WO2019157879A1

WO2019157879A1 - Heterocyclic compound which acts as trk inhibitor

Info

Publication number: WO2019157879A1
Application number: PCT/CN2019/000040
Authority: WO
Inventors: 孔祥龙; 周超; 郑之祥
Original assignee: 北京诺诚健华医药科技有限公司
Priority date: 2018-02-13
Filing date: 2019-03-04
Publication date: 2019-08-22
Also published as: CN110156813A; CN110156813B

Abstract

The present invention relates to a compound, a pharmaceutical composition containing the compound, a preparation method for the compound, and a use of the compound as a TRK inhibitor. The compound is the compound as shown in formula (I), or a pharmaceutically acceptable salt, prodrug, solvent compound, polymorph, isomer or stable isotope derivative thereof. The present invention also relates to a use of the compound in treating or preventing related TRK-mediated diseases such as tumours, and a method for applying the compound to treat said diseases.

Description

Heterocyclic compound as a TRK inhibitor

Technical field

The present invention relates to compounds, pharmaceutical compositions containing the same and their use as TRK inhibitors. More specifically, the present invention provides novel compounds as TRK inhibitors, pharmaceutical compositions containing such compounds, and methods of using the compounds to treat or prevent related diseases mediated by TRK, such as tumors. The invention also relates to a process for the preparation of the compounds described below.

Background technique

TRK (Tropomyosin-related kinase) is a tyrosine kinase that is present in neurotrophic receptors in a variety of tissues and activates a variety of downstream processes during cell proliferation and survival. The TRK proto-oncogene family has three members: TRK A, B, and C, encoded by NTRK1, NTRK2, and NTRK3, respectively. Binding of neurotrophins and TRK proteins leads to receptor dimerization, phosphorylation, and activation of downstream signaling pathways, including Ras/MAPK, PI3K/AKT, and PLCγ pathways, thereby regulating cell proliferation, differentiation, metabolism, and apoptosis (Brodeur GM) , Minturn JE, Ho R, et al. Clinical Cancer Research, 2009, 15, 3244-50). Genomic analysis of kinase fusion confirms that NTRK gene fusion occurs in a variety of cancers: for example, glioma, hepatobiliary liver cancer, papillary thyroid cancer, colon cancer, non-small cell lung cancer, head and neck squamous cell carcinoma, pancreatic cancer , sarcoma and melanoma (Khotskaya, YB et al. Pharmacology & Therapeutics, 2017, 173, 58-66). The research and development of TRK inhibitors can treat various tumors of NTRK fusion protein with great potential and broad market prospects. The condition of 38 (76%) patients treated with the TRK inhibitor larotrectinib (LOXO-101) in the early clinical trials was objectively relieved. Six of them (12%) had complete remission, and the presence of tumors was not detected by existing methods. Of these patients, 30 patients had a remission time of more than one year (2017 American Society of Clinical Oncology Annual Meeting). This result has aroused great interest in the medical community. Therefore, it is necessary to develop a TRK inhibitor which has high activity, small side effects, and is effective for TRK mutation.

Summary of the invention

It is an object of the present invention to provide a compound of the formula I, an isomer, a prodrug, a solvate thereof, a stable isotopic derivative or a pharmaceutically acceptable salt thereof, which is useful as a TRK inhibitor:

among them:

One of X ₁ and X ₂ is C and the other is N;

X _{3 is} selected from N and CR ⁴ , preferably X _{3 is} selected from N;

Ar is selected from the group consisting of arylene and heteroarylene, wherein the arylene or heteroarylene is optionally substituted by one or more G1, and Ar is preferably selected from 6 optionally substituted by one or more G1 Up to 10 membered arylene and 5 to 10 membered heteroarylene, said 6 to 10 membered arylene group such as phenylene and naphthylene, most preferably phenylene, said 5 to 10 membered heteroarylene Preferred is a 5- or 6-membered heteroarylene group, such as a furylene group, a thienylene group, a pyridylene group, a pyridylene group, a pyridone group, a pyrimidinyl group, a pyridazinyl group, an imidazolyl group, and a tetrazolium group. , a oxazolyl group and an isoxazolyl group, preferably a pyridylene group and a pyridone group, more preferably a 1,2-pyridinylene group and a 1,3 pyridinylene group;

Y and Z are independently selected from -N(R ^5a )- and -C(R ^5b R ^5c )-, provided that Y and Z are not simultaneously selected from -N(R ^5a )-, and Y is preferably selected from -N(R ^5a -, Z is preferably selected from -C(R ^5b R ^5c )-;

L _{1 is} selected from -NR ⁵ C(O)-, -NR ⁵ CON(R ⁶ )-, -NR ⁵ S(O) _m - and -NR ⁵ S(O) _m N(R ⁶ )-, wherein NR ^{5 is} linked to the nitrogen-containing heteroaryl group substituted by R ¹ , R ² , R ³ , preferably, L _{1 is} selected from the group consisting of -NR ⁵ C(O)- and -NR ⁵ CON(R ⁶ )-, wherein NR ^{5 is} linked to the bicyclic heterocycle;

L _{2 is} selected from the group consisting of a C1-C8 alkylene group, a C2-C8 alkenylene group, a C2-C8 alkynylene group, and a C3-C8 cyclocyclylene group, wherein the alkylene group, the alkenylene group, the alkynylene group, and the cyclocyclylene group may be optionally substituted with one or more G2, L ₂ is preferably selected from optionally substituted with one or more G2, and C1-C6 alkylene C2-C6 alkenylene group, L ₂ is more preferably selected from optionally a C1-C4 alkylene group substituted by one or more G2;

L _{3 is} selected from the group consisting of a chemical single bond, -O- and -N(R ^x )-, and L ₃ is preferably selected from the group consisting of a chemical single bond and -O-;

R ¹ , R ² and R ³ are each independently selected from the group consisting of hydrogen, halogen, cyano, C1-C8 alkyl, C3-C8 cyclic, 3-8 membered heterocyclic, aryl, heteroaryl, aldehyde, - C(O)R ⁷ ,carboxy, alkenyl, alkynyl, -OR ⁷ , -NR ⁸ R ⁹ -OC(O)NR ⁸ R ⁹ , -C(O)OR ⁷ , -C(O)NR ⁸ R ⁹ , -NR ⁸ C(O)R ⁷ , -NR ⁷ C(O)NR ⁸ R ⁹ , -S(O)mR ⁷ , -NR ⁸ S(O)mR ⁷ , -SR ⁷ , -S(O mNR ⁸ R ⁹ and -NR ⁷ S(O)mNR ⁸ R ⁹ , wherein the alkyl, cyclo, heterocyclyl, aryl or heteroaryl group is optionally selected from one or more selected from the group consisting of halogen and cyano , C1-C8 alkyl, C3-C8 cyclic, 3-8 membered heterocyclic, -OR ¹⁰ , -NR ¹¹ R ¹² , -OC(O)NR ¹⁰ R ¹¹ , -C(O)OR ¹⁰ ,- C(O)R ¹⁰ , -C(O)NR ¹¹ R ¹² , -NR ¹¹ C(O)R ¹⁰ , -NR ¹⁰ C(O)NR ¹¹ R ¹² , -S(O)mR ¹⁰ , -NR ¹¹ Substituting the substituents of S(O)mR ¹² , -SR ¹⁰ , -S(O)mNR ¹¹ R ¹² and -NR ¹⁰ S(O)mNR ¹¹ R ¹² , preferably R ² and R ³ are all hydrogen; more preferably R ¹ , R ² and R ³ are all hydrogen;

R ^{4 is} selected from the group consisting of hydrogen, C1-C8 alkyl, C1-C8 haloalkyl, heteroalkyl, C3-C8 cyclic, 3-8 membered monocyclic heterocyclic, monocyclic heteroaryl, monocyclic aryl, alkene and alkynyl groups, preferably R ⁴ is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl group, more preferably R ⁴ is selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, more preferably R ⁴ is hydrogen ;

R ^5a , R ^5b and R ^5c are each independently selected from hydrogen, C1-C8 alkyl, C3-C8 cyclic, 3-8 membered monocyclic heterocyclic, monocyclic heteroaryl, monocyclic aryl, alkenyl And alkynyl groups, preferably R ^5a , R ^5b and R ^5c are each independently selected from hydrogen, C1-C6 alkyl, further preferably R ^5a , R ^5b and R ^5c are each independently selected from hydrogen, C1-C4 alkyl, wherein The alkyl, cyclo, monocyclic heterocyclic, monocyclic heteroaryl, monocyclic aryl, alkenyl and alkynyl groups are optionally selected from one or more selected from the group consisting of halogen, cyano, C1-C8 alkyl, C3-C8 cyclic group, 3-8 membered heterocyclic group, -OR ¹⁰ , -NR ¹¹ R ¹² , -OC(O)NR ¹⁰ R ¹¹ , -NR ¹¹ C(O)R ¹⁰ , -NR ¹⁰ C(O Substituting a substituent of NR ¹¹ R ¹² ; or any two of R ^5a , R ^5b , R ^5c attached to an adjacent atom may form a 4 to 8 member optionally substituted by G3 together with the atom to which they are attached a cyclo group or a heterocyclic group, preferably a 3- to 6-membered heterocyclic group optionally substituted by G3;

R ⁵ , R ⁶ , R ^x are each independently selected from the group consisting of hydrogen, C1-C8 alkyl, C1-C8 haloalkyl, heteroalkyl, C3-C8 cyclo, 3-8 membered monocyclic heterocyclic, monocyclic Aryl, monocyclic aryl, alkenyl and alkynyl, preferably R ⁵ , R ⁶ , R ^x are each independently selected from hydrogen, C1-C6 alkyl and C1-C6 haloalkyl, further preferably R ⁵ , R ⁶ , R ^x are each independently selected from the group consisting of hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl;

G1 is selected from halogen, cyano, C1-C8 alkyl, C3-C8 cycloalkyl group, a 3-8-membered heterocyclyl, aryl, heteroaryl, aldehyde, -C (O) R ^7, a carboxyl group, an alkenyl group , alkynyl, -OR ⁷ , -NR ⁸ R ⁹ -OC(O)NR ⁸ R ⁹ , -C(O)OR ⁷ , -C(O)NR ⁸ R ⁹ , -NR ⁸ C(O)R ⁷ -NR ⁷ C(O)NR ⁸ R ⁹ , -S(O)mR ⁷ , -NR ⁸ S(O)mR ⁷ , -SR ⁷ , -S(O)mNR ⁸ R ⁹ and -NR ⁷ S( O) mNR ⁸ R ⁹ , preferably G1 is selected from halogen, C1-C6 alkyl and C3-C6 cyclic, more preferably G1 is selected from halogen, C1-C4 alkyl and C3-C6 cyclic, most preferably G1 is selected from halogen ;

G2 is selected from halogen, cyano, C1-C8 alkyl, C3-C8 cycloalkyl group, a 3-8-membered heterocyclyl, aryl, heteroaryl, aldehyde, -C (O) R ^7, a carboxyl group, an alkenyl group , alkynyl, -OR ⁷ , -NR ⁸ R ⁹ -OC(O)NR ⁸ R ⁹ , -C(O)OR ⁷ , -C(O)NR ⁸ R ⁹ , -NR ⁸ C(O)R ⁷ -NR ⁷ C(O)NR ⁸ R ⁹ , -S(O)mR ⁷ , -NR ⁸ S(O)mR ⁷ , -SR ⁷ , -S(O)mNR ⁸ R ⁹ and -NR ⁷ S( O) mNR ⁸ R ⁹ , preferably G2 is selected from halogen, C1-C6 alkyl, -OR ⁷ , -NR ⁸ R ⁹ ; more preferably G 2 is selected from halogen, C1-C4 alkyl, -OR ⁷ , -NR ⁸ R ⁹ ; wherein the alkyl group is optionally substituted by one or more halogens, -OR ¹⁰ , -NR ¹¹ R ¹² ; when two G 2 are on the same carbon atom or on adjacent carbon atoms, the two G 2 Optionally forming a 3-8 membered ring group together with the carbon atom to which it is attached, preferably forming a 3-6 membered cycloalkyl group, the cycloalkyl group formed optionally being one or more halogens, -OR ¹⁰ , -NR ¹¹ R ¹² Replaced

G3 is selected from halogen, cyano, C1-C8 alkyl, C3-C8 cycloalkyl group, a 3-8-membered heterocyclyl, aryl, heteroaryl, aldehyde, -C (O) R ^7, a carboxyl group, an alkenyl group , alkynyl, -OR ⁷ , -NR ⁸ R ⁹ -OC(O)NR ⁸ R ⁹ , -C(O)OR ⁷ , -C(O)NR ⁸ R ⁹ , -NR ⁸ C(O)R ⁷ -NR ⁷ C(O)NR ⁸ R ⁹ , -S(O)mR ⁷ , -NR ⁸ S(O)mR ⁷ , -SR ⁷ , -S(O)mNR ⁸ R ⁹ and -NR ⁷ S( O) mNR ⁸ R ⁹ , preferably G3 is selected from halogen, more preferably G3 is fluorine;

R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ¹² are each independently selected from the group consisting of hydrogen, C1-C8 alkyl, C1-C8 haloalkyl, heteroalkyl, C3-C8 cyclo, 3-8 Monocyclic heterocyclic group, monocyclic heteroaryl group, monocyclic aryl group, alkenyl group and alkynyl group;

m is 1 or 2.

In a preferred embodiment of the invention, there is provided a compound of the formula I, an isomer, a prodrug, a solvate thereof, a stable isotopic derivative or a pharmaceutically acceptable salt thereof, wherein:

One of X ₁ and X ₂ is C and the other is N;

X _{3 is} selected from N and CR ⁴ ;

Ar is selected from the group consisting of a 6 to 10 membered arylene group and a 5 to 10 membered heteroarylene group optionally substituted by one or more G1;

Y and Z are independently selected from -N(R ^5a )- and -C(R ^5b R ^5c )-, provided that Y and Z are not simultaneously selected from -N(R ^5a )-;

L _{1 is} selected from -NR ⁵ C(O)-, -NR ⁵ CON(R ⁶ )-, -NR ⁵ S(O) _m - and -NR ⁵ S(O) _m N(R ⁶ )-, wherein NR ^{5 is} linked to the nitrogen-containing heteroaryl group substituted by R ¹ , R ² , R ³ ;

L _{2 is} selected from the group consisting of a C1-C6 alkylene group, a C2-C6 alkenylene group, a C2-C6 alkynylene group, and a C3-C6 cyclocyclylene group, wherein the alkylene group, an alkenylene group, an alkynylene group, a cycloalkyl group Optionally substituted by one or more G2;

L _{3 is} selected from the group consisting of a chemical single bond, -O- and -N(R ^x )-;

R ¹ , R ² , R ³ are each independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C3-C6 cyclic, 3-6 membered heterocyclyl, aryl and heteroaryl, wherein the alkyl, ring a group, a heterocyclic group, an aryl group or a heteroaryl group optionally substituted by one or more substituents selected from the group consisting of halogen, cyano, C1-C6 alkyl, C3-C6 cyclic and 3-6 membered heterocyclic ;

R ^{4 is} selected from the group consisting of hydrogen, C1-C6 alkyl and C1-C6 haloalkyl;

R ^5a , R ^5b and R ^5c are each independently selected from hydrogen, C1-C6 alkyl, wherein the alkyl group is optionally selected from one or more selected from the group consisting of halogen, C1-C4 alkyl, C3-C8 cyclo, 3 -8-membered heterocyclic group, -OR ¹⁰ , -NR ¹¹ R ¹² , -OC(O)NR ¹⁰ R ¹¹ , -NR ¹¹ C(O)R ¹⁰ , -NR ¹⁰ C(O)NR ¹¹ R ¹² Substituting; or, any two of R ^5a , R ^5b , R ^5c attached to an adjacent atom may form a 4- to 8-membered ring group or a heterocyclic group which is optionally substituted by G 3 together with the atom to which they are attached;

R ⁵ , R ⁶ , R ^x are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, and C1-C6 haloalkyl;

G1 is selected from the group consisting of halogen, C1-C6 alkyl and C3-C6 ring;

G2 is selected from halogen and C1-C6 ^{^{^{alkyl, -OR 7, -NR 8 R 9}}} , wherein said alkyl is optionally substituted with one or more halo, - OR ^10, substituted with -NR ¹¹ R ^12; when both When G2 is on the same carbon atom or an adjacent carbon atom, the two G2 optionally form a 3-6 membered cycloalkyl group together with the carbon atom to which they are attached; the cycloalkyl group formed is optionally one or more halogen , -OR ¹⁰ , -NR ¹¹ R ¹² replaced;

G3 is selected from the group consisting of halogen, -OR ⁷ and -NR ⁸ R ⁹ ;

R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ¹² are each independently selected from the group consisting of hydrogen, C1-C6 alkyl and C1-C6 haloalkyl.

In another preferred embodiment of the present invention, there is provided a compound of the formula I, an isomer, a prodrug, a solvate thereof, a stable isotopic derivative or a pharmaceutically acceptable salt thereof, wherein:

One of X ₁ and X ₂ is C and the other is N;

X ₃ is N;

Ar is selected from the group consisting of phenylene, naphthylene, furanyl, thienylene, pyridylene, pyridylene, pyridinylene, pyrimidinyl, pyrazine, optionally substituted by one or more G1 a group, an imidazolyl group, a tetrazolium group, a oxazolyl group, and an oxazolyl group;

Y is selected from -N(R ^5a )-;

Z is selected from -C(R ^5b R ^5c )-;

L _{1 is} selected from -NR ⁵ C(O)- and -NR ⁵ CON(R ⁶ )-, wherein NR ⁵ is bonded to the nitrogen-containing heteroaryl group substituted by R ¹ , R ² , R ³ ;

L _{2 is} selected from the group consisting of a C1-C4 alkylene group, a C2-C4 alkenylene group, a C2-C4 alkynylene group, and a C3-C4 cyclocyclylene group, wherein the alkylene group, an alkenylene group, an alkynylene group, a cycloalkyl group Optionally substituted by one or more G2;

L _{3 is} selected from the group consisting of a chemical single bond and -O-;

R ¹ , R ² , and R ³ are each independently selected from the group consisting of hydrogen, halogen, C1-C4 alkyl, C4-C6 cyclo and 4- to 6-membered heterocyclic, wherein the alkyl, cyclo and heterocyclic are optional. Substituted by one or more substituents selected from halogen;

R ^5a , R ^5b and R ^5c are each independently selected from hydrogen, C1-C4 alkyl, wherein said alkyl group is optionally selected from one or more selected from the group consisting of halogen, C1-C4 alkyl, -OR ¹⁰ , -NR ¹¹ Substituted by a substituent of R ¹² , —OC(O)NR ¹⁰ R ¹¹ , —NR ¹¹ C(O)R ¹⁰ , —NR ¹⁰ C(O)NR ¹¹ R ¹² ; or, R attached to an adjacent atom Any two of ^5a , R ^5b , and R ^5c may form a 4- to 6-membered ring group or a heterocyclic group which is optionally substituted by G 3 together with the atom to which they are attached;

R ⁵ , R ⁶ , R ^x are each independently selected from the group consisting of hydrogen, C1-C4 alkyl and C1-C4 haloalkyl;

G1 is selected from the group consisting of halogen, C1-C4 alkyl and C3-C6 cyclo;

G2 is selected from halogen, C1-C4 ^{^{^{alkyl, -OR 7, -NR 5 R 9}}} , wherein said alkyl is optionally substituted with one or more halo, -OR ^10, substituted with -NR ¹¹ R ^12; when both When G2 is on the same carbon atom or an adjacent carbon atom, the two G2s, optionally together with the carbon atom to which they are attached, form a 3-6 membered cycloalkyl group, the cycloalkyl group formed optionally being one or more halogen , -OR ¹⁰ , -NR ¹¹ R ¹² replaced;

R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ¹² are each independently selected from the group consisting of hydrogen, C1-C4 alkyl and C1-C4 haloalkyl.

One of X ₁ and X ₂ is C and the other is N;

X ₃ is N;

Ar is selected from the group consisting of phenylene, naphthylene, pyridylene and pyridenylene, pyrimidinyl and pyrazinyl optionally substituted by one or more G1;

Y is selected from -N(R ^5a )-;

Z is selected from -C(R ^5b R ^5c )-;

L _{2 is} selected from the group consisting of C 1 -C 4 alkylene and C 2 -C 4 alkenylene, wherein the alkylene and alkenylene groups may be optionally substituted by one or more G 2 ;

L _{3 is} selected from the group consisting of a chemical single bond and -O-;

R ¹ , R ² , R ³ are each independently selected from the group consisting of hydrogen, halogen, and C1-C4 alkyl, wherein the alkyl group is optionally substituted with one or more halogens;

R ^5a , R ^5b and R ^5c are each independently selected from hydrogen, C1-C4 alkyl, wherein the alkyl group is optionally substituted by one or more substituents selected from the group consisting of halogen, -OR ¹⁰ , -NR ¹¹ R ¹² Or substituted; or any two of R ^5a , R ^5b , R ^5c attached to an adjacent atom may form a 5- to 6-membered ring group or a 5- to 6-membered heterocyclic ring optionally substituted by G 3 together with the atom to which they are attached. base;

R ⁵ and R ⁶ are each independently selected from hydrogen and C1-C4 alkyl;

G2 is selected from halogen, C1-C4 ^{^{^{alkyl, -OR 7, -NR 8 R 9}}} , wherein said alkyl is optionally substituted with one or more halo, -OR ^10, substituted with -NR ¹¹ R ^12; when both When G2 is on the same carbon atom or an adjacent carbon atom, the two G2s, optionally together with the carbon atom to which they are attached, form a 3-6 membered cycloalkyl group, the cycloalkyl group formed optionally being one or more halogen , -OR ¹⁰ , -NR ¹¹ R ¹² replaced;

One of X ₁ and X ₂ is C and the other is N;

X ₃ is N;

Ar is selected from the group consisting of phenylene, pyridylene and pyridenylene groups optionally substituted by one or more G1;

Y is selected from -N(R ^5a )-;

Z is selected from -C(R ^5b R ^5c )-;

L _{3 is} selected from the group consisting of a chemical single bond and -O-;

R ⁵ and R ⁶ are each independently selected from hydrogen and C1-C4 alkyl;

One of X ₁ and X ₂ is C and the other is N;

X ₃ is N;

Ar is selected from the group consisting of phenylene, 2,3-pyridinylene and 1,3-pyridinone optionally substituted with one or more G1;

Y is selected from -N(R ^5a )-;

Z is selected from -C(R ^5b R ^5c )-;

L _{3 is} selected from the group consisting of a chemical single bond and -O-;

R ⁵ and R ⁶ are each independently selected from hydrogen and C1-C4 alkyl;

G2 is selected from halogen and C1-C4 ^{^{^{alkyl, -OR 7, -NR 8 R 9}}} , wherein said alkyl is optionally substituted with one or more halo, -OR ^10, substituted with -NR ¹¹ R ^12; when both When G2 is on the same carbon atom or an adjacent carbon atom, the two G2s, optionally together with the carbon atom to which they are attached, form a 3-6 membered cycloalkyl group, the cycloalkyl group formed optionally being one or more halogen , -OR ¹⁰ , -NR ¹¹ R ¹² replaced;

One of X ₁ and X ₂ is C and the other is N;

X ₃ is N;

Y is selected from -N(R ^5a )-;

Z is selected from -C(R ^5b R ^5c )-;

L _{2 is} selected from C 1 -C 4 alkylene, wherein the alkylene group may be optionally substituted by one or more G 2 ;

L _{3 is} selected from the group consisting of a chemical single bond and -O-;

R ⁵ and R ⁶ are each independently selected from hydrogen and C1-C4 alkyl;

G1 is selected from the group consisting of halogen and C1-C4 alkyl;

In still another preferred embodiment of the present invention, there is provided a compound of the formula I, an isomer, a prodrug, a solvate thereof, a stable isotopic derivative or a pharmaceutically acceptable salt thereof, wherein:

One of X ₁ and X ₂ is C and the other is N;

X ₃ is N;

Ar is selected from the group consisting of phenylene, 2,3-pyridinylene and 1,3-pyridinone optionally substituted with one or two G1;

Y is selected from -N(R ^5a )-;

Z is selected from -C(R ^5b R ^5c )-;

L _{2 is} selected from a C 1 -C 4 alkylene group, wherein the alkylene group may be optionally substituted by one or two G 2 ;

L _{3 is} selected from the group consisting of a chemical single bond and -O-;

R ¹ , R ² , and R ³ are each independently selected from the group consisting of hydrogen and halogen;

R ^5a, R ^5b and R ^5c are each independently selected from hydrogen, C1-C4 alkyl, wherein said alkyl is optionally substituted with one or more substituents selected from halo, _- OR ^10, -NR ¹¹ R ¹² substituents Or substituted; or any two of R ^5a , R ^5b , R ^5c attached to an adjacent atom may form a 5- to 6-membered ring group or a 5- to 6-membered heterocyclic ring optionally substituted by G 3 together with the atom to which they are attached. base;

R ⁵ and R ⁶ are each independently selected from hydrogen and C1-C4 alkyl;

G1 is selected from the group consisting of halogen and C1-C4 alkyl;

One of X ₁ and X ₂ is C and the other is N;

X ₃ is N;

Ar is selected from the group consisting of phenylene, 2,3-pyridinyl and 1,3-pyridinone optionally substituted by one G1, said substituent being in the para position of L ₃ ;

Y is selected from -N(R ^5a )-;

Z is selected from -C(R ^5b R ^5c )-;

L _{3 is} selected from the group consisting of a chemical single bond and -O-;

R ⁵ and R ⁶ are each independently selected from hydrogen and C1-C4 alkyl;

G1 is selected from halogen;

G3 is selected from the group consisting of halogen, -OR ⁷ , and -NR ⁸ R ⁹ ;

In still another preferred embodiment of the present invention, there is provided a compound, an isomer, a prodrug, a solvate thereof, a stable isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, according to Formula I, wherein The compound is:

The invention further relates to a pharmaceutical composition comprising a compound of any one of the embodiments of the invention, or an isomer, prodrug, stable isotope derivative thereof, or a pharmaceutically acceptable salt thereof, and A pharmaceutically acceptable carrier, diluent, excipient.

The present invention also relates to a compound according to any one of the embodiments of the present invention, or an isomer thereof, a prodrug, a stable isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the present invention Use in the preparation of a medicament for the treatment or prevention of a TRK mediated disease, such as cancer, especially hematological malignancies, lung cancer, breast cancer, ovarian cancer, prostate cancer, pancreatic cancer, glioma.

The invention also relates to a method of treating or preventing a TRK-mediated disease, such as a tumor, in particular a hematological malignancy, a lung cancer, a breast cancer, an ovarian cancer, a prostate cancer, a pancreatic cancer, a glioma, which comprises administering A patient in need thereof, a therapeutically effective amount of a compound described in any one of the embodiments of the present invention, or an isomer, prodrug, solvate, stable isotope derivative or pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of the present invention Pharmaceutical composition.

Another aspect of the invention relates to a compound, or an isomer, prodrug, solvate, stable isotope derivative or pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof, in any one embodiment of the invention, It is used for the treatment or prevention of TRK-mediated diseases such as tumors, especially hematological malignancies, lung cancer, breast cancer, ovarian cancer, prostate cancer, pancreatic cancer, glioma.

Another aspect of the invention relates to a compound of formula I, or a tautomer, mesogen, racemate thereof, as described in any one of the embodiments of the invention for treating and/or preventing a disease such as a tumor , enantiomers, diastereomers, mixtures thereof, and pharmaceutically acceptable salts thereof.

Typical compounds of the invention include, but are not limited to:

And their isomers, prodrugs, solvates, stable isotopic derivatives or pharmaceutically acceptable salts thereof.

The compound of the present invention is a TRK inhibitor, and thus the compound of the present invention, or an isomer thereof, a prodrug, a stable isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, can be used for treating or preventing a TRK-mediated disease such as a tumor, especially Hematologic malignancies, lung cancer, breast cancer, ovarian cancer, prostate cancer, pancreatic cancer, glioma.

The invention further relates to a pharmaceutical composition comprising a compound of the invention, or an isomer thereof, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluted Agents, excipients.

Another aspect of the invention relates to a compound of formula I or an isomer, prodrug, solvate, stable isotope derivative thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament Use of the medicament for the treatment or prevention of TRK-mediated diseases such as tumors, especially hematological malignancies, lung cancer, breast cancer, ovarian cancer, prostate cancer, pancreatic cancer, glioma.

Another aspect of the invention relates to a compound of formula I or a tautomer, meso, racemate, enantiomer, diastereomer, mixture thereof, and A pharmaceutically acceptable salt, or use of the pharmaceutical composition in the manufacture of a medicament for the treatment and/or prevention of a tumor.

According to the invention, the medicament may be in any pharmaceutical dosage form including, but not limited to, tablets, capsules, solutions, lyophilized preparations, injections.

The pharmaceutical preparation of the present invention can be administered in the form of a dosage unit containing a predetermined amount of the active ingredient per dosage unit. Such a unit may comprise, for example, from 0.5 mg to 1 g, preferably from 1 mg to 700 mg, particularly preferably from 5 mg to 300 mg, of a compound of the invention, or a drug, depending on the condition being treated, the method of administration, and the age, weight and condition of the patient. The formulations may be administered in the form of dosage units containing a predetermined amount of active ingredient per dosage unit. Preferred dosage unit formulations are those containing the daily or divided doses indicated above or their corresponding fractions of the active ingredient. Furthermore, pharmaceutical preparations of this type can be prepared using methods well known in the pharmaceutical art.

The pharmaceutical preparations of the invention may be adapted for administration by any suitable method desired, for example by oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral. (including subcutaneous, intramuscular, intravenous or intradermal) methods of administration. Such formulations can be prepared by, for example, combining the active ingredient with one or more excipients or one or more adjuvants, using all methods known in the art of pharmacy.

The invention also relates to a method of treating or preventing a TRK-mediated disease, such as a tumor, in particular a hematological malignancy, a lung cancer, a breast cancer, an ovarian cancer, a prostate cancer, a pancreatic cancer, a glioma, which comprises administering A patient in need thereof is a therapeutically effective amount of a compound of the invention, or an isomer, prodrug, solvate, stable isotope derivative or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the invention.

Another aspect of the invention relates to a compound of formula I, or an isomer, prodrug, solvate, stable isotope derivative or pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof, for use in therapy or Prevention of TRK-mediated diseases such as tumors, especially hematological malignancies, lung cancer, breast cancer, ovarian cancer, prostate cancer, pancreatic cancer, glioma.

Another aspect of the invention relates to a compound of formula I, or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer thereof, as a compound for the treatment and/or prevention of a disease such as a tumor Isomers, mixtures thereof, and pharmaceutically acceptable salts thereof.

Preparation process

The invention also provides methods of making the compounds.

Process 1

R ^5a , R ⁵ ^b are each independently selected from hydrogen, C 1 -C 4 alkyl, wherein the alkyl group is optionally substituted by one or more substituents selected from the group consisting of halogen, —OR ¹⁰ , —NR ¹¹ R ¹² ; ^5a and R ^5b may form a 4-8 membered heterocyclic group together with the carbon atom to which they are attached, and the ring may be optionally substituted by one or more halogens, -OR ⁷ , -NR ⁸ R ⁹ ;

R ^{13 is} each independently selected from hydrogen, C1-C4 alkyl;

L _{2 is} independently selected from C 1 -C 4 alkylene, wherein the alkylene group may be optionally substituted by one or more G 2 ; G 2 is selected from halogen, C 1 -C 4 alkyl, -OR ⁷ , -NR ⁸ R ⁹ , wherein the alkyl group may be optionally substituted by one or more halogens, -OR ¹⁰ , -NR ¹¹ R ¹² ; when two G 2 are on the same carbon atom or adjacent carbon atoms, the two G 2 are optionally Forming a 3-6 membered cycloalkyl group together with the carbon atom to which it is attached, the cycloalkyl group formed may be optionally substituted by one or more halogens, -OR ¹⁰ , -NR ¹¹ R ¹² ;

One of X ₁ and X ₂ is C and the other is N;

M is selected from N or CH;

first step:

In a solvent such as n-butanol or N,N-dimethylacetamide, for example, N,N-diisopropylethylamine or 1,8-diazabicycloundec-7-ene (DBU) is added. And the like, the substitution reaction is carried out under microwave or oil bath heating at 60 to 150 ° C to obtain a compound (II);

The second step:

LG ¹ is a leaving group such as halogen or OTf, OTs, OMs, etc., and a base such as cesium carbonate is added to a solvent such as acetonitrile, and the substitution reaction is carried out under microwave or oil bath heating at 50 to 100 ° C to obtain a compound (III). );

third step:

LG ² is a leaving group such as halogen or OTf, OTs, OMs, etc., and a base such as sodium hydride is added to a solvent such as N,N-dimethylformamide, and the substitution reaction is carried out at 0 to 25 ° C. Obtaining compound (IV);

the fourth step:

Using, for example, zinc powder as a reducing agent, adding a saturated ammonium chloride solution, in a solvent such as dichloromethane, at a temperature of 0 to 25 ° C to carry out a reduction of the nitro group to obtain a compound (V);

the fifth step:

Deprotection of the tert-butoxycarbonyl group using a solvent such as trifluoroacetic acid in an acid such as dichloromethane at 0 to 25 ° C to obtain a compound (VI);

The sixth step:

Use, for example, N,N'-carbonyldiimidazole or N,N'-carbonylbis(1,2,4-triazole) in a solvent such as NN-dimethylformamide at room temperature of 20 to 50 ° C or oil The reaction of diamine (VI) to urea is carried out under heating with a bath to obtain a compound (VII).

Process 2

R ^5a and R ^5b are each independently selected from hydrogen, C1-C4 alkyl, wherein said alkyl group is optionally substituted by one or more substituents selected from the group consisting of halogen, -OR ¹⁰ , -NR ¹¹ R ¹² ; ^5a and R ^5b may form a 4-8 membered heterocyclic group together with the carbon atom to which they are attached, and the ring may be optionally substituted by one or more halogens, -OR ⁷ , -NR ⁸ R ⁹ ;

R ^{13 is} selected from the group consisting of hydrogen and C1-C4 alkyl;

R ^{14 is} selected from the group consisting of halogen, C1-C4 alkyl, -OR ⁷ , -NR ⁸ R ⁹ ; wherein the alkyl group may be optionally substituted by one or more halogens, -OR ¹⁰ , -NR ¹¹ R ¹² ;

One of X ₁ and X ₂ is C and the other is N;

M is selected from N or CH;

first step:

In a solvent such as N,N-dimethylformamide, a base such as triethylamine or the like is added simultaneously, and N-phenylbis(trifluoromethanesulfonimide) is added thereto, and trifluoromethane is carried out at 0 to 25 ° C. Preparation of a sulfonate to obtain a compound (VIII);

The second step:

Under the protection of nitrogen or argon, in a solvent such as N,N-dimethylformamide, a base such as triethylamine or the like is added, and a catalyst such as bis(triphenylphosphine)palladium dichloride and cuprous iodide is added. Et., the Sonogashira coupling reaction of the compound (VIII) with propargylamine is carried out under microwave or oil bath heating at 80 to 120 ° C to obtain a compound (IX);

third step:

LG ² is a leaving group such as halogen or OTf, OTs, OMs, etc., and a base such as sodium hydride is added to a solvent such as N,N-dimethylformamide at a temperature of 0 to 25 ° C to obtain a substitution reaction. Compound (X);

the fourth step:

Under a hydrogen atmosphere, in a solvent such as methanol or ethanol, while adding a catalyst palladium hydroxide or palladium acetate, the alkynyl reduction reaction is carried out at 0 to 25 ° C to obtain a compound (XI);

the fifth step:

Using zinc powder as a reducing agent, adding a saturated ammonium chloride solution, and performing a reduction reaction of the nitro group in a solvent such as dichloromethane at 0 to 25 ° C to obtain a compound (XII);

The sixth step:

Using trifluoroacetic acid as the acid, deprotection of the tert-butoxycarbonyl group in a solvent such as dichloromethane at 0 to 25 ° C to obtain the compound (XIII);

Step 7:

Using N,N'-carbonyldiimidazole or N,N'-carbonylbis(1,2,4-triazole) in a solvent such as N,N-dimethylformamide at room temperature of 20 to 50 ° C or The reaction of diamine (VII) into urea is carried out under heating in an oil bath to obtain a compound (XIV).

Process 3

R ^5a and R ^5b are each independently selected from hydrogen, C1-C4 alkyl, wherein said alkyl group is optionally substituted by one or more substituents selected from the group consisting of halogen, -OR ¹⁰ , -NR ¹¹ R ¹² ; ^5a formed therewith and R5 ^b together with the carbon atom 4 to 8-membered heterocyclyl ring optionally substituted with one or more halogen, -OR ^7, -NR ⁸ R ⁹ substituted;

One of X ₁ and X ₂ is C and the other is N;

M is selected from N or CH;

first step:

LG ³ is a leaving group such as halogen or OTf, OTs, OMs, etc., and a base such as cesium carbonate is added in a solvent such as acetonitrile, and a substitution reaction is carried out under microwave or oil bath heating at 50 to 100 ° C to obtain a compound (XV). );

The second step:

Using zinc powder as a reducing agent, adding a saturated ammonium chloride solution, and performing a reduction reaction of the nitro group in a solvent such as dichloromethane at 0 to 25 ° C to obtain a compound (XVI);

third step:

Using a lithium hydroxide as a base, a hydrolysis reaction of a carboxylic acid ester in water and a solvent such as methanol or ethanol or tetrahydrofuran at room temperature of 20 to 70 ° C or an oil bath to obtain a compound (XVII);

the fourth step:

Using 2-(7-oxobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) or 1H-benzotriazol-1-yloxytripyrolidine a hexafluorophosphate or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole as a condensing agent in N,N-dimethylmethyl In a solvent such as an amide, a base such as potassium carbonate or triethylamine or N,N-diisopropylethylamine is added at the same time, and an acid amine condensation cyclization reaction is carried out at room temperature of 20 to 60 ° C or an oil bath to obtain a compound. (XVIII).

