranyl, benzothienyl, indolyl (e.g., 2-indolyl), purinyl, quinolyl (e.g., 2-quinolyl, 3-quinolyl, 4-quinolyl), isoquinolyl (e.g., 1-isoquinolyl, 3-isoquinolyl, or 4-isoquinolyl), imidazo [1,2-a ] pyridyl, 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 ] pyridyl, and the like. When heteroaryl is a linking group, and heteroaryl is enumerated for this markush group definition, heteroaryl represents a linked heteroarylene group. When M is heteroaryl as defined herein, it means M is a linked heteroarylene group. The term "heteroarylene" refers to a divalent heteroaromatic ring group formed by removing two hydrogen atoms from a ring atom of a heteroaryl group. The heteroaryl group can be independently optionally substituted with one or more substituents described herein.
The term "bridged ring radical" refers to divalent, non-aromatic, saturated or partially unsaturated bicyclic or polycyclic ring systems that share two or more nonadjacent ring atoms, including bridged carbocyclyl and bridged heterocyclyl. In some embodiments, the bridged ring group is a 5-12 membered bridged ring group. The bridgering group may independently be optionally substituted with one or more substituents described herein.
The term "fused cyclic group" denotes divalent, non-aromatic, saturated or partially unsaturated bicyclic or polycyclic ring systems that share two adjacent ring atoms, including fused carbocyclic and fused heterocyclic groups. In some embodiments, the fused cyclic group is a 5-12 membered fused cyclic group. The fused cyclic group may be independently optionally substituted with one or more substituents described herein.
The term "spiroylene" refers to a non-aromatic, saturated or partially unsaturated, bicyclic or polycyclic ring system formed from two rings sharing a single carbon atom, including spiroylene carbocyclylene and spiroylene heterocyclyl. In some embodiments, the spirocyclic idene is a 5-12 membered spirocyclic idene. The spirocyclic idene group may be independently optionally substituted with one or more substituents described herein.
The terms "carbocyclyl" and "carbocycle" are used interchangeably to refer to a saturated or partially unsaturated monocyclic, bicyclic, or polycyclic system in which the ring atoms are all carbon atoms, including mono-, bridged-, and fused-and spiro-carbocyclyl.
The terms "bridged carbocycle" and "bridged carbocyclyl" are used interchangeably and both represent a non-aromatic, saturated or partially unsaturated bicyclic or polycyclic ring system that shares two or more nonadjacent ring carbon atoms, with the ring atoms being carbon atoms. C-CH in bridged carbocycle2-the group may optionally be replaced by-C (═ O) -. In some embodiments, bridged carbocycles contain 6 to 12 ring carbon atoms, i.e., represent 6 to 12 membered bridged carbocycles; in other embodiments, bridged carbocycles contain 6 to 10 ring carbon atoms, i.e., represent 6 to 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 a bridged carbocycle or carbocyclyl group is the linking group, and bridged carbocycle or bridged carbocyclyl is enumerated for this markush group definition, then bridged carbocycle or bridged carbocyclyl represents the linked bridged carbocyclylene group. The term "bridged carbocyclyl" refers to a divalent bridged carbocyclic group formed by the removal of two hydrogen atoms from a ring atom bridging a carbocyclic ring. The bridged carbocycle or carbocyclyl may independently be optionally substituted with one or more substituents described herein.
The terms "spirocarbocycle" and "spirocarbocyclyl" are used interchangeably to refer to a non-aromatic, saturated or partially unsaturated bicyclic or polycyclic system formed by two carbocycles sharing a single carbon atom. Spiro carbocyclic ring-CH2-the group may optionally be replaced by-C (═ O) -. In some embodiments, a spiro carbonThe ring contains 7 to 12 ring carbon atoms, i.e., represents a 7 to 12 membered spiro carbocyclic ring; in other embodiments, spiro carbocyclic rings contain 7 to 10 ring carbon atoms, i.e., represent 7 to 10 membered spiro carbocyclic rings. Examples of spiro carbocycles include, but are not limited to: spiro [4.4 ]]Nonane, spiro [3.4]]Octane, spiro [4.5]]Decane, etc. When a spiro carbocyclic or spiro carbocyclic group is the linking group and spiro carbocyclic or spiro carbocyclic groups are listed for the markush group definition, the spiro carbocyclic or spiro carbocyclic group represents the linked spirocyclic carbocyclylene group. The term "spirorylene carbocyclyl" refers to a divalent spirocarbocyclic group formed by removing two hydrogen atoms from a ring atom of a spirocarbocyclic ring. The spiro carbocycle or spiro carbocyclyl may independently be optionally substituted with one or more substituents described herein.
The terms "heterocycle" or "heterocyclyl" are used interchangeably and all refer to a monovalent non-aromatic saturated or partially unsaturated monocyclic, bicyclic, or polycyclic ring system of 3 to 12 ring atoms containing at least 1 carbon atom and containing 1,2, or 3 heteroatoms selected from O, N, S. Unless otherwise specified, heterocyclyl may be carbon-or nitrogen-based, and-CH2-the group may optionally be replaced by-C (═ O) -. The sulfur atom of the ring may optionally be oxidized to the S-oxide and the nitrogen atom of the ring may optionally be oxidized to the N-oxygen compound. In some embodiments, heterocyclyl contains 4-7 ring atoms, i.e., represents a 4-7 membered heterocyclyl; examples of heterocyclyl groups include, but are not limited to: oxirane, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuryl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1, 3-dioxolanyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thiaxanyl, homopiperazinyl, homopiperidinyl, 1-dioxo-1, 3-thiomorpholinyl, and the like. In heterocyclic radicals of-CH2Examples of-groups substituted by-C (═ O) -include, but are not limited to, 2-oxopyrrolidinyl, oxo-1, 3-thiazolidinyl, 2-piperidinonyl, 3, 5-dioxopiperidinyl. In heterocyclic radicalsExamples of nitrogen atoms oxidized to N-oxygen compounds 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 listed for this markush group definition, then a heterocycle or heterocyclyl represents the linked heterocyclylene group. The term "heterocyclylene" refers to a divalent heterocyclic group formed by removing two hydrogen atoms from a ring atom of a heterocycle. The heterocyclic or heterocyclic group may be independently optionally substituted with one or more substituents described herein.
The terms "bridged heterocyclic ring" or "bridged heterocyclic group" are used interchangeably and both refer to a non-aromatic, saturated or partially unsaturated bicyclic or polycyclic ring system that shares two or more non-adjacent ring atoms and that contains at least 1 carbon atom and contains 1,2 or 3 heteroatoms selected from O, N, S. Bridged heterocycle-CH2-the group may optionally be replaced by-C (═ O) -. The sulfur atom of the ring may optionally be oxidized to the S-oxide and the nitrogen atom of the ring may optionally be oxidized to the N-oxygen compound. In some embodiments, bridged heterocycles contain 6 to 12 ring atoms, i.e., represent 6-12 membered bridged heterocycles; in other embodiments, bridged heterocycles contain 6 to 10 ring atoms, i.e., represent 6 to 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, etc. When a bridged heterocyclic or bridged heterocyclic group is a linking group, and bridged heterocyclic or bridged heterocyclic group is enumerated for this markush group definition, then bridged heterocyclic or bridged heterocyclic group represents an attached bridged heterocyclylene group. The term "bridged heterocyclic group" means a divalent bridged heterocyclic group formed by removing two hydrogen atoms from a ring atom of the bridged heterocyclic ring. The bridged heterocyclic or bridged heterocyclic group may be independently optionally substituted with one or more substituents described herein.
The terms "spiroheterocycle" or "spiroheterocyclyl" are used interchangeably and both refer to a non-aromatic, saturated or partially unsaturated ring system formed by two rings sharing a single carbon atomAnd the system comprises 1,2 or 3 heteroatoms selected from O, N, S. Spiro-heterocyclic ring-CH2-the group may optionally be replaced by-C (═ O) -. The sulfur atom of the ring may optionally be oxidized to the S-oxide and the nitrogen atom of the ring may optionally be oxidized to the N-oxygen compound. 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 [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 ]]Nonan-1-one, and the like. When a spiroheterocycle or spiroheterocyclyl is a linking group and a spiroheterocycle or spiroheterocyclyl is listed for this markush group definition, then a spiroheterocycle or spiroheterocyclyl represents the linked spiroheterocyclylene. The term "spiroheterocyclylene" denotes a divalent spiroheterocyclylene group formed by removing two hydrogen atoms from the ring atoms of a spiroheterocycle. The spiroheterocycle or spiroheterocyclyl may be independently optionally substituted with one or more substituents described herein.
The term "aminoalkyl" denotes an alkyl group substituted with one or more amino groups. In some embodiments, the term "aminoalkyl" denotes an alkyl group substituted with one amino group. In some embodiments, the term "aminoalkyl" denotes amino C1-6An alkyl group. In other embodiments, the term "aminoalkyl" denotes amino C1-4An alkyl group. In other embodiments, the term "aminoalkyl" denotes amino C1-3An alkyl group. Examples of aminoalkyl groups include, but are not limited to, aminomethyl, aminoethyl, amino-n-propyl, amino-isopropyl, amino-isobutyl, amino-tert-butyl, 1, 2-diaminoethyl, and the like.
The term "alkylamino" denotes an amino group substituted by one or two alkyl groups. In some embodiments, the term "alkylamino" denotes C1-6Alkylamino, i.e. representing a bond of one or two C1-6Alkyl-substituted amino groups. In other embodimentsIn the schemes, the term "alkylamino" denotes C1-4An alkylamino group. In other embodiments, the term "alkylamino" denotes C1-3An alkylamino group. Examples of alkylamino include, but are not limited to, methylamino, ethylamino, n-propylamino, isopropylamino, isobutylamino, tert-butylamino, dimethylamino, diethylamino, di-n-propylamino, diisopropylamino, diisobutylamino, di-tert-butylamino, and the like.
The term "alkylsulfonyl" denotes alkyl-S (═ O)2-, i.e. alkyl by-S (═ O)2-to the rest of the molecule. In some embodiments, alkylsulfonyl represents C1-6An alkylsulfonyl group; in other embodiments, alkylsulfonyl represents C1-4An alkylsulfonyl group; in other embodiments, alkylsulfonyl represents C1-4An alkylsulfonyl group. Examples of alkylsulfonyl include, but are not limited to, methylsulfonyl, ethylmethylsulfonyl, n-propylmethylsulfonyl, isopropylmethylsulfonyl, n-butylmethylsulfonyl, and the like.
Compounds of the general formula (I) are those wherein Q is attached to ring A at the left end and M at the right end, e.g. when Q is- (S ═ O)2NR6When it is, then
Figure BDA0002665034780000181
To represent
Figure BDA0002665034780000182
Similarly, the left end of ring A is connected to E and the right end of A is connected to Q.
In the general formula of the compounds of the present invention, when T is alkylene-O-or alkylene-NH-,
Figure BDA0002665034780000183
to represent
Figure BDA0002665034780000184
As described herein, unless otherwise specified, a ring substituent may be attached to the rest 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.
The term "protecting group" or "PG" refers to a substituent that, when reacted with other functional groups, is generally used to block or protect a particular functionality. For example, "amino protecting group" means a substituent attached to an amino group to block or protect the functionality of the amino group in a compound, and suitable amino protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC ), benzyloxycarbonyl (CBZ ) and 9-fluorenylmethyleneoxycarbonyl (Fmoc). Similarly, "hydroxyl protecting group" refers to the functionality of a substituent of a hydroxyl group to block or protect the hydroxyl group, and suitable protecting groups include acetyl and silyl groups. "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-CH2CH2SO2Ph, cyanoethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxymethyl, 2- (p-toluenesulfonyl) ethyl, 2- (p-nitrobenzenesulfonyl) ethyl, 2- (diphenylphosphino) ethyl, nitroethyl, and the like. General descriptions of protecting groups can be found in the literature: 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, represents 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 by enzymatic conversion to the parent structure in the blood or tissue. The prodrug compound of the invention can be ester, and in the prior invention, the ester can be used as the prodrug and comprises phenyl ester and aliphatic (C)1-24) Esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, a compound of the present invention contains a hydroxy group, i.e., it can be acylated to provide the compound in prodrug form. Other prodrug forms include phosphate esters, 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: higuchi andV.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 the product of a particular compound or salt thereof obtained by metabolism in vivo. Metabolites of a compound can be identified by techniques well known in the art, and its activity can be characterized by assay methods as described herein. Such products may be obtained by administering the compound by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, and the like. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting a compound of the present invention with a mammal for a sufficient period of time.
As used herein, "pharmaceutically acceptable salts" refer to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as are: berge et al, description of the scientific acceptable salts in detail in J. pharmaceutical Sciences,1977,66:1-19. Pharmaceutically acceptable non-toxic acid salts include, but are not limited to, salts of inorganic acids formed by reaction with amino groups such as hydrochlorides, hydrobromides, phosphates, sulfates, perchlorates, and salts of organic acids such as acetates, oxalates, maleates, tartrates, citrates, succinates, malonates, or those obtained by other methods described in the literature above, such as ion exchange. Other pharmaceutically acceptable salts include adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, cyclopentylpropionates, digluconates, dodecylsulfates, ethanesulfonates,formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, embonate, pectate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Salts obtained with appropriate bases include alkali metals, alkaline earth metals, ammonium and N+(C1-4Alkyl radical)4A salt. The present invention also contemplates quaternary ammonium salts formed from compounds containing groups of N. Water-soluble or oil-soluble or dispersion products can 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 amine cations resistant to formation of counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C1-8Sulfonates and aromatic sulfonates.
The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, basic or acidic moiety, by conventional chemical methods. In general, such salts can be prepared by reacting the free acid forms of these compounds with a stoichiometric amount of the appropriate 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 the appropriate acid. Such reactions are usually carried out in water or an organic solvent or a mixture of both. Generally, where appropriate, it is desirable to use a non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile. In, for example, "Remington's Pharmaceutical Sciences", 20 th edition, Mack Publishing Company, Easton, Pa., (1985); and "handbook of pharmaceutically acceptable salts: properties, Selection and application (Handbook of Pharmaceutical Salts: Properties, Selection, and Use) ", Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002) may find some additional lists of suitable Salts.
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 containing them (e.g., ethanol, DMSO, etc.), for their crystallization. The compounds disclosed herein may form solvates with pharmaceutically acceptable solvents (including water), either inherently or by design; thus, the present invention is intended to include both solvated and unsolvated forms.
"solvate" of the present invention refers to an association of one or more solvent molecules with a compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol. The term "hydrate" refers to an association of solvent molecules that is water.
"nitroxide" in the context of the present invention means that when a compound contains several amine functional groups, 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-containing heterocyclic nitrogen atoms. The corresponding amines can be treated with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid) to form the N-oxide (see Advanced Organic Chemistry, Wiley Interscience, 4 th edition, Jerry March, pages). In particular, the N-oxide may be prepared by the method of 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 dichloromethane.
The term "treating" or "treatment" as used herein refers, in some embodiments, to ameliorating a disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one clinical symptom thereof). In other embodiments, "treating" or "treatment" 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" or "treatment" refers to modulating the disease or disorder, either physically (e.g., stabilizing a perceptible symptom) or physiologically (e.g., stabilizing a parameter of the body), or both. In other embodiments, "treating" or "treatment" refers to preventing or delaying the onset, occurrence, or worsening of a disease or disorder.
The term "RET-associated cancer" as used herein refers to a cancer that is associated with or has dysregulation 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 one thereof. Non-limiting examples of RET-associated cancers are described herein. The deregulation of the expression or activity or level of either of the RET gene, RET kinase or any of these is one or more point mutations in the RET gene.
The phrase "deregulated expression or activity or level of a RET gene, RET kinase, or any of them" refers to a gene mutation (e.g., a mutation in a RET gene that results in the translocation of the RET gene resulting in the expression of a fusion protein, a RET gene that results in the expression of a RET protein that comprises a deletion of at least one amino acid as compared to the wild-type RET protein, or a mutation in a RET gene that results in the expression of a RET protein having one or more point mutations, or an alternatively spliced form of the RET mRNA of a RET protein that results in the deletion of at least one amino acid in a RET protein as compared to the wild-type RET protein), or a RET gene amplification that results in the overexpression of a RET protein or autocrine activity resulting from overexpression of a cellular RET gene, resulting in a pathogenic increase in the activity of the kinase domain of the RET protein in the cell (e.g., constitutive activation of the kinase domain of the RET protein). As another example, a deregulated expression or activity or level of a RET gene, RET kinase, or any of these may be a mutation in the RET gene encoding a RET protein that is constitutively active or has increased activity compared to the protein encoded by the RET gene that does not contain the mutation. For example, a deregulated expression or activity or level of a RET gene, RET kinase, or any of them may be the result of a gene or chromosome translocation that results in the expression of a fusion protein that includes a first RET portion that includes a functional kinase domain and a second portion of a chaperone protein (i.e., not RET). In some examples, deregulation of a RET gene, RET protein, or expression or activity can be the result of gene translation of one RET gene with another RET gene.
Dysregulation of the expression or activity or level of RET kinase, RET gene, or any (e.g., one or more) thereof, may contribute to tumorigenesis. For example, a disorder of RET kinase, RET gene, or a disorder of expression or activity or level of any of these may be translocation, overexpression, activation, amplification, or mutation of the RET kinase, RET gene, or RET kinase domain. Translocation may include translocation involving the RET kinase domain, mutation may include mutation involving the RET ligand binding site, and 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 a RET gene, RET kinase, or any of these includes one or more deletions (e.g., deletion of amino acid 4), insertions, or point mutations in RET kinase. In some embodiments, deregulation of the expression or activity or level of a RET gene, RET kinase, or any of these, includes deletion of one or more residues of RET kinase, resulting in constitutive activity of the RET kinase domain.
The term "irritable bowel syndrome" includes diarrhea predominant, constipation predominant or alternating pattern of bowel movement, functional bloating, functional constipation, functional diarrhea, non-specific 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 the non-isotopically enriched forms as well as the isotopically enriched forms of these compounds. Isotopically enriched compounds have the structure depicted by the formulae given herein, except that one or more atoms are replaced by an atom having a selected atomic mass 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 as2H，3H，11C，13C，14C，15N，17O，18O，18F，31P，32P，35S，36Cl and125I。
in another aspect of the inventionThe compounds include isotopically enriched compounds as defined herein, e.g. wherein a radioisotope, e.g. is present3H，14C and18those compounds of F, or in which a non-radioactive isotope is present, e.g.2H and13C. the isotopically enriched compounds can be used for metabolic studies (use)14C) Reaction kinetics study (using, for example2H or3H) Detection or imaging techniques such as Positron Emission Tomography (PET) or Single Photon Emission Computed Tomography (SPECT) including drug or substrate tissue distribution determination, or may be used in radiotherapy of a patient.18F-enriched compounds are particularly desirable for PET or SPECT studies. Isotopically enriched compounds of formula (I) can be prepared by conventional techniques known to those skilled in the art or by the procedures and examples described in the present specification using a suitable isotopically labelled reagent in place of the original used unlabelled reagent.
In addition, heavier isotopes are, in particular, deuterium (i.e.,2substitution of H or D) may provide certain therapeutic advantages resulting from greater metabolic stability. For example, increased in vivo half-life or decreased dosage requirements or improved therapeutic index. It is to be understood that deuterium in the present invention is to be considered as a substituent of the 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 isotopic enrichment factors. The term "isotopic enrichment factor" as used herein refers to the ratio between the isotopic and natural abundance of a given 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 invention include those wherein the crystallization solvent may be the same asSubstituted by substituents, e.g. D2O, acetone-d6、DMSO-d6Those solvates of (a).
Description of the Compounds of the invention
The invention provides a novel compound showing inhibition of transfection phase Rearrangement (RET) kinase, which has good inhibition effect on RET wild type and RET gene mutants and has better inhibition selectivity on the RET wild type and the RET gene mutants.
In one aspect, the invention provides a compound of formula (I), or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of a compound of formula (I),
Figure BDA0002665034780000211
wherein R is1、X1、X2、X3、X4、X5、E、A、Q、M、T、RaQ has the meaning as defined in the invention.
In some embodiments, X1、X2、X3、X4And X5Each independently is CR4Or N.
In some embodiments, Y is O, NH or S.
