Compounds, pharmaceutical compositions, and preparation methods and uses thereof as MASP-2 inhibitors

Abstract

The present invention relates to compounds having complement lectin pathway inhibitory activity, methods for preparing the compounds, and uses thereof. Specifically, the present invention relates to a compound represented by general formula (I'), a pharmaceutically acceptable salt thereof, a method for preparing the compounds, and uses thereof as MASP-2 inhibitors, particularly in the preparation of medicaments for treating diseases such as IgA nephropathy, TA-TMA, aHUS, and lupus nephritis.

Description

[0001] This application claims priority to a prior application filed with the State Intellectual Property Office of China on January 28, 2022, with patent application number 202210116158.X, entitled “Compounds, pharmaceutical compositions, preparation methods and uses thereof as MASP-2 inhibitors”, the entire text of which is incorporated herein by reference. Technical Field

[0002] The present invention belongs to the field of medicine, and in particular relates to a compound serving as a MASP-2 inhibitor, a pharmaceutical composition, and a preparation method and use thereof. Background Art

[0003] In addition to Ig molecules, another class of macromolecules involved in immune responses is found in blood or body fluids, known as complement molecules. These molecules are a group of enzymatically active immunoglobulins, accounting for approximately 10% of the total serum globulin content. Complement molecules are extremely unstable, with most being heat-sensitive and losing their activity within 30 minutes at 56°C. Early immunological research revealed that complement is essential for hemolytic and bacteriolytic reactions, hence the name complement. Recent research has confirmed that complement is composed of 11 serum proteins, designated C1 through C9, according to the order of their discovery. C1, in turn, consists of three subunits: Clq, Clr, and Cls, collectively referred to as the complement system.

[0004] The complement system can be activated through three independent yet overlapping pathways: the classical pathway, the alternative pathway, and the lectin pathway. The three complement activation pathways include the classical pathway (C1q, C1r, C1s, C4, C2, C3, C5, and C6-9); the mannan-binding lectin pathway (MBL pathway): MBL, MASP1-2, C4, C2, C3, C5, and C6-9; and the alternative pathway (alternative pathway): C3, factor B, factor D, factor P (properdin), C5, and C6-9.

[0005] Activation of the lectin pathway is initiated by the binding of mannose-binding lectin (MBL), collectin 11 (CL-K1), and ficolins (ficolin-1, ficolin-2, and ficolin-3) to pathogen-associated molecular patterns (PAMPs) (D-mannose, N-acetyl-D-glucosamine, or acetyl groups). Upon binding to the target molecule, MBL, CL-K1, and ficolins form a complex with MBL-associated serine proteases 1 and 2 (MASP-1 and MASP-2) and cleave C4 and C2 to form C3 convertase (C4b2a). Subsequently, activation of the complement cascade leads to opsonization, phagocytosis, and lysis of the target microorganism through the formation of the membrane attack complex.

[0006] Mannose-binding lectin-associated serine protease 2 (MASP-2) is an effector enzyme of the complement system's lectin pathway. Currently, the most rapidly developing projects targeting the complement lectin pathway are all antibody-related. For example, the MASP-2-targeting monoclonal antibody Narsoplimab (OMS-721) has been granted Breakthrough Therapy Designation for the treatment of high-risk HSCT-TMA patients, Orphan Drug Designation for the prevention of complement-mediated thrombotic microangiopathy (TMA), and for the treatment of HSCT-TMA in the United States. It has also been granted Orphan Drug Designation for the treatment of hematopoietic stem cell transplantation (HSCT) in the European Union. Narsoplimab is currently in Phase III clinical trials for the treatment of IgA nephropathy (IgAN) and atypical hemolytic uremic syndrome (aHUS). Previously, the drug was granted Orphan Drug and Breakthrough Therapy Designations for the treatment of IgAN, Fast Track Designation for the treatment of aHUS, and Orphan Drug Designation for the treatment of IgAN in the European Union.

[0007] MASP-2-dependent complement activation has been implicated in the pathogenesis of numerous acute and chronic disease states. Thus, there is a need for small molecule compounds useful in the treatment of diseases and disorders associated with the MASP-2 complement pathway. Summary of the Invention

[0008] To improve the above technical problems, the present invention provides a compound represented by formula (I'), its racemate, stereoisomer, tautomer, nitrogen oxide or pharmaceutically acceptable salt thereof:

[0009]

[0010] in:

[0011] Cy 3 Selected from

[0012] Z is selected from CR 2 or N;

[0013] R 1 、R 2 and R 3 are independently selected from H, halogen, -NH2, -OH, -NO2, -CN, C 1-6 Alkyl, C 1-6 aminoalkyl or C 1-6 alkoxy;

[0014] X is selected from CR 4 or N; R 4 Selected from H, halogen, C 1-6 Alkyl or C 1-6 alkoxy;

[0015] Y is selected from -CH2-, -C(C1-3 alkyl) 2-, -NH-, -O- or -S-; m is selected from 0, 1, 2 or 3;

[0016] Each R is the same or different and is independently selected from H, halogen, C 1-6 Alkyl or C 1-6 alkoxy;

[0017] p is selected from 0, 1, 2, 3 or 4;

[0018] R 5 Selected from H, C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Haloalkyl or C 3-6 Cycloalkyl;

[0019] R 5’ Selected from H or C 1-6 alkyl;

[0020] or R 5 and R 5’ Together with the carbon atom to which they are attached, they form C 3-6 Cycloalkyl;

[0021] R 6 Selected from H or C 1-6 alkyl;

[0022] or R 5 and R 6 Together with the C and N atoms to which they are attached, they form a 3-12 membered heterocycloalkyl group which is unsubstituted or optionally substituted with 1, 2 or 3 R 5a replaced by;

[0023] Each R 5a the same or different, independently selected from halogen, C 1-6 Alkyl, -OH, -NO2, -CN, oxo (=O), C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy; or R on the same carbon or on two adjacent carbons 5a Together with the carbon atom to which they are attached, they form C 3-6 Cycloalkyl, the C 3-6 Cycloalkyl is unsubstituted or optionally substituted with 1, 2 or 3 halogens;

[0024] Cy 1 is selected from unsubstituted or optionally substituted with 1, 2, 3 or 4 R 7Substituted: 5-8 membered heterocyclic group or 5-6 membered heteroaryl group;

[0025] Each R 7 The same or different, independently selected from H, oxo (=O), halogen or C 1-6 alkyl;

[0026] L is selected from -(CR a R b ) q -or-(CR a R b ) q -O-, q is selected from 0, 1 or 2, each R a and R b The same or different, independently selected from H, halogen or C 1-6 Alkyl, or R a and R b Together with the carbon atom to which they are attached, they form C 3-6 Cycloalkyl;

[0027] Cy 2 is selected from unsubstituted or optionally substituted with 1, 2, 3 or 4 R 8 Substituted with the following groups: C 6-10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl or 5-12 membered heterocyclic group;

[0028] Each R 8 the same or different, independently selected from -CN, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 3-10 Cycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl.

[0029] According to an embodiment of the present invention, the compound represented by formula (I') has the structure represented by the following formula (I):

[0030]

[0031]

[0032] in:

[0033] R 1 、R 2 and R 3 are independently selected from H, halogen, -NH2, -OH, -NO2, -CN, C 1-6 Alkyl, C 1-6 aminoalkyl or C1-6 alkoxy;

[0034] X is selected from CR 4 or N; R 4 Selected from H, halogen, C 1-6 Alkyl or C 1-6 alkoxy;

[0035] Y is selected from -CH2-, -C(C 1-3 alkyl) 2-, -NH-, -O- or -S-; m is selected from 0, 1, 2 or 3;

[0036] Each R is the same or different and is independently selected from H, halogen, C 1-6 Alkyl or C 1-6 alkoxy;

[0037] p is selected from 0, 1, 2, 3 or 4;

[0038] R 5 Selected from H, C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Haloalkyl or C 3-6 Cycloalkyl; R 6 Selected from H or C 1-6 Alkyl, or R 5 and R 6 Together with the C and N atoms to which they are attached, they form a 3-12 membered heterocycloalkyl group which is unsubstituted or optionally substituted with 1, 2 or 3 R 5a replaced by;

[0039] Each R 5a the same or different, independently selected from halogen, C 1-6 Alkyl, -OH, -NO2, -CN, oxo (=O), C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy; or R on the same carbon or on two adjacent carbons 5a Together with the carbon atom to which they are attached, they form C 3-6 Cycloalkyl, the C 3-6 Cycloalkyl is unsubstituted or optionally substituted with 1, 2 or 3 halogens;

[0040] Cy 1 is selected from unsubstituted or optionally substituted with 1, 2, 3 or 4 R 7 Substituted: 5-8 membered heterocyclic group or 5-6 membered heteroaryl group;

[0041] Each R 7The same or different, independently selected from H, oxo (=O), halogen or C 1-6 alkyl;

[0042] L is selected from -(CR a R b ) q -or-(CR a R b ) q -O-, q is selected from 0, 1 or 2, each R a and R b The same or different, independently selected from H, halogen or C 1-6 Alkyl, or R a and R b Together with the carbon atom to which they are attached, they form C 3-6 Cycloalkyl;

[0043] Cy 2 is selected from unsubstituted or optionally substituted with 1, 2, 3 or 4 R 8 Substituted with the following groups: C 6-10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl or 5-12 membered heterocyclic group;

[0044] Each R 8 the same or different, independently selected from -CN, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 3-10 Cycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl.

[0045] According to an embodiment of the present invention, the compound represented by formula (I') has the structure represented by the following formula (I):

[0046]

[0047] in:

[0048] R 1 、R 2 and R 3 are independently selected from H, halogen, -NH2, -OH, -NO2, -CN, C 1-6 Alkyl or C 1-6 alkoxy;

[0049] X is selected from CR 4 or N; R 4 Selected from H, halogen, C 1-6 Alkyl or C 1-6 alkoxy;

[0050] Y is selected from -CH2-, -NH-, -O- or -S-; m is selected from 0, 1, 2 or 3;

[0051] Each R is the same or different and is independently selected from H, halogen, C 1-6 Alkyl or C 1-6 Alkoxy; p is selected from 0, 1, 2, 3 or 4;

[0052] R 5 and R 6 are independently selected from H or C 1-6 Alkyl, or R 5 and R 6 Together with the C and N atoms to which they are attached, they form a 3-12 membered heterocycloalkyl group;

[0053] Cy 1 is selected from unsubstituted or optionally substituted with 1, 2, 3 or 4 R 7 Substituted: 5-6 membered heterocyclic group or 5-6 membered heteroaryl group;

[0054] Each R 7 The same or different, independently selected from H, halogen or C 1-6 alkyl;

[0055] L means -(CR a R b ) p -, p is selected from 0, 1 or 2, each R a and R b The same or different, independently selected from H, halogen or C 1-6 Alkyl, or R a and R b Together with the carbon atom to which they are attached, they form C 3-6 Cycloalkyl;

[0056] Cy 2 is selected from unsubstituted or optionally substituted with 1, 2, 3 or 4 R 8 Substituted with the following groups: C 6-10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl or 5-12 membered heterocyclic group;

[0057] Each R 8 The same or different, independently selected from CN, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 3-10 Cycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl.

[0058] According to an embodiment of the present invention, when Cy 1 Through the chiral carbon atom on its ring and -C(=O)NR 6 -When connected, the compound represented by formula (I') has the structure represented by formula (II):

[0059]

[0060] Among them, R 5 Selected from C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Haloalkyl or C 3-6 Cycloalkyl; m, p, X, Y, R, R 1 、R 2 、R 3 、R 6 ,L,Cy 1 and Cy 2 As defined herein.

[0061] According to an embodiment of the present invention, when Cy 1 Through the chiral carbon atom on its ring and -C(=O)NR 6 -When connected, the compound represented by formula (I) has the structure represented by formula (II):

[0062]

[0063] Among them, R 5 C 1-6 Alkyl; m, p, X, Y, R, R 1 、R 2 、R 3 、R 6 ,L,Cy 1 and Cy 2 As defined herein.

[0064] According to an embodiment of the present invention, the compound represented by formula (I') has a structure represented by any one of the following formulas (Ia) to (I-j'):

[0065]

[0066]

[0067] Among them, R 5 Selected from C 1-3 Alkyl, C 2-3 Alkynyl, C 1-3 Haloalkyl or C 3-4 Cycloalkyl; R 5a are independently selected from halogen, C 1-3Alkyl, -OH, -NO2, -CN, oxo (=O), C 1-3 Halogenated alkyl, C 1-3 Alkoxy or C 1-3 Haloalkoxy; or R on the same carbon or on two adjacent carbons 5a Together with the carbon atom to which they are attached, they form C 3-6 Cycloalkyl, the C 3-6 Cycloalkyl is unsubstituted or optionally substituted with 1, 2 or 3 halogens; n is 0, 1, 2 or 3; m, X, R 1 、R 2 、R 3 、R 7 , L and Cy 2 As defined herein.

[0068] According to an embodiment of the present invention, the compound represented by formula (I) has a structure represented by any one of the following formulas (Ia) to (Ij):

[0069]

[0070]

[0071] Among them, R 5 C 1-3 Alkyl; m, X, R 1 、R 2 、R 3 、R 5 、R 7 , L and Cy 2 As defined herein.

[0072] According to an embodiment of the present invention, the compound represented by formula (I') has a structure represented by any one of the following formulas (Il) to (I-u'):

[0073]

[0074]

[0075] Among them, R 5 Selected from C 1-3 Alkyl, C 2-3 Alkynyl, C 1-3 Haloalkyl or C 3-4 Cycloalkyl; R 5a are independently selected from halogen, C 1-3 Alkyl, -OH, -NO2, -CN, oxo (=O), C 1-3 Halogenated alkyl, C 1-3 Alkoxy or C 1-3 Haloalkoxy; or R on the same carbon or on two adjacent carbons5a Together with the carbon atom to which they are attached, they form C 3-6 Cycloalkyl, the C 3-6 Cycloalkyl is unsubstituted or optionally substituted with 1, 2 or 3 halogens; n is 0, 1, 2 or 3; m, X, R 1 、R 2 、R 3 、R 7 , L and Cy 2 As defined herein.

[0076] According to an embodiment of the present invention, the compound represented by formula (I) has a structure represented by any one of the following formulas (Il) to (Iu):

[0077]

[0078]

[0079] Among them, R 5 C 1-3 Alkyl; m, X, R 1 、R 2 、R 3 、R 5 、R 7 , L and Cy 2 As defined herein.

[0080] According to an embodiment of the present invention, the compound represented by formula (I') has a structure represented by any one of the following formulas (Iv) to (I-z'):

[0081]

[0082]

[0083] Among them, R 5 is selected from methyl, ethyl, ethynyl, propynyl, -CH2F, -CHF2, -CF3 or cyclopropyl; R 5a are independently selected from halogen, methyl, ethyl, -CH2F, -CHF2, -CF3 or methoxy; or R on the same carbon or on two adjacent carbons 5a Together with the carbon atoms to which they are attached, they form a cyclopropyl or cyclobutyl group, said cyclopropyl and cyclobutyl groups being unsubstituted or optionally substituted with 1, 2 or 3 halogens; n is 0, 1, 2 or 3; m, X, R 1 、R 2 、R 3 、R 7 , L and Cy 2 As defined herein.

[0084] According to an embodiment of the present invention, Cy 3 Selected from the following structural formula:

[0085] According to an embodiment of the present invention, Cy 3 Selected from the following structural formula:

[0086] According to an embodiment of the present invention, Cy 3 Selected from the following structural formula:

[0087] According to an embodiment of the present invention, R 5 Selected from H, C 1-3 Alkyl, C 2-3 Alkynyl, C 1-3 Haloalkyl or C 3-4 Cycloalkyl; R 5’ Selected from H or C 1-3 Alkyl; or R 5 and R 5’ Together with the carbon atom to which they are attached, they form C 3-4 Cycloalkyl.

[0088] According to an embodiment of the present invention, R 5 R is selected from H, methyl, ethyl, ethynyl, propynyl, -CH2F, -CHF2, -CF3 or cyclopropyl; 5’ is selected from H, methyl or ethyl; or R 5 and R 5’ Together with the carbon atom to which they are attached they form a cyclopropyl group.

[0089] According to an embodiment of the present invention, R 1 、R 2 and R 3 are independently selected from H, F, Cl, Br, -NH2, -OH, -CN, methyl, ethyl, -CH2NH2 or methoxy.

[0090] According to an embodiment of the present invention, R 1 Selected from H, F, Cl, Br, -NH2 or methyl.

[0091] According to an embodiment of the present invention, R 2 is selected from H, F, Cl, Br, -CN, methyl, ethyl or methoxy.

[0092] According to an embodiment of the present invention, R 3 is selected from H, F, -NH2, -OH, -CH2NH2 or methoxy.

[0093] According to an embodiment of the present invention, X is selected from CR 4 or N; R 4 is selected from H, halogen, methyl or ethyl.

[0094] According to an embodiment of the present invention, Y is selected from -CH2-, -C(CH3)2-, -NH- or -O-; m is selected from 0, 1 or 2.

[0095] According to an embodiment of the present invention, each R is the same or different and is independently selected from H, halogen, C 1-3 Alkyl or C 1-3 Alkoxy; p is selected from 0, 1 or 2.

[0096] According to an embodiment of the present invention, R 5 Selected from H, methyl or ethyl.

[0097] According to an embodiment of the present invention, R 6 Selected from H, methyl or ethyl.

[0098] According to an embodiment of the present invention, R 5 and R 6 Together with the C and N atoms to which they are attached, they form a 4-, 5- or 6-membered heterocycloalkyl group which is unsubstituted or optionally substituted with 1, 2 or 3 R 5a Replaced by; R 5a independently selected from F, Cl, Br, methyl or ethyl; or R on the same carbon or on two adjacent carbons 5a Together with the carbon atom to which they are attached they form a cyclopropyl or cyclobutyl group, said cyclopropyl and cyclobutyl groups being unsubstituted or optionally substituted with 1, 2 or 3 halogens.

[0099] According to an embodiment of the present invention, R 5 and R 6 Together with the C and N atoms to which they are attached, they form a 4-membered, 5-membered or 6-membered heterocycloalkyl group.

[0100] According to an embodiment of the present invention, R 5 and R 6 Together with the C and N atoms to which they are attached, they form the following structure:

[0101] The structure formed is preferably selected from:

[0102] According to an embodiment of the present invention, L is absent or selected from -C(R a )(R b )-, -O- or -C(Ra )(R b )-O-,R a and R b are independently H, halogen, methyl or ethyl, or R a and R b Together with the carbon atom to which they are attached they form a cyclopropyl or cyclobutyl group.

[0103] According to an embodiment of the present invention, L is absent or selected from -CH 2- , -CH(CH3)-, -CF2-, -O-, -CH2-O-, -CH(CH3)-O- or

[0104] According to an embodiment of the present invention, Cy 1 Selected from unsubstituted or substituted with 1 or 2 R 7 Substituted from the following groups: tetrahydropyrrolyl, 2,5-dihydro-1H-pyrrolyl, pyrrolyl, piperidinyl, 1,2,3,6-tetrahydropyridinyl, 1,2,5,6-tetrahydropyridinyl, piperazinyl, 4-azaspiro[2.5]octanyl, 1,2-dihydropyridinyl or 1,4-dihydropyrazinyl; each R 7 are the same or different and are independently selected from H, oxo (=O), F, Cl or CH3.

[0105] According to an embodiment of the present invention, Cy 1 Select from the following structures:

[0106]

[0107] Preferably selected from:

[0108]

[0109]

[0110] According to an embodiment of the present invention, Cy 2 is selected from unsubstituted or optionally substituted with 1, 2, 3 or 4 R 8 Substituted with the following groups: C 6-10 aryl, 5-9 membered heteroaryl or 6-11 membered heterocyclic group; each R 8 are the same or different and are independently selected from -CN, F, Br, Cl, -CH2F, -CHF2, -CF3, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, methoxy, ethoxy, phenyl, pyridyl or trifluoromethoxy.

[0111] According to an embodiment of the present invention, Cy 2 is selected from unsubstituted or optionally substituted with 1, 2, 3 or 4 R 8Substituted with the following groups: C 6-10 aryl, 6-9 membered heteroaryl or 6-11 membered heterocyclic group; each R 8 are identical or different and are independently selected from F, Br, Cl, CH2F, CHF2, CF3, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, methoxy, ethoxy, phenyl, pyridyl or trifluoromethoxy.

[0112] According to an embodiment of the present invention, Cy 2 Selected from unsubstituted or substituted with 1, 2, 3 or 4 R 8 substituted phenyl, naphthyl, pyrrolyl, pyridyl, benzothiazolyl, piperidinyl, 6-azaspiro[2.5]octyl, 7-azaspiro[3.5]nonyl, 8-azaspiro[4.5]decyl or 3-azaspiro[5.5]undecyl; each R 8 are identical or different and are independently selected from F, Br, Cl, CH2F, CHF2, CF3, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, methoxy, ethoxy, phenyl, pyridyl or trifluoromethoxy.

[0113] According to an embodiment of the present invention, Cy 2 Select from the following structures:

[0114]

[0115] According to an embodiment of the present invention, Cy 3 Select from the following structures:

[0116] R 1 、R 2 and R 3 independently selected from H, F, Cl, Br, -NH2, -OH, -CN, C 1-3 Alkyl or C 1-3 aminoalkyl;

[0117] R 4 Selected from H, halogen or C 1-3 alkyl;

[0118] Y is selected from -CH2-, -C(CH3)2-, -NH-, -O- or -S-; m is selected from 0, 1 or 2;

[0119] Each R is the same or different and is independently selected from H, halogen or C 1-3 Alkyl; p is selected from 0, 1 or 2;

[0120] R 5 Selected from H, C 1-3 Alkyl, C2-3 Alkynyl, C 1-3 Haloalkyl or C 3-4 Cycloalkyl;

[0121] R 5’ Selected from H or C 1-3 alkyl;

[0122] or R 5 and R 5’ Together with the carbon atom to which they are attached, they form C 3-4 Cycloalkyl;

[0123] R 6 Selected from H or C 1-3 alkyl;

[0124] Or, R 5 and R 6 Together with the C and N atoms to which they are attached, they form a 4-, 5- or 6-membered heterocycloalkyl group which is unsubstituted or optionally substituted with 1, 2 or 3 R 5a Replaced by; R 5a independently selected from F, Cl, Br, methyl or ethyl; or R on the same carbon or on two adjacent carbons 5a Together with the carbon atom to which they are attached, they form cyclopropyl or cyclobutyl, said cyclopropyl and cyclobutyl being unsubstituted or optionally substituted with 1, 2 or 3 halogens;

[0125] L is absent or selected from -C(R a )(R b )-, -O- or -C(R a )(R b )-O-,R a and R b are independently selected from H, halogen or C 1-3 Alkyl, or R a and R b Together with the carbon atom to which they are attached, they form a cyclopropyl group;

[0126] Cy 1 Selected from unsubstituted or substituted with 1 or 2 R 7 Substituted from the following groups: tetrahydropyrrolyl, 2,5-dihydro-1H-pyrrolyl, pyrrolyl, piperidinyl, 1,2,3,6-tetrahydropyridinyl, 1,2,5,6-tetrahydropyridinyl, piperazinyl, 4-azaspiro[2.5]octanyl, 1,2-dihydropyridinyl or 1,4-dihydropyrazinyl; each R 7 are the same or different and are independently selected from H, oxo (=O), F or Cl;

[0127] Cy 2Selected from unsubstituted or substituted with 1, 2, 3 or 4 R 8 Substituted from the following groups: phenyl, naphthyl, pyrrolyl, pyridyl, benzothiazolyl, piperidinyl, 6-azaspiro[2.5]octyl, 7-azaspiro[3.5]nonyl, 8-azaspiro[4.5]decyl or 3-azaspiro[5.5]undecyl;

[0128] Each R 8 are the same or different and are independently selected from -CN, F, Cl, -CH2F, -CHF2, CF3, methyl, ethyl, n-propyl, isopropyl, tert-butyl, methoxy, phenyl, pyridyl or trifluoromethoxy.

[0129] According to an embodiment of the present invention,

[0130] R 1 、R 2 and R 3 independently selected from H, F, Cl, Br, -NH2, -OH or C 1-3 alkyl;

[0131] X is selected from CR 4 or N;

[0132] R 4 Selected from H, halogen or C 1-3 alkyl;

[0133] Y may be selected from -CH2- or -NH-;

[0134] m is selected from 0, 1 or 2;

[0135] Each R may be the same or different and is independently selected from H, halogen or C 1-3 Alkyl; p may be selected from 0, 1 or 2;

[0136] R 5 Can be selected from H or C 1-3 alkyl;

[0137] R 6 Can be selected from H or C 1-3 alkyl;

[0138] Or, R 5 and R 6 Together with the C and N atoms to which they are attached, they form a 4-, 5- or 6-membered heterocycloalkyl group;

[0139] L may be absent or selected from -C(R a )(R b )-,R a and R b are independently H, halogen or C 1-3 Alkyl, or Ra and R b Together with the carbon atom to which they are attached, they form a cyclopropyl group;

[0140] Cy 1 Can be selected from unsubstituted or substituted with 1 or 2 R 7 Substituted from the following groups: tetrahydropyrrolyl, 2,5-dihydro-1H-pyrrolyl, pyrrolyl, piperidinyl, 1,2,3,6-tetrahydropyridinyl, 1,2,5,6-tetrahydropyridinyl or piperazinyl; R 7 is selected from H, F or Cl;

[0141] Cy 2 can be selected from unsubstituted or substituted with 1, 2, 3 or 4 R 8 Substituted from the following groups: phenyl, naphthyl, pyridyl, benzothiazolyl, piperidinyl, 6-azaspiro[2.5]octyl, 7-azaspiro[3.5]nonyl, 8-azaspiro[4.5]decyl or 3-azaspiro[5.5]undecyl;

[0142] Each R 8 They may be identical or different and independently selected from F, Cl, CF3, methyl, isopropyl, tert-butyl, methoxy, phenyl, pyridyl or trifluoromethoxy.

[0143] According to an embodiment of the present invention, Cy 3 Select from the following structures:

[0144] R 1 Selected from H, F, Cl, -NH2 or methyl;

[0145] R 2 Selected from H, F, Cl, -CN or methyl;

[0146] R 3 Selected from H, F, -NH2, -OH, -CH2NH2 or methoxy;

[0147] R 4 Selected from H or F;

[0148] Y is selected from -CH2-, -C(CH3)2-, -NH- or -O-;

[0149] m is 1 or 2;

[0150] R is selected from H, methyl or ethyl;

[0151] R 5 is selected from H, methyl, ethyl, ethynyl, propynyl, -CH2F, -CHF2, -CF3 or cyclopropyl;

[0152] R5’ Selected from H, methyl or ethyl;

[0153] or R 5 and R 5’ Together with the carbon atom to which they are attached, they form a cyclopropyl group;

[0154] R 6 is H;

[0155] Or, R 5 and R 6 Together with the C and N atoms to which they are attached, they form the following structure:

[0156] The structure formed is preferably selected from:

[0157] L may be absent or selected from -CH2-, -CH(CH3)-, -CF2-, -O-, -CH2-O- or

[0158] Cy 1 The structure can be selected from the following:

[0159]

[0160] Preferably selected from:

[0161] and / or

[0162] Cy 2 The structure can be selected from the following:

[0163]

[0164]

[0165] According to an embodiment of the present invention, R 1 Can be selected from H or F;

[0166] R 2 Can be selected from H, F, Cl or methyl;

[0167] R 3 Can be selected from -NH2, -OH or methoxy;

[0168] X can be selected from CR 4 or N; R 4 Selected from H or F;

[0169] Y can be selected from -CH2-; m is 1 or 2;

[0170] R may be selected from H;

[0171] R 5 Can be selected from H or methyl;

[0172] R 6 Can be selected from H;

[0173] Or, R 5 and R 6 Together with the C and N atoms to which they are attached, they form the following structure: The structure formed is preferably selected from: L may be absent or selected from -CH2-, -CH(CH3)-, -CF2- or Cy 1 The structure can be selected from the following:

[0174]

[0175] Preferably selected from:

[0176] and / or Cy 2 The structure can be selected from the following:

[0177]

[0178] According to an embodiment of the present invention, the compound represented by formula (I') is selected from the structures shown below:

[0179]

[0180]

[0181]

[0182]

[0183]

[0184]

[0185]

[0186]

[0187]

[0188] Preferably, the compound represented by formula (I') is selected from the following structures:

[0189]

[0190]

[0191]

[0192]

[0193]

[0194]

[0195]

[0196]

[0197]

[0198]

[0199]

[0200] The present invention also provides a method for preparing the compound represented by formula (I'), comprising the following steps:

[0201] Compound I-A' and compound I-B' undergo condensation reaction to generate compound I-1', and then compound I-1' is deprotected to obtain a compound represented by formula (I');

[0202]

[0203] Compound I-C' undergoes a condensation reaction with compound I-D' to generate compound I-1', and then compound I-1' is deprotected to obtain a compound represented by formula (I');

[0204]

[0205] Among them, R 5 、R 5’ 、R 6 ,L,Cy 1 、Cy 2 and Cy 3 have the definitions described herein independently of one another; Cy is Cy 1 The active group is protected by PG; PG is a protecting group, for example, an amino protecting group, such as tert-butyloxycarbonyl.

[0206] The present invention also provides a method for preparing the compound represented by formula (I), comprising the following steps: condensing compound IA with compound IB to generate compound I-1, and then deprotecting compound I-1 to obtain the compound represented by formula (I);

[0207]

[0208] Compound IC and compound ID undergo condensation reaction to generate compound I-1, and then compound I-1 is deprotected to obtain the compound represented by formula (I);

[0209]

[0210] Among them, R 1 、R 2 、R 3 、R 5 、R 6 , R, X, Y, L, Cy 1 、Cy 2 , m and p are independently defined as described herein; Cy is Cy 1 The active group is protected by PG; PG is a protecting group, for example, an amino protecting group, such as tert-butyloxycarbonyl.

[0211] The present invention also provides a compound represented by formula (IA) to (IG), its racemate, stereoisomer or its hydrochloride:

[0212]

[0213] Among them, R 1 、R 2 、R 3 、R 5 、R 6 , R, X, Y, m and p are independently defined as described herein;

[0214] Preferably, the compound represented by formula (IA) is selected from the following compounds:

[0215]

[0216]

[0217] The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of at least one of the compound represented by formula (I'), its racemate, stereoisomer, tautomer, nitrogen oxide or pharmaceutically acceptable salts thereof.

[0218] According to an embodiment of the present invention, the pharmaceutical composition further comprises at least one pharmaceutically acceptable excipient.

[0219] These pharmaceutical compositions can be prepared in a manner well known in the pharmaceutical art and can be administered by a variety of routes, depending on whether local or systemic treatment is desired and the area to be treated. Administration can be topical (e.g., transdermal, skin, eye, and mucous membranes, including intranasal, vaginal, and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal, intranasal), oral, or parenteral. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal, or intramuscular injection or infusion; or intracranial, such as intrathecal or intraventricular administration. Parenteral administration can be in the form of a single large dose, or can be administered by, for example, a continuous infusion pump. Topically administered pharmaceutical compositions and preparations may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids, powder formulations, and powders. Conventional pharmaceutical carriers, water, powder or oily bases, thickeners, and the like may be necessary or desirable.

[0220] In preparing the pharmaceutical compositions of the present invention, the active ingredient is typically mixed with an excipient, diluted by the excipient, or enclosed in a carrier such as a capsule, sachet, paper, or other container. When the excipient serves as a diluent, it can be a solid, semisolid, or liquid substance that acts as a solvent, carrier, or medium for the active ingredient. Thus, the pharmaceutical compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (solid or dissolved in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.

[0221] Some examples of suitable excipients include lactose, glucose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginates, tragacanth gum, gelatin, calcium silicate, microcrystalline cellulose, polyvinyl pyrrolidone, cellulose, water, syrup and methylcellulose. The excipients may also be selected from lubricants such as talc, sodium stearate, magnesium stearate, sodium oleate, sodium benzoate, sodium acetate, sodium chloride and mineral oil; wetting agents; emulsifiers and suspending agents; preservatives such as methyl benzoate and hydroxypropyl benzoate; sweeteners and flavoring agents. The compositions of the present invention may be formulated using methods known in the art to provide immediate, sustained or delayed release of the active ingredient after administration to the patient.

[0222] The compositions can be formulated in unit dosage form, each dose containing about 5 to 1000 mg, more usually about 100 to 500 mg, of the active ingredient. The term "unit dosage form" refers to physically discrete units suitable as single dosage units for human patients and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in admixture with a suitable pharmaceutical excipient.

[0223] The effective dosage of the active compound can range widely, and is generally administered in a pharmaceutically effective amount. However, it will be understood that the actual amount of compound administered is generally determined by the physician based on relevant circumstances, including the condition being treated, the route of administration chosen, the actual compound being administered; the age, weight, and response of the individual patient; the severity of the patient's symptoms, etc.

[0224] For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition comprising a homogeneous mixture of a compound of the invention. When these preformulation compositions are referred to as homogeneous, it is meant that the active ingredient is generally evenly distributed throughout the composition, so that the composition can be readily divided into equally effective unit dosage forms such as tablets, pills, and capsules. This solid preformulation is then divided into unit dosage forms of the type described above containing, for example, about 0.1 to 1000 mg of the active ingredient of the invention.