Process 4

R ^5a and R ^5b are each independently selected from hydrogen, C1-C4 alkyl, wherein said alkyl group is optionally substituted by one or more substituents selected from the group consisting of halogen, -OR ¹⁰ , -NR ¹¹ R ¹² ; R ^5a And R ^5b may form a 4-8 membered heterocyclic group together with the carbon atom to which it is attached, and the ring may be optionally substituted with one or more halogens, -OR ⁷ , -NR ⁸ R ⁹ ;

R ^{15 is} selected from the group consisting of hydrogen and C1-C4 alkyl;

One of X ₁ and X ₂ is C and the other is N;

M is selected from N or CH;

first step:

Under the protection of nitrogen or argon, in a solvent such as N,N-dimethylformamide, a base such as triethylamine or the like is added, or triethylamine or the like is directly used as a solvent, and a catalyst bis(triphenylphosphine) is added. Palladium dichloride and cuprous iodide, the Sonogashira coupling reaction of the compound (XIX) with 3-butyn-1-ol is carried out under microwave or oil bath heating at 80 to 120 ° C to obtain a compound (XX);

The second step:

The catalyst (XXI) is obtained by adding a catalyst palladium hydroxide or palladium acetate or the like in a solvent such as methanol or ethanol under a hydrogen atmosphere at 0 to 25 ° C to obtain a compound (XXI);

third step:

In a solvent such as acetone, the internal temperature is controlled at 0 to 15 ° C in a cold bath, and the oxidizing agent Jones reagent is slowly added. After the dropwise addition is completed, the reaction is continued at 0 to 25 ° C to carry out oxidation of the alcohol and aldehyde/ketocarbonyl group. Deprotection to give compound (XXII);

the fourth step:

The aldehyde/ketone compound (XXII) is mixed with the corresponding amine, and a reducing agent such as sodium borohydride or the like is added to a solvent such as methanol or ethanol, and the reductive amination reaction of the aldehyde/ketone is carried out at 0 to 25 ° C to obtain a compound. (XXIII);

the fifth step:

In a solvent such as n-butanol or N,N-dimethylacetamide, N,N-diisopropylethylamine or 1,8-diazabicycloundec-7-ene (also added as a base) DBU), etc., the substitution reaction is carried out under microwave or oil bath heating conditions at 50 to 120 ° C to obtain a compound (XXIV);

The sixth step:

Using zinc powder as a reducing agent, adding a saturated ammonium chloride solution, and performing a reduction reaction of the nitro group in a solvent such as dichloromethane at 0 to 25 ° C to obtain a compound (XXV);

Step 7:

Using 2-(7-oxobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) or 1H-benzotriazol-1-yloxytripyrolidine a hexafluorophosphate or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole as a condensing agent in N,N-dimethylmethyl In a solvent such as an amide, a base such as potassium carbonate, triethylamine or N,N-diisopropylethylamine or the like is added simultaneously, and an acid amine condensation cyclization reaction is carried out at room temperature of 20 to 60 ° C or an oil bath to obtain a compound. (XXVI).

Detailed ways

definition

Unless otherwise stated, the following terms used in the specification and claims have the following meanings.

The expression "Cx-Cy" as used herein denotes a range of the number of carbon atoms, wherein x and y are both integers, for example, a C3-C8 cyclic group represents a cyclic group having 3 to 8 carbon atoms, and a C0-C2 alkyl group. Represents an alkyl group having 0 to 2 carbon atoms, wherein C0 alkyl refers to a chemical single bond.

As used herein, the term "alkyl" refers to a saturated aliphatic hydrocarbon group, including straight and branched chain groups of 1 to 20 carbon atoms, for example, may be from 1 to 18 carbon atoms, from 1 to 12 carbon atoms, Linear and branched groups of 1 to 8 carbon atoms, 1 to 6 carbon atoms or 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 ,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 - dimethylbutyl, 2-ethylbutyl, various branched isomers thereof, and the like. The alkyl group can be optionally substituted or unsubstituted.

As used herein, the term "alkenyl" refers to a straight-chain, branched hydrocarbon group containing at least one carbon-carbon double bond, which may include from 2 to 20 carbon atoms, for example from 2 to 18 carbon atoms, from 2 to 12 A linear or branched group of carbon atoms, 2 to 8 carbon atoms, 2 to 6 carbon atoms or 2 to 4 carbon atoms. There may be from 1 to 3 carbon-carbon double bonds, preferably one carbon-carbon double bond. The term "C2-4 alkenyl" refers to an alkenyl group having 2 to 4 carbon atoms. It includes a vinyl group, a propenyl group, a butenyl group, a buten-2-yl group, and a 2-methylbutenyl group. The alkenyl group may be substituted.

As used herein, the term "alkynyl" refers to a straight-chain, branched hydrocarbon group containing at least one carbon-carbon triple bond, which may include from 2 to 20 carbon atoms, for example from 2 to 18 carbon atoms, from 2 to 12 Linear and branched groups of one carbon atom, 2 to 8 carbon atoms, 2 to 6 carbon atoms or 2 to 4 carbon atoms. There may be 1-3 carbon-carbon triple bonds, preferably one carbon-carbon triple bond. The term "C2-4 alkynyl" refers to an alkynyl group having 2 to 4 carbon atoms. Non-limiting examples include ethynyl, propynyl, butynyl and butyn-2-yl, 3-methylbutynyl.

As used herein, the terms "alkylene", "alkenylene", "alkynylene" mean respectively substituted or unsubstituted alkyl, alkenyl and alkynyl groups having two terminal monovalent group cores, which are Produced by removing one hydrogen atom from each carbon atom of two terminal carbon atoms; said "alkylene", "alkenylene", "alkynylene" usually having from 1 to 8 carbon atoms, preferably It is 1 to 6 carbon atoms, more preferably 1 to 4 carbon atoms. Non-limiting examples of "alkylene" include substituted or unsubstituted methylene, ethylene, propylene, butylene, and the like; non-limiting examples of "alkenylene" include substituted or unsubstituted vinylene a non-limiting example of a "alkynylene group", including a substituted or unsubstituted ethynylene group, a propynylene group, a butynylene group, and the like;

As used herein, the term "cyclic group" refers to a fully carbon-saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon group comprising from 3 to 12 ring atoms, for example from 3 to 12, from 3 to 10, from 3 to 3 8 or 3 to 6 ring atoms, or may be 3, 4, 5, 6 membered rings. Non-limiting examples of monocyclic ring groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl , cyclooctyl and so on. The cyclic group can be substituted or unsubstituted.

As used herein, the term "ringylene" refers to a substituted or unsubstituted ring group having two terminal monovalent group cores, the ring group having the definitions previously described. Non-limiting examples of "ringylene" include cyclopropylene, cyclobutylene, cyclopentylene, cyclopentenylene, cyclohexylene, cyclohexylene, cyclohexadienyl, arylene Cycloheptyl, cycloheptatrienyl, cyclooctylene, and the like. A cyclocyclylene group can be substituted or unsubstituted.

As used herein, the term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic, bicyclic or polycyclic cyclic hydrocarbon group comprising from 3 to 20 ring atoms, for example from 3 to 16, 3 to 12, 3 Up to 10, 3 to 8, or 3 to 6 ring atoms, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O)m (where m is an integer from 0 to 2), but not included The ring portion of -OO-, -OS- or -SS-, the remaining ring atoms are carbon. Preferably, it comprises 3 to 12 ring atoms, of which 1 to 4 are hetero atoms, more preferably the heterocyclic ring contains 3 to 10 ring atoms, more preferably 3 to 8 ring atoms, still more preferably 3 to 6 ring atoms. Most preferably, a 5-membered ring or a 6-membered ring, wherein 1 to 4 are heteroatoms, more preferably 1 to 3 are heteroatoms, and most preferably 1 to 2 are heteroatoms. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl and the like. Bicyclic and polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups.

"Spiroheterocyclyl" means a polycyclic heterocyclic group of 5 to 20 members in which one atom (referred to as a spiro atom) is shared between the monocyclic rings, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O)m The hetero atom (where m is an integer from 0 to 2) and the remaining ring atoms are carbon. These may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. The spiro group is classified into a monospiroheterocyclic group, a dispiroheterocyclic group or a polyspirocyclic group according to the number of common spiro atoms between the ring and the ring, and is preferably a monospirocyclic group and a bispirocyclic group. More preferably, it is 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan single spiro ring group. Non-limiting examples of spiro groups include

"Fused heterocyclyl" refers to 5 to 20 members, each ring of the system sharing an adjacent pair of atoms of a polycyclic heterocyclic group with other rings in the system, and one or more rings may contain one or more a bond, but none of the rings have a fully conjugated π-electron system in which one or more ring atoms are selected from nitrogen, oxygen or S(O)m (where m is an integer from 0 to 2), and the remaining ring atoms are carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably a bicyclic or tricyclic ring, more preferably a 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic group. Non-limiting examples of fused heterocyclic groups include

The heterocyclyl ring may be fused to an aryl, heteroaryl or cyclic ring wherein the ring to which the parent structure is attached is a heterocyclic group, non-limiting examples comprising:

Wait. The heterocyclic group may be optionally substituted or unsubstituted.

As used herein, the term "aryl" refers to an all-carbon monocyclic or fused polycyclic ring (ie, a ring that shares a pair of adjacent carbon atoms) containing from 6 to 14 carbon ring atoms, having a conjugated pi-electron system. Polycyclic (ie, a ring with an adjacent pair of carbon atoms) groups. The aryl group can be monocyclic or polycyclic (ie, can contain more than one ring). In the case of polycyclic aromatic rings, only one of the rings in the polycyclic system is required to be an aromatic ring, while the remaining rings may be saturated, partially saturated or unsaturated rings. The aryl group is preferably 6 to 10 members such as a phenyl group and a naphthyl group, and most preferably a phenyl group. The aryl ring may be fused to a heteroaryl, heterocyclyl or cyclic ring wherein the ring to which the parent structure is attached is an aryl ring, non-limiting examples comprising:

The aryl group can be substituted or unsubstituted.

As used herein, the term "arylene" refers to a substituted or unsubstituted aryl group having two monovalent group cores, respectively, the definition of which is as previously described. Non-limiting examples of arylene groups are phenylene, naphthylene and the like. The arylene group can be optionally substituted or unsubstituted.

As used herein, the term "heteroaryl" refers to a heteroaromatic system comprising from 1 to 4 heteroatoms, from 5 to 14 ring atoms, wherein the heteroatoms include oxygen, sulfur and nitrogen. The heteroaryl group is preferably from 5 to 10 members. More preferably, it is 5- or 6-membered, such as furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, oxazolyl, isoxazole And the heteroaryl ring may be fused to an aryl, heterocyclic or cyclic ring wherein the ring to which the parent structure is attached is a heteroaryl ring, non-limiting examples comprising:

The heteroaryl group can be optionally substituted or unsubstituted.

As used herein, the term "heteroarylene" refers to a substituted or unsubstituted heteroaryl group having two monovalent group cores, respectively, the definition of which is the same as previously described. Non-limiting examples of heteroarylenes such as furanyl, thienylene, pyridylene, pyrrolylene, N-alkylpyrrolyl, pyrimidinyl, pyridazinyl, imidazolyl, tetrazolium Base, oxazolyl, oxazolylyl and the like. The heteroarylene group can be optionally substituted or unsubstituted.

"Halogen" means fluoro, chloro, bromo or iodo.

"Haloalkyl" means an alkyl substituent wherein at least one hydrogen is replaced by a halo group. Typical halogen groups include chlorine, fluorine, bromine and iodine. Examples of haloalkyl groups include fluoromethyl, fluoroethyl, chloromethyl, chloroethyl, 1-bromoethyl, difluoromethyl, trifluoromethyl and 1,1,1-trifluoroethyl. It will be appreciated that if a substituent is substituted with more than one halo group, those halo groups may be the same or different (unless otherwise stated).

"Aldehyde" means -CHO.

"Carboxy" means -COOH.

"Cyano" means -CN.

"Heteroalkyl" means a stable straight or branched chain hydrocarbon radical consisting of a specified number of carbon atoms and at least one heteroatom selected from the group consisting of oxygen, nitrogen, and sulfur, wherein the nitrogen and sulfur atoms may be optionally oxidized, and the nitrogen atom may Optionally, quaternization, hetero atomic oxygen, nitrogen, sulfur may be located at any internal position of the heteroalkyl group, or may be located where the alkyl group is attached to the remaining portion of the molecule, and two or more heteroatoms may be independent. It can also be continuous.

"Optional" or "optionally" means that the subsequently described event or environment may, but need not, occur, including where the event or environment occurs or does not occur. For example, "heterocyclic group optionally substituted by an alkyl group" means that an alkyl group may be, but not necessarily, present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group. .

"Substituted" refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3, hydrogen atoms, independently of each other, substituted by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art will be able to determine (by experiment or theory) substitutions that may or may not be possible without undue effort. For example, an amino group or a hydroxyl group having a free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) bond.

The substituents include, but are not limited to, the respective substituents described above.

"Pharmaceutical composition" means a mixture comprising one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiological/pharmaceutically acceptable carriers. And excipients. The purpose of the pharmaceutical composition is to promote the administration of the organism, which facilitates the absorption of the active ingredient and thereby exerts biological activity.

"Room temperature" as used herein means 15-30 °C.

The compounds of the invention may also exist as isomers, prodrugs, solvates or stable isotope derivatives thereof. Those skilled in the art will appreciate that such isomers, prodrugs, solvates or stabilized isotopic derivatives generally have similar activities as the compounds of the present invention or pharmaceutically acceptable salts thereof, and thus are also encompassed by the present invention. Within the scope of protection.

As used herein, a "stable isotope derivative" includes an isotope-substituted derivative obtained by substituting any one of the hydrogen atoms of the formula I with 1-5 deuterium atoms, and any carbon atom of the formula I is 1-3 carbon 14 An isotope-substituted derivative obtained by atom substitution or an isotope-substituted derivative obtained by substituting an oxygen atom of any one of Formula I with 1-3 oxygen atoms.

"Pharmaceutically acceptable salts" as described herein are discussed in Berge, et al., "Pharmaceutically acceptable salts", J. Pharm. Sci., 66, 1-19 (1977), and for pharmaceutical chemists It is apparent that the salts are substantially non-toxic and provide the desired pharmacokinetic properties, palatability, absorption, distribution, metabolism or excretion, and the like.

The pharmaceutically acceptable salts of the present invention can be synthesized by general chemical methods.

In general, the preparation of the salt can be carried out by reacting the free base or acid with an equivalent stoichiometric or excess acid (inorganic or organic acid) or base in a suitable solvent or solvent composition.

The "prodrug" as used in the present invention means that the compound is converted into the original active compound after being metabolized in the body. Typically, the prodrug is inactive or less active than the active parent compound, but can provide convenient handling, administration or improved metabolic properties.

As used herein, "isomer" means that the compound of formula (I) of the present invention may have asymmetric centers and racemates, racemic mixtures and individual diastereomers, all of which include Stereoisomers, geometric isomers are all included in the present invention. The geometric isomers include cis and trans isomers.

The invention includes any polymorph of the compound or salt thereof, as well as any hydrate or other solvate.

As used herein, the term "tumor" includes both benign and malignant tumors, such as cancer.

As used herein, the term "cancer" includes TRK-mediated various tumors including, but not limited to, hematological malignancies, lung cancer, breast cancer, ovarian cancer, prostate cancer, pancreatic cancer, glioma.

As used herein, the term "therapeutically effective amount" refers to an amount of a compound of the invention that includes a compound of the invention effective to treat or prevent a disease mediated by TRK.

Example

The invention is further illustrated by the following examples, which are not intended to limit the invention. The experimental methods in the following examples which do not specify the specific conditions are selected according to conventional methods and conditions, or according to the product specifications.

The structures of all compounds of the invention can be identified by nuclear magnetic resonance ( ¹ H NMR) and/or mass spectrometry (MS).

^{The 1} H NMR chemical shift (δ) is reported in ppm (unit: 10 ^-6 PPM). NMR was performed on a Bruker AVANCE-400 spectrometer. Suitable solvents are deuterated chloroform (CDCl ₃ ), deuterated methanol (CD ₃ OD), deuterated dimethyl sulfoxide (DMSO-d ₆ ), and tetramethylsilane as internal standard (TMS).

Low resolution mass spectrometry (MS) was determined by an Agilent 1260 HPLC/6120 mass spectrometer using Agilent ZORBAX XDB-C18, 4.6 x 50 mm, 3.5 μm, gradient elution conditions: 0: 95% solvent A1 and 5% solvent B1, 1- 2: 5% Solvent A1 and 95% Solvent B1; 2.01-2.50: 95% Solvent A1 and 5% Solvent B1. The percentage is the volume percent of a solvent as a percentage of the total solvent volume. Solvent A1: 0.01% aqueous formic acid; solvent B1: 0.01% formic acid in acetonitrile; percentage is the volume fraction of solute in solution.

The thin layer silica gel plate is Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate. Column chromatography generally uses Yantai Yellow Sea 100-200 or 200-300 mesh silica gel as a carrier.

Preparative liquid chromatography (prep-HPLC) using a Waters SQD2 mass spectrometric high pressure liquid chromatography separator, XBridge-C18; 30X 150 mm preparative column, 5 um; Method 1: acetonitrile-water (0.2% formic acid), flow rate 25 mL / min; Two: acetonitrile-water (0.8% ammonium hydrogencarbonate), flow rate 25mL / min;

The known starting materials of the present invention may be synthesized by or according to methods known in the art, or may be purchased from Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Shanghai Bied Pharmaceutical, Shanghai A. Latin Chemical, Shanghai Miner Chemical, Belling Chemical, An Nai and Chemical.

Unless otherwise specified in the examples, the solvent used in the reaction is an anhydrous solvent, wherein anhydrous tetrahydrofuran is commercially available as tetrahydrofuran, sodium block is used as a water removing agent, benzophenone is used as an indicator, and refluxed to a solution under argon gas protection. It is blue-violet, distilled and stored under argon atmosphere. Other anhydrous solvents are purchased from An Nai and Chemical and Belling Chemical. The transfer and use of all anhydrous solvents are carried out under argon protection unless otherwise specified.

In the examples, unless otherwise specified, the reactions were all carried out under an argon atmosphere or a nitrogen atmosphere.

An argon atmosphere or a nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon having a volume of about 1 L.

The hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1 L volume.

The hydrogenation reaction is usually evacuated, charged with hydrogen, and operated three times.

Unless otherwise specified in the examples, the reaction temperature is room temperature, and the temperature range is from 15 ° C to 30 ° C.

The reaction progress in the examples was monitored by thin layer chromatography (TLC), and the system used for the reaction was A: dichloromethane and methanol system; B: petroleum ether and ethyl acetate system, the volume ratio of the solvent was based on The polarity of the compound is adjusted to adjust.

The system for purifying the compound using the column chromatography eluent and the system for developing the thin layer chromatography include A: dichloromethane and methanol systems; B: petroleum ether and ethyl acetate system, the volume ratio of the solvent according to the compound The polarity is adjusted to adjust, and a small amount of triethylamine and an acidic or alkaline reagent may be added for adjustment.

Example 1

(3R,6S)-3,6-Dimethyl-4 ⁵ -fluoro-5-oxa-2,8,10-triaza-1(5,3)-pyrazolo[1,5-a Pyrimidine-4(1,2)-benzocyclodecane-9-one

first step

(R)-(2-hydroxypropyl)carbamic acid tert-butyl ester

(R)-1-Aminopropan-2-ol 1a (1.11 g, 14.80 mmol) was dissolved in 15 mL of tetrahydrofuran, di-tert-butyl dicarbonate (3.55 g, 16.30 mmol) was slowly added, and the reaction was stirred at room temperature after addition. minute. After completion of the reaction, it was directly dried to give (R)-(2-hydroxypropyl)carbamic acid tert-butyl ester 1b (2.60 g, colorless liquid).

¹ H NMR (400 MHz, CDCl ₃ ) δ 3.28-3.25 (m, 1H), 3.04-2.97 (m, 1H), 2.29-2.27 (m, 1H), 1.45 (s, 9H), 1.18 (d, J) =6.4 Hz, 3H).

Second step

(R)-1-((tert-Butoxycarbonyl)amino)propan-2-yl-4-methylbenzenesulfonate

(R)-(2-Hydroxypropyl)carbamic acid tert-butyl ester 1b (3.90 g, 22.00 mmol) was dissolved in dichloromethane (40 mL), triethylamine (3.50 g, 34. Chlorobenzenesulfonate (4.18 g, 22.00 mmol) and N,N-dimethyl-4-aminopyridine (0.39 g, 3.20 mmol) were stirred and stirred at 30 ° C for 18 h. The reaction mixture was washed with brine (30 mL×3), dried over anhydrous sodium sulfate Ester 1c (7.00 g, yellow oil, cooled to a yellow solid).

MS m/z (ESI): 352 [M+23].

third step

(S,E)-N-(5-fluoro-2-hydroxybenzylidene)-2-methylpropane-2-sulfinamide

5-Fluoricylaldehyde 1d (14.00 g, 0.10 mol) was dissolved in tetrahydrofuran (150 mL), and cesium carbonate (49.00 g, 0.15 mol) and (S)-2-methylpropane-2- The sulfonamide (13.30 g, 0.11 mol) was reacted at room temperature for 18 hours after the addition. After completion of the reaction, the mixture was filtered, and 150 mL of water was added, and dichloromethane (200 mL×3) was evaporated, dried over anhydrous sodium sulfate and dried to give (S,E)-N-(5-fluoro-2-hydroxybenzylidene)- 2-Methylpropane-2-sulfinamide 1e (24.00 g, yellow solid) was taken directly to the next step without further purification.

MS m/z (ESI): 244 [M + 1];

¹ H NMR (400 MHz, CDCl ₃ ) δ 10.85 (s, 1H), 8.63 (s, 1H), 7.18-7.16 (m, 2H), 6.99-6.97 (m, 1H), 1.27 (s, 9H).

the fourth step

(S)-N-((S)-1-(5-fluoro-2-hydroxyphenyl)ethyl)-2-methylpropane-2-sulfinamide

(S)-N-(5-fluoro-2-hydroxybenzylidene)-2-methylpropane-2-sulfinamide 1e (24.00 g, 0.10 mol) was dissolved in tetrahydrofuran (250 mL) and cooled. Methylmagnesium chloride (3M tetrahydrofuran solution, 165 mL, 0.50 mol) was slowly added dropwise at -65 ° C under nitrogen atmosphere. After completion of the dropwise addition, the mixture was naturally stirred at room temperature for 18 hours. The reaction mixture was quenched by the addition of 150 mL of water under ice-cooling, ethyl acetate (300 mL×3), washed with brine (400 mL), dried over anhydrous sodium sulfate and evaporated. Purification of ethyl ester = 10:1 to 1:1) gives (S)-N-((S)-1-(5-fluoro-2-hydroxyphenyl)ethyl)-2-methylpropane-2- Sulfonamide 1f' (10.00 g, pale yellow oil, yield 38.6%) and (S)-N-((R)-1-(5-fluoro-2-hydroxyphenyl)ethyl)-2-methyl Propane-2-sulfinamide 1f (6.40 g, pale yellow solid, yield 24.7%).

(S)-N-((R)-1-(5-fluoro-2-hydroxyphenyl)ethyl)-2-methylpropane-2-sulfinamide 1f

MS m/z (ESI): 260 [M + 1];

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.35 (s, 1H), 6.88-6.80 (m, 2H), 6.75-6.73 (m, 1H), 4.68-4.66 (m, 1H), 4.15-4.10 (m , 1H), 1.58 (d, J = 6.4 Hz, 3H), 1.26 (s, 9H).

(S)-N-((S)-1-(5-fluoro-2-hydroxyphenyl)ethyl)-2-methylpropane-2-sulfinamide 1f'

MS m/z (ESI): 260 [M + 1];

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.88 (s, 1H), 6.79-6.77 (m, 1H), 6.63-6.59 (m, 1H), 6.50-6.47 (m, 1H), 4.88-4.86 (m) , 1H), 4.42-4.38 (m, 1H), 1.52 (d, J = 6.8 Hz, 3H), 1.27 (s, 9H).

the fifth step

(R)-2-(1-aminoethyl)-4-fluorophenol hydrochloride

(S)-N-((R)-1-(5-fluoro-2-hydroxyphenyl)ethyl)-2-methylpropane-2-sulfinyl 1f (1.00 g, 3.86 mmol) was dissolved in The solution of hydrochloric acid in dioxane (10 mL, 4 M) was stirred at room temperature for 2 hr. After the reaction mixture was dried, 50 mL of ethyl acetate was added, stirred for 5 min, filtered, and the filter cake was dried to give (R)-2-(1-aminoethyl)-4-fluorophenol hydrochloride 1 g (0.68 g, white solid ), the yield is 92%.

MS m/z (ESI): 156 [M + 1];

^{1 H NMR (400MHz, DMSO-} d 6) δ10.13 (s, 1H), 8.32 (s, 3H), 7.26-7.23 (m, 1H), 7.03-7.01 (m, 1H), 6.93-6.90 (m , 1H), 4.53-4.52 (m, 1H), 1.45 (d, J = 6.4 Hz, 3H).

Step 6

(R)-4-fluoro-2-(1-((3-nitropyrazolo[1,5-a]pyrimidin-5-yl)amino)ethyl)phenol

1 g (0.68 g, 3.55 mmol) of (R)-2-(1-aminoethyl)-4-fluorophenol hydrochloride was dissolved in n-butanol (10 mL), followed by diisopropylethylamine (1 mL) and 5-Chloro-3-nitropyrazolo[1,5-a]pyrimidine (0.74 g, 3.73 mmol) was reacted at 60 ° C for 2 hours after the addition. After the reaction was completed, the solution was spun dry, and 50 mL of dichloromethane and 20 mL of water were added, and the mixture was separated, extracted with 50 mL of dichloromethane, washed with 50 mL of brine, dried over anhydrous sodium sulfate (1-((3-Nitropyrazolo[1,5-a]pyrimidin-5-yl)amino)ethyl)phenol 1 h (1.25 g, white solid)

MS m/z (ESI): 318 [M + 1];

^{_{1 H NMR (400MHz, CDCl 3}} ) δ10.87 (s, 1H), 8.87 (s, 1H), 8.43 (s, 1H), 8.11 (d, J = 7.2Hz, 1H), 7.08-7.03 (m, 1H), 6.98-6.95 (m, 1H), 6.87-6.83 (m, 1H), 6.55 (d, J = 7.2 Hz, 1H), 5.69-5.66 (m, 1H), 1.54 (d, J = 4.8 Hz) , 3H).

Seventh step

((S)-2-(4-fluoro-2-((R)-1-((3-nitropyrazolo[1,5-a]pyrimidin-5-yl)amino)ethyl)phenoxy) Tertyl)propyl)carbamic acid tert-butyl ester compound (R)-4-fluoro-2-(1-((3-nitropyrazolo[1,5-a]pyrimidin-5-yl)amino) Phenol 1h (0.20g, 0.63mmol) and cesium carbonate (0.62g, 1.89mmol) were dissolved in acetonitrile (20mL), stirred in an oil bath at 50°C for 10 minutes, (R)-1-((tert-butoxy) Alkylcarbonyl)amino)propan-2-yl-4-methylbenzenesulfonate (0.42 g, 1.26 mmol) was stirred at 50 ° C overnight. The reaction mixture was diluted with water (50 mL), EtOAc (EtOAc)EtOAc. : 1 to 3: 2) to obtain the target compound ((S)-2-(4-fluoro-2-((R)-1-((3-nitropyrazolo[1,5-a]pyrimidine-5) tert-Butyl 1 -amino)phenoxy)propyl)carbamate 1i (90 mg, yellow solid), yield: 30%.

MS m/z (ESI): 475 [M + 1];

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.37 (s, 1H), 8.07 (d, J = 8.0Hz, 1H), 7.89-7.87 (m, 1H), 7.21-7.18 (m, 1H), 6.87- 6.85 (m, 1H), 6.78-6.76 (m, 1H), 6.67 (d, J = 8.0 Hz, 1H), 5.47-5.45 (m, 1H), 5.21-5.19 (m, 1H), 5.03-5.01 ( m, 1H), 3.32-3.13 (m, 2H), 1.57 (d, J = 6.4 Hz, 3H), 1.45 (s, 9H), 1.35 (d, J = 5.2 Hz, 3H).

Eighth step

((S)-2-(4-fluoro-2-((R)-1-((3-aminopyrazolo[1,5-a]pyrimidin-5-yl)amino)ethyl)phenoxy) ) propyl)-tert-butyl carbamate compound ((S)-2-(4-fluoro-2-((R)-1-((3-nitropyrazolo[1,5-a]pyrimidine- tert-Butyl 5-(amino)ethyl)ethyl)phenoxy)propyl)carbamate (90 mg, 0.19 mmol), dichloromethane (5 mL), methanol (5 mL), sat. The powder (0.12 g, 1.90 mmol) was mixed and stirred at room temperature for 30 minutes. Dichloromethane (30 mL) was added, and the mixture was washed with water (3 mL×3). The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to give the title compound ((S)-2-(4-fluoro-2-(( R)-1-((3-Aminopyrazolo[1,5-a]pyrimidin-5-yl)amino)ethyl)phenoxy)propyl)carbamic acid tert-butyl ester 1j (80 mg, yellow solid) ,Crude.

MS m/z (ESI): 445 [M + 1].

Step 9

N ⁵ -((R)-1-(2-((S)-1-aminopropan-2-yl)oxy)-5-fluorophenyl)ethyl)pyrazolo[1,5-a Pyrimidine-3,5-diamine trifluoroacetate

Compound ((S)-2-(4-fluoro-2-((R)-1-((3-aminopyrazolo[1,5-a]pyrimidin-5-yl)amino)ethyl)benzene The oxy)propyl)carbamic acid tert-butyl ester 1j (80 mg, 0.18 mmol) was dissolved in dichloromethane (5 mL). The reaction solution was desolvated under reduced pressure to give the title compound N ⁵ -((R)-1-(2-((())-1-aminopropan-2-yl)oxy)-5-fluorophenyl)ethyl Pyrazolo[1,5-a]pyrimidine-3,5-diamine trifluoroacetate 1k (90 mg, yellow solid), crude.

MS m/z (ESI): 344 [M + 1].

Step 10

(3R,6S)-4 ⁵ -fluoro-3,6-dimethyl-5-oxa-2,8,10-triaza-1(5,3)-pyrazolo[1,5-a Pyrimidine-4(1,2)-benzocyclodecane-9-one

Compound N ⁵ -((R)-1-(2-((S)-1-aminopropan-2-yl)oxy)-5-fluorophenyl)ethyl)pyrazolo[1,5 -a]pyrimidine-3,5-diamine trifluoroacetate 1k (90 mg, 0.18 mmol) dissolved in N,N-dimethylformamide (5 mL), N,N'-carbonyldiimidazole (0.16 g) , 0.36 mmol) and triethylamine (1 mL) were stirred in a 35 ° C oil bath for 2 hours. The reaction mixture was diluted with ethyl acetate (50 mL), EtOAc (EtOAc m. 3R,6S)-4 ⁵ -fluoro-3,6-dimethyl-5-oxa-2,8,10-triaza-1(5,3)-pyrazolo[1,5-a] Pyrimidine-4(1,2)-benzocyclodecane-9-one 1 (14 mg, yellow solid), yield: 20%.

MS m/z (ESI): 371 [M + 1];

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.28 (s, 1H), 8.06 (d, J = 7.2Hz, 1H), 7.54 (s, 1H), 6.97-6.95 (m, 1H), 6.84-6.80 ( m, 2H), 6.42 (s, 1H), 6.03 (d, J = 7.2 Hz, 1H), 5.63-5.60 (m, 1H), 5.48-5.46 (m, 1H), 4.55-4.52 (m, 1H) , 3.83-3.76 (m, 1H), 3.25-3.18 (m, 1H), 1.48 (d, J = 6.4 Hz, 3H), 1.46 (d, J = 5.2 Hz, 3H).

Example 2

(3R,6R)-4 ⁵ -fluoro-3,6-dimethyl-5-oxa-2,8,10-triaza-1(5,3)-pyrazolo[1,5-a Pyrimidine-4(1,2)-benzocyclodecane-9-one

Synthesis Example 2 was carried out in accordance with the procedure of Example 1, to give the title compound (3R,6R)-4 ⁵ -fluoro-3,6-dimethyl-5-oxa-2,8,10-triaza-1 (5,3)-pyrazolo[1,5-a]pyrimidin-4(1,2)-benzocyclodecane-9-one 2.

MS m/z (ESI): 371 [M + 1];

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.31-8.29 (m, 1H), 8.06 (d, J = 8.0Hz, 1H), 7.64-7.62 (m, 1H), 7.12-7.10 (m, 1H), 6.99-6.90 (m, 1H), 6.82-6.80 (m, 1H), 6.37-6.35 (m, 1H), 5.83 (d, J = 8.0 Hz, 1H), 4.82-4.80 (m, 1H), 4.65- 4.63 (m, 1H), 3.73-3.71 (m, 1H), 3.48-3.46 (m, 1H), 1.57 (d, J = 6.0 Hz, 3H), 1.22 (d, J = 6.0 Hz, 3H).

Example 3

(3S,6R)-4 ⁵ -fluoro-3,6-dimethyl-5-oxa-2,8,10-triaza-1(5,3)-pyrazolo[1,5-a Pyrimidine-4(1,2)-benzocyclodecane-9-one

Synthesis Example 3 was carried out in accordance with the procedure of Example 1, to give the title compound (3S,6R)-4 ⁵ -fluoro-3,6-dimethyl-5-oxa-2,8,10-triaza-1 (5,3)-pyrazolo[1,5-a]pyrimidin-4(1,2)-benzocyclodecane-9-one 3.

MS m/z (ESI): 371 [M + 1];

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.23 - 8.22 (m, 1H), 8.09 (d, J = 7.2 Hz, 1H), 7.52 (s, 1H), 6.96-6.93 (m, 1H), 6.87- 6.83 (m, 2H), 6.04 (d, J = 7.2 Hz, 1H), 6.04-6.01 (m, 1H), 5.61-5.60 (m, 1H), 5.27-5.23 (m, 1H), 4.55-4.53 ( m, 1H), 3.82-3.76 (m, 1H), 3.22-3.19 (m, 1H), 1.49 (d, J = 6.0 Hz, 3H), 1.47 (d, J = 6.0 Hz, 3H).

Example 4

(3S,6S)-4 ⁵ -fluoro-3,6-dimethyl-5-oxa-2,8,10-triaza-1(5,3)-pyrazolo[1,5-a Pyrimidine-4(1,2)-benzocyclodecane-9-one

Synthesis Example 4 was carried out in accordance with the procedure of Example 1, to give the title compound (3S,6S)-4 ⁵ -fluoro-3,6-dimethyl-5-oxa-2,8,10-triaza-1 (5,3)-pyrazolo[1,5-a]pyrimidin-4(1,2)-benzocyclodecane-9-one 4.

MS m/z (ESI): 371 [M + 1];

¹ H NMR (400 MHz, CDCl ₆ ) δ 8.14 - 8.12 (m, 1H), 8.06 (d, J = 7.2 Hz, 1H), 7.53 (s, 1H), 7.01-6.99 (m, 1H), 6.91 6.86 (m, 1H), 6.78-6.76 (m, 1H), 5.96-5.94 (m, 1H), 5.95 (d, J = 7.2 Hz, 1H), 5.86-5.82 (m, 1H), 5.11-5.09 ( m, 1H), 4.19-4.17 (m, 1H), 4.15-4.10 (m, 2H), 1.54 (d, J = 4.8 Hz, 3H), 1.47 (d, J = 6.0 Hz, 3H).

Example 5

(3R,7R)-4 ⁵ -fluoro-3,7-dimethyl-5-oxa-2,8,10-triaza-1(5,3)-pyrazolo[1,5-a Pyrimidine-4(1,2)-benzocyclodecane-9-one

Synthesis Example 5 was carried out by referring to the procedure of Example 1 to give the title compound (3R,7R)-4 ⁵ -fluoro-3,7-dimethyl-5-oxa-2,8,10-triaza-1 (5,3)-pyrazolo[1,5-a]pyrimidin-4(1,2)-benzocyclodecane-9-one 5.

MS m/z (ESI): 371 [M + 1];

¹ H NM[R(400MHz, CDCl ₃ ) δ 8.23 - 8.21 (m, 1H), 8.03 (d, J = 8.0 Hz, 1H), 7.56 (s, 1H), 7.03-7.01 (m, 1H), 6.89-6.87 (m, 1H), 6.81-6.72 (m, 1H), 6.44 (s, 1H), 5.98 (d, J = 8.0 Hz, 1H), 5.84 (s, 1H), 4.26-4.24 (m, 1H), 4.19-4.17 (m, 1H), 4.13-4.10 (m, 2H), 1.54 (d, J = 6.4 Hz, 3H), 1.48 (d, J = 6.4 Hz, 3H).

Example 6

(3R,7S)-4 ⁵ -fluoro-3,7-dimethyl-5-oxa-2,8,10-triaza-1(5,3)-pyrazolo[1,5-a Pyrimidine-4(1,2)-benzocyclodecane-9-one

Synthesis Example 6 was carried out in accordance with the procedure of Example 1, to give the title compound (3R,7S)-4 ⁵ -fluoro-3,7-dimethyl-5-oxa-2,8,10-triaza-1 (5,3)-pyrazolo[1,5-a]pyrimidin-4(1,2)-benzocyclodecane-9-one 6.

MS m/z (ESI): 371 [M + 1];

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.10-7.86 (m, 1H), 7.65 (s, 1H), 7.22-7.10 (m, 1H), 7.07 (s, 1H), 6.96-6.86 (m, 1H ), 6.85-6.64 (m, 2H), 6.60-6.39 (m, 1H), 5.98-5.80 (m, 1H), 5.74-5.47 (m, 1H), 4.31-4.17 (m, 1H), 4.16-4.00 (m, 1H), 3.72-3.47 (m, 1H), 1.55 (d, J = 4.0 Hz, 3H), 1.38 (d, J = 4.0 Hz, 3H).