In some embodiments, T is a bond, alkylene-O-, or alkylene-NH-, and said T is optionally substituted with 1,2,3, or 4 groups selected from D, OH, F, Cl, Br, I, CN, NH2、CF3Alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, heterocyclyl, alkoxy, aryl, heteroaryl or alkylamino.
In some embodiments, ring G is a spiro carbocyclyl or spiro heterocyclyl.
In some embodiments, q is 0, 1,2,3, or 4.
In some embodiments, RaIs D, OH, NH2、F、CF3、Cl、Br、I、CN、NR5R6、OR7、-NR6C(＝O)R7、-S(＝O)2R7、-S(＝O)R7、-C(＝O)R7、-C(＝O)OR7Oxo, alkyl, alkoxy, cycloalkyl, alkoxyalkyl or hydroxyalkyl.
In some embodiments, E is a bond, -NR6-, or-O-.
In some embodiments, ring a is a bridged, fused, or spirocyclic ring, and a is optionally substituted with 1,2,3, or 4 substituents selected from F, Cl, Br, OH, oxo, NR5R6、R5(C＝O)NR6-, aminoalkyl, alkyl, alkoxy, haloalkyl, hydroxyalkyl, carbocyclyl, heterocyclyl, heterocyclylalkyl, alkoxyalkyl, cycloalkylene, and monoheterocyclylene.
In some embodiments, Q is a bond, - (CR)2R3)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-NR6(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, CF3、OH、NR5R6、OR7Alkyl, haloalkyl, hydroxyalkyl, haloalkoxy, aryl, alkoxyalkyl, oxo, alkanoyl, heterocyclyl, cycloalkyl.
In some embodiments, R1Is H, D, CN, F, Cl, Br, alkyl or cycloalkyl, wherein said alkyl and cycloalkyl may independently optionally be substituted with 1,2,3 or 4 substituents selected from F, Cl, Br, CN, NH2OH and NO2Substituted with the substituent(s).
In some embodiments, each R is2、R3Independently OH, F, CF3、H、D、CN、Cl、Br、NH2Hydroxyalkyl, alkyl, alkylamino, alkoxy, haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl;
or, R2、R3And the same C atom to which it is attached form a carbocyclic or heterocyclic ring;
in some embodiments, R4Is H, D, F, Cl, Br, alkyl or alkoxy, wherein the alkyl and alkoxy are each independently optionally substituted by 1,2,3 or 4 groups selected from F, Cl, Br, CN, NH2OH and NO2Substituted with the substituent(s).
In some embodiments, R5H, D, an alkyl group, a carbocyclyl group, a heterocyclyl group, an aryl group or a heteroaryl group, wherein said alkyl, carbocyclyl, heterocyclyl, aryl and heteroaryl groups are each independently optionally substituted with 1,2,3 or 4 substituents selected from F, Cl, Br, OH, NH2Alkylamino, alkyl, alkylsulfonyl, alkoxy, aryl and heteroaryl.
In some embodiments, R6Is H, D, alkyl or alkoxyalkyl, wherein the alkyl and alkoxyalkyl are each independently optionally substituted with 1,2,3, or 4 substituents selected from F, Cl, Br, CN, NH2OH and NO2Substituted with the substituent(s).
In some embodiments, R7OH, alkyl, cycloalkyl, heterocyclic radical, aryl and heteroaryl.
In some embodiments, T is a bond, C1-6Alkylene radical, C1-6alkylene-O-or C1-6alkylene-NH-, and T is optionally substituted by 1,2,3 or 4 groups selected from D, OH, F, Cl, Br, I, CN, CF3、C1-6Alkyl radical, C1-6Hydroxyalkyl radical, C1-6Haloalkyl, C3-7Cycloalkyl, 3-7 membered heterocyclyl, C1-6Alkoxy radical, C6-10Aryl, 5-12 membered heteroaryl or C1-6Substituted by a substituent of 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 said T is optionally substituted by 1,2,3 or 4 groups selected from D, OH, F, Cl, Br, I, CN, CF3Methyl, 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, G is 6-12 membered spirocarbocyclyl or 6-12 membered spiroheterocyclyl.
In some embodiments, RaIs D, OH, NH2、F、CF3、Cl、Br、I、CN、NR5R6、OR7、-NR6C(＝O)R7、-S(＝O)2R7、-S(＝O)R7、-C(＝O)R7、-C(＝O)OR7Oxo, C1-6Alkyl radical, C1-6Alkoxy radical, C3-7Cycloalkyl radical, C1-6Alkoxy radical C1-6Alkyl radical, C1-6A hydroxyalkyl group.
In some embodiments, R5Is H, D, C1-6Alkyl, 3-12 membered carbocyclyl, 3-12 membered heterocyclyl, C6-10Aryl or 5-10 membered heteroaryl, wherein said C1-6Alkyl, 3-12 membered carbocyclyl, 3-12 membered heterocyclyl, C6-10Aryl and 5-10 membered heteroaryl are each independently optionally substituted by 1,2,3 or 4 substituents selected from F, Cl, Br, OH, NH2、C1-6Alkylamino, alkyl, alkylsulfonyl, alkoxy, aryl and heteroaryl.
In some embodiments, R6Is H, D, C1-6Alkyl or C1-6Alkoxy radical C1-6Alkyl radical, wherein said C1-6Alkyl and C1-6Alkoxy radical C1-6Each alkyl is independently optionally substituted by 1,2,3 or 4 substituents selected from F, Cl, Br, CN, NH2OH and NO2Substituted with the substituent(s).
R7Is OH, C1-6Alkyl radical, C3-6Cycloalkyl, 3-12 membered heterocyclyl, C6-10Aryl, 5-10 membered heteroaryl.
In some embodiments, G is the following substructure:
Figure BDA0002665034780000231
wherein each ring T1 is independently a 4-7 membered monocyclic or heteromonocyclic carbon;
Z1and Z2Independently is-CH2-、-O-、-S-、-NH-；
Z3is-O-, -S-, -NH-;
n1 is 0, 1 or 2;
n2 is 1,2 or 3;
n3 is 0 or 1.
In some embodiments, G is the following substructure:
Figure BDA0002665034780000241
at one endIn some embodiments, RaIs D, OH, NH2、F、CF3、Cl、Br、I、CN、NH2、NHCH3、-NHC(＝O)CH3、-S(＝O)2CH3、-S(＝O)CH3、-C(＝O)CH3-C (═ O) OH, oxo, methyl, ethyl, propyl, butyl, methoxy, ethoxy, cyclopropyl, cyclopentyl, methoxymethyl, ethoxymethyl, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 2-hydroxypropyl, 2-hydroxy-2-methylpropyl.
In some embodiments, R5H, 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, NH2Methyl, -S (═ O)2CH3Methoxy, ethoxy and phenyl.
In some embodiments, R6H, D, methyl, ethyl, n-propyl, n-butyl, methoxymethyl, ethoxymethyl or methoxyethyl, wherein the methyl, ethyl, n-propyl, n-butyl, methoxymethyl, ethoxymethyl and methoxyethyl radicals are each independently optionally substituted by 1,2,3 or 4 radicals selected from the group consisting of F, Cl, Br, CN, NH2OH and NO2Substituted with the substituent(s).
In some embodiments, R7Is OH, methyl, ethyl, NH2、N(CH3)2N-propyl, isopropyl, tert-butyl, cyclopropyl or phenyl.
In some embodiments, A is 5-12 membered bridged cyclyl, 5-12 membered fused cyclyl, or 5-12 membered spirocyclyl, and A is optionally substituted with 1,2,3, or 4 substituents selected from F, Cl, Br, OH, oxo, NR, and5R6、R5(C＝O)NR6-, amino C1-6Alkyl radical, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Haloalkyl, C1-6Hydroxyalkyl, 3-12 membered carbocyclyl, 3-12 membered heterocyclyl, 3-12 membered heterocycleRadical C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkyl radical, C3-6Cycloalkylene and 3-6 membered heteromonocyclic group.
In some embodiments, a is the following substructure:
Figure BDA0002665034780000251
wherein Z is1aAnd Z2aEach independently is-CH2-or-NH-;
Z3ais-CH-or-N-;
Z4ais-O-, -S-or-NH-;
each Z5a、Z6aIndependently is-CH2-、-O-、-S-、-S(＝O)-、-S(＝O)2--C (═ O) -, or-NH-;
m and t are each independently 0, 1 or 2;
n and t1 are each independently 0 or 1;
wherein each sub-structural formula of A is independently and optionally substituted by 1,2,3 or 4 selected from F, Cl, Br, OH, oxo, NR5R6、R5(C＝O)NR6-, amino C1-4Alkyl radical, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl, C1-4Hydroxyalkyl, 3-12 membered carbocyclyl, 3-12 membered heterocyclyl C1-4Alkyl radical, C1-4Alkoxy radical C1-4Alkyl radical, C3-6Cycloalkylene and 3-6 membered heterocyclylene.
In some embodiments, a is the following substructure:
Figure BDA0002665034780000261
wherein each sub-structural formula of A is independently and optionally substituted by 1,2,3 or 4 selected from F, Cl, Br, OH, oxo, NH2、NHCH3、CH3(C ═ O) NH-, methyl, ethyl, n-propyl, methoxy, ethoxy, isopropylOxy radical, CF3Hydroxymethyl, 2-hydroxyethyl, cyclopropyl, cyclohexyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, cyclopropylene, cyclohexylene and pyrrolidinylidene.
In some embodiments, M is H, D, 5-10 membered heteroaryl, C6-10Aryl radical, C3-7Cycloalkyl or 3-12 membered heterocyclyl; and M is optionally substituted by 1,2,3 or 4 groups selected from D, F, Cl, CN, OH, CF3、NR5R6、OR7、C1-6Alkyl radical, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Haloalkoxy, C6-10Aryl radical, C1-6Alkoxy radical C1-6Alkyl, oxo, C1-6Alkanoyl, 3-7 membered heterocyclic group, C3-7Cycloalkyl substituents.
In some embodiments, M is H, D, pyridinyl, pyrimidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, pyrazinyl, phenyl, cyclopentyl, cyclopropyl, cyclohexyl, cyclobutyl, pyrrolidinyl, piperidinyl, tetrahydrofuryl, tetrahydropyranyl, piperazinyl, morpholinyl, tetrahydrothiopyranyl, oxetanyl, 1, 2-dihydropyridinyl, 7-azabicyclo [2.2.1]Heptalkyl, hexahydrofuro [3,4-c ]]Azolyl, 3-azabicyclo [3.1.0 ]]Hexane radical, octahydropyrrolo [1,2-a ] radical]Pyrazinyl or 5-azaspiro [2.4 ]]A heptalkyl group; and M is optionally substituted by 1,2,3 or 4 groups selected from D, F, Cl, CN, OH, CF3、NH2、NHCH3、N(CH3)2Trifluoromethoxy, 2,2, 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,
Figure BDA0002665034780000271
Figure BDA0002665034780000272
And M is optionally substituted by 1,2,3 or 4 groups selected from D, F, Cl, CN, OH, CF3、NH2、NHCH3、N(CH3)2Trifluoromethoxy, 2,2, 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
Figure BDA0002665034780000273
In some embodiments, R1Is H, D, CN, F, Cl, Br, methyl, ethyl or cyclopropyl, wherein said methyl, ethyl and cyclopropyl are independently optionally substituted by 1,2,3 or 4 substituents selected from F, Cl, Br, CN, NH2OH and NO2Substituted with the substituent(s).
In some embodiments, R4Is H, D, F, Cl, Br, methyl, ethyl, n-propyl, methoxy or ethoxy, wherein the methyl, ethyl, n-propyl, methoxy and ethoxy groups can be independently and optionally substituted by 1,2,3 or 4 groups selected from F, Cl, Br, CN, NH2OH and NO2Substituted with the substituent(s).
In some embodiments, each R is2、R3Independently OH, F, CF3、H、D、CN、Cl、Br、NH2、C1-6Hydroxyalkyl radical, C1-6Alkyl radical, C1-6Alkylamino radical, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-7Cycloalkyl radical, C3-7Cycloalkyl radical C1-6Alkyl radical, C6-10Aryl or 5-10 membered heteroaryl;
or, R2、R3And the same C atom to which it is attached form a 3-7 membered carbocyclic or 3-7 membered heterocyclic ring.
At one endIn some embodiments, each R is2、R3Independently OH, F, CF3、H、D、CN、Cl、Br、NH2Hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, methyl, ethyl, N (CH)3)2Methoxy, ethoxy, isopropoxy, tert-butoxy, trifluoromethoxy, cyclopropyl, cyclopentyl, cyclopropylmethyl, cyclopentylethyl, cyclopentylmethyl, phenyl, pyridyl, pyrazinyl;
or, R2、R3And the same C atom to which it is attached to cyclopentane, cyclopropane, cyclobutane, tetrahydropyran, tetrahydrofuran, piperidine, or pyrrolidine.
In some embodiments, Q is a bond, -O-, - (CH)2)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)CH2-、-(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-、
Figure BDA0002665034780000281
Figure BDA0002665034780000282
In some embodiments, the compounds of the present invention have the structure of formula (IA), or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the structure of formula (IA),
Figure BDA0002665034780000283
in some embodiments, the compounds of the present invention have the structure of formula (I-1), or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt, or prodrug of the structure of formula (I-1),
Figure BDA0002665034780000291
wherein,
ring a1 is of the subformula:
Figure BDA0002665034780000292
wherein Z1aAnd Z2aEach independently is CH2Or NH;
and each sub-formula of A1 is independently optionally substituted by 1,2,3 or 4 substituents selected from F, Cl, Br, OH, oxo, NR5R6、R5(C＝O)NR6-, amino C1-4Alkyl radical, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl, C1-4Hydroxyalkyl, 3-12 membered carbocyclyl, 3-12 membered heterocyclyl C1-4Alkyl radical, C1-4Alkoxy radical C1-4Alkyl radical, C3-6Cycloalkylene and 3-6 memberedSubstituted by a substituent of the heteromonocyclic group.
In some embodiments, a1 is a subformula:
Figure BDA0002665034780000293
wherein each sub-formula of A1 is independently and optionally substituted by 1,2,3 or 4 substituents selected from F, Cl, Br, OH, oxo, NH2、NHCH3、CH3(C ═ O) NH-, methyl, ethyl, n-propyl, methoxy, ethoxy, isopropoxy, CF3Hydroxymethyl, 2-hydroxyethyl, cyclopropyl, cyclohexyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, cyclopropylene, cyclohexylene and pyrrolidinylidene.
In some embodiments, the compounds of the present invention have the structure of formula (I-2) or (I-3), or a stereoisomer, geometric isomer, tautomer, nitroxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the structure of formula (I-2) or (I-3),
Figure BDA0002665034780000301
wherein Z is1、Z2And Z3aEach independently is CH or N;
m and t are each independently 0, 1 or 2;
n and t1 are each independently 0 or 1;
wherein
Figure BDA0002665034780000302
Independently optionally substituted by 1,2,3 or 4 substituents selected from F, Cl, Br, OH, oxo, NR5R6、R5(C＝O)NR6-, amino C1-4Alkyl radical, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl, C1-4Hydroxyalkyl, 3-12 membered carbocyclyl, 3-12 membered heterocyclyl C1-4Alkyl radical, C1-4Alkoxy radical C1-4Alkyl radical, C3-6Cycloalkylene and 3-6 membered heterocyclylene.
In some embodiments of the present invention, the substrate is,
Figure BDA0002665034780000303
is of the sub-structure:
Figure BDA0002665034780000304
Figure BDA0002665034780000311
is of the sub-structure:
Figure BDA0002665034780000312
wherein
Figure BDA0002665034780000313
Each of the sub-formulae of (1) is independently optionally substituted by 1,2,3 or 4 substituents selected from F, Cl, Br, OH, oxo, NH2、NHCH3、CH3(C ═ O) NH-, methyl, ethyl, n-propyl, methoxy, ethoxy, isopropoxy, CF3Hydroxymethyl, 2-hydroxyethyl, cyclopropyl, cyclohexyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, cyclopropylene, cyclohexylene and pyrrolidinylidene.
In some embodiments, the compounds of the present invention have one of the following structures, or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt, or prodrug thereof,
Figure BDA0002665034780000314
Figure BDA0002665034780000321
Figure BDA0002665034780000331
Figure BDA0002665034780000341
Figure BDA0002665034780000351
Figure BDA0002665034780000361
Figure BDA0002665034780000371
Figure BDA0002665034780000381
Figure BDA0002665034780000391
Figure BDA0002665034780000401
Figure BDA0002665034780000411
Figure BDA0002665034780000421
Figure BDA0002665034780000431
Figure BDA0002665034780000441
Figure BDA0002665034780000451
Figure BDA0002665034780000461
Figure BDA0002665034780000471
Figure BDA0002665034780000481
Figure BDA0002665034780000491
Figure BDA0002665034780000501
Figure BDA0002665034780000511
Figure BDA0002665034780000521
Figure BDA0002665034780000531
Figure BDA0002665034780000541
Figure BDA0002665034780000551
Figure BDA0002665034780000561
in another aspect, the invention provides a pharmaceutical composition comprising a compound of the invention, and a pharmaceutically acceptable adjuvant.
In another aspect, the present invention also provides a use of the compound of the present invention or the pharmaceutical composition of the present invention for the preparation of a medicament for preventing or treating a RET-related disease.
In some embodiments, the RET-associated disease includes cancer, irritable bowel syndrome, and/or pain associated with irritable bowel syndrome.
In another aspect, the present invention also provides a compound according to the present invention or a pharmaceutical composition according to the present invention for use in preventing or treating RET-related diseases.
In some embodiments, the RET-associated disease includes cancer, irritable bowel syndrome, and/or pain associated with irritable bowel syndrome.
In another aspect, the present invention also provides a method for preventing or treating a RET-associated disease, the method comprising administering to a patient a therapeutically effective amount of a compound of the present invention or a pharmaceutical composition thereof.
In some embodiments, the RET-associated disease includes cancer, irritable bowel syndrome, and/or pain associated with irritable bowel syndrome.
In another aspect, the invention relates to intermediates useful in the preparation of compounds of formula (I), (I-1), (IA), (I-2) or (I-3).
In another aspect, the present invention relates to a process for the preparation, isolation and purification of a compound of formula (I), (I-1), (IA), (I-2) or (I-3).
In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention and pharmaceutically acceptable adjuvants thereof. In some embodiments, adjuvants of the present invention 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 dosage 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 prevention or treatment of Irritable Bowel Syndrome (IBS) and/or pain associated with IBS.
The invention also provides a compound of the invention or a pharmaceutical composition of the invention for use in the prevention 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 present invention.
In particular, the salts are pharmaceutically acceptable salts. The term "pharmaceutically acceptable" includes substances or compositions which must be compatible with chemical or toxicological considerations, in connection with the other components which make up the formulation and the mammal being treated.
The salts of the compounds of the present invention also include, but are not necessarily pharmaceutically acceptable salts of the intermediates used in the preparation or purification of the compounds of formula (I), (IA), (I-1), (I-2) or (I-3) or isolated enantiomers of the compounds of formula (I), (I-1), (IA), (I-2) or (I-3).
In the structures disclosed herein, when the stereochemistry of any particular chiral atom is not specified, then all stereoisomers of that structure are contemplated as within this invention and are included as disclosed compounds in this invention. When stereochemistry is indicated by a solid wedge (solid wedge) or dashed line representing a particular configuration, then the stereoisomers of the structure are so well-defined and defined.
Nitroxides of the compounds of the present invention are also included within the scope of the present invention. The nitroxides of the compounds of the present invention may be prepared by oxidation of the corresponding nitrogen-containing basic species using a common oxidizing agent (e.g. hydrogen peroxide) in the presence of an acid such as acetic acid at elevated temperature, or by reaction with a peracid in a suitable solvent, for example peracetic acid in dichloromethane, ethyl acetate or methyl acetate, or 3-chloroperoxybenzoic acid in chloroform or dichloromethane.
If the compounds of the invention are basic, the desired salts may be prepared by any suitable method provided in the literature, for example, using inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric and phosphoric acids and the like. Or using 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; pyranonic 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, e.g., 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 amines, and cyclic amines such as piperidine, morpholine, piperazine and the like, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.
Compounds of the invention and pharmaceutical compositions, formulations and administrations 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 therapy ("RET resistant mutants"). In addition, the compounds of the invention or pharmaceutical compositions thereof may be selective for wild-type RET over other kinases, resulting in reduced toxicity associated with inhibition of other kinases.