[0225] The tablets or pills of the present invention can be coated or compounded to obtain dosage forms that provide the advantage of long-lasting action. For example, the tablet or pill contains an inner dose component and an outer dose component, the latter being a film-coated form of the former. The two components can be separated by an enteric layer that is used to prevent disintegration in the stomach so that the inner component can pass intact through the duodenum or to delay release. A variety of materials can be used for such enteric layers or coatings, including a variety of polymeric acids and mixtures of polymeric acids with such materials, such as shellac, cetyl alcohol, and cellulose acetate.

[0226] Liquid forms in which the compounds and pharmaceutical compositions of the present invention can be incorporated for oral or parenteral administration include aqueous solutions, appropriately flavored syrups, aqueous or oily suspensions; and emulsions flavored with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil; as well as elixirs and similar pharmaceutically acceptable vehicles.

[0227] Pharmaceutical compositions for inhalation or insufflation include solutions, suspensions, and powders dissolved in pharmaceutically acceptable water or organic solvents, or mixtures thereof. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. In certain embodiments, the pharmaceutical compositions are administered by the oral or nasal respiratory route for local or systemic effect. The compositions may be aerosolized using an inert gas. The aerosolized solution may be inhaled directly from a nebulizing device, or the nebulizing device may be connected to a mask curtain or intermittent positive pressure breathing machine. Pharmaceutical compositions in solution, suspension, or powder form may be administered orally or nasally using a device that delivers the formulation in an appropriate manner.

[0228] The amount of compound or pharmaceutical composition administered to a patient is not fixed and depends on the agent being administered, the purpose of administration, e.g., prevention or treatment; the patient's condition; the mode of administration; and the like. In therapeutic applications, the composition may be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. The effective dose will depend on the disease being treated and the judgment of the attending clinician, which will depend on factors such as the severity of the disease, the patient's age, weight, and general condition.

[0229] The pharmaceutical compositions administered to patients can be in the form of the pharmaceutical compositions described above. These compositions can be sterilized by conventional sterilization techniques or by filtration. Aqueous solutions can be packaged for use as is or lyophilized, and the lyophilized formulation can be mixed with a sterile aqueous carrier prior to administration. The pH of the compound formulation is typically 3 to 11, more preferably 5 to 9, and most preferably 7 to 8. It will be appreciated that the use of some of the aforementioned excipients, carriers, or stabilizers may result in the formation of pharmaceutical salts.

[0230] The therapeutic dosage of the compounds of the invention may depend, for example, on the specific therapeutic application, the method of administering the compound, the patient's health and condition, and the discretion of the prescribing physician. The proportion or concentration of the compounds of the invention in a pharmaceutical composition may vary and depend on a variety of factors, including dosage, chemical properties (e.g., hydrophobicity), and route of administration. For example, the compounds of the invention may be provided in a physiologically buffered aqueous solution containing about 0.1 to 10% (w / v) of the compound for parenteral administration. Certain typical dosages range from about 1 μg / kg to about 1 g / kg of body weight per day. In certain embodiments, the dosage range is from about 1 mg / kg to about 2000 mg / kg of body weight per day, preferably from about 50 mg / kg to about 500 mg / kg of body weight per day. The dosage will likely depend on such variables as the type and extent of the disease or condition, the general health of the particular patient, the relative biological potency of the selected compound, the excipient formulation, and its route of administration. Effective dosages may be obtained by extrapolation from dose-response curves derived from in vitro or animal model test systems.

[0231] The present invention also provides the use of the compound represented by formula (I'), its racemate, stereoisomer, tautomer, nitrogen oxide or pharmaceutically acceptable salt thereof, and the pharmaceutical composition thereof in preparing drugs.

[0232] According to an embodiment of the present invention, the medicament is used for preventing and / or treating diseases associated with the complement lectin pathway.

[0233] According to an embodiment of the present invention, the drug is a MASP-2 inhibitory agent.

[0234] The present invention also provides the use of the compound represented by formula (I'), its racemate, stereoisomer, tautomer, nitrogen oxide or pharmaceutically acceptable salts thereof and the above-mentioned pharmaceutical composition in treating and / or preventing diseases related to the complement lectin pathway.

[0235] The present invention also provides a method for treating and / or preventing diseases related to the complement lectin pathway, comprising administering to a patient a therapeutically or preventively effective amount of at least one of the compounds represented by formula (I'), their racemates, stereoisomers, tautomers, nitrogen oxides, or pharmaceutically acceptable salts thereof, and the aforementioned pharmaceutical compositions.

[0236] According to an embodiment of the present invention, the disease associated with the complement lectin pathway is selected from thrombotic microangiopathy (TMA), kidney disease, respiratory distress syndrome caused by coronavirus infection, blood system disease, complications caused by type I or type II diabetes, cardiovascular disease or disorder, inflammatory gastrointestinal disorder, lung disorder, ophthalmic disease or disorder, ocular angiogenesis disease or disorder, disseminated intravascular coagulation (DIC) or other complement-mediated coagulation disorder, angiogenesis-dependent cancer or tumor, peripheral nervous system and / or central nervous system disorder or injury, sepsis or disorder caused by sepsis, inflammatory response caused by tissue or organ transplantation, ischemia-reperfusion injury, graft-versus-host disease, diffuse alveolar hemorrhage (DAH), veno-occlusive disease (VOD), skin disorder, endocrine disorder, atherosclerosis or autoimmune disease; the thrombotic microangiopathy is selected from thrombotic thrombocytopenic purpura (TTP), refractory TTP, Upshaw disease, Schulman syndrome (USS), hemolytic uremic syndrome (HUS), atypical hemolytic syndrome (aHUS), non-H factor-dependent atypical hemolytic syndrome, aHUS secondary to infection, plasma therapy-resistant aHUS, TMA secondary to cancer, TMA secondary to chemotherapy, TMA secondary to transplantation, or TMA associated with hematopoietic stem cell transplantation (HSCT-TMA); the kidney disease is selected from IgA nephropathy, mesangial proliferative glomerulonephritis, membranous glomerulonephritis, membranoproliferative glomerulonephritis, acute post-infectious glomerulonephritis, C3 glomerulopathy, cryoglobulinemia glomerulonephritis, pauci-immune necrotizing crescentic glomerulonephritis, lupus nephritis, or Henoch-Schonlein purpura nephritis; the respiratory distress syndrome caused by coronavirus infection is selected from respiratory distress syndrome caused by influenza A virus, influenza B virus, or influenza C virus, and SARS-COV-2, SA Respiratory distress syndrome caused by RS-COV or MERS-COV; the blood system disease is selected from paroxysmal nocturnal hemoglobinuria (PNH), cold agglutinin syndrome, disseminated intravascular coagulation or autoimmune hemolytic anemia; the inflammatory gastrointestinal disorder is selected from pancreatitis, Crohn's disease, ulcerative colitis, irritable bowel syndrome or inflammatory bowel disease (IBD); the peripheral nervous system and / or central nervous system disorder or injury is selected from multiple sclerosis (MS), myasthenia gravis (MG), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), Guillain-Barre syndrome, post-stroke reperfusion, degenerative intervertebral disc, brain trauma, Parkinson's disease (PD), Alzheimer's disease (AD), Miller-Ferguson syndrome, brain trauma and / or hemorrhage, traumatic brain injury, demyelination or meningitis; the autoimmune disease is selected from systemic lupus erythematosus, rheumatoid arthritis, psoriatic arthritis, polymyositis or psoriasis.

[0237] According to an embodiment of the present invention, the disease associated with the complement lectin pathway is selected from kidney disease, thrombotic microangiopathy (TMA), atypical hemolytic syndrome (aHUS), thrombotic microangiopathy (TMA), ischemia-reperfusion injury, aHUS secondary to infection, ophthalmic disease, inflammatory gastrointestinal disease, lung disease, inflammatory response caused by organ or tissue transplantation surgery, blood disease, complications caused by type I or type II diabetes, wherein the kidney disease is selected from immunoglobulin A nephropathy (IgA nephropathy), C3 glomerulopathy, lupus nephritis, glomerulonephritis, etc.

[0238] Beneficial effects

[0239] The compounds of the present invention can be used to prevent and / or treat diseases associated with the complement lectin pathway, as well as to prepare medicaments for diseases associated with the complement lectin pathway. The compounds have excellent inhibitory activity against MASP-2 and have excellent pharmacokinetic and pharmacodynamic activities.

[0240] Definitions and Explanations of Terms

[0241] Unless otherwise indicated, the definitions of groups and terms in this specification and claims, including definitions used as examples, exemplary definitions, preferred definitions, definitions in tables, and definitions of specific compounds in the Examples, may be arbitrarily combined and coupled with one another. The group definitions and compound structures resulting from such combinations and couplings should be understood to be within the scope of this specification and / or claims.

[0242] The term "C n-m ” and “C n -C m ", where n and m are integers, represents a group containing n to m carbon atoms. Examples include C 1-6 、C 1-3 etc. The term is intended to specifically disclose each member within the scope, i.e., C n 、C n+1 、C n+2 ......C m-2 、C m-1 、C m For example, C 1-6 Intended to disclose C1, C2, C3, C4, C5 and C6. n-m " means the same as "C n -C m "same.

[0243] The term "n-membered," where n is an integer, generally describes a ring wherein the number of atoms forming the ring is n.

[0244] The term "nm-membered," where n and m are integers, describes a range in which the number of ring atoms is n to m. For example, piperidinyl is an example of a 6-membered heterocycloalkyl ring, pyrazolyl is an example of a 5-membered heteroaryl ring, and pyridinyl is an example of a 6-membered heteroaryl ring.

[0245] Unless otherwise indicated, numerical ranges recited in this specification and claims are equivalent to reciting at least each specific integer value therein. For example, the numerical range "1-20" is equivalent to reciting each integer value in the numerical range "1-20", namely, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20.

[0246] Depending on their molecular structure, the compounds of the present invention may be chiral (having one or more stereocenters), and unless otherwise indicated, all stereoisomers, such as enantiomers and diastereomers, are desired. Thus, these compounds may exist in racemic or optically active forms. The compounds of the present invention encompass isomers or mixtures thereof, racemates, in which each chiral carbon is in the R or S configuration. The compounds of the present invention or their intermediates can be separated into enantiomeric compounds by chemical or physical methods well known to those skilled in the art, or used in this form for synthesis. In the case of racemic amines, diastereomers are prepared from the mixture by reaction with an optically active resolving agent. Examples of suitable resolving agents are optically active acids, such as R and S forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, appropriate N-protected amino acids (e.g., N-benzoylproline or N-phenylsulfonylproline), or various optically active camphorsulfonic acids. Chromatographic enantiomer resolution can also be advantageously performed with the aid of optically active resolving agents (e.g., dinitrobenzoylphenylglycine, cellulose triacetate, or other carbohydrate derivatives or chirally derivatized methacrylate polymers immobilized on silica gel). Suitable eluents for this purpose are aqueous or alcoholic solvent mixtures, for example, hexane / isopropanol / acetonitrile. The corresponding stable isomers can be separated according to known methods, for example, by extraction, filtration, or column chromatography.

[0247] In some embodiments, the compounds of the present invention have the (R)-configuration. In other embodiments, the compounds have the (S)-configuration. In compounds with more than one chiral center, unless otherwise indicated, each chiral center in the compound can independently be (R) or (S).

[0248] Compounds described herein may also include tautomeric forms. Tautomeric forms are produced by the exchange of a single bond with an adjacent double bond and the accompanying proton migration. Tautomeric forms include prototropic tautomers, which are isomeric protonation states with the same empirical formula and total charge. Examples of prototropic tautomers include keto-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, enamine-imine pairs, and cyclic forms in which protons can occupy two or more positions of a heterocyclic ring system, such as 1H- and 3H-imidazoles, 1H-, 2H-, and 4H-1,2,4-triazoles, 1H- and 2H-isoindoles, and 1H- and 2H-pyrazoles. Tautomeric forms may be in equilibrium or spatially locked into one form by appropriate substitution. The present disclosure is intended to include all of these tautomers of the compounds.

[0249] The compounds described herein may also include all isotopes of atoms present in the intermediates or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium.

[0250] The term "pharmaceutically acceptable salt" refers to a salt prepared from a compound of the present invention with a relatively nontoxic, pharmaceutically acceptable acid or base. When the compound of the present invention contains a relatively acidic functional group, a base addition salt can be obtained by contacting the prototype of such compound with a sufficient amount of a pharmaceutically acceptable base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include, but are not limited to, lithium salts, sodium salts, potassium salts, calcium salts, aluminum salts, magnesium salts, zinc salts, bismuth salts, ammonium salts, and diethanolamine salts. When the compound of the present invention contains a relatively basic functional group, an acid addition salt can be obtained by contacting the prototype of such compound with a sufficient amount of a pharmaceutically acceptable acid in a pure solution or a suitable inert solvent. The pharmaceutically acceptable acid includes inorganic acids, including, but not limited to, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, phosphoric acid, phosphorous acid, sulfuric acid, and the like. The pharmaceutically acceptable acid includes organic acids, including but not limited to acetic acid, propionic acid, oxalic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, salicylic acid, tartaric acid, methanesulfonic acid, isonicotinic acid, oleic acid, tannic acid, pantothenic acid, bitartrate, ascorbic acid, gentisic acid, fumaric acid, gluconic acid, sugar acid, formic acid, ethanesulfonic acid, pamoic acid (i.e., 4,4'-methylene-bis(3-hydroxy-2-naphthoic acid)), amino acids (e.g., glutamic acid, arginine), etc. When the compounds of the present invention contain relatively acidic and relatively basic functional groups, they can be converted into base addition salts or acid addition salts. For details, see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66: 1-19 (1977), or Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl and Camille G. Wermuth, ed., Wiley-VCH, 2002). In some embodiments, the "pharmaceutically acceptable salt" is hydrochloride.

[0251] The term "halogen" or "halo" refers to fluorine, chlorine, bromine and iodine.

[0252] The term "C 1-10 "Alkyl" refers to a linear or branched saturated monovalent hydrocarbon group having 1 to 10 carbon atoms. For example, it represents a linear or branched alkyl group having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. "C 1-6 "Alkyl" refers to a straight or branched chain alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms. 1-3“Alkyl” refers to a straight or branched chain alkyl group having 1, 2 or 3 carbon atoms. The alkyl group includes, but is not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, or the like or isomers thereof.

[0253] The term "alkoxy" refers to a group having the formula "-O-alkyl" wherein alkyl is as defined above. 1-6 The term "alkoxy" refers to an alkyl group having 1 to 6 carbon atoms. The alkoxy group includes, but is not limited to, methoxy, ethoxy, propoxy (eg, n-propoxy and isopropoxy), tert-butoxy, and the like.

[0254] The term "haloalkyl" refers to an alkyl group as defined above that is substituted with one or more halogen groups as defined above. The haloalkyl group includes, but is not limited to, monofluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, 3-bromo-2-fluoropropyl, 1-bromomethyl-2-bromoethyl, and the like.

[0255] The term "haloalkoxy" refers to an alkoxy group as defined above, the alkyl portion of which is substituted by one or more halogen groups as defined above. The haloalkoxy group includes, but is not limited to, trifluoromethoxy, difluoromethoxy, pentafluoroethoxy, and the like.

[0256] The term "C 2-6 "Alkenyl" refers to a straight or branched monovalent hydrocarbon group containing 2 to 6 carbon atoms and at least one carbon-carbon double bond. The alkenyl group includes but is not limited to vinyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl, etc.

[0257] The term "C 2-6 "Alkynyl" refers to a straight or branched chain monovalent hydrocarbon radical containing 2 to 6 carbon atoms and containing at least one carbon-carbon triple bond. The alkynyl radical includes, but is not limited to, ethynyl, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and 1-butynyl.

[0258] The term "C 1-6 "Aminoalkyl" refers to a C 1-6 Alkyl. C 1-3 "Aminoalkyl" refers to a C 1-3Alkyl, the aminoalkyl group includes but is not limited to aminomethyl, i.e., -CH2NH2, aminoethyl, i.e., -CH2CH2NH2.

[0259] The term "C 3-10 "Cycloalkyl" refers to a saturated monovalent or polyvalent monocyclic, bicyclic or tricyclic hydrocarbon group having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. The bicyclic and tricyclic hydrocarbon groups include bridged rings, fused rings and spiro rings. The C 3-10 The cycloalkyl group may be selected from C 3-6 Cycloalkyl or C 3-4 Cycloalkyl. 3-10 The cycloalkyl group may be a monocyclic hydrocarbon group, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, or a bicyclic hydrocarbon group, such as borneol, hexahydroindolyl, decahydronaphthyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, 6,6-dimethylbicyclo[3.1.1]heptyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, or a tricyclic hydrocarbon group, such as adamantyl.

[0260] The term "3-12 membered heterocycloalkyl" refers to a saturated monovalent or multivalent monocyclic, bicyclic or tricyclic ring system containing 3 to 12 ring atoms, and its ring atoms contain 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, wherein N and S can also be optionally oxidized to various oxidation states to form nitrogen oxides, -S(=O)- or -S(=O)2-. The "3-12 membered heterocycloalkyl" is selected from 3-6 membered heterocycloalkyl or 6-11 membered heterocycloalkyl. The heterocycloalkyl can be attached to the rest of the molecule through any carbon atom or nitrogen atom (if present) on its ring. The heterocycloalkyl group may include, but is not limited to, azetidinyl, pyrrolidinyl, piperidinyl, piperidinyl, 6-azaspiro[2.5]octanyl, diazaspiro[3,5]nonanyl, 2,6-diazaspiro[3,4]octanyl, 7-azaspiro[3.5]nonanyl, 8-azaspiro[4.5]decane or 3-azaspiro[5.5]undecane, etc.

[0261] The term "3-12 membered heterocyclyl" refers to a saturated or unsaturated non-aromatic monovalent or polyvalent ring system, for example, a monocyclic ring containing 4, 5, 6 or 7 ring atoms, a bicyclic ring containing 7, 8, 9, 10, 11 or 12 ring atoms, or a tricyclic ring system containing 10, 11 or 12 ring atoms, and its ring atoms contain at least one, for example 1, 2, 3, 4, 5 or 6 heteroatoms independently selected from O, S and N, wherein N and S can also be optionally oxidized to various oxidation states to form nitrogen oxides, -S(=O)- or -S(=O)2-. The bicyclic and tricyclic ring systems include fused rings, bridged rings or spiro rings. The 3-12 membered heterocyclyl may be selected from “3-10 membered heterocyclyl”, “5-12 membered heterocyclyl” or “6-11 membered heterocyclyl”; the term “3-10 membered heterocyclyl” means a saturated or unsaturated non-aromatic ring or ring system containing 3 to 10 ring atoms, and its ring atoms contain at least one heteroatom selected from O, S and N. The term “5-12 membered heterocyclyl” refers to a saturated or unsaturated non-aromatic ring or ring system containing 5 to 12 ring atoms, and its ring atoms contain at least one heteroatom selected from O, S and N. The term “6-11 membered heterocyclyl” refers to a saturated or unsaturated non-aromatic ring or ring system containing 6 to 11 ring atoms, and its ring atoms contain at least one heteroatom selected from O, S and N. In some embodiments, the heterocyclyl may be a heterocycloalkyl. The heterocyclic group can be connected to the rest of the molecule by any carbon atom or nitrogen atom (if present) on its ring, for example, when a 3-12 membered heterocyclic group is selected from piperidinyl, the nitrogen atom on the piperidinyl ring and the carbon atom on its para position can be connected to other groups. The heterocyclic group can include but is not limited to: a 4-membered ring, such as azetidinyl, oxetane; a 5-membered ring, such as tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or a 6-membered ring, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl or trithianyl; or a 7-membered ring, such as diazepanyl. Optionally, the heterocyclic group can be benzo-fused. The heterocyclic group can be bicyclic, such as, but not limited to, 6-azaspiro[2.5]octanyl, diazaspiro[3,5]nonanyl, 2,6-diazaspiro[3,4]octanyl, 7-azaspiro[3.5]nonanyl, 8-azaspiro[4.5]decane or 3-azaspiro[5.5]undecane, hexahydrocyclopenta[c]pyrrol-2(1H)-yl ring, hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl ring, 4-azaspiro[2.5]octanyl, 1,2-dihydropyridinyl and 1,4-dihydropyrazinyl.The heterocyclyl group may be partially unsaturated, i.e., it may contain one or more double bonds, such as, but not limited to, dihydrofuranyl, dihydropyranyl, 2,5-dihydro-1H-pyrrolyl, 4H-[1,3,4]thiadiazinyl, 1,2,3,5-tetrahydrooxazolyl or 4H-[1,4]thiazinyl, or it may be benzo-fused, such as, but not limited to, dihydroisoquinolinyl.

[0262] The term "C 6-10 "Aryl" refers to a monovalent aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring containing 6, 7, 8, 9 or 10 carbon atoms, in particular a ring having 6 carbon atoms ("C6 aryl"), such as phenyl; or a ring having 9 carbon atoms ("C9 aryl"), such as indanyl or indenyl, or a ring having 10 carbon atoms ("C 10 Aryl "), such as naphthyl. When the C 6-10 When the aryl group is substituted, it may be monosubstituted or polysubstituted. Furthermore, there is no limitation on the position of substitution, and for example, substitution may be at the ortho, para or meta position.

[0263] The term "5-10 membered heteroaryl" refers to a monovalent or polyvalent monocyclic, bicyclic or tricyclic aromatic ring system containing 5 to 10 ring atoms, and whose ring atoms contain 1, 2, 3, 4 or 5 heteroatoms independently selected from N, O and S. The term "5-8 membered heteroaryl" refers to a monovalent or polyvalent monocyclic, bicyclic or tricyclic aromatic ring system containing 5, 6, 7 or 8 ring atoms, in particular, it contains 5 or 6 carbon atoms and it contains 1-3, preferably 1 or 2 heteroatoms independently selected from N, O and S. The bicyclic and tricyclic ring systems include fused rings. In some embodiments, they may be benzo-fused. When the 5-10 membered heteroaryl is substituted, it may be monosubstituted or polysubstituted. In addition, there is no limitation on the substitution site, for example, a hydrogen attached to a carbon atom on the heteroaryl ring may be substituted, or a hydrogen attached to a heteroatom on the heteroaryl ring may be substituted. The heteroaryl group may include, but is not limited to, pyridyl, pyrazinyl, pyrimidinyl, triazinyl, pyridazinyl, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, indole, benzothiazole, benzofuran, or benzimidazole.

[0264] The term "spirocyclic" refers to a ring system in which two rings share one ring atom.

[0265] The term "fused ring" refers to a ring system in which two rings share two ring atoms.

[0266] The term "bridged ring" refers to ring systems that share two or more ring atoms.

[0267] The compounds of the present invention may exist in the form of solvates (e.g., hydrates), wherein the compounds of the present invention contain a polar solvent as a structural element of the crystal lattice of the compound, in particular water, methanol or ethanol. The amount of polar solvent, in particular water, may be present in a stoichiometric or non-stoichiometric ratio.

[0268] The term "patient" refers to any animal including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses or primates, and most preferably humans.

[0269] The term "therapeutically effective amount" refers to the amount of an active compound or drug that will elicit the biological or medical response that a researcher, veterinarian, physician, or other clinician is seeking in a tissue, system, animal, individual, or human, and includes one or more of the following: (1) Preventing disease: e.g., preventing a disease, disorder, or condition in an individual who is susceptible to the disease, disorder, or condition but has not yet experienced or developed the pathology or symptoms of the disease. (2) Inhibiting disease: e.g., inhibiting the disease, disorder, or condition (i.e., preventing further development of the pathology and / or symptoms) in an individual who is experiencing or developing the pathology or symptoms of the disease, disorder, or condition. (3) Alleviating disease: e.g., alleviating the disease, disorder, or condition (i.e., reversing the pathology and / or symptoms) in an individual who is experiencing or developing the pathology or symptoms of the disease, disorder, or condition. The therapeutically effective amount can be initially estimated from cell culture assays, and initial doses can also be estimated from in vivo data. Using these preliminary guidelines, one of ordinary skill in the art can determine the effective dose in humans. In addition, the toxicity and therapeutic efficacy of the compounds described herein can also be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., by determining the LD 50 and ED 50 .

[0270] Those skilled in the art will understand that resolved chiral compounds can be distinguished by their retention times on a chiral chromatographic column. The absolute configurations of compounds listed in the examples do not necessarily correspond to the compound numbers; they are merely illustrative of two possible forms of the absolute configurations. The absolute configuration corresponding to the compound number is determined by the absolute configuration objectively corresponding to the specific retention time. DETAILED DESCRIPTION

[0271] The technical solutions of the present invention will be described in further detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanations of the present invention and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are encompassed within the scope of protection that the present invention is intended to protect.

[0272] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0273] Unless otherwise specified, the nouns used in the following experimental descriptions represent the following reagents:

[0274] NaBH4: sodium borohydride; PPh3: triphenylphosphine; DIAD: diisopropyl azodicarboxylate; m-CPBA: m-chloroperbenzoic acid; PyBOP-PF6: tripyrrolidinylphosphonium bromide hexafluorophosphate; EDCI: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; HOBT: 1-hydroxybenzotriazole; DIEA: N,N-diisopropylethylamine; LiHMDS: lithium bis(trimethylsilyl)amide; LiEt3BH: lithium triethylborohydride; BF3·Et2O: boron trifluoride diethyl etherate compound; Pd(Ph3P)4: tetrakis(triphenylphosphine)palladium; Rh(PPh3)3Cl: tris(triphenylphosphine)rhodium chloride; Et3SiH: triethylsilane; LAH: lithium aluminum tetrahydride; Et2Zn: diethylzinc; KHF2: potassium hydrogen fluoride; PBr3: phosphorus tribromide; SEM-Cl: 2-(trimethylsilyl)ethoxymethyl chloride; Cu(OAc)2: copper acetate; EtOAc: ethyl acetate; TEA: triethylamine; THF: tetrahydrofuran; TBAF: tetrabutylammonium fluoride; T3P: 1-propylphosphoric acid cyclic anhydride;

[0275] <Preparation Example>

[0276] Example 1. Synthesis of (2R,4S)-N-((2S)-1-((2-amino-6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)amino)-1-oxopropan-2-yl)-4-(4-fluorobenzyl)pyrrolidine-2-carboxamide (Compound L001) Hydrochloride

[0277]

[0278] 1.1 Synthesis of compound L001-1

[0279] L001-a (4.0 g, 30.40 mmol) was dissolved in methanol (60 mL) at room temperature, cooled to 0°C, and sodium borohydride (3.4 g, 91.20 mmol) was added portionwise. The reaction solution was stirred at 0°C for 0.5 hours, then warmed to 25°C and continued to react for 2 hours. The reaction solution was quenched with water (10 mL) and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain compound L001-1 (3.8 g, 93.60% yield).

[0280] 1.2 Synthesis of compound L001-2

[0281] L001-1 (3.8 g, 28.11 mmol), triphenylphosphine (8.8 g, 33.74 mmol), and L001-b (4.6 g, 33.74 mmol) were dissolved in tetrahydrofuran (40 mL) at room temperature. After cooling to 0°C, diisopropyl azodicarboxylate (6.82 g, 33.74 mmol) was slowly added dropwise under nitrogen. After the addition was complete, the reaction solution was warmed to room temperature and the reaction continued for 2 hours. The reaction solution was directly concentrated, and the residue was diluted with water (100 mL). The pH of the aqueous phase was adjusted to 3-4 with dilute hydrochloric acid (1 M) and then washed with ethyl acetate (50 mL x 3). The pH of the aqueous phase was adjusted to 8-9 with saturated sodium bicarbonate solution, and then extracted with dichloromethane (50 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound L001-2 (3.6 g, yield 48.45%). LC-MS: [M+H] + =265.05.

[0282] 1.3 Synthesis of compound L001-3

[0283] L001-2 (3.6 g, 13.62 mmol) was dissolved in dichloromethane (70 mL). Meta-chloroperbenzoic acid (3.06 g, 17.71 mmol) was added portionwise at 0°C, and the temperature was raised to 25°C for 2 hours. The reaction solution was diluted with dichloromethane (200 mL) and washed with saturated aqueous sodium bicarbonate solution (50 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound L001-3 (3.7 g, crude product), which was used directly in the next step. LC-MS: [M+H] + =280.95.

[0284] 1.4 Synthesis of compound L001-4

[0285] L001-3 (2.6 g, 9.28 mmol) was dissolved in dichloromethane (50 mL) at room temperature, and L001-c (2.0 g, 12.06 mmol), tripyrrolidinylphosphonium bromide hexafluorophosphate (7.8 g, 16.70 mmol), and N,N-diisopropylethylamine (3.0 g, 23.19 mmol) were added sequentially. The reaction solution was stirred at room temperature for 12 hours. The reaction solution was directly concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain compound L001-4 (2.0 g). LC-MS: [M+H] + =430.00.

[0286] 1.5 Synthesis of compound L001-5

[0287] L001-4 (2.0 g, 4.66 mmol) was dissolved in ethanol (20 mL), hydrazine hydrate (20 mL, 85%) was added, and the mixture was stirred at 25°C for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was diluted with water (20 mL) and extracted with dichloromethane (20 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound L001-5 (1.5 g, crude product), which was used directly in the next step. LC-MS: [M+H] + =300.05.

[0288] 1.6 Synthesis of compound L001-6

[0289] L001-5 (1.5 g, 5.01 mmol) was dissolved in tetrahydrofuran (20 mL) at room temperature. Concentrated hydrochloric acid (20 mL, 37%) was added, and the reaction mixture was heated to 70°C and stirred for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was added with ethyl acetate / methanol (20 mL, 10 / 1 (v / v)) and stirred at room temperature for 1 hour. The mixture was filtered, and the filter cake was dried under reduced pressure to obtain the hydrochloride salt of compound L001-6 (600 mg, yield 64.52%). LC-MS: [M+H] + =150.20.

[0290] 1.7 Synthesis of Compound L001-7

[0291] L001-d (1.5 g, 8.08 mmol) was dissolved in N,N-dimethylformamide (20 mL). 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.7 g, 8.89 mmol) and 1-hydroxybenzotriazole (1.2 g, 8.89 mmol) were added sequentially. The mixture was allowed to react at 25°C for 10 minutes. Then, a solution of N,N-diisopropylethylamine (5.2 g, 40.40 mmol) and L001-6 (1.5 g, 8.08 mmol) in N,N-dimethylformamide (10 mL) was added and the reaction continued at 25°C for 30 minutes. The reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (30 mL x 3). The organic phase was washed with saturated aqueous ammonium chloride (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the intermediate. The intermediate (1.5 g, 4.68 mmol) was dissolved in dichloromethane (20 mL), and a solution of hydrogen chloride in 1,4-dioxane (20 mL, 4 M) was added. The mixture was allowed to react at 25°C for 30 minutes. The reaction solution was directly concentrated under reduced pressure, and the residue was added with dichloromethane (10 mL) and stirred at room temperature for 30 minutes. The mixture was then filtered and the filter cake was dried under reduced pressure to obtain compound L001-7 hydrochloride (1.3 g), which was used directly in the next reaction. LC-MS: [M+H] + =221.15

[0292] 1.8 Synthesis of compound L001-8

[0293] L001-e (1.0 g, 3.13 mmol) was dissolved in tetrahydrofuran (15 mL) at room temperature and then cooled to -70°C. Lithium bis(trimethylsilyl)amide (3.8 mL, 3.80 mmol, 1 M solution in tetrahydrofuran) was slowly added dropwise under nitrogen. After the addition was complete, the mixture was stirred at -70°C for 0.5 hour. L001-f (0.7 g, 3.76 mmol) was then slowly added dropwise. After the addition was complete, the reaction mixture was stirred at -70°C for 2 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (10 mL) at -70°C. After the system temperature returned to room temperature, it was extracted with ethyl acetate (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to yield compound L001-8 (800 mg, 59.70% yield).

[0294] 1.9 Synthesis of Compound L001-9

[0295] L001-8 (800 mg, 1.87 mmol) was dissolved in tetrahydrofuran (10 mL) at room temperature. The reaction solution was cooled to -70°C and lithium triethylborohydride (2 mL, 2.0 mmol, 1 M tetrahydrofuran solution) was slowly added dropwise under nitrogen. After the addition was complete, the reaction was continued at -70°C for 0.5 hours. The reaction solution was quenched with saturated aqueous sodium bicarbonate solution (10 mL) at -70°C and extracted with ethyl acetate (10 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound L001-9 (800 mg, crude product). LC-MS: [M-OH] + =412.05.

[0296] 1.10 Synthesis of Compound L001-10

[0297] L001-9 (800 mg, 1.86 mmol) was dissolved in dichloromethane (15 mL) at room temperature. The reaction mixture was cooled to -70°C. Triethylsilane (259 mg, 2.34 mmol) and boron trifluoride etherate (332 mg, 2.34 mmol) were slowly added dropwise under nitrogen. After the addition was complete, the mixture was stirred at -70°C for 0.5 hour. Additional triethylsilane (259 mg, 2.34 mmol) and boron trifluoride etherate (332 mg, 2.34 mmol) were added, and the reaction mixture was stirred at -70°C for another 1 hour. The reaction mixture was quenched by the addition of saturated aqueous sodium bicarbonate (10 mL) at -70°C and extracted with dichloromethane (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give compound L001-10 (500 mg, yield 64.94%).