Example 7

(3R,6S)-4 ⁵ -fluoro-2,3,6-trimethyl-5-oxa-2,8,10-triaza-1(5,3)-pyrazolo[1,5 -a]pyrimidine-4(1,2)-benzocyclodecane-9-one

first step

(R)-N-(1-(5-fluoro-2-methoxyphenyl)ethyl)-N-methyl-3-nitropyrazolo[1,5-a]pyrimidin-5-amine

Compound (R)-4-fluoro-2-(1-((3-nitropyrazolo[1,5-a]pyrimidin-5-yl)amino)ethyl)benzene 1h under ice bath 0.22 g, 0.71 mmol) and sodium hydride (0.10 g, 4.20 mmol, 60%, mineral oil dispersion) were dissolved in N,N-dimethylformamide (5 mL), stirred at room temperature for 20 min, and then io (0.30 g, 2.00 mmol). The mixture was stirred at room temperature for 1 hr. EtOAc (EtOAc) (EtOAc) The organic phase was dried over anhydrous sodium sulfate, and then filtered, evaporated, evaporated, evaporated, evaporated, evaporated. (5-fluoro-2-methoxyphenyl)ethyl)-N-methyl-3-nitropyrazolo[1,5-a]pyrimidin-5-amine 7b (0.16 g, mp. Yield: 65%.

MS m/z (ESI): 346 [M + 1];

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.46 (s, 1H), 8.25 (d, J = 7.6Hz, 1H), 7.03-4.01 (m, 2H), 6.79-6.77 (m, 1H), 6.73- 6.32 (m, 1H), 5.47-5.45 (m, 1H), 3.76 (s, 3H), 3.14 (s, 3H), 1.64 (d, J = 6.0 Hz, 3H).

Second step

(R)-4-fluoro-2-(1-(methyl(3-nitropyrazolo[1,5-a]pyrimidin-5-yl)amino)ethyl)phenol

Compound (R)-N-(1-(5-fluoro-2-methoxyphenyl)ethyl)-N-methyl-3-nitropyrazolo[1,5-a under ice-bath conditions Pyrimidine-5-amine 7b (0.16 g, 0.46 mmol) was dissolved in dichloromethane (5 mL), and boron tribromide (8 mL) was added. The mixture was stirred at room temperature for 1 hour, and the reaction solution was evaporated to dryness to give a yellow solid. The solid was dissolved in ethyl acetate (50 mL). The organic phase was dried over anhydrous sodium sulfate and filtered to remove desiccant, and then evaporated to give the desired product (R)-4-fluoro-2-(1-(methyl(3-nitropyrazolo[1,5- a] Pyrimidin-5-yl)amino)ethyl)phenol 7c (0.12 g, yellow solid), yield: 81%.

MS m/z (ESI): 332 [M+1].

third step

((S)-2-(4-fluoro-2-((R)-1-(methyl(3-nitropyrazole[1,5-a]pyrimidin-5-yl)amino)ethyl)benzene Oxy)propyl)carbamic acid tert-butyl ester

Compound (R)-4-fluoro-2-(1-(methyl(3-nitropyrazolo[1,5-a]pyrimidin-5-yl)amino)ethyl)phenol under ice bath 7c (0.12 g, 0.36 mmol) and the compound (R)-1-((tert-butoxycarbonyl)amino)propan-2-yl-4-methylbenzenesulfonate 1c (0.24 g, 0.72 mmol) were dissolved. Potassium carbonate (0.25 g, 1.80 mmol) was added to N,N-dimethylacetamide (2 mL). The mixture was reacted at 80 ° C for 22 hours, water (50 mL) was added and ethyl acetate (50 mL) was evaporated. It was washed with saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated to dryness. -Fluoro-2-((R)-1-(methyl(3-nitropyrazol[1,5-a]pyrimidin-5-yl)amino)ethyl)phenoxy)propyl)carbamic acid Butyl ester 7d (0.10 g, gray oil), yield: 56%.

MS m/z (ESI): 495 [M + 1].

the fourth step

((S)-2-(4-fluoro-2-((R)-1-(methyl(3-aminopyrazole[1,5-a]pyrimidin-5-yl)amino)ethyl)phenoxy Tert-butyl)carbamic acid tert-butyl ester

Compound ((S)-2-(4-fluoro-2-((R)-1-(methyl(3-nitropyrazole[1,5-a]pyrimidin-5-yl)amino)ethyl) Benzyloxy)propyl)carbamic acid tert-butyl ester 7d (0.10 g, 0.20 mmol), zinc powder (0.18 g, 2.70 mmol), saturated aqueous ammonium chloride (3 mL), dichloromethane (10 mL) 5 mL) was mixed, and the reaction was stirred at room temperature for 1 hour. The reaction solution was filtered, and the filtrate was diluted with dichloromethane (40 mL) The organic phase is dried over anhydrous sodium sulfate, and the desiccant is removed by filtration, and the residue is evaporated to give the desired product ((S)-2-(4-fluoro-2-((R)-1-(methyl) tert-Butyl 710 (90 mg, yellow solid) of oxazol[1,5-a]pyrimidine-5-yl)amino)ethyl)phenoxy)propyl)carbamate, yield: 98%.

MS m/z (ESI): 459 [M+1].

the fifth step

N ⁵ -((R)-1-(2-((S)-1-aminopropan-2-yl)oxy)-5-fluorophenyl)ethyl)-N ⁵ -methylpyrazole [1,5-a]pyrimidine-3,5-diamine trifluoroacetate

Compound ((S)-2-(4-fluoro-2-((R)-1-(methyl(3-aminopyrazole[1,5-a]pyrimidin-5-yl)amino)ethyl) To the dichloromethane (5 mL), phenoxy) propyl) carbamic acid tert-butyl ester 7e (90 mg, 0.19 mmol) was added to trifluoroacetic acid (1 mL). The mixture was stirred at room temperature for 1 h. The reaction solution was directly dried to obtain the desired product N ⁵ -((R)-1-(2-((()))))))) The crude product was N ⁵ -methylpyrazolo[1,5-a]pyrimidine-3,5-diamine trifluoroacetate 7f (0.10 g, yellow solid).

MS m/z (ESI): 359 [M + 1].

Step 6

The compound N ⁵ -((R)-1-(2-((())-1-aminopropan-2-yl)oxy)-5-fluorophenyl)ethyl)-N ⁵ -methylpyridyl Zyrazolo[1,5-a]pyrimidine-3,5-diamine trifluoroacetate 7f (0.10 g, 0.21 mmol) was dissolved in N,N-dimethylformamide (3 mL), N-carbonyldiimidazole (30 mg, 0.18 mmol) and triethylamine (0.5 mL). The mixture was stirred at room temperature for 1 h. The reaction solution is purified (acetonitrile:water = 20% to 50%) to obtain the target product (3R,6S)-4 ⁵ -fluoro-2,3,6-trimethyl-5-oxa-2,8,10- Triaza-1(5,3)-pyrazolo[1,5-a]pyrimidin-4(1,2)-benzocyclodecane-9-one 7 (5.8 mg, yellow solid), yield : 8%.

MS m/z (ESI): 385 [M + 1];

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.22 - 8.19 (m, 1H), 8.15 (d, J = 8.0 Hz, 1H), 7.69 (s, 1H), 7.18-7.16 (m, 1H), 6.99- 6.84 (m, 3H), 6.20 (s, 1H), 6.19 (d, J = 8.0 Hz, 1H), 4.57-4.55 (m, 1H), 3.66-3.63 (m, 1H), 3.41-3.32 (m, 1H), 3.50 (s, 3H), 1.48 (d, J = 4.0 Hz, 3H), 1.24 (d, J = 4.8 Hz, 3H).

Example 8

(3S,6S)-4 ⁵ -fluoro-2,3,6-trimethyl-5-oxa-2,8,10-triaza-1(5,3)-pyrazolo[1,5 -a]pyrimidine-4(1,2)-benzocyclodecane-9-one

Synthesis Example 8 was carried out in accordance with the procedure of Example 7, to give the title compound (3S,6S)-4 ⁵ -fluoro-2,3,6-trimethyl-5-oxa-2,8,10-triaza -1(5,3)-pyrazolo[1,5-a]pyrimidin-4(1,2)-benzocyclodecane-9-one 8.

MS m/z (ESI): 385 [M + 1];

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.16-8.14 (m, 1H), 8.15 (d, J = 8.0Hz, 1H), 7.69 (s, 1H), 7.18-716 (m, 1H), 6.99- 6.90 (m, 2H), 6.85-6.83 (m, 1H), 6.20 (d, J = 8.0 Hz, 1H), 4.57-4.55 (m, 1H), 3.73-3.72 (m, 1H), 3.66-3.63 ( m, 1H), 3.49 (s, 3H), 3.41-3.39 (m, 1H), 2.84 (s, 3H), 1.49 (d, J = 4.0 Hz, 3H).

Example 9

4 ⁵ -fluoro-3-methyl-5-oxa-2,8,10-triaza-1(5,3)-pyrazolo[1,5-a]pyrimidine-4(1,2) -benzocyclodecane-9-one

first step

Pyrazolo[1,5-a]pyrimidine-5-ol sodium

The compound 1,3-dimethylpyrimidine-2,4(1H,3H)-dione 9a (24.50 g, 0.18 mol) and 1H-pyrazol-3-amine (16.00 g, 0.19 mol) were dissolved in ethanol. (600 mL), sodium ethoxide (52.50 g, 0.77 mol) was added and refluxed in a 90 ° C oil bath overnight. Cooled, filtered, washed with EtOAc (EtOAc) (EtOAc)EtOAc.

MS m/z (ESI): 136 [M-Na+1].

Second step

3-nitropyrazolo[1,5-a]pyrimidin-5-ol

Under the ice bath condition, the compound pyrazolo[1,5-a]pyrimidin-5-ol sodium 9b (10.00 g, 74.00 mmol) was dissolved in concentrated sulfuric acid (80 mL), and concentrated nitric acid (20 mL) was added slowly. The temperature was continued to 50 ° C and stirring was continued for one hour. The reaction mixture was poured into water, filtered, and the filter cake was dried under reduced pressure to give 3-nitropyrazolo[1,5-a]pyrimidin-5-ol 9c (8.60 g, yellow solid), yield: 65%.

MS m/z (ESI): 181 [M + 1].

third step

5-chloro-3-nitropyrazolo[1,5-a]pyrimidine

The compound 3-nitropyrazolo[1,5-a]pyrimidin-5-ol 9c (8.60 g, 48.00 mmol) was dissolved in acetonitrile (50 mL) and 2,6-dimethylpyridine (7.70 g, 72.00 mmol) and warmed to 50 ° C and stirred for 10 minutes. Phosphorus oxychloride (50 mL) was then added and the mixture was warmed to 80 ° C and stirred overnight. After cooling, the reaction mixture was poured into EtOAc (3 mL / EtOAc, EtOAc) -a] Pyrimidine 9d (7.00 g, yellow solid), yield: 74%.

MS m/z (ESI): 199 & 201 [M+1];

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.46 (d, J = 8.0 Hz, 1H), 9.10 (s, 1H), 7.64 (d, J = 8.0 Hz, 1H).

the fourth step

4-fluoro-2-(1-((3-nitropyrazolo[1,5-a]pyrimidin-5-yl)amino)ethyl)phenol

The compound 2-(1-aminoethyl)-4-fluorophenol (0.25 g, 1.61 mmol), 5-chloro-3-nitropyrazolo[1,5-a]pyrimidine 9d (0.35 g, 1.78 mmol And diisopropylethylamine (0.64 g, 4.98 mmol) was dissolved in n-butanol (8 mL) and stirred in a 60 ° C oil bath for one hour. After cooling, it was quenched with 1N EtOAc EtOAc. Desolvation under reduced pressure gave the desired product 4-fluoro-2-(1-((3-nitropyrazolo[1,5-a]pyrimidin-5-yl)amino)ethyl)phenol 9e (0.51 g, Brownish black solid), crude.

MS m/z (ESI): 318 [M + 1].

the fifth step

(2-(4-Fluoro-2-(1-(3-nitropyrazolo[1,5-a]pyrimidin-5-yl)amino)ethyl)phenoxy)ethyl)carbamic acid Butyl ester

The compound 4-fluoro-2-(1-((3-nitropyrazolo[1,5-a]pyrimidin-5-yl)amino)ethyl)phenol 9e (0.51 g, 1.61 mmol) and cesium carbonate (1.57 g, 4.82 mmol) dissolved in acetonitrile (20 mL), EtOAc (EtOAc) Stir overnight. After cooling, the reaction mixture was diluted with water (30 mL), and the mixture was extracted with dichloromethane (50mL×3). The organic phase was combined and dried over anhydrous sodium sulfate. Ethyl ester = 19:1 to 3:2) to give the title compound (2-(4-fluoro-2-(1-(3-nitropyrazolo[1,5-a]pyrimidin-5-yl)amino) tert-Butyl ester of ethyl)phenoxy)ethyl)carbamate 9f (0.46 g, yellow solid), yield: 62%.

MS m/z (ESI): 461 [M + 1];

^{1 H NMR (400MHz, CDCl3)} δ8.36 (s, 1H), 8.10 (d, J = 8.0Hz, 1H), 7.74-7.72 (m, 1H), 7.30-7.28 (m, 1H), 6.91-6.89 (m,1H), 6.73(s,1H),6.63-6.61(m,1H),5.58-5.56(m,1H),5.34-5.32(m,1H),4.03-3.98(m,2H),3.88 -3.86 (m, 1H), 3.40-3.37 (m, 1H), 1.56 (d, J = 6.0 Hz, 3H), 1.45 (s, 9H).

Step 6

(2-(2-(1-Aminopyrazolo[1,5-a]pyrimidin-5-yl)amino)ethyl)-4-fluorophenoxy)ethyl)carbamic acid tert-butyl ester

The compound (2-(4-fluoro-2-(1-((3-nitropyrazolo[1,5-a]pyrimidin-5-yl)amino)ethyl)phenoxy)ethyl)amino Tert-butyl formate 9f (0.46 g, 1.00 mmol), dichloromethane (10 mL), MeOH (10 mL), EtOAc (EtOAc) Dichloromethane (30 mL × 2) was added for extraction, and the organic phase was washed with water (30 mL × 3), dried over anhydrous sodium sulfate, and evaporated to give the title compound (2-(2-(1-((3-aminopypy Imidazo[1,5-a]pyrimidin-5-yl)amino)ethyl)-4-fluorophenoxy)ethyl)carbamic acid tert-butyl ester 9 g (0.26 g, yellow liquid), crude.

MS m/z (ESI): 431 [M + 1].

Seventh step

N ⁵ -(1-(2-(2-Aminoethoxy)-5-fluorophenyl)ethyl)pyrazolo[1,5-a]pyrimidine-3,5-diamine trifluoroacetate

The compound (2-(2-(1-(3-aminopyrazolo[1,5-a]pyrimidin-5-yl)amino)ethyl)-4-fluorophenoxy)ethyl)carbamic acid 9 g (0.42 g, 1.00 mmol) of tert-butyl ester was dissolved in dichloromethane (5 mL). The reaction solution was desolvated under reduced pressure to give the title compound N ⁵ -(1-(2-(2-aminoethoxy)-5-fluorophenyl)ethyl)pyrazolo[1,5-a]pyrimidine-3 , 5-diamine trifluoroacetate 9h (0.32 g, yellow solid), crude.

MS m/z (ESI): 331 [M + 1].

Eighth step

The compound N ⁵ -(1-(2-(2-aminoethoxy)-5-fluorophenyl)ethyl)pyrazolo[1,5-a]pyrimidine-3,5-diamine trifluoroethane The acid salt was dissolved in N,N-dimethylformamide (5 mL), and N,N'-carbonyldiimidazole (52 mg, 0.32 mmol). The reaction mixture was extracted with ethyl acetate (50 mL×3), washed with saturated sodium chloride solution (5 mL×3), and the organic phase was evaporated to dryness to afford silica gel. 4 ⁵ -fluoro-3-methyl-5-oxa-2,8,10-triaza-1(5,3)-pyrazolo[1,5-a]pyrimidine-4(1,2) - benzocyclodecane-9-one 9 (60 mg, yellow solid), yield: 56%.

MS m/z (ESI): 357 [M + 1];

^{1 H NMR (400MHz, CDCl3)} δ8.06 (d, J = 8.0Hz, 1H), 7.90 (s, 1H), 7.57 (s, 1H), 7.03-7.01 (m, 1H), 6.92-6.88 (m , 1H), 6.82-6.80 (m, 1H), 6.17 (s, 1H), 6.06-6.03 (m, 1H), 5.95 (d, J = 8.0 Hz, 1H), 5.24-5.22 (m, 1H), 4.39-4.37 (m, 1H), 4.17-4.13 (m, 1H), 3.70-3.66 (m, 2H), 1.52 (d, J = 6.8 Hz, 3H).

Example 10

4 ⁵ -fluoro-2-methyl-5-oxa-2,8,10-triaza-1(5,3)-pyrazolo[1,5-a]pyrimidine-4(1,2) -benzocyclodecane-9-one

Synthesis Example 10 was carried out in accordance with the procedure of Example 9 to give the desired product 4 ⁵ -fluoro-2-methyl-5-oxa-2,8,10-triaza-1(5,3)-pyrazole. [1,5-a]pyrimidine-4(1,2)-benzocyclodecane-9-one 10.

MS m/z (ESI): 357 [M + 1];

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.22 (d, J = 8.0Hz, 1H), 8.02 (s, 1H), 7.02-6.94 (m, 2H), 6.81 (d, J = 8.0Hz, 1H) , 6.04 (s, 1H), 4.21 (s, 2H), 3.60 (m, 2H), 3.23 (s, 3H), 2.09-1.98 (m, 2H).

Example 11

(S)-4 ⁵ -fluoro-2,6-dimethyl-5-oxa-2,8,10-triaza-1(5,3)-pyrazolo[1,5-a]pyrimidine -4(1,2)-benzocyclodecane-9-one

first step

4-fluoro-2-((methylamino)methyl)phenol

The compound 5-fluoro-2-hydroxybenzaldehyde 11a (1.40 g, 10.00 mmol) and methylamine solution (33%, 2 mL) were dissolved in methanol (5 mL) under ice-cooling, and stirred for 30 minutes. Sodium borohydride (0.57 g, 15.00 mmol) was added. The mixture was stirred at room temperature for 0.5 hour. The reaction mixture was quenched with EtOAc EtOAc (EtOAc) The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated to dryness, and then evaporated to give the desired product 4-fluoro-2-((methylamino)methyl)phenol 11b (1.50 g, bright yellow oil). 97%.

MS m/z (ESI): 156 [M + 1];

^{1 H NMR (400MHz, DMSO-} d 6) δ6.95-6.92 (m, 1H), 6.90-6.85 (m, 1H), 6.70-6.60 (m, 1H), 6.59 (brs, 1H), 3.74 (s , 2H), 2.28 (s, 3H).

Second step

4-fluoro-2-((methyl(3-nitropyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)phenol

The compound 4-fluoro-2-((methylamino)methyl)phenol 11b (0.19 g, 1.20 mmol), 5-chloro-3-nitropyrazolo[1,5-a]pyrimidine 9d (0.16 g , 0.80 mmol) and N,N-diisopropylethylamine (0.31 g, 2.40 mmol) were dissolved in n-butanol (5 mL), stirred at 65 ° C for 15 hours, cooled, solid precipitated, filtered and dried to give the desired product. 4-fluoro-2-((methyl(3-nitropyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)phenol 11c (0.20 g, white solid), yield: 76 %.

MS m/z (ESI): 318 [M + 1];

^{1 H NMR (400MHz, DMSO-} d 6) δ9.84-9.72 (m, 1H), 8.85-8.75 (m, 1H), 8.62 (s, 1H), 7.25-6.85 (m, 4H), 4.90-4.74 (m, 2H), 3.25 (s, 3H).

third step

(S)-(2-(4-fluoro-2-((methyl(3-nitropyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)phenoxy)propyl) a tert-butyl carbamate compound 4-fluoro-2-((methyl(3-nitropyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)phenol 11c (4.50 g, 14.20 mmol) and cesium carbonate (18.40 g, 56.78 mmol) in acetonitrile (100 mL), (R)-1-((tert-butoxycarbonyl)amino)propan-2-yl-4-methylbenzenesulfonate The acid ester 1c (16.30 g, 49.68 mmol) was stirred in an oil bath of 60 ° C for 6 hours, the reaction mixture was diluted with water (50 mL), and extracted with dichloromethane (50 mL×2). The desiccant was removed, and the solution was decomposed under reduced pressure. Purified on silica gel column ( petroleum ether: ethyl acetate = 9:1 to 3:2) to give the title compound (S)-(2-(4-fluoro-2-((methyl) tert-Butyl 3-nitropyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)phenoxy)propyl)carbamate 11d (5.50 g, yellow solid), yield: 82 %.

MS m/z (ESI): 475 [M + 1];

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.84 (d, J = 7.2 Hz, 0.6H), 8.76 (d, J = 7.2 Hz, 0.4H), 8.63 (s, 1H), 7.43-5.41 ( m, 1H), 7.09-7.05 (m, 3H), 6.93 (d, J = 7.2 Hz, 0.4H), 6.85 (d, J = 7.2 Hz, 0.6H), 4.94 - 4.92 (m, 1H), 4.81 -4.70 (m, 1H), 4.47-4.45 (m, 1H), 3.37-3.38 (m, 1H), 3.27 (s, 3H), 3.11-3.09 (m, 1H), 1.37 (s, 9H), 1.18 (d, J = 6.4 Hz, 3H).

the fourth step

(S)-(2-(4-fluoro-2-((methyl(3-aminopyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)phenoxy)propyl) Tert-butyl carbamate compound (S)-(2-(4-fluoro-2-((methyl(3-nitropyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl) Benzyloxy)propyl)carbamic acid tert-butyl ester 11d (2.00 g, 4.21 mmol), dichloromethane (40 mL), methanol (40 mL), saturated aqueous ammonium chloride (40 mL) and zinc powder (4.10 g, 63.16 Mix well and stir at room temperature for 1 hour. Filtration, the filtrate was extracted with dichloromethane (300 mL), washed with water (100 mL×2), and the organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to give the title compound (S)-(2-(4-fluoro) 2-((methyl(3-aminopyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)phenoxy)propyl)carbamic acid tert-butyl ester 11e (1.50 g, yellow Solid), crude.

MS m/z (ESI): 445 [M + 1];

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.14 (d, J = 7.6Hz, 1H), 7.66 (s, 1H), 6.97-6.73 (m, 3H), 6.16 (d, J = 7.6Hz, 1H) , 5.07-5.05 (m, 1H), 4.78-4.76 (m, 2H), 4.50-4.48 (m, 1H), 3.43-3.41 (m, 1H), 3.17 (s, 3H), 3.00-2.98 (m, 2H), 1.44 (s, 9H), 1.27 (d, J = 4.2 Hz, 3H).

the fifth step

(S)-N ⁵ -(2-((1-aminopropan-2-yl)oxy)-5-fluorobenzyl)-N ⁵ -methylpyrazolo[1,5-a]pyrimidine- 3,5-diamine trifluoroacetate salt Compound (S)-(2-(4-fluoro-2-((methyl(3-aminopyrazolo[1,5-a]pyrimidin-5-yl) Amino)methyl)phenoxy)propyl)carbamic acid tert-butyl ester 11e (1.50 g, 3.37 mmol) was dissolved in dichloromethane (30 mL). The reaction solution is desolvated under reduced pressure to give the title compound (S)-N ⁵ -(2-((1-aminopropan-2-yl)oxy)-5-fluorobenzyl)-N ⁵ -methylpyrazole And [1,5-a]pyrimidine-3,5-diamine trifluoroacetate 11f (3.00 g, yellow solid), crude.

MS m/z (ESI): 344 [M + 1].

Step 6

(S)-4 ⁵ -fluoro-2,6-dimethyl-5-oxa-2,8,10-triaza-1(5,3)-pyrazolo[1,5-a]pyrimidine -4(1,2)-benzocyclodecane-9-one compound (S)-N ⁵ -(2-((1-aminopropan-2-yl)oxy)-5-fluorobenzyl -N ⁵ -methylpyrazolo[1,5-a]pyrimidine-3,5-diamine trifluoroacetate 11f (3.00 g, 3.37 mmol) was dissolved in N,N-dimethylformamide ( 15 mL), N,N'-carbonyldiimidazole (0.55 g, 3.37 mmol) and triethylamine (0.5 mL) were added and stirred in a 35 ° C oil bath for 1.5 hours. The reaction solution was diluted with water (70 mL), filtered, and the filtrate was extracted with ethyl acetate (50mL×3). The filter cake was washed with dichloromethane. The organic phase was combined, dried and filtered. Methane:methanol = 100:1 to 70:1) The target compound (S)-4 ⁵ -fluoro-2,6-dimethyl-5-oxa-2,8,10-triaza-1 (5) was obtained. , 3)-pyrazolo[1,5-a]pyrimidin-4(1,2)-benzocyclodecane-9-one 11 (0.59 g, yellow solid), yield: 47% (two-step production) rate).

MS m/z (ESI): 371 [M + 1];

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.21 (d, J = 7.2Hz, 1H), 7.94 (brs, 1H), 7.61 (s, 1H), 6.93-6.90 (m, 3H), 6.31 (d, J=7.2 Hz, 1H), 6.07 (s, 1H), 5.82-5.80 (m, 1H), 4.56-4.54 (m, 1H), 3.81-3.68 (m, 1H), 3.66-3.63 (m, 1H) , 3.49 (s, 3H), 3.49-3.35 (m, 1H), 1.39 (d, J = 6.0 Hz, 3H).

Example 12

(S)-4 ⁵ -fluoro-2-fluoroethyl-6-methyl-5-oxa-2,8,10-triaza-1(5,3)-pyrazolo[1,5- a]pyrimidine-4(1,2)-benzocyclodecane-9-one

Synthesis Example 12 was carried out in accordance with the procedure of Example 11 to give the desired product (S)-4 ⁵ -fluoro-2-fluoroethyl-6-methyl-5-oxa-2,8,10-triaza- 1(5,3)-pyrazolo[1,5-a]pyrimidin-4(1,2)-benzocyclodecane-9-one 12 (6.7 mg, pale yellow solid), yield: 17% .

MS m/z (ESI): 403 [M + 1];

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.21 (d, J = 7.2Hz, 1H), 8.03 (s, 1H), 7.59 (s, 1H), 6.90-6.88 (m, 3H), 6.36 (d, J=7.2 Hz, 1H), 6.24 (s, 1H), 5.66-5.64 (m, 1H), 4.79-4.78 (m, 1H), 4.67-4.65 (m, 1H), 4.58-4.55 (m, 1H) 4.13-3.87 (m, 4H), 3.22-3.17 (m, 1H), 1.41 (d, J = 5.2 Hz, 3H).

Example 13

5'-Fluoro-2'-methylspiro[cyclopropane-1,7'-5-oxa-2,9,11-triaza-1(5,3)-pyrazolo[1,5- a]pyrimidine-4(1,2)-benzocycloundecyl]-10'-one

first step

N-(2-((1-(Bromomethyl)cyclopropyl)methoxy)-5-fluorobenzyl)-N-methyl-3-nitropyrazolo[1,5-a] Pyrimidine-5-amine

4-Fluoro-2-((methyl(3-nitropyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)phenol 11c (0.30 g, 0.94 mmol), 1,1 -Bis(bromomethyl)cyclopropane 13a (0.27 g, 1.20 mmol) was dissolved in acetonitrile (20 mL), and cesium carbonate (0.98 g, 3.00 mmol) was added, and the mixture was heated to 60 ° C for 2 hours. After the completion of the reaction, the reaction mixture was concentrated to dryness and purified by column chromatography (ethyl ether: ethyl acetate = 3:1) to give the desired compound N-(2-((1-(bromomethyl)cyclopropyl) methoxy. -5-fluorobenzyl)-N-methyl-3-nitropyrazolo[1,5-a]pyrimidine-5-amine 13b (0.10 g, yellow solid), yield 23%.

MS m/z (ESI): 464 & 466 [M+1];

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.50 (s, 1H), 8.28-8.22 (m, 1H), 7.68-7.40 (m, 1H), 6.97-6.95 (m, 1H), 6.86-6.84 (m) , 1H), 6.46-6.39 (m, 1H), 5.14 (s, 1H), 4.74 (s, 1H), 3.96 (s, 2H), 3.58-3.51 (m, 1H), 3.56 (s, 3H), 3.20(s,1H), 1.37-1.26(m,4H).

Second step

N-(2-((1-(Aminomethyl)cyclopropyl)methoxy)-5-fluorobenzyl)-N-methyl-3-nitropyrazolo[1,5-a] Pyrimidine-5-amine

N-(2-((1-(Bromomethyl)cyclopropyl)methoxy)-5-fluorobenzyl)-N-methyl-3-nitropyrazolo[1,5-a Pyrimidine-5-amine 13b (40 mg, 0.10 mmol) was placed in a closed reaction tube with a solution of polytetrafluoroethylene in an ammonia ethanol solution (2M, 8 mL), and heated to 100 ° C for 18 hours. After the completion of the reaction, the reaction mixture was concentrated to dryness and purified by preparative chromatography (dichloromethane:methanol = 10:1) to give the desired compound N-(2-((1-(aminomethyl)cyclopropyl) methoxy. -5-fluorobenzyl)-N-methyl-3-nitropyrazolo[1,5-a]pyrimidine-5-amine 13c (20 mg, yellow solid), yield 58%.

MS m/z (ESI): 401 [M + 1];

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.38 (s, 1H), 8.23 (d, J = 7.2Hz, 1H), 7.68-7.35 (m, 1H), 6.91-6.86 (m, 1H), 6.82- 6.77 (m, 1H), 6.52 (d, J = 7.2 Hz, 1H), 4.96 (s, 1H), 4.00 (s, 1H), 3.98 (s, 2H), 3.34 (s, 3H), 3.13 (s) , 2H), 1.37-1.26 (m, 4H).

third step

N ⁵ -(2-((1-(Aminomethyl)cyclopropyl)methoxy)-5-fluorobenzyl)-N ⁵ -methylpyrazolo[1,5-a]pyrimidine-3 , 5-diamine

Referring to the fourth step of Example 11, N-(2-((1-(aminomethyl))cyclopropyl)methoxy)-5-fluorobenzyl)-N-methyl-3-nitro Pyrazolo[1,5-a]pyrimidine-5-amine in place of (S)-(2-(4-fluoro-2-((methyl(3-nitropyrazolo[1,5-a]pyrimidine) -5-yl)amino)methyl)phenoxy)propyl)carbamic acid tert-butyl ester gave the desired product N ⁵ -(2-((1-(aminomethyl))cyclopropyl)methoxy)-5 -fluorobenzyl)-N ⁵ -methylpyrazolo[1,5-a]pyrimidine-3,5-diamine 13d.

MS m/z (ESI): 371 [M + 1];

the fourth step

Referring to the sixth step of Example 11, N ⁵ -(2-((1-(aminomethyl)cyclopropyl)methoxy)-5-fluorobenzyl)-N ⁵ -methylpyrazole [1,5-a]pyrimidine-3,5-diamine in place of (S)-N ⁵ -(2-((1-aminopropan-2-yl)oxy)-5-fluorobenzyl)-N ⁵ -methylpyrazolo[1,5-a]pyrimidine-3,5-diamine trifluoroacetate gives the desired product 5-fluoro-2-methylspiro[cyclopropane-1,7-5-oxo Hetero-2,9,11-triaza-1(5,3)-pyrazolo[1,5-a]pyrimidin-4(1,2)-benzocycloundecyl]-10-one 13 .

MS m/z (ESI): 397 [M + 1];

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.16 (d, J = 7.6 Hz, 1H), 7.72 (d, J = 7.2 Hz, 1H), 7.45 (s, 1H), 7.30 (d, J = 7.2 Hz) , 1H), 6.91-6.89 (m, 2H), 6.22 (d, J = 7.6 Hz, 1H), 5.90-5.88 (m, 1H), 4.87-4.85 (m, 1H), 4.60-4.58 (m, 1H) ), 3.76 (s, 3H), 3.59-3.57 (m, 2H), 3.24 - 3.09 (m, 2H), 0.80 - 0.78 (m, 4H).

Example 14

(R)-4 ⁵ -fluoro-2,7-dimethyl-5-oxa-2,8,10-triaza-1(5,3)-pyrazolo[1,5-a]pyrimidine -4(1,2)-benzocyclodecane-9-one

Synthesis Example 14 was carried out in accordance with the procedure of Example 11 to give the desired product (R)-4 ⁵ -fluoro-2,7-dimethyl-5-oxa-2,8,10-triaza-1 (5 , 3)-pyrazolo[1,5-a]pyrimidin-4(1,2)-benzocyclodecane-9-one 14.

MS m/z (ESI): 371 [M + 1];

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.20 (d, J = 7.2Hz, 1H), 7.68 (s, 1H), 7.10-6.79 (m, 3H), 6.33 (s, 1H), 6.24 (d, J=7.2 Hz, 1H), 6.15-5.85 (m, 1H), 4.40-4.00 (m, 3H), 3.85-3.57 (m, 1H), 3.14 (s, 3H), 1.36 (d, J = 6.0 Hz) , 3H).

Example 15

(R)-4 ⁵ -fluoro-2,6-dimethyl-5-oxa-2,8,10-triaza-1(5,3)-pyrazolo[1,5-a]pyrimidine -4(1,2)-benzocyclodecane 9-one

Synthesis Example 15 was carried out in accordance with the procedure of Example 11 to give the desired product (R)-4 ⁵ -fluoro-2,6-dimethyl-5-oxa-2,8,10-triaza-1 (5 , 3)-pyrazolo[1,5-a]pyrimidin-4(1,2)-benzocyclodecane-9-one 15.

MS m/z (ESI): 371 [M + 1];

^{1 H NMR (400MHz, CDCl3)} δ8.21 (d, J = 7.6Hz, 1H), 7.96 (s, 1H), 7.62 (s, 1H), 6.93-6.90 (m, 3H), 6.31 (d, J = 7.6 Hz, 1H), 6.25 (s, 1H), 4.56-4.54 (m, 1H), 3.75-3.65 (m, 3H), 3.50-3.46 (m, 1H), 3.35 (s, 3H), 1.39 ( d, J = 6.0 Hz, 3H).

Example 16

3 ⁵ -fluoro-4-oxa-7,9-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidin-2(1,2)-pyrrole-3 (1, 2)-benzocyclodecane-8-one

Example 16 was synthesized by following the procedure of Example 11, wherein the second step was replaced by 4-fluoro-2-(pyrrolidin-2-yl)phenol (synthesized with reference to WO2011146336A1) instead of 4-fluoro-2-((methylamino). Methyl)phenol, the target compound 3 ⁵ -fluoro-4-oxa-7,9-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidine-2 (1,2) )-pyrrole-3(1,2)-benzocyclodecane-8-one 16.

MS m/z (ESI): 383 [M + 1];

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.34 (d, J = 7.6Hz, 1H), 8.19 (d, J = 7.6Hz, 1H), 7.54 (s, 1H), 6.87-6.85 (m, 2H) , 6.73 (d, J = 9.2 Hz, 1H), 6.43 (s, 1H), 6.23 (d, J = 7.6 Hz, 1H), 5.66-5.64 (m, 1H), 4.45 - 4.33 (m, 2H), 3.91-3.85 (m, 2H), 3.69-3.67 (m, 1H), 3.31-3.29 (m, 1H), 2.48-2.32 (m, 2H), 2.22-2.15 (m, 1H), 1.87-1.85 (m) , 1H).

Example 17

(5S)-3 ⁵ -fluoro-5-methyl-4-oxa-7,9-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidine-2 (1, 2)-pyrrole-3(1,2)-benzocyclodecane-8-one

Synthesis of Example 17 by the procedure of Example 11 gave the desired product (5S)-3 ⁵ -fluoro-5-methyl-4-oxa-7,9-diaza-1(5,3)-pyridyl Zizo[1,5-a]pyrimidin-2(1,2)-pyrrole-3(1,2)-benzocyclodecane-8-one 17.

MS m/z (ESI): 397 [M + 1];

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.42 - 8.40 (m, 1H), 8.32 (d, J = 7.6 Hz, 1H), 7.53 (s, 1H), 6.84-6.83 (m, 2H), 6.73 6.71 (m, 1H), 6.35 (s, 1H), 6.22 (d, J = 7.2 Hz, 1H), 5.57-5.55 (m, 1H), 4.54-4.52 (m, 1H), 3.92-3.91 (m, 2H), 3.85-3.82 (m, 1H), 2.99-2.97 (m, 1H), 2.43-2.42 (m, 2H), 2.36-2.34 (m, 1H), 1.88-1.86 (m, 1H), 1.48 ( d, J = 6.0 Hz, 3H).

Example 18

(R)-3 ⁵ -fluoro-4-oxa-7,9-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidin-2(1,2)-pyrrole- 3(1,2)-benzocyclodecane-8-one

first step

(R)-N-(5-fluoro-2-methoxybenzylidene)-2-methylpropane-2-sulfinamide

5-Fluoro-2-methoxybenzaldehyde 18a (4.60 g, 30.00 mmol) was dissolved in dichloromethane (50 mL) and EtOAc (16.30 g, 50.00 mmol) and (R)-2-methyl Propane-2-sulfinamide (3.60 g, 31.00 mmol) was reacted at room temperature for 18 hours after the addition. After completion of the reaction, the mixture was filtered, and then added with 150 mL of water, dichloromethane (200 mL × 3), dried over anhydrous sodium sulfate, filtered, and dried to give (R)-N-(5-fluoro-2-methoxybenzylidene 2-methylpropane-2-sulfinamide 18b (7.70 g, yellow solid) was taken directly to the next step without further purification.