The pharmaceutical compositions of the present invention include a compound of formula (I), (IA), (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 alleviate RET-associated diseases or disorders in a patient, including RET-associated cancer, 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, as used herein, including any solvents, diluents, or other liquid excipients, dispersing or suspending agents, surfactants, isotonic agents, thickening agents, emulsifiers, preservatives, solid binders or lubricants, and the like, as appropriate for the particular target dosage form. As described in the following documents: 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. Annu 1999, Marcel Dekker, New York, taken together with The disclosure of this document, indicates that different adjuvants can be used In The preparation of pharmaceutically acceptable compositions and their well-known methods of preparation. Except insofar as any conventional adjuvant is incompatible with the compounds of the present invention, e.g., any adverse biological effect produced or interaction in a deleterious manner with any other component of a pharmaceutically acceptable composition, their use is 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 encapsulated in such a carrier, for example, in the form of a capsule, sachet, paper, or other container. If the excipient serves as a diluent, it may be a solid, semi-solid, or liquid material that serves as a vehicle, carrier, 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, methyl cellulose, sodium carboxymethyl cellulose, 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 (in solid form 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), (I-1), (I-2) or (I-3), and pharmaceutically acceptable salts thereof, may be administered as a raw chemical, and may also be provided as the active ingredient of 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), (I-1), (I-2) or (I-3), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable adjuvants, including but not limited to carriers, diluents, or excipients, and the like. The term "therapeutically effective amount" as used herein refers to the total amount of each active component sufficient to show meaningful patient benefit (e.g., cancer cell reduction). When the active ingredient alone is used for separate administration, the term refers only to that ingredient. When used in combination, the term refers to the combined amounts of the active ingredients that, when combined, administered sequentially or simultaneously, result in a therapeutic effect. Compounds of the present invention, especially compounds of formula (I), (IA), (I-1), (I-2) or (I-3) and pharmaceutically acceptable salts thereof, 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 comprises mixing a compound of the present invention, especially a compound of formula (I), (IA), (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 which are effective for their intended use.
The amount of active ingredient that is combined with one or more adjuvants to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration. The amount of active ingredient mixed with a carrier material to prepare a single dosage form of a compound of formula (I), (IA), (I-1), (I-2) or (I-3) will vary depending on 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 used, the time of treatment and the age, sex, body weight and condition of the patient. Preferred unit dosage forms are those containing a daily or divided dose or suitable fraction thereof of the active ingredient described herein above. Treatment can be initiated with small doses, which are clearly below the optimal dose of the compound. Thereafter, the dosage is increased in smaller increments until the optimum effect is achieved in this case. In general, the compounds are most desirably administered at concentration levels that generally provide effective results in antitumor terms without causing any harmful or toxic side effects.
Compositions containing the compounds of the present invention may be formulated in unit dosage forms, each dosage containing from about 5 to about 1,000mg (1g), 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 herein provided) 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. One of ordinary skill in the art will appreciate that this embodies compounds or compositions 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. One of ordinary skill in the art will appreciate that this embodies compounds or compositions 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 active ingredient. One of ordinary skill in the art will appreciate that this embodies compounds or compositions 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 active ingredient.
The pharmaceutical compositions are suitable for administration by any suitable route, for example by the oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intradermal, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intralesional, intravenous or subdermal injection or infusion) route. Such formulations may be prepared by any method known in the art of pharmacy, for example by mixing the active ingredient with a carrier or excipient. Oral administration or injection administration is preferred.
The invention also provides methods of treating an individual having a RET-associated cancer comprising administering a compound of the invention before, during, or after administering another anti-cancer agent (e.g., other than 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-associated cancer (e.g., a RET-associated cancer including RET-associated cancers with one or more RET inhibitor resistance mutations) (e.g., using regulatory agency-approved, e.g., FDA-approved, kits to identify a dysregulation of expression or activity or levels of a RET gene, RET kinase, or any one thereof in a patient or in a biopsy sample of a patient, or by performing any non-limiting example of the assay described herein); and (b) administering to the patient a therapeutically effective amount of a compound of formula (I), (IA), (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 present invention). In some embodiments, the subject has been previously treated with a RET inhibitor that is not a compound of formula (I), (IA), (I-1), (I-2), or (I-3), or a pharmaceutically acceptable salt or solvate thereof, or has been previously treated (e.g., after tumor resection or radiotherapy) with other anti-cancer agents.
In some embodiments of any of the methods described herein, the compound of formula (I), (IA), (I-1), (I-2), or (I-3) (or a pharmaceutically acceptable salt or solvate thereof) is combined with a therapeutically effective amount of at least one additional therapeutic agent selected from one or more additional therapeutic or therapeutic (e.g., chemotherapeutic) agents.
Non-limiting examples of other therapeutic agents include: other RET-targeted therapeutics (i.e., other RET kinase inhibitors: RET inhibitors that are not compounds described herein), receptor tyrosine kinase-targeted therapeutics, signal transduction pathway inhibitors, checkpoint inhibitors, apoptosis pathway modulators (e.g., obataclx); cytotoxic chemotherapeutic agents, angiogenesis targeted therapeutic agents, immune targeted agents and radiotherapy.
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 therapeutics include alatinib, apatinib, cabozantinib (XL-184), multidimensional, lenvatinib, motaxanib, nintedanib, ponatinib, ragrafenib, statinib (sitravatinib) (MGCD516), sunitinib, sorafenib, vatanib, vandetanib, AUY-922(5- (2, 4-dihydroxy-5-isopropyl-phenyl) -N-ethyl-4- [4- (morpholinomethyl) phenyl ] isoxazole-3-carboxamide), BLU6864, BLU-667, DCC-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- [ (4-hydroxyphenyl) methylene ] -H-indol-2-one), RXDX-105(1- (3- (6, 7-dimethoxyquinazolin-4-yl) oxy) phenyl) -3- (5- (1,1, 1-trifluoro-2-methylpropan-2-yl) isoxazol-3-yl) 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-methyl-4-amine) -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 nos. 7,504,509; 8,299,057, respectively; 8,399,442, respectively; 8,067,434, respectively; 8,937,071, respectively; 9,006,256, respectively; and 9,035,063; U.S. publication No. 2014/0121239; 20160176865, respectively; 2011/0053934, respectively; 2011/0301157, respectively; 2010/0324065, respectively; 2009/0227556, respectively; 2009/0130229, respectively; 2009/0099167, respectively; 2005/0209195, respectively; international publication nos. WO 2014/184069; WO 2014/072220; WO 2012/053606; WO 2009/017838; WO 2008/031551; WO 2007/136103; WO 2007/087245; WO 2007/057399; WO 2005/051366; WO 2005/062795; and WO 2005/044835; and j.med.chem.2012,55(10), 4872-.
Also provided herein are methods of treating cancer comprising administering to a patient in need thereof a pharmaceutical combination for treating cancer comprising (a) a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, (b) an additional therapeutic agent, 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 additional therapeutic agent are jointly effective in treating cancer.
The compounds and compositions described herein can be administered alone or in combination with other compounds (including other RET modulating compounds) or other therapeutic agents. In some embodiments, a compound or composition of the 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), ragrafenib (STAVARGA), ponatinib (icluti), 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 present invention may be included in a single formulation with other therapeutic agents or in separate formulations.
In some embodiments, the compounds of the 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 as part of the same or separate dosage forms, via the same or different routes of administration, and according to the same or different schedules of administration, with the compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, according to standard pharmaceutical practice known to those skilled in the art. Non-limiting examples of other therapeutic agents for treating Irritable Bowel Syndrome (IBS) include probiotics, fibrous supplements (e.g., psyllium, methylcellulose), antidiarrheals (e.g., loperamide), bile acid binders (e.g., cholestyramine, colestipol, colesevelam), anticholinergics and antispasmodics (e.g., hyoscyamine, dicyclomine), antidepressants (e.g., tricyclic antidepressants such as imipramine or nortriptyline or selective 5-hydroxytryptamine reuptake inhibitors (SSRIs) such as fluoxetine or paroxetine), antibiotics (e.g., rifaximin), alosetron and rubiprostone.
Use of the Compounds and pharmaceutical compositions of the invention
The present invention also provides use of a compound of the present invention or a pharmaceutical composition of the present invention in the manufacture of a medicament for preventing or treating a RET-associated disease or disorder, wherein the RET-associated disease or disorder comprises RET-associated 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 therapy ("RET resistant mutants"). In addition, the compounds of the invention or pharmaceutical compositions thereof may be selective for wild-type RET over other kinases, resulting in reduced toxicity associated with inhibition of other kinases.
The invention provides application of the compound for inhibiting wild type RET and RET mutants or a pharmaceutical composition thereof in preparing a medicament for preventing or treating diseases or symptoms related to the wild type RET and RET mutants.
In some embodiments of any of the methods or uses described herein, the cancer (e.g., a RET-associated cancer) is a hematologic cancer. In some embodiments of any of the methods or uses described herein, the cancer (e.g., a RET-associated cancer) is a solid tumor. In some embodiments of any of the methods or uses described herein, the cancer (e.g., a RET-associated 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, ganglioneuroma disease 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., a RET-associated cancer) is selected from the group consisting of: acute Lymphocytic Leukemia (ALL), Acute Myelogenous Leukemia (AML), juvenile cancer, adrenocortical cancer, anal cancer, appendiceal cancer, astrocytoma, atypical teratoma/rhabdoid tumor, basal cell carcinoma, cholangiocarcinoma, bladder cancer, bone cancer, brain stem glioma, brain tumor, breast cancer, bronchial tumor, Burkitt's lymphoma, carcinoid tumor, unknown primary cancer, heart tumor, cervical cancer, childhood cancer, chordoma, Chronic Lymphocytic Leukemia (CLL), Chronic Myelogenous Leukemia (CML), chronic myeloproliferative tumor, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, cholangiocarcinoma, ductal carcinoma in situ, embryonal tumor, endometrial cancer, ependymoma, esophageal cancer, adult neuroblastoma, Ewing's sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, extrahepatic bile duct cancer, ocular cancer, fallopian tube cancer, fibroblastic bone cancer, gallbladder cancer, gastric cancer, 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, hypopharynx cancer, intraocular melanoma, islet cell tumor, pancreatic neuroendocrine tumor, Kaposi's sarcoma, kidney cancer, Langerhans ' cell histiocytosis, laryngeal cancer, leukemia, lip and oral cancer, liver cancer, lung cancer, lymphoma, macroglobulinemia, malignant fibrous histiocytoma of bone, bone cancer, melanoma, Merkel cell cancer, mesothelioma, metastatic neck cancer, midline cancer, squamous cell cancer, oral cancer, multiple endocrine syndrome, multiple myeloma, mycosis fungoides granulomatosis, myelodysplastic syndrome, myelodysplastic/myeloproliferative tumors, myelogenous leukemia, multiple myeloma, myeloproliferative tumors, cancers of the nasal cavity and sinuses, nasopharyngeal carcinoma, neuroblastoma, non-hodgkin's lymphoma, non-small cell lung cancer, oral cancer, lip cancer, oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, papillomatosis, paragangliomas, paranasal sinuses and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pituitary cancer, plasmacytoma, pleuropneumonias, pregnancy and breast cancer, primary central nervous system lymphoma, primary peritoneal cancer, prostate cancer, rectal cancer, renal cell cancer, retinoblastoma, rhabdomyosarcoma, salivary gland carcinoma, sarcoma, sezary syndrome, skin cancer, small cell lung cancer, small bowel cancer, soft tissue sarcoma, squamous cell carcinoma, squamous neck cancer, gastric cancer, T-cell lymphoma, testicular cancer, cancer of the throat, cancer of the thymus and thymus, cancer of the thyroid gland, transitional cell carcinoma of the renal pelvis and ureter, cancer of unknown primary, cancer of the urethra, cancer of the uterus, sarcoma of the uterus, cancer of the vagina, cancer of the vulva and wilm's tumor.
In some embodiments, the RET-associated cancer of the invention is selected from lung cancer, papillary thyroid carcinoma, medullary thyroid carcinoma, differentiated thyroid carcinoma, recurrent thyroid carcinoma, refractory differentiated thyroid carcinoma, 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 ganglionic cell tumors, and cervical cancer. In some embodiments, the RET-associated cancer is RET fusion lung cancer or medullary thyroid cancer.
In some embodiments, compounds of formula (I), (IA), (I-1), (I-2), or (I-3), and pharmaceutically acceptable salts and solvates thereof, are useful for treating patients with RET inhibitor resistance mutations that result in increased resistance, e.g., a substitution at amino acid position 804, e.g., V804M, V804L, or V804E, to a compound that is not of formula (I), (IA), (I-1), (I-2), or (I-3), or a pharmaceutically acceptable salt or solvate thereof, the treatment is by co-administration or subsequent treatment with existing drug therapy (e.g., other RET kinase inhibitors that are not compounds of formula (I), (IA), (I-1), (I-2), or (I-3), or a pharmaceutically acceptable salt or solvate thereof). Described herein are exemplary RET kinase inhibitors (e.g., other RET kinase inhibitors that are not compounds of formula (I), (IA), (I-1), (I-2), or (I-3), or a pharmaceutically acceptable salt or solvate thereof). In some embodiments, the RET kinase inhibitor may be selected from cabozantinib, vandetanib, alatinib, sorafenib, lenvatinib, ponatinib, multidimensional, sunitinib, fortinib (foretinib), BLU667, and BLU 6864.
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 bloating, functional constipation, functional diarrhea, unspecified 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 present invention can be administered in any amount and by any route effective to treat or reduce the severity of the disease. The exact amount necessary will vary depending on the patient, depending on the race, age, general condition of the patient, severity of infection, particular factors, mode of administration, and the like. The compound or composition may be administered in combination with one or more other therapeutic agents, as discussed herein.
General Synthesis of Compounds of the invention
In general, the compounds of the invention can be prepared by the methods described herein, unless otherwise indicated, wherein the substituents are as defined in formula (I), (IA), (I-1), (I-2) or (I-3). The following reaction schemes and examples serve to further illustrate the context of the invention.
Those skilled in the art will recognize that: the chemical reactions described herein may be used to suitably prepare a number of other compounds of the invention, and other methods for preparing the compounds of the invention are considered to be within the scope of the invention. For example, the synthesis of those non-exemplified compounds according to the present invention can be successfully accomplished by those skilled in the art by modification, such as appropriate protection of interfering groups, by the use of other known reagents in addition to those described herein, or by some routine modification of reaction conditions. In addition, the reactions disclosed herein or known reaction conditions are also recognized as being applicable to the preparation of other compounds of the present invention.
The examples described below, unless otherwise indicated, are all temperatures set forth in degrees Celsius. Unless otherwise indicated, reagents are commercially available, for example, from commercial suppliers such as Lingkai medicine, Aldrich Chemical Company, Inc., Arco Chemical Company and Alfa Chemical Company, and are used without further purification. General reagents were purchased from Shantou Wen Long chemical reagent factory, Guangdong Guanghua chemical reagent factory, Guangzhou chemical reagent factory, Tianjin HaoLiyu Chemicals Co., Ltd, Qingdao Tenglong chemical reagent Co., Ltd, and Qingdao Kaseiki chemical plant.
The anhydrous tetrahydrofuran is obtained by refluxing and drying the metallic sodium. The anhydrous dichloromethane and chloroform are obtained by calcium hydride reflux drying. Ethyl acetate, N, N-dimethylacetamide and petroleum ether were used dried over anhydrous sodium sulfate in advance.
The following reactions are generally carried out under positive pressure of nitrogen or argon or by sleeving a dry tube over an anhydrous solvent (unless otherwise indicated), the reaction vial being stoppered with a suitable rubber stopper and the substrate being injected by syringe. The glassware was dried.
The column chromatography is performed using a silica gel column. Silica gel (300 and 400 meshes) was purchased from Qingdao oceanic chemical plants. Nuclear magnetic resonance spectroscopy with CDC13Or DMSO-d6As solvent (reported in ppm) TMS (0ppm) or chloroform (7.25ppm) was used as reference standard. When multiple peaks occur, the following abbreviations will be used: s (singleton), d (doublet), t (triplet ), m (multiplet, multiplet), br (broad ), dd (doublet of doublets), dt (doublet of triplets ). Coupling constants are expressed in hertz (Hz).
Low resolution Mass Spectral (MS) data were measured by an Agilent 6320 series LC-MS spectrometer equipped with a G1312A binary pump and a G1316A TCC (column temperature maintained 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 Spectral (MS) data were determined by Agilent 6120 series LC-MS spectrometer equipped with a G1311A quaternary pump and a G1316A TCC (column temperature maintained at 30 ℃), a G1329A autosampler and a G1315D DAD detector were used for analysis, and an ESI source was used for the LC-MS spectrometer.
Both spectrometers were equipped with an Agilent Zorbax SB-C18 column, 2.1X 30mm, 5 μm. The injection volume is determined by the sample concentration; the flow rate is 0.6 mL/min; peaks of HPLC were recorded by UV-Vis wavelength at 210nm and 254 nm. The mobile phases were 0.1% formic acid in acetonitrile (phase a) and 0.1% formic acid in ultrapure water (phase B).
Compound purification was assessed by Agilent 1100 series High Performance Liquid Chromatography (HPLC) with UV detection at 210nm and 254nm, a Zorbax SB-C18 column, 2.1X 30mm, 4 μm, 10min, flow rate 0.6mL/min, 5-95% (0.1% formic acid in acetonitrile) in (0.1% formic acid in water), the column temperature was maintained at 40 ℃.
The following acronyms are used throughout the invention:
Figure BDA0002665034780000631
Figure BDA0002665034780000641
the following synthetic schemes describe the steps for preparing the compounds disclosed herein. Unless otherwise indicated, R1、X1、X2、X3、X4、X5、E、A、Q、M、T、RaQ has the meaning as defined in the invention.
Synthesis scheme 1
Intermediate (IA-1a) synthetic scheme:
Figure BDA0002665034780000642
the intermediate compounds of formula (IA-1a) may be obtained by reference to the synthetic procedures of the intermediate synthetic schemes above. Wherein ring a is of the sub-structure:
Figure BDA0002665034780000643
Hal1and Hal2Each independently is F, Cl, Br, I, preferably Cl, Br; pg1Is an amino protecting group such as Boc, etc.; pg2A hydroxyl protecting group such as benzyl, and the like. Compounds of formula (IA-1a-1) and formula (IA-1a-2) in the presence of a suitable coupling agent (e.g. a palladium coupling agent, preferably PdCl2(dppf)CH2Cl2) Then carrying out coupling reaction in a suitable solvent (such as dioxane, etc.) to obtain a compound of a formula (IA-1 a-3); a compound of formula (IA-1a-3) is reacted with a compound of formula (IA-1a-4) under suitable coupling reagent conditions (e.g., a palladium coupling reagent, preferably PdCl2(dppf)CH2Cl2) Then carrying out coupling reaction in a suitable solvent (such as toluene, and the like) to obtain a compound of the formula (IA-1 a-5); reacting the compound of formula (IA-1a-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); carrying out coupling reaction on the compound of the formula (IA-1a-6) and the compound of the formula (IA-1a-7) to obtain a compound of the formula (IA-1 a-8); reacting a compound of formula (IA-1a-8) with a compound of formula (IA-1a-9) under basic conditions to give a compound of formula (IA-1 a-10); deamination of a compound of formula (IA-1a-10) under acidic conditions to give a compound of formula (IA-1 a-11); reacting a compound of formula (IA-1a-11) with a compound of formula (IA-1a-12) under basic conditions to give a compound of formula (IA-1 a-13); a compound of formula (IA-1a-13) under suitable conditions (e.g., H)2Reduction under Pd/C) to obtain the compound of formula (IA-1 a).
Intermediate (IA-2a) synthetic scheme:
Figure BDA0002665034780000651
intermediate compounds of formula (IA-2a) may be obtained by reference to the synthetic steps of the synthetic schemes for intermediate (IA-2 a). Wherein Hal and Hal2Each independently is F, Cl, Br, I, preferably Cl, Br. A compound of formula (IA-1a-6) is reacted with a compound of formula (IA-2) under suitable conditions (e.g., basic conditions, the base is K)2CO3) The reaction is carried out in a suitable solvent, such as N, N-dimethylacetamide, to give the compound of formula (IA-2 a).