[0298] 1.11 Synthesis of Compound L001-11

[0299] L001-10 (500 mg, 1.21 mmol) was dissolved in methanol (20 mL) at room temperature, and wet palladium on carbon (100 mg, 10% palladium content) was added. The mixture was replaced with hydrogen three times, and then stirred at room temperature under a hydrogen atmosphere for 4 hours. The reaction mixture was directly filtered, and the filtrate was concentrated under reduced pressure to obtain compound L001-11 (410 mg, crude product), which was directly used in the next step. LC-MS: [M-tBu+H] + =268.05.

[0300] 1.12 Synthesis of Compound L001-12 Hydrochloride

[0301] L001-11 (70 mg, 0.22 mmol) was dissolved in N,N-dimethylformamide (2 mL) at room temperature. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (50 mg, 0.26 mmol) and 1-hydroxybenzotriazole (35 mg, 0.26 mmol) were added. The mixture was allowed to react at 25°C for 10 minutes. Then, a solution of N,N-diisopropylethylamine (141 mg, 1.09 mmol) and L001-7 (67 mg, 0.26 mmol) in N,N-dimethylformamide (2 mL) was added. The reaction system was allowed to react at 25°C for 30 minutes. The reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated aqueous ammonium chloride (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by HPLC (acidic conditions) to give compound L001-12 hydrochloride (50 mg, yield 61.52%). LC-MS: [M+H] + =526.10.

[0302] 1.13 Synthesis of Compound L001 Hydrochloride

[0303] Dissolve L001-12 hydrochloride (50 mg, 0.10 mmol) in dichloromethane (2 mL). Add hydrogen chloride in ethyl acetate (2 mL, 4 M) and stir at room temperature for 2 hours. A solid forms. The reaction mixture is filtered, and the filter cake is dissolved in deionized water (10 mL) and freeze-dried to yield compound L001 hydrochloride (24.3 mg).

[0304] 1H NMR (400MHz, DMSO-d6): δ10.52(s,1H),8.89(s,1H),8.50-8.64(m,2H),8.03(s,2H),7.71-7.64 (m,1H),7.48-7.28(m,3H),7.20-7.11(m,2H),6.84(d,J=8.0Hz,1H),5.17-5.12(m,1H),4.38(s, 1H),4.32-4.19(m,1H),3.36-3.26(m,1H),3.09-2.98(m,1H),2.94-2.86(m,2H),2.79-2.59(m,2 H),2.49-2.40(m,2H),2.10-2.02(m,1H),1.98-1.86(m,3H),1.23(d,J=8.0Hz,3H); LC-MS:[M+H] + =426.10.

[0305] Example 2, (2R,4S)-4-([1,1'-biphenyl]-4-ylmethyl)-N-((2S)-1-((2-amino-6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)amino)-1-oxopropan-2-yl)pyrrolidine-2-carboxamide (Compound L002) and (2R,4S)-4-([1,1'-biphenyl]-4-ylmethyl)-N-((S)-1-(((S)-2-amino-6,7-dihydro-5H-cyclopenta[b]pyridin-5 Synthesis of (2R,4S)-4-([1,1'-biphenyl]-4-ylmethyl)-N-((S)-1-((R)-2-amino-6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)amino)-1-oxopropan-2-yl)pyrrolidine-2-carboxamide (compound L002-IS-02 or L002-IS-01)

[0306]

[0307] 2.1 Synthesis of compound L002-1

[0308] L001-e (2.0 g, 6.20 mmol) was dissolved in tetrahydrofuran (25 mL) at room temperature and cooled to -78°C. Lithium bis(trimethylsilyl)amide (7.0 mL, 7.0 mmol, 1 M solution in tetrahydrofuran) was added dropwise under nitrogen. After the addition was complete, stirring was continued at -78°C for 0.5 hours. L002-a (1.8 g, 7.44 mmol) was then added dropwise. After the addition was complete, the reaction solution was stirred at -78°C for 2 hours. At this temperature, water (50 mL) was added to the reaction solution to quench the mixture. After the system temperature rose to room temperature, the mixture was extracted with ethyl acetate (40 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound L002-1 (1.8 g, 58% yield).

[0309] 2.2 Synthesis of compound L002-2

[0310] At room temperature, L002-1 (1.8 g, 3.71 mmol) was dissolved in tetrahydrofuran (30 mL). The reaction mixture was cooled to -78°C and lithium triethylborohydride (4.1 mL, 4.10 mmol, 1 M solution in tetrahydrofuran) was slowly added dropwise under nitrogen. After the addition was complete, the reaction mixture was allowed to react at -78°C for 0.5 hours. Water (30 mL) was added to the reaction mixture to quench the reaction mixture. After the system temperature was raised to room temperature, the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to yield compound L002-2 (1.4 g, crude product), which was used directly in the next step.

[0311] 2.3 Synthesis of compound L002-3

[0312] L002-2 (1.4 g, crude product) was dissolved in dichloromethane (20 mL) at room temperature and cooled to -78°C. Triethylsilane (400 mg, 3.44 mmol) and boron trifluoride etherate (488 mg, 3.44 mmol) were slowly added dropwise under nitrogen. The reaction solution was stirred at -78°C for 0.5 hours. Triethylsilane (400 mg, 3.44 mmol) and boron trifluoride etherate (488 mg, 3.44 mmol) were then added, and the reaction solution was stirred at -78°C for another 2 hours. Saturated aqueous sodium bicarbonate solution (30 mL) was added to the reaction solution at -78°C to quench the reaction. After the system temperature rose to room temperature, it was extracted with ethyl acetate (30 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound L002-3 (900 mg, yield 50.68%). LC-MS: [M+H] + =472.59.

[0313] 2.4 Synthesis of compound L002-4

[0314] L002-3 (900 mg, 1.91 mmol) was dissolved in ethanol (15 mL) at room temperature, and wet palladium on carbon (100 mg, 10% palladium content) was added. The mixture was stirred under a hydrogen atmosphere for 3 hours. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain compound L002-4 (780 mg, crude product), which was used directly in the next reaction. LC-MS: [M-tBu+H] + =326.15.

[0315] 2.5 Synthesis of compound L002-5

[0316] L002-4 (400 mg, crude product) was dissolved in N,N-dimethylformamide (5 mL). 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (223 mg, 1.16 mmol) and 1-hydroxybenzotriazole (157 mg, 1.16 mmol) were added. After stirring at 25°C for 10 minutes, a solution of N,N-diisopropylethylamine (677 mg, 5.25 mmol) and L001-7 (324 mg, 1.26 mmol) in N,N-dimethylformamide (5 mL) was added. The reaction was continued at 25°C for 0.5 hours. The reaction solution was poured into water (20 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic phases were washed with saturated aqueous ammonium chloride (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound L002-5 (500 mg, yield 81.97%). LC-MS: [M+H] + =584.05.

[0317] 2.6 Synthesis of compound L002

[0318] L002-5 (500 mg, 0.85 mmol) was dissolved in dichloromethane (5 mL), and a solution of hydrogen chloride in ethyl acetate (5 mL, 4 M) was added. The mixture was allowed to react at 25°C for 0.5 h. The reaction solution was then concentrated under reduced pressure, and the residue was purified by preparative HPLC (basic conditions) and freeze-dried to afford compound L002 (200 mg, 48.28% yield).

[0319] 1H NMR (400MHz, DMSO-d6): δ8.20-8.13(m,2H),7.64(d,J=8.0Hz,2H),7.57(d,J=8.0Hz,2H),7.45(t,J=8.0H z,2H),7.34(t,J=8.0Hz,1H),7.27(dd,J=8.0,4.0Hz,2H),7.16–7.12(m,1H),6.22(d,J=8.0Hz,1H),5.84( s,2H),5.14–5.03(m,1H),4.28–4.16(m,1H),3.69–3.58(m,1H),3.09-3.04(m,1H),2.93–2.83(m,1H),2. 79–2.54(m,5H),2.37–2.27(m,1H),2.22-2.13(m,1H),1.84–1.62(m,3H),1.21-1.18(m,3H); LC-MS:[M+H] + =484.15.

[0320] 2.7 Synthesis of compounds L002-IS-01 and L002-IS-02

[0321] Compound L002 (200 mg) was separated by high performance liquid chromatography (basic, CHIRAL ART Amylose-C NEO, 30*250 mm, 10 μm, mobile phase, A: n-hexane (0.1% diethylamine), B: isopropanol, flow rate: 30 mL / min) to give compounds L002-IS-01 (retention time Rt = 6.184 min in the spectrum, 69.9 mg) and L002-IS-02 (retention time Rt = 7.442 min in the spectrum, 80.6 mg).

[0322] L002-IS-01:

[0323] 1H NMR(400MHz,DMSO-d6):δ8.19-8.12(m,2H),7.67-7.61(m,2H),7.57(d,J=8.0Hz,2H),7.45(t,J=8.0Hz,2H),7.34(t,J=8.0Hz,1H),7.26(d,J=8.0Hz,2H),7.11(d,J=8.0Hz,1H),6.24(d,J=12.0Hz,1H),5.83(s,2H),5.09(q,J=8.0Hz,1H),4.22(p,J=8.0Hz,1H),3.64(dd,J1=8.0,J2=4.0Hz,1H),2.86(dd,J1=10.0,J2=6.8Hz,1H),2.80-2.51(m,5H),2.37-2.29(m,1H),2.20-2.13(m,1H),1.82-1.63(m,3H),1.35-1.23(m,1H),1.19(d,J=8.0Hz,3H);LC-MS:[M+H] + =484.15。

[0324] L002-IS-02:

[0325] 1 H NMR(400MHz,DMSO-d6):δ8.16(t,J=8.0Hz,2H),7.64(d,J=8.0Hz,2H),7.57(d,J=8.0Hz,2H),7.45(t,J=8.0Hz,2H),7.34(t,J=8.0Hz,1H),7.27(d,J=8.0Hz,2H),7.15(d,J=8.0Hz,1H),6.23(d,J=8.0Hz,1H),5.84(s,2H),5.07(q,J=8.0Hz,1H),4.21(p,J=8.0Hz,1H),3.64(dd,J1=8.0,J2=4.0Hz,1H),2.89(dd,J1=8.0,J2=4.0Hz,1H),2.78-2.55(m,5H),2.38-2.27(m,1H),2.22-2.19(m,1H),1.83-1.61(m,3H),1.27-1.21(m,1H),1.19(d,J=8.0Hz,3H);LC-MS:[M+H] + =484.15。

[0326] Example 3. Synthesis of (2R,4S)-N-(2S)-1-(2-amino-6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)amino)-1-oxopropan-2-yl)-4-(4-chlorobenzyl)pyrrolidine-2-carboxamide (Compound L003) Hydrochloride

[0327]

[0328] 3.1 Synthesis of compound L003-1

[0329] L001-e (1.0 g, 3.13 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL). Under a nitrogen atmosphere, the reaction system was cooled to -78°C, and lithium bis(trimethylsilyl)amide (3.4 mL, 3.44 mmol, 1 M solution in tetrahydrofuran) was slowly added dropwise. The mixture was stirred at this temperature for 0.5 hours. L003-a (804 mg, 3.91 mmol) was then added dropwise to the reaction solution, maintaining the reaction temperature at -78°C. After the addition was complete, stirring was continued for 2 hours. At this temperature, the reaction solution was quenched by the addition of saturated aqueous sodium bicarbonate (15 mL), extracted with ethyl acetate (30 mL x 3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to yield compound L003-1 (310 mg, 22.4% yield). LC-MS: [M-Boc+H] + =344.00.

[0330] 3.2 Synthesis of compound L003-2

[0331] L003-1 (310 mg, 0.70 mmol) was dissolved in tetrahydrofuran (4 mL). Under a nitrogen atmosphere, the reaction solution was cooled to -78°C and lithium triethylborohydride (0.77 mL, 0.77 mmol, 1 M tetrahydrofuran solution) was slowly added dropwise. After the addition was complete, the reaction solution was stirred at -78°C for 2 hours. At this temperature, saturated aqueous sodium bicarbonate (10 mL) was added to the reaction solution to quench the mixture. The mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound L003-2 (260 mg, yield 83.6%). LC-MS: [M-OH] + =427.95.

[0332] 3.3 Synthesis of compound L003-3

[0333] L003-2 (260 mg, 0.58 mmol) was dissolved in dichloromethane (10 mL). Under a nitrogen atmosphere, the reaction system was cooled to -78°C, and triethylsilane (75 mg, 0.64 mmol) and boron trifluoride etherate (98.7 mg, 0.70 mmol) were slowly added dropwise. After the addition was complete, the reaction solution was stirred at -78°C for 2 hours. At this temperature, a saturated aqueous solution of sodium bicarbonate (10 mL) was added to the reaction solution to quench the mixture. The mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound L003-3 (200 mg, yield 80.6%). LC-MS: [M+H] + =430.05.

[0334] 3.4 Synthesis of compound L003-4

[0335] L003-3 (100 mg, 0.23 mmol) was dissolved in methanol (3 mL) and water (3 mL), followed by the addition of sodium hydroxide (18.6 mg, 0.46 mmol) and stirring at room temperature for 16 hours. The reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (5 mL). The organic phase was discarded, and the aqueous phase was adjusted to a pH of 5-6 with formic acid and then extracted with ethyl acetate (15 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to yield compound L003-4 (90 mg, crude product), which was used directly in the next step.

[0336] 3.5 Synthesis of compound L003-5

[0337] L003-4 (90 mg, crude), 1-hydroxybenzotriazole (39 mg, 0.29 mmol), N,N-dimethylformamide (2 mL), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (55 mg, 0.29 mmol) were added to a reaction flask and stirred at room temperature for 0.5 hour. Meanwhile, L001-7 (92 mg, 0.31 mmol) and N,N-diisopropylethylamine (134.2 mg, 1.04 mmol) were dissolved in N,N-dimethylformamide (2 mL) and stirred at room temperature for 0.5 hour. This solution was then added to the reaction mixture and stirred for another 0.5 hour. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (acidic conditions) to give compound L003-5 (58.0 mg, yield 40.1%). LC-MS: [M+H] + =542.00.

[0338] 3.6 Synthesis of Compound L003 Hydrochloride

[0339] L003-5 (58 mg, 0.11 mmol) was dissolved in dichloromethane (2 mL), and a solution of hydrogen chloride in ethyl acetate (2 mL, 4 M) was added. The reaction mixture was stirred at room temperature for 0.5 hours, during which time a solid precipitated. The solid was filtered, and the filter cake was washed with dichloromethane (15 mL), dissolved in deionized water (15 mL), and freeze-dried to afford compound L003 hydrochloride (36 mg, 76.1% yield).

[0340] 1 H NMR (400MHz, DMSO-d6): δ10.45-10.37(m,1H),8.86(d,J=6.4Hz,1H),8.57-8.55(m,2H), 7.94(s,2H),7.66(dd,J1=8.0Hz,J2=4.0Hz,1H),7.33(dd,J1=8.0,J2=4.0Hz,4H),6.81(d ,J=8.0Hz,1H),5.14(d,J=4.0Hz,1H),4.42-4.17(m,2H),3.27(s,1H),3.09-2.82(m,3H), 2.77-2.64(m,2H),2.48-2.35(m,2H),2.06-1.90(m,3H),1.24-1.22(m,4H); LC-MS:[M+H] + =442.00.

[0341] Example 4. Synthesis of (2R,4S)-N-((2S)-1-((2-amino-6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)amino)-1-oxopropan-2-yl)-4-(4-methylbenzyl)pyrrolidine-2-carboxamide (Compound L004) Hydrochloride

[0342]

[0343] 4.1 Synthesis of compound L004-1

[0344] L001-e (1 g, 3.13 mmol) was added to a reaction flask under a nitrogen atmosphere. Tetrahydrofuran (10 mL) was added to dissolve the mixture and placed in a -78°C cold bath. Lithium bis(trimethylsilyl)amide (3.2 mL, 3.20 mmol, 1 M tetrahydrofuran solution) was added while maintaining the temperature at -78°C and stirred for 0.5 hours. L004-a (576 mg, 3.13 mmol) was then added and the reaction continued at -78°C for 2 hours. A small amount of insoluble matter was generated, which was removed by filtration. The filtrate was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound L004-1 (650 mg, 49% yield). LC-MS: [M-Boc+H] + =324.05.

[0345] 4.2 Synthesis of compound L004-2

[0346] L004-1 (600 mg, 1.42 mmol) was added to a reaction flask under a nitrogen atmosphere. Tetrahydrofuran (5 mL) was added to dissolve the mixture and placed in a -78°C cold bath. Lithium triethylborohydride (1.42 mL, 1.42 mmol) was added while maintaining the temperature at -78°C and stirred for 0.5 hours. The reaction solution was quenched with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound L004-2 (810 mg, crude product). LC-MS: [M-OH] + =408.05

[0347] 4.3 Synthesis of compound L004-3

[0348] L004-2 (600 mg, 1.41 mmol) was added to a reaction flask under a nitrogen atmosphere. Dichloromethane (5 mL) was added to dissolve the mixture and placed in a -78°C cold bath. Triethylsilane (163.9 mg, 1.41 mmol) and boron trifluoride etherate (200 mg, 1.41 mmol) were added while maintaining the temperature at -78°C, and the mixture was stirred for 0.5 hours. Triethylsilane (164 mg, 1.41 mmol) and boron trifluoride etherate (200 mg, 1.41 mmol) were further added, and stirring was continued at -78°C for 2 hours. At this temperature, the reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound L004-3 (402 mg, 70% yield). LC-MS: [M+H] + =410.00.

[0349] 4.4 Synthesis of compound L004-4

[0350] L004-3 (402 mg, 0.98 mmol) was added to a reaction flask and dissolved in methanol (5 mL). Wet palladium on carbon (30 mg, 10% palladium content) was then added. The mixture was reacted at room temperature under a hydrogen atmosphere for 3 hours. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain compound L004-4 (267 mg, crude product), which was used directly in the next step. LC-MS: [M-tBu+H] + =264.05.

[0351] 4.5 Synthesis of compound L004-5

[0352] L004-4 (100 mg, 0.31 mmol), 1-hydroxybenzotriazole (47 mg, 0.34 mmol), N,N-dimethylformamide (3 mL), N,N-diisopropylethylamine (170 mg, 1.24 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (65 mg, 0.34 mmol) were added to a reaction flask and allowed to react at room temperature for 0.5 hour. Compound L001-7 (82 mg, 0.37 mmol) was then added and the reaction continued at room temperature for 1 hour. The mixture was diluted with water (40 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated sodium chloride (40 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The residue was purified by preparative HPLC (acidic conditions) to afford compound L004-5 (57.8 mg, 35.5% yield). LC-MS: [M+H] + =522.10.

[0353] 4.6 Synthesis of Compound L004 Hydrochloride

[0354] L004-5 (57.8 mg, 0.11 mmol) was dissolved in dichloromethane (2 mL), and a solution of hydrogen chloride in ethyl acetate (1 mL, 4 M) was added. The mixture was stirred at room temperature for 0.5 hours. A solid precipitated, which was filtered and the filter cake washed with ethyl acetate (10 mL). The filter cake was dissolved in water (3 mL) and freeze-dried to afford compound L004 hydrochloride (40.2 mg, 81.1% yield).

[0355] 1H NMR (400MHz, DMSO-d6): δ10.45-10.37(m,1H),8.86(d,J=6.4Hz,1H),8.57-8.55(m,2H), 7.94(s,2H),7.66(dd,J1=8.0Hz,J2=4.0Hz,1H),7.33(dd,J1=8.0,J2=4.0Hz,4H),6.81(d ,J=8.0Hz,1H),5.14(d,J=4.0Hz,1H),4.42-4.17(m,2H),3.27(s,1H),3.09-2.82(m,3H), 2.77-2.64(m,2H),2.48-2.35(m,2H),2.06-1.90(m,3H),1.24-1.22(m,4H); LC-MS:[M+H] + =422.15.

[0356] Example 5, (2R,4S)-N-((2S)-1-((2-amino-6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)amino)-1-oxopropan-2-yl)-4-(4-(trifluoromethyl)benzyl)pyrrolidine-2-carboxamide (Compound L005) hydrochloride and (2R,4S)-N-((S)-1-(((R)-2-amino-6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)amino)-1-oxopropan-2-yl)-4-(4 Synthesis of (2R,4S)-N-((S)-1-(((S)-2-amino-6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)amino)-1-oxopropan-2-yl)-4-(4-(trifluoromethyl)benzyl)pyrrolidine-2-carboxamide (compound L005-IS-02 or compound L005-IS-01) hydrochloride

[0357]

[0358] 5.1 Synthesis of Compound L005-1

[0359] L001-e (2.0 g, 6.26 mmol) was added to tetrahydrofuran (20 mL) at room temperature. The reaction mixture was cooled to -78°C and lithium bis(trimethylsilyl)amide (6.80 mL, 6.80 mmol, 1 M solution in tetrahydrofuran) was added dropwise under nitrogen. After the addition was complete, stirring was continued at -78°C for 0.5 hour. A solution of L005-a (1.64 g, 6.88 mmol) in tetrahydrofuran (10 mL) was added dropwise to the reaction mixture. After the addition was complete, stirring was continued at -78°C for 2 hours. The mixture was quenched by the addition of an aqueous solution of ammonium chloride (10 mL) at -78°C. The reaction system was warmed to room temperature and extracted with ethyl acetate (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to yield compound L005-1 (1.2 g, 50.6% yield). LC-MS: [M-Boc+H] + =377.95.

[0360] 5.2 Synthesis of compound L005-2

[0361] L005-1 (1.1 g, 2.30 mmol) was dissolved in tetrahydrofuran (15 mL) at room temperature, cooled to -78°C, and lithium triethylborohydride (2.5 mL, 2.5 mmol, 1 M tetrahydrofuran solution) was added dropwise under nitrogen. After the addition was complete, stirring was continued at -78°C for 0.5 hours. Saturated aqueous sodium bicarbonate solution (10 mL) was added to the reaction solution at -78°C to quench the mixture. After the reaction solution was warmed to room temperature, it was extracted with ethyl acetate (30 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound L005-2 (500 mg, crude product), which was used directly in the next step. LC-MS: [M-OH] + =461.95.

[0362] 5.3 Synthesis of compound L005-3

[0363] L005-2 (500 mg, 1.04 mmol) was dissolved in dichloromethane (5 mL) at room temperature, and the reaction solution was cooled to -78°C. Triethylsilane (312 mg, 2.70 mmol) and boron trifluoride etherate (384 mg, 2.70 mmol) were added dropwise to the reaction solution under nitrogen protection. After the addition was complete, the mixture was stirred at -78°C for 1 hour. Saturated aqueous sodium bicarbonate solution (10 mL) was added to the reaction solution at -78°C to quench the mixture. After the system temperature rose to room temperature, it was extracted with ethyl acetate (30 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound L005-3 (450 mg, crude product), which was used directly in the next step. LC-MS: [M-tBu+H] + =407.95.

[0364] 5.4 Synthesis of Compound L005-4

[0365] L005-3 (450 mg, crude product) was dissolved in methanol (5 mL), and wet palladium carbon (200 mg, 10% palladium content) was added. The mixture was stirred at 20°C under a hydrogen atmosphere for 1 hour. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain compound L005-4 (300 mg, crude product), which was used directly in the next step.

[0366] 5.5 Synthesis of compound L005-5

[0367] L005-4 (127 mg, crude product), L001-7 (100 mg, 0.34 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (88 mg, 0.46 mmol), 1-hydroxybenzotriazole (69 mg, 0.46 mmol) and triethylamine (93 mg, 0.92 mmol) were dissolved in N,N-dimethylformamide (2 mL) and stirred at room temperature for 1 hour. Water (20 mL) was added to the reaction solution and diluted, and extracted with dichloromethane (20 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by high-performance liquid chromatography (acidic conditions) to obtain compound L005-5 (150 mg). LC-MS: [M+H] + =576.10.

[0368] 5.6 Synthesis of Compound L005 Hydrochloride

[0369] L005-5 (150 mg, 0.19 mmol) was dissolved in dichloromethane (1 mL). A solution of hydrogen chloride in 1,4-dioxane (1 mL, 4 M) was added dropwise. The mixture was stirred at room temperature for 1 hour, resulting in the precipitation of a white solid. The reaction mixture was filtered, and the filter cake was washed with dichloromethane (3 mL). The filter cake was dissolved in deionized water (10 mL) and freeze-dried to afford compound L005 hydrochloride (52.0 mg, 57.4% yield).

[0370] 1H NMR (400MHz, DMSO-d6): δ10.54–10.52(m,1H),8.87(dd,J=7.2,4.0Hz,1H),8.73–8.42(m,2H), 8.04(s,2H),7.66(dt,J=8.8,7.2Hz,3H),7.49(d,J=8.0Hz,2H),6.82(d,J=8.0Hz,1H),5.13(d, J=7.2Hz,1H),4.50–4.10(m,2H),3.26(s,1H),3.10–2.97(m,1H),2.96–2.71(m,4H),2.52(d,J= 7.2Hz, 1H), 2.06 (dt, J=8.8, 6.8Hz, 1H), 1.99–1.83 (m, 2H), 1.21 (d, J=7.2Hz, 3H); LC-MS: [M+H] + =476.05.

[0371] 5.7 Synthesis of Compounds L005-IS-01 Hydrochloride and L005-IS-02 Hydrochloride

[0372] L005 hydrochloride (52.0 mg, 0.11 mmol) was separated and purified by supercritical fluid chromatography (SFC) (chromatographic column: Daicel Chiralpak AD, 50×25 mm, 10 μm, mobile phase: A: carbon dioxide, B: ethanol, flow rate: 70 g / min) to obtain two compounds: L005-IS-01 (retention time Rt = 1.660 min, 7.7 mg) and L005-IS-02 (retention time Rt = 1.989 min, 9.8 mg).

[0373] L005-IS-01:

[0374] 1 H NMR (400MHz, DMSO-d6): δ8.13(d,J=7.6Hz,2H),7.62(d,J=8.0Hz,2H),7.40(d,J= 8.0Hz,2H),7.12(d,J=8.4Hz,1H),6.21(d,J=8.4Hz,1H),5.82(s,2H),5.05(dd,J= 14.4,7.6Hz,1H),4.32-4.08(m,1H),3.61-3.59(m,1H),2.82-2.66(m,1H),2.65-2 .62(m,5H),2.37-2.12(m,2H),1.85-1.52(m,3H),1.20-1.17(m,4H); LC-MS:[M+H] + =476.05.

[0375] L005-IS-02:

[0376] 1 H NMR (400MHz, DMSO-d6): δ8.16-8.10(m,2H),7.62(d,J=8.4Hz,2H),7.39(d,J =8.0Hz,2H),7.08(d,J=8.0Hz,1H),6.21(d,J=8.4Hz,1H),5.81(s,2H),5.07( dd,J=14.8,7.6Hz,1H),4.24-4.15(m,1H),3.62-3.59(m,1H),2.78-2.53(m,6 H),2.58-2.30(m,2H),1.70-1.62(m,2H),1.19(t,J=8.8Hz,4H); LC-MS:[M+H] + =476.05.

[0377] Example 6. Synthesis of (2R,4R)-N-((S)-1-(((R)-2-amino-6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)amino)-1-oxopropan-2-yl)-4-phenylpyrrolidine-2-carboxamide hydrochloride (Compound L006-IS-01 or L006-IS-02) and (2R,4R)-N-((S)-1-(((S)-2-amino-6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)amino)-1-oxopropan-2-yl)-4-phenylpyrrolidine-2-carboxamide hydrochloride (Compound L006-IS-02 or L006-IS-01)

[0378]

[0379] 6.1 Synthesis of Compound L006-1

[0380] L006-a (1 g, 4.12 mmol) was added to a reaction flask under a nitrogen atmosphere. Tetrahydrofuran (10 mL) was added to dissolve the mixture, and the mixture was placed in a -78°C cold bath. Lithium bis(trimethylsilyl)amide (4.9 mL, 4.90 mmol, 1 M solution in tetrahydrofuran) was slowly added dropwise, maintaining the temperature at -78°C. After the addition was complete, the reaction was continued at this temperature for 1 hour. Then, a solution of N-(5-chloro-2-pyridyl)bis(trifluoromethanesulfonamide) (2 g, 5.10 mmol) in tetrahydrofuran (4 mL) was slowly added dropwise at -78°C. After the addition was complete, the reaction was continued at this temperature for 1 hour. The reaction solution was warmed to -20°C and allowed to react for 16 hours. The reaction solution was quenched with saturated aqueous sodium bicarbonate (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give compound L006-1 (1.1 g, yield 71%).

[0381] 6.2 Synthesis of Compound L006-2

[0382] L006-1 (600 mg, 1.60 mmol), phenylboronic acid (235 mg, 1.93 mmol), tetrakis(triphenylphosphine)palladium (185 mg, 0.16 mmol) and potassium carbonate (664 mg, 4.81 mmol) were added to a reaction flask under a nitrogen atmosphere. 1,4-dioxane (10 mL) and water (2 mL) were added to dissolve the mixture. The reaction solution was placed in an 80°C oil bath and reacted for 16 hours. The reaction solution was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound L006-2 (420 mg, yield 87%). LC-MS: [M+H] + =304.10.

[0383] 6.3 Synthesis of Compound L006-3

[0384] L006-2 (420 mg, 1.36 mmol) and lithium hydroxide monohydrate (873 mg, 20.78 mmol) were added to a reaction flask, and tetrahydrofuran (4 mL), methanol (2 mL), and water (2 mL) were added to dissolve. The reaction solution was stirred at room temperature for 2 hours. The pH value of the reaction solution was adjusted to 5-6 with dilute hydrochloric acid (1 M), diluted with water (10 mL), and extracted with ethyl acetate (20 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound L006-3 (350 mg, yield 87.1%). LC-MS: [M-tBu+H] + =234.05.

[0385] 6.4 Synthesis of Compound L006-4

[0386] L006-3 (350 mg, 1.21 mmol), tris(triphenylphosphine)rhodium chloride (113 mg, 0.12 mmol), triethylamine (123 mg, 1.21 mmol) and methanol (10 mL) were added to the reaction flask, replaced with a hydrogen atmosphere, and stirred at room temperature for 2 days. The reaction solution was filtered, and the filtrate was adjusted to pH 10 with aqueous sodium hydroxide solution (1 M). It was extracted with ethyl acetate (40 mL), and the organic phase was washed once with saturated aqueous sodium bicarbonate solution (20 mL) and discarded. All aqueous phases were combined, the pH was adjusted to about 5-6 with dilute hydrochloric acid (0.5 M), and then extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound L006-4 (209 mg, yield 73.2%). LC-MS: [M-Boc+H] + =192.10.

[0387] 6.5 Synthesis of Compounds L006-5-IS-01 and L006-5-IS-02

[0388] L006-4 (100 mg, 0.34 mmol), 1-hydroxybenzotriazole (53 mg, 0.38 mmol), N,N-dimethylformamide (3 mL), N,N-diisopropylethylamine (177 mg, 1.37 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (73 mg, 0.38 mmol) were added to a reaction flask and stirred at room temperature for 0.5 hours. L001-7 (91 mg, 0.41 mmol) was then added and the reaction continued at room temperature for 1 hour. The reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated sodium chloride aqueous solution (40 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (acidic conditions) to give compounds L006-5-IS-01 (retention time: Rt = 18.349 min, 20 mg) and L006-5-IS-02 (retention time: Rt = 20.877 min, 30 mg). LC-MS: [M+H] + =494.10.

[0389] 6.6 Synthesis of Compound L006-IS-01 Hydrochloride

[0390] The resulting L006-5-IS-01 (retention time: Rt = 18.349 min, 20 mg) was dissolved in dichloromethane (2 mL). A solution of hydrogen chloride in ethyl acetate (1 mL, 4 M) was added and stirred at room temperature for 1 hour. A solid precipitated, and the reaction mixture was filtered, and the filter cake was washed with ethyl acetate (10 mL). The solid was dissolved in deionized water (5 mL) and freeze-dried to yield compound L006-IS-01 hydrochloride (13.5 mg).

[0391] 1 H NMR (400MHz, CH3OH-d4): δ7.85-7.75(m,1H),7.38-7.28(m,5H),6.85-6.80(m ,1H),5.33-5.29(m,1H),4.63-4.49(m,1H),4.37-4.30(m,1H),3.84-3.76(m, 1H),3.68-3.47(m,1H),3.36-3.31(m,1H),3.17-3.09(m,1H),3.02-2.88(m,2 H),2.66-2.56(m,1H),2.22-1.99(m,2H),1.42(d,J=7.2Hz,3H); LC-MS:[M+H] + =394.10.

[0392] 6.7 Synthesis of Compound L006-IS-02 Hydrochloride

[0393] The resulting L006-5-IS-02 (retention time: Rt = 20.877 min, 30 mg) was dissolved in dichloromethane (2 mL). A solution of hydrogen chloride in ethyl acetate (1 mL, 4 M) was added and stirred at room temperature for 1 hour. A solid precipitated, and the reaction mixture was filtered, and the filter cake was washed with ethyl acetate (10 mL). The solid was dissolved in deionized water (5 mL) and freeze-dried to yield compound L006-IS-02 hydrochloride (22.2 mg).