MS m/z (ESI): 258 [M + 1];

^{_{1 H NMR (400MHz, CDCl 3}} ) δ9.01 (s, 1H), 7.67 (d, J = 8.4Hz, 1H), 7.27-7.17 (m, 1H), 6.93-6.91 (m, 1H), 3.88 ( s, 3H), 1.27 (s, 9H).

Second step

(R)-N-((R)-3-(1,3-dioxan-2-yl)-1-(5-fluoro-2-methoxyphenyl)propyl)-2-methylpropane -2-sulfinamide

Magnesium chips (1.40 g, 60.00 mmol) were dissolved in dry tetrahydrofuran (80 mL), diisobutylaluminum hydride (0.5 mL, 1 M tetrahydrofuran solution) was added, stirred at 50 ° C for 20 min, then 2-(2-bromo) A solution of ethyl)-1,3-dioxane (12.00 g, 60 mmol) in tetrahydrofuran (40 mL) was added dropwise to the above solution, stirred at 50 ° C for 2 hours, and the reaction mixture was cooled to -40 ° C, dropwise (R)- a solution of N-(5-fluoro-2-methoxybenzylidene)-2-methylpropane-2-sulfinamide 18b (7.70 g, 30.00 mmol) in tetrahydrofuran (40 mL). After an hour, slowly return to room temperature, quenched with a saturated aqueous solution of citric acid, extracted with methyl tert-butyl ether (100 mL × 3), and washed with 40% aqueous sodium hydroxide (100 mL) and brine (100 mL) The crude product was obtained by spin-drying, and the mixture was slurried with a mixture of methyl tert-butyl ether (100 mL) and n-hexane (300 mL), and dried by filtration to give (R)-N-((R)-3-(1,3-) Ester-2-yl)-1-(5-fluoro-2-methoxyphenyl)propyl)-2-methylpropane-2-sulfinamide 18c (7.60 g, white solid).

MS m/z (ESI): 374 [M + 1];

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.25 (d, J = 8.4 Hz, 1H), 7.04-6.95 (m, 2H), 5.63 (d, J = 9.6 Hz, 1H), 4.46-4.41 ( m, 2H), 3.96-3.93 (m, 2H), 3.78 (s, 3H), 3.67-3.61 (m, 2H), 1.82-1.81 (m, 1H), 1.79-1.58 (m, 2H), 1.37- 1.31 (m, 3H), 1.28 (s, 9H).

third step

(R)-2-(5-fluoro-2-methoxyphenyl)pyrrolidine

(R)-N-((R)-3-(1,3-dioxan-2-yl)-1-(5-fluoro-2-methoxyphenyl)propyl)-2-methyl Propane-2-sulfinamide 18c (7.60 g, 20.00 mmol) was dissolved in trifluoroacetic acid (20 mL) and water (5 mL), and stirred at room temperature for 1 hour, then triethylsilane (13 mL) was added to the mixture. Stir at 40 ° C for 16 hours, evaporate the solvent, the residue is dissolved in water (100 mL), extracted with methyl tert-butyl ether (100 mL), and the aqueous phase is adjusted to pH 12 with 40% aqueous sodium hydroxide. Methane (100×3) was extracted, and the organic phase was washed with brine (100 mL), dried, filtered, and evaporated to give (R)-2-(5-fluoro-2-methoxyphenyl)pyrrolidine 18d (2.00 g, yellow oil).

MS m/z (ESI): 196 [M + 1];

^{_{1 H NMR (400MHz, CDCl 3}} ) δ7.19 (d, J = 8.4Hz, 1H), 6.88-6.83 (m, 1H), 6.77-6.74 (m, 1H), 4.39-4.35 (m, 1H), 3.80 (s, 3H), 3.18-3.12 (m, 1H), 3.04-2.98 (m, 1H), 2.22-2.16 (m, 1H), 1.99-1.78 (m, 2H), 1.61-1.57 (m, 1H) ).

the fourth step

(R)-4-fluoro-2-(pyrrolidin-2-yl)phenol

(R)-2-(5-Fluoro-2-methoxyphenyl)pyrrolidine 18d (0.50 g, 2.56 mmol) was dissolved in dry dichloromethane (20 mL) and then boron tribromide (3.20) g, 25.60 mmol), stirred at room temperature for 2 h, quenched with EtOAc EtOAc (EtOAc) solid).

MS m/z (ESI): 182 [M + 1].

the fifth step

(R)-4-fluoro-2-(1-(3-nitropyrazolo[1,5-a]pyrimidin-5-yl)pyrrolidin-2-yl)phenol

Referring to the fourth step of Example 9, the desired product (R) was obtained by substituting (R)-4-fluoro-2-(pyrrolidin-2-yl)phenol for 2-(1-aminoethyl)-4-fluorophenol. 4-fluoro-2-(1-(3-nitropyrazolo[1,5-a]pyrimidin-5-yl)pyrrolidin-2-yl)phenol 18f.

MS m/z (ESI): 344 [M + 1];

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.45 (s, 1H), 8.24-8.22 (m, 1H), 6.95-6.84 (m, 3H), 6.34-6.31 (m, 0.5H), 5.88-5.85 ( m, 0.5H), 4.08-3.78 (m, 2H), 2.55-2.50 (m, 1H), 2.28-2.12 (m, 2H), 1.34-1.28 (m, 2H).

Step 6

(R)-(2-(4-fluoro-2-(1-(3-nitropyrazolo[1,5-a]pyrimidin-5-yl)pyrrolidin-2-yl)phenoxy)B Tert-butyl carbamate, referring to the fifth step of Example 9, using (R)-4-fluoro-2-(1-(3-nitropyrazolo[1,5-a]pyrimidin-5-yl) Substituting pyrrolidin-2-yl)phenol for 4-fluoro-2-(1-((3-nitropyrazolo[1,5-a]pyrimidin-5-yl)amino)ethyl)phenol to give the desired product (R)-(2-(4-fluoro-2-(1-(3-nitropyrazolo[1,5-a]pyrimidin-5-yl)pyrrolidin-2-yl)phenoxy)B Tert-butyl carbamate 18 g.

MS m/z (ESI): 495 [M + 1].

Seventh step

(R)-(2-(4-fluoro-2-(1-(3-aminopyrazolo[1,5-a]pyrimidin-5-yl)pyrrolidin-2-yl)phenoxy)ethyl Tert-butyl carbamate refers to the sixth step of Example 9, using (R)-(2-(4-fluoro-2-(1-(3-nitropyrazolo[1,5-a]pyrimidine- Substituted tert-butyl 5-phenyl)pyrrolidin-2-yl)phenoxy)ethyl)carbamate (2-(4-fluoro-2-(1-((3-nitropyrazolo[1,5] -a]pyrimidin-5-yl)amino)ethyl)phenoxy)ethyl)carbamic acid tert-butyl ester to give the desired product (R)-(2-(4-fluoro-2-(1-(3-amino)) Pyrazolo[1,5-a]pyrimidin-5-yl)pyrrolidin-2-yl)phenoxy)ethyl)carbamic acid tert-butyl ester 18 h.

MS m/z (ESI): 457 [M + 1].

Eighth step

(R)-5-(2-(2-(2-aminoethoxy)-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-amine III Fluoroacetate

Referring to the seventh step of Example 9, (R)-(2-(4-fluoro-2-(1-(3-aminopyrazolo[1,5-a]pyrimidin-5-yl)pyrrolidine- Tert-butyl 2-yl)phenoxy)ethyl)carbamate (2-(2-(1-(3-aminopyrazolo[1,5-a]pyrimidin-5-yl)amino)) Tert-butyl 4-(4-fluorophenoxy)ethyl)carbamate gives the desired product (R)-5-(2-(2-(2-aminoethoxy)-5-fluorophenyl)pyrrolidine 1-yl)pyrazolo[1,5-a]pyrimidin-3-amine trifluoroacetate 18i.

MS m/z (ESI): 357 [M + 1].

Step 9

(R)-3 ⁵ -fluoro-4-oxa-7,9-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidin-2(1,2)-pyrrole- 3(1,2)-benzocyclodecane-8-one Referring to the eighth step of Example 9, using (R)-5-(2-(2-(2-aminoethoxy)-5-fluoro) Phenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-amine trifluoroacetate instead of N-(1-(2-(2-aminoethoxy)-5-) Fluorophenyl)ethyl)pyrazolo[1,5-a]pyrimidine-3,5-diamine trifluoroacetate gives the desired product (R)-3 ⁵ -fluoro-4-oxa-7,9 -diaza-1(5,3)-pyrazolo[1,5-a]pyrimidin-2(1,2)-pyrrole-3(1,2)-benzocyclodecane-8-one 18 (11.8 mg, 0.031 mmol, pale yellow solid). Yield: 31%.

MS m/z (ESI): 383 [M + 1];

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.33-8.31 (m, 1H), 8.18 (d, J = 7.6Hz, 1H), 7.53 (s, 1H), 6.89- 6.84 (m, 2H), 6.75- 6.69 (m, 1H), 6.31 (s, 1H), 6.23 (d, J = 7.6 Hz, 1H), 5.68-5.61 (m, 1H), 4.45-4.31 (m, 2H), 3.95-3.85 (m, 2H), 3.76-3.63 (m, 1H), 3.35-3.24 (m, 1H), 2.48-2.29 (m, 2H), 2.19-2.12 (m, 1H), 1.89-1.83 (m, 1H).

Example 19

(2 ² R,5S)-3 ⁵ -fluoro-5-methyl-4-oxa-7,9-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidine- 2(1,2)-pyrrole-3(1,2)-benzocyclodecane-8-one

Example 19 was synthesized by following the procedure of Example 18 to give the desired product (2 ² R,5S)-3 ⁵ -fluoro-5-methyl-4-oxa-7,9-diaza-1 (5, 3)-Pyrazolo[1,5-a]pyrimidin-2(1,2)-pyrrole-3(1,2)-benzocyclodecane-8-one 19.

MS m/z (ESI): 397 [M + 1];

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.41 - 8.39 (m, 1H), 8.17 (d, J = 7.6 Hz, 1H), 7.54 (s, 1H), 6.84-6.83 (m, 2H), 6.72 6.70 (m, 1H), 6.63 (s, 1H), 6.21 (d, J = 7.6 Hz, 1H), 5.57-5.55 (m, 1H), 4.53-4.51 (m, 1H), 3.90-3.80 (m, 2H), 3.72-3.66 (m, 1H), 3.02-2.96 (m, 1H), 2.46-2.41 (m, 2H), 2.33-2.32 (m, 1H), 1.85-1.83 (m, 1H), 1.48 ( d, J = 4.8 Hz, 3H).

Example 20

(2 ² R,6R)-3 ⁵ -fluoro-6-methyl-4-oxa-7,9-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidine- 2(1,2)-pyrrole-3(1,2)-benzocyclodecane-8-one

Example 20 was synthesized by following the procedure of Example 18 to give the desired product (2 ² R,6R)-3 ⁵ -fluoro-6-methyl-4-oxa-7,9-diaza-1 (5, 3)-Pyrazolo[1,5-a]pyrimidin-2(1,2)-pyrrole-3(1,2)-benzocyclodecane-8-one 20.

MS m/z (ESI): 397 [M + 1];

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.19-8.17 (m, 1H), 7.82 (d, J = 8.8Hz, 1H), 7.52 (s, 1H), 6.90-6.78 (m, 2H), 6.73- 6.71 (m, 1H), 6.29 (s, 1H), 6.23 (d, J = 8.8 Hz, 1H), 5.63-5.60 (m, 1H), 4.48-4.46 (m, 1H), 4.27-4.26 (m, 1H), 4.26-4.20 (m, 1H), 3.91-3.89 (m, 1H), 3.72-3.64 (m, 1H), 2.52-2.28 (m, 2H), 2.22-2.09 (m, 1H), 1.92 1.81 (m, 1H), 1.38 (d, J = 6.0 Hz, 3H).

Example 21

(2 ² R,2 ⁴ S)-2 ⁴ ,3 ⁵ -Difluoro-4-oxa-7,9-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidine -2(1,2)-pyrrole-3(1,2)-benzocyclodecane-8-one

first step

(S)-N-((R)-1-(5-fluoro-2-methoxyphenyl)but-3-en-1-yl)-2-methylpropane-2-sulfinamide

5-Fluoro-2-methoxybenzaldehyde 18a (3.00 g, 20.00 mmol) was dissolved in tetrahydrofuran (50 mL), and indium powder (3.00 g, 26.00 mmol), (S)-2-methyl Propane-2-sulfinamide (2.90 g, 24.00 mmol) and tetraethoxytitanium (6.80 g, 30.00 mmol), stirred at 70 ° C for 2 hours, cooled to 0 ° C, then added 3-bromopropene 21a (3.10) g, 26.00 mmol), and reacted at 70 ° C for 16 hours after the addition. The mixture was cooled with ice-cooled, EtOAc (EtOAc)EtOAc.EtOAc. : 0 to 1:1) to give (S)-N-((R)-1-(5-fluoro-2-methoxyphenyl)but-3-en-1-yl)-2-methylpropane- 2-sulfinamide 21b (3.50 g, yellow solid), yield 60%.

MS m/z (ESI): 300 [M + 1];

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.01 (d, J = 9.2 Hz, 1H), 6.93-6.89 (m, 1H), 6.81-6.79 (m, 1H), 5.76-5.68 (m, 1H), 5.16 (d, J = 13.6 Hz, 2H), 4.88-4.86 (m, 1H), 3.82 (s, 3H), 3.76 (s, 1H), 2.66- 2.62 (m, 1H), 2.45-2.40 (m, 1H), 1.21 (s, 9H).

Second step

(R)-1-(5-fluoro-2-methoxyphenyl)but-3-en-1-amine hydrochloride

(S)-N-((R)-1-(5-fluoro-2-methoxyphenyl)but-3-en-1-yl)-2-methylpropane-2-sulfinamide 21b ( 3.50 g, 11.70 mmol) was dissolved in hydrogen chloride in dioxane (4M, 20 mL) and stirred at room temperature for 2 hr. (R)-1-(5-Fluoro-2-methoxyphenyl)but-3-en-1-amine hydrochloride 21c (4.00 g, white solid)

MS m/z (ESI): 196 [M + 1].

third step

(R)-N-(1-(5-fluoro-2-methoxyphenyl)but-3-en-1-yl)acetamide

(R)-1-(5-Fluoro-2-methoxyphenyl)but-3-en-1-amine hydrochloride 21c (4.00 g, 17.32 mmol) was dissolved in dichloromethane (20 mL) and stirred Add triethylamine (5 mL), stir at room temperature for 5 minutes, then add acetic anhydride (2.00 g, 19.61 mmol) at room temperature for 2 hours, add 150 mL of water to dilute, extract with dichloromethane (200 mL×3), Dry over sodium sulfate, filter, spin dry, and purified by silica gel column ( petroleum ether: ethyl acetate = 1:0 to 1:1) to give (R)-N-(1-(5-fluoro-2-methoxyphenyl) But-3-en-1-yl)acetamide 21d (1.70 g, yellow solid), yield 42%.

MS m/z (ESI): 238 [M + 1];

^{_{1 H NMR (400MHz, CDCl 3}} ) δ6.93-6.87 (m, 2H), 6.82-6.80 (m, 1H), 6.21 (brs, 1H), 5.68-5.62 (m, 1H), 5.20-5.18 (m , 1H), 5.06-5.03 (m, 2H), 3.86 (s, 3H), 2.55-2.53 (m, 2H), 2.00 (s, 3H).

the fourth step

(5R)-5-(5-fluoro-2-methoxyphenyl)pyrrolidin-3-yl acetate

(R)-N-(1-(5-fluoro-2-methoxyphenyl)but-3-en-1-yl)acetamide 21d (1.40 g, 6.00 mmol) was dissolved in tetrahydrofuran (40 mL) and water (10 mL), iodine (5.00 g, 20.00 mmol) was added under stirring, and stirred at room temperature for 6 hours. Add 150 mL of saturated aqueous sodium sulfite solution and stir for 0.5 hour, then add 100 mL of saturated aqueous sodium hydrogencarbonate solution and extract with ethyl acetate (200 mL×3) The combined organic phase was washed with water (100 mL×2) and brine (100 mL×2), and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was dried to give (5R)-5-(5-fluoro-2) -Methoxyphenyl)pyrrolidin-3-ylacetate 21e (1.20 g, yellow solid), crude.

MS m/z (ESI): 254 [M + 1].

the fifth step

(2R)-4-acetoxy-2-(5-fluoro-2-methoxyphenyl)pyrrolidine-1-carboxylic acid tert-butyl ester

(5R)-5-(5-Fluoro-2-methoxyphenyl)pyrrolidin-3-yl acetate 21e (1.20 g, 4.74 mmol) was dissolved in tetrahydrofuran (20 mL) and water (20 mL) and stirred. Aqueous sodium hydroxide (1M, 5mL) and di-tert-butyl dicarbonate (2.20g, 10.09mmol) were added, stirred at room temperature for 3 hours, diluted with 100 mL of water, extracted with ethyl acetate (200 mL × 3), combined with organic water (100 mL × 2) and saturated brine (100 mL × 2), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was dried and purified on silica gel column ( petroleum ether: ethyl acetate = 1:0 to 5:1) ((2R)-4-Acetoxy-2-(5-fluoro-2-methoxyphenyl)pyrrolidine-1-carboxylic acid tert-butyl ester 21f (1.40 g, yellow solid).

MS m/z (ESI): 376 [M+23].

Step 6

(2R)-2-(5-fluoro-2-methoxyphenyl)-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester

((2R)-4-Acetoxy-2-(5-fluoro-2-methoxyphenyl)pyrrolidine-1-carboxylic acid tert-butyl ester 21f (1.40 g, 3.97 mmol) was dissolved in methanol (20 mL) Aqueous sodium hydroxide solution (1 M, 5 mL) was added under stirring, and the mixture was stirred at room temperature for 2 hours, diluted with 100 mL of water, extracted with ethyl acetate (100 mL×3), and the organic phase was combined with water (100 mL×2) and brine (100 mL) ×2) Washing, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was dried to give (2R)-2-(5-fluoro-2-methoxyphenyl)-4-hydroxypyrrolidin-1-carboxylic acid T-butyl ester 21 g (1.10 g, yellow solid), crude.

MS m/z (ESI): 334 [M+23];

^{_{1 H NMR (400MHz, CDCl 3}} ) δ6.93-6.85 (m, 2H), 6.78-6.75 (m, 1H), 5.30-5.05 (m, 1H), 4.46-4.44 (m, 1H), 3.79 (s , 3H), 3.71-3.57 (m, 2H), 2.57-2.38 (m, 1H), 1.96-1.92 (m, 1H), 1.46 (s, 4H), 1.18 (s, 5H).

Seventh step

(R)-2-(5-fluoro-2-methoxyphenyl)-4-carbonylpyrrolidin-1-carboxylic acid tert-butyl ester

21 g (0.90 g, 3.00 mmol) of (2R)-2-(5-fluoro-2-methoxyphenyl)-4-hydroxypyrrolidin-1-carboxylic acid tert-butyl ester was dissolved in dichloromethane (20 mL) Add Dess-Martin oxidizing agent (1.70 g, 4.00 mmol) at room temperature, stir at room temperature for 6 hours, quench with 50 mL of a saturated aqueous solution of sodium hydrogencarbonate, extract with dichloromethane (100 mL×3), and combine the organic phase with water (100 mL×2) The organic phase was washed with anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness eluting with silica gel column ( petroleum ether: ethyl acetate = 1:0 to 1:4) to obtain (R) tert-Butyl 2-(5-fluoro-2-methoxyphenyl)-4-carbonylpyrrolidin-1-carboxylate 21 h (0.85 g, yellow solid).

MS m/z (ESI): 332 [M+23];

^{_{1 H NMR (400MHz, CDCl 3}} ) δ6.94-6.91 (m, 2H), 6.80-6.77 (m, 1H), 5.36-5.15 (m, 1H), 4.00-3.95 (m, 1H), 3.90-3.86 (m, 1H), 3.74 (s, 3H), 3.08-3.01 (m, 1H), 2.58-2.54 (m, 1H), 1.45 (s, 4H), 1.35 (s, 5H).

Eighth step

(2R,4R)-2-(5-fluoro-2-methoxyphenyl)-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester

(R)-2-(5-Fluoro-2-methoxyphenyl)-4-carbonylpyrrolidin-1-carboxylic acid tert-butyl ester 21 h (1.10 g, 3.50 mmol) was dissolved in methanol (20 mL) Sodium borohydride (0.19 g, 5.00 mmol) was added at -20 ° C, and stirred at 0 ° C for 0.5 h, then added with 10 mL of a saturated aqueous solution of ammonium chloride, and extracted with ethyl acetate (50 mL×3), and the organic phase was combined with water (100 mL×2) The organic phase was washed with anhydrous sodium sulfate, filtered, and the filtrate was dried to give (2R,4R)-2-(5-fluoro-2-methoxyphenyl)-4. - Hydroxypyrrolidine-1-carboxylic acid tert-butyl ester 21i (1.00 g, yellow solid), crude.

MS m/z (ESI): 334 [M+23];

^{_{1 H NMR (400MHz, CDCl 3}} ) δ7.00-6.97 (m, 1H), 6.89-6.85 (m, 1H), 6.78-6.75 (m, 1H), 5.17-5.05 (m, 1H), 4.45-4.43 (m, 1H), 3.85-3.70 (m, 1H), 3.80 (s, 3H), 3.60-3.58 (m, 1H), 2.56-2.54 (m, 1H), 1.96-1.92 (m, 1H), 1.47 (s, 4H), 1.21 (s, 5H).

Step 9

(2R,4S)-4-fluoro-2-(5-fluoro-2-methoxyphenyl)pyrrolidine-1-carboxylic acid tert-butyl ester

(2R,4R)-2-(5-fluoro-2-methoxyphenyl)-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester 21i (0.90 g, 3.00 mmol) was dissolved in dichloromethane (20 mL) Add diethylaminosulfur trifluoride (0.97 g, 6.00 mmol) at -78 ° C, slowly return to room temperature and stir for 16 hours, add 100 mL of saturated aqueous sodium hydrogencarbonate solution, and extract with ethyl acetate (100 mL×) 3) The organic phase was washed with water (100 mL×2) and brine (100 mL×2). The organic phase was dried over anhydrous sodium sulfate : 0 to 9:1) to give (2R,4S)-4-fluoro-2-(5-fluoro-2-methoxyphenyl)pyrrolidine-1-carboxylic acid tert-butyl ester 21j (0.49 g, colorless oil ), the yield was 54%.

MS m/z (ESI): 336 [M+23];

^{_{1 H NMR (400MHz, CDCl 3}} ) δ7.89-6.87 (m, 2H), 6.80-6.76 (m, 1H), 5.27-5.23 (m, 1H), 5.16-5.12 (m, 1H), 4.13-4.08 (m, 1H), 3.79 (s, 3H), 3.73-3.60 (m, 1H), 2.75-2.65 (m, 1H), 2.06-1.91 (m, 1H), 1.46 (s, 3H), 1.18 (s) , 6H).

Step 10

(2R,4S)-4-fluoro-2-(5-fluoro-2-methoxyphenyl)pyrrolidine hydrochloride

(2R,4S)-4-fluoro-2-(5-fluoro-2-methoxyphenyl)pyrrolidine-1-carboxylic acid tert-butyl ester 21j (0.52 g, 1.66 mmol) dissolved in hydrogen chloride dioxane The mixture was stirred at room temperature for 2 hours, then dried with EtOAc EtOAc EtOAc (EtOAc) Pyrrolidine hydrochloride 21k (0.40 g, white solid), yield 96%.

MS m/z (ESI): 214 [M-HCl +1];

¹ H NMR (400 MHz, CD ₃ OD) δ 7.24 - 7.14 (m, 3H), 5.64 - 5.51 (m, 1H), 5.08 - 5.03 (m, 1H), 3.95 (s, 3H), 3.73 - 3.67 ( m, 2H), 2.69-2.53 (m, 2H).

The eleventh step

4-fluoro-2-((2R,4S)-4-fluoropyrrolidin-2-yl)phenol hydrobromide

The compound (2R,4S)-4-fluoro-2-(5-fluoro-2-methoxyphenyl)pyrrolidine hydrochloride 21k (0.20 g, 0.80 mmol) was dissolved in hydrobromic acid (47% aq. In the mixture, stirring at 100 ° C for 10 hours, and desolvation under reduced pressure to give the desired product, 4-fluoro-2-((2R,4S)-4-fluoropyrrolidin-2-yl)phenol hydrobromide, 21 l (0.25 g, Bright yellow oil), crude.

MS m/z (ESI): 200 [M-HBr+1];

^{_{1 H NMR (400MHz, CD 3}} OD) δ7.16-7.13 (m, 1H), 7.08-7.03 (m, 1H), 6.96-6.93 (m, 1H), 5.65-5.53 (m, 1H), 5.05- 4.94 (m, 1H), 3.80-3.66 (m, 2H), 2.69-2.63 (m, 2H).

Step 12

4-fluoro-2-((2R,4S)-4-fluoro-1-(3-nitropyrazolo[1,5-a]pyrimidin-5-yl)pyrrolidin-2-yl)phenol

Compound 4-fluoro-2-((2R,4S)-4-fluoropyrrolidin-2-yl)phenol hydrobromide 21 l (0.25 g, 1.06 mmol), 5-chloro-3-nitropyrazole [1,5-a]pyrimidine 9d (0.30 g, 1.50 mmol) and N,N-diisopropylethylamine (1 mL) were dissolved in isopropyl alcohol (5 mL), and stirred at 60 ° C for 2 hours. (50 mL), diluted with methylene chloride (50 mL × 2), dried over anhydrous sodium sulfate, filtered, evaporated, evaporated. 7) Obtain the desired product 4-fluoro-2-((2R,4S)-4-fluoro-1-(3-nitropyrazolo[1,5-a]pyrimidin-5-yl)pyrrolidine-2 Phenyl 21 m (0.35 g, yellow solid), yield: 64%.

MS m/z (ESI): 362 [M + 1].

Step 13

(2-(4-R)-2-((2R,4S)-4-fluoro-1-(3-nitropyrazolo[1,5-a]pyrimidin-5-yl)pyrrol-2-yl) Tert-butyl phenoxy)ethyl)carbamate

The compound 4-fluoro-2-((2R,4S)-4-fluoro-1-(3-nitropyrazolo[1,5-a]pyrimidin-5-yl)pyrrolidin-2-yl)phenol 21m (0.35g, 1.00mmol) and cesium carbonate (1.00g, 3.00mmol) were dissolved in acetonitrile (10mL), tert-butyl 2-bromoethylcarbamate (0.45g, 2.00mmol), oil bath at 70 ° C After stirring for 2 hours, the reaction solution was diluted with water (50 mL) and extracted with dichloromethane (50 mL×2). The organic phase was dried over anhydrous sodium sulfate. 120 g C18 sperical 50 um 60 A column, eluent: water: acetonitrile = 1:9 to 1.2:1) to give the title compound (2-(4-fluoro-2-((2R,4S)-4-fluoro-1) -(3-Nitropyrazolo[1,5-a]pyrimidin-5-yl)pyrrol-2-yl)phenoxy)ethyl)carbamic acid tert-butyl ester 21n (0.14 g, yellow solid) Rate: 29%.

MS m/z (ESI): 505 [M + 1];

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.49 (s, 1H), 8.13 (d, J = 7.2Hz, 1H), 6.94-6.78 (m, 3H), 6.03 (d, J = 7.2Hz, 1H) , 5.47-5.34 (m, 2H), 4.93-4.84 (m, 2H), 4.11-3.99 (m, 2H), 3.59-3.57 (m, 2H), 3.06-2.98 (m, 1H), 2.26-2.01 ( m, 1H), 1.36 (s, 9H).

Fourteenth step

(2-(4-R)-2-((2R,4S)-4-fluoro-1-(3-aminopyrazolo[1,5-a]pyrimidin-5-yl)pyrrole-2-yl)benzene Oxy)ethyl)carbamic acid tert-butyl ester

Compound (2-(4-fluoro-2-((2R,4S)-4-fluoro-1-(3-nitropyrazolo[1,5-a]pyrimidin-5-yl)pyrrole-2- tert-Butyl phenoxy)ethyl)carbamate 21n (0.14 g, 0.30 mmol), dichloromethane (10 mL), methanol (5 mL), saturated aqueous ammonium chloride (10 mL) 3.00 mmol) was mixed and stirred at room temperature for 3 hours. Dichloromethane (300 mL) was added, and the mixture was washed with water (100 mL×2). 4-fluoro-1-(3-aminopyrazolo[1,5-a]pyrimidin-5-yl)pyrrole-2-yl)phenoxy)ethyl)carbamic acid tert-butyl ester 21o (0.12g, Yellow oil), crude.

MS m/z (ESI): 495 [M + 1].

Step fifteenth

5-((2R,4S)-2-(2-(2-Aminoethoxy)-5-fluorophenyl)-4-fluoropyrrolidin-1-yl)pyrazolo[1,5-a] Pyrimidine-3-amine trifluoroacetate salt (2-(4-R)-2-((2R,4S)-4-fluoro-1-(3-aminopyrazolo[1,5-a]pyrimidine -5-yl)pyrrol-2-yl)phenoxy)ethyl)carbamic acid tert-butyl ester 21o (0.12 g, 3.37 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (2 mL) 2 hours. The reaction solution was desolvated under reduced pressure to give the title compound 5-((2R,4S)-2-(2-(2-aminoethoxy)-5-fluorophenyl)-4-fluoropyrrolidin-1-yl) Pyrazolo[1,5-a]pyrimidin-3-amine trifluoroacetate 21p (0.10 g, yellow oil), crude.

MS m/z (ESI): 355 [M + 1].

Step 16

The compound 5-((2R,4S)-2-(2-(2-aminoethoxy)-5-fluorophenyl)-4-fluoropyrrolidin-1-yl)pyrazolo[1,5- a] pyrimidine-3-amine trifluoroacetate 21p (50 mg, 0.15 mmol) was dissolved in N,N-dimethylformamide (2 mL), and N,N'-carbonyldiimidazole (16 mg, 0.1 mmol) and Triethylamine (0.5 mL) was stirred in a 35 ° C oil bath for 1 hour. The reaction solution was diluted with water (20 mL), filtered, and the filtrate was extracted with ethyl acetate (50mL×3). The filter cake was washed with dichloromethane, and the organic phase was combined, dried and filtered, and the organic phase was evaporated under reduced pressure. Methyl chloride:methanol = 30:1) to give the desired product (2 ² R, 2 ⁴ S) - 2 ⁴ , 3 ⁵ -difluoro-4-oxa-7,9-diaza-1 (5,3) -pyrazolo[1,5-a]pyrimidin-2(1,2)-pyrrole-3(1,2)-benzocyclodecane-8-one 21 (22.3 mg, 0.056 mmol, pale yellow solid) . Yield: 37%.

MS m/z (ESI): 401 [M + 1];

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.37 (s, 1H), 8.33 (d, J = 7.2Hz, 1H), 7.36-7.34 (m, 1H), 7.22-7.20 (m, 1H), 7.18- 7.16 (m, 1H), 7.04-7.02 (m, 1H), 6.30 (d, J = 7.2 Hz, 1H), 6.20 (s, 1H), 5.39-5.37 (m, 2H), 4.57-4.55 (m, 1H), 3.73 - 3.57 (m, 5H), 2.13 - 2.05 (m, 2H).

Example 22

(2 ² R,2 ⁴ S,5S)-2 ⁴ ,3 ⁵ -difluoro-5-methyl-4-oxa-7,9-diaza-1(5,3)-pyrazolo[ 1,5-a]pyrimidine-2(1,2)-pyrrole-3(1,2)-benzocyclodecane-8-one

Example 22 was synthesized by following the procedure of Example 21 to give the desired product (2 ² R, 2 ⁴ S, 5S) - 2 ⁴ , 3 ⁵ -difluoro-5-methyl-4-oxa-7,9- Diaza-1(5,3)-pyrazolo[1,5-a]pyrimidin-2(1,2)-pyrrole-3(1,2)-benzocyclodecane-8-one 22 ( 20.6 mg, pale yellow solid). Yield: 33%.

MS m/z (ESI): 415 [M + 1];

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.25-8.23 (m, 1H), 8.22 (d, J = 8.0 Hz, 1H), 7.57 (s, 1H), 6.84-6.80 (m, 2H), 6.74 6.72 (m, 1H), 6.56 (s, 1H), 6.20 (d, J = 8.0 Hz, 1H), 5.70-5.67 (m, 1H), 5.52-5.39 (m, 1H), 4.63-4.59 (m, 1H), 4.19-3.98 (m, 3H), 3.82-3.80 (m, 1H), 2.98-2.96 (m, 1H), 2.91-2.81 (m, 1H), 1.46 (d, J = 5.6 Hz, 3H) .

Example 23

(2 ² R,5S)-3 ⁵ -fluoro-5-methyl-4-oxa-7,9-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidine- 3(3,2)-pyridine-2(1,2)-pyrrolocyclodecane-8-one

first step

(R)-N-((5-fluoro-2-methoxypyridin-3-yl)methylene)-2-methylpropane-2-sulfinamide

5-Fluoro-2-methoxypyridine 3-carbaldehyde 23a (10.00 g, 64.5 mmol) was dissolved in dichloromethane (120 mL), and then yttrium carbonate (42.00 g, 129.00 mmol) and (R)-2- Methylpropane-2-sulfinamide (8.26 g, 67.70 mmol) was reacted at 30 ° C for 4 hours after the addition. After completion of the reaction, the mixture was filtered, and the filtrate was directly dried to give (R)-N-((5-fluoro-2-methoxypyridin-3-yl)methylene)-2-methylpropane-2-sulfinamide 23b (17.50g, yellow oil), directly to the next step without further purification.

MS m/z (ESI): 259 [M + 1];

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.88 (s, 1H), 8.16 (s, 1H), 7.78 (d, J = 8.0 Hz, 1H), 4.01 (s, 3H), 1.27 (s, 9H) .

Second step

(R)-N-((R)-3-(1,3-dioxan-2-yl)-1-(5-fluoro-2-methoxypyridin-3-yl)propyl)-2 -methylpropane-2-sulfinamide

Magnesium chips (3.30 g, 136.00 mmol) were dissolved in dry tetrahydrofuran (200 mL), diisobutylaluminum hydride (0.3 mL, 1M in tetrahydrofuran) was added and stirred at 50 ° C for 15 min then 2-(2-bromo) A solution of ethyl)-1,3-dioxane (26.50 g, 60 mmol) in tetrahydrofuran (50 mL) was added dropwise to the above solution, stirred at 50 ° C for 1 hour, and the reaction mixture was cooled to -40 ° C, dropwise (R)- a solution of N-((5-fluoro-2-methoxypyridin-3-yl)methylene)-2-methylpropane-2-sulfinamide 23b (17.50 g, 68.00 mmol) in tetrahydrofuran (50 mL) Stir at -40 ° C for 1 hour, slowly return to room temperature, stir for 1 hour, quench with aqueous citric acid (10%), extract with methyl tert-butyl ether (400 mL), the organic phase with saturated aqueous sodium hydrogen carbonate and water Wash, dry filter and spin dry to give (R)-N-((R)-3-(1,3-dioxan-2-yl)-1-(5-fluoro-2-methoxypyridine-3 -yl)propyl)-2-methylpropane-2-sulfinamide 23c (20.0 g, white solid).

MS m/z (ESI): 375 [M + 1];

^{_{1 H NMR (400MHz, CDCl 3}} ) δ7.89 (s, 1H), 7.30 (d, J = 8.0Hz, 1H), 4.52-4.50 (m, 1H), 4.35-4.33 (m, 1H), 4.18- 4.16 (m, 1H), 4.10-4.08 (m, 2H), 3.95 (s, 3H), 3.77-3.70 (m, 2H), 2.07-2.04 (m, 2H), 1.90-1.85 (m, 1H), 1.73-1.69 (m, 1H), 1.55-1.52 (m, 1H), 1.35-1.32 (m, 1H), 1.21 (s, 9H).

third step

(R)-5-fluoro-2-methoxy-3-(pyrrolidin-2-yl)pyridine

(R)-N-((R)-3-(1,3-dioxan-2-yl)-1-(5-fluoro-2-methoxypyridin-3-yl)propyl)- 2-Methylpropane-2-sulfinamide 23c (20.00 g, 20.00 mmol) was dissolved in trifluoroacetic acid (100 mL) and water (10 mL) and stirred at 20 ° C for 1 hour, then triethylsilane (80 mL) The mixture was added to the above mixture and stirred at 20 ° C for 16 hours. The solvent was evaporated to dryness. mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj The mixture was extracted with dichloromethane (200×3), and the organic phase was washed with brine (100 mL), dried and filtered and evaporated to give (R)-5-fluoro-2-methoxy-3-(pyrrolidine- 2-Base)pyridine 23d (9.00 g, bright yellow oil).

MS m/z (ESI): 197 [M+1];

^{_{1 H NMR (400MHz, CDCl 3}} ) δ7.83 (s, 1H), 7.57 (d, J = 8.8Hz, 1H), 4.31-4.29 (m, 1H), 3.93 (s, 3H), 3.15-3.11 ( m, 1H), 3.07-3.00 (m, 1H), 2.28-2.25 (m, 1H), 1.85-1.80 (m, 2H), 1.57-1.55 (m, 1H).

the fourth step

(R)-5-fluoro-3-(pyrrolidin-2-yl)pyridin-2-ol

(R)-5-Fluoro-2-methoxy-3-(pyrrolidin-2-yl)pyridine 23d (1.20 g, 11.0 mmol) was dissolved in acetonitrile (20 mL) and potassium iodide (3.70 g, 44.0 mmol) Then, trimethylchlorosilane (2.30 g, 22.0 mmol) was added dropwise, and the mixture was stirred at 50 ° C for 24 hours, filtered, and the filtrate was concentrated to give a solid, washed with dichloromethane:methanol = 5:1, filtered, (R)-5-Fluoro-3-(pyrrolidin-2-yl)pyridin-2-ol 23e (1.6 g, crude product, yellow solid).