Synthesis scheme 1:
Figure BDA0002665034780000652
a compound of formula (IA) canObtained by reference to the synthetic procedure of scheme 1. Wherein Hal is F, Cl, Br, I, preferably Cl, Br. A compound of formula (IA-1) is reacted with a compound of formula (IA-2) under suitable conditions (e.g., basic conditions, with the base K)2CO3) The reaction is carried out in a suitable solvent, such as N, N-dimethylacetamide, to give the compound of formula (IA).
Synthesis scheme 2
Figure BDA0002665034780000653
The compound of formula (IA1) may be obtained by reference to the synthetic procedures of synthesis scheme 2. A compound of formula (IA-1) is reacted with a compound of formula (IA-3) under suitable conditions (e.g., basic conditions, with the base K)2CO3) The reaction is carried out in a suitable solvent, such as N, N-dimethylformamide amide, to give the compound of formula (IA 1).
Synthesis scheme 3
Figure BDA0002665034780000661
The compounds of formula (IA) can be obtained by reference to the synthetic procedures of synthesis scheme 3. A compound of formula (IA-1) is reacted with a compound of formula (IA-4) under suitable conditions (e.g., basic conditions, with the base K)2CO3) The reaction is carried out in a suitable solvent, such as N, N-dimethylformamide amide, to give the compound of formula (IA).
Synthesis scheme 4
Figure BDA0002665034780000662
The compound of formula (IA2) may be obtained by reference to the synthetic procedure of scheme 4. A compound of formula (IA-2a) is reacted with a compound of formula (IA-5) under suitable conditions (e.g., basic conditions, with the base K)2CO3) The reaction is carried out by heating in a suitable solvent (such as DMSO) to obtain the compound of formula (IA 2).
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
Figure BDA0002665034780000663
Step 1: 6-bromo-4-hydroxypyrazolo [1,5-a ] pyridine-3-carbonitrile
Sequentially adding 6-bromo-4-methoxy pyrazolo [1,5-a ] into a 1L single-mouth bottle at room temperature]Pyridine-3-carbonitrile (50g,198.36mmol), water (16.5mL,916mmol), sodium hydroxide (16.03g,396.8mmol), and DMA (500mL) was stirred at room temperature for 5min, then dodecanethiol (97mL,397mmol) was added slowly at 0 deg.C, and after the addition, the reaction was allowed to proceed to 45 deg.C overnight. Pouring the reaction solution into 3L of ice water, slowly adding saturated citric acid water to adjust the pH value to be 5, stirring for half an hour, standing, filtering, washing a filter cake with water and petroleum ether for multiple times, and drying at 60 ℃ to obtain 44.1g of yellow solid, namely the target product (the yield is 93.4%). Rf 0.35(PE/EA 3: 1); LC-MS: 239.05[ M + H ] M/z]+。
Step 2: 3-bromo-3-cyanopyrazolo [1,5-a ] pyridin-4-yl trifluoromethanesulfonate
6-bromo-4-hydroxypyrazolo [1,5-a ] pyridine-3-carbonitrile (44.1g,185mmol), pyridine (45mL,559mmol), DCM (800mL) were added to a 1L single-necked flask, the temperature was lowered to-10 deg.C or below, trifluoromethanesulfonic anhydride (50mL,297.2mmol) was slowly added, and after stirring for 1h, the mixture was allowed to naturally warm to room temperature for reaction overnight. DCM was spin-dried under reduced pressure, diluted with water (250mL), extracted with EA (500mL × 3), the organic phase was collected, washed with saturated brine (250mL), dried over anhydrous sodium sulfate, filtered, the filtrate was spin-dried, and purified by silica gel column chromatography (eluent PE/EA ═ 50: 1-25: 1) to give 61.5g of a yellow-like solid as the target product, with a yield of 89.7%. Rf is 0.45(PE/EA 5: 1).
And step 3: 6-bromo-4- (6-fluoropyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile
Adding 3-bromo-3-cyano pyrazolo [1,5-a ] into a 1L three-necked bottle under the protection of nitrogen]Pyridin-4-yl trifluoromethanesulfonate (61.5g,166mmol), 2-fluoropyridine-5-boronic acid ester (44.5g,200mmol), [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride dichloromethane complex (6.8g,8.3mmol)1, 4-dioxane (850mL), potassium acetate solution (115mL,345mmol,3mol/L) is slowly added when the temperature is reduced to-10 ℃, and the reaction is naturally returned to room temperature after stirring for 1h at the temperature and continued overnight. Filtering, washing a filter cake by EA (500ml multiplied by 3), washing an organic phase by water (500ml), washing a saturated saline solution (250ml), drying by anhydrous sodium sulfate, filtering, spin-drying a filtrate, and purifying by silica gel column chromatography (an eluent PE/DCM is 2:1-0:1), collecting a target point, and spin-drying to obtain 49g of a white solid, namely the target product, with the yield of 93.0%. Rf is 0.50(PE/EA 1: 1). LC-MS: 318.10[ M + H ] M/z]+；1H NMR(400MHz,DMSO):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)。
And 4, step 4: 4- (6-Fluoropyridin-3-yl) -6- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile
Adding 6-bromo-4- (6-fluoropyridin-3-yl) pyrazolo [1,5-a into a 250mL single-mouth bottle in sequence under the protection of nitrogen]Pyridine-3-carbonitrile (8g,25.23mmol), pinacol diboron (10g,39.39mmol), potassium acetate (10g,101.9mmol), toluene (150mL) evaporated, nitrogen purged and bubbled for 10min before addition of [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride dichloromethane complex (2.1g,2.6mmo), nitrogen displacement bubbling for 10min, 120 ℃ heating reaction overnight. Celite was filtered, EA washed (50mL × 3) cake, organic phase washed with water (250m L), saturated brine washed (250mL), dried over anhydrous sodium sulfate, filtered, spin-dried, silica gel column chromatographed (eluent PE/DCM ═ 2:1-0:1) collected spin-dried to give 8.5g of orange solid as the target product (yield 93.0%). Rf is 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)。
And 5: 4- (6-Fluoropyridin-3-yl) -6-hydroxypyrazolo [1,5-a ] pyridine-3-carbonitrile
4- (6-Fluoropyridin-3-yl) -6- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrazolo [1,5-a ] was added in sequence in a 250mL single-necked flask]Pyridine-3-carbonitrile (8.5g,23mmol), tetrahydrofuran (120mL) under ice-bath conditions, hydrogen and oxygen were slowly addedSodium hydroxide solution (60mL,120mmol,2mol/L), hydrogen peroxide (14mL,140mmol,30 mass%), stirring at low temperature. After completion of the reaction, sodium thiosulfate solution (50mL,150mmol,3mol/L) was slowly added, and after returning to room temperature, water (250mL) was added, EA was extracted (250 mL. times.2), and the combined organic phases were washed with 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, filtered to give a wet cake. Mother liquor EA extraction (250M l × 3), combining all organic phases, drying over anhydrous sodium sulfate, filtering, spin-drying, silica gel column chromatography (eluent DCM \ MeOH (v/v ═ 100/0-100/1) to obtain light yellow solid, combining all solids, drying at 50 ℃ to obtain light yellow solid 5.1g which is the target product (yield 86.0%). Rf ═ 0.25(DCM \ MeOH (v/v ═ 100/1)). LC-MS: M/z ═ 255.10[ M + H ═ 100/1 ], (M + H + M-0.25)]+。
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 ester carboxylic acid
To a 30mL microwave tube, 4- (6-fluoropyridin-3-yl) -6-hydroxypyrazolo [1,5-a ] was added in this order]Pyridine-3-carbonitrile (1.5g,5.9mmol), 6- (tert-Butoxycarbonyl) -3, 6-diazabicyclo [3.1.1]Heptane (2.3g,12mmol), N-diisopropylethylamine (2.0mL,12mmol), dimethylsulfoxide (15mL), sealed, and reacted at 80 ℃ for 8h with microwave. At low temperature, water (50mL) is added for dilution, EA extraction (100mL × 5) is carried out, organic phases are combined and washed by saturated saline (250mL), dried by anhydrous sodium sulfate, filtered, filtrate is purified by spin-drying silica gel chromatography (eluent PE/EA is 5: 1-1; 1.5), and 1.9g of yellow product is collected, namely the target product (yield is 74.0%). Rf is 0.5(PE/EA is 1/1.5). LC-MS: 433.10[ M + H ] M/z]+。
And 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 ester-6-carboxylic acid ethyl ester
3- (5- (3-cyano-6-hydroxypyrazolo [1,5-a ] was sequentially added to a 25mL single-necked flask]Pyridin-4-yl) pyridin-2-yl) -3, 6-diazabicyclo [3.1.1]Heptane-6-tert-butyl ester carboxylic acid (1g,2.312mmol), benzyl bromide (0.302mL,2.54mmol), potassium carbonate (0.9683g,6.936mmol), N, N-dimethylformamide (10mL), stirred at 80 ℃ overnight. Quenching with saturated ammonium chloride (100mL) at room temperatureDCM (100mL × 3) was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, filtered and the filtrate was purified by spin-drying on a silica gel column (eluent PE/EA ═ 5: 1-2: 1) to give 1.06g of a yellow solid as the target product (yield 87.7%). Rf is 0.7(PE/EA 1: 1). LC-MS: 523.30[ M + H ] M/z]；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)。
And 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 ester-6-carboxylate (1.06g,2.03 mmol), ethyl acetate hydrochloride solution (5mL,20mmol,4mol/L) and reacted at room temperature overnight. The reaction solution was spin-dried to obtain a yellow viscous substance, which was dried at 60 ℃ to obtain 1.0g of a yellow solid, i.e., the desired product (yield 100%). LC-MS: and M/z is 423.30[ M-2HCl ].
And step 9: (6-methoxypyridin-3-yl) methanol
6-methoxy-3-pyridinecarboxaldehyde (0.4g,3mmol), lithium aluminum hydride (0.06g,2mmol) and tetrahydrofuran (10mL) were added in this order to a 25mL single-neck flask at 0 ℃ and reacted overnight at this temperature. EA (50m L) was added, the reaction mixture was diluted with water (50mL), extracted, separated, and then saturated NH4The organic layer was washed with Cl (50mL) solution, dried over anhydrous sodium sulfate, filtered, the filtrate was dried and purified by silica gel column chromatography (eluent DCM/EA ═ 4: 1) to obtain 0.38g of pale yellow liquid as the target product (yield 90.0%). LC-MS: 140.15[ M + H ] M/z]+；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-neck flask, (6-methoxypyridin-3-yl) methanol (0.38g,2.7mmol), methylene chloride (8mL), phosphorus tribromide were added sequentially(0.31mL,3.3mmol), and reacted at 0 ℃ for 30 min. Dilute with DCM (25m l) and saturate K2CO3(25mL), washed with aqueous solution, dried organic phase over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried and directly 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
4- (6- (3, 6-diazabicyclo [3.1.1] was added to a 25ml single-neck flask in sequence]Heptane-3-yl) pyridin-3-yl) -6- (benzyloxy) pyrazolo [1,5-a]Pyridine-3-carbonitrile (400mg,0.8074mmol), potassium carbonate (0.3382g,2.423mmol), N, N-dimethylformamide (8mL), then 5- (bromomethyl) -2-methoxypyridine (0.50g,2.5mmol) was added slowly and stirred at room temperature overnight. The reaction mixture was diluted with water (25mL), extracted with EA (50mL × 3), washed with saturated brine (50mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was purified by spin-drying on a silica gel column (eluent DCM/MeOH (v/v ═ 1/0-20/1) to give 0.2889g of a pale yellow solid, which was the target product (yield 65.82%). LC-MS: M/z ═ 544.10[ M + H544.10 ]]+；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
A50 ml single-necked flask was charged with 6- (benzyloxy) -4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1]Heptane-3-yl) pyridin-3-yl) pyrazolo [1,5-a]Pyridine-3-carbonitrile (0.288g,0.530mmol), methanol (5mL), palladium on carbon (0.03g, 10% mass), hydrogen substitution several times, and stirring at room temperature overnight. The reaction solution was filtered, the filter cake was washed with methanol, and the filtrate was spin-dried to obtain 240mg of a pale yellow solid as the objective product (yield 100.0%). LC-MS: 454.30[ M + H ] M/z]+；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: 6- (2- (2-oxa-6-azaspiro [3.3] heptan-6-yl) ethoxy) -4- (6-fluoropyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile
Figure BDA0002665034780000691
Step 1: 6- (2-chloroethyl) -2-oxa-6-azaspiro [3.3] heptane
Adding 2-oxa-6-azaspiro [3.3] into a 100mL single-mouth bottle]Heptane (2.0g,20mmol), potassium carbonate (15g,108.5mmol), 1-bromo-2-chloroethane (8.0mL,97.0mmol), acetonitrile (20mL), after the addition was complete, the reaction was carried out at room temperature. After the reaction is finished, insoluble solids are removed by suction filtration, the filter cake is washed by methanol, the organic phase is combined, and the product is obtained by silica gel column chromatography concentration and 860 mg.1H NMR(400MHz,CDCl3):δ4.74(s,4H),3.473.39(m,6H),2.72(t,J＝6.3Hz,2H)。
Step 2: 6- (2- (2-oxa-6-azaspiro [3.3] heptan-6-yl) ethoxy) -4- (6-fluoropyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile
A25 mL flask was charged with 4- (6-fluoropyridin-3-yl) -6-hydroxypyrazolo [1,5-a ] in that order]Pyridine-3-carbonitrile (500mg,1.97mmol), potassium carbonate (825mg,5.97mmol), 6- (2-chloroethyl) -2-oxa-6-azaspiro [ 3.3%]Heptane (850mg,5.26mmol), DMA (6mL), reacted at 80 ℃. After the completion of the TLC detection reaction, 20mL of water was added to the reaction mixture, EA (80 mL. times.2) was extracted, the organic phase was washed with water (15 mL. times.3), washed with saturated brine (15 mL. times.6), dried over anhydrous sodium sulfate and filtered, and the filtrate was subjected to silica gel column chromatography to obtain 210mg of a yellow solid as the product, wherein the eluent was EA-EA/MeOH (v/v. 20/1). LC-MS: 380.20[ M + H ] M/z]+；1H NMR(400MHz,CDCl3)δ8.38(d,J＝2.2Hz,1H),8.21(s,1H),8.19(d,J＝2.0Hz,1H),8.01(td,J＝8.4,2.5Hz,1H),7.18(d,J＝2.0Hz,1H),7.13(dd,J＝8.4,2.8Hz,1H),4.75(s,4H),4.03(t,J＝5.2Hz,2H),3.52(s,4H),2.87(t,J＝5.2Hz,2H)。
Example 1: 6- (2- (8-oxa-2-azaspiro [4.5] decan-2-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
Figure BDA0002665034780000701
Step 1: 2- (2-chloroethyl) -8-oxa-2-azaspiro [4.5] decane
A10 mL flask was charged with 8-oxa-2-azaspiro [4.5] in sequence]Decane (300mg,2.12mmol), potassium carbonate (882mg,6.38mmol), acetonitrile (3mL) were added after 10min of ice-bath reaction, 1-bromo-2-chloroethane (0.2mL,2.55mmol) was added and the reaction was continued for 10min of ice-bath reaction overnight at room temperature. The reaction solution was directly spin-dried and subjected to silica gel column chromatography (eluent PE: EA ═ 1:1) to obtain 41mg of pale yellow solid, i.e., the target product (yield 9.5%).1H NMR(400MHz,CDCl3):δ3.62(t,J＝5.3Hz,4H),3.55(t,J＝7.0Hz,2H),2.77(t,J＝7.0Hz,2H),2.64(t,J＝6.9Hz,2H),2.47(s,2H),1.68(t,J＝6.9Hz,2H),1.63-1.47(m,4H)。
Step 2: 6- (2- (8-oxa-2-azaspiro [4.5] decan-2-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
A5 mL flask was charged with 6-hydroxy-4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1]Heptane-3-yl) pyridin-3-yl) pyrazolo [1,5-a]Pyridine-3-carbonitrile (20mg,0.04mmol, see Synthesis of intermediate 1), 3- (2-chloroethyl) -8-oxa-3-azaspiro [4.5]]Decane (28mg,0.14mmol), potassium carbonate (31mg,0.22mmol), N, N-dimethylacetamide (0.8mL), and oil bath at 85 ℃ overnight. After the reaction, ethyl acetate (30mL × 3) was extracted, the combined organic phases were dried over anhydrous sodium sulfate, and silica gel column chromatography (eluent DCM/MeOH (v/v ═ 30/1-10/1) was performed to obtain 16mg of a pale yellow solid, i.e., the target product (yield: 58.4%). Rf ═ 0.1(DCM/MeOH ═ 20/1). LC-MS (ES-API): M/z ═ 621.35[ M + H ═ 621.35: (M + H-20/1))]+。1H NMR(400MHz,CDCl3):δ8.40(d,J＝2.1Hz,1H),8.21(s,1H),8.16(d,J＝2.1Hz,1H),8.10(s,1H),7.78(dd,J＝8.8,2.4Hz,1H),7.63(dd,J＝8.5,2.2Hz,1H),7.15(d,J＝1.9Hz,1H),6.70(dd,J＝11.9,8.7Hz,2H),4.17(t,J＝5.5Hz,2H),3.92(s,3H),3.83(d,J＝11.7Hz,2H),3.77(d,J＝5.7Hz,2H),3.65(t,J＝5.2Hz,4H),3.60(s,1H),3.58(s,2H),2.96(t,J＝5.5Hz,2H),2.76(t,J＝6.7Hz,2H),2.69(dd,J＝13.7,6.7Hz,1H),2.59(s,2H),2.03(d,J＝6.3Hz,2H),1.74(t,J＝6.9Hz,2H),1.63-1.54(m,4H)。
Example 2: 6- (2- (2-oxa-6-azaspiro [3.3] hept-6-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
Figure BDA0002665034780000711
Step 1: 6- (2-chloroethyl) -2-oxa-6-azaspiro [3.3] heptane
A 10mL single-mouth bottle is added with 2-oxa-6-azaspiro [ 3.3%]Heptane (250mg,2.52mmol), potassium carbonate (2.1g,15.1mmol), 1-bromo-2-chloroethane (2.1mL,13.0mmol), acetonitrile (2.5mL), reacted at room temperature. After the reaction, the reaction mixture was filtered, the filter cake was washed with methanol, the organic phase was concentrated, and silica gel column chromatography was performed to obtain 210mg of a colorless transparent liquid (yield: 51.5%) as the target product, and Rf was 0.3(EA/MeOH (v/v) ═ 5/1).1H NMR(400MHz,CDCl3):δ4.74(s,4H),3.47-3.40(m,6H),2.72(t,J＝6.3Hz,2H)。
Step 2: 6- (2- (2-oxa-6-azaspiro [3.3] hept-6-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
A5 mL flask was charged with 6-hydroxy-4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1]Heptane-3-yl) pyridin-3-yl) pyrazolo [1,5-a]Pyridine-3-carbonitrile (25mg,0.06mmol, see Synthesis of intermediate 1), 6- (2-chloroethyl) -2-oxa-6-azaspiro [ 3.3%]Heptane (5mg,0.34mmol), potassium carbonate (60mg,0.43mmol), N-dimethylacetamide (0.8mL), reacted overnight in an oil bath at 85 ℃. After the reaction was completed, ethyl acetate (10 mL. times.3) was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, and the filtrate was filtered and spin-driedSilica gel column chromatography (eluent DCM/MeOH 30/1-10/1) to collect light yellow solid 6mg as target product (yield: 3.0%). Rf 0.1(DCM/MeOH (v/v-20/1): LC-MS (ES-API) M/z 579.80[ M + H ═ g]+；1H NMR(400MHz,CDCl3):δ8.41(d,J＝2.1Hz,1H),8.23(s,1H),8.13(s,2H),7.80(dd,J＝8.8,2.5Hz,1H),7.74(s,1H),7.10(dd,J＝8.5,2.5Hz,1H),6.73(dd,J＝16.0,8.7Hz,2H),4.78(s,4H),4.05(t,J＝4.8Hz,2H),3.94(s,3H),3.89(s,2H),3.66(s,4H),3.56(s,4H),2.90(s,2H),2.80(s,1H),2.63(s,1H),2.40-2.29(m,1H),2.28-2.18(m,1H)。
Example 3: 6- (2- (1, 4-dioxa-8-azaspiro [4.5] decan-8-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
Figure BDA0002665034780000712
Step 1: 8- (2-chloroethyl) -1, 4-dioxa-8-azaspiro [4.5] decane
1, 4-dioxa-8-azaspiro [4.5] was added to a 10mL single-necked flask]Decane hydrochloride (300mg,1.67mmol), potassium carbonate (693mg,5.01mmol) and acetone (3.0mL) were added, and after completion of the addition, 1-bromo-2-chloroethane (0.2mL,2.004mmol) was slowly added under ice-bath conditions, and after stirring for 10min, the reaction was returned to room temperature overnight. After the reaction, acetone was removed by rotary evaporation, dichloromethane (10ml × 2) was extracted, the organic phases were combined, washed with water (10ml × 2), dried over anhydrous sodium sulfate, filtered, and then subjected to silica gel column chromatography (eluent PE/EA (v/v) ═ 1/1) to collect and dry, to obtain 43mg of a white solid, i.e., the objective product (yield: 12.519%, Rf ═ 0.3(EA/MeOH (v/v) ═ 5/1)).1H NMR(400MHz,CDCl3)：δ＝3.93(s,4H),3.56(t,J＝7.1Hz,2H),2.74(t,J＝7.1Hz,2H),2.63-2.52(m,4H),1.79-1.68(m,4H)。
Step 2: 6- (2- (7-oxa-2-azaspiro [4.5] decan-2-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
The 6-hydroxy is added into a 5ml single-mouth bottle in sequenceYl-4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1]Heptane-3-yl) pyridin-3-yl) pyrazolo [1,5-a]Pyridine-3-carbonitrile (20mg,0.04410mmol, see Synthesis of intermediate 1), 8- (2-chloroethyl) -1, 4-dioxa-8-azaspiro [4.5]]Decane (18.2mg,0.0885mmol), potassium carbonate (30.78mg,0.2205mmol), DMA (0.5mL), oil bath 80 ℃ heating overnight. After the reaction, the reaction mixture was diluted with water (10mL), extracted with EA (20mL × 3), the organic phase was collected, washed with saturated brine (20mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was purified by spin-drying on a silica gel column to obtain 21mg of a yellow solid (yield 76.47%) (Rf ═ 0.45, DCM/MeOH (v/v) ═ 15/1). LC-MS M/z 623.1[ M + H ]]+；1H NMR(400MHz,CDCl3):δ8.39(s,1H),8.20(s,1H),8.16(s,1H),8.10(s,1H),7.77(d,J＝7.2Hz,1H),7.63(d,J＝6.8Hz,1H),7.14(s,1H),6.70(dd,J＝12.9,8.7Hz,2H),4.17(t,2H),3.96(s,4H),3.92(s,3H),3.84(d,J＝11.3Hz,2H),3.78(d,J＝4.9Hz,2H),3.66-3.53(m,4H),2.92(t,J＝5.3Hz,2H),2.73-2.67(m,4H),2.10-2.01(m,2H),1.82-1.76(m,4H)。
Example 4: 6- ((3, 3-dimethyl-1, 5-dioxaspiro [5.5] undecan-9-yl) oxy) -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
Figure BDA0002665034780000721
Step 1: 3, 3-dimethyl-1, 5-dioxaspiro [5.5] undecan-9-ol
In a cryotank at-10 deg.C, a 25mL two-necked flask was charged with lithium aluminum hydroxide in THF (2.0mol/L,100mg,3mmol) and 3, 3-dimethyl-1, 5-dioxaspiro [5.5] spiro was added slowly under nitrogen protection]A THF solution (10mL) of undecane-9-one was slowly returned to room temperature after the addition was completed, and stirring was continued for 2 hours. Quenching with saturated aqueous ammonium chloride (10mL) at low temperature, decanting, extracting with EA (30 mL. times.3), combining the organic phases, washing with saturated brine (50mL), drying the organic phase with anhydrous sodium sulfate, filtering, and purifying with silica gel column chromatography(eluent DCM/EA (v/v) ═ 5/1), collect target solution and spin dry to obtain white solid as target product (yield: 90.0%, Rf ═ 0.5(EA/DCM (v/v) ═ 1/8)).1H NMR(400MHz,CDCl3):δ3.85-3.76(m,1H),3.52(d,J＝3.3Hz,4H),2.12-2.09(m,1H),1.81(dd,J＝11.8,5.6Hz,2H),1.61(d,J＝9.9Hz,6H),0.99(s,6H)。
Step 2: 3, 3-dimethyl-1, 5-dioxaspiro [5.5] undecan-9-yl methanesulfonate
Under ice-bath conditions, 3-dimethyl-1, 5-dioxaspiro [5.5] is added into a 5mL single-neck bottle in sequence]Undecane-9-ol (100mg,0.4993mmol), dichloromethane (1mL), triethylamine (0.105mL, 0.748mmol), methanesulfonyl chloride (0.05mL, 0.649mmol) was added slowly, and after the addition, the reaction was allowed to return slowly to room temperature for 2 h. At low temperature, water (10mL) was added for dilution, DCM extraction (25 mL. times.3) was used to extract the combined organic layers with saturated NaHCO respectively3Washing the mixture (30mL), washing the mixture with saturated saline solution (30mL), drying the mixture with anhydrous sodium sulfate, and performing silica gel column chromatography purification (DCM/EA (v/v) ═ 10/1) to obtain a pale yellow solution, wherein 131mg of the pale yellow solution is the target product. (yield: 94.2%, Rf 0.8(EA/DCM (v/v) ═ 1/10)).1H NMR(400MHz,CDCl3):δ4.86-4.79(m,1H),3.49(d,J＝13.9Hz,4H),3.01(s,3H),1.99(dd,J＝15.4,9.2Hz,2H),1.91(dd,J＝10.9,5.6Hz,4H),1.82(dd,J＝13.1,4.6Hz,2H),0.96(s,6H).