[0394] 1 H NMR (400 MHz, CH3OH-d4): 1H NMR (400MHz, CH3OH-d4): δ7.86-7.78(m,1H),7.38-7.28(m,5H),6.85-6.82(m ,1H),5.35-5.30(m,1H),4.63-4.46(m,1H),4.39-4.28(m,1H),3.86-3.76(m, 1H),3.69-3.48(m,1H),3.38-3.35(m,1H),3.19-3.11(m,1H),3.05-2.97(m,1 H),2.67-2.50(m,3H),2.11-1.99(m,1H),1.42(d,J=7.2Hz,3H); LC-MS:[M+H] + =394.10.

[0395] Example 7. Synthesis of (2R,4R)-N-((2S)-1-((2-amino-6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)amino)-1-oxopropan-2-yl)-4-(4-fluorophenyl)pyrrolidine-2-carboxamide (Compound L007) Hydrochloride

[0396]

[0397] 7.1 Synthesis of Compound L007-1

[0398] L006-1 (450 mg, 1.2 mmol), p-fluorophenylboronic acid (202 mg, 1.44 mmol), tetrakis(triphenylphosphine)palladium (129 mg, 0.12 mmol) and potassium carbonate (497 mg, 3.6 mmol) were added to 1,4-dioxane (10 mL) and water (2 mL) at room temperature. Under nitrogen protection, the reaction was carried out at 80°C for 16 hours. The reaction solution was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound L007-1 (361 mg, yield 94%). LC-MS: [M+H] + =322.05.

[0399] 7.2 Synthesis of Compound L007-2

[0400] L007-1 (361 mg, 1.12 mmol) and lithium hydroxide monohydrate (708 mg, 16.86 mmol) were added to a reaction flask, and tetrahydrofuran (4 mL), methanol (2 mL), and water (2 mL) were added to dissolve the mixture. The mixture was stirred at room temperature for 2 hours. The pH of the reaction solution was adjusted to 5-6 with dilute hydrochloric acid (1 M), diluted with water (10 mL), and extracted with ethyl acetate (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound L007-2 (325 mg, 94% yield), which was used directly in the next step. LC-MS: [M-tBu+H] + =252.05.

[0401] 7.3 Synthesis of Compound L007-3

[0402] L007-2 (325 mg, 1.06 mmol), tris(triphenylphosphine rhodium chloride) (102 mg, 0.11 mmol) and triethylamine (107 mg, 1.06 mmol) were added to the reaction flask, dissolved in methanol (10 mL), replaced with a hydrogen atmosphere, and stirred at room temperature for 4 days. The reaction solution was filtered, the filtrate was adjusted to pH = 10 with aqueous sodium hydroxide solution (1 M), extracted with ethyl acetate (40 mL), and the organic phase was washed once with saturated aqueous sodium bicarbonate solution (20 mL) and discarded. The combined aqueous phase was adjusted to pH 5-6 with dilute hydrochloric acid (0.5 M), and then extracted with ethyl acetate (20 mL × 3). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound L007-3 (crude product), which can be directly carried out to the next step. LC-MS: [M-tBu+H] + =254.00.

[0403] 7.4 Synthesis of Compound L007-4

[0404] L007-3 (100 mg, 0.32 mmol), 1-hydroxybenzotriazole (49 mg, 0.36 mmol), N,N-dimethylformamide (2 mL), N,N-diisopropylethylamine (167 mg, 1.29 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (68 mg, 0.36 mmol) were added to a reaction flask and stirred at room temperature for 0.5 hours. L001-7 (86 mg, 0.39 mmol) was then added and the reaction continued at room temperature for 1 hour. The reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated sodium chloride aqueous solution (40 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (acidic conditions) to yield compound L007-4 (40 mg). LC-MS: [M+H]+ =512.05.

[0405] 7.5 Synthesis of Compound L007 Hydrochloride

[0406] L007-4 (40 mg, 0.078 mmol) was dissolved in dichloromethane (2 mL), and a solution of hydrogen chloride in ethyl acetate (1 mL, 4 M) was added. The mixture was stirred at room temperature for 1 hour. A solid precipitated, and the reaction mixture was filtered. The filter cake was washed with ethyl acetate (5 mL), dissolved in deionized water (5 mL), and freeze-dried to afford compound L007 hydrochloride (5.2 mg).

[0407] 1 H NMR (400MHz, CH3OH-d4): δ7.87-7.73(m,1H),7.64-7.55(m,1H),7.37(dd,J=8.8Hz,5.2H z,1H),7.21-7.08(m,2H),6.86-6.74(m,1H),5.36-5.32(m,1.5H),4.59-4.48(m,1.5H), 4.37-4.29(m,1H),3.80-3.69(m,1H),3.35-3.33(m,1H),3.16-3.13(m,1H),3.06-3.00( m,1H),2.91-2.84(m,0.5H),2.68-2.62(m,1H),2.21-1.95(m,2.5H),1.47-1.41(m,3H); 19 F NMR (400MHz, CH3OH-d4): δ-113.09,-116.89; LC-MS: [M+H] + =412.15.

[0408] Example 8. Synthesis of (2R,4R)-N-((2S)-1-((2-amino-6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)amino)-1-oxopropan-2-yl)-4-(4-(trifluoromethyl)phenyl)pyrrolidine-2-carboxamide (Compound L008) Hydrochloride

[0409]

[0410] 8.1 Synthesis of Compound L008-1

[0411] L006-1 (450 mg, 1.2 mmol), p-trifluoromethylphenylboronic acid (274 mg, 1.44 mmol), tetrakis(triphenylphosphine)palladium (139 mg, 0.12 mmol), and potassium carbonate (496.5 mg, 3.6 mmol) were added to a reaction flask. 1,4-Dioxane (10 mL) and water (2 mL) were added for dissolution. The mixture was reacted at 80°C under nitrogen for 16 hours. The reaction solution was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound L008-1 (386 mg, 88% yield). LC-MS: [M-tBu+H] + =316.00.

[0412] 8.2 Synthesis of Compound L008-2

[0413] L008-1 (386 mg, 1.04 mmol) and lithium hydroxide monohydrate (16 mg, 16.86 mmol) were added to a reaction flask, and tetrahydrofuran (4 mL), methanol (2 mL), and water (2 mL) were added to dissolve the mixture. The mixture was stirred at room temperature for 2 hours. The pH of the reaction solution was adjusted to 5-6 with dilute hydrochloric acid (1 M). The mixture was diluted with water (10 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound L008-2 (310 mg, 83% yield). LC-MS: [M-tBu+H] + =302.00.

[0414] 8.3 Synthesis of Compound L008-3

[0415] L008-2 (310 mg, 0.87 mmol), tris(triphenylphosphine)rhodium chloride (81 mg, 0.09 mmol) and triethylamine (88 mg, 0.87 mmol) were added to a reaction flask, methanol (15 mL) and tetrahydrofuran (15 mL) were added to dissolve, and stirred at room temperature for 4 days under a hydrogen atmosphere. The reaction solution was filtered, the pH value of the filtrate was adjusted to pH = 10 with aqueous sodium hydroxide solution (1 M), extracted with ethyl acetate (40 mL), and the organic phase was washed once with saturated aqueous sodium bicarbonate solution (20 mL) and discarded. All aqueous phases were combined, the pH value of the aqueous phase was adjusted to 5-6 with dilute hydrochloric acid (0.5 M), and extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound L008-3 (crude product), which can be directly carried out to the next step. LC-MS: [M-tBu+H] + =304.00.

[0416] 8.4 Synthesis of Compound L008-4

[0417] L008-3 (100 mg, 0.28 mmol), 1-hydroxybenzotriazole (42.2 mg, 0.31 mmol), N,N-dimethylformamide (2 mL), N,N-diisopropylethylamine (143.7 mg, 1.11 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (58.5 mg, 0.31 mmol) were added to a reaction flask and stirred at room temperature for 0.5 hour. L001-7 (73.5 mg, 0.33 mmol) was then added and the reaction continued at room temperature for 1 hour. The reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (40 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The residue was purified by preparative HPLC (acidic conditions) to yield compound L008-4 (35.2 mg). LC-MS: [M+H] + =562.05.

[0418] 8.5 Synthesis of Compound L008 Hydrochloride

[0419] L008-4 (35.2 mg, 0.063 mmol) was dissolved in dichloromethane (2 mL). A solution of hydrogen chloride in ethyl acetate (1 mL, 4 M) was added and stirred at room temperature for 1 hour. A solid precipitated. The reaction mixture was filtered and the filter cake was washed with ethyl acetate (5 mL). The filter cake was dissolved in deionized water (5 mL) and freeze-dried to yield compound L008 hydrochloride (23.7 mg).

[0420] 1 H NMR (400MHz, CH3OH-d4): δ7.87-7.77(m,1H),7.68(d,J=8.0Hz,2H),7.56(t,J=8.0Hz,2H),6.85-6.80(m,1H),5.35-5.28(m,1H),4.55-4.49(m, 1H),4.40-4.28(m,1H),3.88-3.78(m,2H),3.42-3.37(m,1H),3.17-3.0 9(m,1H),3.05-2.89(m,2H),2.67-2.63(m,1H),2.29-2.02(m,2H),1.44 -1.40(m,3H); LC-MS:[M+H] + =462.05.

[0421] Example 9. Synthesis of (2R,4S)-N-((2S)-1-((2-amino-6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)amino)-1-oxopropan-2-yl)-4-(1-phenylethyl)pyrrolidine-2-carboxamide (Compound L009) Hydrochloride

[0422]

[0423] 9.1 Synthesis of Compound L009-1

[0424] L006-1 (600 mg, 1.6 mmol), L009-a (442 mg, 1.92 mmol), tetrakis(triphenylphosphine)palladium (185 mg, 0.16 mmol) and potassium carbonate (661.9 mg, 4.8 mmol) were added to a reaction flask, 1,4-dioxane (10 mL) and water (2 mL) were added to dissolve under nitrogen atmosphere, and the mixture was reacted at 80°C for 16 hours. The reaction solution was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (50 mL × 3). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound L009-1 (480 mg, yield 91%). LC-MS: [M+H] + =330.10.

[0425] 9.2 Synthesis of Compound L009-2

[0426] L009-1 (120 mg, 0.4 mmol) was added to a reaction flask and dissolved in methanol (10 mL). Wet palladium on carbon (30 mg, 10% palladium content) was then added and the mixture was allowed to react at room temperature under a hydrogen atmosphere for 3 hours. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain compound L009-2 (crude product), which was used directly in the next step. LC-MS: [M+H] + =334.10.

[0427] 9.3 Synthesis of Compound L009-3

[0428] L009-2 (122.7 mg, crude product) and lithium hydroxide monohydrate (129.7 mg, 5.4 mmol) were added to a reaction flask, and tetrahydrofuran (4 mL), methanol (2 mL), and water (2 mL) were added to dissolve the mixture. The mixture was stirred at room temperature for 2 hours. The pH of the reaction solution was adjusted to 5-6 with dilute hydrochloric acid (1 M). The mixture was diluted with water (10 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound L009-3 (100 mg) as a colorless oily liquid. LC-MS: [M-tBu+H] + =264.10.

[0429] 9.4 Synthesis of Compound L009-4

[0430] L009-3 (100 mg, 0.31 mmol), 1-hydroxybenzotriazole (48 mg, 0.35 mmol), N,N-dimethylformamide (2 mL), N,N-diisopropylethylamine (162 mg, 1.25 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (66 mg, 0.35 mmol) were added to a reaction flask and allowed to react at room temperature for 0.5 hours. L001-7 (83 mg, 0.38 mmol) was then added and the reaction continued at room temperature for 1 hour. The reaction solution was diluted with water (40 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated sodium chloride aqueous solution (40 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The residue was purified by preparative HPLC (acidic conditions) to yield compound L009-4 (51.7 mg, 36.7% yield). LC-MS: [M+H] + =522.05.

[0431] 9.5 Synthesis of Compound L009 Hydrochloride

[0432] L009-4 (51.7 mg, 0.1 mmol) was dissolved in dichloromethane (2 mL). A solution of hydrogen chloride in ethyl acetate (1 mL, 4 M) was added at room temperature and stirred for 0.5 hours, resulting in the precipitation of a solid. The reaction mixture was filtered, and the filter cake was washed with ethyl acetate (5 mL). The filter cake was dissolved in deionized water (2 mL) and freeze-dried to afford compound L009 hydrochloride (35.9 mg, 73.1% yield).

[0433] 1 H NMR (400MHz, CH3OH-d4): δ7.71-7.59(m,1H),7.17(t,J=7.2Hz,2H),7.11-7.07 (m,3H),6.72-6.67(m,1H),5.18-5.09(m,1H),4.23-4.19(m,1H),4.16-4.07(m, 1H),3.52-3.48(m,0.5H),3.03-2.96(m,1.5H),2.89-2.60(m,3H),2.53-2.46(m ,3H),2.05-1.87(m,2H),1.28(d,J=7.2Hz,2H),1.21-1.15(m,4H); LC-MS:[M+H] + =422.15.

[0434] Example 10. Synthesis of (2R,4S)-N-((2S)-1-((2-amino-6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)amino)-1-oxopropan-2-yl)-4-(4-(pyridin-3-yl)benzyl)pyrrolidine-2-carboxamide (Compound L010) Hydrochloride

[0435]

[0436] 10.1 Synthesis of Compound L010-1

[0437] L001-e (5.1 g, 16.0 mmol) was dissolved in tetrahydrofuran (40 mL) under nitrogen protection. The temperature was lowered to -78°C, and lithium bis(trimethylsilyl)amide (24 mL, 24.0 mmol, 1 M tetrahydrofuran solution) was slowly added. The mixture was stirred at this temperature for 0.5 hours. L010-a (4.0 g, 16.0 mmol) was then slowly added, and the reaction was continued at -78°C for 2 hours. At -78°C, the reaction solution was quenched with saturated ammonium chloride solution (30 mL). The reaction system was warmed to room temperature and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated sodium chloride (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound L010-1 (2.8 g, 35.8% yield). LC-MS: [M-Boc+H] + =387.90

[0438] 10.2 Synthesis of Compound L010-2

[0439] L010-1 (2.0 g, 4.1 mmol) was dissolved in tetrahydrofuran (25 mL) under nitrogen protection, cooled to -78°C, and lithium triethylborohydride (4.5 mL, 4.5 mmol, 1 M tetrahydrofuran solution) was slowly added. The reaction was stirred and maintained at -78°C for 2 hours. Water (15 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated sodium chloride aqueous solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound L010-2 (1.1 g, yield 54.77%). LC-MS: [M-OH] + =473.95.

[0440] 10.3 Synthesis of Compound L010-3

[0441] L010-2 (1.0 g, 2.1 mmol) was dissolved in dichloromethane (10 mL), protected by nitrogen, and cooled to -78°C. Triethylsilane (360 mg, 3.1 mmol) was slowly added, followed by the slow dropwise addition of boron trifluoride etherate complex (436 mg, 3.1 mmol). The reaction was stirred at -78°C for 2 hours. At this temperature, water (15 mL) was added to quench the reaction. After the reaction system was warmed to room temperature, it was extracted with dichloromethane (15 mL × 3). The combined organic phase was washed with saturated sodium chloride aqueous solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound L010-3 (400 mg, yield 41.35%). LC-MS: [M-Boc+H] + =375.95.

[0442] 10.4 Synthesis of Compound L010-4

[0443] L010-4 (400 mg, 0.84 mmol), L010-b (181.6 mg, 0.89 mmol), cesium carbonate (550 mg, 1.69 mmol), and tetrakis(triphenylphosphine)palladium (107 mg, 0.08 mmol) were added sequentially to 1,4-dioxane (5 mL) and water (1 mL). The mixture was stirred at 100°C under nitrogen for 2 hours. The reaction solution was cooled to room temperature, and undissolved solids were present. After filtration, the filtrate was added with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated sodium chloride aqueous solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to yield compound L010-4 (300 mg, 75.29% yield).

[0444] 10.5 Synthesis of Compound L010-5

[0445] L010-4 (300 mg, 0.63 mmol) was dissolved in methanol (2 mL), and wet palladium carbon (100 mg, 10% palladium content) was added. The mixture was stirred at 20°C under a hydrogen atmosphere for 1 hour. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound L010-5 (140 mg, yield 57.66%). LC-MS: [M+H] + =383.05.

[0446] 10.6 Synthesis of Compound L010-6

[0447] L010-5 (130 mg, 0.34 mmol) was dissolved in N,N-dimethylformamide (2 mL). 1-Hydroxybenzotriazole (50.5 mg, 0.37 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (70.1 mg, 0.37 mmol) were added. After stirring at room temperature for 10 minutes, a solution of L001-7 (74.9 mg, 0.34 mmol) and N,N-diisopropylethylamine (175.4 mg, 1.36 mmol) in N,N-dimethylformamide (2 mL) was added. Stirring was continued at room temperature for 1.5 hours. The reaction mixture was poured directly into water (10 mL) and extracted with ethyl acetate (15 mL × 3). The combined organic phases were washed with saturated aqueous ammonium chloride (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (basic conditions) and freeze-dried to give compound L010-6 (49 mg, yield 24.65%). LC-MS: [M+H] + =585.15.

[0448] 10.7 Synthesis of Compound L010 Hydrochloride

[0449] L010-6 (49 mg, 0.084 mmol) was dissolved in dichloromethane (2 mL). A solution of hydrogen chloride in ethyl acetate (1 mL, 4 M) was added at room temperature and stirred for 0.5 hours, resulting in the precipitation of a solid. The reaction mixture was filtered, and the filter cake was washed with ethyl acetate (10 mL). The filter cake was dissolved in deionized water (10 mL) and freeze-dried to afford compound L010 hydrochloride (18.5 mg, 45.6% yield).

[0450] 1H NMR (400MHz, DMSO-d6): δ10.70(s,1H),9.24(s,1H),8.99(t,J=7.2Hz,1H),8.85(d,J=6.0Hz,2H),8.70(t,J=7.6Hz ,1H),8.61(s,1H),8.33-7.98(m,3H),7.85(d,J=8.0Hz,2H),7.68(d,J=8.8Hz,1H),7.48(d,J=8.0Hz,2H),6.87(d,J =8.8Hz,1H),5.14(q,J=7.2Hz,1H),4.43(s,1H),4.1-4.19(m,1H),3.30(s,1H),3.12-2.99(m,1H),2.98-2.73(m,4 H),2.61-2.51(m,1H),2.48-2.38(m,1H),2.16-2.07(m,1H),2.01-1.90(m,2H),1.23(d,J=7.2Hz,3H); LC-MS:[M+H] + =485.10.

[0451] Example 11. Synthesis of (2R,4S)-N-((2S)-1-((2-amino-6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)amino)-1-oxopropan-2-yl)-4-((2-methylpyridin-4-yl)methyl)pyrrolidine-2-carboxamide (Compound L011) Hydrochloride

[0452]

[0453] 11.1 Synthesis of Compound L011-1

[0454] L011-a (3.0 g, 21.90 mmol) was added to tetrahydrofuran (40 mL), and L011-b (3.6 g, 26.30 mmol) was added dropwise at 0°C. After the addition was complete, the temperature was raised to 20°C and stirred for 0.5 hours. A large amount of white solid precipitated, which was filtered, and the filtrate was cooled to 0°C. A solution of sodium borohydride (1.25 g, 32.90 mmol) in water (5 mL) was added, and the reaction solution was stirred at 0°C for 0.5 hours. The pH of the reaction solution was adjusted to 5-6 with dilute hydrochloric acid (1 M), and extracted with ethyl acetate (20 mL × 3). The organic phase was discarded, and the pH of the aqueous phase was adjusted to 8 with sodium carbonate and extracted with ethyl acetate (20 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound L011-1 (1.0 g, yield 38.5%). LC-MS: [M+H] + =124.20.

[0455] 11.2 Synthesis of Compound L011-2

[0456] L011-1 (1.3 g, 10.60 mmol) and triphenylphosphine (3.6 g, 13.70 mmol) were added to dichloromethane (20 mL), and a solution of carbon tetrabromide (4.5 g, 13.70 mmol) in dichloromethane (5 mL) was added dropwise at 0°C. After the addition, the reaction was stirred at 20°C for 0.5 hours. The reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and toluene (20 mL) was added to the filtrate, and the solution was concentrated under reduced pressure to 10 mL. Toluene (20 mL) was added again and the solution was concentrated under reduced pressure to 5 mL to obtain a toluene solution of compound L011-2. This solution was used directly in the next step. LC-MS: [M+H] + =188.00.

[0457] 11.3 Synthesis of Compound L011-3

[0458] L001-e (2.2 g, 7.00 mmol) was added to tetrahydrofuran (20 mL) and cooled to -78°C. Lithium bis(trimethylsilyl)amide (7.7 mL, 7.70 mmol, 1 M tetrahydrofuran solution) was added dropwise under nitrogen. After the addition was complete, the mixture was stirred at -78°C for 0.5 hours. A toluene solution of L011-2 (~5 mL, crude product solution obtained in the previous step) was then added dropwise. The reaction was stirred at -78°C for 1 hour. An aqueous solution of ammonium chloride (10 mL) was added to the reaction solution at -78°C to quench the reaction. After the system temperature rose to room temperature, the mixture was extracted with ethyl acetate (10 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound L011-3 (1.28 g, yield 43.1%). LC-MS: [M+H] + =425.10.

[0459] 11.4 Synthesis of Compound L011-4

[0460] At room temperature, L011-3 (1.28 g, 3.00 mmol) was added to tetrahydrofuran (15 mL) and cooled to -78 ° C. Lithium triethylborohydride (3.6 mL, 3.6 mmol, 1 M tetrahydrofuran solution) was added dropwise under nitrogen protection. After the addition was complete, the mixture was stirred at -78 ° C for 0.5 hours. Saturated sodium bicarbonate aqueous solution (10 mL) was added to the reaction solution at -78 ° C for quenching. After the reaction system was warmed to room temperature, it was extracted with ethyl acetate (10 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound L011-4 (crude product), which was used directly in the next step. LC-MS: [M+H] +=427.10.

[0461] 11.5 Synthesis of Compound L011-5

[0462] At room temperature, L011-4 (1.3 g, 3.00 mmol) was dissolved in dichloromethane (20 mL) and cooled to -78 ° C. Triethylsilane (650 mg, 4.50 mmol) and boron trifluoride ether complex (522 mg, 4.50 mmol) were added dropwise under nitrogen protection. The reaction solution was reacted at -78 ° C for 1 hour. Saturated sodium bicarbonate aqueous solution (10 mL) was added at -78 ° C to quench the solution. After the system was warmed to room temperature, it was extracted with ethyl acetate (10 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound L011-5 (crude product), which was used directly in the next step. LC-MS: [M+H] + =411.10.

[0463] 11.6 Synthesis of Compound L011-6

[0464] L011-5 (400 mg, 0.98 mmol) and wet palladium on carbon (200 mg, 10% palladium content) were added to methanol (4 mL) and stirred at room temperature under a hydrogen atmosphere for 0.5 hours. The reaction solution was filtered and the filtrate was concentrated under reduced pressure to obtain L011-6 (crude product), which was used directly in the next step. LC-MS: [M+H] + =321.10.

[0465] 11.7 Synthesis of Compound L011-7

[0466] L011-6 (110 mg, crude product), L001-7 (100 mg, 0.34 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (97 mg, 0.51 mmol), 1-hydroxybenzotriazole (77 mg, 0.51 mmol) and triethylamine (104 mg, 1.02 mmol) were added to dichloromethane (3 mL) and stirred at room temperature for 0.5 hours. Water (20 mL) was added to the reaction solution to dilute it and extract it with dichloromethane (10 mL×3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (acidic conditions) to give compound L011-7 (70 mg, yield 38.5%). LC-MS: [M+H] + =523.10.

[0467] 11.8 Synthesis of Compound L011 Hydrochloride

[0468] L011-7 (70 mg, 0.13 mmol) was dissolved in dichloromethane (2 mL). A solution of hydrogen chloride in 1,4-dioxane (2 mL, 4 M) was added dropwise at room temperature and stirred for 0.5 hours. A solid precipitated, and the reaction mixture was filtered, and the filter cake was washed with dichloromethane (5 mL). The filter cake was dissolved in deionized water (10 mL) and freeze-dried to obtain compound L011 hydrochloride (39.0 mg, 63.8% yield).

[0469] 1 H NMR (400MHz, DMSO-d6): δ10.75-10.69(m,1H),8.93(t,J=6.8Hz,1H),8.71-8.58(m,3H),8.05(s,2H) ,7.86(s,1H),7.80(d,J=5.6Hz,1H),7.85-7.63(m,1H),6.83(d,J=8.8Hz,1H),5.13(m,1H),4.41(s,1 H),4.33-4.16(m,1H),3.29(d,J=4.4Hz,2H),3.10-2.97(m,1H),2.96-2.84(m,3H),2.70(s,3H),2.62 (s,1H),2.46-2.32(m,1H),2.15-2.04(m,1H),2.02-1.87(m,2H),1.22(d,J=7.2Hz,3H); LC-MS:[M+H] + =423.10.

[0470] Example 12. Synthesis of (2R,4S)-N-((2S)-1-((2-amino-6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)amino)-1-oxopropan-2-yl)-4-(3-chloro-4-fluorobenzyl)pyrrolidine-2-carboxamide (Compound L012) Hydrochloride

[0471]

[0472] 12.1 Synthesis of Compound L012-1

[0473] At room temperature, L001-e (1.5 g, 4.69 mmol) was dissolved in tetrahydrofuran (15 mL), cooled to -78°C, and lithium bis(trimethylsilyl)amide (5.16 mL, 5.16 mmol, 1 M tetrahydrofuran solution) was added dropwise under nitrogen. After the addition was complete, the mixture was stirred at -78°C for 0.5 hours. A solution of L012-a (1.15 g, 5.16 mmol) in tetrahydrofuran (10 mL) was added, and stirring was continued at -78°C for 2 hours. At this temperature, an aqueous solution of ammonium chloride (10 mL) was added to the reaction mixture to quench the mixture. After the system was warmed to room temperature, it was extracted with ethyl acetate (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound L012-1 (1.5 g, 69.1% yield). LC-MS: [M-Boc+H] + =361.95.

[0474] 12.2 Synthesis of Compound L012-2

[0475] At room temperature, L012-1 (1.5 g, 3.20 mmol) was dissolved in tetrahydrofuran (25 mL) and cooled to -78°C. Lithium triethylborohydride (3.5 mL, 3.5 mmol, 1 M solution in tetrahydrofuran) was added dropwise under nitrogen. After the addition was complete, the mixture was stirred at -78°C for 0.5 hours. Saturated aqueous sodium bicarbonate (10 mL) was added to the reaction mixture to quench the mixture. After the mixture was warmed to room temperature, it was extracted with ethyl acetate (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound L012-2 (crude product), which was used directly in the next step.

[0476] 12.3 Synthesis of Compound L012-3

[0477] L012-2 (1.5 g, crude product) was dissolved in dichloromethane (15 mL) at room temperature, and the reaction solution was cooled to -78°C. Triethylsilane (487 mg, 4.20 mmol) was added under nitrogen protection, followed by dropwise addition of boron trifluoride etherate complex (600 mg, 4.20 mmol). After the addition was complete, the mixture was stirred at -78°C for 1 hour. At this temperature, saturated aqueous sodium bicarbonate solution (10 mL) was added to the reaction solution to quench the reaction. After the system was warmed to room temperature, it was extracted with ethyl acetate (50 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound L012-3 (crude product), which was used directly in the next step. LC-MS: [M+H] + =447.95.

[0478] 12.4 Synthesis of Compound L012-4

[0479] L012-3 (500 mg, 1.16 mmol) was dissolved in tetrahydrofuran (4 mL) and water (2 mL) at room temperature, and lithium hydroxide monohydrate (180 mg, 4.46 mmol) was added. The mixture was stirred at room temperature for 16 hours. The reaction solution was directly concentrated under reduced pressure, and the residue was dissolved in water (10 mL). The pH of the aqueous phase was adjusted to 5-6 with dilute hydrochloric acid (1 M), and then extracted with ethyl acetate (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound L012-4 (crude product), which was used directly in the next step. LC-MS: [M-tBu+H] + =301.95.

[0480] 12.5 Synthesis of Compound L012-5

[0481] L012-4 (170 mg, crude product), L001-7 (140 mg, 0.48 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (137 mg, 0.72 mmol), 1-hydroxybenzotriazole (109 mg, 0.72 mmol) and triethylamine (146 mg, 1.44 mmol) were added to dichloromethane (3 mL) and stirred at room temperature for 0.5 hours. The reaction solution was diluted with water (20 mL) and extracted with dichloromethane (10 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography to give compound L012-5 (100 mg, yield 37.5%). LC-MS: [M+H] + =560.00.

[0482] 12.6 Synthesis of Compound L012 Hydrochloride

[0483] L012-5 (100 mg, 0.18 mmol) was dissolved in dichloromethane (1 mL). A solution of hydrogen chloride in 1,4-dioxane (1 mL, 4 M) was added and stirred at room temperature for 1 hour. A solid precipitated, which was filtered. The filter cake was dissolved in deionized water (10 mL) and freeze-dried to afford compound L012 hydrochloride (69.7 mg, 78.7% yield).

[0484] 1H NMR (400MHz, DMSO-d6): δ10.29-10.19(m,1H),8.82-8.78(m,1H),8.54-8.52(m,2H),7.94( s,2H),7.66-7.65(m,1H),7.48-7.45(m,1H),7.34(t,J=8.8Hz,1H),7.29-7.17(m,1H),6.80 (d,J=8.8Hz,1H),5.14-5.12(m,1H),4.35-4.18(m,2H),3.26-3.24(m,1H),2.94-2.84(m,3H ),2.78-2.59(m,2H),2.46-2.40(m,1H),2.10-1.83(m,3H),1.24-1.21(m,4H); LC-MS:[M+H] + =459.95.

[0485] Example 13. Synthesis of (2R,4R)-N-((2S)-1-((2-amino-6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)amino)-1-oxopropan-2-yl)-4-((5-chlorobenzo[d]thiazol-2-yl)methyl)pyrrolidine-2-carboxamide (Compound L013) Hydrochloride

[0486]

[0487] 13.1 Synthesis of Compound L013-1

[0488] L013-a (2 g, 12.50 mmol) was added to toluene (15 mL), and L013-b (2.8 g, 25.00 mmol) was added dropwise at room temperature. After the addition was complete, the mixture was stirred at 100°C for 2 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to remove the toluene. Petroleum ether (100 mL) was added to the residue, stirred at room temperature for 1 hour, filtered, and the filtrate was concentrated under reduced pressure to obtain compound L013-1 (1.5 g, yield 55.5%). LC-MS: [M+H] + =217.95.

[0489] 13.2 Synthesis of Compound L013-2

[0490] L013-1 (1.5 g, 6.88 mmol) and sodium iodide (2.1 g, 13.76 mmol) were added to tetrahydrofuran (20 mL) and stirred at 40°C for 2 hours. The reaction mixture was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound L013-2 (2.05 g, yield 96.2%). LC-MS: [M+H] + =309.80.

[0491] 13.3 Synthesis of Compound L013-3

[0492] L001-e (2.11 g, 6.60 mmol) was dissolved in tetrahydrofuran (20 mL) at room temperature and cooled to -78°C. Under nitrogen, lithium bis(trimethylsilyl)amide (7.3 mL, 7.3 mmol, 1 M solution in tetrahydrofuran) was added dropwise. After the addition was complete, stirring was continued for 0.5 hours. A solution of L013-2 (2.05 g, 6.6 mmol) in tetrahydrofuran (10 mL) was then added dropwise. After the addition was complete, the reaction mixture was stirred at -78°C for 1 hour. At this temperature, an aqueous solution of ammonium chloride (10 mL) was added to the reaction mixture to quench the mixture. After the system temperature rose to room temperature, the mixture was extracted with ethyl acetate (10 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to yield compound L013-3 (2 g, 60.6% yield). LC-MS: [M+H] + =500.90.

[0493] 13.4 Synthesis of Compound L013-4

[0494] L013-3 (1.3 g, 2.60 mmol) was dissolved in tetrahydrofuran (15 mL) at room temperature and then cooled to -78°C. Lithium triethylborohydride (2.9 mL, 2.90 mmol, 1 M solution in tetrahydrofuran) was added dropwise under nitrogen. After the addition was complete, the mixture was stirred at -78°C for 0.5 hours. Saturated aqueous sodium bicarbonate (10 mL) was added to quench the reaction. After the system temperature returned to room temperature, the mixture was extracted with ethyl acetate (10 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to yield compound L013-4 (crude product), which was used directly in the next step. LC-MS: [M-OH] + =484.90.