MS m/z (ESI): 183 [M + 1];

^{1 H NMR (400MHz, DMSO-} d 6) δ9.23 (s, 1H), 8.61 (s, 1H), 7.83-7.81 (m, 1H), 7.76 (d, J = 2.0Hz, 1H), 4.48- 4.44 (m, 1H), 3.25-3.17 (m, 2H), 2.22-2.18 (m, 1H), 2.09-2.07 (m, 2H), 1.93-1.91 (m, 1H).

the fifth step

(R)-5-fluoro-3-(1-(3-nitropyrazolo[1,5-a]pyrimidin-5-yl)pyrrolidin-2-yl)pyridin-2-ol

Referring to the fourth step of Example 9, substituting (R)-5-fluoro-3-(pyrrolidin-2-yl)pyridin-2-ol 23e for 2-(1-aminoethyl)-4-fluorophenol The objective product (R)-5-fluoro-3-(1-(3-nitropyrazolo[1,5-a]pyrimidin-5-yl)pyrrolidin-2-yl)pyridin-2-phenol 23f.

MS m/z (ESI): 345 [M + 1];

^{1 H NMR (400MHz, DMSO-} d 6) δ11.69 (brs, 1H), 8.83 (d, J = 7.6Hz, 0.44H), 8.72-8.60 (m, 1.12H), 8.56 (s, 0.44H) , 7.56 (s, 0.56H), 7.45 (s, 0.44H), 7.35-7.18 (m, 1H), 6.76 (d, J = 7.9 Hz, 0.44H), 6.14 (d, J = 7.6 Hz, 0.56H) ), 5.36 (d, J = 7.8 Hz, 0.44H), 5.07 (d, J = 8.0 Hz, 0.56H), 4.12-4.03 (m, 0.56H), 4.02-3.93 (m, 0.44H), 3.82 3.71 (m, 0.56H), 3.68-3.54 (m, 0.44H), 2.44-2.31 (m, 0.56H), 2.29-2.15 (m, 0.44H), 2.10-1.77 (m, 3H).

Step 6

(R)-(2-(4-fluoro-2-(1-(3-nitropyrazolo[1,5-a]pyrimidin-5-yl)pyrrolidin-2-yl)phenoxy)B Tert-butyl carbamate, referring to the seventh step of Example 1, using (R)-5-fluoro-3-(1-(3-nitropyrazolo[1,5-a]pyrimidin-5-yl) Pyrrolidin-2-yl)pyridin-2-ol 23f in place of (R)-4-fluoro-2-(1-((3-nitropyrazolo[1,5-a]pyrimidin-5-yl) Amino)ethyl)phenol 1h gives the target product ((S)-2-(4-fluoro-2-((R)-1-((3-nitropyrazolo[1,5-a]pyrimidine-5) -Pyryl-2-pyridin-2-yl)propyl)carbamic acid tert-butyl ester 23 g.

MS m/z (ESI): 502 [M + 1].

Seventh step

(R)-(2-(4-fluoro-2-(1-(3-aminopyrazolo[1,5-a]pyrimidin-5-yl)pyrrolidin-2-yl)phenoxy)B Tert-butyl carbamate refers to the eighth step of Example 1, using ((S)-2-(4-fluoro-2-((R)-1-((3-nitropyrazolo[1, 5-a]pyrimidin-5-yl)pyrrolidin-2-yl)pyridin-2-yl)propyl)carbamic acid tert-butyl ester 23 g instead of ((S)-2-(4-fluoro-2-((R) --1-((3-Nitropyrazolo[1,5-a]pyrimidin-5-yl)amino)ethyl)phenoxy)propyl)carbamic acid tert-butyl ester 1i to give the target product (R) -(2-(4-fluoro-2-(1-(3-aminopyrazolo[1,5-a]pyrimidin-5-yl)pyrrolidin-2-yl)phenoxy)ethyl)amino Tert-butyl formate 23h.

MS m/z (ESI): 472 [M + 1].

Eighth step

5-((R)-2-(2-((())-1-aminopropan-2-yl)oxy)-5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazole [1,5-a]pyrimidine-3-amine trifluoroacetate

Referring to the ninth step of Example 1, (R)-(2-(4-fluoro-2-(1-(3-aminopyrazolo[1,5-a]pyrimidin-5-yl)pyrrolidine) Tert-butyl 2-yl)phenoxy)ethyl)carbamate for 23h instead ((S)-2-(4-fluoro-2-((R)-1-((3-aminopyrazolo[1] , 5-a]pyrimidin-5-yl)amino)ethyl)phenoxy)propyl)carbamic acid tert-butyl ester 1j to give the target product 5-((R)-2-(2-((())) 1-aminopropan-2-yl)oxo)-5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-amine trifluoroacetate 23i .

MS m/z (ESI): 372 [M+1].

Step 9

Referring to the tenth step of Example 1, 5-((R)-2-(2-((())-1-aminopropan-2-yl)oxy)-5-fluoropyridin-3-yl) Pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-amine trifluoroacetate 23i instead of N ⁵ -((R)-1-(2-((())) Aminopropan-2-yl)oxo)-5-fluorophenyl)ethyl)pyrazolo[1,5-a]pyrimidine-3,5-diamine trifluoroacetate 1k to give the desired product (2 ² R,5S)-3 ⁵ -fluoro-5-methyl-4-oxa-7,9-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidine-3 (3 2)-Pyridin-2(1,2)-pyrrolocyclodecane-8-one 23 (11.8 mg, 0.031 mmol, pale yellow solid). Yield: 31%.

MS m/z (ESI): 398 [M + 1];

^{1 H NMR (400MHz, DMSO-} d 6) δ8.67-8.41 (m, 1H), 8.11-7.88 (m, 2H), 7.67-7.41 (m, 3H), 6.58-6.37 (m, 1H), 5.46 -5.17(m,2H),4.12-3.89(m,1H),3.73-3.53(m,2H), 3.00-2.81(m,1H),2.43-2.32(m,1H), 2.30-2.16(m, 1H), 2.12-2.01 (m, 1H), 1.84-1.68 (m, 1H), 1.44 (d, J = 5.6 Hz, 3H).

Example 24

(R)-3 ⁵ -fluoro-4-oxa-7,9-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidin-3(3,2)-pyridine- 2(1,2)-pyrrolocyclodecane-8-one

Synthesis Example 24 was carried out in accordance with the procedure of Example 23 to give the desired product (R)-3 ⁵ -fluoro-4-oxa-7,9-diaza-1(5,3)-pyrazolo[1, 5-a]pyrimidine-3(3,2)-pyridine-2(1,2)-pyrrolocyclodecane-8-one 24.

MS m/z (ESI): 384 [M + 1];

^{1 H NMR (400MHz, CDCl3)} δ8.19 (d, J = 8.0Hz, 1H), 7.90-7.88 (m, 1H), 7.60-7.56 (m, 1H), 7.55 (s, 1H), 7.15-7.13 (m, 1H), 6.23 (d, J = 8.0 Hz, 1H), 6.06 (s, 1H), 5.57-5.55 (m, 1H), 5.30-5.24 (m, 1H), 4.24 - 4.19 (m, 1H) ), 3.96-3.90 (m, 1H), 3.88-3.82 (m, 1H), 3.73-3.67 (m, 1H), 3.38-3.30 (m, 1H), 2.53-2.46 (m, 1H), 2.36-2.31 (m, 1H), 2.22 - 2.13 (m, 1H), 1.96-1.88 (m, 1H).

Example 25

(2 ² R,6R)-3 ⁵ -fluoro-6-methyl-4-oxa-7,9-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidine- 3(3,2)-pyridine-2(1,2)-pyrrolocyclodecane-8-one

Synthesis Example 25 was carried out in accordance with the procedure of Example 23 to give the desired product (2 ² R,6R)-3 ⁵ -fluoro-6-methyl-4-oxa-7,9-diaza-1 (5, 3)-Pyrazolo[1,5-a]pyrimidine-3(3,2)-pyridine-2(1,2)-pyrrolocyclodecane-8-one 25.

MS m/z (ESI): 398 [M + 1];

^{_{1 H NMR (400MHz, CDCl 6}} ) δ8.19 (d, J = 7.2Hz, 1H), 7.85 (s, 1H), 7.54 (s, 1H), 7.11 (d, J = 7.6Hz, 1H), 6.29 (s, 1H), 6.22 (d, J = 7.2 Hz, 1H), 5.48-5.42 (m, 2H), 4.28-4.25 (m, 1H), 4.04-4.02 (m, 1H), 3.91-3.89 (m , 1H), 3.73-3.71 (m, 1H), 3.50-3.48 (m, 1H), 2.53-2.49 (m, 1H), 2.35-2.33 (m, 1H), 2.21-2.20 (m, 1H), 1.98 -1.87 (m, 1H), 1.38 (d, J = 6.4 Hz, 3H).

Example 26

(2 ² R,5R)-3 ⁵ -fluoro-5-methyl-3 ¹ ,3 ² -dihydro-6,8-diaza-1(5,3)-pyrazolo[1,5- a]pyrimidine-3(3,1)-pyridine-2(1,2)-pyrrolocyclooctane-3 ² ,7-dione

Example 26 was synthesized by following the procedure of Example 23 to give the desired product (2 ² R,5R)-3 ⁵ -fluoro-5-methyl-3 ¹ ,3 ² -dihydro-6,8-diaza- 1(5,3)-pyrazolo[1,5-a]pyrimidin-3(3,1)-pyridine-2(1,2)-pyrrolocyclooctane-3 ² ,7-dione 26.

MS m/z (ESI): 398 [M + 1];

^{_{1 H NMR (400MHz, CDCl 3}} ) δ7.87 (d, J = 7.2Hz, 1H), 7.25-7.20 (m, 1H), 7.11-7.08 (m, 2H), 6.98 (s, 1H), 6.71 ( s,1H), 5.99 (d, J=7.6 Hz, 1H), 5.45-5.41 (m, 1H), 4.95-4.89 (m, 1H), 4.49-4.47 (m, 1H), 3.81-3.75 (m, 1H), 3.67-3.35 (m, 1H), 2.56-2.55 (m, 1H), 2.40-2.14 (m, 2H), 2.03-2.01 (m, 1H), 1.87-1.83 (m, 1H), 1.45 ( d, J = 6.0 Hz, 3H).

Example 27

(S)-4 ⁵ -fluoro-2,6-dimethyl-5-oxa-2,8,10-triaza-1(5,3)-pyrazolo[1,5-a]pyrimidine -4(3,2)-pyridocyclodecane-9-one

Example 27 was synthesized by referring to the procedure of Example 23 to give the desired product (S)-4 ⁵ -fluoro-2,6-dimethyl-5-oxa-2,8,10-triaza-1 (5 , 3)-pyrazolo[1,5-a]pyrimidin-4(3,2)-pyridocyclodecane-9-one 27.

MS m/z (ESI): 372 [M + 1];

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.23 (d, J = 8.0Hz, 1H), 8.12 (s, 1H), 7.93 (s, 1H), 7.34-7.28 (m, 1H), 6.33 (s, 1H), 6.30 (d, J = 8.0 Hz, 1H), 5.45-5.41 (m, 2H), 3.75-3.72 (m, 2H), 3.52-3.33 (m, 2H), 3.27 (s, 3H), 1.43 (d, J = 5.2 Hz, 3H).

Example 28

(S)-4 ⁵ -fluoro-2,6,8-trimethyl-5-oxa-2,8,10-triaza-1(5,3)-pyrazolo[1,5-a Pyrimidine-4(1,2)-benzocyclodecane-9-one

first step

(S)-(2-(4-fluoro-2-((methyl(3-nitropyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)phenoxy)propyl) a tert-butyl carbamate compound (S)-(2-(4-fluoro-2-((methyl(3-nitropyrazolo[1,5-a]pyrimidin-5-yl)amino)) Tert-butyl phenoxy)propyl)carbamate 11e (0.15 g, 0.34 mmol) was dissolved in N,N-dimethylformamide (5 mL), and sodium hydrogen (40 mg, 1.01 mmol, 60 %, mineral oil dispersion), stirring at room temperature for 10 minutes. Methyl iodide (0.14 g, 1.01 mmol) was added and stirred at room temperature for 30 min. Ethyl acetate (10 mL × 3) was added for extraction, washed with water (10 mL × 3), and the organic phase was dried over anhydrous sodium sulfate and evaporated to dryness to give (S)-(2-(4-fluoro-2-(() (3-Nitropyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)phenoxy)propyl)carbamic acid tert-butyl ester 28a (0.16 g, yellow liquid). The product was used in the next reaction without purification.

MS m/z (ESI): 384 [M-99].

Second step

(S)-(2-(2-((3-Aminopyrazolo[1,5-a]pyrimidin-5-yl)(methyl)amino)methyl)-4-fluorophenoxy)propyl) a tert-butyl carbamate compound (S)-(2-(4-fluoro-2-((methyl(3-nitropyrazolo[1,5-a]pyrimidin-5-yl)amino)) Phenyloxy)propyl) 28a (0.16 g, 0.33 mmol) was dissolved in dichloromethane (5 mL), methanol (5 mL), saturated aqueous ammonium chloride (5 mL) and zinc powder (0.21 g, 3.30 mmol) Stir at room temperature for 20 minutes. Dichloromethane (10 mL × 2) was added for extraction, washed with water (5 mL × 3), the organic phase was dried over anhydrous sodium sulfate, and the filtrate was evaporated under reduced pressure to give (S)-(2-(2-((3-amino) Zyrazo[1,5-a]pyrimidin-5-yl)(methyl)amino)methyl)-4-fluorophenoxy)propyl)carbamic acid tert-butyl ester 28b (0.13 g, yellow liquid). The product was used in the next reaction without purification.

MS m/z (ESI): 459 [M + 1];

^{1 H NMR (400MHz, CDCl3)} δ8.12 (d, J = 7.2Hz, 1H), 7.65 (s, 1H), 6.89-6.79 (m, 3H), 6.13 (d, J = 7.2Hz, 1H), 4.74-4.59 (m, 3H), 3.50-3.35 (m, 1H), 3.20 (s, 3H), 2.98-2.88 (m, 1H), 2.93 (s, 3H), 1.46 (s, 9H), 1.28 ( d, J = 4.8 Hz, 3H).

third step

(S)-N-5-(5-fluoro-2-((1-(methylamino)propan-2-yl)oxy)benzyl)-N-5-methylpyrazolo[1,5 -a]pyrimidine-3,5-diamine trifluoroacetate

Compound (S)-(2-(2-((3-aminopyrazolo[1,5-a]pyrimidin-5-yl)(methyl)amino)methyl)-4-fluorophenoxy) The propyl)-tert-butyl carbamate 28b (0.13 g, 0.30 mmol) was dissolved in dichloromethane (4 mL). The reaction solution was desolvated under reduced pressure to give (S)-N-5-(5-fluoro-2-((1-(methylamino)propan-2-yl)oxy)benzyl)-N-5- Pyrazolo[1,5-a]pyrimidine-3,5-diamine trifluoroacetate 28c (0.10 g, yellow solid). The product was used in the next reaction without purification.

MS m/z (ESI): 359 [M + 1].

the fourth step

(S)-4 ⁵ -fluoro-2,6,8-trimethyl-5-oxa-2,8,10-triaza-1(5,3)-pyrazolo[1,5-a Pyrimidine-4-(1,2)-benzocyclodecane-9-one compound (S)-N-5-(5-fluoro-2-((1-(methylamino)propan-2-) Alkyloxy)benzyl)-N-5-methylpyrazolo[1,5-a]pyrimidine-3,5-diamine trifluoroacetate 28c (0.10 g, 0.30 mmol) was dissolved in N. N-Dimethylformamide (3 mL) was added triethylamine (0.5 mL) and N,N'-carbonyldiimimazole (49 mg, 0.30 mmol). The reaction solution is filtered and separated by high performance liquid chromatography (acetonitrile:water = 3:1 to 2:1) to give the compound (S)-4 ⁵ -fluoro-2,6,8-trimethyl-5-oxa-2. 8,10-Triaza-1(5,3)-pyrazolo[1,5-a]pyrimidin-4(1,2)-benzocyclodecane-9-one 28 (15 mg, yellow solid) , Yield: 13%.

MS m/z (ESI): 385 [M + 1];

^{1 H NMR (400MHz, CDCl3)} δ8.25 (d, J = 8.0Hz, 1H), 8.05 (s, 1H), 7.89 (s, 1H), 6.96-6.93 (m, 1H), 6.83-6.79 (m , 2H), 6.24 (d, J = 8.0 Hz, 1H), 5.56-5.54 (m, 1H), 4.82-4.80 (m, 1H), 4.12-4.10 (m, 1H), 3.82-3.80 (m, 1H) ), 3.45 (s, 3H), 3.39-3.37 (m, 1H), 3.11 (s, 3H), 1.34 (d, J = 6.0 Hz, 3H).

Example 29

(2 ² S,5S)-3 ⁵ -fluoro-5,7-dimethyl-4-oxa-7,9-diaza-1(5,3)-pyrazolo[1,5-a Pyrimidine-2(1,2)-pyrrole-3(1,2)-benzocyclodecane-8-one

Example 29 was synthesized by following the procedure of Example 28 to give the desired product (2 ² S,5S)-3 ⁵ -fluoro-5,7-dimethyl-4-oxa-7,9-diaza-1 (5,3)-pyrazolo[1,5-a]pyrimidin-2(1,2)-pyrrole-3(1,2)-benzocyclodecane-8-one 29.

MS m/z (ESI): 411 [M + 1];

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.19 (d, J = 7.2Hz, 1H), 7.91 (s, 1H), 6.99-6.97 (m, 1H), 6.80-6.78 (m, 2H), 6.20 ( d, J=7.2 Hz, 1H), 5.98-5.96 (m, 1H), 5.49-5.47 (m, 1H), 5.14-5.12 (m, 1H), 4.16-4.14 (m, 1H), 3.87-3.84 ( m,1H),3.73-3.71(m,1H),3.06(s,3H),2.52-2.49(m,1H), 2.30-2.27(m,1H),2.15-2.12(m,1H),2.03- 2.01 (m, 1H), 1.88-1.85 (m, 1H), 1.47 (d, J = 4.8 Hz, 3H).

Example 30

(2 ² R,5S)-3 ⁵ -fluoro-5,7-dimethyl-4-oxa-7,9-diaza-1(5,3)-pyrazolo[1,5-a Pyrimidine-2(1,2)-pyrrole-3(1,2)-benzocyclodecane-8-one

Example 30 was synthesized by following the procedure of Example 28 to give the desired product (2 ² R,5S)-3 ⁵ -fluoro-5,7-dimethyl-4-oxa-7,9-diaza-1 (5,3)-pyrazolo[1,5-a]pyrimidine-2(1,2)-pyrrole-3(1,2)-benzocyclodecane-8-one 30.

MS m/z (ESI): 411 [M + 1];

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.20 (d, J = 7.2Hz, 1H), 7.79 (s, 1H), 6.87-6.85 (m, 1H), 6.78-6.75 (m, 2H), 6.33 ( d, J = 7.2 Hz, 1H), 5.70-5.68 (m, 1H), 4.83-4.81 (m, 1H), 4.36-4.34 (m, 1H), 3.86-3.84 (m, 1H), 3.59-3.56 ( m,1H), 3.18-3.15 (m,1H), 3.06 (s,3H), 2.55-2.53 (m,1H), 2.32-2.29 (m,1H),2.14-2.12 (m,1H),2.05- 2.01 (m, 1H), 1.87-1.85 (m, 1H), 1.39 (d, J = 4.8 Hz, 3H).

Example 31

(2 ² R,6R)-3 ⁵ -fluoro-6,7-dimethyl-4-oxa-7,9-diaza-1(5,3)-pyrazolo[1,5-a Pyrimidine-2(1,2)-pyrrole-3(1,2)-benzocyclodecane-8-one

Example 31 was synthesized by the procedure of Example 28 to give the desired product (2 ² R,6R)-3 ⁵ -fluoro-6,7-dimethyl-4-oxa-7,9-diaza-1 (5,3)-pyrazolo[1,5-a]pyrimidin-2(1,2)-pyrrole-3(1,2)-benzocyclodecane-8-one 31.

MS m/z (ESI): 411 [M + 1];

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.15 (d, J = 8.0Hz, 1H), 7.73 (s, 1H), 6.83-6.74 (m, 3H), 6.17 (d, J = 8.0Hz, 1H) , 5.82-5.80 (m, 1H), 5.62-5.60 (m, 1H), 4.22-4.20 (m, 1H), 3.88-3.86 (m, 1H), 3.68-3.66 (m, 1H), 3.60-3.56 ( m,1H), 2.99(s,3H), 2.38-2.36(m,2H),2.11-2.05(m,1H),,1.85-1.86(m,1H),1.41(d,J=6.0Hz,3H ).

Example 32

(S)-4 ⁵ -fluoro-2,6,8-trimethyl-5-oxa-2,8,10-triaza-1(5,3)-pyrazolo[1,5-a Pyrimidine-4(3,2)-pyridocyclodecane-9-one

Synthesis Example 32 was carried out in accordance with the procedure of Example 28 to give the desired product (S)-4 ⁵ -fluoro-2,6,8-trimethyl-5-oxa-2,8,10-triaza-1 (5,3)-pyrazolo[1,5-a]pyrimidin-4(3,2)-pyridocyclodecane-9-one 32.

MS m/z (ESI): 386 [M + 1];

^{1 H NMR (400MHz, CDCl3)} δ8.21 (d, J = 7.6Hz, 1H), 7.83 (s, 1H), 7.79-7.47 (m, 1H), 7.24-7.22 (m, 1H), 6.29 (d , J=7.6 Hz, 1H), 5.87 (s, 1H), 5.43-5.34 (m, 2H), 3.75-3.66 (m, 1H), 3.44 (s, 3H), 3.17-3.11 (m, 2H), 3.04 (s, 3H), 1.38 (d, J = 4.8 Hz, 3H).

Example 33

(2 ² R,5S)-3 ⁵ -fluoro-5,7-dimethyl-4-oxa-7,9-diaza-1(5,3)-pyrazolo[1,5-a Pyrimidine-3-(3,2)-pyridine-2-(1,2)-pyrrolocyclodecane-8-one

Example 33 was synthesized by following the procedure of Example 28 to give the desired product (2 ² R,5S)-3 ⁵ -fluoro-5,7-dimethyl-4-oxa-7,9-diaza-1 (5,3)-pyrazolo[1,5-a]pyrimidin-3-(3,2)-pyridine-2-(1,2)-pyrrolocyclodecane-8-one 33.

MS m/z (ESI): 412 [M + 1];

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.17 (d, J = 7.6Hz, 1H), 7.84-7.67 (m, 2H), 7.16-7.14 (m, 1H), 6.18 (d, J = 7.6Hz, 1H), 6.08-5.88 (m, 1H), 5.75-5.49 (m, 1H), 5.49-5.39 (m, 1H), 4.81-4.41 (m, 1H), 3.90-3.76 (m, 1H), 3.63 3.50 (m, 1H), 3.00 (s, 3H), 2.47-2.32 (m, 1H), 2.31-2.19 (m, 1H), 2.18-2.06 (m, 1H), 1.84-1.72 (m, 1H), 1.36 (d, J = 4.8 Hz, 3H).

Example 34

(2 ² R,6R)-3 ⁵ -fluoro-6-methyl-7,9-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidine-2 (1,2 )-pyrrole-3(1,2)-benzocyclodecane-8-one

first step

(R)-4-fluoro-2-(1-(3-nitropyrazolo[1,5-a]pyrimidin-5-yl)pyrrolidin-2-yl)phenyl trifluoromethanesulfonate

Compound (R)-4-fluoro-2-(1-(3-nitropyrazolo[1,5-a]pyrimidin-5-yl)pyrrolidin-2-yl)phenol 18f (0.20 g, 0.63 Methyl acetate (0.19 g, 1.88 mmol) was dissolved in N,N-dimethylformamide (3 mL). N-phenylbis(trifluoromethanesulfonyl)imide 34a (0.25 g, 0.69) Methyl), the reaction was stirred at room temperature for 12 hours. The reaction mixture was dissolved in ethyl acetate (100 mL), EtOAc (EtOAc) (1-(3-Nitropyrazolo[1,5-a]pyrimidin-5-yl)pyrrolidin-2-yl)phenyltrifluoromethanesulfonate 34b (0.25 g, yellow solid). The product was used in the next reaction without purification.

MS m/z (ESI): 476 [M + 1].

Second step

(R)-(4-((R)-4-fluoro-2-(1-(3-nitropyrazolo[1,5-a]pyrimidin-5-yl)pyrrolidin-2-yl)benzene Tert-butyl 3-butyl-3-yn-2-yl)carbamate

Compound (R)-4-fluoro-2-(1-(3-nitropyrazolo[1,5-a]pyrimidin-5-yl)pyrrolidin-2-yl)phenyltrifluoromethanesulfonic acid Ester 34b (0.25 g, 0.53 mmol), tert-butyl (R)-but-3-yn-2-ylcarbamate 34c (synthesis according to J. Org. Chem, 79, 1254- 1264) (0.18 g, 1.05 mmol Triethylamine (0.17 g, 1.68 mmol) and lithium chloride (22 mg, 0.53 mmol) were dissolved in N,N-dimethylformamide (5 mL) and bis(triphenylphosphine) was added under argon. Palladium dichloride (37 mg, 0.05 mmol) and cuprous iodide (20 mg, 0.11 mmol) were reacted at 100 ° C for 1 hour under microwave. The reaction mixture was dissolved with ethyl acetate (100 mL). The residue was purified by silica gel chromatography (ethyl ether: ethyl acetate=2:3) to afford the desired product (R)-(4-((R)-4-fluoro-2-(1-(3-) Zircon[1,5-a]pyrimidin-5-yl)pyrrolidin-2-yl)phenyl)-but-3-yn-2-yl)carbamic acid tert-butyl ester 34d (0.25 g, 0.51 mmol, yellow Solid), yield: 96%.

MS m/z (ESI):495 m.

third step

((R)-4-(4-fluoro-2-((R)-(1-(3-nitropyrazolo[1,5-a]pyrimidin-5-yl)pyrrolidin-2-yl) Tert-butyl phenyl)butyl-2-yl)carbamate

Compound (R)-(4-((R)-4-fluoro-2-(1-(3-nitropyrazolo[1,5-a]pyrimidin-5-yl)pyrrolidin-2-yl) Benzyl)-but-3-yn-2-yl)carbamic acid tert-butyl ester 34d (40 mg, 0.08 mmol), dissolved in methanol (3 mL), EtOAc (EtOAc) The reaction was carried out at room temperature for 15 minutes. Filtration and the filtrate was desolvated under reduced pressure. The target product was obtained ((R)-4-(4-fluoro-2-((R)-(1-(3-nitropyrazolo[1,5-a]pyrimidin-5-yl)pyrrolidine-2 -Phenyl)phenyl-2-butyl)carbamic acid tert-butyl ester 34e (40 mg, yellow solid).

MS m/z (ESI): 499 [M + 1].

the fourth step

((R)-4-(4-fluoro-2-((R)-(1-(3-aminopyrazolo[1,5-a]pyrimidin-5-yl)pyrrolidin-2-yl)benzene Tert-butyl 2-butyl)carbamate

Referring to the second step of Example 28, using ((R)-4-(4-fluoro-2-((R)-(1-(3-nitropyrazolo[1,5-a]pyrimidine-5) Tert-butyl pyrrolidin-2-yl)phenyl)butyl-2-yl)carbamate instead of (S)-(2-(4-fluoro-2-((methyl(3-nitropyridyl)) Zoxao[1,5-a]pyrimidin-5-yl)amino)methyl)phenoxy)propyl) gives the desired product ((R)-4-(4-fluoro-2-((R)-( 1-(3-Aminopyrazolo[1,5-a]pyrimidin-5-yl)pyrrolidin-2-yl)phenyl)butyl-2-yl)carbamic acid tert-butyl ester 34f.

MS m/z (ESI): 469 [M + 1].

the fifth step

5-((R)-2-(2-((R)-3-aminobutyl)-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3 -amine trifluoroacetate

Referring to the third step of Example 28, ((R)-4-(4-fluoro-2-((R)-(1-(3-aminopyrazolo[1,5-a]pyrimidine-5-) Tert-butyl pyrrolidin-2-yl)phenyl)butyl-2-yl)carbamate instead of (S)-(2-(2-((3-aminopyrazolo[1,5-a]) Pyrimidin-5-yl)(methyl)amino)methyl)-4-fluorophenoxy)propyl) gives the desired product 5-((R)-2-(2-((R)-3-amino) 5-)-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-amine trifluoroacetate 34h.

MS m/z (ESI): 369 [M + 1].

Step 6

Referring to the fourth step of Example 28, 5-((R)-2-(2-((R)-3-aminobutyl)-5-fluorophenyl)pyrrolidin-1-yl)pyrazole was used. [1,5-a]pyrimidin-3-amine trifluoroacetate instead of (S)-N-5-(5-fluoro-2-((1-(methylamino)propan-2-yl)oxy) Benzyl)-N-5-methylpyrazolo[1,5-a]pyrimidine-3,5-diamine trifluoroacetate gives the desired product (2 ² R,6R)-3 ⁵ -fluoro- 6-methyl-7,9-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidin-2(1,2)-pyrrole-3(1,2)-benzo Cyclodecane-8-one 34.

MS m/z (ESI): 395 [M + 1];

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.18 (d, J = 7.6Hz, 1H), 7.51 (s, 1H), 7.22-7.18 (m, 1H), 6.87-6.79 (m, 1H), 6.65- 6.63 (m, 1H), 6.23 (d, J = 7.6 Hz, 1H), 6.11 (s, 1H), 5.26-5.24 (m, 1H), 3.99-3.95 (m, 1H), 3.92-3.84 (m, 1H), 3.79-3.73 (m, 1H), 3.08-3.03 (m, 1H), 2.72-2.65 (m, 1H), 2.56-2.50 (m, 1H), 2.33-2.26 (m, 1H), 2.24 2.08 (m, 3H), 1.93-1.85 (m, 1H), 1.25 (d, J = 6.8 Hz, 3H).

Example 35

(2 ² R,6R)-3 ⁵ -fluoro-6-methyl-7,9-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidine-3 (3,2 )-pyridine-2(1,2)-pyrrolocyclodecane-8-one

Example 35 was synthesized by following the procedure of Example 34 to give the desired product (2 ² R,6R)-3 ⁵ -fluoro-6-methyl-7,9-diaza-1(5,3)-pyrazole And [1,5-a]pyrimidin-3(3,2)-pyridine-2(1,2)-pyrrolocyclodecane-8-one 35.

MS m/z (ESI): 396 [M+1];

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.27 (d, J = 2.8Hz, 1H), 8.21 (d, J = 7.6Hz, 1H), 7.58 (s, 1H), 7.03-7.00 (m, 1H) , 6.24 (d, J = 7.6 Hz, 1H), 5.79 (brs, 1H), 5.41-5.23 (m, 1H), 4.06-3.86 (m, 2H), 3.83-3.68 (m, 1H), 3.39-3.26 (m, 1H), 2.89-2.75 (m, 1H), 2.61-2.46 (m, 2H), 2.37-2.24 (m, 1H), 2.22-2.09 (m, 2H), 1.95-1.83 (m, 1H) , 1.30 (d, J = 6.8 Hz, 3H).

Example 36

(R)-4 ⁵ -fluoro-2,7-dimethyl-2,8,10-triaza-1(5,3)-pyrazolo[1,5-a]pyrimidine-4 (3, 2)-pyridocyclodecane-9-one

Example 36 was synthesized by following the procedure of Example 34 to give the desired product (R)-4 ⁵ -fluoro-2,7-dimethyl-2,8,10-triaza-1(5,3)-pyridin. Zoxao[1,5-a]pyrimidine-4(3,2)-pyridocyclodecane-9-one 36.

MS m/z (ESI): 370 [M + 1];

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.41 (d, J = 2.4Hz, 1H), 8.33 (d, J = 8.0Hz, 1H), 8.13 (s, 1H), 7.84 (s, 1H), 7.39 -7.37(m,1H),6.76(s,1H),6.34(d,J=8.0Hz,1H),5.45-5.43(m,1H),4.36-4.33(m,1H),3.66-3.63(m , 1H), 2.99 (s, 3H), 2.97-2.84 (m, 2H), 2.09-2.02 (m, 1H), 1.74-1.67 (m, 1H), 1.14 (d, J = 6.8 Hz, 3H).

Example 37

4 ⁵ -fluoro-2-methyl-5-oxa-2,10-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidin-4(1,2)-benzene Cyclodecane-9-one

first step

Ethyl 4-(4-fluoro-2-((methyl(3-nitropyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)phenoxy)butanoate

The compound 4-fluoro-2-((methyl(3-nitropyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)phenol 11c (0.10 g, 0.33 mmol), 4- Ethyl bromobutyrate 37a (0.20 g, 1.00 mmol) and cesium carbonate (0.33 g, 1.00 mmol) were dissolved in EtOAc (5 mL). 50 mL × 3) was extracted, and the organic phase was washed with saturated brine (50 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, evaporated, evaporated, evaporated, evaporated, evaporated. ((methyl(3-nitropyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)phenoxy)butanoate 37b (0.12 g, white solid), yield: 82%.

MS m/z (ESI): 422 [M + 1].

Second step

Ethyl 4-(2-(((3-aminopyrazolo[1,5-a]pyrimidin-5-yl)(methyl)amino)methyl)-4-fluorophenoxy)butanoate

The compound 4-(4-fluoro-2-((methyl(3-nitropyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)phenoxy)butanoate ethyl ester 37b (0.12 g, 0.27 mmol), and zinc powder (0.20 g, 3.00 mmol), EtOAc (EtOAc m. It was extracted with dichloromethane (20 mL × 3), and the organic phase was washed with brine (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated to dryness, and then evaporated to give the desired product 4-(2-((3-aminopyrazolo[1,5-a]pyrimidin-5-yl) ( Ethyl methyl)amino)methyl)-4-fluorophenoxy)butanoate 37c (0.10 g, yellow oil), crude.

MS m/z (ESI): 402 [M + 1];

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.49 (s, 1H), 8.27-8.22 (m, 1H), 7.25-7.22 (m, 0.5H), 6.94-6.71 (m, 2.5H), 6.45-6.40 (m, 1H), 5.08 (s, 1H), 4.69 (s, 1H), 4.16-4.14 (m, 2H), 4.04-4.01 (m, 2H), 3.49 (s, 1.5H), 3.20 (s, 1.5H), 2.50-2.48 (m, 2H), 2.13-2.10 (m, 2H), 1.28-1.24 (m, 3H).

third step

Lithium 4-(2-((3-aminopyrazolo[1,5-a]pyrimidin-5-yl)(methyl)amino)methyl)-4-fluorophenoxy)butanoate

The compound 4-(2-(((3-aminopyrazolo[1,5-a]pyrimidin-5-yl)(methyl)amino)methyl)-4-fluorophenoxy)butanoic acid ethyl ester 37c (0.10g, 0.25mmol), and lithium hydroxide (24mg, 1.00mmol) were dissolved in tetrahydrofuran (3mL) and water (2mL), stirred at room temperature for 16 hours, then desolvated under reduced pressure to give the desired product 4-(2) -((3-Aminopyrazolo[1,5-a]pyrimidin-5-yl)(methyl)amino)methyl)-4-fluorophenoxy)butanoic acid lithium 37d (93 mg, yellow solid) ,Crude.

MS m/z (ESI): 374 [M-Li + 1].

the fourth step

The compound 4-(2-((3-aminopyrazolo[1,5-a]pyrimidin-5-yl)(methyl)amino)methyl)-4-fluorophenoxy)butanoic acid 37d ( 93 mg, 0.25 mmol), 2-(7-oxobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.12 g, 0.3 mmol) and N,N-di Isopropylethylamine (0.3 mL) was dissolved in EtOAc (2 mL). The phase was washed with saturated brine (20 mL x 3). The organic phase was dried over anhydrous sodium sulfate, the drying agent was removed by filtration, solvent removal under reduced pressure, the residue was slurried with methanol, filtered and dried to give the desired product 4 ⁵ - fluoro-2-methyl-5-oxa-2,10- Diaza-1(5,3)-pyrazolo[1,5-a]pyrimidin-4(1,2)-benzocyclodecane-9-one 37 (37 mg, yellow solid).

MS m/z (ESI): 356 [M + 1];

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.23 - 8.21 (m, 1H), 7.78 (s, 1H), 7.07-6.85 (m, 3H), 6.72 (s, 1H), 6.31-6.29 (m, 1H) ), 4.09-4.28 (m, 2H), 3.50-3.47 (m, 2H), 3.25 (s, 3H), 2.47-2.05 (m, 2H), 1.60-1.57 (m, 2H).

Example 38

4 ⁵ -fluoro-2,10-dimethyl-5-oxa-2,10-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidine-4 (1,2 )-benzocyclodecane-9-one

The compound 4-fluoro-2-methyl-5-oxa-2,10-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidin-4(1,2)- Benzocyclodecane-9-one 37 (7 mg, 0.02 mmol), sodium hydride (8 mg, 0.20 mmol, 60%, mineral oil dispersion) and methyl iodide (3 mg, 0.02 mmol) dissolved in N,N-dimethyl The mixture was stirred at room temperature for 1 hour, then quenched with water (10 mL). The target product 4 ⁵ -fluoro-2,10-dimethyl-5-oxa-2,10-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidine-4 was obtained. 1,2)-benzocyclodecane-9-one 38 (3 mg, white solid), yield 50%.

MS m/z (ESI): 370 [M + 1];

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.22 (d, J = 8.0Hz, 1H), 7.84 (s, 1H), 7.07-7.05 (m, 1H), 6.95-6.93 (m, 1H), 6.87- 6.86 (m, 1H), 6.28 (d, J = 8.0 Hz, 1H), 4.18-4.11 (m, 2H), 3.52-3.50 (m, 2H), 3.33 (s, 3H), 3.17 (s, 3H) , 2.18-2.10 (m, 2H), 1.59-1.56 (m, 2H).