And step 3: 6- ((3, 3-dimethyl-1, 5-dioxaspiro [5.5] undecan-9-yl) oxy) -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
In a 5mL single-necked flask was added 6-hydroxy-4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1]Heptane-3-yl) pyridin-3-yl) pyrazolo [1,5-a]Pyridine-3-carbonitrile (25mg,0.05513mmol, intermediate 1), 3, 3-dimethyl-1, 5-dioxaspiro [5.5]]Undecane-9-yl methanesulfonate (30.69mg,0.1102mmol), potassium carbonate (24.06mg,0.1654mmol), DMF (0.25mL), and the oil bath was heated at 80 ℃ overnight. After completion of the reaction, the reaction mixture was diluted with water (10mL), extracted with EA (20 mL. times.3), the organic phase was collected, washed with saturated brine (20mL), dried over anhydrous sodium sulfate, filtered, the filtrate was spin-dried, and purified by silica gel column chromatography(eluent DCM/MeOH (v/v) ═ 50/1-40/1) to give 14.3mg of yellow solid, i.e. the target product (yield 40.8%), (Rf ═ 0.4, DCM/MeOH (v/v) ═ 30/1). LC-MS M/z 636.2[ M + H ]]+；1H NMR(400MHz,CDCl3):δ8.40(d,J＝2.2Hz,1H),8.21(s,1H),8.16(d,J＝1.7Hz,1H),8.10(d,J＝1.3Hz,1H),7.77(dd,J＝8.7,2.3Hz,1H),7.63(d,J＝6.3Hz,1H),7.11(d,J＝1.8Hz,1H),6.70(dd,J＝12.9,8.7Hz,2H),4.43-4.34(m,1H),3.92(s,3H),3.84(d,J＝10.8Hz,2H),3.78(d,J＝5.3Hz,2H),3.61(s,2H),3.58(s,2H),3.53(d,J＝9.2Hz,4H),2.69(dd,J＝13.2,7.0Hz,1H),2.04(dd,J＝12.4,5.9Hz,3H),1.94(dd,4H),1.84(dd,J＝12.5,6.0Hz,2H),0.98(s,6H)。
Example 5: 6- ((2-oxaspiro [3.3] heptan-6-yl) oxy) -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
Figure BDA0002665034780000741
Step 1: 2-oxaspiro [3.3] hept-6-yl methanesulfonate
Under the ice-bath condition, 2-oxaspiro [3.3] is added into a 5mL single-mouth bottle in sequence]Hept-6-ol (100mg,0.9mmol), dichloromethane (1mL), triethylamine (0.2mL, 1.0mmol), methanesulfonyl chloride (0.09mL, 1mmol) was added slowly, and after the addition was complete, the reaction was allowed to return slowly to room temperature for 2 h. At low temperature, water (10mL) was added for dilution, and saturated Na was added2SO4The aqueous solution (10mL) was quenched and the combined organic layers were extracted with EA (30 mL. times.3) and separately saturated NaHCO3Washing (30mL), washing with saturated saline solution (30mL), drying with anhydrous sodium sulfate, and spin drying to obtain light yellow oil 0.16 g. (yield: 100%, Rf 0.8(EA/PE (v/v) ═ 1/10)).1H NMR(400MHz,CDCl3):δ4.83(p,J＝7.2Hz,1H),4.68(d,J＝8.2Hz,4H),2.97(s,3H),2.82–2.74(m,2H),2.52–2.44(m,2H)。
Step 2: 6- ((2-oxaspiro [3.3] heptan-6-yl) oxy) -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
In a 5mL single-necked flask was added 6-hydroxy-4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1]Heptane-3-yl) pyridin-3-yl) pyrazolo [1,5-a]Pyridine-3-carbonitrile (25mg,0.05513mmol, intermediate 1), 2-oxaspiro [3.3]]Hept-6-yl methanesulfonate (21.2mg,0.11mmol), potassium carbonate (24.06mg,0.1654mmol), DMF (0.5mL), and was heated in an oil bath at 80 ℃ overnight. After the reaction, the reaction mixture was diluted with water (10mL), extracted with EA (25mL × 3), the organic phase was collected, washed with saturated brine (20mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was purified by spin-drying on a silica gel column to obtain DCM/MeOH (v/v) ═ 100/1-20/1, and the yellow solid was collected and dried to obtain 11.5mg (yield 38%) of the desired product (Rf ═ 0.2, DCM/MeOH (v/v) ═ 30/1). LC-MS M/z 550.30[ M + H ]]+。1H NMR(400MHz,CDCl3)δ8.39(d,J＝2.1Hz,1H),8.21(s,1H),8.12(d,J＝1.8Hz,1H),7.95(d,J＝1.9Hz,1H),7.79(dd,J＝8.9,2.4Hz,1H),7.53(d,J＝8.5Hz,1H),7.05(d,J＝2.0Hz,1H),6.93(t,J＝7.4Hz,2H),4.75(d,J＝20.2Hz,4H),4.57–4.52(m,1H),3.97–3.86(m,7H),3.73–3.65(m,4H),2.65–2.56(m,2H),2.48–2.42(m,2H),2.37–2.33(m,1H),2.21(d,J＝7.6Hz,1H)。
Example 6: 6- (2- ((2-oxaspiro [3.3] heptan-6-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
Figure BDA0002665034780000742
Step 1: 2- (6-oxaspiro [3.3] heptan-2-yloxy) acetic acid ethyl ester
A25 mL double-necked flask was charged with NaH (127mg,3.175mmol), evacuated under nitrogen, dissolved in anhydrous THF (10mL) at 0 deg.C, and charged with liquid 6-oxaspiro [3.3] ethanol]Heptane-2-ol (300mg,2.628mmol) was stirred at room temperature for 2 hours after the addition, transferred to 0 ℃ and 2-bromoethyl acetate (0.32mL,2.9mmol) was slowly added and stirred at room temperature for reaction. TLC spot plate, KMnO4Oxidation showed the reaction was complete, quenched with 15mL of water, extracted with EA (60 mL. times.2) withThe organic phase was washed with 30mL of saturated brine, dried over anhydrous sodium sulfate, filtered, spun-dried, and subjected to silica gel column chromatography (eluent PE/EA (v/v) ═ 10/1-1/1) to obtain 0.222g of an oily liquid (yield 42.2%), which was the target product.1H NMR(400MHz,CDCl3):δ4.63(d,J＝12.0Hz,4H),4.19(q,J＝7.1Hz,2H),3.94(s,2H),3.93–3.85(m,1H),2.61–2.52(m,2H),2.23–2.14(m,2H),1.26(t,J＝7.1Hz,3H)。
Step 2: 2- (6-oxaspiro [3.3] heptan-2-yloxy) ethanol
In a 25mL double-necked flask, LiAlH was added4(0.085g,2.2mmol) and THF 5mL, evacuated under nitrogen, and 2- (6-oxaspiro [3.3] was added]Heptane-2-yloxy) ethyl acetate (222mg,1.109mmol) was dissolved in 3mL THF, added slowly to a two-necked flask at 0 deg.C and allowed to incubate. TLC spot plate (KMnO)4Oxidation) shows that the reaction is finished, 10mL of saturated ammonium chloride solution is added to quench the reaction, EA (20mL multiplied by 2) is extracted, the organic phase is washed by 15mL of saturated saline, dried by anhydrous sodium sulfate, filtered, dried by spinning, and subjected to silica gel column chromatography (eluent pure DCM-DCM/EA ((v/v)4/1-1/4)) to obtain 0.103g of light yellow oily matter (yield 58.7 percent), namely the target product.1H NMR(400MHz,CDCl3):δ4.65(d,J＝16.7Hz,4H),3.83(dd,J＝13.9,7.0Hz,1H),3.73–3.63(m,2H),3.46–3.36(m,2H),2.68–2.47(m,2H),2.15–2.08(m,2H)。
And step 3: 2- (6-oxaspiro [3.3] heptan-2-yloxy) ethyl methanesulfonate
2- (6-oxaspiro [3.3] hept-2-yloxy) ethanol (100mg,0.632mmol) and DCM (1.5mL) were added to a 10mL single-neck flask under ice-bath conditions, and TEA (0.133mL,0.947mmol) was added, followed by slow dropwise addition of methanesulfonyl chloride (0.065mL,0.83mmol), followed by natural warming to room temperature for reaction. TLC showed the reaction was complete, quenched with 3mL water, extracted with DCM (15 mL. times.2), washed with 8mL saturated brine, dried over anhydrous sodium sulfate, filtered, spun-dried, and pumped-dried to give the theoretical amount of yellow liquid, which was directly charged to the next reaction.