[0495] 13.5 Synthesis of Compound L013-5

[0496] L013-4 (1.3 g, crude product) was dissolved in dichloromethane (20 mL) at room temperature and cooled to -78°C. Triethylsilane (382 mg, 3.30 mmol) was added under nitrogen, followed by dropwise addition of boron trifluoride etherate (472 mg, 3.30 mmol). After the addition was complete, the mixture was stirred at -78°C for 1 hour. Saturated aqueous sodium bicarbonate solution (10 mL) was added to the reaction mixture at this temperature to quench the reaction. After the system temperature rose to room temperature, it was extracted with ethyl acetate (10 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound L013-5 (crude product), which was used directly in the next step. LC-MS: [M+H] + =487.00.

[0497] 13.6 Synthesis of Compound L013-6

[0498] L013-5 (300 mg, 0.61 mmol) and lithium hydroxide monohydrate (100 mg, 2.40 mmol) were added to tetrahydrofuran (6 mL) and water (2 mL) and stirred at room temperature for 16 hours. The reaction solution was directly concentrated under reduced pressure and diluted with water (10 mL). The pH of the aqueous phase was adjusted to 5-6 with hydrochloric acid (1 M) and extracted with ethyl acetate (10 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound L013-6 (150 mg, crude product), which was used directly in the next step. LC-MS: [M+H] + =396.95.

[0499] 13.7 Synthesis of Compound L013-7

[0500] L013-6 (150 mg, crude product), L001-7 (110 mg, 0.37 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (106 mg, 0.55 mmol), 1-hydroxybenzotriazole (84 mg, 0.55 mmol) and triethylamine (112 mg, 1.10 mmol) were added to dichloromethane (3 mL) and the reaction was stirred at room temperature for 0.5 hours. Water (20 mL) was added to the reaction solution to dilute it and extract it with dichloromethane (10 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (acidic conditions) to give compound L013-7 (120 mg, yield 49.6%). LC-MS: [M+H] + =599.00.

[0501] 13.8 Synthesis of Compound L013 Hydrochloride

[0502] Dissolve L013-7 (120 mg, 0.20 mmol) in dichloromethane (2 mL). Add a 4 M solution of hydrogen chloride in 1,4-dioxane (2 mL) dropwise at room temperature and stir for 0.5 hours. Solid precipitates. Filter the reaction mixture, and wash the filter cake with dichloromethane (3 mL). Dissolve the filter cake in deionized water (10 mL) and freeze-dry to obtain compound L013 hydrochloride (50.4 mg, 78.7% yield).

[0503] 1 H NMR (400MHz, DMSO-d6): δ10.46-10.44(m,1H),8.87(dd,J1=7.2Hz,J2=2.8Hz,1H),8.72-8.53(m,2H),8.11(d,J= 8.8Hz,1H),8.03-8.00(m,3H),7.68-7.64(m,1H),7.47(dd,J1=8.8Hz,J2=2.0Hz,1H),6.82(dd,J1=8.8Hz,J2=2.4 Hz,1H),5.17-5.11(m,1H),4.38(s,1H),4.26-4.22(m,1H),3.54-3.42(m,1H),3.31(d,J=7.2Hz,2H),3.13-2.96( m,2H),2.85-2.82(m,2H),2.47-2.37(m,1H),2.12(m,2H),1.98-1.87(m,1H),1.22(d,J=7.2Hz,3H); LC-MS:[M+H] + =499.00.

[0504] Example 14. Synthesis of (2R,4S)-N-((2S)-1-((2-amino-6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)amino)-1-oxopropan-2-yl)-4-(3-chlorobenzyl)pyrrolidine-2-carboxamide (Compound L014) Hydrochloride

[0505]

[0506] 14.1 Synthesis of Compound L014-1

[0507] L001-e (1.0 g, 3.13 mmol) was added to a reaction flask. Tetrahydrofuran (10 mL) was added to dissolve the mixture under a nitrogen atmosphere and placed in a -78°C cold bath. Lithium bis(trimethylsilyl)amide (3.2 mL, 3.2 mmol, 1 M tetrahydrofuran solution) was added while maintaining the temperature at -78°C and stirred for 0.5 hours. L014-a (639 mg, 3.13 mmol) was then added and the reaction continued at -78°C for two hours. A small amount of solid precipitated, and the reaction solution was quenched with saturated aqueous ammonium chloride (10 mL) at -78°C. After the system temperature rose to room temperature, it was extracted with ethyl acetate (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to yield compound L014-1 (950 mg, 68% yield). LC-MS: [M-Boc+H] + =344.00.

[0508] 14.2 Synthesis of Compound L014-2

[0509] L014-1 (950 mg, 2.14 mmol) was added to a reaction flask. Tetrahydrofuran (10 mL) was added to dissolve the mixture under a nitrogen atmosphere and placed in a -78°C cold bath. Lithium triethylborohydride (3.2 mL, 3.20 mmol, 1 M tetrahydrofuran solution) was added, maintaining the temperature at -78°C, and stirred for 0.5 hours after the addition. Water (50 mL) was added to the reaction solution at this temperature to quench the reaction. After the system temperature rose to room temperature, it was extracted with ethyl acetate (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound L014-2 (crude product), which was used directly in the next step. LC-MS: [M-OH] + =428.05.

[0510] 14.3 Synthesis of Compound L014-3

[0511] L014-2 (1.1 g crude product) was added to a reaction flask. Dichloromethane (10 mL) was added to dissolve the mixture under a nitrogen atmosphere and placed in a -78°C cold bath. Triethylsilane (345 mg, 2.97 mmol) and boron trifluoride etherate (421 mg, 2.97 mmol) were added separately at -78°C and stirred for 0.5 hours. Triethylsilane (345 mg, 2.97 mmol) and boron trifluoride etherate (421 mg, 2.97 mmol) were further added and stirred at -78°C for two hours. At this temperature, the reaction solution was quenched by adding water (50 mL). After the system temperature rose to room temperature, it was extracted with ethyl acetate (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound L014-3 (830 mg, 84% yield). LC-MS: [M+H] + =430.05.

[0512] 14.4 Synthesis of Compound L014-4

[0513] L014-3 (830 mg, 1.93 mmol) and sodium hydroxide (154 mg, 3.87 mmol) were added to a reaction flask, and methanol (10 mL) and water (5 mL) were added to dissolve the mixture. The mixture was allowed to react at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure to a volume of 2-3 mL, diluted with water (40 mL), and the pH was adjusted to 5-6 with dilute hydrochloric acid (0.5 M). The mixture was then extracted with ethyl acetate (30 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound L014-4 (crude product), which was used directly in the next step. LC-MS: [M+Na] + =362.00.

[0514] 14.5 Synthesis of Compound L014-5

[0515] L014-4 (100 mg, crude), 1-hydroxybenzotriazole (78 mg, 0.32 mmol), N,N-dimethylformamide (2 mL), N,N-diisopropylethylamine (170 mg, 1.18 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (62 mg, 0.32 mmol) were added to a reaction flask and reacted at room temperature for 0.5 hours. L001-7 (78 mg, 0.35 mmol) was then added and the reaction continued at room temperature for 1 hour. The reaction solution was diluted with water (40 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated sodium chloride aqueous solution (40 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (acidic conditions) to yield compound L014-5 (16 mg). LC-MS: [M+H]+ =542.00.

[0516] 14.6 Synthesis of Compound L014 Hydrochloride

[0517] L014-5 (16 mg, 0.03 mmol) was dissolved in dichloromethane (2 mL). A solution of hydrogen chloride in ethyl acetate (1 mL, 4 M) was added at room temperature and stirred for 0.5 hours, resulting in the precipitation of a white solid. The reaction mixture was filtered, and the filter cake was washed with ethyl acetate (10 mL). The filter cake was dissolved in deionized water (2 mL) and freeze-dried to afford compound L014 hydrochloride (10.5 mg).

[0518] 1 H NMR (400MHz, CH3OH-d4): δ7.84 -7.76(m,1H),7.33–7.16(m,4H),6.82(d,J=9.2Hz,1H),5.34–5.27(m,1H),4.47–4.45(m,1H),4.33–4.23(m,1H),3.51–3. 45(m,1H),3.16–2.96(m,3H),2.79–2.74(m,2H),2.66–2.62(m,2H),2.20–1.02(m,3H),1.38(d,J=7.2Hz,3H); LC-MS:[M+H] + =442.05.

[0519] Example 15. Synthesis of (2R,4S)-N-((2S)-1-((2-amino-6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)amino)-1-oxopropan-2-yl)-4-((3-methoxynaphthalen-2-yl)methyl)pyrrolidine-2-carboxamide (Compound L015) Hydrochloride

[0520]

[0521] 15.1 Synthesis of Compound L015-1

[0522] At 0°C, slowly add L015-a (2.0 g, 9.25 mmol) in tetrahydrofuran (10 mL) dropwise to a suspension of lithium aluminum tetrahydride (386 mg, 10.17 mmol) in tetrahydrofuran (10 mL). After the addition is complete, warm the reaction system to 25°C and continue stirring for 3 hours. Cool the reaction mixture to 0°C, quench with aqueous sodium hydroxide (5 mL, 5N), and dilute with tetrahydrofuran (30 mL). After drying over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to yield compound L015-1 (crude product), which can be used directly in the next step.

[0523] 15.2 Synthesis of Compound L015-2

[0524] Dissolve L015-1 (1.7 g, crude product) in tetrahydrofuran (30 mL), cool to 0°C, and slowly add a solution of phosphorus tribromide (1.2 g, 4.52 mmol) in tetrahydrofuran (10 mL) dropwise. After the addition is complete, warm the reaction system to 25°C and stir for 2.5 hours. Quench the reaction mixture with water (20 mL) and extract with ethyl acetate (20 mL x 3). The combined organic phases are dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography to yield compound L015-2 (1.3 g, 57.3% yield).

[0525] 15.3 Synthesis of Compound L015-3

[0526] L001-e (1.3 g, 4.07 mmol) was dissolved in tetrahydrofuran (20 mL). Lithium bis(trimethylsilyl)amide (4.5 mL, 4.5 mmol, 1 M tetrahydrofuran solution) was slowly added dropwise at -70°C under nitrogen. After the addition was complete, the reaction solution was stirred at -70°C for 0.5 hours. A solution of L015-2 (1.2 g, 4.88 mmol) in tetrahydrofuran (10 mL) was then slowly added dropwise. After the addition was complete, the reaction solution was stirred at -70°C for 2 hours. At this temperature, saturated aqueous ammonium chloride (20 mL) was added to the reaction solution to quench the mixture. After the system temperature rose to room temperature, the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound L015-3 (900 mg, 38.5% yield). LC-MS: [M-Boc+H] + =390.00.

[0527] 15.4 Synthesis of Compound L015-4

[0528] L015-3 (900 mg, 1.84 mmol) was dissolved in tetrahydrofuran (20 mL). Lithium triethylborohydride (2.1 mL, 2.1 mmol, 1 M tetrahydrofuran solution) was slowly added dropwise at -70°C under nitrogen protection. After the addition was complete, the reaction solution was stirred at -70°C for 2 hours. At this temperature, saturated aqueous sodium bicarbonate solution (10 mL) was added to the reaction solution to quench the reaction. After the system temperature rose to room temperature, it was extracted with ethyl acetate (15 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound L015-4 (400 mg, yield 44.3%). LC-MS: [M-OH] + =474.00.

[0529] 15.5 Synthesis of Compound L015-5

[0530] L015-5 (400 mg, 0.81 mmol) was dissolved in dichloromethane (10 mL). Triethylsilane (113 mg, 0.98 mmol) and boron trifluoride etherate (139 mg, 0.98 mmol) were added at -70°C under nitrogen and stirred for 0.5 hours. Triethylsilane (113 mg, 0.98 mmol) and boron trifluoride etherate (139 mg, 0.98 mmol) were then added and stirring continued at -70°C for 2 hours. At this temperature, the reaction mixture was quenched by the addition of saturated aqueous sodium bicarbonate (10 mL). After the system warmed to room temperature, it was extracted with dichloromethane (15 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to yield compound L015-5 (300 mg, 77.5% yield). LC-MS: [M-tBu+H] + =420.00.

[0531] 15.6 Synthesis of Compound L015-6

[0532] Dissolve L015-5 (300 mg, 0.63 mmol) in methanol (10 mL), add wet palladium on carbon (30 mg, 10% palladium content), and stir at 25°C under a hydrogen atmosphere for 1 hour. The reaction mixture is filtered through celite, and the filtrate is concentrated under reduced pressure to obtain compound L015-6 (crude product), which can be used directly in the next step. LC-MS: [M-tBu+H] + =330.00.

[0533] 15.7 Synthesis of Compound L015-7

[0534] L015-6 (100 mg, crude product) was dissolved in N,N-dimethylformamide (2 mL). 1-Hydroxybenzotriazole (39 mg, 0.29 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (55 mg, 0.29 mmol) were added, and the mixture was stirred at 20°C for 10 minutes. A solution of L001-7 (80 mg, 0.31 mmol) and N,N-diisopropylethylamine (167 mg, 1.30 mmol) in N,N-dimethylformamide (2 mL) was then added, and the reaction was continued for 1.5 hours. The reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic phases were washed with saturated sodium chloride aqueous solution (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by HPLC (acidic conditions) to give compound L015-7 (60 mg, yield 39.4%). LC-MS: [M+H] + =588.05.

[0535] 15.8 Synthesis of Compound L015 Hydrochloride

[0536] L015-7 (60 mg, 0.05 mmol) was dissolved in dichloromethane (2 mL), and a solution of hydrogen chloride in ethyl acetate (2 mL, 4 M) was added. The mixture was stirred at 25°C for 0.5 hours. Solid precipitated in the reaction solution, which was filtered and the filter cake washed with ethyl acetate (5 mL). The filter cake was dissolved in deionized water (15 mL) and freeze-dried to afford compound L015 hydrochloride (29.2 mg, 58% yield).

[0537] 1 H NMR (400MHz, DMSO-d6): δ10.27–10.16(m,1H),8.85(d,J=8.0Hz,1H),8.56(t,J=8.0Hz,2H),7.97(s,1H),7. 89–7.65(m,2H),7.45–7.41(m,4H),7.37–7.33(m,2H),6.82(dd,J1=8.8Hz,J2=2.0Hz,1H),5.18–5.12(m,1H ),4.43-4.35(m,1H),4.34–4.19(m,1H),3.92(s,3H),3.36–3.28(m,1H),3.13–2.78(m,5H),2.66–2.63(m,1 H),2.48–2.41(m,1H),2.16–2.08(m,1H),1.97–1.88(m,2H),1.23(d,J=8.0Hz,3H); LC / MS(ESI+)m / z: [M+H] + =488.10.

[0538] Example 16. Synthesis of (2R,4S)-N-((2S)-1-((2-amino-6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)amino)-1-oxopropan-2-yl)-4-(3-methylbenzyl)pyrrolidine-2-carboxamide (Compound L016) Hydrochloride

[0539]

[0540] 16.1 Synthesis of Compound L016-1

[0541] L001-e (1.0 g, 3.13 mmol) was dissolved in tetrahydrofuran (10 mL). Lithium bis(trimethylsilyl)amide (3.2 mL, 3.2 mmol, 1 M tetrahydrofuran solution) was added dropwise at -78°C under nitrogen protection. After the addition, the mixture was stirred at -78°C for 0.5 hours. L016-a (576 mg, 3.13 mmol) was added to the reaction system and the reaction was continued at -78°C for 2 hours. The reaction solution was quenched with water (50 mL) and extracted with ethyl acetate (40 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound L016-1 (697 mg, 53% yield). LC-MS [M-Boc+H] + =324.0.

[0542] 16.2 Synthesis of Compound L016-2

[0543] L016-1 (697 mg, 1.65 mmol) was dissolved in tetrahydrofuran (10 mL). Lithium triethylborohydride (2.5 mL, 2.5 mmol, 1 M solution in tetrahydrofuran) was added dropwise at -78°C under nitrogen. After complete addition, the mixture was stirred at -78°C for 0.5 hours. At this temperature, the reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (40 mL x 3). The combined organic phases were dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to yield compound L016-2 (crude product), which was used directly in the next step.

[0544] 16.3 Synthesis of Compound L016-3

[0545] L016-2 (810 mg, crude product) was dissolved in dichloromethane (10 mL). Triethylsilane (284 mg, 2.45 mmol) and boron trifluoride etherate (347 mg, 2.45 mmol) were added at -78°C under nitrogen protection. After the addition, the mixture was stirred at -78°C for 0.5 hours. Triethylsilane (284 mg, 2.45 mmol) and boron trifluoride etherate (347 mg, 2.45 mmol) were further added, and stirring was continued at -78°C for 2 hours. At this temperature, the reaction solution was quenched with water (50 mL) and extracted with ethyl acetate (40 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound L016-3 (432 mg, 56% yield). LC-MS [M-Boc+H] + =310.1.

[0546] 16.4 Synthesis of Compound L016-4

[0547] Dissolve L016-3 (432 mg, 1.93 mmol) in methanol (10 mL), add wet palladium on carbon (20 mg, 10% palladium content), and stir at room temperature under a hydrogen atmosphere for 3 hours. The reaction mixture is filtered through a pad of celite, and the filtrate is concentrated under reduced pressure to afford compound L016-4 (307 mg, crude product), which is used directly in the next step.

[0548] 16.5 Synthesis of Compound L016-5

[0549] L016-4 (100 mg, 0.31 mmol), 1-hydroxybenzotriazole (48 mg, 0.35 mmol), N,N-dimethylformamide (2 mL), N,N-diisopropylethylamine (162 mg, 1.25 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (66 mg, 0.35 mmol) were added to a reaction flask and stirred at room temperature for 0.5 hours. L001-7 (83 mg, 0.38 mmol) was then added and the reaction continued at room temperature for 1 hour. The reaction solution was diluted with water (40 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated sodium chloride (40 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (basic conditions) to give compound L016-5 (25.2 mg). LC-MS [M+H] + =522.1.

[0550] 16.6 Synthesis of Compound L016 Hydrochloride

[0551] L016-5 (25.2 mg, 0.05 mmol) was dissolved in dichloromethane (2 mL). A solution of hydrogen chloride in ethyl acetate (1 mL, 4 M) was added and stirred at room temperature for 0.5 hours, resulting in the precipitation of a solid. The reaction mixture was filtered, and the filter cake was washed with ethyl acetate (5 mL). The filter cake was dissolved in water (15 mL) and freeze-dried to afford compound L016 hydrochloride (17.1 mg, 71.8% yield).

[0552] 1H NMR (400MHz, CH3OH-d4): δ7.84-7.76(m,1H),7.19(t,J=7.2Hz,1H),7.05–6 .98(m,3H),6.83(d,J=8.8Hz,1H),5.30(m,1H),4.48–4.23(m,2H),3.49–3. 40(m,1H),3.13–3.11(m,1H),3.06–2.96(m,2H),2.78–2.73(m,2H),2.68–2 .47(m,2H),2.32(s,3H),2.21–1.97(m,3H),1.39–1.36(m,3H); LC-MS[M+H] + =422.2.

[0553] Example 17. Synthesis of (2R,4R)-N-((2S)-1-((2-amino-6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)amino)-1-oxopropan-2-yl)-4-(1-phenylcyclopropyl)pyrrolidine-2-carboxamide (Compound L017)

[0554]

[0555] 17.1 Synthesis of Compound L017-1

[0556] At room temperature, diiodomethane (5.9 g, 21.72 mmol) was added to dichloromethane (40 mL). The mixture was cooled to 0°C and stirred under nitrogen for 5 minutes. Then, a toluene solution of diethylzinc (10.8 mL, 10.8 mmol, 1 M in toluene) was slowly added, and the reaction mixture was stirred at 0°C for 0.5 hours. A solution of L017-a (1 g, 4.35 mmol) in dichloromethane (10 mL) was then slowly added dropwise. The reaction mixture was stirred at 0°C for 0.5 hours, then warmed to room temperature and stirred for 16 hours. The reaction mixture was quenched by the addition of saturated aqueous ammonium chloride (50 mL) and stirred for 3-5 minutes. The mixture was extracted with dichloromethane (50 mL x 3), and the combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The residue was purified by silica gel column chromatography to yield compound L017-1 (979 mg, 92% yield). LC-MS: [M+H] + =245.15.

[0557] 17.2 Synthesis of Compound L017-2

[0558] At room temperature, L017-1 (900 mg, 3.69 mmol), potassium bifluoride (1.73 g, 22.1 mmol) and methanol (30 mL) were added to a 100 mL sealed tube and stirred at 80°C for 5 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure to about 10 mL. Solid precipitated and was filtered. The filter cake was placed in a round-bottom flask, and ether / n-heptane solution (40 mL, 1 / 1 (v / v)) was added and stirred at room temperature for 0.5 hours. The suspension was filtered and the filter cake was washed with ether (30 mL). The washed filter cake was then added to acetonitrile (40 mL), stirred at 60°C for 5 minutes, filtered while hot, and the filter cake was dried under reduced pressure to obtain compound L017-2 (471 mg, yield 57%).

[0559] 17.3 Synthesis of Compound L017-3

[0560] L017-2 (471 mg, 2.10 mmol), L006-1 (790 mg, 2.10 mmol), [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (70 mg, 0.11 mmol), and cesium carbonate (1.37 g, 4.20 mmol) were dissolved in toluene (20 mL) and water (2 mL). After nitrogen displacement for 15 minutes, the mixture was reacted at 95°C for 2 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure to remove toluene. The mixture was then diluted with water (40 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound L017-3 (270 mg, 37% yield). LC-MS: [M-tBu+H] + =288.05.

[0561] 17.4 Synthesis of Compound L017-4

[0562] L017-3 (270 mg, 0.79 mmol) and lithium hydroxide monohydrate (485.6 mg, 11.8 mmol) were dissolved in tetrahydrofuran (4 mL), methanol (2 mL), and water (2 mL) and stirred at room temperature for 2 hours. The pH of the reaction solution was adjusted to 5-6 with dilute hydrochloric acid (1 M), diluted with water (20 mL), and extracted with ethyl acetate (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound L017-4 (157 mg). LC-MS: [M-tBu+H] + =274.05.

[0563] 17.5 Synthesis of Compound L017-5

[0564] At room temperature, L017-4 (157 mg, 0.48 mmol), tris(triphenylphosphine)rhodium chloride (44.6 mg, 0.05 mmol), and triethylamine (48.6 mg, 0.48 mmol) were dissolved in methanol (15 mL) and tetrahydrofuran (15 mL) and stirred at room temperature under a hydrogen atmosphere for 4 days. The reaction mixture was filtered, and the pH of the filtrate was adjusted to 10 with aqueous sodium hydroxide solution (1 M), then extracted with ethyl acetate (40 mL). The organic phase was washed with saturated aqueous sodium bicarbonate solution (20 mL) and discarded. All aqueous phases were combined, the pH was adjusted to 5-6 with dilute hydrochloric acid (1 M), and then extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound L017-5 (140 mg, crude product), which was used directly in the next step. LC-MS: [M-tBu+H] + =276.00.

[0565] 17.6 Synthesis of Compound L017-6

[0566] At room temperature, L017-5 (140 mg, crude) and 1-hydroxybenzotriazole (59 mg, 0.42 mmol) were dissolved in N,N-dimethylformamide (2 mL). N,N-diisopropylethylamine (217 mg, 1.68 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (81 mg, 0.42 mmol) were added, and the mixture was stirred at room temperature for 0.5 hour. L001-7 (111 mg, 0.5 mmol) was then added, and the reaction was continued at room temperature for 1 hour. The reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated sodium chloride (40 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (acidic conditions) to yield compound L017-6 (120 mg, 53.6% yield). LC-MS: [M+H] + =534.00.

[0567] 17.7 Synthesis of Compound L017

[0568] L017-6 (120 mg, 0.225 mmol) was dissolved in dichloromethane (2 mL), and a solution of hydrogen chloride in ethyl acetate (1 mL, 4 M) was added. The mixture was stirred at room temperature for 1 hour. A solid precipitated, and the reaction mixture was filtered, and the filter cake was washed with ethyl acetate (10 mL). The crude product obtained by filtration was purified by preparative HPLC (alkaline conditions) to afford compound L017 (19.1 mg).

[0569] 1H NMR (400MHz, DMSO-d6): δ8 8.91-8.90(m,1H),8.58–8.51(m,1H),7.97(s,2H),7.68–7.62(m,1H),7.35–7.23(m,5H),6.80( d,J=8.8Hz,1H),5.30(s,0.5H),5.16–5.09(m,1H),4.97(s,0.5H),4.38–4.36(m,1H),4.23–4.1 7(m,1H),3.83–3.81(m,1H),3.05–2.98(s,1H),2.93–2.85(m,1H),2.45–2.42(m,1H),2.35(s,1 H),2.01–1.74(m,2H),1.33(t,J=7.2Hz,2H),1.22–1.07(m,6H),0.80–0.72(m,1H); LC-MS:[M+H] + =434.10.

[0570] Example 18. Synthesis of (2R,4S)-N-((2S)-1-((2-amino-6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)amino)-1-oxopropan-2-yl)-4-(3-chloro-4-(trifluoromethoxy)benzyl)pyrrolidine-2-carboxamide (Compound L018)

[0571]

[0572] 18.1 Synthesis of Compound L018-1

[0573] L018-a (2.0 g, 8.52 mmol) was dissolved in dichloromethane (30 mL). A solution of phosphorus tribromide (1.2 g, 4.52 mmol) in dichloromethane (10 mL) was slowly added dropwise at 0°C. After the addition was complete, the mixture was stirred at 0°C for 1 hour. The reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound L018-1 (1.5 g, 59.1% yield).

[0574] 18.2 Synthesis of Compound L018-2

[0575] L001-e (1.5 g, 4.70 mmol) was dissolved in tetrahydrofuran (20 mL) and cooled to -70°C. Under nitrogen, lithium bis(trimethylsilyl)amide (5.2 mL, 5.2 mmol, 1 M solution in tetrahydrofuran) was slowly added dropwise. After the addition was complete, the reaction solution was stirred at -70°C for 0.5 hours. A solution of L018-1 (1.5 g, 5.17 mmol) in tetrahydrofuran (10 mL) was then added dropwise. After the addition was complete, the reaction system was stirred at -70°C for another 2 hours. At this temperature, the reaction was quenched with saturated aqueous ammonium chloride (20 mL). After the system temperature rose to room temperature, it was extracted with ethyl acetate (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to yield compound L018-2 (1.2 g, 48% yield). LC-MS: [M-Boc+H] + =427.90.

[0576] 18.3 Synthesis of Compound L018-3

[0577] L018-2 (1.2 g, 2.27 mmol) was dissolved in tetrahydrofuran (20 mL), cooled to -70°C, and lithium triethylborohydride (2.5 mL, 2.5 mmol, 1 M solution in tetrahydrofuran) was slowly added dropwise under nitrogen. After the addition was complete, the reaction solution was stirred at -70°C for 2 hours. At this temperature, saturated aqueous sodium bicarbonate solution (10 mL) was added to the reaction solution to quench the mixture. After the system temperature rose to room temperature, it was extracted with ethyl acetate (15 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound L018-3 (900 mg, 49.5% yield). LC-MS: [M-OH] + =512.00.

[0578] 18.4 Synthesis of Compound L018-4

[0579] L018-3 (900 mg, 1.71 mmol) was dissolved in dichloromethane (20 mL) and cooled to -70°C. Triethylsilane (237 mg, 2.04 mmol) and boron trifluoride etherate (290 mg, 2.04 mmol) were added under nitrogen, and the mixture was stirred at -70°C for 0.5 hours. Additional triethylsilane (237 mg, 2.04 mmol) and boron trifluoride etherate (290 mg, 2.04 mmol) were added, and stirring was continued at -70°C for 2 hours. The reaction mixture was quenched by the addition of saturated aqueous sodium bicarbonate (10 mL). After the system warmed to room temperature, it was extracted with dichloromethane (15 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford compound L018-4 (450 mg, 38.8% yield). LC-MS: [M-tBu+H] + =457.90.

[0580] 18.5 Synthesis of Compound L018-5

[0581] L018-4 (450 mg, 0.88 mmol) was dissolved in methanol (10 mL) and water (10 mL), and lithium hydroxide monohydrate (110 mg, 2.63 mmol) was added and stirred at 25°C for 4 hours. The reaction solution was directly concentrated under reduced pressure, the residue was diluted with water (10 mL), then washed with ethyl acetate (10 mL × 3), and the organic phase was discarded. The pH value of the aqueous phase was adjusted to 4-5 with dilute hydrochloric acid (1 M), and then extracted with dichloromethane (10 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound L018-5 (350 mg, crude product), which can be used directly in the next step. LC-MS: [M-tBu+H] + =367.95.

[0582] 18.6 Synthesis of Compound L018-6

[0583] L018-5 (150 mg, 0.35 mmol) was dissolved in N,N-dimethylformamide (2 mL), and 1-hydroxybenzotriazole (57 mg, 0.42 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (82 mg, 0.42 mmol) were added. After stirring at room temperature for 10 minutes, a solution of L001-7 (91 mg, 0.35 mmol) and N,N-diisopropylethylamine (129 mg, 1.77 mmol) in N,N-dimethylformamide (2 mL) was added, and stirring was continued at room temperature for 1.5 hours. The reaction solution was directly poured into water (10 mL) and extracted with ethyl acetate (15 mL × 3). The combined organic phases were washed with saturated aqueous ammonium chloride (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound L018-6 (200 mg, crude product). LC-MS: [M+H] + =626.05.

[0584] 18.7 Synthesis of Compound L018

[0585] L018-6 (200 mg, 0.32 mmol) was dissolved in dichloromethane (2 mL). A solution of hydrogen chloride in ethyl acetate (2 mL, 4 M) was added at room temperature and stirred for 0.5 hours, resulting in the precipitation of a solid. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative HPLC (alkaline conditions) and freeze-dried to afford compound L018 (50.3 mg, 29.94% yield).

[0586] 1 H NMR (400MHz, DMSO-d6): δ8.28-8.13(m,2H),7.54-7.52(m,1H),7.50 -7.44(m,1H),7.31-7.27(m,1H),7.14 -7.09(m,1H),6.24-6.22(m,1H),5.83(s,2H),5.14-5.02(m,1H),4.26-4.15(m,1H),3.62(dd,J1=8 .0,J2=4.0Hz,1H),2.89-2.51(m,7H),2.39-2.26(m,1H),2.20-2.11(m,1H),1.78-1.62(m,3H),1.24 -1.18 (m, 3H); LC-MS: [M+H] + =526.00.

[0587] Example 19. Synthesis of (2R)-N-((2S)-1-((2-amino-6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)amino)-1-oxopropan-2-yl)-4-phenyl-2,5-dihydro-1H-pyrrole-2-carboxamide (Compound L019) Hydrochloride

[0588]

[0589] 19.1 Synthesis of Compound L019-1

[0590] L006-3 (100 mg, 0.35 mmol), 1-hydroxybenzotriazole (53 mg, 0.38 mmol), N,N-dimethylformamide (3 mL), N,N-diisopropylethylamine (178 mg, 1.38 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (73 mg, 0.38 mmol) were added to a reaction flask and stirred at room temperature for 0.5 hour. L001-7 (92 mg, 0.42 mmol) was then added and the reaction continued at room temperature for 1 hour. The reaction solution was diluted with water (40 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated sodium chloride aqueous solution (40 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC to yield compound L019-1 (68 mg, 40.1% yield). LC-MS: [M+H] + =492.10.

[0591] 19.2 Synthesis of Compound L019 Hydrochloride

[0592] L019-1 (68 mg, 0.14 mmol) was dissolved in dichloromethane (2 mL), and a solution of hydrogen chloride in ethyl acetate (1 mL, 4 M) was added. The mixture was stirred at room temperature for 0.5 hours. Solid precipitated in the reaction solution, which was filtered and the filter cake washed with ethyl acetate (10 mL). The filter cake was dissolved in deionized water (10 mL) and freeze-dried to afford compound L019 hydrochloride (24.0 mg, 37.4% yield).

[0593] 1H NMR (400MHz, DMSO-d6): δ7.85-7.79(m,1H),7.57-7.46(m,2H),7.46-7.37(m,3H),6.95-6.74(m,1H),6.50-6.28(m,1H),5.33(m,2H),4.57- 4.52(m,2H),4.39-4.24(m,1H),3.22-3.07(m,1H),3.06-2.95(m,1H), 2.77-2.56(m,1H),2.25-1.98(m,1H),1.46-1.44(m,3H); LC-MS:[M+H] + =392.10.

[0594] Example 20, N-((2S)-1-((2-amino-6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)amino)-1-oxopropan-2-yl)-4-phenyl-1H-pyrrole-2-carboxamide (Compound L020) and N-((S)-1-(((R)-2-amino-6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)amino)-1-oxopropan-2-yl) Synthesis of N-((S)-1-(((S)-2-amino-6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)amino)-1-oxopropan-2-yl)-4-phenyl-1H-pyrrole-2-carboxamide (compound L020-IS-02 or L020-IS-01)

[0595]

[0596] 20.1 Synthesis of Compound L020-1

[0597] L020-a (2 g, 9.85 mmol) was dissolved in N,N-dimethylformamide (20 mL), potassium tert-butoxide (1.3 g, 11.76 mmol) was added, and the mixture was stirred at 0°C for 0.5 hours. 2-(Trimethylsilyl)ethoxymethyl chloride (1.8 g, 10.77 mmol) was then added, and the reaction was continued at 0°C for 2 hours. A small amount of insoluble matter precipitated in the reaction solution, and the reaction solution was filtered. The filtrate was diluted with water (50 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound L020-1 (2.4 g, yield 73%). LC-MS: [M+H] + =334.28.