Example 39

5'-Fluoro-2'-methylspiro[cyclopropane-1,7'-5-oxa-2,9-diaza-1(5,3)-pyrazolo[1,5-a] Pyrimidine-4(1,2)-benzocyclodecane]-8'-one

Synthesis Example 39 was carried out by following the procedure of Example 37 to give the desired product 5'-fluoro-2'-methylspiro[cyclopropane-1,7'-5-oxa-2,9-diaza-1( 5,3)-Pyrazolo[1,5-a]pyrimidin-4(1,2)-benzocyclodecane]-8'-one 39.

MS m/z (ESI): 368 [M + 1];

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.31 (d, J = 7.2Hz, 1H), 7.74 (s, 1H), 7.12-7.10 (m, 1H), 6.88-6.85 (m, 2H), 6.54 ( d, J = 7.2 Hz, 1H), 5.75-5.71 (m, 1H), 3.81-3.72 (m, 2H), 3.51 (s, 3H), 3.36-3.32 (m, 2H), 1.02-0.88 (m, 4H).

Example 40

4 ⁵ -Fluoro-3-methyl-5-oxa-2,10-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidin-4(1,2)-benzene Cyclodecane-9-one

Example 40 was synthesized by following the procedure of Example 37 to give the desired product 4 ⁵ -fluoro-3-methyl-5-oxa-2,10-diaza-1(5,3)-pyrazolo[1 , 5-a]pyrimidin-4(1,2)-benzocyclodecane-9-one 40.

MS m/z (ESI): 356 [M + 1];

^{1 H NMR (400MHz, CDCl3)} δ8.06 (d, J = 8.0Hz, 1H), 7.70 (s, 1H), 7.04-6.98 (m, 1H), 6.88-6.76 (m, 2H), 6.20-6.18 (m, 1H), 6.00 (d, J = 8.0 Hz, 1H), 5.38-5.16 (m, 1H), 4.41-4.39 (m, 1H), 4.15-4.07 (m, 1H), 3.34-3.29 (m) , 1H), 2.56-2.49 (m, 1H), 2.16-2.14 (m, 2H), 1.47 (d, J = 6.8 Hz, 3H).

Example 41

3 ⁵ -Fluoro-4-oxa-9-aza-1(5,3)-pyrazolo[1,5-a]pyrimidin-2(1,2)-pyrrole-3(1,2)- Benzocyclodecane-8-one

Synthesis of Example 41 by the procedure of Example 37 gave the desired product 3 ⁵ -fluoro-4-oxa-9-aza-1(5,3)-pyrazolo[1,5-a]pyrimidine-2 (1,2)-pyrrole-3(1,2)-benzocyclodecane-8-one 41.

MS m/z (ESI): 382 [M + 1];

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.23 (d, J = 6.8Hz, 1H), 7.73-7.63 (m, 1H), 6.98 (s, 1H), 6.91-6.81 (m, 3H), 6.30- 6.27 (m, 1H), 5.79-5.74 (m, 1H), 4.48-4.41 (m, 1H), 4.22-4.17 (m, 1H), 3.90-3.80 (m, 1H), 3.60-3.59 (m, 1H) ), 2.48-2.02 (m, 6H), 1.58-1.52 (m, 2H).

Example 42

(2 ² R,2 ⁴ S,5S)-2 ⁴ ,3 ⁵ -difluoro-5-methyl-4-oxa-9-aza-1(5,3)-pyrazolo[1,5 -a]pyrimidine-2(1,2)-pyrrole-3(1,2)-benzocyclodecane-8-one

Example 42 was synthesized by following the procedure of Example 37, wherein (R)-4-hydroxypentanoic acid ethyl ester was used as a reference (J. Org. Chem., 67 (15), 5315-5319; 2002 synthesis) to give the desired product. (2 ² R,2 ⁴ S,5S)-2 ⁴ ,3 ⁵ -difluoro-5-methyl-4-oxa-9-aza-1(5,3)-pyrazolo[1,5 -a] Pyrimidine-2(1,2)-pyrrole-3(1,2)-benzocyclodecane-8-one 42.

MS m/z (ESI): 414 [M + 1];

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.23 (d, J = 7.6Hz, 1H), 7.62 (s, 1H), 6.83 (s, 1H), 6.82-6.78 (m, 3H), 6.25 (d, J=7.6 Hz, 1H), 5.74-5.73 (m, 1H), 5.51-5.38 (m, 1H), 4.67-4.65 (m, 1H), 4.13-4.04 (m, 3H), 2.86-2.78 (m, 1H), 2.17-2.06 (m, 3H), 1.80-1.77 (m, 1H), 1.45 (d, J = 6.0 Hz, 3H).

Example 43

3 ⁵ -Fluoro-4-oxa-9-aza-1(5,3)-pyrazolo[1,5-a]pyrimidin-3(3,2)-pyridine-2(1,2)- Pyrrolocyclodecan-8-one

first step

5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)-3-nitropyrazolo[1,5-a]pyrimidine

The compound 5-fluoro-2-methoxy-3-(pyrrolidin-2-yl)pyridine (synthesized according to US20160168156A1) 43a (0.20 g, 1.01 mmol), 5-chloro-3-nitropyrazolo[1] , 5-a]pyrimidine 9d (0.20 g, 1.01 mmol) and N,N-diisopropylethylamine (0.39 g, 3.03 mmol) were dissolved in n-butanol (20 mL), stirred at 65 ° C for 1 hour, then cooled Solid precipitated, filtered and dried to give the desired product 5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)-3-nitropyrazolo[1,5 -a] Pyrimidine 43b (0.32 g, yellow solid), yield: 88%.

MS m/z (ESI): 359 [M + 1].

Second step

5-fluoro-3-(1-(3-nitropyrazolo[1,5-a]pyrimidin-5-yl)pyrrolidin-2-yl)pyridin-2-ol

The compound 5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)-3-nitropyrazolo[1,5-a]pyrimidine 43b (0.25 g , 0.70 mmol), potassium iodide (0.50 g, 3.01 mmol) and trimethylchlorosilane (1 mL) were dissolved in acetonitrile (20 mL), stirred at 65 ° C for 3 hours, then cooled, quenched with methanol The target product 5-fluoro-3-(1-(3-nitropyrazolo[1,5-a]pyrimidin-5-yl)pyrrolidin-2-yl)pyridin-2-ol 43c (0.24 g, yellow Solid), crude.

MS m/z (ESI): 344 [M + 1].

third step

4-((5-Fluoro-3-(1-(3-nitropyrazolo[1,5-a]pyrimidin-5-yl)pyrrolidin-2-yl)pyridin-2-yl)oxo) Ethyl butyrate

The compound 5-fluoro-3-(1-(3-nitropyrazolo[1,5-a]pyrimidin-5-yl)pyrrolidin-2-yl)pyridin-2-ol 43c (0.24 g, 0.70 Ethyl 4-bromobutyrate (0.17 g, 0.84 mmol) and cesium carbonate (0.68 g, 2.10 mmol) were dissolved in acetonitrile (20 mL) and stirred at 50 ° C for 2 h then quenched with water (20 mL) The organic layer was washed with saturated brine (50 mL×3). The organic phase was dried over anhydrous sodium sulfate, filtered, evaporated, evaporated, evaporated, evaporated, evaporated. Ethyl 1-(3-nitropyrazolo[1,5-a]pyrimidin-5-yl)pyrrolidin-2-yl)pyridin-2-yl)oxobutanoate 43d (80 mg, yellow gum ()), yield: 25%.

MS m/z (ESI): 459 [M + 1];

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.48 (s, 1H), 8.16 (d, J = 7.6Hz, 1H), 7.89-7.87 (m, 1H), 7.01 (d, J = 7.6Hz, 1H) , 5.98-5.96 (m, 1H), 5.15-5.13 (m, 1H), 4.44 (t, J = 6.0 Hz, 2H), 2.50-2.48 (m, 4H), 2.2-1.88 (m, 8H), 1.29 -1.27 (m, 3H).

And 4-(5-fluoro-3-(1-(3-nitropyrazolo[1,5-a]pyrimidin-5-yl)pyrrolidin-2-yl)-2-carbonylpyridine-1 (2H )-based ethyl butyrate 43d', yield: 25%.

MS m/z (ESI): 459 [M + 1];

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.72 (s, 1H), 8.18 (d, J = 7.6Hz, 1H), 7.28-7.26 (m, 1H), 7.00-6.98 (m, 1H), 6.09 ( d, J = 7.6 Hz, 1H), 5.20-5.18 (m, 1H), 4.24 - 4.08 (m, 2H), 3.98-3.96 (m, 2H), 2.59-2.30 (m, 4H), 2.23 - 2.08 ( m, 6H), 1.34-1.14 (m, 3H).

the fourth step

4-((3-(1-(3-Aminopyrazolo[1,5-a]pyrimidin-5-yl)pyrrolidin-2-yl)-5-fluoropyridin-2-yl)oxo) Ethyl acetate

The compound 4-((5-fluoro-3-(1-(3-nitropyrazolo[1,5-a]pyrimidin-5-yl)pyrrolidin-2-yl)pyridin-2-yl)oxy Ethyl butyrate 43d (80 mg, 0.17 mmol), and zinc powder (0.13 g, 2.20 mmol) were dissolved in saturated aqueous ammonium chloride (4 mL) and dichloromethane (10 mL). It was diluted with water (20 mL), extracted with dichloromethane (20 mL×3), and the organic phase was washed with saturated brine (20 mL×3). The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated to dryness, and then evaporated to give the desired product 4-((3-(1-(3-aminopyrazolo[1,5-a]pyrimidin-5-yl) Ethyl pyrrolidin-2-yl)-5-fluoropyridin-2-yl)oxobutanoate 43e (52 mg, yellow oil), crude.

MS m/z (ESI): 429 [M + 1].

the fifth step

4-((3-(1-(3-Aminopyrazolo[1,5-a]pyrimidin-5-yl)pyrrolidin-2-yl)-5-fluoropyridin-2-yl)oxo) Lithium acid

The compound 4-((3-(1-(3-aminopyrazolo[1,5-a]pyrimidin-5-yl)pyrrolidin-2-yl)-5-fluoropyridin-2-yl)oxo Ethyl butyrate 43e (52 mg, 0.11 mmol), and lithium hydroxide (7 mg, 0.24 mmol) were dissolved in tetrahydrofuran (4 mL) and water (1 mL). 4-((3-(1-(3-Aminopyrazolo[1,5-a]pyrimidin-5-yl)pyrrolidin-2-yl)-5-fluoropyridin-2-yl)oxo) Lithium hydride 43f (43 mg, yellow solid), crude.

MS m/z (ESI): 401 [M-Li + 1].

Step 6

The compound 4-((3-(1-(3-aminopyrazolo[1,5-a]pyrimidin-5-yl)pyrrolidin-2-yl)-5-fluoropyridin-2-yl)oxo Butyric acid 43f (43 mg, 0.11 mmol), 2-(7-oxobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (63 mg, 0.16 mmol) and N N-Diisopropylethylamine (1 mL) was dissolved in EtOAc (2 mL). The organic phase was washed with saturated brine (20 mL×3). The organic phase was dried over anhydrous sodium sulfate, the drying agent was removed by filtration, solvent removal under reduced pressure, the residue was purified by preparative plate silica gel (petroleum ether: ethyl acetate = 1:4) was purified to give the desired product ³⁵ - oxa-fluoro-4- -9-aza-1(5,3)-pyrazolo[1,5-a]pyrimidin-3(3,2)-pyridine-2(1,2)-pyrrolocyclodecane-8-one 43 (17 mg, yellow solid), yield: 41%.

MS m/z (ESI): 383 [M + 1];

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.22 - 8.15 (m, 1H), 7.85-7.79 (m, 1H), 7.68-7.64 (m, 1H), 7.20 (d, J = 7.4 Hz, 1H), 6.69-6.62 (m, 1H), 6.27-6.17 (m, 1H), 5.66-5.54 (m, 1H), 5.07-5.05 (m, 1H), 4.27-4.17 (m, 1H), 3.73-3.71 (m , 1H), 3.62-3.60 (m, 1H), 2.69-2.11 (m, 6H), 1.95-1.51 (m, 2H).

Example 44

3 ⁵ -Fluoro-3 ¹ ,3 ² -dihydro-8-aza-1(5,3)-pyrazolo[1,5-a]pyrimidin-3(3,1)-pyridine-2 (1 , 2)-pyrrolocyclooctane-32,7-dione

Example 44 was synthesized by following the procedure of Example 43 to give 4-((5-fluoro-3-(1-(3-nitropyrazolo[1,5-a]pyrimidin-5-yl)pyrrolidine- Ethyl 2-yl)pyridin-2-yl)oxobutanoate 43d was replaced by 4-(5-fluoro-3-(1-(3-nitropyrazolo[1,5-a]pyrimidine-5) -Pyryl pyrrolidin-2-yl)-2-carbonylpyridine-1(2H)-yl)butyrate 43d', the desired product 3 ⁵ -fluoro-3 ¹ ,3 ² -dihydro-8-nitro Hetero-1(5,3)-pyrazolo[1,5-a]pyrimidin-3(3,1)-pyridine-2(1,2)-pyrrolocyclooctane-3 ² ,7-dione 44.

MS m/z (ESI): 383 [M + 1];

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.08 (d, J = 7.6Hz, 1H), 7.59 (s, 1H), 7.19 (s, 1H), 7.14 (s, 1H), 6.99-6.97 (m, 1H), 6.09 (d, J = 7.6 Hz, 1H), 5.36-5.28 (m, 1H), 3.65 (m, 1H), 3.39-3.37 (m, 1H), 2.89-2.86 (m, 1H), 2.74 -2.43 (m, 3H), 2.24 - 2.22 (m, 1H), 2.16 - 2.14 (m, 1H), 2.03-1.76 (m, 4H).

Example 45

4 ⁵ -fluoro-2-methyl-5-oxa-2,10-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidin-4(3,2)-pyridine Cyclodecane-9-one

Synthesis Example 45 was carried out by following the procedure of Example 43 to give the desired product 4 ⁵ -fluoro-2-methyl-5-oxa-2,10-diaza-1(5,3)-pyrazolo[1] , 5-a]pyrimidin-4(3,2)-pyridocyclodecane-9-one 45.

MS m/z (ESI): 357 [M + 1];

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.94-8.77 (m, 1H), 8.65-8.61 (m, 1H), 8.09-8.00 (m, 1H), 7.76-7.62 (m, 2H), 6.64-6.62 (m, 1H), 5.37-5.34 (m, 1H), 4.80-4.77 (m, 1H), 4.17-4.12 (m, 1H), 3.97-3.94 (m, 1H), 3.55 (s, 3H), 2.40 -2.23 (m, 2H), 2.09-2.05 (m, 2H).

Example 46

(2 ² R,5S)-3 ⁵ -fluoro-5-methyl-4-oxa-9-aza-1(5,3)-pyrazolo[1,5-a]pyrimidine-3 (3 , 2)-pyridine-2(1,2)-pyrrolocyclodecane-8-one

Example 46 was synthesized by following the procedure of Example 43 to give the desired product (2 ² R,5S)-3 ⁵ -fluoro-5-methyl-4-oxa-9-aza-1(5,3)- Pyrazolo[1,5-a]pyrimidin-3(3,2)-pyridine-2(1,2)-pyrrolocyclodecane-8-one 46.

MS m/z (ESI): 397 [M + 1];

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.3 (s, 1H), 7.83-7.80 (m, 1H), 7.68-7.62 (m, 1H), 7.18-7.15 (m, 1H), 6.58 (s, 0.5 H), 6.43 (s, 0.5H), 6.26 (d, J = 7.6 Hz, 0.5H), 6.24 (d, J = 7.6 Hz, 0.5H), 5.48-5.42 (m, 2H), 3.87-3.82 ( m, 1H), 3.63 - 3.61 (m, 1H), 2.43 - 2.36 (m, 1H), 2.33-1.90 (m, 7H), 1.46 (d, J = 4.8 Hz, 3H).

Example 47

4 ⁵ -fluoro-2-methyl-5-oxa-2,9-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidin-4(1,2)-benzene Cyclodecane-8-one

first step

(5-fluoro-2-hydroxybenzyl)(methyl)carbamic acid tert-butyl ester

The compound 4-fluoro-2-((methylamino)methyl)phenol 11b (2.00 g, 0.16 mol) was dissolved in dichloromethane (60 mL), triethylamine (2.61 g, 25.80 mmol) and dicarbonic acid. Di-tert-butyl ester (3.37 g, 15.50 mmol) was stirred at room temperature for 4 hours. The reaction mixture was washed with EtOAc EtOAc (EtOAc) Yield: 95%.

MS m/z (ESI): 278 [M+23];

^{1 H NMR (400MHz, CDCl3)} δ9.14 (s, 1H), 6.96-6.85 (m, 2H), 6.81 (d, J = 8.0Hz, 1H), 4.27 (s, 2H), 2.89 (s, 3H ), 1.48 (s, 9H).

Second step

Ethyl 3-(2-(((tert-butoxycarbonyl))(methyl)amino)methyl)-4-fluorophenoxy)acrylate

The compound (5-fluoro-2-hydroxybenzyl)(methyl)carbamic acid tert-butyl ester 47a (0.56 g, 2.20 mmol) was dissolved in acetonitrile (10 mL) and diisopropylethylamine (0.42 g, 3.3 Methyl) and ethyl propargyl propionate 47b (0.32 g, 3.30 mmol) were stirred at room temperature for 0.5 h. The reaction mixture was washed with saturated aqueous sodium chloride (30 mL), EtOAc (EtOAc) Ethyl (meth)amino)methyl)-4-fluorophenoxy)acrylate 47c (0.73 g, yellow liquid), yield: 95%.

MS m/z (ESI): 376 [M+23].

third step

Ethyl 3-(2-((tert-butoxycarbonyl)(methyl)amino)methyl)-4-fluorophenoxy)propanoate

The compound 3-(2-(((tert-butoxycarbonyl)(methyl)amino)methyl)-4-fluorophenoxy)acrylate 47c (0.73 g, 2.00 mmol) was dissolved in methanol (10 mL) ), palladium on carbon (75 mg, 10%) was added, and the mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere. The reaction solution was filtered, washed with methanol (20 mL), and evaporated. Ethyl propionate 47d (0.68 g, yellow liquid), yield: 93%.

MS m/z (ESI): 378 [M+23].

the fourth step

(2-((tert-Butoxycarbonyl)(methyl)amino)methyl)-4-fluorophenoxy)propanoic acid

The compound 3-(2-((tert-butoxycarbonyl)(methyl)amino)methyl)-4-fluorophenoxy)propanoic acid ethyl ester 47d (0.68 g, 1.90 mmol) was dissolved in tetrahydrofuran (6 mL) Lithium hydroxide (0.19 g, 9.50 mmol) was added to water (6 mL), and stirred at room temperature for 1 hour. The reaction solution was de-dissolved under reduced pressure, washed with dichloromethane (20 mL), water (10 mL), and the aqueous phase was adjusted to pH 3, and the aqueous phase was extracted with dichloromethane. ((tert-Butoxycarbonyl)(methyl)amino)methyl)-4-fluorophenoxy)propanoic acid 47e (0.30 g, yellow liquid), crude.

MS m/z (ESI): 328 [M + 1].

the fifth step

3-(4-fluoro-2-((methylamino)methyl)phenoxy)propionic acid trifluoroacetate

The compound (2-((tert-butoxycarbonyl)(methyl)amino)methyl).4-fluorophenoxy)propanoic acid 47e (0.30 g, 0.90 mmol) was dissolved in dichloromethane (5 mL) Stir in acetic acid (1 mL) at room temperature for half an hour. The reaction solution was dissolved under reduced pressure to give the title compound (yield: 3-(4-fluoro-2-((methylamino)methyl)phenoxy)propanoic acid trifluoroacetate 47f (0.21 g, yellow liquid).

MS m/z (ESI): 228 [M + 1].

Step 6

3-(4-Fluoro-2-((methyl(3-nitropyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)phenoxy)propanoic acid

The compound 3-(4-fluoro-2-((methylamino)methyl)phenoxy)propanoic acid trifluoroacetate 47f (0.21 g, 0.92 mmol), 5-chloro-3-nitropyrazole [1,5-a]pyrimidine 9d (0.20 g, 1.01 mmol) and diisopropylethylamine (1 mL) were dissolved in n-butanol (5 mL) and stirred for one hour in a 60 ° C oil bath. The reaction solution was desolvated under reduced pressure to give the desired product 3-(4-fluoro-2-((methyl(3-nitropyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)benzene 47 g (oxygen) propionic acid (0.35 g, brownish black solid), crude.

MS m/z (ESI): 390 [M + 1].

Seventh step

(2-((3-Aminopyrazolo[1,5-a]pyrimidin-5-yl)(methyl)amino)methyl)-4-fluorophenoxy)propanoic acid

The compound 3-(4-fluoro-2-((methyl(3-nitropyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)phenoxy)propanoic acid 47g (0.35 g, 0.92 mmol) was dissolved in dichloromethane (10 mL) and methanol (10 mL), and then a saturated aqueous solution of ammonium chloride (10 mL), followed by the addition of zinc powder (0.60 g, 9.21 mmol), and stirred at room temperature for one hour. The reaction solution was filtered, the layers were separated, and the organic phase was evaporated to give the desired product (2-((3-aminopyrazolo[1,5-a]pyrimidin-5-yl) (methyl)amino)methyl -4-fluorophenoxy)propanoic acid 47h (73 mg, yellow solid), crude.

MS m/z (ESI): 360 [M + 1].

Eighth step

4 ⁵ -fluoro-2-methyl-5-oxa-2,9-diaza-1-(5,3)-pyrazolo[1,5-α]pyrimidine-4-(1,2) -benzocyclodecane-8-one

Compound (2-((3-aminopyrazolo[1,5-a]pyrimidin-5-yl)(methyl)amino)methyl)-4-fluorophenoxy)propanoic acid 47h (73mg, 0.20 mmol) was dissolved in N,N-dimethylformamide (3 mL), triethylamine (41 mg, 0.40 mmol) and 2-(7-benzobenzotriazole)-N,N,N'- N'-tetramethyluronium hexafluorophosphate (0.12 g, 0.30 mmol) was stirred at room temperature for 2 hr. The target product is 4 ⁵ -fluoro-2-methyl-5-oxa-2,9-diaza-1-(5,3)-pyrazolo[1,5-α]pyrimidine-4-(1, 2)-benzocyclodecane-8-one 47 (1.2 mg, yellow solid), yield: 2%.

MS m/z (ESI): 342 [M + 1];

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.22-8.18 (m, 1H), 8.17 (d, J = 8.0 Hz, 1H), 6.96-6.90 m, 1H), 6.81-6.73 (m, 2H), 6.28 (d, J=8.0 Hz, 1H), 4.47-4.45 (m, 1H), 3.98-3.96 (m, 1H), 3.49-3.48 (m, 2H), 3.08 (s, 3H), 2.70-2.68 (m , 2H).

Example 48

4 ⁵ -fluoro-2-methyl-2,9-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidin-4(1,2)-benzocyclodecane- 8-ketone

first step

2-(2-bromo-5-fluorophenyl)-1,3-dioxolane

The compound 2-bromo-5-fluorobenzaldehyde 48a (2.07 g, 10.20 mmol), ethylene glycol (0.95 g, 15.30 mmol) and p-toluenesulfonic acid (35 mg, 0.20 mmol) were dissolved in toluene (100 mL) and heated. After refluxing for 16 h, the residue was dissolved in ethyl acetate (200 mL). The organic phase was washed with saturated sodium carbonate (100 mL×2) and brine (100 mL×2), dried, filtered, The title product 2-(2-bromo-5-fluorophenyl)-1,3-dioxolane 48b (2.50 g,yield of yellow oil) was obtained.

^{_{1 H NMR (400MHz, CDCl 3}} ) δ7.51 (dd, J = 8.8 & 5.6Hz, 1H), 7.32 (dd, J = 8.8 & 2.8Hz, 1H), 7.00-6.91 (m, 1H), 6.03 ( s, 1H), 4.19-4.09 (m, 2H), 4.08-4.01 (m, 2H).

Second step

4-(2-(1,3-dioxalan-2-yl)-4-fluorophenyl)but-3-yn-1-ol

The compound 2-(2-bromo-5-fluorophenyl)-1,3-dioxolane 48b (2.50 g, 10.00 mmol), 3-butyn-1-ol (0.84 g, 12.00 mmol) was dissolved. In anhydrous triethylamine (50 mL), ditriphenylphosphine palladium dichloride (70 mg, 0.10 mmol), cuprous iodide (38 mg, 0.20 mmol) was added under nitrogen, and the reaction flask was sealed under nitrogen and heated. The reaction was continued at 85 ° C for 16 hours, desolvent under reduced pressure, and separated by column chromatography (petroleum ether: ethyl acetate = 20:1 to 3:1) to give the desired product 4-(2-(1,3-dioxapentane). 2-yl)-4-fluorophenyl)but-3-yn-1-ol 48c (2.10 g, colorless oil), yield: 89%.

^{_{1 H NMR (400MHz, CDCl 3}} ) δ7.42-7.33 (m, 1H), 7.23 (s, 1H), 7.01-6.94 (m, 1H), 6.15 (s, 1H), 4.14-4.01 (m, 4H ), 3.83 - 3.74 (m, 2H), 2.75 (brs, 1H), 2.66 (t, J = 6.0 Hz, 2H).

third step

4-(2-(1,3-dioxalan-2-yl)-4-fluorophenyl)butan-1-ol

The compound 4-(2-(1,3-dioxalan-2-yl)-4-fluorophenyl)but-3-yn-1-ol 48c (2.00 g, 9.00 mmol) was dissolved in 100 mL of methanol. Palladium hydroxide (0.40 g, 10%) was added, and the mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere. Filtration and dehydration of the filtrate under reduced pressure gave 4-(2-(1,3-dioxapentan-2-yl)-4-fluorophenyl)butan-1-ol as the title product 48d (2.00 g, yellow oil ), yield: 98%.

MS m/z (ESI): 241 [M + 1].

the fourth step

4-(4-fluoro-2-formylphenyl)butyric acid

The compound 4-(2-(1,3-dioxalan-2-yl)-4-fluorophenyl)butan-1-ol 48d (1.50 g, 6.00 mmol) was dissolved in 30 mL of acetone, ice bath Jones reagent (12 mL, 2N) was added and stirred at room temperature for 2 hours. The reaction was quenched with EtOAc (EtOAc)EtOAc. Desolvation under reduced pressure gave the title product 4-(4-fluoro-2-formylphenyl)butanoic acid 48e (1.20 g, m.

MS m/z (ESI): 211 [M + 1].

the fifth step

4-(4-fluoro-2-((methylamino)methyl)phenyl)butyric acid

The compound 4-(2-(1,3-dioxolane-2-yl)-4-fluorophenyl)butan-1-ol 48e (1.20 g, 6.0 mmol) was dissolved in 30 mL of methylamine in ethanol ( In 33%), the mixture was stirred at room temperature for 2 hours. Sodium borohydride (1.80 g, 30.00 mmol) was added and stirring was continued for 30 min. The reaction was quenched with EtOAc (EtOAc)EtOAc. Desolvation under reduced pressure gave 4-(4-fluoro-2-((methylamino)methyl)phenyl)butanoic acid 48f (1.20 g, m.

MS m/z (ESI): 226 [M + 1].

Step 6

4-(4-Fluoro-2-((methyl(3-nitropyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)phenyl)butanoic acid

The compound 4-(4-fluoro-2-((methylamino)methyl)phenyl)butanoic acid 48f (0.17 g, 0.75 mmol), 5-chloro-3-nitropyrazolo[1,5- a] Pyrimidine 9d (0.15 g, 0.75 mmol) was dissolved in 10 mL of n-butanol solution, and N,N-diisopropylethylamine (1 mL) was added at room temperature, and stirred at 60 ° C for 2 hours. It was extracted with 1N diluted hydrochloric acid and ethyl acetate (50 mL×3). Desolvation under reduced pressure gave the desired product 4-(4-fluoro-2-((methyl(3-nitropyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)phenyl) Butyric acid 48h (0.25g, yellow solid), crude.

MS m/z (ESI): 388 [M + 1].

Seventh step

4-(2-((3-amino-3,3a-dihydropyrazolo[1,5-a]pyrimidin-5-yl)(methyl)amino)methyl)-4-fluorophenyl) Butyric acid

The compound 4-(4-fluoro-2-((methyl(3-nitropyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)phenyl)butanoic acid 48h (0.25g A solution of methanol (10 mL) and methylene chloride (10 mL) was added, and then a mixture of zinc powder (0.42 g, 6.60 mmol) and saturated aqueous ammonium chloride (20 mL) was stirred at room temperature for 2 hours. Extracted with dichloromethane (20 mL x 3). Desolvation under reduced pressure gave the desired product 4-(2-((3-amino-3,3a-dihydropyrazolo[1,5-a]pyrimidin-5-yl)(methyl)amino)methyl )-4-fluorophenyl)butyric acid 48 g (0.11 g, yellow solid), crude.

MS m/z (ESI): 358 [M + 1].

Eighth step

The compound 4-(2-(((3-amino-3,3a-dihydropyrazolo[1,5-a]pyrimidin-5-yl)(methyl)amino)methyl)-4-fluorobenzene) 48 g (0.11 g, 0.30 mmol) of butyric acid was dissolved in N,N-dimethylformamide (10 mL), and triethylamine (60 mg, 0.60 mmol) and 2-(7-benzobenzotriazine) were added at room temperature. Oxyl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.17 g, 0.45 mmol) was stirred at room temperature overnight. 20 mL of ethyl acetate was added and washed with water (20 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated and evaporated to silica gel column (dichloromethane:methanol = 15:1 to 10:1) to give the desired product 4 ⁵ -fluoro-2-methyl-2 ,9-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidin-4(1,2)-benzocyclodecane-8-one 48 (4 mg, white solid) Yield: 5%.

MS m/z (ESI): 340 [M + 1];

¹ H NMR (400 MHz, CD ₃ OD) δ 8.42 - 8.33 (m, 1H), 7.79 - 7.73 (m, 1H), 7.21-7.10 (m, 2H), 6.96-6.91 (m, 1H), 6.61 6.60 (m, 1H), 5.34-5.31 (m, 1H), 4.06-3.94 (m, 1H), 3.30 (s, 3H), 2.75-2.72 (m, 1H), 2.55-2.51 (m, 1H), 2.38-2.36 (m, 1H), 2.16-2.10 (m, 2H), 1.60-1.58 (m, 1H).

Example 49

(3R,6S)-4 ⁵ -fluoro-3,6-dimethyl-5-oxa-2,8,10-triaza-1(6,3)-imidazo[1,2-b] Pyrazine-4(1,2)-benzocyclodecane-9-one

first step

6-chloro-3-nitroimidazo[1,2-b]pyridazine

The compound 6-chloroimidazo[1,2-b]pyridazine 49a (2.50 g, 16.30 mmol) was dissolved in concentrated sulfuric acid (25 mL), and concentrated nitric acid (5 mL) was slowly added dropwise in an ice bath, and stirred at room temperature. three hours. The reaction solution was slowly added to ice water to precipitate a gray solid, and the pH of the system was adjusted to neutral with sodium hydroxide. The precipitated solid was filtered to give 6-chloro-3-nitroimidazo[1,2-b]pyridazine 49b (2.50 g, 12.60 mmol, pale yellow powder). Yield: 77%.

MS m/z (ESI): 199 & 201 [M+1];

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.63 (s, 1H), 8.12 (d, J = 9.2 Hz, 1H), 7.46 (d, J = 9.2 Hz, 1H).

Second step

(R)-4-fluoro-2-(1-((3-nitroimidazo[1,2-b]pyridazin-6-yl)amino)ethyl)phenol

The compound 6-chloro-3-nitroimidazo[1,2-b]pyridazine 49b (0.30 g, 1.50 mmol), (R)-2-(1-aminoethyl)-4-fluorophenol 1 g' (from neutralization of intermediate 1g, 0.30 g, 1.50 mmol), 1,8-diazabicycloundec-7-ene (1 mL) was dissolved in N,N-dimethylformamide (4 mL) The reaction was carried out at 100 ° C for one hour. After cooling to room temperature, it was diluted with ethyl acetate (20 mL), washed with water (50 mL×3), and the organic phase was dried over anhydrous sodium sulfate. Methyl chloride:methanol = 50:1) gave the desired product (R)-4-fluoro-2-(1-((3-nitroimidazo[1,2-b]pyridazin-6-yl)amino) Phenol 49c (0.25 g, yellow solid), yield: 53%.

MS m/z (ESI): 318 [M + 1];

^{1 H NMR (400MHz, DMSO-} d 6) δ8.70 (s, 1H), 8.46 (s, 0.4H), 8.43 (s, 0.6H), 8.39-8.37 (m, 0.5H), 8.31 (s, 0.6H), 8.28 (s, 0.4H), 7.97-7.95 (m, 0.5H), 7.86-7.84 (m, 0.5H), 7.11-7.09 (m, 1H), 6.91-6.64 (m, 0.5H) , 5.33-5.24 (m, 0.5H), 4.10-4.15 (m, 0.5H), 1.47 (d, J = 6.4 Hz, 1.5H), 1.29 (d, J = 6.4 Hz, 1.5H).

third step

((S)-2-(4-fluoro-2-((R)-1-((3-nitroimidazo[1,2-b]pyrazine-6-yl)amino)ethyl)phenoxy) Propyl)-tert-butyl carbamate compound (R)-4-fluoro-2-(1-((3-nitroimidazo[1,2-b]pyridazin-6-yl)amino)ethyl) Phenol 49c (0.25 g, 0.79 mmol), (R)-1-((tert-butoxycarbonyl)amino)propan-2-yl-4-methylbenzenesulfonate 1c (0.52 g, 1.58 mmol) Cesium carbonate (0.77 g, 2.4 mmol) was added to acetonitrile (5 mL) and stirred at 50 ° C for 48 hours. Diluted with 200 mL of ethyl acetate, washed with water (50 mL×3), dried over anhydrous sodium sulfate, filtered and evaporated. 10:1 to 1:10) to the target product ((S)-2-(4-fluoro-2-((R)-1-((3-nitroimidazo[1,2-b]pyrazine-6) tert-Butylamino)ethyl)phenoxy)propyl)carbamate 49d (90 mg, 0.19 mmol, yellow solid).

MS m/z (ESI): 475 [M + 1];

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.30 (s, 1H), 7.71 (d, J = 9.6Hz, 1H), 7.08 (d, J = 8.8Hz, 1H), 6.86-6.84 (m, 3H) , 5.90 (s, 1H), 5.39-5.31 (m, 2H), 4.60-4.58 (m, 1H), 3.52-3.47 (m, 1H), 3.43-3.32 (m, 1H), 1.56 (d, J = 6.4 Hz, 3H), 1.36 (s, 9H), 1.30 (d, J = 4.8 Hz, 3H).

the fourth step

((S)-2-(2-((R)-1-((3-aminoimidazo[1,2-b]pyrazin-6-yl)amino)ethyl)-4-fluorophenoxy) Propyl) tert-butyl carbamate compound ((S)-2-(4-fluoro-2-((R)-1-((3-nitroimidazo[1,2-b]pyrazine-6-) Tert-butyl)amino)ethyl)phenoxy)propyl)carbamic acid tert-butyl ester 49d (90 mg, 0.19 mmol) was dissolved in EtOAc m. Zinc powder (0.13 g, 1.90 mmol) was added at room temperature. After stirring at room temperature for 30 minutes, the reaction solution was diluted with 100 mL of dichloromethane and washed with water (50mL). The organic phase was dried over anhydrous sodium sulfate, and the residue was filtered, and then evaporated R)-1-((3-aminoimidazo[1,2-b]pyrazine-6-yl)amino)ethyl)-4-fluorophenoxy)propyl)carbamic acid tert-butyl ester 49e (30 mg, Reddish brown solid), yield: 35%.

MS m/z (ESI): 445 [M + 1].

the fifth step

N ⁶ -((R)-1-(2-((())-1-aminopropan-2-yl)oxy)-5-fluorophenyl)ethyl)imidazo[1,2-b] Pyridazine-3,6-diamine

Compound (((S)-2-(2-((R)-1-((3-aminoimidazo[1,2-b]pyrazin-6-yl)amino)ethyl)-4-fluorobenzene) tert-Butyl oxy) propyl)carbamate 49e (30 mg, 0.07 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (0.5 mL) was added at room temperature and stirred at room temperature for 30 min. The methane was diluted, the system was made alkaline with triethylamine, and concentrated to give the crude product N ⁶ -((R)-1-(2-((())))) 5-fluorophenyl)ethyl)imidazo[1,2-b]pyridazine-3,6-diamine 49f (24 mg, reddish brown oil), yield: 99%.

MS m/z (ESI): 344 [M + 1].

Step 6

(3R,6S)-4 ⁵ -fluoro-3,6-dimethyl-5-oxa-2,8,10-triaza-1(6,3)-imidazo[1,2-b] Pyrimidine-4(1,2)-benzocyclodecane-9-one

The compound N ⁶ -((R)-1-(2-((S)-1-aminopropan-2-yl)oxy)-5-fluorophenyl)ethyl)imidazo[1,2- b]pyridazine-3,6-diamine 49f (24 mg, 0.07 mmol) was dissolved in N,N-dimethylformamide (2 mL). N, N'-carbonyldiimidazole (22 mg, 0.14 mmol) Stir for 12 hours. The reaction solution was diluted with 20 mL of dichloromethane, and washed with water (50 mL×3). The organic phase was dried over anhydrous sodium sulfate. 1) The target product (3R,6S)-4 ⁵ -fluoro-3,6-dimethyl-5-oxa-2,8,10-triaza-1(6,3)-imidazo[1] is obtained. , 2-b]pyrimidin-4(1,2)-benzocyclodecane-9-one 49 (1 mg, white solid), yield: 3.8%.