And 4, step 4: 6- (2- ((2-oxaspiro [3.3] heptan-6-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
5mL Single-necked flask was charged with 2- (6-oxaspiro [3.3]]Heptane-2-yloxy) ethyl methanesulfonate (32mg,0.135mmol), K2CO3(37mg,0.265mmol), 6-hydroxy-4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1]Heptane-3-yl) pyridin-3-yl) pyrazolo [1,5-a]Pyridine-3-carbonitrile (30mg,0.066mmol, intermediate 1), DMF (1.5mL) was dissolved and reacted at 60 ℃ with stirring for 8 h. TLC plates showed the reaction was complete, washed with 10mL water, extracted with EA (40mL × 2), combined organic phases washed with 20mL brine, dried over anhydrous sodium sulfate, filtered, spun-dried, and chromatographed on silica gel (eluent pure DCM-DCM/MeOH (v/v ═ 10/1)) to give 0.011g of pale yellow solid (28% yield), which was the target product. LC-MS M/z 594.10[ M + H ]]+；1H NMR(400MHz,CDCl3)；δ8.40(s,1H),8.21(s,1H),8.16(s,1H),8.11(s,1H),7.78(dd,J＝8.7,2.1Hz,1H),7.69(d,J＝8.6Hz,1H),7.16(s,1H),6.71(dd,J＝15.4,8.6Hz,2H),4.67(d,J＝18.4Hz,4H),4.17–4.13(m,2H),3.92(s,3H),3.90–3.87(m,1H),3.85(s,3H),3.75–3.72(m,2H),3.66(dd,J＝14.5,7.5Hz,5H),2.76(dd,J＝6.0,3.6Hz,1H),2.65–2.57(m,2H),2.21–2.15(m,2H),2.07–2.00(m,1H)。
Example 7: 6- ((1, 4-dioxaspiro [4.5] decan-8-yl) oxy) -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
Figure BDA0002665034780000761
Step 1:1, 4-dioxaspiro [4.5] decan-8-ol
Under ice-bath conditions, 1, 4-cyclohexanedione monoethylene ketal (2.0g,13mmol) and methanol (40mL) were added sequentially to a 100mL single-neck flask. Sodium borohydride (1.5g,40mmol) was added in portions and, after the addition was complete, the mixture was allowed to return to room temperature and stirring continued. TLC after 2h showed the reaction was complete. Concentrating the reaction solution to solid, adding water (20mL), extracting with EA (50 mL. times.3), combining the organic phases, washing with saturated brine (100mL), drying the organic phase over anhydrous sodium sulfate, filtering, spin-drying, purifying with silica gel column chromatography, and eluting with DCM/EA (v/v) ═ 5/1 to obtain the eluent1.89g of colorless transparent liquid.1H NMR(400MHz,CDCl3):δ4.02-3.85(m,4H),3.84-3.73(m,1H),1.93-1.74(m,5H),1.63(ddd,J＝14.2,10.0,6.5Hz,4H)。
Step 2:1, 4-dioxaspiro [4.5] decan-8-yl methanesulfonate
Under ice-bath conditions, 1, 4-dioxaspiro [4.5] was added to a 5mL single-neck flask in sequence]Decan-8-ol (200mg,1.26mmol), dichloromethane (2mL), triethylamine (0.27mL,1.89mmol) was added slowly to methanesulfonyl chloride (0.13mL,1.64mmol), and after the addition was complete, stirring was allowed to resume at room temperature for 2 h. TLC showed the reaction was complete. At low temperature, 30mL of water was added for dilution, extracted with dichloromethane (50 mL. times.3), and the combined organic phases were saturated NaHCO3The reaction solution was washed with saturated brine, dried over anhydrous sodium sulfate, and subjected to silica gel column chromatography (DCM/EA (v/v) ═ 10/1), whereby 290mg of a pale yellow solution was collected.1H NMR(400MHz,CDCl3):δ4.90-4.78(m,1H),3.95(dd,J＝6.0,3.9Hz,4H),3.01(s,3H),2.00(dd,J＝12.2,6.8Hz,4H),1.90-1.81(m,2H),1.68-1.61(m,2H)。
And step 3: 6- ((1, 4-dioxaspiro [4.5] decan-8-yl) oxy) -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
A5 mL single-necked flask was charged with 6-hydroxy-4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1]Heptane-3-yl) pyridin-3-yl) pyrazolo [1,5-a]Pyridine-3-carbonitrile (40mg,0.09mmol, intermediate 1), 1, 4-dioxaspiro [4.5]]Deca-8-methanesulfonate (65mg,0.27mmol), cesium carbonate (115mg,0.35mmol), DMA (1mL), reacted at 60 ℃ overnight. The reaction solution was poured into 10mL of ice water, EA extraction (30mL × 3) was performed, the combined organic phases were washed with saturated brine (20mL × 3), the organic phases were dried over anhydrous sodium sulfate, filtration was performed, the filtrate was spun dry, and silica gel column chromatography was performed as a residue (eluent DCM/MeOH ═ 25/1), whereby 22mg of a white solid was collected. LC-MS M/z 594.30[ M + H ]]+；1H NMR(400MHz,CDCl3)δ8.40(d,J＝2.1Hz,1H),8.21(s,1H),8.17(d,J＝1.8Hz,1H),8.11(d,J＝1.5Hz,1H),7.78(dd,J＝8.8,2.3Hz,1H),7.70(d,J＝6.6Hz,1H),7.12(d,J＝1.8Hz,1H),6.70(dd,J＝15.5,8.7Hz,2H),4.43-4.36(m,1H),4.01-3.95(m,4H),3.92(s,3H),3.90-3.80(m,4H),3.70-3.59(m,4H),2.81-2.71(m,1H),2.05-1.98(m,4H),1.96-1.93(m,1H),1.71-1.62(m,4H)。
Example 8: 6- (2- ((6-azaspiro [3.4] heptan-2-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
Figure BDA0002665034780000771
Under the ice-bath condition, the mixture is filled with 6- (2- ((6-azaspiro [3.4]]Octane-2-yl) oxy) ethoxy) -4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1]Heptane-3-yl) pyridin-3-yl) pyrazolo [1,5-a]Pyridine-3-carbonitrile dihydrochloride (10.8mg,0.016mmol, example 9 compound) in a 5mL single-neck flask was added 1mL of saturated sodium bicarbonate solution, the pH was adjusted to basic, 3mL of DCM was added, and the mixture was stirred for 5 min. The organic phase was separated, extracted with DCM (5 mL. times.2), washed with 5mL of saturated brine, dried over anhydrous sodium sulfate, filtered, spun-dried and drained. The desired product was obtained in the form of a pale yellow solid (6 mg, yield 60%). LC-MS, M/z 607.2[ M + H ]]+；1H NMR(400MHz,CDCl3)δ8.41–8.37(m,1H),8.21(s,1H),8.16(d,J＝1.8Hz,1H),8.10(d,J＝1.3Hz,1H),7.78(dd,J＝8.8,2.3Hz,1H),7.62(dd,J＝8.5,2.1Hz,1H),7.17(d,J＝1.7Hz,1H),6.70(dd,J＝12.2,8.7Hz,2H),4.21–4.14(m,2H),4.11–4.02(m,1H),3.92(s,3H),3.83(d,J＝10.9Hz,2H),3.76(d,J＝5.2Hz,4H),3.67–3.58(m,2H),3.57(s,2H),3.14–2.86(m,4H),2.71–2.64(m,1H),2.37–2.29(m,2H),2.24–2.19(m,1H),2.05(dd,J＝11.3,5.7Hz,3H),1.86(d,J＝7.1Hz,2H)。
Example 9: 6- (2- ((6-azaspiro [3.4] octan-2-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 dihydrochloride
Figure BDA0002665034780000772
Step 1: 2- (2-ethoxy-2-oxoethoxy) -6-azaspiro [3.4] octane-6-carboxylic acid tert-butyl ester
Adding NaH (72mg,1.8mmol) into a 25mL double-mouth bottle, vacuumizing for multiple times under the protection of nitrogen, placing at 0 ℃, adding anhydrous THF (17mL) to prepare a suspension, and adding 2-hydroxy-6-azaspiro [3.4]]Octane-6-carboxylic acid tert-butyl ester (340mg,1.496mmol), after which it was heated to room temperature and stirred for 2 h. The mixture was transferred to 0 ℃ and ethyl 2-bromoacetate (0.183mL,1.65mmol) was added slowly, followed by stirring at room temperature overnight. TLC showed that the reaction was complete, the reaction mixture was quenched with 15mL of water, extracted with EA (60mL × 2), washed with 30mL of saturated brine, dried over anhydrous sodium sulfate, filtered, spun-dried, and chromatographed on silica gel (eluent PE/EA (v/v) ═ 10/1-2/1) to give 0.143g of oily liquid (yield 31%), which was the target product. LC-MS (M/z: 258.1) [ M-56+ H ]]+。1H NMR(400MHz,CDCl3):δ4.21(q,J＝7.1Hz,2H),4.11–4.03(m,1H),4.00–3.95(m,2H),3.37–3.21(m,4H),2.33–2.21(m,2H),2.10–1.97(m,2H),1.88–1.75(m,2H),1.44(s,9H),1.28(t,J＝7.1Hz,3H)。
Step 2: 2- (2-Hydroxyethoxy) -6-azaspiro [3.4] octane-6-carboxylic acid tert-butyl ester
In a 25mL double-necked flask, LiAlH was added4(40.5mg,1.07mmol), 3mL THF was added to make a suspension, and vacuum was applied under nitrogen to 2- (2-ethoxy-2-oxoethoxy) -6-azaspiro [3.4]]Octane-6-carboxylic acid tert-butyl ester (134mg,0.428mmol) was dissolved in 3mL THF, slowly added to a two-necked flask at-40 ℃ in a cryotank, and reacted for 1h with incubation. TLC showed the reaction was complete, and the reaction was quenched with 12mL of water, extracted with EA (25mL × 2), washed with 15mL of saturated organic brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried and chromatographed on silica gel (eluent PE/EA (v/v) ═ 4/1-1/4) to give 0.101g of a clear oil (yield 87%), which was the desired product. LC-MS: 216.3[ M-56+ H ] M/z]+；1H NMR(400MHz,CDCl3):δ4.04–3.94(m,1H),3.75–3.67(m,2H),3.46–3.41(m,2H),3.37–3.21(m,4H),2.32–2.20(m,2H),2.14(s,1H),2.00–1.89(m,2H),1.85–1.78(m,2H),1.43(s,9H)。
And step 3: 2- (2-Methylsulfonyloxyethoxy) -6-azaspiro [3.4] octane-6-carboxylic acid tert-butyl ester
Under ice-bath conditions, 2- (2-hydroxyethoxy) -6-azaspiro [3.4] was added to a 5mL single-neck flask]Tert-butyl octane-6-carboxylate (95mg,0.350mmol) and DCM (1.5mL) were dissolved, TEA (0.074mL,0.53mmol) was added, methanesulfonyl chloride (0.036mL,0.46mmol) was slowly added dropwise, and the mixture was allowed to warm to room temperature naturally for 1 h. TLC showed the reaction was complete, quenched with 3mL water, extracted with DCM (10mL × 2), washed with 5mL of saturated organic brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was dried by spinning and flash column chromatographed on silica gel (eluent PE/EA (v/v) ═ 4/1-1/2) to give 0.117g of yellow clear oil (96% yield) as the desired product.1H NMR(400MHz,CDCl3):δ4.37–4.31(m,2H),4.01(p,J＝6.8Hz,1H),3.63–3.57(m,2H),3.37–3.21(m,4H),3.05(s,3H),2.33–2.21(m,2H),2.02–1.90(m,2H),1.87–1.77(m,2H),1.44(s,9H)。
And 4, step 4: 2- (2- ((3-cyano-4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridin-6-yl) oxy) ethoxy) -6-azaspiro [3.4] octane-6-carboxylic acid tert-butyl ester
Adding 2- (2-methylsulfonyloxy ethoxy) -6-azaspiro [3.4] into a 5mL single-mouth bottle]Octane-6-carboxylic acid tert-butyl ester (46mg,0.132mmol), K2CO3(37mg,0.265mmol), 6-hydroxy-4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1]Heptane-3-yl) pyridin-3-yl) pyrazolo [1,5-a]Pyridine-3-carbonitrile (30mg,0.066mmol, intermediate 1) was dissolved in DMF (1.5mL) and reacted with stirring at 60 ℃ overnight. TLC showed the reaction was complete, washed with 10mL water, extracted with EA (40mL × 2), washed with 20mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was dried by spinning and chromatographed on silica gel (eluent pure DCM-DCM/MeOH ((v/v) ═ 10/1)) to give 22.6mg of pale yellow solid (yield 48.3%), which was the desired product. LC-MS (LC-MS) M/z 707.30[ M + H [ ]]+；1H NMR(400MHz,CDCl3)δ8.40(d,J＝2.1Hz,1H),8.21(s,1H),8.16(d,J＝1.5Hz,1H),8.11(d,J＝0.8Hz,1H),7.78(dd,J＝8.8,2.4Hz,1H),7.65(dd,J＝4.4,2.3Hz,1H),7.17(s,1H),6.70(dd,J＝13.4,8.7Hz,2H),4.21–4.13(m,2H),4.12–4.04(m,1H),3.92(s,3H),3.87–3.74(m,6H),3.65–3.54(m,4H),3.38–3.24(m,4H),2.71(s,1H),2.37–2.24(m,2H),2.18–1.89(m,3H),1.87–1.79(m,2H),1.45(s,9H)。
And 5: 6- (2- ((6-azaspiro [3.4] octan-2-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 dihydrochloride
A10 mL single-necked bottle was charged with 2- (2- ((3-cyano-4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [ 3.1.1)]Heptane-3-yl) pyridin-3-yl) pyrazolo [1,5-a]Pyridin-6-yl) oxy) ethoxy) -6-azaspiro [3.4]Octane-6-carboxylic acid tert-butyl ester (19.2mg,0.027mmol, ethyl acetate hydrochloride solution (2mL,8mmol,4mol/L), stirred at room temperature for 1 h.TLC showed the reaction was complete, the reaction was directly spun dry and drained to give the theoretical amount of a yellowish white solid product LC-MS: M/z 607.2[ M + H ]. The]+。
Example 10: 4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- ((6-methoxyspiro [3.3] heptan-2-yl) methoxy) pyrazolo [1,5-a ] pyridine-3-carbonitrile
Figure BDA0002665034780000791
Step 1: 6-Hydroxyspiro [3.3] heptane-2-carboxylic acid methyl ester
Adding 6-oxo spiro [3.3] into 100mL double-mouth bottle]Methyl heptane-2-carboxylate (1.4g,8.3mmol), nitrogen replaced and 10mL of THF was added to dissolve it, lithium tri-tert-butoxyaluminum hydride (4.6g,17mmol) in 15mL of THF was added dropwise at-78 deg.C, and the reaction was carried out at this temperature after the addition. After the reaction is finished, adding 15mL of water for quenching, generating a large amount of white jelly, performing suction filtration, extracting an aqueous phase by ethyl acetate, concentrating silica gel column chromatography, and obtaining 1.2g of colorless liquid, namely the target product, wherein an eluent PE/EA (v/v) ═ 10/1. Rf is 0.3(PE/EA (v/v) ═ 5/1); LC-MS M/z 171.15[ M + H ]]+；1H NMR(400MHz,CDCl3):δ4.15(p,J＝7.2Hz,1H),3.64(s,3H),3.01(p,J＝8.5Hz,1H),2.50-2.40(m,1H),2.36-2.24(m,3H),2.23-2.11(m,2H),2.03(s,1H),1.89(m,2H)。
Step 2: 6-Methoxysiliro [3.3] heptane-2-carboxylic acid methyl ester
Adding 6-hydroxy spiro [3.3] into 100mL single-mouth bottle]Methyl heptane-2-carboxylate (1.2g,7.1mmol) was dissolved in THF (18mL), sodium hydride (560mg,14.0mmol,60 mass%) was added in two portions at-10 deg.C, and after 15min methyl iodide (1.0mL,16mmol) was added and the reaction was carried out at room temperature. After the reaction, water was added to quench, and the mixture was extracted with ethyl acetate (20mL × 2), the organic phase was washed twice with water, dried over anhydrous sodium sulfate, and concentrated by silica gel column chromatography to obtain a colorless liquid 480mg with PE/EA (v/v) ═ 20/1-5/1 as an eluent. Rf is 0.8(PE/EA (v/v) ═ 5/1),1H NMR(400MHz,CDCl3):δ3.79-3.70(m,1H),3.66(s,3H),3.19(s,3H),3.03(p,J＝8.5Hz,1H),2.44-2.36(m,1H),2.33-2.13(m,5H),1.91(m,2H)。
and step 3: (6-Methoxispiro [3.3] heptan-2-yl) methanol
After nitrogen gas was replaced in a 25mL double-necked flask, methyl 6-methoxyspiro [3.3] heptane-2-carboxylate (480mg,2.6mmol) dissolved in 10mL THF was added, and after stirring at 10 ℃ for 10min, diisobutylaluminum hydride (8.0mL,8.0mmol,1mol/L) was added dropwise, followed by reaction at room temperature. After the reaction, water was added to quench the reaction, the reaction solution became gel-like, 14mL of HCl (1N) was added to dissolve it completely, extraction was performed with ethyl acetate (80mL × 2), the organic phase was washed twice with water, once with saturated brine, and silica gel column chromatography was concentrated to obtain 330mg of a colorless liquid, eluent PE/EA (v/v) ═ 5/1.
Rf＝0.3(PE/EA(v/v)＝5/1)，1H NMR(400MHz,CDCl3):δ3.76(p,J＝7.1Hz,1H),3.56(d,J＝6.8Hz,2H),3.21(s,3H),2.46-2.33(m,2H),2.23(dt,J＝11.6,6.0Hz,1H),2.13-2.00(m,2H),1.96-1.84(m,2H),1.78(dd,J＝11.5,5.8Hz,2H)。
Step 4: (6-Methoxyspiro [3.3] hept-2-yl) methyl methanesulfonate
Adding (6-methoxyspiro [3.3] into a 25mL single-mouth bottle]Heptane-2-yl) methanol (340mg,2.2mmol) was dissolved by adding 4mL of EDCM, triethylamine (0.7mL,5mmol) was added, methanesulfonyl chloride (0.3mL,3mmol) was added dropwise at 0 deg.C, and the reaction was carried out at room temperature. After the reaction, the reaction mixture was extracted with DCM (20mL × 2), the organic phase was washed three times with water, once with saturated brine, and column chromatography was performed by concentration to obtain a liquid eluent PE/EA (v/v) ═ 5/1340mg。Rf＝0.3(PE/EA(v/v)＝5/1)。1H NMR(400MHz,CDCl3):δ4.17(d,J＝6.8Hz,2H),3.77(p,J＝7.1Hz,1H),3.21(s,3H),3.01(s,3H),2.70-2.56(m,1H),2.46-2.37(m,1H),2.27(dt,J＝11.6,5.9Hz,1H),2.21-2.08(m,2H),1.91(m,4H)。
And 5: 4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- ((6-methoxyspiro [3.3] heptan-2-yl) methoxy) pyrazolo [1,5-a ] pyridine-3-carbonitrile
A5 mL single vial 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 (20mg,0.044mmol, intermediate 1), potassium carbonate (24mg,0.17mmol), (6-methoxyspiro [3.3] hept-2-yl) methyl methanesulfonate (65mg,0.28mmol), DMF (0.8mL,100 mass%), and reacted at 90 ℃. The reaction was carried out overnight. After the reaction, the reaction mixture was cooled to room temperature, 5mL of water was added, extraction was performed with ethyl acetate (20mL × 2), the organic phase was washed with water 8 times, washed with saturated brine once, dried over anhydrous sodium sulfate and concentrated by column chromatography, and 13mg of a yellow solid was obtained as an eluent, DCM/MeOH (v/v) ═ 40: 1.
Rf＝0.3(DCM/MeOH(v/v)＝15/1)，LC-MS：m/z＝592.25[M+H]+，1H NMR(400MHz,CDCl3)：δ8.40(d,J＝2.1Hz,1H),8.20(s,1H),8.10(d,J＝1.9Hz,2H),7.77(dd,J＝8.8,2.5Hz,1H),7.63(dd,J＝8.5,2.1Hz,1H),7.11(d,J＝2.0Hz,1H),6.69(dd,J＝12.9,8.7Hz,2H),3.95(d,J＝6.5Hz,2H),3.92(s,3H),3.83(d,J＝12.7Hz,2H),3.77(d,J＝6.5Hz,2H),3.60(s,1H),3.58(s,2H),3.21(s,3H),2.76-2.71(m,2H),2.46-2.40(m,1H),2.35-2.10(m,4H),2.08-1.88(m,2H),1.98-1.91(m,4H)。
Example 11: 6- ((6-hydroxy-6-methylspiro [3.3] heptan-2-yl) methoxy) -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
Figure BDA0002665034780000801
Step 1: (6-hydroxy-6-methylspiro [3.3] heptan-2-yl) methyl methanesulfonate
2- (hydroxymethyl) -6-methyl-spiro [3.3] was added to a 10mL single-neck bottle]Heptane-6-ol (65mg,0.42mmol), dichloromethane (0.8mL) was added and dissolved, triethylamine (0.08mL,0.6mmol) was added, methanesulfonyl chloride (0.06mL,0.7mmol) was added at 0 ℃ and the reaction was carried out at room temperature. TLC detects that the raw material reaction is finished, the reaction is stopped, 5mL of water is added into reaction liquid, DCM (15mL multiplied by 2) is used for extraction, an organic phase is washed by water (5mL multiplied by 2), saturated salt water is washed, anhydrous sodium sulfate is dried, filtrate is concentrated by silica gel column chromatography, and eluent is PE/EA (v/v) ═ 5/1-2/1, and 30mg of colorless liquid is obtained, namely the product.1H NMR(400MHz,CDCl3)δ4.15(d,J＝6.8Hz,2H),3.00(s,3H),2.66-2.52(m,1H),2.25-2.11(m,4H),2.09(s,2H),1.88(dd,J＝19.5,8.6Hz,2H),1.72(s,1H),1.32(s,3H)。
Step 2: 6- ((6-hydroxy-6-methylspiro [3.3] heptan-2-yl) methoxy) -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
A5 mL single-necked flask was charged with 6-hydroxy-4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1]Heptane-3-yl) pyridin-3-yl) pyrazolo [1,5-a]Pyridine-3-carbonitrile (23mg,0.05mmol, intermediate 1), (6-hydroxy-6-methylspiro [3.3]]Hept-2-yl) methyl methanesulfonate (30mg,0.13mmol), potassium carbonate (18mg,0.13mmol), DMF (0.8mL), and reacted at 60 ℃ in an oil bath overnight. After TLC detection, the reaction solution was cooled to room temperature, 5mL of water was added, EA (20 mL. times.2) was extracted, the organic phase was washed with water (5 mL. times.4), washed with saturated brine, dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated on silica gel column chromatography, and the eluent was DCM/MeOH (v/v) ═ 30/1-20/1, and 3mg of a yellow solid was obtained. LC-MS: 592.20[ M + H ] M/z]+。1H NMR(400MHz,CDCl3)δ8.40(d,J＝1.9Hz,1H),8.21(s,1H),8.11(s,2H),7.78(dd,J＝8.8,2.2Hz,1H),7.69(s,1H),7.11(s,1H),6.71(dd,J＝15.3,8.7Hz,2H),3.95(d,J＝6.4Hz,2H),3.92(s,3H),3.90-3.80(m,4H),3.70-3.60(m,4H),2.76-2.70(m,2H),2.37-2.30(d,J＝13.6Hz,1H),2.27-2.24(m,3H),2.13(s,2H),2.04(s,1H),2.01-1.84(m,3H),1.35(s,3H)。
Example 12: 6- (2- (2-oxa-6-azaspiro [3.3] heptan-6-yl) ethoxy) -4- (6- (5- (4-methoxybenzoyl) hexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile
Figure BDA0002665034780000811
Step 1: 5- (4-Methoxybenzoyl) hexahydropyrrolo [3,4-c ] pyrrole-2 (1H) -carboxylic acid tert-butyl ester