[0598] 20.2 Synthesis of Compound L020-2

[0599] L020-1 (1.7 g, 5.01 mmol), tetrakis(triphenylphosphine)palladium (576 mg, 0.50 mmol), phenylboronic acid (917 mg, 7.52 mmol), and cesium carbonate (3.3 g, 10.02 mmol) were added to a reaction flask. The atmosphere was purged with nitrogen. 1,4-dioxane (24 mL) and water (6 mL) were added to dissolve the mixture, and the mixture was refluxed at 90°C for 5 hours. The reaction mixture was cooled to room temperature, diluted with ethanol (50 mL), and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound L020-2 (1.45 g, yield 87%). LC-MS: [M+H] + =332.05.

[0600] 20.3 Synthesis of Compound L020-3

[0601] L020-2 (1.45 g, 4.38 mmol) and tetrabutylammonium fluoride (2.29 g, 8.76 mmol) were added to a reaction flask, dissolved in tetrahydrofuran (10 mL), and stirred at 80°C for 6 hours. The reaction solution was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound L020-3 (570 mg, yield 65%). LC-MS: [M+H] + =202.10

[0602] 20.4 Synthesis of Compound L020-4

[0603] L020-3 (570 mg, 2.83 mmol) was added to a reaction flask, and tetrahydrofuran (2 mL), methanol (2 mL) and water (1 mL) were added to dissolve. Lithium hydroxide monohydrate (357 mg, 8.49 mmol) was added at room temperature and stirred at 80°C for 3 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure to obtain a crude product. Water (30 mL) was added to the crude product for dilution, and the pH of the solution was adjusted to 5-6 with aqueous hydrochloric acid solution (1 M). It was extracted with ethyl acetate (50 mL × 3), and the combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound L020-4 (511 mg, yield 96.3%). LC-MS: [M+H] + =188.10.

[0604] 20.5 Synthesis of Compound L020

[0605] L020-4 (100 mg, 0.53 mmol), 1-hydroxybenzotriazole (81 mg, 0.58 mmol), N,N-dimethylformamide (2 mL), N,N-diisopropylethylamine (290 mg, 2.12 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (111 mg, 0.58 mmol) were added to a reaction flask and reacted at room temperature for 0.5 hour. Compound L001-7 (141 mg, 0.64 mmol) was then added and the reaction continued at room temperature for 1 hour. The reaction mixture was diluted with water (40 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated sodium chloride (40 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The residue was purified by preparative HPLC to yield compound L020 (50.8 mg, 24.4% yield).

[0606] 1 H NMR (400MHz, DMSO-d6): δ11.67(s,1H),8.32-8.26(m,1H),8.17-8.02(m,1H),7.55(d,J=8.0Hz,2H),7.39-7.27(m,4H),7.25(s,1H),7.18-7.07(m ,2H),6.83(s,1H),6.51(d,J=8.8Hz,1H),5.15(d,J=6.8Hz,1H),4.61-4. 24(m,1H),2.99-2.82(m,1H),2.81-2.65(m,1H),2.48-2.29(m,1H),1.96 -1.72(m,1H),1.34(d,J=7.2Hz,3H); LC-MS:[M+H] + =390.05.

[0607] 20.6 Preparation of Compound L020-IS-01 or L020-IS-02

[0608] Compound L020 (50.8 mg) was separated by supercritical fluid chromatography (SFC) (Method: Cellulose-2-3-MeOH+CAN(DEA)-40-3mL-35T, chromatographic column: Lux Cellulose-2, 50X25 mm, 10 μm, mobile phase, A: carbon dioxide, B: methanol, flow rate: 75 g / min) to give compounds L020-IS-01 (retention time Rt = 0.952 min, 14.9 mg) and L020-IS-02 (retention time Rt = 1.418 min, 8.5 mg).

[0609] L020-IS-01:

[0610] 1 H NMR (400MHz, DMSO-d6): δ11.63(s,1H),8.14(d,J=8.2Hz,1H),8.00(d,J=7.6H z,1H),7.54(d,J=7.2Hz,2H),7.37-7.24(m,4H),7.18(d,J=8.0Hz,1H),7.12( t,J=7.2Hz,1H),6.21(d,J=8.4Hz,1H),5.79(s,2H),5.11(q,J=7.6Hz,1H),4. 44-4.36(m,1H),2.73-2.68(m,1H),2.65-2.57(m,1H),2.35-2.27(m,1H),1.76 -1.67(m,1H),1.31(d,J=7.2Hz,3H); LC-MS:[M+H] + =390.05.

[0611] L020-IS-02:

[0612] 1 H NMR (400MHz, DMSO-d6): δ11.64(s,1H),8.13(d,J=8.4Hz,1H),8.02(d,J=7.6Hz,1H) ,7.55(d,J=7.4Hz,2H),7.35-7.29(m,4H),7.16-7.13(m,2H),6.24(d,J=8.4Hz,1H) ,5.81(s,2H),5.13(q,J=7.6Hz,1H),4.47-4.40(m,1H),2.77-2.69(m,1H),2.67-2. 59(m,1H),2.38-2.30(m,1H),1.81-1.72(m,1H),1.33(d,J=7.2Hz,3H); LC-MS:[M+H] + =390.05.

[0613] Example 21. Synthesis of N-((2S)-1-((2-amino-6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)amino)-1-oxopropan-2-yl)-4-phenylpiperidine-2-carboxamide (Compound L021) Hydrochloride

[0614]

[0615] 21.1 Synthesis of Compound L021-1

[0616] L021-a (100 mg, 0.33 mmol) was dissolved in N,N-dimethylformamide (2 mL), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (69 mg, 0.36 mmol) and 1-hydroxybenzotriazole (49 mg, 0.36 mmol) were added. The mixture was stirred at 20°C for 10 minutes, and then a solution of N,N-diisopropylethylamine (211 mg, 1.64 mmol) and L001-7 (106 mg, 0.36 mmol) in N,N-dimethylformamide (2 mL) was added. The reaction was continued at 20°C for 30 minutes. The reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (15 mL × 3). The combined organic phases were washed with saturated aqueous ammonium chloride (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (acidic conditions) and freeze-dried to obtain compound L021-1 (60 mg, yield 36.09%). LC-MS: [M+H] + =508.15.

[0617] 21.2 Synthesis of Compound L021 Hydrochloride

[0618] L021-1 (60 mg, 0.12 mmol) was dissolved in dichloromethane (2 mL). A solution of hydrogen chloride in ethyl acetate (2 mL, 4 M) was added and the mixture was allowed to react at 25°C for 1 hour, resulting in the formation of a solid. The reaction mixture was filtered, and the filter cake was dissolved in deionized water (10 mL) and freeze-dried to afford compound L021 hydrochloride (38.7 mg, 68.3% yield).

[0619] 1 H NMR (400MHz, DMSO-d6): δ9.93-9.38(m,1H),9.02-8.69(m,2H),8.59-8.48(m,1H),8.0 4(s,2H),7.74-7.61(m,1H),7.55-7.09(m,6H),6.87-6.81(m,1H),5.24-4.97(m,1H),4 .36-4.17(m,1H),3.95(t,J=12.0Hz,1H),3.34(d,J=12.0Hz,1H),3.21-2.78(m,4H),2. 49-2.21(m,2H),2.01-1.98(m,3H),1.80-1.55(m,1H),1.27-1.23(m,3H); LC-MS:[M+H] + =408.10.

[0620] Example 22. Synthesis of (2R)-N-((2S)-1-((2-amino-6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)amino)-1-oxopropan-2-yl)-4-(naphthalen-1-yl)piperidine-2-carboxamide (Compound L022) Hydrochloride

[0621]

[0622] 22.1 Synthesis of Compound L022-1

[0623] L022-a (1.0 g, 3.85 mmol) was added to tetrahydrofuran (10 mL) at room temperature. The reaction mixture was cooled to -78°C and lithium bis(trimethylsilyl)amide (4.2 mL, 4.2 mmol, 1 M solution in tetrahydrofuran) was added dropwise under nitrogen. After the addition was complete, the mixture was stirred at -78°C for 10 minutes. A solution of N-(5-chloro-2-pyridyl)bis(trifluoromethanesulfonamide) (1.58 g, 4.04 mmol) in tetrahydrofuran (5 mL) was then added. After the addition was complete, the mixture was warmed to room temperature and stirred for 1.5 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to yield compound L022-1 (600 mg, crude product, a mixture of double bond isomers).

[0624] 22.2 Synthesis of Compound L022-2

[0625] L022-1 (440 mg, 1.13 mmol), L022-b (233 mg, 1.36 mmol), tetrakis(triphenylphosphine)palladium (130 mg, 0.11 mmol), and potassium carbonate (311 mg, 2.26 mmol) were added to 1,4-dioxane (10 mL) and water (1 mL) and stirred at 75°C for 16 hours under nitrogen. The reaction solution was cooled to room temperature, diluted with water (20 mL), and then extracted with ethyl acetate (20 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain a double bond isomeric mixture L022-2 (430 mg, crude product). LC-MS: [M-Boc+H] + =268.05.

[0626] 22.3 Synthesis of Compound L022-3

[0627] L022-2 (430 mg, 1.17 mmol) was dissolved in tetrahydrofuran (5 mL), methanol (1 mL) and water (1 mL), and lithium hydroxide monohydrate (147 mg, 3.50 mmol) was added and stirred at room temperature for 3 hours. Water (10 mL) was added to the reaction solution to dilute it, and it was extracted with ethyl acetate (20 mL × 3). The organic phase was discarded. The aqueous phase was adjusted to pH 5-6 with dilute hydrochloric acid (1 M), and then extracted with ethyl acetate (20 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a double bond isomeric mixture L022-3 (260 mg, crude product). LC-MS: [M-Boc+H] + =254.10.

[0628] 22.4 Synthesis of Compound L022-4

[0629] L022-3 (200 mg, 0.56 mmol), tris(triphenylphosphine)rhodium chloride (92 mg, 0.10 mmol), and triethylamine (57 mg, 0.56 mmol) were dissolved in tetrahydrofuran (2.5 mL) and methanol (2.5 mL) and stirred at room temperature under a hydrogen atmosphere for 3 days. The reaction mixture was filtered, and the filtrate was directly concentrated under reduced pressure to obtain compound L022-4 (200 mg, crude product). LC-MS: [M-Boc+H] + =256.10.

[0630] 22.5 Synthesis of Compound L022-5

[0631] L022-4 (120 mg, 0.34 mmol), L001-7 (100 mg, 0.34 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (88 mg, 0.46 mmol), 1-hydroxybenzotriazole (69 mg, 0.46 mmol) and triethylamine (93 mg, 0.92 mmol) were added to dichloromethane (2 mL) and stirred at room temperature for 0.5 hours. Water (20 mL) was added to the reaction solution and diluted, and extracted with dichloromethane (10 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography to give compound L022-5 (150 mg, yield 79%), LC-MS: [M+H] + =558.10.

[0632] 22.6 Synthesis of Compound L022 Hydrochloride

[0633] L022-5 (50 mg, 0.09 mmol) was dissolved in dichloromethane (1 mL). A solution of hydrogen chloride in 1,4-dioxane (1 mL, 4 M) was added dropwise and stirred at room temperature for 1 hour. A solid precipitated, and the reaction mixture was filtered, and the filter cake was washed with dichloromethane (3 mL). The filter cake was dissolved in deionized water (15 mL) and freeze-dried to afford compound L022 hydrochloride (11.1 mg, 25.1% yield).

[0634] 1 H NMR (400MHz, DMSO-d6): δ9.91(s,1H),9.05-9.04(m,1H),8.94-8.70(m,1H),8.55(d,J=8.0H z,1H),8.34-7.98(m,1H),7.92-7.80(m,1H),7.85-7.78(m,1H),7.67-7.45(m,5H),7.38(d,J =7.2Hz,1H),6.78-6.57(m,1H),5.26-5.09(m,1H),4.48-4.24(m,2H),3.58(m,2H),2.97-2.8 7(m,2H),2.44-2.34(m,1H),2.13(s,2H),2.06-1.88(m,2H),1.42-1.21(m,4H); LC-MS:[M+H] + =458.10.

[0635] Example 23. Synthesis of (2R)-N-((2S)-1-((2-amino-6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)amino)-1-oxopropan-2-yl)-4-phenyl-1,2,5,6-tetrahydropyridine-2-carboxamide (L023-IS-01 or L023-IS-02) and (2R)-N-((2S)-1-((2-amino-6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)amino)-1-oxopropan-2-yl)-4-phenyl-1,2,3,6-tetrahydropyridine-2-carboxamide (L023-IS-02 or L023-IS-01) hydrochloride

[0636]

[0637] 23.1 Synthesis of Compound L023-1

[0638] L022-1 (2.5 g, 6.42 mmol), L006-b (1.17 g, 9.63 mmol), tetrakis(triphenylphosphine)palladium (226 mg, 0.32 mmol), and sodium carbonate (1.36 g, 12.84 mmol) were dissolved in tetrahydrofuran (75 mL) and water (15 mL) at room temperature and stirred at 40°C for 4 hours. The reaction solution was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound L023-1 (2.1 g, a mixture of double bond isomers). LC-MS: [M-Boc+H] + =218.10.

[0639] 23.2 Synthesis of Compound L023-2

[0640] L023-1 (1.5 g, 4.73 mmol) was dissolved in tetrahydrofuran (20 mL), methanol (10 mL), and water (10 mL). Lithium hydroxide monohydrate (600 mg, 14.2 mmol) was added at room temperature and stirred for 2 hours. The reaction solution was directly concentrated under reduced pressure, and the residue was diluted with water (30 mL), washed with ethyl acetate (30 mL × 3), and the organic phase was discarded. The pH of the aqueous phase was adjusted to 5-6 with dilute hydrochloric acid (1 M), and then extracted with ethyl acetate (30 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound L023-2 (1.2 g, a mixture of double bond isomers). LC-MS: [M-Boc+H] + =204.10.

[0641] 23.3 Synthesis of Compounds L023-2-IS-01 and L023-2-IS-02

[0642] Compound L023-2 (1.2 g, 3.96 mmol) was separated by high performance liquid chromatography (Prep-HPLC) (chromatographic column: CHIRAL ART Amylose-C NEO, 30*250 mm, 10 μm, mobile phase, A: n-hexane (0.1% acetic acid), B: isopropanol, flow rate: 30 mL / min) to give compounds L023-2-IS-01 (retention time Rt = 10.854 min, 400 mg) and L023-2-IS-02 (retention time Rt = 17.612 min, 540 mg).

[0643] L023-2-IS-01:

[0644] 1H NMR (400MHz, CH3OH-d4): δ7.45–7.28(m,5H),6.34–6.07(m,1H),5.04–4.98(m,1H),4.26 –4.21(m,1H),3.31–3.15(m,1H),2.67–2.46(m,2H),1.53–1.49(m,9H); LC-MS:[M-Boc+H] + =204.10

[0645] L023-2-IS-02:

[0646] 1 H NMR (400MHz, CH3OH-d4): δ7.58–7.16(m,5H),6.41–6.19(m,1H),5.06–4.94(m,1H),4.27 –4.21(m,1H),3.23–3.11(m,1H),2.59–2.47(m,2H),1.53–1.49(m,9H); LC-MS:[M-Boc+H] + =204.10

[0647] 23.4 Synthesis of Compounds L023-3-IS-01 and L023-3-IS-02

[0648] At room temperature, L023-2-IS-01 (100 mg, 0.33 mmol) was dissolved in dichloromethane (3 mL), and 1-propylphosphonic acid cyclic anhydride (315 mg, 0.49 mmol, 50% ethyl acetate solution), N,N-diisopropylethylamine (213 mg, 1.65 mmol), and L001-7 (85 mg, 0.33 mmol) were added. The mixture was stirred at 20°C for 1 hour. The reaction solution was diluted with water (10 mL) and extracted with dichloromethane (10 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by high-performance liquid chromatography (acidic conditions) and freeze-dried to obtain compound L023-3-IS-01 (60 mg, 36% yield). LC-MS: [M-Boc+H] + =406.10.

[0649] At room temperature, L023-2-IS-02 (100 mg, 0.33 mmol) was dissolved in dichloromethane (3 mL). 1-Propylphosphonic acid cyclic anhydride (315 mg, 0.49 mmol, 50% ethyl acetate solution), N,N-diisopropylethylamine (213 mg, 1.65 mmol), and L001-7 (85 mg, 0.33 mmol) were added. The mixture was stirred at 20°C for 1 hour. The reaction solution was diluted with water (10 mL) and extracted with dichloromethane (10 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by HPLC (acidic conditions) and freeze-dried to obtain compound L023-3-IS-02 (75 mg, 45% yield). LC-MS: [M-Boc+H] + =406.10.

[0650] 23.5 Synthesis of Compounds L023-IS-01 Hydrochloride and L023-IS-02 Hydrochloride

[0651] L023-3-IS-01 (60 mg, 0.12 mmol) was dissolved in ethyl acetate (2 mL). A 4 M solution of hydrogen chloride in ethyl acetate (2 mL) was added and allowed to react at room temperature for 2 hours, resulting in the precipitation of a white solid. The reaction solution was then concentrated under reduced pressure. The residue was dissolved in deionized water (10 mL) and freeze-dried to afford the hydrochloride salt of compound L023-IS-01 (48.6 mg, 92.66% yield).

[0652] L023-3-IS-02 (75 mg, 0.15 mmol) was dissolved in ethyl acetate (2 mL). A 4 M solution of hydrogen chloride in ethyl acetate (2 mL) was added and allowed to react at room temperature for 2 hours, resulting in the precipitation of a white solid. The reaction solution was then concentrated under reduced pressure. The residue was dissolved in deionized water (10 mL) and freeze-dried to afford compound L023-IS-02 hydrochloride (43.2 mg, 65.89% yield).

[0653] L023-IS-01 hydrochloride:

[0654] 1H NMR (400MHz, DMSO-d6): δ10.09(s,1H),9.07(dd,J=7.2,3.6Hz,1H),8.94(s,1H),8.54(dd,J=24.4, 8.0Hz,1H),7.83(d,J=24.4Hz,2H),7.59(dd,J=32.0,8.8Hz,1H),7.50–7.31(m,5H),6.71(t,J=9.6 Hz,1H),6.34(d,J=8.8Hz,1H),5.20–5.09(m,1H),4.77(s,1H),4.33–4.26(m,1H),3.43(s,2H),3.0 5–2.81(m,2H),2.69(s,2H),2.48–2.37(m,1H),2.04–1.79(m,1H),1.35-1.32(m,3H); LC-MS:[M+H] + =406.10.

[0655] L023-IS-02 hydrochloride:

[0656] 1 H NMR (400MHz, DMSO-d6): δ10.09(d,J=38.4Hz,1H),9.08(dd,J=7.2,4.4Hz,1H),8.96–8.94(m,1H),8.61– 8.48(m,1H),7.93–7.52(m,3H),7.51–7.44(m,2H),7.43–7.30(m,3H),6.75(d,J=8.0Hz,1H),6.30(s,1H ),5.17(q,J=7.6Hz,1H),4.78(s,1H),4.35–4.22(m,1H),3.44–3.38(m,2H),3.16–2.96(m,1H),2.94–2. 81(m,1H),2.81–2.54(m,2H),2.46–2.39(m,1H),2.00–1.93(m,1H),1.31(d,J=7.2Hz,3H); LC-MS:[M+H] + =406.10.

[0657] Example 24. Synthesis of (2R)-N-((2S)-1-((2-amino-6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)amino)-1-oxopropan-2-yl)-4-benzylpiperazine-2-carboxamide (Compound L024) Hydrochloride

[0658]

[0659] 24.1 Synthesis of Compound L024-1

[0660] L024-a (300 mg, 1.23 mmol) was dissolved in N,N-dimethylformamide (3 mL). N,N-diisopropylethylamine (239 mg, 1.85 mmol) and benzyl bromide (221 mg, 1.29 mmol) were added to the system and stirred at room temperature for 1 hour. The reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic phase was washed with saturated aqueous ammonium chloride (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound L024-1 (344 mg, yield 83.7%). LC-MS: [M+H] + =335.10.

[0661] 24.2 Synthesis of Compound L024-2

[0662] L024-1 (344 mg, 1.03 mmol) was dissolved in tetrahydrofuran (4 mL) and water (4 mL), and lithium hydroxide monohydrate (169 mg, 4.12 mmol) was added and stirred at room temperature for 16 hours. Water (5 mL) was added to the reaction solution and extracted with ethyl acetate (10 mL). The organic phase was discarded, and the pH value of the aqueous phase was adjusted to about 5-6 with formic acid, then extracted with ethyl acetate (15 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound L024-2 (343 mg, crude product), which was used directly in the next step. LC-MS: [M+H] + =321.10.

[0663] 24.3 Synthesis of Compound L024-3

[0664] L024-2 (90 mg, 0.28 mmol) was dissolved in N,N-dimethylformamide (2 mL), and 1-hydroxybenzotriazole (41.6 mg, 0.31 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (59.1 mg, 0.31 mmol) were added. The mixture was reacted at room temperature for 0.5 hour. Meanwhile, L001-7 (100 mg, 0.34 mmol) and N,N-diisopropylethylamine (145 mg, 1.12 mmol) were dissolved in N,N-dimethylformamide (2 mL) and stirred at room temperature for 0.5 hour. This solution was then added to the reaction mixture and stirred at room temperature for 0.5 hour. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated aqueous ammonium chloride (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (acidic conditions) to obtain compound L024-3 (61.0 mg, yield 41.5%). LC-MS: [M+H] + =523.10.

[0665] 24.4 Synthesis of Compound L024 Hydrochloride

[0666] L024-3 (61.0 mg, 0.12 mmol) was dissolved in dichloromethane (2 mL). A solution of hydrogen chloride in ethyl acetate (2 mL, 4 M) was added at room temperature and stirred for 0.5 hours, resulting in the precipitation of solids. The reaction mixture was filtered and the filter cake was washed with dichloromethane (15 mL). The filter cake was dissolved in deionized water (15 mL) and freeze-dried to obtain compound L024 hydrochloride (46 mg, 93.1% yield). LC-MS: [M+H] + =423.15.

[0667] 1 H NMR (400MHz, DMSO-d6): δ10.63(s,1H),9.50–9.27(m,2H),8.63–8.38(m,1H) ),8.03(s,2H),7.73–7.52(m,3H),7.45–7.41(m,4H),6.83(d,J=4.0Hz,1H) ,5.16–5.14(m,1H),4.48–4.14(m,4H),4.10-3.80(m,5H),3.11–2.84(m,4H ),2.50-2.43(m,1H),2.02-2.00(m,1H),1.23(d,J=4.0Hz,3H); LC-MS:[M+H] + =423.15.

[0668] Example 25. Synthesis of (2R)-N-(2S)-1-(2-amino-6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)amino)-1-oxoaceton-2-yl)-4-(naphthalen-1-yl)piperazine-2-carboxamide (Compound L025) Hydrochloride

[0669]

[0670] 25.1 Synthesis of Compound L025-1

[0671] L024-a (600 mg, 2.46 mmol) was dissolved in dichloromethane (6 mL), and copper acetate (489 mg, 2.70 mmol) and L022-b (847 mg, 4.92 mmol) were added. Molecular sieves (300 mg) and pyridine (389 mg, 4.92 mmol) were stirred at room temperature under an oxygen atmosphere for 16 hours. The reaction solution was directly concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain compound L025-1 (167 mg, yield 18.3%). LC-MS: [M+H] + =371.05.

[0672] 25.2 Synthesis of Compound L025-2

[0673] L025-1 (167 mg, 0.45 mmol) was dissolved in tetrahydrofuran (2 mL) and water (2 mL), and lithium hydroxide monohydrate (74 mg, 1.81 mmol) was added. The mixture was stirred at room temperature for 16 hours. Water (5 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL). The organic phase was discarded, and the pH of the aqueous phase was adjusted to 5-6 with formic acid, followed by extraction with ethyl acetate (15 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound L025-2 (50 mg, 30.5% yield). LC-MS: [M+H] + =357.05.

[0674] 25.3 Synthesis of Compound L025-3

[0675] L025-2 (50 mg, 0.14 mmol) was dissolved in N,N-dimethylformamide (1 mL), and 1-hydroxybenzotriazole (21 mg, 0.15 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (30 mg, 0.15 mmol) were added. The mixture was allowed to react at room temperature for 0.5 hour. Meanwhile, L001-7 (49 mg, 0.17 mmol) and N,N-diisopropylethylamine (72.3 mg, 0.56 mmol) were dissolved in N,N-dimethylformamide (1 mL) and stirred at room temperature for 0.5 hour. This solution was then added to the reaction mixture and stirred for 0.5 hour. The reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic phases were washed with saturated aqueous ammonium chloride (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (acidic conditions) to obtain compound L025-3 (38.0 mg, 48.5% yield). LC-MS: [M+H] + =559.05.

[0676] 25.4 Synthesis of Compound L025 Hydrochloride

[0677] L025-3 (38 mg, 0.07 mmol) was dissolved in dichloromethane (2 mL). A solution of hydrogen chloride in ethyl acetate (2 mL, 4 M) was added at room temperature and stirred for 0.5 hours. A solid precipitated, and the reaction mixture was filtered, and the filter cake was washed with dichloromethane (15 mL). The filter cake was dissolved in deionized water (15 mL) and freeze-dried to afford compound L025 hydrochloride (9 mg, 28.9% yield).

[0678] 1 H NMR (400MHz, DMSO-d6): δ10.10(m,1H),9.17–9.04(m,2H),8.53(dd,J=8.0,4.0Hz,1H),8. 23(s,1H),8.02–7.76(m,3H),7.69(d,J=8.0Hz,2H),7.64–7.54(m,2H),7.46(m,1H),7.40– 7.12(m,2H),6.80–6.76(m,1H),5.33–5.16(m,1H),4.34–4.24(m,2H),3.60(m,1H),3.09( s,2H),2.93–2.85(m,1H),2.47–2.40(m,1H),2.07–1.93(m,2H),1.24(m,7H); LC-MS:[M+H] + =459.05.

[0679] Example 26. Synthesis of (2R)-N-(2S)-1-(2-amino-6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)amino)-1-oxopropan-2-yl)-4-(4-fluorophenyl)piperazine-2-carboxamide (Compound L026) hydrochloride

[0680]

[0681] 26.1 Synthesis of Compound L026-1

[0682] L024-a (400 mg, 1.64 mmol) and L007-a (459 mg, 3.28 mmol) were dissolved in dichloromethane (3 mL), and copper acetate (327 mg, 1.81 mmol) was added to the system. Molecular sieves (200 mg) and pyridine (259 mg, 3.28 mmol) were stirred at room temperature under an oxygen atmosphere for 16 hours. The reaction solution was directly concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain compound L026-1 (424 mg, yield 76.5%). LC-MS: [M+H] + =339.05.

[0683] 26.2 Synthesis of Compound L026-2

[0684] L026-1 (424 mg, 1.25 mmol) was dissolved in tetrahydrofuran (4 mL) and water (4 mL), and lithium hydroxide monohydrate (154 mg, 3.76 mmol) was added. The mixture was stirred at room temperature for 16 hours. Water (5 mL) was added to dilute the reaction solution, which was then extracted with ethyl acetate (10 mL). The organic phase was discarded, and the aqueous phase was adjusted to a pH of 5-6 with formic acid, followed by extraction with ethyl acetate (15 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to yield compound L026-2 (325 mg). LC-MS: [M+H] + =325.05.

[0685] 26.3 Synthesis of Compound L026-3

[0686] Dissolve L026-2 (81 mg, 0.25 mmol) in N,N-dimethylformamide (2 mL), add 1-hydroxybenzotriazole (37 mg, 0.27 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (53 mg, 0.27 mmol), and stir at room temperature for 0.5 hour. Simultaneously, dissolve L001-7 (80 mg, 0.27 mmol) and N,N-diisopropylethylamine (160.0 mg, 1.24 mmol) in N,N-dimethylformamide (2 mL) and stir at room temperature for 0.5 hour. This solution is then added to the reaction mixture and stirred at room temperature for 0.5 hour. Dilute the reaction mixture with water (10 mL) and extract with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (acidic conditions) to give compound L026-3 (50 mg, yield 38.2%). LC-MS: [M+H] + =527.05.

[0687] 26.4 Synthesis of Compound L026 Hydrochloride

[0688] L026-3 (50 mg, 0.10 mmol) was dissolved in dichloromethane (2 mL). A solution of hydrogen chloride in ethyl acetate (2 mL, 4 M) was added at room temperature and stirred for 0.5 hours, resulting in the precipitation of a solid. The solid was filtered and the filter cake washed with dichloromethane (15 mL). The filter cake was dissolved in deionized water (15 mL) and freeze-dried to afford compound L026 hydrochloride (36.0 mg, 88.8% yield).

[0689] 1 H NMR (400MHz, DMSO-d6): δ10.08-9.95(m,1H),9.14(d,J=4.0Hz,2H),8.58(dd,J1=8.0Hz,J2=2.0Hz,1H ),8.04(s,1H),7.74-7.67(m,1H),7.46-7.17(m,1H),7.15-7.03(m,4H),6.84(dd,J1=12.0Hz,J2=4.0 Hz,1H),5.20-5.15(m,1H),4.35-4.23(m,1H),4.01-3.98(m,2H),3.58(d,J=12.0Hz,1H),3.32(d,J=1 2.0Hz,1H),3.20-2.78(m,6H),2.48-2.41(m,1H),2.03-1.99(m,1H),1.30-1.23(m,4H); LC-MS:[M+H] + =427.05.

[0690] Example 27. Synthesis of (2S)-1-(2R,4S)-4-([1,1'-biphenyl]-4-(4-methyl)pyrrolidine-2-carbonyl)-N-(2-amino-6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)azetidine-2-carboxamide (Compound L027) hydrochloride

[0691]

[0692] 27.1 Synthesis of Compound L027-1

[0693] L027-a (91 mg, 0.45 mmol), 1-hydroxybenzotriazole (67 mg, 0.50 mmol), N,N-dimethylformamide (2 mL), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (95 mg, 0.50 mmol) were added to a reaction flask and allowed to react at room temperature for 0.5 hour. Simultaneously, a solution of L001-6 (150 mg, 0.68 mmol) and N,N-diisopropylethylamine (232 mg, 1.80 mmol) in N,N-dimethylformamide (2 mL) was stirred at room temperature for 0.5 hour. This solution was then added to the reaction mixture at room temperature and stirred for another 0.5 hour. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic phases were washed with saturated sodium chloride (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to yield compound L027-1 (160 mg, crude product). LC-MS: [M+H] + =333.10.

[0694] 27.2 Synthesis of Compound L027-2

[0695] L027-1 (160 mg, crude product) was dissolved in dichloromethane (4 mL), and a solution of hydrogen chloride in ethyl acetate (4 mL, 4 M) was added. The mixture was stirred at room temperature for 0.5 hours, and solid precipitated. The reaction mixture was filtered, and the filter cake was washed with dichloromethane (5 mL). The filter cake was dried under reduced pressure to obtain compound L027-2 hydrochloride (130 mg, crude product). LC-MS: [M+H] + =233.15.

[0696] 27.3 Synthesis of Compound L027-3

[0697] At room temperature, L002-3 (141 mg, 0.37 mmol), 1-hydroxybenzotriazole (55 mg, 0.41 mmol), N,N-dimethylformamide (2 mL), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (78 mg, 0.41 mmol) were added to a reaction flask and stirred at room temperature for 0.5 hour. Meanwhile, L027-2 (130 mg, crude) and N,N-diisopropylethylamine (191 mg, 1.48 mmol) were dissolved in N,N-dimethylformamide (2 mL) and stirred at room temperature for 0.5 hour. This solution was then added to the reaction mixture and stirred for another 0.5 hour. The reaction mixture was added with water (10 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic phases were washed with saturated sodium chloride (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound L027-3 (260 mg, crude product). LC-MS: [M+H] + =596.10.

[0698] 27.4 Synthesis of Compound L027 Hydrochloride

[0699] L027-3 (260 mg, crude product) was dissolved in dichloromethane (5 mL). A solution of hydrogen chloride in ethyl acetate (5 mL, 4 M) was added at room temperature and stirred for 0.5 hours, resulting in the precipitation of a solid. The reaction mixture was filtered, and the filter cake was washed with dichloromethane (5 mL) to afford the crude product. The crude product was purified by HPLC (acidic conditions) to afford compound L027 hydrochloride (10 mg).

[0700] 1 H NMR (400MHz, DMSO-d6): δ10.43(s,1H),9.03–8.60(m,2H),8.12–7.81(m,2H),7.74–7 .60(m,5H),7.45(t,J=8.0Hz,2H),7.35–7.29(m,3H),6.84(t,J=8.0Hz,1H),5.21–5. 08(m,1H),4.66–4.39(m,1H),4.28–4.09(m,2H),3.96–3.80(m,1H),3.29(s,1H),3.0 7–3.02(m,1H),2.98–2.52(m,6H),2.48–2.39(m,1H),2.18–1.74(m,4H); LC-MS:[M+H] + =496.15.