MS m/z (ESI): 371 [M + 1];

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.08 (brs, 1H), 7.64 (d, J = 9.8Hz, 1H), 7.03-7.00 (m, 2H), 6.89-6.87 (m, 2H), 6.47 ( d, J=9.8 Hz, 1H), 4.87-4.85 (m, 1H), 4.73-4.70 (m, 1H), 3.66-3.64 (m, 1H), 3.20-3.11 (m, 1H), 1.45-1.43 ( m, 6H).

Example 50

(3S,6S)-4 ⁵ -fluoro-3,6-dimethyl-5-oxa-2,8,10-triaza-1(6,3)-imidazo[1,2-b] Pyrazine-4(1,2)-benzocyclodecane-9-one

The title compound (3S,6S)-4 ⁵ -fluoro-3,6-dimethyl-5-oxa-2,8,10-triaza-1 was synthesized according to the procedure of Example 49. (6,3)-Imidazo[1,2-b]pyrazine-4(1,2)-benzocyclodecane-9-one 50.

MS m/z (ESI): 371 [M + 1];

¹ H NMR (400 MHz, CD ₃ OD) δ 7.63 (s, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.04 (d, J = 8.0 Hz, 1H), 6.87-6.81 (m, 3H) ), 5.68-5.66 (m, 1H), 4.60-4.58 (m, 1H), 3.96-3.90 (m, 1H), 3.10-3.06 (m, 1H), 1.34 (d, J = 6.0 Hz, 3H), 1.20 (d, J = 6.0 Hz, 3H).

Example 51

4 ⁵ -fluoro-2-methyl-5-oxa-2,8,10-triaza-1(6,3)-imidazo[1,2-b]pyrazine-4(1,2) -benzocyclodecane-9-one

Example 51 was synthesized by following the procedure of Example 49 to give the title compound 4 ⁵ -fluoro-2-methyl-5-oxa-2,8,10-triaza-1(6,3)-imidazo[ 1,2-b]pyrazine-4(1,2)-benzocyclodecane-9-one 51.

MS m/z (ESI): 357 [M + 1];

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.31-8.12 (m, 1H), 7.64 (d, J = 9.4Hz, 1H), 7.11 (d, J = 8.0Hz, 1H), 7.06-6.87 (m, 3H), 4.24 (s, 2H), 4.06-4.02 (m, 1H), 3.66-3.64 (m, 2H), 3.48-3.46 (m, 1H), 3.31 (s, 3H).

Example 52

(S)-4 ⁵ -fluoro-2,6-dimethyl-5-oxa-2,8,10-triaza-1(6,3)-imidazo[1,2-b]pyrazine -4(1,2)-benzocyclodecane-9-one

The title compound (S)-4 ⁵ -fluoro-2,6-dimethyl-5-oxa-2,8,10-triaza-1 (6) was obtained by the procedure of Example 49. , 3)-Imidazo[1,2-b]pyrazine-4(1,2)-benzocyclodecane-9-one 52.

MS m/z (ESI): 371 [M + 1];

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.13 (s, 1H), 7.69 (d, J = 10.0 Hz, 1H), 7.03 (d, J = 10.0 Hz, 1H), 7.00-6.95 (m, 3H) , 5.35-5.31 (m, 1H), 4.65-4.64 (m, 1H), 3.75 (s, 3H), 3.71-3.3.70 (m, 1H), 3.68-3.65 (m, 1H), 3.22-3.18 ( m, 1H), 1.34 (d, J = 6.0 Hz, 3H).

Example 53

(2 ² R,5S)-3 ⁵ -fluoro-5-methyl-4-oxa-7,9-diaza-1(6,3)-imidazo[1,2-b]pyrazine- 2(1,2)-pyrrole-3(1,2)-benzocyclodecane-8-one

The title compound (2 ² R,5S)-3 ⁵ -fluoro-5-methyl-4-oxa-7,9-diaza-1 (6, was synthesized according to the procedure of Example 49. 3)-Imidazo[1,2-b]pyrazine-2-(1,2)-pyrrole-3-(1,2)-benzocyclodecane-8-one 53.

MS m/z (ESI): 397 [M + 1];

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.06 (s, 1H), 7.76 (d, J = 9.0Hz, 1H), 7.25 (d, J = 9.0Hz, 1H), 6.88-6.76 (m, 3H) , 5.36-5.34 (m, 1H), 4.76-4.75 (m, 1H), 3.92-3.90 (m, 1H), 3.51-3.49 (m, 1H), 3.14 - 3.12 (m, 1H), 2.45-2.43 ( m, 1H), 2.23-2.20 (m, 2H), 1.78-1.68 (m, 2H), 1.34 (d, J = 6.0 Hz, 3H).

Example 54

(2 ² R,2 ⁴ S,5S)-2 ⁴ ,3 ⁵ -difluoro-5-methyl-4-oxa-7,9-diaza-1(6,3)-imidazo[1 ,2-b]pyrazine-2(1,2)-pyrrole-3(1,2)-benzocyclodecane-8-one

The title compound (2 ² R, 2 ⁴ S, 5S) - 2 ⁴ , 3 ⁵ -difluoro-5-methyl-4-oxa-7,9- was obtained by the procedure of Example 49. Diaza-1(6,3)-imidazo[1,2-b]pyrazine-2(1,2)-pyrrole-3(1,2)-benzocyclodecane-8-one 54.

MS m/z (ESI): 415 [M + 1];

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.16 (s, 1H), 7.77 (d, J = 9.6Hz, 1H), 6.88-6.76 (m, 3H), 6.66 (d, J = 9.6Hz, 1H) , 5.47-5.43 (m, 1H), 5.40-5.31 (m, 0.5H), 4.90-4.86 (m, 0.5H), 4.23-4.20 (m, 1H), 4.15-4.10 (m, 1H), 3.99- 3.93 (m, 1H), 3.58-3.55 (m, 1H), 3.25-3.16 (m, 1H), 2.45-2.43 (m, 1H), 2.23-2.20 (m, 1H), 1.43 (d, J = 6.0) Hz, 3H).

Example 55

(2 ² R,2 ⁴ S,5S)-2 ⁴ ,3 ⁵ -difluoro-5,7-dimethyl-4-oxa-7,9-diaza-1(5,3)-pyridyl Zizo[1,5-a]pyrimidin-2(1,2)-pyrrole-3(1,2)-benzocyclodecane-8-one

Example 55 was synthesized by following the procedure of Example 28 to give the desired product (2 ² R, 2 ⁴ S, 5S) - 2 ⁴ , 3 ⁵ -difluoro-5,7-dimethyl-4-oxa-7 ,9-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidin-2(1,2)-pyrrole-3(1,2)-benzocyclodecane-8- Ketone 55.

MS m/z (ESI): 429 [M + 1];

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.24 (d, J = 7.6Hz, 1H), 7.97-7.95 (m, 1H), 7.23 (s, 1H), 6.87-6.84 (m, 2H), 6.83- 6.74 (m, 1H), 6.23 (d, J = 7.6 Hz, 1H), 5.68-5.64 (m, 1H), 5.52-5.50 (m, 0.5H), 5.39-5.37 (m, 0.5H), 4.73 4.68 (m, 1H), 4.07-3.96 (m, 2H), 3.73-3.69 (m, 1H), 3.19 (s, 3H), 2.90-2.87 (m, 2H), 2.08-1.98 (m, 1H), 1.44 (d, J = 6.4 Hz, 3H).

Example 56

(2 ² R,2 ⁴ S)-2 ⁴ ,3 ⁵ -difluoro-7-methyl-4-oxa-7,9-diaza-1(5,3)-pyrazolo[1, 5-a]pyrimidine-2(1,2)-pyrrole-3(1,2)-benzocyclodecane-8-one

Example 56 was synthesized by following the procedure of Example 28 to give the desired product (2 ² R, 2 ⁴ S) - 2 ⁴ , 3 ⁵ -difluoro-7-methyl-4-oxa-7,9-diaza Hetero-1(5,3)-pyrazolo[1,5-a]pyrimidin-2(1,2)-pyrrole-3(1,2)-benzocyclodecane-8-one 56.

MS m/z (ESI): 415 [M + 1];

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.19-8.17 (m, 1H), 7.84 (s, 1H), 6.82-6.79 (m, 3H), 6.27-6.25 (m, 1H), 6.13-6.11 (m , 1H), 5.88-5.84 (m, 1H), 5.50-5.52 (m, 0.5H), 5.39-5.37 (m, 0.5H), 4.53-4.49 (m, 1H), 4.45-4.41 (m, 1H) , 4.12-4.09 (m, 1H), 4.02-3.88 (m, 2H), 3.71-3.67 (m, 1H), 3.10 (s, 3H), 2.80-2.73 (m, 1H), 2.13-2.04 (m, 1H).

Example 57

(S)-4 ⁵ -fluoro-2-(2-fluoroethyl)-6-methyl-5-oxa-2,8,10-triaza-1(5,3)-pyrazolo[ 1,5-a]pyrimidin-4(3,2)-pyridocyclodecane-9-one

first step

2-fluoro-N-((5-fluoro-2-methoxypyridin-3-yl)methyl)ethane-1-amine hydrochloride

The compound 2-fluoroethylamine hydrochloride (0.14 g, 1.42 mmol) and triethylamine (0.3 mL) were dissolved in methanol (5 mL), stirred at room temperature for 5 min, and the compound 5-fluoro-2-methoxy- 3-pyridinecarboxaldehyde 57a (0.20 g, 1.29 mmol). The mixture was stirred at room temperature for 2 hr. EtOAc (EtOAc) (EtOAc,EtOAc. Washed with water (50 mL) and brine (50 mL), EtOAc (EtOAc m. Methoxypyridin-3-yl)methyl)ethane-1-amine hydrochloride 57b (0.22 g, white solid).

MS m/z (ESI): 203 [M-HCl +1];

^{1 H NMR (400MHz, DMSO-} d 6) δ9.97 (s, 2H), 8.21 (d, J = 3.2Hz, 1H), 8.08-8.05 (m, 1H), 4.88-4.86 (m, 1H), 4.76-4.74 (m, 1H), 4.16-4.13 (m, 2H), 3.88 (s, 3H), 3.36-3.34 (m, 1H), 3.29-3.27 (m, 1H).

Second step

N-((5-fluoro-2-methoxypyridin-3-yl)methyl)-N-(2-fluoroethyl)-3-nitropyrazolo[1,5-a]pyrimidine-5 -amine

The compound 2-fluoro-N-((5-fluoro-2-methoxypyridin-3-yl)methyl)ethane-1-amine hydrochloride 57b (0.20 g, 0.91 mmol), 5-chloro- 3-Nitropyrazolo[1,5-a]pyrimidine 9d (0.20 g, 1.01 mmol) and N,N-diisopropylethylamine (3 mL) were dissolved in n-butanol (15 mL) and stirred at 67 ° C 4 hours. The mixture was cooled to room temperature, suction filtered, and the filter cake was washed with n-butanol (10mL), and the solid was dried under reduced pressure to give the desired product N-((5-fluoro-2-methoxypyridin-3-yl)methyl)-N -(2-Fluoroethyl)-3-nitropyrazolo[1,5-a]pyrimidine-5-amine 57c (0.27 g, yellow solid), yield: 82%.

MS m/z (ESI): 365 [M + 1];

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.51 (s, 1H), 8.33 - 8.31 (m, 1.5H), 7.96-7.94 (m, 1H), 7.08-7.07 (m, 0.5H), 6.63-6.61 (m, 0.5H), 6.34-6.32 (m, 0.5H), 5.02-4.64 (m, 4H), 4.18-4.15 (m, 2H), 3.99 (s, 3H).

third step

5-fluoro-3-(((2-fluoroethyl)(3-nitropyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)pyridin-2-ol

The compound N-((5-fluoro-2-methoxypyridin-3-yl)methyl)-N-(2-fluoroethyl)-3-nitropyrazolo[1,5-a]pyrimidine 5-5-amine 57c (0.27 g, 0.74 mmol), trimethylchlorosilane (0.81 g, 7.49 mmol) and potassium iodide (1.25 g, 7.49 mmol) were added to acetonitrile, reacted at 50 ° C for 2 hours, and added water (150 mL) Dichloromethane (120 mL) was extracted, and the organic phase was dried over anhydrous sodium sulfate, filtered and evaporated to remove the solvent and evaporated to give the desired product 5-fluoro-3-(((2-fluoroethyl)) Pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)pyridin-2-ol 57d (0.25 g, yellow solid), crude.

MS m/z (ESI): 351 [M + 1];

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.82 (d, J = 7.6 Hz, 0.6H), 8.79 (d, J = 7.6 Hz, 0.4H), 8.66 (s, 0.4H), 8.64 (s) , 0.6H), 8.00-7.98 (m, 0.6H), 7.54-7.51 (m, 1H), 7.40-7.38 (m, 0.4H), 6.99 (d, J = 7.6 Hz, 0.6H), 6.76 (d , J = 7.6 Hz, 0.4H), 4.85-4.67 (m, 4H), 4.25-4.13 (m, 2H).

the fourth step

(S)-(2-((5-fluoro-3-((2-fluoroethyl)(3-nitropyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl) Pyridin-2-yl)oxo)propyl)carbamic acid tert-butyl ester

Referring to the third step of Example 49, 5-fluoro-3-(((2-fluoroethyl)(3-nitropyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl) Pyridin-2-phenol instead of (R)-4-fluoro-2-(1-((3-nitroimidazo[1,2-b]pyridazin-6-yl)amino)ethyl)phenol Product (S)-(2-((5-fluoro-3-(((2-fluoroethyl)(3-nitropyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl) Pyridin-2-yl)oxo)propyl)carbamic acid tert-butyl ester 57e.

MS m/z (ESI): 508 [M + 1];

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.50 (s, 1H), 8.31-8.29 (m, 1.5H), 7.91-7.89 (m, 1H), 7.12-7.10 (m, 0.5H), 6.61-6.59 (m, 0.5H), 6.57-6.54 (m, 0.5H), 5.35-5.32 (m, 1H), 5.01-4.65 (m, 5H), 4.32-4.04 (m, 2H), 3.47-3.24 (m, 2H), 1.45 (s, 9H), 1.23 (d, J = 6.0 Hz, 3H).

the fifth step

(S)-(2-((3-((3-aminopyrazolo[1,5-a]pyrimidin-5-yl)(2-fluoroethyl)amino)methyl)-5-fluoropyridine -2-yl)oxo)propyl)carbamic acid tert-butyl ester

Referring to the fourth step of Example 49, (S)-(2-((5-fluoro-3-(((2-fluoroethyl)(3-nitropyrazolo[1,5-a]pyrimidine) -5-yl)amino)methyl)pyridin-2-yl)oxo)propyl)carbamic acid tert-butyl ester instead ((S)-2-(4-fluoro-2-((R)-1-) (3-Nitroimidazo[1,2-b]pyrazine-6-yl)amino)ethyl)phenoxy)propyl)carbamic acid tert-butyl ester to give the target product (S)-(2-((3) -(((3-Aminopyrazolo[1,5-a]pyrimidin-5-yl)(2-fluoroethyl)amino)methyl)-5-fluoropyridin-2-yl)oxo)propyl ) tert-butyl carbamate 57f.

MS m/z (ESI): 478 [M + 1];

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.14 (d, J = 7.6Hz, 1H), 7.87 (d, J = 2.8Hz, 1H), 7.67 (s, 1H), 7.19-7.17 (m, 1H) , 6.10 (d, J = 7.6 Hz, 1H), 4.93-4.91 (m, 1H), 4.82-4.80 (m, 1H), 4.73 (brs, 2H), 4.72-4.70 (m, 2H), 4.06-4.04 (m, 1H), 3.98-3.96 (m, 1H), 3.92-3.88 (m, 1H), 3.53-3.44 (m, 1H), 3.36-3.29 (m, 2H), 3.04-2.98 (m, 1H) , 1.38 (s, 9H), 1.34 (d, J = 6.0 Hz, 3H).

Step 6

(S)-N ⁵ -((2-((1-aminopropan-2-yl)oxy)-5-fluoropyridin-3-yl)methyl)-N ⁵ -(2-fluoroethyl)pyridyl Oxazo[1,5-a]pyrimidine-3,5-diamine

Referring to the fifth step of Example 49, (S)-(2-((3-((3-aminopyrazolo[1,5-a]pyrimidin-5-yl))) Instead of ((S)-2-(4-fluoro-2-((R)-1-)(), amino)methyl)-5-fluoropyridin-2-yl)oxy)propyl)carbamic acid tert-butyl ester 3-aminoimidazo[1,2-b]pyrazine-6-yl)amino)ethyl)phenoxy)propyl)carbamic acid tert-butyl ester to give the desired product (S)-N ⁵ -((2- (1-Aminopropan-2-yl)oxo)-5-fluoropyridin-3-yl)methyl)-N ⁵ -(2-fluoroethyl)pyrazolo[1,5-a]pyrimidine-3 , 5-diamine 57g.

MS m/z (ESI): 378 [M + 1].

Seventh step

Referring to the sixth step of Example 49, using (S)-N ⁵ -((2-((1-aminopropan-2-yl)oxy)-5-fluoropyridin-3-yl)methyl)-N ^5- (2-Fluoroethyl)pyrazolo[1,5-a]pyrimidine-3,5-diamine in place of N ⁶ -((R)-1-(2-((()))) Propane-2-yl)oxo-5-fluorophenyl)ethyl)imidazo[1,2-b]pyridazine-3,6-diamine gives the target product (S)-4 ⁵ -fluoro-2 -(2-fluoroethyl)-6-methyl-5-oxa-2,8,10-triaza-1(5,3)-pyrazolo[1,5-a]pyrimidine-4 ( 3,2)-Pyridocyclodecane-9-one 57.

MS m/z (ESI): 404 [M + 1];

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.23 (d, J = 8.0Hz, 1H), 7.91-7.90 (m, 1H), 7.62 (s, 1H), 7.53 (s, 1H), 7.27 (s, 1H), 6.33 (d, J = 8.0 Hz, 1H), 6.24 (s, 1H), 5.53-5.49 (m, 1H), 5.35-5.32 (m, 1H), 4.79-4.78 (m, 1H), 4.67 .4.65 (m, 1H), 4.05-3.95 (m, 2H) 3.76-3.73 (m, 2H), 3.12-3.10 (m, 1H), 1.34 (d, J = 6.0 Hz, 3H).

Example 58

(2 ² R,5S)-3 ⁵ -fluoro-5-methyl-4-oxa-9-aza-1(5,3)-pyrazolo[1,5-a]pyrimidine-2 (1 , 2)-pyrrole-3(1,2)-benzocyclodecane-8-one

Example 58 was synthesized by following the procedure of Example 37, wherein (R)-4-hydroxypentanoic acid ethyl ester was used as reference (J. Org. Chem., 67 (15), 5315-5319; 2002 synthesis) to give the desired product. (2 ² R,5S)-3 ⁵ -fluoro-5-methyl-4-oxa-9-aza-1(5,3)-pyrazolo[1,5-a]pyrimidine-2 (1 2)-pyrrole-3(1,2)-benzocyclodecane-8-one 58.

MS m/z (ESI): 396 [M+1];

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.20 (d, J = 8.0Hz, 1H), 7.60 (s, 1H), 6.83 (s, 1H), 6.81-6.79 (m, 2H), 6.79-6.76 ( m, 1H), 6.27 (d, J = 8.0 Hz, 1H), 5.61-5.58 (m, 1H), 4.61-4.59 (m, 1H), 3.88-3.86 (m, 1H), 3.68-3.58 (m, 1H), 2.42-2.35 (m, 2H), 2.22-2.20 (m, 1H), 2.15-2.13 (m, 1H), 2.13-2.11 (m, 1H), 1.91-1.83 (m, 2H), 1.79- 1.72 (m, 1H), 1.48 (d, J = 6.0 Hz, 3H).

Example 59

(S)-4 ⁵ -fluoro-2,6-dimethyl-5-oxa-2,10-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidine-4 (1,2)-benzocyclodecane-9-one

Example 59 was synthesized by following the procedure of Example 37 to give the desired product (S)-4 ⁵ -fluoro-2,6-dimethyl-5-oxa-2,10-diaza-1 (5,3) )-pyrazolo[1,5-a]pyrimidin-4(1,2)-benzocyclodecane-9-one 59.

MS m/z (ESI): 370 [M + 1];

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.22 (s, 1H), 7.72-7.67 (m, 1H), 6.95-6.84 (m, 4H), 6.34 (s, 1H), 5.75-5.73 (m, 1H) ), 4.54-4.51 (m, 2H), 3.71-3.68 (m, 1H), 3.46 (s, 3H), 2.31-2.20 (m, 2H), 2.10.10.98 (m, 1H), 1.26 (d, J) =6.0 Hz, 3H).

Example 60

(S)-4 ⁵ -fluoro-2,6-dimethyl-5-oxa-2,10-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidine-4 (3,2)-pyridocyclodecane-9-one

Example 60 was synthesized by following the procedure of Example 37 to give the desired product (S)-4 ⁵ -fluoro-2,6-dimethyl-5-oxa-2,10-diaza-1 (5,3) )-pyrazolo[1,5-a]pyrimidine-4(3,2)-pyridocyclodecane-9-one 60.

MS m/z (ESI): 371 [M + 1];

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.23-8.18 (m, IH), 7.88-7.81 (m, 1H), 7.70 (s, 1H), 7.22-7.21 (m, 1H), 6.76-6.66 (m ,1H),6.34-6.28(m,1H),5.48-5.30(m,2H),3.74-3.71(m,1H),3.63(s,3H),3.48-3.45(m,1H),2.67-2.51 (m, 1H), 2.39-2.23 (m, 2H), 1.27 (d, J = 6.0 Hz, 3H).

Example 61

(S)-4 ⁵ -fluoro-2-(2-fluoroethyl)-6-methyl-5-oxa-2,10-diaza-1(5,3)-pyrazolo[1, 5-a]pyrimidin-4(3,2)-pyridocyclodecane-9-one

Synthesis of Example 61 by the procedure of Example 37 gave the desired product (S)-4 ⁵ -fluoro-2-(2-fluoroethyl)-6-methyl-5-oxa-2,10-dinitro Hetero-1(5,3)-pyrazolo[1,5-a]pyrimidin-4(3,2)-pyridocyclodecane-9-one 61.

MS m/z (ESI): 403 [M + 1];

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.22 (d, J = 7.6 Hz, 0.4H), 8.18 (d, J = 7.6 Hz, 0.6H), 7.85-7.83 (m, 0.4H), 7.81-7.79 (m, 0.6H), 7.72 (s, 0.6H), 7.68 (s, 0.4H), 7.30-7.28 (m, 1H), 6.73 (s, 0.4H), 6.65 (s, 0.6H), 6.36 ( d, J = 7.6 Hz, 0.4H), 6.29 (d, J = 7.6 Hz, 0.6H), 5.53-5.43 (m, 2H), 4.81-4.79 (m, 1H), 4.69-4.67 (m, 1H) , 4.02-4.00 (m, 1H), 3.95-3.93 (m, 1H), 3.81-3.77 (m, 1H), 2.68-2.53 (m, 1H), 2.38-2.14 (m, 1H), 1.83-1.67 ( m, 2H), 1.43 (d, J = 6.0 Hz, 3H).

Example 62

(3R,6S)-4 ⁵ -fluoro-3,6-dimethyl-5-oxa-2,8,10-triaza-1(5,3)-pyrazolo[1,5-a Pyrimidine-4(3,2)-pyridocyclodecane-9-one

first step

(R)-N-((R)-1-(5-fluoro-2-methoxypyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide

Compound (R,E)-N-((5-fluoro-2-methoxypyridin-3-yl)methylene)-2-methylpropane-2-sulfinamide 23b (1.18 g, 4.60 mmol Dissolved in dry tetrahydrofuran (20 mL), and slowly added methyl magnesium chloride (3M tetrahydrofuran solution, 5.4 mL) at -70 °C under argon atmosphere. The reaction solution was slowly warmed to room temperature and stirred for 1 hour. The reaction was quenched with aq. EtOAc (EtOAc) (EtOAc (EtOAc) Ether/ethyl acetate = 100:1 to 10:1) to the desired product (R)-N-((R)-1-(5-fluoro-2-methoxypyridin-3-yl)ethyl)- 2-Methylpropane-2-sulfinamide 62a (0.50 g, 1.80 mmol, white solid), yield: 40%.

MS m/z (ESI): 275 [M + 1].

Second step

(R)-1-(5-fluoro-2-methoxypyridin-3-yl)ethane-1-amine hydrochloride

The compound N-((R)-1-(5-fluoro-2-methoxypyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide 62a (0.20 g, 0.73 mmol) Dissolved in hydrochloric acid dioxane solution (4M, 10mL). After stirring overnight at room temperature, the solvent was evaporated under reduced pressure to give the title compound (jjjjjjjjjjjjjjjjjjjjjj ),Crude.

MS m/z (ESI): 171 [M-HCl-1].

third step

(R)-3-(1-aminoethyl)-5-fluoropyridin-2-ol

Compound (R)-1-(5-fluoro-2-methoxypyridin-3-yl)ethane-1-amine hydrochloride 62b (0.12 g, 0.70 mmol) was dissolved in 10 mL of acetonitrile, slow at room temperature Trimethylsilyl iodide (0.29 g, 130 mmol) was slowly added and stirred at 50 ° C for one hour. 20 mL of water was added and the aqueous phase was washed with 20 mL of ethyl acetate. The aqueous phase was evaporated under reduced pressure to give crude crystallite.

MS m/z (ESI): 157 [M + 1];

¹ H NMR (400 MHz, CD ₃ OD) δ 7.84 - 7.75 (m, 1H), 7.61 (s, 1H), 4.57 - 4.52 (m, 1H), 1.65 (d, J = 6.8 Hz, 3H).

the fourth step

(R)-5-fluoro-3-(1-((3-nitropyrazolo[1,5-a]pyrimidin-5-yl)amino)ethyl)pyridin-2-ol

Referring to the sixth step of Example 1, substituting (R)-3-(1-aminoethyl)-5-fluoropyridin-2-ol for (R)-2-(1-aminoethyl)-4-fluoro Phenol hydrochloride gives the target product (R)-5-fluoro-3-(1-((3-nitropyrazolo[1,5-a]pyrimidin-5-yl)amino)ethyl)pyridin-2-ol 62d.

MS m/z (ESI): 319 [M + 1].

the fifth step

((S)-2-((5-fluoro-3-((R)-1-((3-nitropyrazolo[1,5-a]pyrimidin-5-yl)amino)ethyl)pyridine Tert-butyl ester of -2-yl)oxy)propyl)carbamate

Referring to the seventh step of Example 1, using (R)-5-fluoro-3-(1-((3-nitropyrazolo[1,5-a]pyrimidin-5-yl)amino)ethyl) Pyridin-2-phenol instead of (R)-4-fluoro-2-(1-((3-nitropyrazolo[1,5-a]pyrimidin-5-yl)amino)ethyl)phenol to give the desired product ((S)-2-((5-fluoro-3-((R)-1-((3-nitropyrazolo[1,5-a]pyrimidin-5-yl)amino)ethyl)pyridine tert-Butyl ester 62e-2-yl)oxy)propyl)carbamate.

MS m/z (ESI): 476 [M + 1].

Step 6

((S)-2-((5-fluoro-3-((R)-1-((3-aminopyrazolo[1,5-a]pyrimidin-5-yl)amino)ethyl)pyridine- Tert-butyl 2-yl)oxy)propyl)carbamate

Referring to the eighth step of Example 1, using ((S)-2-(4-fluoro-2-((R)-1-((3-nitropyrazolo[1,5-a]pyrimidine-5) -(S)-2-(4-fluoro-2-((R)-1-((3-nitropyrazole) And [1,5-a]pyrimidin-5-yl)amino)ethyl)phenoxy)propyl)carbamic acid tert-butyl ester gives the desired product ((S)-2-((5-fluoro-3-) (R)-1-((3-Aminopyrazolo[1,5-a]pyrimidin-5-yl)amino)ethyl)pyridin-2-yl)oxy)propyl)carbamic acid tert-butyl ester 62f .

MS m/z (ESI): 446[M+1].

Seventh step

N ⁵ -((R)-1-(2-((()))))))) 5-a]pyrimidine-3,5-diamine Referring to the ninth step of Example 1, using ((S)-2-((5-fluoro-3-((R)-1-)(3-aminopyridyl) (Z)-[1,5-a]pyrimidin-5-yl)amino)ethyl)pyridin-2-yl)oxy)propyl)carbamic acid tert-butyl ester instead ((S)-2-(4-fluoro- 2-((R)-1-((3-Aminopyrazolo[1,5-a]pyrimidin-5-yl)amino)ethyl)phenoxy)propyl)carbamic acid tert-butyl ester gives the desired product N ⁵ -((R)-1-(2-((()))))))) 5-a]pyrimidine-3,5-diamine 62g.

MS m/z (ESI): 346 [M + 1].

Eighth step

Referring to the tenth step of Example 1, N ⁵ -((R)-1-(2-((())-1-aminopropan-2-yl)oxy)-5-fluoropyridin-3-yl) Ethyl)pyrazolo[1,5-a]pyrimidine-3,5-diamine in place of N ⁵ -((R)-1-(2-((())))) Oxo)-5-fluorophenyl)ethyl)pyrazolo[1,5-a]pyrimidine-3,5-diamine trifluoroacetate gives the desired product (3R,6S)-4 ⁵ -fluoro -3,6-Dimethyl-5-oxa-2,8,10-triaza-1(5,3)-pyrazolo[1,5-a]pyrimidin-4(3,2)- Pyridocyclodecane-9-one 62.

MS m/z (ESI): 372 [M + 1];

^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.08 (d, J = 8.0Hz, 1H), 7.85 (s, 1H), 7.81-7.78 (m, 1H), 7.56 (s, 1H), 7.35-7.32 ( m,1H), 6.34(s,1H), 6.04(d,J=8.0Hz,1H),5.59-5.57(m,1H),5.52-5.49(m,1H),5.39-5.35(m,1H) , 3.81-3.75 (m, 1H), 3.26-3.21 (m, 1H), 1.50 (d, J = 4.0 Hz, 3H), 1.47 (d, J = 6.8 Hz, 3H).

Biological experiment

TRKA activity inhibition test

Evaluation of the effects of the compounds of the invention on TRKA activity using in vitro kinase assays

The experimental methods are summarized as follows:

The in vitro activity of TRKA was determined by measuring the phosphorylation level of the substrate in the kinase reaction using a homogeneous time-resolved fluorescence (HTRF) kinase assay kit (Cisbio, Cat. No. 62TK0PEC). The reaction buffer contains the following components: the kit comes with enzymatic reaction buffer (1×), 5 mM MgCl ₂ , 1 mM DTT; human recombinant TRKA protein is entrusted to Tsinghua University protein purification and identification platform for expression and purification, and diluted with reaction buffer. 3 ng/μl of kinase solution; substrate reaction solution including dilution with reaction buffer to 0.23 μM biotinylated tyrosine kinase substrate and 8.4 μM ATP; assay buffer including dilution with reaction buffer to 0.1 ng/μl Eu3+ Labeled cage antibody and 14.375 nM streptavidin-labeled XL665.

Compounds were diluted in 100% DMSO to 100 or 10 [mu]M and then serially diluted 4 fold with DMSO to a minimum concentration of 6.1 or 0.61 nM, each concentration point diluted 40-fold with reaction buffer.

4 μl of the compound solution and 2 μl of the TRKA kinase solution were added to a 384-well assay plate (Corning, Cat. No. 4512), mixed uniformly, and incubated at room temperature for 15 minutes. Subsequently, 4 μl of the substrate reaction solution was added, and the reaction mixture was incubated at room temperature for 60 minutes. Subsequently, an equal volume of 10 μl of the detection buffer was added to the reaction, mixed well and allowed to stand at room temperature for 30 minutes, and then the progress of the reaction was examined using an Envision plate reader (Perkin Elmer) at a wavelength of 620 nm and 665 nm. The ratio of 665/620 is positively correlated with the degree of phosphorylation of the substrate, thereby detecting the activity of TRKA kinase. In this experiment, the TRKA kinase protein group was not added as a negative control (100% inhibition), and the TRKA kinase protein was added but the compound group was not added as a positive control (0% inhibition). The percent inhibition of TRKA activity by a compound can be calculated using the following formula:

Compound IC50 values were calculated from the 8 concentration points using XLfit (ID Business Solutions Ltd., UK) software by the following formula:

Y=Bottom+(Top-Bottom)/(1+10^((logIC50-X)*slope factor))

Where Y is the percent inhibition, X is the logarithm of the concentration of the test compound, Bottom is the maximum percent inhibition, Top is the minimum percent inhibition, and slope factor is the slope coefficient of the curve.

TRKB activity inhibition test

Evaluation of the effects of the compounds of the invention on TRKB activity using in vitro kinase assays

The experimental methods are summarized as follows:

The in vitro activity of TRKB was determined by measuring the phosphorylation level of the substrate in the kinase reaction using the HTRF Kinase Assay Kit (Cisbio, Cat. No. 62TK0PEC). The reaction buffer contains the following components: the kit comes with enzymatic reaction buffer (1×), 5 mM MgCl ₂ , 1 mM MnCl ₂ and 1 mM DTT; human recombinant TRKB protein (Cat. No. 08-187) was purchased from Carna Biosciences. The buffer was diluted to 0.162 ng/μl of the kinase solution; the substrate reaction solution was diluted with the reaction buffer to 0.18 μM biotinylated tyrosine kinase substrate and 5 μM ATP; the assay buffer was diluted to 0.1 with reaction buffer. Ng/μl Eu3+ labeled cage antibody and 11.25 nM streptavidin-labeled XL665.

Compounds were diluted in 100% DMSO to 100 or 50 [mu]M and then serially diluted 4 fold with DMSO to a minimum concentration of 6.1 or 3.05 nM, each concentration point diluted 40-fold with reaction buffer.

4 μl of the compound solution and 2 μl of the TRKB kinase solution were added to a 384-well assay plate (Corning, Cat. No. 4512), mixed uniformly, and incubated at room temperature for 15 minutes. Subsequently, 4 μl of the substrate reaction solution was added, and the reaction mixture was incubated at room temperature for 60 minutes. Subsequently, an equal volume of 10 μl of the detection buffer was added to the reaction, mixed uniformly and allowed to stand at room temperature for 30 minutes, and then the progress of the reaction was examined using an Envision plate reader (Perkin Elmer) at a wavelength of 620 nm and 665 nm. The ratio of 665/620 was positively correlated with the degree of phosphorylation of the substrate, thereby detecting the activity of TRKB kinase. In this experiment, the TRKB kinase protein group was not added as a negative control (100% inhibition), and the TRKB kinase protein was added but the compound group was not added as a positive control (0% inhibition). The percent inhibition of TRKB activity by a compound can be calculated using the following formula:

Percent inhibition = 100-100* (signal value at a specific concentration of the test compound - negative control signal value) / (positive control signal value - negative control signal value)

Y=Bottom+(Top-Bottom)/(1+10^((logIC50-X)*slope factor))

TRKC activity inhibition test

Evaluation of the effects of the compounds of the invention on TRKC activity using in vitro kinase assays

The experimental methods are summarized as follows:

The in vitro activity of TRKC was determined by measuring the phosphorylation level of the substrate in the kinase reaction using a homogeneous time-resolved fluorescence (HTRF) kinase assay kit (Cisbio, Cat. No. 62TK0PEC). The reaction buffer contains the following components: the kit comes with enzymatic reaction buffer (1×), 5 mM MgCl ₂ , 1 mM DTT; human recombinant TRKC protein (Cat. No. 08-197) was purchased from Carna Biosciences and diluted with reaction buffer. 0.145 ng/μl of kinase solution; substrate reaction solution including dilution with reaction buffer to 0.13 μM biotinylated tyrosine kinase substrate and 4.1 μM ATP; assay buffer including dilution with reaction buffer to 0.1 ng/μl Eu3+ labeled cage antibody and 8.125 nM streptavidin labeled XL665.

4 μl of the compound solution and 2 μl of the TRKC kinase solution were added to a 384-well assay plate (Corning, Cat. No. 4512), mixed uniformly, and incubated at room temperature for 15 minutes. Subsequently, 4 μl of the substrate reaction solution was added, and the reaction mixture was incubated at room temperature for 60 minutes. Subsequently, an equal volume of 10 μl of the detection buffer was added to the reaction, mixed uniformly and allowed to stand at room temperature for 30 minutes, and then the progress of the reaction was examined using an Envision plate reader (Perkin Elmer) at a wavelength of 620 nm and 665 nm. The ratio of 665/620 was positively correlated with the degree of phosphorylation of the substrate, thereby detecting the activity of TRKC kinase. In this experiment, the TRKC kinase protein group was not added as a negative control (100% inhibition), and the TRKC kinase protein was added but the compound group was not added as a positive control (0% inhibition). The percent inhibition of TRKC activity by a compound can be calculated using the following formula:

Y=Bottom+(Top-Bottom)/(1+10^((logIC50-X)*slope factor))

TRKA G595R activity inhibition test

Evaluation of the effect of the compounds of the invention on the activity of TRKA G595R using an in vitro kinase assay

The experimental methods are summarized as follows:

The in vitro activity of TRKA G595R was determined by measuring the phosphorylation level of the substrate in the kinase reaction using the HTRF Kinase Assay Kit (Cisbio, Cat. No. 62TK0PEC). The reaction buffer contains the following components: the kit comes with enzymatic reaction buffer (1×), 5 mM MgCl ₂ , 1 mM DTT; human recombinant TRKA G595R protein (Cat. No. N16-12BG) purchased from SignalChem Lifesciences, with reaction buffer Diluted to 0.25 ng/μl of kinase solution; substrate reaction solution including dilution with reaction buffer to 0.51 μM biotinylated tyrosine kinase substrate and 2.9 μM ATP; assay buffer including dilution with reaction buffer to 0.15 ng /μl Eu3+ labeled cage antibody and 31.875 nM streptavidin labeled XL665.