A 25mL single-mouth bottle is added with hexahydropyrrolo [3,4-c]Pyrrole-2 (1H) -carboxylic acid tert-butyl ester (1.0g,4.7mmol), 4-methoxybenzoic acid (1.1g,7.2mmol), DCM was added and dissolved, after which 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.8g,9.4mmol), 4-dimethylaminopyridine (1.2g,9.8mmol) were added and reacted at room temperature for 20H. After the reaction was stopped, 10mL of water was added to the reaction mixture, aqueous DCM (30mL) was extracted, the organic phases were combined and washed with water (10mL × 2), dried over anhydrous sodium sulfate, concentrated, and subjected to silica gel column chromatography with DCM-DCM/MeOH (v/v ═ 50/1) as eluent to obtain 1.3g of colorless liquid as the product, with a yield of 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 hydrochloride
A 25mL single-neck bottle is added with 5- (4-methoxybenzoyl) hexahydropyrrolo [3,4-c]Pyrrole-2 (1H) -carboxylic acid tert-butyl ester (600mg,1.732mmol), EA (5mL) was added to dissolve it, HCl/EA (4mL,4mol/L) was added, and after the addition was completed, the reaction was carried out at room temperature for 1H. After TLC detection reaction, reaction liquid is directly concentrated and dried to obtain 470mg of solid, namely the product, and the yield is 95.95%. LC-MS M/z 247.25[ M + H ]]+；1H NMR(400MHz,DMSO-d6):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)。
And 4, step 4: 6- (2- (2-oxa-6-azaspiro [3.3] hept-6-yl) ethoxy) -4- (6- (5- (4-methoxybenzoyl) hexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile
A5 mL single-neck flask was charged with 6- (2- (2-oxa-6-azaspiro [3.3]]Heptane-6-yl) ethoxy) -4- (6-fluoropyridin-3-yl) pyrazolo [1,5-a]Pyridine-3-carbonitrile (26mg,0.06853mmol, intermediate 2), hexahydropyrrolo [3,4-c]Pyrrol-2 (1H) -yl) (4-methoxyphenyl) methanone hydrochloride (35mg,0.1096mmol), potassium carbonate (55mg,0.39795mmol), DMSO (1.5mL), reacted at 90 ℃ in an oil bath for 15H. After the reaction mixture was cooled to room temperature, 5mL of water was added, EA (20mL × 2) was extracted, the organic phase was washed with water (5mL × 3), saturated brine was washed with water (5mL × 2), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure and subjected to silica gel column chromatography to obtain an eluent of DCM-DCM/MeOH (v/v ═ 10/1) as an off-white solid, which was 7mg of the product, in yield: 16.86 percent. LC-MS: m/z 606.30[ M + H ]]+；1H NMR(400MHz,CDCl3):δ8.33(s,1H),8.21(s,1H),8.13(s,1H),7.71(d,J＝7.1Hz,1H),7.54(d,J＝8.4Hz,2H),7.12(s,1H),6.93(d,J＝8.5Hz,2H),6.51(d,J＝8.9Hz,1H),4.78(s,4H),4.06(s,3H),3.91–3.70(m,7H),3.61(s,4H),3.54(s,3H),3.11(d,J＝18.5Hz,2H),2.93(s,2H)。
Example 13: 6- (2- (2-oxa-6-azaspiro [3.3] heptan-6-yl) ethoxy) -4- (6- (5- (2, 3-dimethylbenzoyl) hexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile
Figure BDA0002665034780000821
Step 1: 5- (2, 3-Dimethylbenzoyl) hexahydropyrrolo [3,4-c ] pyrrole-2 (1H) -carboxylic acid tert-butyl ester
A 25mL single-mouth bottle is added with hexahydropyrrolo [3,4-c]Tert-butyl pyrrole-2 (1H) -carboxylate (500mg,2.3553mmol), 2, 3-dimethylbenzoic acid (530mg,3.5293 mmol), DCM was added and dissolved, followed by addition of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (903mg,4.710mmol), 4-dimethylaminopyridine (580mg,4.7475mmol) and reaction at room temperature for 17H. Adding 10mL of water into the reaction solution, extracting with aqueous phase DCM (30mL), combining organic phases, washing with water (10mL multiplied by 2), drying with anhydrous sodium sulfate, concentrating, performing silica gel column chromatography,the eluent was PE-PE/EA (v/v-1/1) to give 660mg of a colorless viscous liquid as the product in 81.37% yield. LC-MS: 289.25[ M-tBu + H ] M/z]+；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 hydrochloride
A 25mL single-neck flask is added with 5- (2, 3-dimethylbenzoyl) hexahydropyrrolo [3,4-c]Pyrrole-2 (1H) -carboxylic acid tert-butyl ester (330mg,0.9582mmol), EA (3mL) was added to dissolve it, HCl/EA (2mL,4mol/L) was added, and after the addition was complete, the reaction was carried out at room temperature for 1H. White solid is separated out in the reaction process, the reaction liquid is directly concentrated after TLC detection of the raw materials finishes the reaction to obtain the white solid, and the white solid is dried in a vacuum drying oven at the temperature of 60 ℃ to obtain 260mg of the product, namely the yield is 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)。
And 4, step 4: 6- (2- (2-oxa-6-azaspiro [3.3] heptan-6-yl) ethoxy) -4- (6- (5- (2, 3-dimethylbenzoyl) hexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile
A10 mL single-neck flask was charged with 6- (2- (2-oxa-6-azaspiro [3.3]]Heptane-6-yl) ethoxy) -4- (6-fluoropyridin-3-yl) pyrazolo [1,5-a]Pyridine-3-carbonitrile (26mg,0.07mmol, intermediate 2), (hexahydropyrrolo [3, 4-c)]Pyrrol-2 (1H) -yl) (2, 3-dimethylphenyl) methanone hydrochloride (32mg,0.1009mmol), potassium carbonate (70mg,0.51mmol), DMSO (1.5mL), reacted at 90 ℃ in an oil bath for 13H. The reaction mixture was cooled to room temperature, 5mL of water was added, EA (20 mL. times.2) was extracted, the organic phase was washed with water (5 mL. times.3), saturated brine was washed with water (5 mL. times.2), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure on silica gelColumn chromatography with DCM/MeOH (v/v ═ 50/1-10/1) afforded the product as a yellow solid 7mg, 16.92% yield. LC-MS: 604.35[ M + H ] M/z]+；1H NMR(400MHz,CDCl3)：δ8.31(d,J＝2.1Hz,1H),8.19(s,1H),8.10(d,J＝1.6Hz,1H),7.70(dd,J＝8.7,2.4Hz,1H),7.18–7.12(m,2H),7.10(d,J＝2.0Hz,1H),7.05(d,J＝7.4Hz,1H),6.49(d,J＝8.7Hz,1H),4.76(s,4H),4.07–3.97(m,3H),3.89–3.84(m,1H),3.80–3.70(m,3H),3.60–3.54(m,2H),3.49(dd,J＝9.6,5.3Hz,2H),3.41(dd,J＝11.5,4.6Hz,1H),3.19–3.12(m,2H),3.09–2.99(m,2H),2.95–2.86(m,2H),2.28(s,3H),2.21(s,3H)。
Example 14: 6- (2- (2-oxa-6-azaspiro [3.3] heptan-6-yl) ethoxy) -4- (6- (6- (4-methoxybenzoyl) -2, 6-diazaspiro [3.3] heptan-2-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile
Figure BDA0002665034780000831
Step 1: 6- (4-Methoxybenzoyl) -2, 6-diazaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester
Adding 2, 6-diazaspiro [3.3] into a 50mL single-mouth bottle]Tert-butyl heptane-2-carboxylate (500mg,2.52mmol), 4-methoxybenzoic acid (576mg,3.79mmol), DCM was added, followed by 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (980mg,5.11mmol), 4-dimethylaminopyridine (636mg,5.2059mmol), and reaction at room temperature for 18 h. After the reaction was stopped, 5mL of water was added to the reaction mixture, aqueous DCM (20mL) was extracted, the organic phases were combined and washed with water (5mL × 2), dried over anhydrous sodium sulfate and chromatographed on silica gel column with DCM-DCM/MeOH (v/v ═ 50/1) to give 270mg of white solid, i.e. 32.21% yield. LC-MS: 333.20[ M + H ] M/z]+；1H NMR(400MHz,CDCl3):δ7.60(d,J＝8.7Hz,2H),6.91(d,J＝8.7Hz,2H),4.35(d,J＝28.9Hz,4H),4.10(s,4H),3.84(s,3H),1.44(s,9H)。
Step 2: (4-methoxyphenyl) (2, 6-diazaspiro [3.3] hept-2-yl) methanone
A25 mL single neck bottle was charged with 6- (4-methoxybenzoyl) -2, 6-diazaspiro [3.3]Heptane (Heptane)Tert-butyl-2-carboxylate (200mg,0.6017mmol), DCM (2mL) was added and dissolved, and trifluoroacetic acid (0.9mL,10mmol) was added at 0 ℃ and reacted at room temperature for 6 h. The reaction solution is directly concentrated to obtain 130mg of colorless liquid which is the product, and the yield is 93.01%. LC-MS 233.20[ M + H ]]+。
And step 3: 6- (2- (2-oxa-6-azaspiro [3.3] heptan-6-yl) ethoxy) -4- (6- (6- (4-methoxybenzoyl) -2, 6-diazaspiro [3.3] heptan-2-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile
A5 mL single-neck flask was charged with 6- (2- (2-oxa-6-azaspiro [3.3]]Heptane-6-yl) ethoxy) -4- (6-fluoropyridin-3-yl) pyrazolo [1,5-a]Pyridine-3-carbonitrile (26mg,0.06853mmol, intermediate 2), (4-methoxyphenyl) (2, 6-diazaspiro [3.3]]Hept-2-yl) methanone (70mg,0.2605mmol), potassium carbonate (55mg,0.39795mmol), DMSO (1.5mL), reacted in an oil bath at 90 ℃ for 20.5 h. The reaction mixture was cooled to room temperature, then 5mL of water was added, EA (20mL × 2) was extracted, the organic phase was washed with water (5mL × 3), saturated brine was washed with water (5mL × 2), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure and subjected to silica gel column chromatography, the eluent was DCM-DCM/MeOH (v/v ═ 20/1), a yellow solid was obtained, and then TLC purification was performed again to obtain 5mg of off-white solid, i.e., the product, with a yield of 12.33%. LC-MS: m/z 592.30[ M + H ]]+；1H NMR(400MHz,CDCl3)：δ8.29(s,1H),8.19(s,1H),8.11(s,1H),7.68(dd,J＝8.7,2.1Hz,1H),7.65(d,2H),7.10(s,1H),6.93(d,J＝8.6Hz,2H),6.43(d,J＝8.6Hz,1H),4.76(s,4H),4.47(d,J＝36.3Hz,4H),4.27(s,4H),4.02(t,J＝4.8Hz,2H),3.86(s,3H),3.55(s,4H),2.92–2.83(m,2H)。
Example 15: 6- (2- (2-oxa-6-azaspiro [3.3] heptan-6-yl) ethoxy) -4- (6- (5- (3-fluoro-2-methylbenzoyl) hexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile
Figure BDA0002665034780000841
Step 1: 5- (3-fluoro-2-methylbenzoyl) hexahydropyrrolo [3,4-c ] pyrrole-2 (1H) -carboxylic acid tert-butyl ester
Adding hexahydropyrrole into a 100mL single-mouth bottleAnd [3,4-c ]]Pyrrole-2 (1H) -carboxylic acid tert-butyl ester (500mg,2.36 mmol), 3-fluoro-2-methylbenzoic acid (550mg,3.57mmol), was dissolved by addition of DCM, followed by addition of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (903mg,4.710mmol), 4-dimethylaminopyridine (580mg,4.75mmol), and reaction at room temperature for 15H. After the reaction is stopped, the reaction solution is directly concentrated and is subjected to silica gel column chromatography, and an eluent is DCM-DCM/MeOH (v/v ═ 50/1), so that 620mg of colorless viscous liquid is obtained, namely the product, and the yield is 75.56%. LC-MS: 293.20[ M-tBu + H ] M/z]+；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 2: (hexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) (3-fluoro-2-methylphenyl) methanone hydrochloride
A 25mL single-neck bottle is added with 5- (3-fluoro-2-methylbenzoyl) hexahydropyrrolo [3,4-c]Pyrrole-2 (1H) -carboxylic acid tert-butyl ester (620mg,1.780mmol), EA (5mL) was added to dissolve it, HCl/EA (11mL,4mol/L) was added, and after the addition was complete, the reaction was carried out at room temperature for 2H. After the reaction is stopped, the reaction solution is directly concentrated to obtain 410mg of white solid, namely the product, and the yield is 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)。
And step 3: 6- (2- (2-oxa-6-azaspiro [3.3] heptan-6-yl) ethoxy) -4- (6- (5- (3-fluoro-2-methylbenzoyl) hexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile
A10 mL single-neck flask was charged with 6- (2- (2-oxa-6-azaspiro [3.3]]Heptane-6-yl) ethoxy) -4- (6-fluoropyridin-3-yl) pyrazolo [1,5-a]Pyridine-3-carbonitrile (30mg,0.07907mmol, intermediate 2), (hexahydropyrrolo [3, 4-c)]Pyrrol-2 (1H) -yl) (3-fluoro-2-methylphenyl) methanone hydrochloride (40mg,0.1245mmol), potassium carbonate (70mg,0.50 mmol)648mmol), DMSO (1.5mL), oil bath at 90 ℃ for 12 h. After the reaction was stopped, the reaction mixture was cooled to room temperature, and then 5mL of water was added, EA (30mL × 2) was extracted, the organic phase was washed with water (5mL × 3), washed with saturated brine (5mL × 2), dried over anhydrous sodium sulfate and filtered, the filtrate was subjected to silica gel column chromatography by concentration under reduced pressure to obtain a yellow solid as an eluent, DCM/MeOH (v/v ═ 50/1-10/1) was added, and TLC purification was performed again to obtain 5mg of an off-white solid, i.e., a product, with a yield of 10.41%. LC-MS: 608.35[ M + H ] M/z]+；
1H NMR(400MHz,CDCl3)：δ8.33(s,1H),8.21(s,1H),8.13(s,1H),7.72(d,J＝6.6Hz,1H),7.24–7.20(m,1H),7.12(s,1H),7.07–7.01(m,2H),6.52(d,J＝8.7Hz,1H),4.78(s,4H),4.08–3.99(m,3H),3.91–3.87(m,1H),3.76(dd,J＝18.8,5.6Hz,2H),3.60(s,3H),3.56–3.48(m,3H),3.45–3.41(m,1H),3.21–3.16(m,2H),3.11–3.05(m,1H),2.93(s,2H),2.26(s,3H)。
Example 16: 6- (2- (2-oxa-6-azaspiro [3.3] heptan-6-yl) ethoxy) -4- (6- (6- (3-fluoro-2-methylbenzoyl) -2, 6-diazaspiro [3.3] heptan-2-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile
Figure BDA0002665034780000861
Step 1: 6- (3-fluoro-2-methylbenzoyl) -2, 6-diazaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester
Adding 2, 6-diazaspiro [3.3] into a 50mL single-mouth bottle]Tert-butyl heptane-2-carboxylate (500mg,2.5219mmol), 3-fluoro-2-methylbenzoic acid (580mg,3.76mmol), DCM was added, followed by 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (980mg,5.112mmol), 4-dimethylaminopyridine (636mg,5.2059mmol), and reaction at room temperature for 15 h. After the reaction was stopped, 5mL of saturated ammonium chloride solution was added to the reaction mixture, DCM (40mL × 2) was extracted, the organic phase was washed with water (10mL × 2), dried over anhydrous sodium sulfate and chromatographed on silica gel column with DCM-DCM/MeOH (v/v ═ 50/1) as eluent to give 480mg of colorless liquid as the product in 56.92% yield. LC-MS: 335.20[ M + H ] M/z]+；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] heptan-2-yl) methanone
A25 mL single-neck bottle was charged with 6- (3-fluoro-2-methylbenzoyl) -2, 6-diazaspiro [ 3.3%]Tert-butyl heptane-2-carboxylate (480mg,1.435mmol), DCM (5mL) was added and dissolved, and trifluoroacetic acid (1.2mL,16mmol) was added at 0 ℃ and after completion, the reaction was carried out at room temperature for 2.5 h. After TLC detection reaction, the reaction solution is directly concentrated to obtain 330mg of the product, and the yield is 98.12%. LC-MS 235.15[ M + H ]]+。
And step 3: 6- (2- (2-oxa-6-azaspiro [3.3] heptan-6-yl) ethoxy) -4- (6- (6- (3-fluoro-2-methylbenzoyl) -2, 6-diazaspiro [3.3] heptan-2-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile
A10 mL single-neck flask was charged with 6- (2- (2-oxa-6-azaspiro [3.3]]Heptane-6-yl) ethoxy) -4- (6-fluoropyridin-3-yl) pyrazolo [1,5-a]Pyridine-3-carbonitrile (30mg,0.08mmol, intermediate 1), (3-fluoro-2-methylphenyl) (2, 6-diazaspiro [3.3]]Heptane-2-yl) methanone (62mg,0.2646mmol), potassium carbonate (65mg,0.47030mmol), DMSO (1.5mL), reacted at 90 ℃ in an oil bath for 15 h. After the reaction was terminated, the reaction mixture was cooled to room temperature, and then 5mL of water was added, EA (20mL × 2) was extracted, the organic phase was washed with water (5mL × 3), with saturated brine (5mL × 2), dried over anhydrous sodium sulfate and filtered, and the filtrate was subjected to silica gel column chromatography by concentration under reduced pressure to obtain 27mg of a yellow solid as a product with a yield of 57.52% as an eluent, DCM/MeOH (v/v ═ 50/1-10/1). LC-MS: 594.30[ M + H ] M/z]+；1H NMR(400MHz,CDCl3):δ8.28(d,J＝2.1Hz,1H),8.19(s,1H),8.10(d,J＝1.9Hz,1H),7.68(dd,J＝8.6,2.3Hz,1H),7.22–7.17(m,1H),7.11–7.04(m,3H),6.42(d,J＝8.6Hz,1H),4.75(s,4H),4.41(s,2H),4.30(d,J＝8.7Hz,2H),4.22(d,J＝8.8Hz,2H),4.14(s,2H),4.00(t,J＝5.1Hz,2H),3.51(s,4H),2.85(t,J＝5.1Hz,2H),2.33(d,J＝1.8Hz,3H)。
The target compounds (31) - (33) of examples 31-33, the target compounds (37) - (38) of examples 37-38, the target compounds (40) - (111) of examples 40-111, the target compounds (224) - (244) of example 224-:
TABLE 1
Figure BDA0002665034780000871
Figure BDA0002665034780000881
Figure BDA0002665034780000891
Figure BDA0002665034780000901
Figure BDA0002665034780000911
Figure BDA0002665034780000921
Figure BDA0002665034780000931
Figure BDA0002665034780000941
Figure BDA0002665034780000951
Figure BDA0002665034780000961
Figure BDA0002665034780000971
Figure BDA0002665034780000981
The target compounds (16) - (17) of examples 17, 245 were prepared by reference to example 6 or the synthetic route of scheme 2, using the appropriate starting materials, and the specific structures and characterization data are shown in table 2 below:
TABLE 2
Figure BDA0002665034780000991
Suitable starting materials are employed, the target compounds (18) - (30) of examples 18-30, the target compounds (34) - (36) of examples 34-36, the target compound (39) of example 39, the target compound (114) of example 114, the target compound (117) of example 117, the target compound (120) of example 120, the target compound (123) of example 123, the target compound (125) of example 125, the target compounds (129) - (131) of example 129-131, the target compounds (133) - (134) of example 133-134, the target compounds (144) - (145) of example 144-145, the target compounds (158) - (160) of example 158-160, the target compounds (165) - (171) of example 165-171, and, The target compounds (191) - (195) in example 191-195, the target compound (200) in example 200, and the target compounds (204) - (214) in example 204-214 were prepared by referring to the synthetic route of example 12 or synthetic scheme 4, and the specific structures and characterization data are as follows in table 3:
TABLE 3
Figure BDA0002665034780000992
Figure BDA0002665034780001001
Figure BDA0002665034780001011
Figure BDA0002665034780001021
Figure BDA0002665034780001031
Figure BDA0002665034780001041
Suitable raw materials are adopted, namely target compounds (112) - (113) of example 112-113, target compounds (115) - (116) of example 115-116, target compounds (118) - (119) of example 118-119, target compounds (121) - (122) of example 121-122, target compounds (124) of example 124, target compounds (126) - (128) of example 126-128, target compounds (132) of example 132, target compounds (135) - (143) of example 135-143, target compounds (146) - (157) of example 146-157, target compounds (161) - (164) of example 161-164, target compounds (172) - (190) of example 172-190, target compounds (196) - (199) of example 196-199, The target compounds (201) - (203) in example 201-203 and the target compounds (208) - (209) in example 208-209 can be prepared by referring to the synthetic routes in example 12 or synthetic scheme 4, and the specific structures and characterization data are shown in the following table 4:
TABLE 4
Figure BDA0002665034780001051
Figure BDA0002665034780001061
Figure BDA0002665034780001071
Figure BDA0002665034780001081
Figure BDA0002665034780001091
Figure BDA0002665034780001101
Figure BDA0002665034780001111
Figure BDA0002665034780001121
Biological activity test example:
test example 1:
1. purpose of the experiment:
HTRF method is used for testing the inhibitory activity of series of compounds on 2 kinases of Ret wt and Ret V804M, and IC is determined50The value is obtained.
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，4625-1 CECN/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 1 × 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 the diluted compound per well with an Echo 550 reaction plate (784075, Greiner);
3.3 seal the reaction plate with sealing plate and centrifuge at 1000g for 1 min.
3.4 prepare 2 Xkinase using 1 Xenzyme reaction buffer.
3.5 Add 5. mu.l kinase per well to the reaction plate (prepared in step 3). Plates were centrifuged at 1000g for 30 seconds with a sealing plate membrane and allowed to stand at room temperature for 10 minutes.
3.6 prepare 4 XTK-substrate-biotin and 4 XTATP with 1 Xenzyme reaction buffer, mix well, add 5 u l K-substrate-biotin/ATP mixture to the reaction plate.
3.7 plates were centrifuged at 1000g for 30 seconds with a sealing plate membrane and reacted at room temperature for 40 minutes.