[0701] Example 28. Synthesis of (2S)-1-(2R,4S)-4-([1,1'-biphenyl]-4-(4-ylmethyl)pyrrolidine-2-carbonyl)-N-(2-amino-6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)pyrrolidine-2-carboxamide (Compound L028) Hydrochloride

[0702]

[0703] 28.1 Synthesis of Compound L028-1

[0704] L028-a (97 mg, 0.45 mmol), 1-hydroxybenzotriazole (67 mg, 0.50 mmol), N,N-dimethylformamide (2 mL), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (95 mg, 0.50 mmol) were added to a reaction flask and stirred at room temperature for 0.5 hour. Meanwhile, L001-6 (150 mg, 0.68 mmol) and N,N-diisopropylethylamine (232.2 mg, 1.80 mmol) were dissolved in N,N-dimethylformamide (2 mL) and stirred at room temperature for 0.5 hour. This solution was then added to the reaction mixture and stirred for another 0.5 hour. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic phases were washed with saturated aqueous sodium chloride (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound L028-1 (210 mg, crude product). LCMS: [M+H] + =347.15.

[0705] 28.2 Synthesis of Compound L028-2

[0706] L028-1 (210 mg, 0.61 mmol) was dissolved in dichloromethane (4 mL), and a solution of hydrogen chloride in ethyl acetate (4 mL, 4 M) was added. The mixture was stirred at room temperature for 0.5 hours, and a solid precipitated. The reaction mixture was filtered, and the filter cake was washed with dichloromethane (5 mL). The solid was dried under reduced pressure to obtain compound L028-2 (120 mg, crude product). LC-MS: [M+H] + =247.15.

[0707] 28.3 Synthesis of Compound L028-3

[0708] L002-3 (125.7 mg, 0.33 mmol), 1-hydroxybenzotriazole (49 mg, 0.36 mmol), N,N-dimethylformamide (2 mL), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (69.7 mg, 0.36 mmol) were added to a reaction flask and stirred at room temperature for 0.5 hour. Meanwhile, L028-2 (120 mg, crude) and N,N-diisopropylethylamine (170 mg, 1.32 mmol) were dissolved in N,N-dimethylformamide (2 mL) and stirred at room temperature for 0.5 hour. This solution was then added to the reaction mixture and stirred for another 0.5 hour. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic phases were washed with saturated aqueous sodium chloride (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound L028-3 (240 mg, crude product). LC-MS: [M+H] + =610.10.

[0709] 28.4 Synthesis of Compound L028 Hydrochloride

[0710] L028-3 (240 mg, crude product) was dissolved in dichloromethane (5 mL) at room temperature. A solution of hydrogen chloride in ethyl acetate (5 mL, 4 M) was added and stirred at room temperature for 0.5 hours, resulting in the precipitation of a solid. The reaction mixture was filtered, and the filter cake was washed with dichloromethane (5 mL). The filter cake was then dried under reduced pressure to afford the crude product. The crude product was purified by HPLC (acidic conditions) to afford compound L028 hydrochloride (27 mg).

[0711] 1 H NMR (400MHz, DMSO-d6): δ10.53–10.50(m,1H),8.93–8.58(m,2H),8.09(s,2H),7. 77–7.58(m,5H),7.45(t,J=8.0Hz,2H),7.35–7.31(m,3H),6.87–6.83(m,1H),5.2 3–4.99(m,1H),4.71–4.51(m,1H),4.26–4.23(m,1H),3.50–3.32(m,3H),3.09–2. 74(m,5H),2.64–2.52(m,1H),2.46–2.30(m,1H),2.17–1.82(m,7H); LC-MS:[M+H] + =510.15.

[0712] Example 29. Synthesis of (2S)-1-(2R,4S)-4-([1,1'-biphenyl]-4-(4-ylmethyl)pyrrolidine-2-carbonyl)-N-(2-amino-6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)pyrrolidine-2-carboxamide (Compound L029) Hydrochloride

[0713]

[0714] 29.1 Synthesis of Compound L029-1

[0715] L029-a (103 mg, 0.45 mmol), 1-hydroxybenzotriazole (67 mg, 0.50 mmol), N,N-dimethylformamide (2 mL), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (95 mg, 0.50 mmol) were added to a reaction flask and allowed to react at room temperature for 0.5 hour. Meanwhile, L001-6 (150 mg, 0.68 mmol) and N,N-diisopropylethylamine (232 mg, 1.80 mmol) were dissolved in N,N-dimethylformamide (2 mL) and stirred at room temperature for 0.5 hour. This solution was then added to the reaction mixture and stirred for another 0.5 hour. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic phases were washed with saturated aqueous sodium chloride (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound L029-1 (300 mg, crude product). LCMS: [M+H] + =361.10.

[0716] 29.2 Synthesis of Compound L029-2

[0717] L029-1 (300 mg, crude product) was dissolved in dichloromethane (5 mL). A solution of hydrogen chloride in ethyl acetate (5 mL, 4 M) was added at room temperature and stirred for 0.5 hours. Solid precipitated. The reaction mixture was filtered and the filter cake was washed with dichloromethane (5 mL). The filter cake was dried under reduced pressure to give compound L029-2 (140 mg, crude product). LC-MS: [M+H] + =261.15.

[0718] 29.3 Synthesis of Compound L029-3

[0719] L002-3 (137 mg, 0.36 mmol), 1-hydroxybenzotriazole (54 mg, 0.40 mmol), N,N-dimethylformamide (2 mL), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (76 mg, 0.40 mmol) were added to a reaction flask and stirred at room temperature for 0.5 hour. Meanwhile, L029-2 (140 mg, 0.54 mmol) and N,N-diisopropylethylamine (185.7 mg, 1.44 mmol) were dissolved in N,N-dimethylformamide (2 mL) and stirred at room temperature for 0.5 hour. This solution was then added to the reaction mixture and stirred for another 0.5 hour. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic phases were washed with saturated aqueous sodium chloride (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound L029-3 (230 mg, crude product). LC-MS: [M+H] + =624.10.

[0720] 29.4 Synthesis of Compound L029 Hydrochloride

[0721] L029-3 (230 mg, 0.37 mmol) was dissolved in dichloromethane (5 mL). A solution of hydrogen chloride in ethyl acetate (5 mL, 4 M) was added and stirred at room temperature for 0.5 hours, resulting in the precipitation of a solid. The reaction mixture was filtered, and the filter cake was washed with dichloromethane (5 mL). The filter cake was purified by HPLC (acidic conditions) to afford compound L029 hydrochloride (65 mg).

[0722] 1 H NMR (400MHz, DMSO-d6): δ10.50(s,1H),8.61–8.54(m,2H),8.08(s,2H),7.72–7.53( m,5H),7.45(t,J=8.0Hz,2H),7.40–7.30(m,3H),6.88–6.80(m,1H),5.34–5.07(m,1H ),4.97–4.80(m,1H),4.77–4.28(m,1H),3.54–3.00(m,3H),2.97–2.53(m,5H),2.47 –2.31(m,1H),2.30–2.06(m,2H),2.03–1.92(m,2H),1.81–1.12(m,6H); LC-MS:[M+H] + =524.10.

[0723] Example 30. Synthesis of (2S)-N-(2-amino-6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)-1-((2R,4S)-4-(4-fluorobenzyl)pyrrolidine-2-carbonyl)azetidine-2-carboxamide (Compound L030) hydrochloride

[0724]

[0725] 30.1 Synthesis of Compound L030-1

[0726] L001-11 (150 mg, 0.46 mmol) was dissolved in N,N-dimethylformamide (3 mL), and 1-hydroxybenzotriazole (75 mg, 0.56 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (107 mg, 0.56 mmol) were added. After stirring at room temperature for 10 minutes, a solution of L027-2 (162 mg, 0.60 mmol) and N,N-diisopropylethylamine (299 mg, 2.32 mmol) in N,N-dimethylformamide (2 mL) was added. The reaction was continued at room temperature for 0.5 hours. The reaction solution was poured into water (10 mL) and extracted with ethyl acetate (15 mL × 3). The combined organic phases were washed with saturated sodium chloride aqueous solution (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound L030-1 (180 mg, yield 72.18%). LCMS: [M+H] + =538.10.

[0727] 30.2 Synthesis of Compound L030 Hydrochloride

[0728] L030-1 (180 mg, 0.33 mmol) was dissolved in dichloromethane (3 mL), and a solution of hydrogen chloride in ethyl acetate (2 mL, 4 M) was added. The mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (acidic conditions) and freeze-dried to afford compound L030 hydrochloride (43.1 mg, 27.10% yield).

[0729] 1H NMR (400MHz, DMSO-d6): δ10.31(s,1H),8.99–8.52(m,2H),8.02(s,2H),7.83–7.64(m,1H),7.31–7.24(m,2H),7.17–7 .08(m,2H),6.82(dd,J=8.0,4.0Hz,1H),5.27–4.84(m,2H),4.62(dd,J=8.0,4.0Hz,1H),4.39(dd,J=12.0,4.0Hz,1H) ,4.27–4.22(m,1H),4.08(dd,J=12.0,8.0Hz,1H),3.94–3.84(m,1H),3.30–3.19(m,1H),3.08–3.02(m,1H),2.98–2.9 0(m,1H),2.88–2.79(m,1H),2.79–2.51(m,3H),2.47–2.38(m,2H),2.20–2.09(m,1H),2.05–1.67(m,3H); LC-MS:[M+H] + =438.10.

[0730] Example 31. Synthesis of (2S)-N-(2-amino-6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)-1-((2R,4S)-4-(4-fluorobenzyl)pyrrolidine-2-carbonyl)pyrrolidine-2-carboxamide (Compound L031) Hydrochloride

[0731]

[0732] 31.1 Synthesis of Compound L031-1

[0733] L001-11 (150 mg, 0.46 mmol) was dissolved in N,N-dimethylformamide (3 mL), and 1-hydroxybenzotriazole (75 mg, 0.56 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (107 mg, 0.56 mmol) were added. The mixture was stirred at room temperature for 10 minutes. A solution of L028-2 (171 mg, 0.60 mmol) and N,N-diisopropylethylamine (299 mg, 2.32 mmol) in N,N-dimethylformamide (2 mL) was added, and stirring was continued at room temperature for 0.5 hours. The reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (15 mL × 3). The combined organic phases were washed with saturated sodium chloride aqueous solution (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound L031-1 (200 mg, yield 78.16%). LCMS: [M+H] + =552.10.

[0734] 31.2 Synthesis of Compound L031 Hydrochloride

[0735] L031-1 (200 mg, 0.36 mmol) was dissolved in dichloromethane (3 mL), and a solution of hydrogen chloride in ethyl acetate (2 mL, 4 M) was added. The mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative HPLC (acidic conditions) and freeze-dried to afford compound L031 hydrochloride (45.7 mg, 25.83% yield).

[0736] 1 H NMR (400MHz, DMSO-d6): δ10.37–10.35(m,1H),8.88–8, 51(m,2H),8.03(s,2H),7.79–7.49(m ,1H),7.31–7.24(m,2H),7.15–7.08(m,2H),6.85–6.78(m,1H),5.23–4.99(m,1H),4.61–4.4 6(m,1H),4.23(td,J=8.0,4.0Hz,1H),3.76–3.64(m,1H),3.53–3.37(m,2H),3.07–2.99(m,1 H),2.95–2.83(m,2H),2.79–2.55(m,2H),2.47–2.31(m,2H),2.24–1.77(m,7H); LC-MS:[M+H] + =452.10.

[0737] Example 32. Synthesis of (2S)-N-(2-amino-6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)-1-((2R,4S)-4-(4-fluorobenzyl)pyrrolidine-2-carbonyl)piperidine-2-carboxamide (Compound L032) Hydrochloride

[0738]

[0739] 32.1 Synthesis of Compound L032-1

[0740] L001-11 (150 mg, 0.46 mmol) was dissolved in N,N-dimethylformamide (3 mL), and 1-hydroxybenzotriazole (75 mg, 0.56 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (107 mg, 0.56 mmol) were added. The mixture was stirred at room temperature for 10 minutes. A solution of L029-2 (179 mg, 0.60 mmol) and N,N-diisopropylethylamine (299 mg, 2.32 mmol) in N,N-dimethylformamide (2 mL) was added, and stirring was continued at room temperature for 0.5 hours. The reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (15 mL × 3). The combined organic phases were washed with saturated sodium chloride aqueous solution (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound L032-1 (160 mg, crude product), which was used directly in the next reaction. LCMS: [M+H] + =566.10.

[0741] 32.2 Synthesis of Compound L032 Hydrochloride

[0742] L032-1 (160 mg, 0.28 mmol) was dissolved in dichloromethane (3 mL), and a solution of hydrogen chloride in ethyl acetate (2 mL, 4 M) was added. The mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (acidic conditions) and freeze-dried to afford compound L032 hydrochloride (29.0 mg, 27.47% yield) as a white solid.

[0743] 1 H NMR (400MHz, DMSO-d6): δ10.41(s,1H),8.62–8.44(m,2H),8.05(s,2H),7.72–7.56 (m,1H),7.35–7.24(m,2H),7.17–7.06(m,2H),6.86–6.79(m,1H),5.27–5.09(m,1H) ,4.91–4.65(m,2H),4.33–3.65(m,1H),3.38–2.79(m,5H),2.76–2.54(m,2H),2.49– 2.40(m,2H),2.38–2.12(m,2H),2.07–1.56(m,5H),1.55–1.20(m,3H); LC-MS:[M+H] + =466.10.

[0744] Example 33. Synthesis of (2R,4S)-N-((S)-1-(((R)-2-amino-6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)amino)-1-oxopropan-2-yl)-4-(4-fluorobenzyl)pyrrolidine-2-carboxamide (Compound L001-IS-01)

[0745]

[0746] 33.1 Synthesis of Compound L001-IS-01-1

[0747] Dissolve L001-g (500.0 g, 4.67 mol) and L001-h (393.0 g, 4.67 mol) in toluene (2750 mL). Add anhydrous magnesium sulfate (589.5 g, 5.0 mol) at room temperature. Heat to 30°C and stir for 16 hours. Filter the reaction mixture directly, and wash the filter cake with toluene (500 mL). Combine the filtrates to obtain a toluene solution of compound L001-IS-01-1, which is used directly in the next step. LC-MS: [M+H] + =174.10.

[0748] 33.2 Synthesis of Compound L001-IS-01-2

[0749] The toluene solution of L001-IS-01-1 was added to a 10L reactor. Triethylamine (491g, 4.85mol) was slowly added at 0°C, with the temperature controlled below 5°C. Acetic anhydride (485g, 4.85mol) was then added dropwise. The reaction solution was allowed to warm to room temperature and stirred for 16 hours. Water (3L) was added to the reaction solution, which was stirred for 10 minutes. The organic phase was then separated and washed with brine (2L), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1) to obtain compound L001-IS-01-2 (580g). LC-MS: [M+H] + =216.10.

[0750] 33.3 Synthesis of Compound L001-IS-01-3

[0751] At room temperature, L001-IS-01-2 (550 g, 2.6 mol) was dissolved in N,N-dimethylformamide (2.2 L) and added to a 10 L reactor. Phosphorus oxychloride (980 g, 6.4 mol) was slowly added, and the mixture was heated to 30°C and stirred for 1.5 hours. The mixture was then heated to 60°C and stirred for 1 hour, then to 70°C and stirred for 1 hour, then to 80°C and stirred for 1 hour, and finally to 95°C and stirred for 16 hours. The reaction mixture was cooled to room temperature, and water (2.2 L) and sodium hydroxide solution (1.8 L, 30% aq.) were added to adjust the pH to 9. Methyl tert-butyl ether (4.8 L) was added and stirred for 0.5 hour. The organic phase was then separated, washed with water (2.2 L x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to yield the crude product. The crude product was dissolved in n-heptane (2.2 L), followed by the addition of water (2.2 L) and concentrated hydrochloric acid (1.1 L, 36%). The organic phase was separated, and the aqueous phase was extracted once more with n-heptane (2.2 L). The organic phase was discarded and the aqueous phase was retained. The pH value of the aqueous phase was adjusted to pH = 9 with sodium hydroxide solution (30% aq.) (control the system temperature below 25°C), and then stirred at room temperature for 1 hour. Solids precipitated, filtered, and the filter cake was washed with water (500 mL). The filter cake was dried under reduced pressure to obtain the crude product. The crude product was added to n-heptane (4.4 L) and heated to 80°C. After reflux for 2 hours, the temperature was lowered to 50°C and a small amount of insoluble matter was removed by hot filtration. The filtrate was concentrated under reduced pressure to obtain compound L001-IS-01-3 (224.3 g, yield 66.9%). LC-MS: [M+H] + =154.10.

[0752] 33.4 Synthesis of Compound L001-IS-01-4

[0753] At room temperature, add L001-IS-01-3 (50 g, 325.5 mmol), anhydrous magnesium sulfate (78 g, 325.5 mmol), and tert-butanol (1 L) to a 10 L reactor. Cool to 0°C, and add a solution of potassium permanganate (103 g, 325.5 mmol) in water (2.8 L) dropwise to the reaction mixture, maintaining the system temperature below 15°C. After the addition is complete, warm the reaction mixture to room temperature and continue stirring for 4 hours. Add water (1 L) and ethyl acetate (2 L) to the reaction mixture, then stir at room temperature for 0.5 hours. Separate the organic phase, extract the aqueous phase with ethyl acetate (1.5 L x 2), combine the organic phases, and wash with brine (2 L). Dry the organic phase over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give compound L001-IS-01-4 (30.3 g, yield 55.6%). LC-MS: [M+H] + =168.05.

[0754] 33.5 Synthesis of Compound L001-IS-01-5

[0755] At room temperature, L001-IS-01-4 (40 g, 0.24 mol), tert-butyl carbamate (31 g, 0.26 mol), cesium carbonate (156 g, 0.48 mol), palladium acetate (2.2 g, 9.6 mmol), and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (9.1 g, 19.2 mmol) were added to 1,4-dioxane (400 mL) and stirred at 85°C under nitrogen for 3 hours. The reaction solution was cooled to room temperature, ethyl acetate (200 mL) was added, and the mixture was stirred for 10 minutes. The mixture was then filtered through celite, and the filter cake was washed with ethyl acetate (200 mL). The filtrate was directly concentrated, and the residue was stirred in ethanol (100 mL) for 3 hours, filtered, and the filter cake was dried. Petroleum ether (200 mL) and methyl tert-butyl ether (200 mL) were added again and stirred for another 3 hours. The mixture was filtered and the filter cake was dried to obtain compound L001-IS-01-5 (36 g, yield 55.6%). LC-MS: [M+H] + =249.10.

[0756] 33.6 Synthesis of Compound L001-IS-01-6

[0757] At room temperature, L001-IS-01-5 (62 g, 0.25 mol) and L001-k (32 g, 0.26 mol) were added to N,N-dimethylformamide (600 mL). Acetic acid (7.5 g, 0.125 mol) was added and stirred at room temperature for 2 hours. Sodium acetate borohydride (159 g, 0.75 mol) was added to the reaction system in 3-4 batches (1 hour / time). After the addition was complete, the mixture was stirred at room temperature for 16 hours. The reaction solution was quenched with saturated ammonium chloride (500 mL) and the pH of the solution was adjusted to 1 with dilute hydrochloric acid (1 M). The solution was extracted once with ethyl acetate (600 mL). The organic phase was discarded, and the aqueous phase was adjusted to pH 8-9 with saturated sodium carbonate solution and extracted with ethyl acetate (600 mL x 2). The combined organic phases were washed with saturated aqueous sodium chloride solution (800 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound L001-IS-01-6 (75 g, yield 85%). LC-MS: [M+H] + =354.05.

[0758] 33.7 Synthesis of Compound L001-IS-01-7

[0759] At room temperature, L001-IS-01-6 (75 g, 0.21 mol) and L001-d (48 g, 0.25 mol) were added to methanol (500 mL), followed by palladium on carbon (7.5 g, 10% wt). The mixture was stirred under a hydrogen atmosphere for 20 hours. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to afford the carboxylate salt of L001-IS-01-7 (L001-d), which was used directly in the next step. LC-MS: [M+H] + =250.10.

[0760] 33.8 Synthesis of Compound L001-IS-01-8

[0761] The carboxylate salt of L001-d of L001-IS-01-7 obtained in the previous step was added to dichloromethane (500 mL) at room temperature. N,N-diisopropylethylamine (81 g, 0.63 mol) was added, followed by 1-propylphosphonic anhydride (203 g, 0.32 mol, 50% ethyl acetate solution) at 0°C. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (500 mL) and extracted with dichloromethane (300 mL x 2). The combined organic phases were washed with dilute hydrochloric acid (400 mL x 2, 0.2 M), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The residue was purified by silica gel column chromatography to yield compound L001-IS-01-8 (71 g, 80.5% yield, 85% chiral purity). L001-IS-01-8 (71 g) was dissolved in isopropanol (142 mL), and the solution was cooled to 0°C. Purified water (142 mL) was added dropwise while stirring. After the addition was complete, the solution was stirred at 0°C for 2 hours. A large amount of white solid precipitated, which was filtered and dried under reduced pressure to obtain compound L001-IS-01-8 (36.5 g, chiral purity 98.2%, yield 51.4%). LC-MS: [M+H] + =421.05.

[0762] 33.9 Synthesis of Compound L001-IS-01-9

[0763] Dissolve L001-IS-01-8 (32 g, 76.2 mmol) in dichloromethane (200 mL). Add a 1,4-dioxane solution of hydrogen chloride (200 mL, 4 M) at 0°C. Warm the reaction mixture to room temperature and continue stirring for 16 hours. Concentrate the reaction mixture under reduced pressure to obtain compound L001-IS-01-9 hydrochloride (22 g). LC-MS: [M+H] + =221.10.

[0764] 33.10 Synthesis of Compound L001-IS-01-10

[0765] L001-IS-01-9 hydrochloride (3.8 g, 14.84 mmol) and diisopropylethylamine (8.0 g, 61.85 mmol) were dissolved in dichloromethane (50 mL) at room temperature. The reaction solution was stirred at room temperature for 30 minutes. Then, a solution of L001-8 (4 g, 12.37 mmol) and 1-propylphosphonic anhydride (15.7 g, 24.74 mmol, 50% ethyl acetate solution) in dichloromethane (50 mL) was added at 0°C and stirred at room temperature for 1 hour. The reaction solution was poured into saturated aqueous sodium chloride solution (200 mL) and extracted with dichloromethane (200 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was added to a mixed solution of petroleum ether (20 mL) and ethyl acetate (10 mL), stirred for 1 hour, filtered, and the filter cake was dried under reduced pressure to obtain compound L001-IS-01-10 (6.15 g, yield 98%). LC-MS: [M+H] + =526.05.

[0766] 33.11 Synthesis of Compound L001-IS-01

[0767] L001-IS-01-10 (32 g, 60.88 mmol) was dissolved in dichloromethane (300 mL) at room temperature. A solution of hydrogen chloride in 1,4-dioxane (200 mL, 4 M) was added and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by HPLC (0.1% hydrochloric acid) and freeze-dried to obtain the hydrochloride salt of compound L001-IS-01. This hydrochloride salt was dissolved in deionized water (200 mL), and a strongly basic deionizing resin (32 g) was added and stirred to free a white solid. The mixture was filtered, and the filter cake was washed with deionized water (100 mL). The resulting solid mixture was added to acetonitrile (200 mL), stirred for 0.5 hours, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was added to ethyl acetate (100 mL), stirred for 0.5 hours, filtered, and the filter cake was dried to obtain compound L001-IS-01 (15.563 g, yield 60.09%).

[0768] 1H NMR (400MHz, DMSO-d6): δ8.16(d,J=8.0Hz,2H),7.22–7.18(m,2H),7.16–7.04(m,3H), 6.23(d,J=8.4Hz,1H),5.85(s,2H),5.07(dd,J=14.4,7.6Hz,1H),4.27–4.15(m,1H),3. 62(dd,J=9.2,4.8Hz,1H),2.85(dd,J=10.0,6.4Hz,1H),2.77–2.69(m,1H),2.66–2.52( m,4H),2.37–2.26(m,1H),2.16–2.07(m,1H),1.78–1.61(m,3H),1.19(d,J=6.8Hz,3H). LC-MS:[M+H] + =426.00.

[0769] Example 34. Synthesis of (2R,4S)-N-((S)-1-(((R)-2-amino-6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)amino)-1-oxopropan-2-yl)-4-(4-chlorobenzyl)pyrrolidine-2-carboxamide (Compound L003-IS-01)

[0770]

[0771] The synthesis of compound L003-IS-01 followed the synthesis method of compound L001-IS-01, except that L001-8 was replaced with L003-4. The crude product was purified by HPLC (0.1% hydrochloric acid conditions) and normal phase chromatography (alkaline conditions) to give compound L003-IS-01 (97.2 mg, yield 26.55%).

[0772] 1H NMR (400MHz, DMSO-d6): δ8.18–8.15(m,2H),7.33(d,J=8.0Hz,2H),7.21(d,J=8.0Hz,2H),7.14 (d,J=8.0Hz,1H),6.23(d,J=8.0Hz,1H),5.84–5.83(m,2H),5.07(dd,J=12.0,8.0Hz,1H),4.24– 4.17(m,1H),3.64(dd,J=8.0,4.0Hz,1H),2.88–2.84(m,1H),2.77–2.69(m,1H),2.67–2.52(m,4 H),2.36–2.27(m,1H),2.19–2.07(m,1H),1.78–1.61(m,3H),1.19(d,J=4.0Hz,3H); LC-MS[M+H] + =442.00.

[0773] Example 35. Synthesis of (2R,4S)-N-((S)-1-(((R)-2-amino-6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)amino)-1-oxopropan-2-yl)-4-phenylpyrrolidine-2-carboxamide (Compound L006-IS-03)

[0774]

[0775] 35.1 Synthesis of Compound L006-IS-03-1

[0776] At room temperature, L006-3 (440 mg, 1.52 mmol) was dissolved in methanol (10 mL), palladium on carbon (88 mg, 10% wt) was added, and the mixture was stirred under a hydrogen atmosphere for 2 hours. The reaction mixture was filtered through celite, and the filter cake was washed with methanol (10 mL). The filtrate was concentrated under reduced pressure to give compound L006-IS-03-1 (360 mg, 81.4% yield). LC-MS: [M-tBu+H] + =236.05.

[0777] 35.2 Synthesis of Compound L006-IS-03

[0778] The synthesis of compound L006-IS-03 followed the synthesis method of compound L001-IS-01, except that L001-8 was replaced with L006-IS-03-1. The crude product was purified by HPLC (0.1% ammonia solution) and freeze-dried to give compound L006-IS-03 (184.1 mg).

[0779] 1H NMR (400MHz, DMSO-d6): δ8.25–8.21(m,2H),7.29–7.15(m,6H),6.24–6.20( m,1H),5.84(s,2H),5.13–5.07(m,1H),4.30–4.23(m,1H),3.79–3.75(m,1H ),3.32–3.27(m,2H),3.20–3.07(m,1H),2.80–2.67(m,1H),2.68–2.56(m,2 H),2.40–2.28(m,1H),1.75–1.65(m,2H),1.24(d,J=4.0Hz,3H); LC-MS[M+H] + =394.05.

[0780] Example 36. Synthesis of (2R,4S)-N-((S)-1-(((R)-2-amino-6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)amino)-1-oxopropan-2-yl)-4-(3-chloro-4-fluorobenzyl)pyrrolidine-2-carboxamide (Compound L012-IS-01) Hydrochloride

[0781]

[0782] The synthesis of compound L012-IS-01 hydrochloride was carried out according to the synthesis method of compound L001-IS-01, except that L001-8 was replaced with L012-4. The crude product was purified by HPLC (0.1% hydrochloric acid) and freeze-dried to give compound L012-IS-01 hydrochloride (61 mg, yield 40.6%).

[0783] 1 H NMR (400MHz, DMSO-d6): δ10.47(s,1H),8.86(d,J=7.2Hz,1H),8.56–8.53(m,2H),8.04(s,1H),7.71(d,J =8.8Hz,1H),7.53(dd,J=7.2,2.4Hz,1H),7.39–7.26(m,2H),6.84(d,J=8.8Hz,1H),5.18–5.14(m,1H),4 .40–4.26(m,1H),4.24(p,J=7.2Hz,1H),3.33–3.24(m,1H),3.04(m,1H),2.91(m,2H),2.72(m,2H),2.52 (s,1H),2.44(dd,J=8.8,4.4Hz,1H),2.12–2.01(m,1H),1.93(m,2H),1.23(d,J=7.2Hz,3H); LC-MS[M+H]+ =460.00.

[0784] Example 37. Synthesis of (2R,4S)-N-((S)-1-(((R)-2-amino-6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)amino)-1-oxopropan-2-yl)-4-(3-chlorobenzyl)pyrrolidine-2-carboxamide (Compound L014-IS-01) Hydrochloride

[0785]

[0786] The synthesis of compound L014-IS-01 hydrochloride was carried out according to the synthesis method of compound L001-IS-01, except that L001-8 was replaced with L014-4. The crude product was purified by HPLC (0.1% hydrochloric acid) and freeze-dried to give compound L014-IS-01 hydrochloride (311.2 mg, yield 73.82%).

[0787] 1 H NMR (400MHz, DMSO-d6): δ10.35(s,1H),8.85(d,J=7.2Hz,1H),8.55(t,J=9.2Hz,2H),8.01(s,2H),7 .70(d,J=8.8Hz,1H),7.49–7.17(m,4H),6.83(d,J=8.8Hz,1H),5.15(q,J=7.6Hz,1H),4.55–4.33(m, 1H),4.24(p,J=7.2Hz,1H),3.28(d,J=4.4Hz,1H),3.05–3.01(m,1H),2.93–2.89(m,2H),2.76–2.72 (m,2H),2.49–2.39(m,2H),2.16–2.02(m,1H),1.99–1.84(m,2H),1.23(d,J=7.2Hz,3H); LC-MS[M+H] + =442.00.

[0788] Example 38. Synthesis of (2R,4S)-N-((S)-1-(((R)-2-amino-6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)amino)-1-oxopropan-2-yl)-4-(3-methylbenzyl)pyrrolidine-2-carboxamide (Compound L016-IS-01) Hydrochloride

[0789]

[0790] The synthesis of compound L016-IS-01 hydrochloride was carried out according to the synthesis method of compound L001-IS-01, except that L001-8 was replaced with L016-4. The crude product was purified by HPLC (0.1% hydrochloric acid) and freeze-dried to give compound L016-IS-01 hydrochloride (140.4 mg, yield 57.92%).

[0791] 1 H NMR (400MHz, DMSO-d6): δ10.39(s,1H),8.87(d,J=7.2Hz,1H),8.57(d,J=7.6Hz,1H),8.52(d,J=4.8Hz,1H),8.03( s,2H),7.71(d,J=8.8Hz,1H),7.19(t,J=7.6Hz,1H),7.06–7.00(m,3H),6.83(d,J=8.8Hz,1H),5.15(d,J=6.8Hz,1H ),4.39–4.34(m,1H),4.26–4.20(m,2H),3.27(d,J=4.0Hz,1H),3.07–3.00(m,1H),2.87-2.93(m,2H),2.66(t,J=7. 6Hz,2H),2.48–2.44(m,1H),2.28(s,3H),2.03-2.10(m,1H),1.89-1.95(m,2H),1.23(d,J=7.2Hz,3H); LC-MS[M+H] + =422.05.

[0792] Example 39. Synthesis of (2R,4S)-N-((2S)-1-((2-amino-6,7-dihydro-5H-cyclopentadien[b]pyridin-5-yl)amino)-1-oxopropan-2-yl)-4-phenylpiperidine-2-carboxamide (Compound L021-IS-01)

[0793]

[0794] 39.1 Synthesis of Compound L021-IS-01-1

[0795] L021-b (25 g, 86.42 mmol) and L021-c (12.5 g, 86.42 mmol) were dissolved in dichloromethane (360 mL). 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (24.8 g, 129.35 mmol) and 4-dimethylaminopyridine (15.8 g, 129.35 mmol) were added at 0°C. The reaction solution was stirred at 0°C for 1 hour, then warmed to room temperature and stirred for another 2 hours. The reaction solution was washed with 1M potassium bisulfide aqueous solution (100 mL x 4). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was added to toluene (800 mL) and refluxed at 110°C for 16 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was added toluene / petroleum ether (100 mL, V / V = 1 / 10) and stirred for 2 hours. The solid was filtered and the filter cake was dried to obtain compound L021-IS-01-1 (16 g, yield 59.08%). LC-MS: [M-Boc+H] + =214.10.

[0796] 39.2 Synthesis of Compound L021-IS-01-2

[0797] L021-IS-01-1 (1.0 g, 3.19 mmol) and N,N-diisopropylethylamine (825 mg, 6.38 mmol) were dissolved in dichloromethane (10 mL). Trifluoromethanesulfonic anhydride (1.4 g, 4.80 mmol) was added dropwise at 0°C and stirred at room temperature for 1 hour. The reaction was quenched by adding saturated aqueous sodium bicarbonate (15 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound L021-IS-01-2 (1.1 g, yield 77.39%). LC-MS: [M-Boc+H] + =345.95.