Compounds were diluted in 100% DMSO to 1 mM or 100 [mu]M and then serially diluted 4-fold with DMSO to a minimum concentration of 61 or 6.1 nM, each concentration point diluted 40-fold with reaction buffer.

4 μl of the compound solution and 2 μl of TRKA G595R kinase solution were added to a 384-well assay plate (Corning, Cat. No. 4512), mixed uniformly, and incubated at room temperature for 15 minutes. Subsequently, 4 μl of the substrate reaction solution was added, and the reaction mixture was incubated at room temperature for 60 minutes. Subsequently, an equal volume of 10 μl of the detection buffer was added to the reaction, mixed uniformly and allowed to stand at room temperature for 30 minutes, and then the progress of the reaction was examined using an Envision plate reader (Perkin Elmer) at a wavelength of 620 nm and 665 nm. The ratio of 665/620 was positively correlated with the degree of phosphorylation of the substrate, thereby detecting the activity of TRKA G595R kinase. In this experiment, the TRKA G595R kinase protein group was not added as a negative control (100% inhibition), and the TRKA G595R kinase protein was added but the compound group was not added as a positive control (0% inhibition). The percent inhibition of TRKA G595R activity by a compound can be calculated using the following formula:

Y=Bottom+(Top-Bottom)/(1+10^((logIC50-X)*slope factor))

TRKA G667C activity inhibition test

Evaluation of the effect of the compounds of the invention on the activity of TRKA G667C using an in vitro kinase assay

The experimental methods are summarized as follows:

The in vitro activity of TRKA G667C was determined by measuring the phosphorylation level of the substrate in the kinase reaction using the HTRF Kinase Assay Kit (Cisbio, Cat. No. 62TK0PEC). The reaction buffer contains the following components: the kit comes with enzymatic reaction buffer (1×), 5 mM MgCl ₂ , 1 mM DTT; human recombinant TRKA G667C protein (catalog number N16-12CG purchased from SignalChem Lifesciences), diluted with reaction buffer 0.09 ng/μl of kinase solution; substrate reaction solution including dilution with reaction buffer to 0.21 μM biotinylated tyrosine kinase substrate and 2.7 μM ATP; assay buffer including dilution with reaction buffer to 0.1 ng/ l Eu3+ labeled cage antibody and 13.125 nM streptavidin-labeled XL665.

Compounds were diluted in 200% DMSO and diluted to 200 [mu]M, then serially diluted 4 fold with DMSO to a minimum concentration of 12.2 nM, and each concentration point was diluted 40-fold with reaction buffer.

4 μl of the compound solution and 2 μl of TRKA G667C kinase solution were added to a 384-well assay plate (Corning, Cat. No. 4512), mixed uniformly, and incubated at room temperature for 15 minutes. Subsequently, 4 μl of the substrate reaction solution was added, and the reaction mixture was incubated at room temperature for 60 minutes. Subsequently, an equal volume of 10 μl of the detection buffer was added to the reaction, mixed uniformly and allowed to stand at room temperature for 30 minutes, and then the progress of the reaction was examined using an Envision plate reader (Perkin Elmer) at a wavelength of 620 nm and 665 nm. The ratio of 665/620 was positively correlated with the degree of phosphorylation of the substrate, thereby detecting the activity of TRKA G667C kinase. In this experiment, the TRKA G667C kinase protein group was not added as a negative control (100% inhibition), and the TRKA G667C kinase protein was added but the compound group was not added as a positive control (0% inhibition). The percent inhibition of TRKA G667C activity by a compound can be calculated using the following formula:

Y=Bottom+(Top-Bottom)/(1+10^((logIC50-X)*slope factor))

The results of the kinase bioassay are shown in Table 1 below.

Table 1. Kinase biological experiment results

Note: ND = not determined.

Determination of half effective inhibitory concentration G150 in KM12 cells

The effect of the compounds of the invention on the proliferation of KM12 cells was assessed using a luminescent cell viability assay.

The experimental methods are summarized as follows:

Using the CellTilter-Glo (CTG) assay kit, the luminescence signal generated in the assay is proportional to the number of viable cells in the medium by using a unique, stable luciferase assay for the indicator ATP of viable cellular metabolism. To detect the cell proliferation status of KM12.

KM12 cell (purchased from Shanghai Xinyu Biotech Co., Ltd.) was cultured in IMDM complete medium (Thermofisher, 12440053) containing 10% FBS (GBICO, 10099-141) and 100units/mL streptomycin mixture (Thermofisher, 15140122). When the cells were covered in the culture vessel for 80-90%, they were digested with 0.25% trypsin (containing EDTA) (Thermofisher, 25200056) and then planted in white 384-well plates (Thermofisher, 164610), and 27 μl of IMDM per well was added. The medium containing 1000 cells was then cultured overnight at 37 ° C in an incubator containing 5% CO ₂ . Compounds were lysed in 100% DMSO and diluted to 1 mM, then serially diluted 4 fold with DMSO to a minimum concentration of 0.061 μM, and each concentration was diluted 50-fold with IMDM medium. If the compound is very low IC ₅₀ values, the concentration of the starting compound can be reduced. Add 3 μl of the diluted compound to each well and mix by gentle centrifugation. Among them, the medium without cells was used as a negative control (100% inhibition), and the 0.2% DMSO group was added as a positive control (0% inhibition). The 384-well plate was placed in a 37 ° C, 5% CO ₂ incubator for further incubation. After 96 hours, it was taken out and allowed to stand at room temperature for 30 minutes. The CTG reagent was also taken out to room temperature, and 15 μl of CTG reagent was added to each well and placed on a shaker. Shake gently for 5 minutes to ensure sufficient cell lysis, leave for 10 minutes to stabilize the luminescence signal, and then read the luminescence signal with EnVision (Perkin Elmer). In addition, in order to correct the number of cells, a T ₀ control was set at the same time, including a blank control containing only the medium and a control containing cells, and the difference between the two was set as the T ₀ control, and was obtained by adding CTG reagent before the administration.

The percentage inhibition of KM12 cell proliferation by the compound can be calculated by the following formula:

Percent inhibition = 100-100*{[(signal _compound- Signal _{negative control} )-T _{0 control} ]/[(signal _{positive control-} Signal _{negative control} )-T _{0 control} ]}

Compound IC ₅₀ values were calculated from the 8 concentration points by XLfit (ID Business Solutions Ltd., UK) software by the following formula:

Y=Bottom+(Top-Bottom)/(1+10^((LogIC ₅₀ -X)*slope factor))

Where Y is the percent inhibition, Bottom is the bottom plateau of the curve, Top is the top plateau of the curve, and X is the concentration of the compound to be tested. Value.

The results of the above cell biology experiments are shown in Table 2.

Table 2: KM12 cell proliferation inhibition test results

化合物编号Compound number	KM12细胞GI50(nM)KM12 cell GI50 (nM)	化合物编号Compound number	KM12细胞G150(nM)KM12 cell G150 (nM)
11	3.613.61	2828	6.406.40
55	44.6444.64	3030	5.955.95
77	14.014.0	3333	16.6316.63
99	40.7140.71	3737	110.32110.32
1010	58.158.1	4242	2.562.56
1111	11.3511.35	4545	61.4761.47
1212	16.7616.76	4646	64.4264.42
1616	13.7713.77	4949	73.9073.90

1717	4.914.91	5252	23.4223.42
1818	9.999.99	5353	19.4519.45
1919	1.221.22	5454	1.491.49
2020	11.7511.75	5555	0.770.77
21twenty one	0.410.41	5656	3.853.85
22twenty two	0.130.13	5757	22.7222.72
23twenty three	3.233.23	5858	28.4828.48
24twenty four	22.0522.05	5959	75.2675.26
2525	22.6922.69	6262	16.3316.33
2727	28.4328.43

Note: ND = not determined.

From the above experimental results, the compounds of the present invention can effectively inhibit the activity of TRK kinases of TrkA, TrkB, TrkC and G595R and G667C mutations, and can be used for treating various cancers caused by NTRK gene fusion: for example, glioma, Hepatobiliary liver cancer, papillary thyroid cancer, colon cancer, non-small cell lung cancer, head and neck squamous cell carcinoma, pancreatic cancer, sarcoma and melanoma (Khotskaya, YB et al. Pharmacology & Therapeutics, 2017, 173, 58-66) . Some compounds are also effective in inhibiting KM12 colon cancer cell proliferation. Fusion of NTRK gene leads to a strong inhibitory effect on colon cancer.

It is obvious to those skilled in the art that the present disclosure is not limited to the above-described illustrative embodiments, and may be embodied in other specific forms without departing from the essential characteristics of the disclosure. Accordingly, the present embodiments are to be considered in all respects as illustrative and not restrict All changes are included.

Claims

A compound, an isomer, a prodrug, a solvate thereof, a stable isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, of formula I:

among them:

One of X 1 and X 2 is C and the other is N;

X 3 is selected from N and CR 4 , preferably X 3 is selected from N;

Ar is selected from the group consisting of arylene and heteroarylene, wherein the arylene or heteroarylene is optionally substituted by one or more G1, and Ar is preferably selected from 6 optionally substituted by one or more G1 Up to 10 membered arylene and 5 to 10 membered heteroarylene, said 6 to 10 membered arylene group such as phenylene and naphthylene, most preferably phenylene, said 5 to 10 membered heteroarylene Preferred is a 5- or 6-membered heteroarylene group, such as a furylene group, a thienylene group, a pyridylene group, a pyridylene group, a pyridone group, a pyrimidinyl group, a pyridazinyl group, an imidazolyl group, and a tetrazolium group. , a oxazolyl group and an isoxazolyl group, preferably a pyridylene group and a pyridone group, more preferably a 1,2-pyridinylene group and a 1,3 pyridinylene group;

Y and Z are independently selected from -N(R 5a )- and -C(R 5b R 5c )-, provided that Y and Z are not simultaneously selected from -N(R 5a )-, and Y is preferably selected from -N(R 5a -, Z is preferably selected from -C(R 5b R 5c )-;

L 1 is selected from -NR 5 C(O)-, -NR 5 CON(R 6 )-, -NR 5 S(O) m - and -NR 5 S(O) m N(R 6 )-, wherein NR 5 is linked to the nitrogen-containing heteroaryl group substituted by R 1 , R 2 , R 3 , preferably, L 1 is selected from the group consisting of -NR 5 C(O)- and -NR 5 CON(R 6 )-, wherein NR 5 is linked to the bicyclic heterocycle;

L 2 is selected from the group consisting of a C1-C8 alkylene group, a C2-C8 alkenylene group, a C2-C8 alkynylene group, and a C3-C8 cyclocyclylene group, wherein the alkylene group, the alkenylene group, the alkynylene group, and the cyclocyclylene group may be optionally substituted with one or more G2, L 2 is preferably selected from optionally substituted with one or more G2, and C1-C6 alkylene C2-C6 alkenylene group, L 2 is more preferably selected from optionally a C1-C4 alkylene group substituted by one or more G2;

L 3 is selected from the group consisting of a chemical single bond, -O- and -N(R x )-, and L 3 is preferably selected from the group consisting of a chemical single bond and -O-;

R 1 , R 2 and R 3 are each independently selected from the group consisting of hydrogen, halogen, cyano, C1-C8 alkyl, C3-C8 cyclic, 3-8 membered heterocyclic, aryl, heteroaryl, aldehyde, - C(O)R 7 ,carboxy, alkenyl, alkynyl, -OR 7 , -NR 8 R 9 -OC(O)NR 8 R 9 , -C(O)OR 7 , -C(O)NR 8 R 9 , -NR 8 C(O)R 7 , -NR 7 C(O)NR 8 R 9 , -S(O)mR 7 , -NR 8 S(O)mR 7 , -SR 7 , - S(O mNR 8 R 9 and -NR 7 S(O)mNR 8 R 9 , wherein the alkyl, cyclo, heterocyclyl, aryl or heteroaryl group is optionally selected from one or more selected from the group consisting of halogen and cyano , C1-C8 alkyl, C3-C8 cyclic, 3-8 membered heterocyclic, -OR 10 , -NR 11 R 12 , -OC(O)NR 10 R 11 , -C(O)OR 10 ,- C(O)R 10 , -C(O)NR 11 R 12 , -NR 11 C(O)R 10 , -NR 10 C(O)NR 11 R 12 , -S(O)mR 10 , -NR 11 Substituting the substituents of S(O)mR 12 , -SR 10 , -S(O)mNR 11 R 12 and -NR 10 S(O)mNR 11 R 12 , preferably R 2 and R 3 are all hydrogen; more preferably R 1 , R 2 and R 3 are all hydrogen;

R 4 is selected from the group consisting of hydrogen, C1-C8 alkyl, C1-C8 haloalkyl, heteroalkyl, C3-C8 cyclic, 3-8 membered monocyclic heterocyclic, monocyclic heteroaryl, monocyclic aryl, alkene and alkynyl groups, preferably R 4 is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl group, more preferably R 4 is selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, more preferably R 4 is hydrogen ;

R 5a , R 5b and R 5c are each independently selected from hydrogen, C1-C8 alkyl, C3-C8 cyclic, 3-8 membered monocyclic heterocyclic, monocyclic heteroaryl, monocyclic aryl, alkenyl And alkynyl groups, preferably R 5a , R 5b and R 5c are each independently selected from hydrogen, C1-C6 alkyl, further preferably R 5a , R 5b and R 5c are each independently selected from hydrogen, C1-C4 alkyl, wherein The alkyl, cyclo, monocyclic heterocyclic, monocyclic heteroaryl, monocyclic aryl, alkenyl and alkynyl groups are optionally selected from one or more selected from the group consisting of halogen, cyano, C1-C8 alkyl, C3-C8 cyclic group, 3-8 membered heterocyclic group, -OR 10 , -NR 11 R 12 , -OC(O)NR 10 R 11 , -NR 11 C(O)R 10 , -NR 10 C(O Substituted by a substituent of NR 11 R 12 ; or

Any two of R 5a , R 5b , R 5c attached to an adjacent atom may form a 4- to 8-membered ring group or a heterocyclic group which is optionally substituted by G 3 together with the atom to which they are attached, preferably formed by G 3 Substituted 3- to 6-membered heterocyclic group;

R 5 , R 6 , R x are each independently selected from the group consisting of hydrogen, C1-C8 alkyl, C1-C8 haloalkyl, heteroalkyl, C3-C8 cyclo, 3-8 membered monocyclic heterocyclic, monocyclic Aryl, monocyclic aryl, alkenyl and alkynyl, preferably R 5 , R 6 , R x are each independently selected from hydrogen, C1-C6 alkyl and C1-C6 haloalkyl, further preferably R 5 , R 6 , R x are each independently selected from the group consisting of hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl;

G1 is selected from halogen, cyano, C1-C8 alkyl, C3-C8 cycloalkyl group, a 3-8-membered heterocyclyl, aryl, heteroaryl, aldehyde, -C (O) R 7, a carboxyl group, an alkenyl group , alkynyl, -OR 7 , -NR 8 R 9 -OC(O)NR 8 R 9 , -C(O)OR 7 , -C(O)NR 8 R 9 , -NR 8 C(O)R 7 -NR 7 C(O)NR 8 R 9 , -S(O)mR 7 , -NR 8 S(O)mR 7 , -SR 7 , -S(O)mNR 8 R 9 and -NR 7 S( O) mNR 8 R 9 , preferably G1 is selected from halogen, C1-C6 alkyl and C3-C6 cyclic, more preferably G1 is selected from halogen, C1-C4 alkyl and C3-C6 cyclic, most preferably G1 is selected from halogen ;

G2 is selected from halogen, cyano, C1-C8 alkyl, C3-C8 cycloalkyl group, a 3-8-membered heterocyclyl, aryl, heteroaryl, aldehyde, -C (O) R 7, a carboxyl group, an alkenyl group , alkynyl, -OR 7 , -NR 8 R 9 -OC(O)NR 8 R 9 , -C(O)OR 7 , -C(O)NR 8 R 9 , -NR 8 C(O)R 7 -NR 7 C(O)NR 8 R 9 , -S(O)mR 7 , -NR 8 S(O)mR 7 , -SR 7 , -S(O)mNR 8 R 9 and -NR 7 S( O) mNR 8 R 9 , preferably G2 is selected from halogen, C1-C6 alkyl, -OR 7 , -NR 8 R 9 ; more preferably G 2 is selected from halogen, C1-C4 alkyl, -OR 7 , -NR 8 R 9 ; wherein the alkyl group is optionally substituted by one or more halogens, -OR 10 , -NR 11 R 12 ; when two G 2 are on the same carbon atom or on adjacent carbon atoms, the two G 2 Optionally forming a 3-8 membered ring group together with the carbon atom to which it is attached, preferably forming a 3-6 membered cycloalkyl group, the cycloalkyl group formed optionally being one or more halogens, -OR 10 , -NR 11 R 12 Replaced

G3 is selected from halogen, cyano, C1-C8 alkyl, C3-C8 cycloalkyl group, a 3-8-membered heterocyclyl, aryl, heteroaryl, aldehyde, -C (O) R 7, a carboxyl group, an alkenyl group , alkynyl, -OR 7 , -NR 8 R 9 -OC(O)NR 8 R 9 , -C(O)OR 7 , -C(O)NR 8 R 9 , -NR 8 C(O)R 7 -NR 7 C(O)NR 8 R 9 , -S(O)mR 7 , -NR 8 S(O)mR 7 , -SR 7 , -S(O)mNR 8 R 9 and -NR 7 S( O) mNR 8 R 9 , preferably G3 is selected from halogen, more preferably G3 is fluorine;

R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are each independently selected from the group consisting of hydrogen, C1-C8 alkyl, C1-C8 haloalkyl, heteroalkyl, C3-C8 cyclo, 3-8 Monocyclic heterocyclic group, monocyclic heteroaryl group, monocyclic aryl group, alkenyl group and alkynyl group;

m is 1 or 2.
A compound according to claim 1, an isomer, a prodrug, a solvate thereof, a stable isotopic derivative or a pharmaceutically acceptable salt thereof,

among them:

One of X 1 and X 2 is C and the other is N;

X 3 is selected from N and CR 4 ;

Ar is selected from the group consisting of a 6 to 10 membered arylene group and a 5 to 10 membered heteroarylene group optionally substituted by one or more G1;

Y and Z are independently selected from -N(R 5a )- and -C(R 5b R 5c )-, provided that Y and Z are not simultaneously selected from -N(R 5a )-;

L 1 is selected from -NR 5 C(O)-, -NR 5 CON(R 6 )-, -NR 5 S(O) m - and -NR 5 S(O) m N(R 6 )-, wherein NR 5 is linked to the nitrogen-containing heteroaryl group substituted by R 1 , R 2 , R 3 ;

L 2 is selected from the group consisting of a C1-C6 alkylene group, a C2-C6 alkenylene group, a C2-C6 alkynylene group, and a C3-C6 cyclocyclylene group, wherein the alkylene group, an alkenylene group, an alkynylene group, a cycloalkyl group Optionally substituted by one or more G2;

L 3 is selected from the group consisting of a chemical single bond, -O- and -N(R x )-;

R 1 , R 2 , R 3 are each independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C3-C6 cyclic, 3-6 membered heterocyclyl, aryl and heteroaryl, wherein the alkyl, ring a group, a heterocyclic group, an aryl group or a heteroaryl group optionally substituted by one or more substituents selected from the group consisting of halogen, cyano, C1-C6 alkyl, C3-C6 cyclic and 3-6 membered heterocyclic ;

R 4 is selected from the group consisting of hydrogen, C1-C6 alkyl and C1-C6 haloalkyl;

R 5a , R 5b and R 5c are each independently selected from hydrogen, C1-C6 alkyl, wherein the alkyl group is optionally selected from one or more selected from the group consisting of halogen, C1-C4 alkyl, C3-C8 cyclo, 3 -8-membered heterocyclic group, -OR 10 , -NR 11 R 12 , -OC(O)NR 10 R 11 , -NR 11 C(O)R 10 , -NR 10 C(O)NR 11 R 12 Replaced by the base; or

Any two of R 5a , R 5b , R 5c attached to an adjacent atom may form a 4- to 8-membered ring group or a heterocyclic group which is optionally substituted by G 3 together with the atom to which they are attached;

R 5 , R 6 , R x are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, and C1-C6 haloalkyl;

G1 is selected from the group consisting of halogen, C1-C6 alkyl and C3-C6 ring;

G2 is selected from halogen and C1-C6 alkyl, -OR 7, -NR 8 R 9 , wherein said alkyl is optionally substituted with one or more halo, -OR 10, substituted with -NR 11 R 12; when both When G2 is on the same carbon atom or an adjacent carbon atom, the two G2 optionally form a 3-6 membered cycloalkyl group together with the carbon atom to which they are attached; the cycloalkyl group formed is optionally one or more halogen , -OR 10 , -NR 11 R 12 replaced;

G3 is selected from the group consisting of halogen, -OR 7 and -NR 8 R 9 ;

R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are each independently selected from the group consisting of hydrogen, C1-C6 alkyl and C1-C6 haloalkyl.
A compound according to claim 1, an isomer, a prodrug, a solvate thereof, a stable isotopic derivative or a pharmaceutically acceptable salt thereof,

among them:

One of X 1 and X 2 is C and the other is N;

X 3 is N;

Ar is selected from the group consisting of phenylene, naphthylene, furanyl, thienylene, pyridylene, pyridylene, pyridinylene, pyrimidinyl, pyrazine, optionally substituted by one or more G1 a group, an imidazolyl group, a tetrazolium group, a oxazolyl group, and an oxazolyl group;

Y is selected from -N(R 5a )-;

Z is selected from -C(R 5b R 5c )-;

L 1 is selected from -NR 5 C(O)- and -NR 5 CON(R 6 )-, wherein NR 5 is bonded to the nitrogen-containing heteroaryl group substituted by R 1 , R 2 , R 3 ;

L 2 is selected from the group consisting of a C1-C4 alkylene group, a C2-C4 alkenylene group, a C2-C4 alkynylene group, and a C3-C4 cyclocyclylene group, wherein the alkylene group, an alkenylene group, an alkynylene group, a cycloalkyl group Optionally substituted by one or more G2;

L 3 is selected from the group consisting of a chemical single bond and -O-;

R 1 , R 2 , and R 3 are each independently selected from the group consisting of hydrogen, halogen, C1-C4 alkyl, C4-C6 cyclo and 4- to 6-membered heterocyclic, wherein the alkyl, cyclo and heterocyclic are optional. Substituted by one or more substituents selected from halogen;

R 5a , R 5b and R 5c are each independently selected from hydrogen, C1-C4 alkyl, wherein said alkyl group is optionally selected from one or more selected from the group consisting of halogen, C1-C4 alkyl, -OR 10 , -NR 11 Substituted with a substituent of R 12 , —OC(O)NR 10 R 11 , —NR 11 C(O)R 10 , —NR 10 C(O)NR 11 R 12 ;

or

Any two of R 5a , R 5b , R 5c attached to an adjacent atom may form a 4- to 6-membered ring group or a heterocyclic group which is optionally substituted by G 3 together with the atom to which they are attached;

R 5 , R 6 , R x are each independently selected from the group consisting of hydrogen, C1-C4 alkyl and C1-C4 haloalkyl;

G1 is selected from the group consisting of halogen, C1-C4 alkyl and C3-C6 cyclo;

G2 is selected from halogen, C1-C4 alkyl, -OR 7, -NR 8 R 9 , wherein said alkyl is optionally substituted with one or more halo, -OR 10, substituted with -NR 11 R 12; when both When G2 is on the same carbon atom or an adjacent carbon atom, the two G2s, optionally together with the carbon atom to which they are attached, form a 3-6 membered cycloalkyl group, the cycloalkyl group formed optionally being one or more halogen , -OR 10 , -NR 11 R 12 replaced;

G3 is selected from the group consisting of halogen, -OR 7 and -NR 8 R 9 ;

R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are each independently selected from the group consisting of hydrogen, C1-C4 alkyl and C1-C4 haloalkyl.
A compound, an isomer, a prodrug, a solvate thereof, a stable isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, of formula I:

among them:

One of X 1 and X 2 is C and the other is N;

X 3 is N;

Ar is selected from the group consisting of phenylene, naphthylene, pyridylene and pyridenylene, pyrimidinyl and pyrazinyl optionally substituted by one or more G1;

Y is selected from -N(R 5a )-;

Z is selected from -C(R 5b R 5c )-;

L 1 is selected from -NR 5 C(O)- and -NR 5 CON(R 6 )-, wherein NR 5 is bonded to the nitrogen-containing heteroaryl group substituted by R 1 , R 2 , R 3 ;

L 2 is selected from the group consisting of C 1 -C 4 alkylene and C 2 -C 4 alkenylene, wherein the alkylene and alkenylene groups may be optionally substituted by one or more G 2 ;

L 3 is selected from the group consisting of a chemical single bond and -O-;

R 1 , R 2 , R 3 are each independently selected from the group consisting of hydrogen, halogen, and C1-C4 alkyl, wherein the alkyl group is optionally substituted with one or more halogens;

R 5a , R 5b and R 5c are each independently selected from hydrogen, C1-C4 alkyl, wherein the alkyl group is optionally substituted by one or more substituents selected from the group consisting of halogen, -OR 10 , -NR 11 R 12 Replace; or

Any two of R 5a , R 5b , R 5c attached to an adjacent atom may form a 5- to 6-membered or 5- to 6-membered heterocyclic group optionally substituted by G 3 together with the atom to which they are attached;

R 5 and R 6 are each independently selected from hydrogen and C1-C4 alkyl;

G1 is selected from the group consisting of halogen, C1-C4 alkyl and C3-C6 cyclo;

G2 is selected from halogen, C1-C4 alkyl, -OR 7, -NR 8 R 9 , wherein said alkyl is optionally substituted with one or more halo, -OR 10, substituted with -NR 11 R 12; when both When G2 is on the same carbon atom or an adjacent carbon atom, the two G2s, optionally together with the carbon atom to which they are attached, form a 3-6 membered cycloalkyl group, the cycloalkyl group formed optionally being one or more halogen , -OR 10 , -NR 11 R 12 replaced;

G3 is selected from the group consisting of halogen, -OR 7 and -NR 8 R 9 ;

R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are each independently selected from the group consisting of hydrogen, C1-C6 alkyl and C1-C6 haloalkyl.
A compound, an isomer, a prodrug, a solvate thereof, a stable isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, of formula I:

among them:

One of X 1 and X 2 is C and the other is N;

X 3 is N;

Ar is selected from the group consisting of phenylene, pyridylene and pyridenylene groups optionally substituted by one or more G1;

Y is selected from -N(R 5a )-;

Z is selected from -C(R 5b R 5c )-;

L 1 is selected from -NR 5 C(O)- and -NR 5 CON(R 6 )-, wherein NR 5 is bonded to the nitrogen-containing heteroaryl group substituted by R 1 , R 2 , R 3 ;

L 2 is selected from the group consisting of C 1 -C 4 alkylene and C 2 -C 4 alkenylene, wherein the alkylene and alkenylene groups may be optionally substituted by one or more G 2 ;

L 3 is selected from the group consisting of a chemical single bond and -O-;

R 1 , R 2 , R 3 are each independently selected from the group consisting of hydrogen, halogen, and C1-C4 alkyl, wherein the alkyl group is optionally substituted with one or more halogens;

R 5a , R 5b and R 5c are each independently selected from hydrogen, C1-C4 alkyl, wherein the alkyl group is optionally substituted by one or more substituents selected from the group consisting of halogen, -OR 10 , -NR 11 R 12 Replace

or

Any two of R 5a , R 5b , R 5c attached to an adjacent atom may form a 5- to 6-membered or 5- to 6-membered heterocyclic group optionally substituted by G 3 together with the atom to which they are attached;

R 5 and R 6 are each independently selected from hydrogen and C1-C4 alkyl;

G1 is selected from the group consisting of halogen, C1-C4 alkyl and C3-C6 cyclo;

G2 is selected from halogen, C1-C4 alkyl, -OR 7, -NR 8 R 9 , wherein said alkyl is optionally substituted with one or more halo, -OR 10, substituted with -NR 11 R 12; when both When G2 is on the same carbon atom or an adjacent carbon atom, the two G2s, optionally together with the carbon atom to which they are attached, form a 3-6 membered cycloalkyl group, the cycloalkyl group formed optionally being one or more halogen , -OR 10 , -NR 11 R 12 replaced;

G3 is selected from the group consisting of halogen, -OR 7 and -NR 8 R 9 ;

R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are each independently selected from the group consisting of hydrogen, C1-C6 alkyl and C1-C6 haloalkyl.
A compound, an isomer, a prodrug, a solvate thereof, a stable isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, of formula I:

among them:

One of X 1 and X 2 is C and the other is N;

X 3 is N;

Ar is selected from the group consisting of phenylene, 2,3-pyridinylene and 1,3-pyridinone optionally substituted with one or more G1;

Y is selected from -N(R 5a )-;

Z is selected from -C(R 5b R 5c )-;

L 1 is selected from -NR 5 C(O)- and -NR 5 CON(R 6 )-, wherein NR 5 is bonded to the nitrogen-containing heteroaryl group substituted by R 1 , R 2 , R 3 ;

L 2 is selected from the group consisting of C 1 -C 4 alkylene and C 2 -C 4 alkenylene, wherein the alkylene and alkenylene groups may be optionally substituted by one or more G 2 ;

L 3 is selected from the group consisting of a chemical single bond and -O-;

R 1 , R 2 , R 3 are each independently selected from the group consisting of hydrogen, halogen, and C1-C4 alkyl, wherein the alkyl group is optionally substituted with one or more halogens;

R 5a , R 5b and R 5c are each independently selected from hydrogen, C1-C4 alkyl, wherein the alkyl group is optionally substituted by one or more substituents selected from the group consisting of halogen, -OR 10 , -NR 11 R 12 Replace

or

Any two of R 5a , R 5b , R 5c attached to an adjacent atom may form a 5- to 6-membered or 5- to 6-membered heterocyclic group optionally substituted by G 3 together with the atom to which they are attached;

R 5 and R 6 are each independently selected from hydrogen and C1-C4 alkyl;

G1 is selected from the group consisting of halogen, C1-C4 alkyl and C3-C6 cyclo;

G2 is selected from halogen and C1-C4 alkyl, -OR 7, -NR 8 R 9 , wherein said alkyl is optionally substituted with one or more halo, -OR 10, substituted with -NR 11 R 12; when both When G2 is on the same carbon atom or an adjacent carbon atom, the two G2s, optionally together with the carbon atom to which they are attached, form a 3-6 membered cycloalkyl group, the cycloalkyl group formed optionally being one or more halogen , -OR 10 , -NR 11 R 12 replaced;

G3 is selected from the group consisting of halogen, -OR 7 and -NR 8 R 9 ;

R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are each independently selected from the group consisting of hydrogen, C1-C6 alkyl and C1-C6 haloalkyl.
A compound, an isomer, a prodrug, a solvate thereof, a stable isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, of formula I:

among them:

One of X 1 and X 2 is C and the other is N;

X 3 is N;

Ar is selected from the group consisting of phenylene, 2,3-pyridinylene and 1,3-pyridinone optionally substituted with one or more G1;

Y is selected from -N(R 5a )-;

Z is selected from -C(R 5b R 5c )-;

L 1 is selected from -NR 5 C(O)- and -NR 5 CON(R 6 )-, wherein NR 5 is bonded to the nitrogen-containing heteroaryl group substituted by R 1 , R 2 , R 3 ;

L 2 is selected from C 1 -C 4 alkylene, wherein the alkylene group may be optionally substituted by one or more G 2 ;

L 3 is selected from the group consisting of a chemical single bond and -O-;

R 1 , R 2 , R 3 are each independently selected from the group consisting of hydrogen, halogen, and C1-C4 alkyl, wherein the alkyl group is optionally substituted with one or more halogens;

R 5a , R 5b and R 5c are each independently selected from hydrogen, C1-C4 alkyl, wherein the alkyl group is optionally substituted by one or more substituents selected from the group consisting of halogen, -OR 10 , -NR 11 R 12 Replace

or

Any two of R 5a , R 5b , R 5c attached to an adjacent atom may form a 5- to 6-membered or 5- to 6-membered heterocyclic group optionally substituted by G 3 together with the atom to which they are attached;

R 5 and R 6 are each independently selected from hydrogen and C1-C4 alkyl;

G1 is selected from the group consisting of halogen and C1-C4 alkyl;

G2 is selected from halogen, C1-C4 alkyl, -OR 7, -NR 8 R 9 , wherein said alkyl is optionally substituted with one or more halo, -OR 10, substituted with -NR 11 R 12; when both When G2 is on the same carbon atom or an adjacent carbon atom, the two G2s, optionally together with the carbon atom to which they are attached, form a 3-6 membered cycloalkyl group, the cycloalkyl group formed optionally being one or more halogen , -OR 10 , -NR 11 R 12 replaced;

G3 is selected from the group consisting of halogen, -OR 7 and -NR 8 R 9 ;

R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are each independently selected from the group consisting of hydrogen, C1-C4 alkyl and C1-C4 haloalkyl.
The compound according to claim 1, an isomer thereof, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt thereof,

among them:

One of X 1 and X 2 is C and the other is N;

X 3 is N;

Ar is selected from the group consisting of phenylene, 2,3-pyridinylene and 1,3-pyridinone optionally substituted with one or two G1;

Y is selected from -N(R 5a )-;

Z is selected from -C(R 5b R 5c )-;

L 1 is selected from -NR 5 C(O)- and -NR 5 CON(R 6 )-, wherein NR 5 is bonded to the nitrogen-containing heteroaryl group substituted by R 1 , R 2 , R 3 ;

L 2 is selected from a C 1 -C 4 alkylene group, wherein the alkylene group may be optionally substituted by one or two G 2 ;

L 3 is selected from the group consisting of a chemical single bond and -O-;

R 1 , R 2 , and R 3 are each independently selected from the group consisting of hydrogen and halogen;

R 5a , R 5b and R 5c are each independently selected from hydrogen, C1-C4 alkyl, wherein the alkyl group is optionally substituted by one or more substituents selected from the group consisting of halogen, -OR 10 , -NR 11 R 12 Replace

or

Any two of R 5a , R 5b , R 5c attached to an adjacent atom may form a 5- to 6-membered or 5- to 6-membered heterocyclic group optionally substituted by G 3 together with the atom to which they are attached;

R 5 and R 6 are each independently selected from hydrogen and C1-C4 alkyl;

G1 is selected from the group consisting of halogen and C1-C4 alkyl;

G2 is selected from halogen, C1-C4 alkyl, -OR 7, -NR 8 R 9 , wherein said alkyl is optionally substituted with one or more halo, -OR 10, substituted with -NR 11 R 12; when both When G2 is on the same carbon atom or an adjacent carbon atom, the two G2s, optionally together with the carbon atom to which they are attached, form a 3-6 membered cycloalkyl group, the cycloalkyl group formed optionally being one or more halogen , -OR 10 , -NR 11 R 12 replaced;

G3 is selected from the group consisting of halogen, -OR 7 and -NR 8 R 9 ;

R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are each independently selected from the group consisting of hydrogen, C1-C4 alkyl and C1-C4 haloalkyl.
The compound according to claim 1, an isomer thereof, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt thereof,

among them:

One of X 1 and X 2 is C and the other is N;

X 3 is N;

Ar is selected from the group consisting of phenylene, 2,3-pyridinyl and 1,3-pyridinone optionally substituted by one G1, said substituent being in the para position of L 3 ;

Y is selected from -N(R 5a )-;

Z is selected from -C(R 5b R 5c )-;

L 1 is selected from -NR 5 C(O)- and -NR 5 CON(R 6 )-, wherein NR 5 is bonded to the nitrogen-containing heteroaryl group substituted by R 1 , R 2 , R 3 ;

L 2 is selected from a C 1 -C 4 alkylene group, wherein the alkylene group may be optionally substituted by one or two G 2 ;

L 3 is selected from the group consisting of a chemical single bond and -O-;

R 1 , R 2 , and R 3 are each independently selected from the group consisting of hydrogen and halogen;

R 5a , R 5b and R 5c are each independently selected from hydrogen, C1-C4 alkyl, wherein the alkyl group is optionally substituted by one or more substituents selected from the group consisting of halogen, -OR 10 , -NR 11 R 12 Replace

or

Any two of R 5a , R 5b , R 5c attached to an adjacent atom may form a 5- to 6-membered or 5- to 6-membered heterocyclic group optionally substituted by G 3 together with the atom to which they are attached;

R 5 and R 6 are each independently selected from hydrogen and C1-C4 alkyl;

G1 is selected from halogen;

G2 is selected from halogen, C1-C4 alkyl, -OR 7, -NR 8 R 9 , wherein said alkyl is optionally substituted with one or more halo, -OR 10, substituted with -NR 11 R 12; when both When G2 is on the same carbon atom or an adjacent carbon atom, the two G2s, optionally together with the carbon atom to which they are attached, form a 3-6 membered cycloalkyl group, the cycloalkyl group formed optionally being one or more halogen , -OR 10 , -NR 11 R 12 replaced;

G3 is selected from the group consisting of halogen, -OR 7 , and -NR 8 R 9 ;

R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are each independently selected from the group consisting of hydrogen, C1-C4 alkyl and C1-C4 haloalkyl.
The compound according to claim 1, an isomer thereof, a prodrug, a stable isotopic derivative or a pharmaceutically acceptable salt thereof, wherein the compound is:

And their isomers, prodrugs, solvates, stable isotopic derivatives or pharmaceutically acceptable salts thereof.
A pharmaceutical composition comprising a compound according to any one of claims 1 to 10, or an isomer thereof, a prodrug, a stable isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable Carrier, diluent, excipient.
The compound according to any one of claims 1 to 10, or an isomer thereof, a prodrug, a stable isotopic derivative or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 11 in the preparation of a medicament Use of the medicament for the treatment or prevention of a TRK-mediated disease, such as cancer, especially hematological malignancies, lung cancer, breast cancer, ovarian cancer, prostate cancer, pancreatic cancer, glioma.