3.8 prepare 4X Sa-XL 665(250nM) in HTRF detection buffer.
3.9 mu.l of Sa-XL 665 and 5. mu.l of TK-antisense-Cryptate were added to each well, centrifuged at 1000g for 30 seconds, and reacted at room temperature for 1 hour.
3.10 reading the fluorescence signals at 615nm (Cryptote) and 665nm (XL665) with Envision 2104.
4. Data analysis
4.1 calculate the Ratio per well (Ratio _665/615nm)
4.2 inhibition was calculated as follows:
Figure BDA0002665034780001131
wherein, the chemical name of CEP-32496 is as follows: n- [3- [ (6, 7-dimethoxy-4-quinazolinyl) oxy ] phenyl ] -N' - [5- (2,2, 2-trifluoro-1, 1-dimethylethyl) -3-isoxazolyl ] urea.
4.3 calculating IC50And the inhibition curves of the compounds were plotted:
IC of the compound was obtained using the following non-linear fit equation50(median inhibitory concentration): data analysis was performed using Graphpad 6.0 software.
Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*Hill Slope))
X is the log value of the concentration of the compound Y is the inhibition ratio (% inhibition)
5. The results of the experiment are shown in table 5:
TABLE 5 kinase inhibitory Activity of Compounds of the invention
Figure BDA0002665034780001132
Figure BDA0002665034780001141
In addition to the activities of the compounds of the present invention in Table 5, other compounds of the present invention also had good Ret kinase inhibitory activity, wherein the activity for Ret wt kinase inhibition was 0-20nM, and the activity for Ret wt kinase inhibition, Ret V804M, was 0-300 nM; preferably, the activity against Ret wt kinase inhibition is 0-5nM, the activity against Ret wt kinase inhibition, Ret V804M, is 0-100nM, more preferably, the activity against Ret wt kinase inhibition is 0-1nM, the activity against Ret wt kinase inhibition, Ret V804M, is 0-50 nM. In particular, the compounds in tables 1 and 3 of the present invention preferably have 0 to 10nM for Ret wt kinase inhibitory activity, and 0 to 100nM for Ret wt kinase inhibitory activity, Ret V804M, more preferably, the compounds in tables 1 and 3 of the present invention have 0 to 5nM for Ret wt kinase inhibitory activity, Ret V804M for Ret wt kinase inhibitory activity is 0 to 50nM, and even more preferably, the compounds in tables 1 and 3 of the present invention have 0 to 1nM for Ret wt kinase inhibitory activity; the compounds in the table 2 of the invention have the activity of inhibiting Ret wt kinase of 0-1nM, and the activity of inhibiting Ret wt kinase of 0-20nM, namely Ret V804M.
In the description herein, reference to the description of the terms "one embodiment," "some embodiments," "an example," "a specific example" or "some examples" or the like means 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, the schematic representations of the terms used above do not necessarily refer to the same embodiment or example. 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 various examples, embodiments, or examples described in this specification, as well as features of various examples, embodiments, or examples, may be combined and combined by one skilled in the art without contradiction.
Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that those skilled in the art can make changes, modifications, substitutions and alterations to the above embodiments without departing from the principle and spirit of the present invention, the scope of which is defined by the appended claims and their equivalents.

Claims (23)

1. A compound which is a compound of formula (I) or a stereoisomer, geometric isomer, tautomer, nitroxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof:
Figure FDA0002665034770000011
wherein,
X1、X2、X3、X4and X5Each independently is CR4Or 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 groups selected from D, OH, F, Cl, Br, I, CN, NH2、CF3Alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, heterocyclyl, alkoxy, aryl, heteroaryl, or alkylamino;
ring G is a spiro carbocyclyl or spiro heterocyclyl;
q is 0, 1,2,3 or 4;
Rais D, OH, NH2、F、CF3、Cl、Br、I、CN、NR5R6、OR7、-NR6C(＝O)R7、-S(＝O)2R7、-S(＝O)R7、-C(＝O)R7、-C(＝O)OR7Oxo, alkyl, alkoxy, cycloalkyl, alkoxyalkyl or hydroxyalkyl;
e is a bond, -NR6-, or-O-;
ring A is a bridged, fused or spirocyclic ring group, and A is optionally substituted with 1,2,3 or 4 substituents selected from F, Cl, Br, OH, oxo, NR5R6、R5(C＝O)NR6-, aminoalkyl, alkyl, alkoxy, haloalkyl, hydroxyalkyl, carbocyclyl, heterocyclyl, heterocyclylalkyl, alkoxyalkyl, cycloalkylene, and monoheterocyclylene;
q is a bond, - (CR)2R3)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-NR6(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, CF3、OH、NR5R6、OR7Alkyl, haloalkyl, hydroxyalkyl, haloalkoxy, aryl, alkoxyalkyl, oxo, alkanoyl, heterocyclyl, cycloalkyl;
R1is H, D, CN, F, Cl, Br, alkyl or cycloalkyl, wherein said alkyl and cycloalkyl may independently optionally be substituted with 1,2,3 or 4 substituents selected from F, Cl, Br, CN, NH2OH and NO2Substituted with the substituent(s);
each R2、R3Independently OH, F, CF3、H、D、CN、Cl、Br、NH2Hydroxyalkyl, alkyl, alkylamino, alkoxy, haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl;
or, R2、R3And the same C atom to which it is attached form a carbocyclic or heterocyclic ring;
R4is H, D, F, Cl, Br, alkyl or alkoxy, wherein the alkyl and alkoxy are each independently optionally substituted by 1,2,3 or 4 groups selected from F, Cl, Br, CN, NH2OH and NO2Substituted with the substituent(s);
R5h, D, an alkyl group, a carbocyclyl group, a heterocyclyl group, an aryl group or a heteroaryl group, wherein said alkyl, carbocyclyl, heterocyclyl, aryl and heteroaryl groups are each independently optionally substituted with 1,2,3 or 4 substituents selected from F, Cl, Br, OH, NH2Alkylamino, alkyl, alkylsulfonyl, alkoxy, aryl and heteroaryl;
R6is H, D, alkyl or alkoxyalkyl, wherein the alkyl and alkoxyalkyl are each independently optionally substituted with 1,2,3, or 4 substituents selected from F, Cl, Br, CN, NH2OH and NO2Substituted with the substituent(s);
R7OH, alkyl, cycloalkyl, heterocyclic radical, aryl and heteroaryl.
2. The compound of claim 1, wherein,
t is a bond, C1-6Alkylene radical, C1-6alkylene-O-or C1-6alkylene-NH-, and T is optionally substituted by 1,2,3 or 4 groups selected from D, OH, F, Cl, Br, I, CN, CF3、C1-6Alkyl radical, C1-6Hydroxyalkyl radical, C1-6Haloalkyl, C3-7Cycloalkyl, 3-7 membered heterocyclyl, C1-6Alkoxy radical, C6-10Aryl, 5-12 membered heteroaryl or C1-6Substituted by a substituent of alkylamino.
3. The compound of 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-, and said T is optionally substituted by 1,2,3 or 4 groups selected from D, OH, F, Cl, Br, I, CN, CF3Methyl, ethyl, propyl, 2-hydroxyethyl, 1-hydroxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrakisHydropyranyl, oxetanyl, methoxy, ethoxy, propoxy, butoxy, phenyl, methylamino and dimethylamino.
4. The compound of claim 1, wherein,
g is 6-12 membered spiro carbocyclyl or 6-12 membered spiro heterocyclyl;
Rais D, OH, NH2、F、CF3、Cl、Br、I、CN、NR5R6、OR7、-NR6C(＝O)R7、-S(＝O)2R7、-S(＝O)R7、-C(＝O)R7、-C(＝O)OR7Oxo, C1-6Alkyl radical, C1-6Alkoxy radical, C3-7Cycloalkyl radical, C1-6Alkoxy radical C1-6Alkyl radical, C1-6A hydroxyalkyl group;
R5is H, D, C1-6Alkyl, 3-12 membered carbocyclyl, 3-12 membered heterocyclyl, C6-10Aryl or 5-10 membered heteroaryl, wherein said C1-6Alkyl, 3-12 membered carbocyclyl, 3-12 membered heterocyclyl, C6-10Aryl and 5-10 membered heteroaryl are each independently optionally substituted by 1,2,3 or 4 substituents selected from F, Cl, Br, OH, NH2、C1-6Alkylamino, alkyl, alkylsulfonyl, alkoxy, aryl and heteroaryl;
R6is H, D, C1-6Alkyl or C1-6Alkoxy radical C1-6Alkyl radical, wherein said C1-6Alkyl and C1-6Alkoxy radical C1-6Each alkyl is independently optionally substituted by 1,2,3 or 4 substituents selected from F, Cl, Br, CN, NH2OH and NO2Substituted with the substituent(s);
R7is OH, C1-6Alkyl radical, C3-6Cycloalkyl, 3-12 membered heterocyclyl, C6-10Aryl, 5-10 membered heteroaryl.
5. The compound of claim 1, wherein,
g is the following subformula:
Figure FDA0002665034770000031
wherein each ring T1 is independently a 4-7 membered monocyclic or heteromonocyclic carbon;
Z1and Z2Independently is-CH2-、-O-、-S-、-NH-；
Z3is-O-, -S-, -NH-;
n1 is 0, 1 or 2;
n2 is 1,2 or 3;
n3 is 0 or 1.
6. The compound of claim 1, wherein,
g is the following subformula:
Figure FDA0002665034770000032
Figure FDA0002665034770000041
Rais D, OH, NH2、F、CF3、Cl、Br、I、CN、NH2、NHCH3、-NHC(＝O)CH3、-S(＝O)2CH3、-S(＝O)CH3、-C(＝O)CH3-C (═ O) OH, oxo, methyl, ethyl, propyl, butyl, methoxy, ethoxy, cyclopropyl, cyclopentyl, methoxymethyl, ethoxymethyl, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 2-hydroxypropyl, 2-hydroxy-2-methylpropyl;
R5h, 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, NH2Methyl, -S (═ O)2CH3Methoxy, ethoxy and phenyl;
R6h, D, methyl, ethyl, n-propyl, n-butyl, methoxymethyl, ethoxymethyl or methoxyethyl, wherein the methyl, ethyl, n-propyl, n-butyl, methoxymethyl, ethoxymethyl and methoxyethyl radicals are each independently optionally substituted by 1,2,3 or 4 radicals selected from the group consisting of F, Cl, Br, CN, NH2OH and NO2Substituted with the substituent(s);
R7is OH, methyl, ethyl, NH2、N(CH3)2N-propyl, isopropyl, tert-butyl, cyclopropyl or phenyl.
7. The compound of claim 1, wherein,
a is 5-12 membered bridged cyclyl, 5-12 membered fused cyclyl or 5-12 membered spirocyclyl, and A is optionally substituted with 1,2,3 or 4 substituents selected from F, Cl, Br, OH, oxo, NR5R6、R5(C＝O)NR6-, amino C1-6Alkyl radical, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Haloalkyl, C1-6Hydroxyalkyl, 3-12 membered carbocyclyl, 3-12 membered heterocyclyl C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkyl radical, C3-6Cycloalkylene and 3-6 membered heterocyclylene.
8. The compound of claim 1, wherein,
a is the following subformula:
Figure FDA0002665034770000042
Figure FDA0002665034770000051
wherein Z is1aAnd Z2aEach independently is-CH2-or-NH-;
Z3ais-CH-or-N-;
Z4ais-O-, -S-or-NH-;
each Z5a、Z6aIndependently is-CH2-、-O-、-S-、-S(＝O)-、-S(＝O)2--C (═ O) -, or-NH-;
m and t are each independently 0, 1 or 2;
n and t1 are each independently 0 or 1;
wherein each sub-structural formula of A is independently and optionally substituted by 1,2,3 or 4 selected from F, Cl, Br, OH, oxo, NR5R6、R5(C＝O)NR6-, amino C1-4Alkyl radical, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl, C1-4Hydroxyalkyl, 3-12 membered carbocyclyl, 3-12 membered heterocyclyl C1-4Alkyl radical, C1-4Alkoxy radical C1-4Alkyl radical, C3-6Cycloalkylene and 3-6 membered heterocyclylene.
9. The compound of claim 1, wherein,
a is the following subformula:
Figure FDA0002665034770000052
Figure FDA0002665034770000061
wherein each sub-structural formula of A is independently and optionally substituted by 1,2,3 or 4 selected from F, Cl, Br, OH, oxo, NH2、NHCH3、CH3(C ═ O) NH-, methyl, ethyl, n-propyl, methoxy, ethoxy, isopropoxy, CF3Hydroxymethyl, 2-hydroxyethyl, cyclopropyl, cyclohexyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, cyclopropylene, cyclohexylene and pyrrolidinylidene.
10. The compound of claim 1, wherein,
m is H, D, 5-10 membered heteroaryl, C6-10Aryl radical, C3-7Cycloalkyl or 3-12 membered heterocyclyl; and M is optionally substituted by 1,2,3 or 4 groups selected from D, F, Cl, CN, OH, CF3、NR5R6、OR7、C1-6Alkyl radical, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Haloalkoxy, C6-10Aryl radical, C1-6Alkoxy radical C1-6Alkyl, oxo, C1-6Alkanoyl, 3-7 membered heterocyclic group, C3-7Cycloalkyl substituents.
11. The compound according to claim 1, wherein,
m is H, D, pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, pyrazinyl, phenyl, cyclopentyl, cyclopropyl, cyclohexyl, cyclobutyl, pyrrolidinyl, piperidinyl, tetrahydrofuryl, tetrahydropyranyl, piperazinyl, morpholinyl, tetrahydrothiopyranyl, oxetanyl, 1, 2-dihydropyridinyl, 7-azabicyclo [2.2.1]Heptalkyl, hexahydrofuro [3,4-c ]]Azolyl, 3-azabicyclo [3.1.0 ]]Hexane radical, octahydropyrrolo [1,2-a ] radical]Pyrazinyl or 5-azaspiro [2.4 ]]A heptalkyl group; and M is optionally substituted by 1,2,3 or 4 groups selected from D, F, Cl, CN, OH, CF3、NH2、NHCH3、N(CH3)2Trifluoromethoxy, 2,2, 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.
12. The compound of claim 1, wherein,
R1is H, D, CN, F, Cl, Br, methyl, ethyl or cyclopropyl, wherein the methyl, the ethylThe radicals and cyclopropyl may be independently optionally substituted by 1,2,3 or 4 radicals selected from F, Cl, Br, CN, NH2OH and NO2Substituted with the substituent(s);
R4is H, D, F, Cl, Br, methyl, ethyl, n-propyl, methoxy or ethoxy, wherein the methyl, ethyl, n-propyl, methoxy and ethoxy groups can be independently and optionally substituted by 1,2,3 or 4 groups selected from F, Cl, Br, CN, NH2OH and NO2Substituted with the substituent(s).
13. The compound of claim 1, wherein,
each R2、R3Independently OH, F, CF3、H、D、CN、Cl、Br、NH2、C1-6Hydroxyalkyl radical, C1-6Alkyl radical, C1-6Alkylamino radical, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-7Cycloalkyl radical, C3-7Cycloalkyl radical C1-6Alkyl radical, C6-10Aryl or 5-10 membered heteroaryl;
or, R2、R3And the same C atom to which it is attached form a 3-7 membered carbocyclic or 3-7 membered heterocyclic ring.
14. The compound of claim 1, wherein,
each R2、R3Independently OH, F, CF3、H、D、CN、Cl、Br、NH2Hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, methyl, ethyl, N (CH)3)2Methoxy, ethoxy, isopropoxy, tert-butoxy, trifluoromethoxy, cyclopropyl, cyclopentyl, cyclopropylmethyl, cyclopentylethyl, cyclopentylmethyl, phenyl, pyridyl, pyrazinyl;
or, R2、R3And the same C atom to which it is attached to cyclopentane, cyclopropane, cyclobutane, tetrahydropyran, tetrahydrofuran, piperidine, or pyrrolidine.
15. The compound of claim 1, wherein,
q is a bond, -O-, - (CH)2)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)CH2-、-(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-、
Figure FDA0002665034770000071
Figure FDA0002665034770000072
16. The compound of claim 1 having the structure of formula (I-1), or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the structure of formula (I-1),
Figure FDA0002665034770000081
wherein,
ring a1 is of the subformula:
Figure FDA0002665034770000082
wherein Z1aAnd Z2aEach independently is CH2Or NH;
and each sub-formula of A1 is independently optionally substituted by 1,2,3 or 4 substituents selected from F, Cl, Br, OH, oxo, NR5R6、R5(C＝O)NR6-, amino C1-4Alkyl radical, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl, C1-4Hydroxyalkyl, 3-12 membered carbocyclyl, 3-12 membered heterocyclyl C1-4Alkyl radical, C1-4Alkoxy radical C1-4Alkyl radical, C3-6Cycloalkylene and 3-6 membered heterocyclylene.
17. The compound of claim 16, wherein,
a1 is a subformula:
Figure FDA0002665034770000083
wherein each sub-formula of A1 is independently and optionally substituted by 1,2,3 or 4 substituents selected from F, Cl, Br, OH, oxo, NH2、NHCH3、CH3(C ═ O) NH-, methyl, ethyl, n-propyl, methoxy, ethoxy, isopropoxy, CF3Hydroxymethyl, 2-hydroxyethyl, cyclopropyl, cyclohexyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, cyclopropylene, cyclohexylene and pyrrolidinylidene.
18. The compound of claim 1 having a structure of formula (I-2) or (I-3), or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of a structure of formula (I-2) or (I-3),
Figure FDA0002665034770000091
wherein Z is1、Z2And Z3aEach independently is CH or N;
m and t are each independently 0, 1 or 2;
n and t1 are each independently 0 or 1;
wherein
Figure FDA0002665034770000092
Independently optionally substituted by 1,2,3 or 4 substituents selected from F, Cl, Br, OH, oxo, NR5R6、R5(C＝O)NR6-, amino C1-4Alkyl radical, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl, C1-4Hydroxyalkyl, 3-12 membered carbocyclyl, 3-12 membered heterocyclyl C1-4Alkyl radical, C1-4Alkoxy radical C1-4Alkyl radical, C3-6Cycloalkylene and 3-6 membered heterocyclylene.
19. The compound of claim 18, wherein,
Figure FDA0002665034770000093
is of the sub-structure:
Figure FDA0002665034770000094
Figure FDA0002665034770000101
Figure FDA0002665034770000102
is of the sub-structure:
Figure FDA0002665034770000103
wherein
Figure FDA0002665034770000104
Each of the sub-formulae of (1) is independently optionally substituted by 1,2,3 or 4 substituents selected from F, Cl, Br, OH, oxo, NH2、NHCH3、CH3(C ═ O) NH-, methyl, ethyl, n-propyl, methoxy, ethoxy, isopropoxy, CF3Hydroxymethyl, 2-hydroxyethyl, cyclopropyl, cyclohexyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, cyclopropylene, cyclohexylene and pyrrolidinylidene.
20. The compound of claim 1 having one of the following structures, or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt, or prodrug thereof,
Figure FDA0002665034770000105
Figure FDA0002665034770000111
Figure FDA0002665034770000121
Figure FDA0002665034770000131
Figure FDA0002665034770000141
Figure FDA0002665034770000151
Figure FDA0002665034770000161
Figure FDA0002665034770000171
Figure FDA0002665034770000181
Figure FDA0002665034770000191
Figure FDA0002665034770000201
Figure FDA0002665034770000211
Figure FDA0002665034770000221
Figure FDA0002665034770000231
Figure FDA0002665034770000241
Figure FDA0002665034770000251
Figure FDA0002665034770000261
Figure FDA0002665034770000271
Figure FDA0002665034770000281
Figure FDA0002665034770000291
Figure FDA0002665034770000301
Figure FDA0002665034770000311
Figure FDA0002665034770000321
Figure FDA0002665034770000331
Figure FDA0002665034770000341
Figure FDA0002665034770000351
21. a pharmaceutical composition comprising a compound according to any one of claims 1 to 20, and pharmaceutically acceptable adjuvants.
22. Use of a compound according to any one of claims 1 to 20 or a pharmaceutical composition according to claim 21 for the manufacture of a medicament for the prevention or treatment of RET related diseases.
23. The use according to claim 22, wherein the RET-associated disease comprises cancer, irritable bowel syndrome and/or pain associated with irritable bowel syndrome.
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