[0798] 39.3 Synthesis of Compound L021-IS-01-3

[0799] L021-IS-01-2 (1 g, 2.33 mmol), L006-b (427 mg, 3.50 mmol), potassium carbonate (387 mg, 2.80 mmol), and bis(triphenylphosphine)palladium dichloride (164 mg, 0.23 mmol) were added to tetrahydrofuran (8 mL) and water (1 mL) and stirred at 40°C for 2 hours under nitrogen. The reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound L021-IS-01-3 (800 mg, yield 95.41%). LC-MS: [M-Boc+H] + =274.10.

[0800] 39.4 Synthesis of Compound L021-IS-01-4

[0801] L021-IS-01-3 (800 mg, 2.14 mmol) and palladium on carbon (200 mg, 10% palladium content) were added to ethyl acetate (10 mL) and stirred at room temperature under a hydrogen atmosphere for 2 hours. After filtration through celite, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain compound L021-IS-01-4 (600 mg, yield 74.6%). LC-MS: [M-Boc+H] + =276.10.

[0802] 39.5 Synthesis of Compound L021-IS-01-5

[0803] L021-IS-01-4 (950 mg, 2.53 mmol) was dissolved in tetrahydrofuran (5 mL) and borane tetrahydrofuran complex (7.6 mL, 7.6 mmol, 1 M tetrahydrofuran solution) was added dropwise at 0°C. After the addition, the mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched by the addition of methanol (15 mL) and stirred at room temperature for 1 hour. The reaction mixture was then concentrated under reduced pressure and the residue was purified by silica gel column chromatography to obtain compound L021-IS-01-5 (550 mg, yield 60.13%). LC-MS: [M+H] + =362.10.

[0804] 39.6 Synthesis of Compound L021-IS-01-6

[0805] Trifluoroacetic acid / dichloromethane (2 mL / 1 mL) was added to L021-IS-01-5 (300 mg, 0.83 mmol) at 0°C, and the reaction mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in dichloromethane (3 mL). Di-tert-butyl dicarbonate (217 mg, 1.0 mmol) and triethylamine (168 mg, 1.66 mmol) were added, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain compound L021-IS-01-6 (100 mg, yield 39.46%). LC-MS: [M-Boc+H] + =206.10.

[0806] 39.7 Synthesis of Compound L021-IS-01-7

[0807] Dissolve L021-IS-01-6 (80 mg, 0.26 mmol), 1-hydroxybenzotriazole (53 mg, 0.39 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (75 mg, 0.39 mmol) in N,N-dimethylformamide (2 mL) and stir at room temperature for 0.5 hour. Dissolve L001-7 (71 mg, 0.27 mmol) and N,N-diisopropylethylamine (135 mg, 1.05 mmol) in N,N-dimethylformamide (2 mL) and stir at room temperature for 0.5 hour. Add the latter to the former reaction mixture and continue stirring for 1 hour. The reaction mixture is diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phases are washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound L021-IS-01-7 (80 mg, yield 60.16%). LC-MS: [M+H] + =508.15.

[0808] 39.8 Synthesis of Compound L021-IS-01

[0809] L021-IS-01-7 (80 mg, 0.16 mmol) was dissolved in dichloromethane (2 mL), and a solution of hydrogen chloride in ethyl acetate (2 mL, 4 M) was added. The mixture was stirred at room temperature for 0.5 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative HPLC (basic conditions) and freeze-dried to provide compound L021-IS-01 (25.4 mg, 39.55% yield).

[0810] 1H NMR (400MHz, DMSO-d6): δ8.13(d,J=8.0Hz,1H),7.72(d,J=7.6Hz,1H),7.33–7.26(m,2H),7.24–7 .09(m,4H),6.22(d,J=8.4Hz,1H),5.83(d,J=3.6Hz,2H),5.09(q,J=7.6Hz,1H),4.30–4.19(m,1H ),3.19(d,J=11.2Hz,1H),3.10(d,J=12.4Hz,1H),2.74–2.59(m,4H),2.38–2.27(m,1H),1.94(d, J=12.4Hz,1H),1.70(d,J=12.0Hz,2H),1.54–1.41(m,1H),1.39–1.27(m,1H),1.24–1.20(m,3H). LC-MS:[M+H] + =408.10.

[0811] Example 40. Synthesis of (2R,4R)-N-((2S)-1-((2-amino-6,7-dihydro-5H-cyclopentadien[b]pyridin-5-yl)amino)-1-oxopropan-2-yl)-4-phenylpiperidine-2-carboxamide (Compound L021-IS-02)

[0812]

[0813] 40.1 Synthesis of Compound L021-IS-02-1

[0814] L021-IS-01-1 (5 g, 16 mmol) was dissolved in dichloromethane (40 mL) and acetic acid (4 mL). Sodium borohydride (607 mg, 16 mmol) was added portionwise at 0°C. The mixture was stirred at 0°C for 0.5 hours, then warmed to room temperature and stirred for 48 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL) and extracted with dichloromethane (40 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound L021-IS-02-1 (3 g, yield 59.62%). LC-MS: [M-Boc+H] + =216.15.

[0815] 40.2 Synthesis of Compound L021-IS-02-2

[0816] L021-IS-02-1 (3 g, 9.5 mmol) was dissolved in toluene (20 mL), triethylamine (2.9 g, 28.5 mmol) was added, and methylsulfonyl chloride (1.6 g, 14.3 mmol) was added dropwise at 0°C, with the temperature controlled not to exceed 5°C. After the addition, the mixture was stirred at 0°C for 0.5 hours, then warmed to room temperature and stirred for 1.5 hours. The reaction solution was quenched with saturated aqueous sodium bicarbonate (15 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound L021-IS-02-2 (1.7 g, yield 60.10%). LC-MS: [M-Boc+H] + =198.15.

[0817] 40.3 Synthesis of Compound L021-IS-02-3

[0818] At room temperature, (1,5-cyclooctadiene)chlororhodium(I) dimer (83 mg, 0.17 mmol) and (S)-1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (105 mg, 0.17 mmol) were added to a reaction flask. After nitrogen purge, toluene (5 mL) was added and the atmosphere was purged with nitrogen for 0.5 hour. L021-IS-02-2 (500 mg, 1.68 mmol), L006-b (307 mg, 2.52 mmol), and triethylamine (340 mg, 3.36 mmol) were dissolved in toluene (4 mL) and water (1 mL) at room temperature. This reaction mixture was then added to the reaction flask containing the catalyst and stirred at 50°C under nitrogen for 1.5 hours. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound L021-IS-02-3 (500 mg, yield 79.20%) as a yellow oil. LC-MS: [M+H] + =376.10.

[0819] 40.4 Synthesis of Compound L021-IS-02

[0820] The synthesis of compound L021-IS-02 followed the synthesis method of compound L021-IS-01, except that L021-IS-01-4 was replaced with L021-IS-02-3. The crude product was purified by HPLC (alkaline conditions) and freeze-dried to give compound L021-IS-02 (71.8 mg, yield 44.72%).

[0821] 1H NMR (400MHz, DMSO-d6): δ8.27–8.06(m,2H),7.34–7.26(m,2H),7.24–7.12(m,4 H),6.23(t,J=7.6Hz,1H),5.84(s,2H),5.17–5.07(m,1H),4.42–4.29(m,1H),3. 54(d,J=4.0Hz,1H),2.95–2.57(m,5H),2.42–2.32(m,1H),2.29(d,J=13.6Hz,1 H),1.80–1.68(m,1H),1.63–1.49(m,2H),1.49–1.36(m,1H),1.28–1.20(m,4H). LC-MS: [M+H] + =408.10.

[0822] Example 41. Synthesis of (2R,4R)-N-((2S)-1-((2-amino-6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)amino)-1-oxopropan-2-yl)-4-(4-fluorophenyl)piperidine-2-carboxamide (Compound L033-IS-01) Hydrochloride

[0823]

[0824] The synthesis of compound L033-IS-01 hydrochloride was carried out according to the synthesis method of compound L021-IS-02, except that L006-b was replaced with L007-a. The crude product was purified by HPLC (acidic conditions) to obtain compound L033-IS-01 hydrochloride (50.2 mg).

[0825] 1 H NMR (400MHz, DMSO-d6): δ9.93(m,1H),9.04(s,1H),8.87-8.84(m,1H),8.57-8.53(m,1H), 8.02(s,1H),7.72-7.65(m,1H),7.36-7.24(m,2H),7.17(t,J=8.8Hz,2H),6.83(d,J=8.0H z,1H),5.17-5.16(m,1H),4.40-4.14(m,2H),3.41-3.39(m,1H),3.15-3.03(m,2H),2.98- 2.77(m,2H),2.48-2.38(m,1H),2.36-2.13(m,2H),2.07-1.85(m,3H),1.30-1.23(m,4H). LC-MS:[M+H] + =426.15.

[0826] Example 42. Synthesis of (2R,4S)-N-((2S)-1-((2-amino-6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)amino)-1-oxopropan-2-yl)-4-(4-fluorophenyl)piperidine-2-carboxamide (Compound L033-IS-02) Hydrochloride

[0827]

[0828] The synthesis of compound L033-IS-02 hydrochloride was carried out according to the synthesis method of compound L021-IS-01, except that L006-b was replaced with L007-a. The crude product was purified by HPLC (acidic conditions) to give compound L033-IS-02 hydrochloride (37.3 mg, yield 32.5%).

[0829] 1 H NMR (400MHz, DMSO-d6): δ9.61–9.46(m,1H),8.81–8.80(m,2H),8.54–8.50(m,1H),7.98(s,1H), 7.73-7.65(m,1H),7.31–7.22(m,2H),7.19–7.15(m,2H),6.82(t,J=8.0Hz,1H),5.17–5.16(m,1H ),4.34–4.16(m,1H),3.93(s,1H),3.33–3.28(m,1H),3.14–3.00(m,2H),2.95–2.88(m,2H),2.4 6–2.44(m,1H),2.30(d,J=12.0Hz,1H),2.02–1.81(m,3H),1.71–1.62(m,1H),1.24-1.22(m,4H). LC-MS:[M+H] + =426.05.

[0830] Example 43. Synthesis of (2R,4S)-N-((2S)-1-((5-amino-2,3-dihydro-1H-inden-1-yl)amino)-1-oxopropan-2-yl)-4-(4-fluorobenzyl)pyrrolidine-2-carboxamide (Compound L034)

[0831]

[0832] 43.1 Synthesis of Compound L034-1

[0833] Dissolve L001-11 (500 mg, 1.55 mmol), 1-hydroxybenzotriazole (231 mg, 1.71 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (328 mg, 1.71 mmol) in N,N-dimethylformamide (3 mL) and react at room temperature for 0.5 hour. Simultaneously, dissolve L034-a (400 mg, 1.86 mmol) and N,N-diisopropylethylamine (800 mg, 6.2 mmol) in N,N-dimethylformamide (2 mL) and react at room temperature for 0.5 hour. Add the latter reaction mixture to the former reaction mixture and continue the reaction for another 0.5 hour. Dilute the reaction mixture with water (20 mL) and extract with ethyl acetate (30 mL x 3). The organic phases were combined and washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound L034-1 (750 mg), which was used directly in the next step. LC-MS: [M+H] + =485.05.

[0834] 43.2 Synthesis of Compound L034-2

[0835] L034-1 (750 mg, 1.55 mmol) and palladium on carbon (75 mg, 10% wt) were added to methanol (8 mL) and reacted under a hydrogen atmosphere for 2 hours. The reaction solution was filtered through celite and the filtrate was concentrated under reduced pressure to obtain compound L034-2 (520 mg), which was used directly in the next step. LC-MS: [M+H] + =395.05.

[0836] 43.3 Synthesis of Compound L034-3

[0837] At room temperature, L034-b (2 g, 9.5 mmol) and tert-butyl carbamate (2.2 g, 19.0 mmol) were dissolved in 1,4-dioxane (20 mL). Palladium acetate (213 mg, 0.95 mmol), 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (549 mg, 0.95 mmol), and cesium carbonate (6.2 g, 19.0 mmol) were then added. The atmosphere was purged with nitrogen three times, and the reaction mixture was heated to 100°C for 16 hours. The reaction mixture was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (40 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to yield compound L034-3 (2 g, 85.5% yield). LCMS: [M+H]+ = 248.10.

[0838] 43.4 Synthesis of Compound L034-4

[0839] L034-3 (500 mg, 2.02 mmol) was dissolved in methanol (6 mL) and water (3 mL). Hydroxylamine hydrochloride (281 mg, 4.04 mmol) and potassium carbonate (419 mg, 3.03 mmol) were added and reacted at room temperature for 16 hours. The reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (20 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound L034-4 (500 mg). LC-MS: [M+H] + =263.10.

[0840] 43.5 Synthesis of Compound L034-5

[0841] L034-4 (500 mg, 1.91 mmol) and palladium on carbon (303 mg, 10% wt) were added to methanol (5 mL), and concentrated hydrochloric acid (0.2 mL) was added. The reaction was allowed to react at room temperature under a hydrogen atmosphere for 4 hours. The reaction solution was filtered through celite, and the filtrate was diluted with water (10 mL). The pH was adjusted to 7-8 with aqueous sodium bicarbonate solution, and the product was extracted with ethyl acetate (20 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound L034-5 (350 mg, crude product), which was used directly in the next step. LC-MS: [M-NH2]+ = 232.10.

[0842] 43.6 Synthesis of Compound L034-6

[0843] L034-2 (442 mg, 1.12 mmol), 1-hydroxybenzotriazole (166 mg, 1.23 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (236 mg, 1.23 mmol) were dissolved in N,N-dimethylformamide (3 mL) and reacted at room temperature for 0.5 hour. Meanwhile, L034-5 (350 mg, 1.4 mmol) and N,N-diisopropylethylamine (578 mg, 4.48 mmol) were dissolved in N,N-dimethylformamide (2 mL) and reacted at room temperature for 0.5 hour. The latter reaction solution was then added to the former reaction solution and the reaction continued for 0.5 hour. The reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound L034-6 (410 mg, yield 69.8%). LC-MS: [M+H] + =525.05.

[0844] 43.7 Synthesis of Compound L034

[0845] L034-6 (410 mg, 0.78 mmol) was dissolved in dichloromethane (5 mL). A solution of hydrogen chloride in ethyl acetate (5 mL, 4 M) was added and the mixture was allowed to react at room temperature for 0.5 h. The solid was filtered, and the filter cake was washed with dichloromethane (5 mL) and dried under reduced pressure. The residue was purified by HPLC to yield compound L034 (89 mg).

[0846] 1 H NMR (400MHz, DMSO-d6): δ8.20–8.07(m,2H),7.25–7.18(m,2H),7.12–7.07(m ,2H),6.81–6.75(m,1H),6.44–6.36(m,2H),5.12–5.04(m,1H),4.95(s,2H), 4.27–4.19(m,1H),3.64–3.61(m,1H),2.88–2.71(m,2H),2.67–2.54(m,4H), 2.30–2.28(m,1H),2.20–1.97(m,1H),1.81–1.58(m,3H),1.24–1.16(m,4H). LC-MS: [M+H] + =425.15.

[0847] Example 44. Synthesis of (2R,4S)-N-((2S)-1-((2-amino-3-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)amino)-1-oxopropan-2-yl)-4-(4-fluorobenzyl)pyrrolidine-2-carboxamide (Compound L035)

[0848]

[0849] 44.1 Synthesis of Compound L035-1

[0850] At room temperature, L035-a (20.0 g, 203.8 mmol), 2-methylacrolein (15.7 g, 224.2 mmol), and ammonium acetate (31.4 g, 407.6 mmol) were dissolved in toluene (100 mL). The reaction mixture was refluxed for 24 hours. The reaction mixture was cooled to room temperature and then filtered through celite. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain compound L035-1 (1.8 g, yield 6.0%). LC-MS: [M+H] + =148.10.

[0851] 44.2 Synthesis of Compound L035-2

[0852] L035-1 (1.7 g, 11.5 mmol) was dissolved in methanol (20 mL) at room temperature, and sodium borohydride (0.87 g, 23.0 mmol) was added portionwise at 0°C, with the reaction temperature controlled to not exceed 5°C. The reaction solution was allowed to react for 2 hours at this temperature. Methanol (15 mL) was added dropwise to the reaction solution to quench the reaction. The reaction solution was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography to obtain compound L035-2 (1.5 g, yield 88%). LC-MS: [M+H] + =150.15.

[0853] 44.3 Synthesis of Compound L035-3

[0854] L035-2 (1.4 g, 9.3 mmol) was dissolved in tetrahydrofuran (10 mL). Phthalimide (1.37 g, 9.3 mmol) and triphenylphosphine (2.05 g, 12.09 mmol) were added under ice-cooling. Diisopropyl azodicarboxylate (2.4 g, 12.09 mmol) was slowly added dropwise under nitrogen. After the addition was complete, the reaction mixture was allowed to warm to room temperature and continued to react for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain compound L035-3 (2.1 g, 80.7% yield). LC-MS: [M+H] + =279.00.

[0855] 44.4 Synthesis of Compound L035-4

[0856] At room temperature, L035-3 (2.0 g, 7.0 mmol) was dissolved in dichloromethane (20 mL), and m-chloroperbenzoic acid (1.86 g, 10.6 mmol) was slowly added. The reaction mixture was allowed to react at room temperature for 2 hours. Saturated sodium bicarbonate (30 mL) was added to the reaction solution to quench it, and the mixture was extracted with ethyl acetate (40 mL × 3). The combined organic phases were washed with saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound L035-4 (900 mg, yield 42.4%). LC-MS: [M+H] + =295.05.

[0857] 44.5 Synthesis of Compound L035-5

[0858] At room temperature, L035-4 (700 mg, 2.5 mmol) was dissolved in dichloromethane (10 mL), and p-toluenesulfonyl chloride (739 mg, 3.9 mmol), N,N-diisopropylethylamine (969 mg, 7.5 mmol), and phthalimide (442 mg, 3.0 mmol) were added. The mixture was allowed to react at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain compound L035-5 (780 mg, 72.2% yield). LC-MS: [M+H] + =423.90.

[0859] 44.6 Synthesis of Compound L035-6

[0860] At room temperature, L035-5 (700 mg, 4.28 mmol) was dissolved in ethanol (10 mL), and hydrazine monohydrate (5 mL, 98%) was added. The mixture was reacted at 80°C for 2 hours, resulting in the precipitation of a white solid. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by HPLC and freeze-dried to obtain compound L035-6 (250 mg, 92.6% yield). LC-MS: [M+H] + =163.1.

[0861] 44.7 Synthesis of Compound L035-7

[0862] L035-6 (50 mg, 0.3 mmol) and L034-2 (120 mg, 0.3 mmol) were dissolved in N,N-dimethylformamide (2 mL). Triethylamine (121.3 mg, 1.2 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (125 mg, 0.33 mmol) were added and reacted at room temperature for 2 hours. The reaction solution was purified by HPLC and freeze-dried to obtain compound L035-7 (18.0 mg, 10.9% yield). LC-MS: [M+H] + =540.0.

[0863] 44.6 Synthesis of Compound L035

[0864] L035-7 (18.0 mg, 0.033 mmol) was added to a solution of hydrogen chloride in 1,4-dioxane (1 mL, 4 M) and allowed to react at room temperature for 1 hour. The reaction solution was concentrated, deionized water (5 mL) was added, and the mixture was freeze-dried to obtain compound L035 (11.0 mg, 92.3% yield).

[0865] 1H NMR (400MHz, DMSO-d6): δ10.46–10.37(m,2H),8.85(t,J=6.4Hz,1H),8.54(t,J=8.0Hz,2H),7.65(s,2 H),7.55(d,J=18.8Hz,1H),7.42(s,1H),7.29(t,J=8.0Hz,2H),7.16–7.10(m,2H),5.14(d,J=6.8Hz,1 H),4.38(s,1H),4.28–4.23(m,1H),3.48–3.38(m,2H),3.03-2.97(m,1H),2.89–2.84(m,2H),2.72–2. 67(m,2H),2.50–2.43(m,1H)2.14(s,3H),2.07–2.05(m,1H),1.91–1.88(m,2H),1.23(d,J=4.4Hz,3H). LC-MS:[M+H] + =440.0.

[0866] Example 45. Synthesis of (2R,4S)-4-(4-fluorobenzyl)-N-((2S)-1-((2-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)amino)-1-oxopropan-2-yl)pyrrolidine-2-carboxamide (Compound L036)

[0867]

[0868] 45.1 Synthesis of Compound L036-1

[0869] L001-3 (1 g, 3.6 mmol) was dissolved in acetic anhydride (10 mL) at room temperature and the temperature was raised to 100°C for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain compound L036-1 (800 mg, yield 69.57%). LC-MS: [M+H] + =323.00.

[0870] 45.2 Synthesis of Compound L036

[0871] The synthesis of compound L036 was carried out by referring to the synthesis method of compound L035, except that L035-5 was replaced with L036-1. The crude product was purified by HPLC (alkaline conditions) and freeze-dried to obtain compound L036 (18.6 mg, yield 22.97%).

[0872] 1H NMR (400MHz, DMSO-d6): δ8.47(d,J=4.0Hz,1H),8.32(d,J=8.0Hz,1H),8.21–8.13(m,1H),7 .60–7.50(m,1H),7.30–7.16(m,3H),7.09(t,J=8.8Hz,2H),5.48–5.36(m,2H),5.01(s,1H) ,4.27–4.16(m,1H),3.62(dd,J=9.2,4.8Hz,1H),2.89–2.78(m,1H),2.63–2.52(m,3H),2.2 7–2.18(m,1H),2.17–2.09(m,1H),2.09–2.01(m,1H),1.79–1.61(m,2H),1.27–1.19(m,4H). LC-MS:[M+H] + =427.05.

[0873] Example 46. Synthesis of (2R,4S)-N-((2S)-1-((2-amino-5,6,7,8-tetrahydroquinolin-5-yl)amino)-1-oxopropan-2-yl)-4-(4-fluorobenzyl)pyrrolidine-2-carboxamide (Compound L037) trifluoroacetate

[0874]

[0875] 46.1 Synthesis of Compound L037-1

[0876] At room temperature, L037-a (900 mg, 4.95 mmol) and tert-butyl carbamate (1.2 g, 9.91 mmol) were dissolved in 1,4-dioxane (10 mL). Palladium acetate (110.8 mg, 0.50 mmol), 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (286.1 mg, 0.50 mmol), and cesium carbonate (3.2 g, 9.91 mmol) were added. The mixture was reacted at 90°C under nitrogen for 3 hours. The reaction solution was cooled to room temperature, diluted with water (30 mL), and extracted with ethyl acetate (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound L037-1 (1.3 g, yield 89%). LC-MS: [M+H] + =263.10.

[0877] 46.2 Synthesis of Compound L037-2

[0878] L037-1 (200 mg, 0.76 mmol) was dissolved in ethanol (2 mL) and water (1 mL). Hydroxylamine hydrochloride (105.6 mg, 1.52 mmol) and potassium carbonate (157.6 mg, 1.14 mmol) were added and allowed to react at room temperature for 16 hours. The reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound L037-2. LC-MS: [M+H] + =278.10.

[0879] 46.3 Synthesis of Compound L037-3

[0880] L037-2 (190 mg, crude product) was dissolved in methanol (2 mL) and palladium on carbon (73 mg, 10% wt) was added. The atmosphere was replaced with hydrogen three times and the reaction was allowed to proceed at room temperature for 4 hours. The reaction solution was filtered through celite and the filter cake was washed with methanol (10 mL). The filtrate was concentrated under reduced pressure to give compound L037-3 (85 mg, crude product). LC-MS: [M+H] + =264.15.

[0881] 46.4 Synthesis of Compound L037-4

[0882] L001-d (60.5 mg, crude) was dissolved in N,N-dimethylformamide (1 mL), and 1-hydroxybenzotriazole (47.5 mg, 0.35 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (67.6 mg, 0.35 mmol) were added. The mixture was allowed to react at room temperature for 10 minutes. A solution of L037-3 (85 mg, 0.32 mmol) and N,N-diisopropylethylamine (165.1 mg, 1.28 mmol) in N,N-dimethylformamide (1 mL) was then added to the reaction system, and the reaction was continued at room temperature for 1 minute. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (30 mL x 3). The organic phases were combined and washed with saturated brine (40 mL). The organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to yield compound L037-4 (70 mg, crude). LC-MS: [M+H] + =435.10.

[0883] 46.5 Synthesis of Compound L037-5

[0884] L037-4 (128 mg, crude product) was dissolved in dichloromethane (2 mL), and a solution of hydrogen chloride in ethyl acetate (2 mL, 4 M) was added. The mixture was allowed to react at room temperature for 0.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was added with dichloromethane (10 mL), stirred for 10 minutes, filtered, and the filter cake was dried under reduced pressure to obtain compound L037-5 (150 mg). LC-MS: [M+H] + =235.15.

[0885] 46.6 Synthesis of Compound L037 Trifluoroacetate

[0886] The synthesis of compound L037 was carried out according to the synthesis method of compound L001, except that L001-7 was replaced with L037-5. The crude product was purified by HPLC (trifluoroacetic acid conditions) to give compound L037 trifluoroacetate (34 mg).

[0887] 1 H NMR (400MHz, DMSO-d6): δ9.61–9.56(m,1H),8.77(d,J=8.0Hz,1H),8.54(s,1H),8.39(d ,J=12.0Hz,1H),8.00–7.89(m,1H),7.67–7.52(m,1H),7.28–7.25(m,2H),7.14(t,J=8.0 Hz,2H),6.79(t,J=12.0Hz,1H),4.81(s,1H),4.35–4.21(m,2H),3.31(s,1H),2.91(s,1H ),2.71–2.62(m,4H),2.49–2.40(m,2H),2.08–1.63(m,6H),1.24(dd,J=8.0,4.0Hz,3H). LC-MS:[M+H] + =440.05.

[0888] Example 47. Synthesis of (2R,4R)-N-((2S)-1-((2-amino-6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)amino)-1-oxopropan-2-yl)-4-(2-fluorophenyl)piperidine-2-carboxamide (Compound L038-IS-01)

[0889]

[0890] The synthesis of compound L038-IS-01 followed the synthesis method of compound L021-IS-02, except that L006-b was replaced with L038-a. The crude product was purified by HPLC (alkaline conditions) and freeze-dried to give compound L038-IS-01 (60.6 mg, yield 29.94%).

[0891] 1 H NMR (400MHz, DMSO-d6): δ7.91(s,1H),7.38(d,J=8.0Hz,1H),7.22–6.95(m,4H),6.73(s,1H),6.39–6.15(m,1H),5.36(s,1H), 4.59–4.50(m,1H),4.45(s,2H),3.74(s,1H),3.08-2.76(m,5H),2.64–2.49(m,2H),2.06–1.50(m,5H),1.43(d,J=7.2Hz,3H). LC-MS:[M+H] + =426.10.

[0892] Example 48. Synthesis of (2R,4S)-N-((2S)-1-((2-amino-6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)amino)-1-oxopropan-2-yl)-4-(2-fluorophenyl)piperidine-2-carboxamide (Compound L038-IS-02) Hydrochloride

[0893]

[0894] The synthesis of compound L038-IS-02 hydrochloride was carried out according to the synthesis method of compound L021-IS-01, except that L006-b was replaced with L038-a. The crude product was purified by HPLC (acidic conditions) and freeze-dried to give compound L038-IS-02 hydrochloride (56.2 mg, yield 29.06%).

[0895] 1 H NMR (400MHz, DMSO-d6): δ9.76-9.62(m,1H),8.86(d,J=7.6Hz,2H),8.55(dd,J=16.0,8.0Hz,1H ),8.03(s,2H),7.72–7.66(m,1H),7.39–7.13(m,4H),6.84(t,J=9.2Hz,1H),5.25–5.06(m,1H), 4.36–4.13(m,1H),3.98(t,J=10.8Hz,1H),3.33(d,J=11.6Hz,1H),3.25–3.02(m,3H),2.96–2. 81(m,1H),2.47–2.41(m,1H),2.26(d,J=13.2Hz,1H),2.03–1.74(m,4H),1.23(d,J=6.8Hz,3H). LC-MS:[M+H] + =426.10.

[0896] The following compounds in Table A were synthesized with reference to the L021-IS-01 / L021-IS-02 synthesis method, wherein Examples 49, 51, 52, 53, 55, 57, and 59 refer to the synthesis method of compound L021-IS-01, and Examples 50, 54, 56, 58, 60, 61, 62, and 63 refer to the synthesis method of compound L021-IS-02.

[0897]

[0898]

[0899]

[0900]

[0901]

[0902] Example 64. Synthesis of N-((2S)-1-((2-amino-6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)amino)-1-oxopropan-2-yl)-4-((4,4-dimethylpiperidin-1-yl)methyl)pyrrolidine-2-carboxamide (Compound L049) Hydrochloride

[0903]

[0904] 64.1 Synthesis of Compound L049-1

[0905] At room temperature, L049-a (1.00 g, 7.19 mmol) was dissolved in dichloromethane (6 mL) and nitromethane (6 mL) under nitrogen. Aluminum trichloride (1.92 g, 14.38 mmol) was added portionwise at -20°C, followed by dropwise addition of L049-b (1.65 g, 14.38 mmol). The reaction was maintained at -20°C for 1 hour. The reaction solution was slowly poured into ice water (20 mL) to quench the mixture. The organic phase was separated, and the aqueous phase was extracted with dichloromethane (15 mL x 3). The organic phases were combined and washed with saturated aqueous sodium bicarbonate (30 mL) and saturated sodium chloride (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to yield compound L049-1 (1.10 g, crude product), which was used directly in the next step. LC-MS: [M+H] + =168.10.

[0906] 64.2 Synthesis of Compound L049-2

[0907] L049-1 (1.10 g, crude product) was dissolved in dichloromethane (10 mL), and di-tert-butyl dicarbonate (2.15 g, 9.87 mmol), 4-dimethylaminopyridine (161 mg, 1.32 mmol), and triethylamine (1.33 g, 13.16 mmol) were added and reacted at room temperature for 4 hours. The reaction solution was diluted with water (20 mL) and extracted with dichloromethane (15 mL × 3). The organic phases were combined and washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to obtain compound L049-2 (660 mg). LC-MS: [M+H] + =268.10.

[0908] 64.3 Synthesis of Compound L049-3

[0909] L049-2 (650 mg, 2.43 mmol) and L049-c (437 mg, 2.92 mmol) were dissolved in dichloromethane (10 mL), and acetic acid (146 mg, 2.43 mmol) was added. The mixture was allowed to react at room temperature for 2 hours. Sodium triacetylborohydride (1.29 g, 6.08 mmol) was then added, and the reaction was continued at room temperature for 16 hours. The reaction solution was poured into ice water (20 mL) to quench the mixture, and extracted with dichloromethane (15 mL x 3). The organic phases were combined and washed with saturated aqueous sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain compound L049-3 (450 mg, yield: 50.3%). LC-MS: [M+H] + =365.05.

[0910] 64.4 Synthesis of Compound L049-4

[0911] L049-3 (450 mg, 1.23 mmol) was dissolved in ethanol (10 mL) and palladium on carbon (200 mg, 10% wt) was added. The reaction was allowed to proceed at room temperature under a hydrogen atmosphere for 16 hours. The reaction solution was filtered through celite, and the filter cake was washed with ethanol (10 mL). The filtrate was concentrated under reduced pressure to give compound L049-4 (450 mg, crude product). LC-MS: [M+H] + =369.10.

[0912] 64.5 Synthesis of Compound L049-5

[0913] L049-4 (450 mg, 1.22 mmol) was dissolved in tetrahydrofuran (10 mL), methanol (5 mL) and water (5 mL), and lithium hydroxide monohydrate (154 mg, 3.66 mmol) was added. The mixture was allowed to react at room temperature for 5 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in water (10 mL). The aqueous phase was adjusted to pH 6-7 with dilute hydrochloric acid (1 M) and extracted with dichloromethane (15 mL × 3). The organic phases were combined and washed with saturated aqueous sodium chloride solution (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound L049-5 (450 mg, crude product). LC-MS: [M+H] + =341.05.

[0914] 64.6 Synthesis of Compound L049-6

[0915] L049-5 (450 mg, crude product), L001-7 (407 mg, 1.58 mmol) and N,N-diisopropylethylamine (668 mg, 6.60 mmol) were dissolved in dichloromethane (5 mL), and 1-propylphosphoric anhydride (630 mg, 1.98 mmol, 50% ethyl acetate solution) was added and reacted at room temperature for 3 hours. The reaction solution was diluted with water (20 mL) and extracted with dichloromethane (15 mL × 3). The organic phases were combined and washed with saturated sodium chloride aqueous solution (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound L049-6 (370 mg, crude product). LC-MS: [M+H] + =543.15.

[0916] 64.7 Synthesis of Compound L049 Hydrochloride

[0917] L049-6 (370 mg, crude product) was dissolved in dichloromethane (6 mL), and a solution of hydrogen chloride in ethyl acetate (4 mL, 4 M) was added and allowed to react at room temperature for 0.5 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by HPLC (0.1% hydrochloric acid) to afford compound L049 hydrochloride (23.4 mg).

[0918] 1H NMR (400MHz, DMSO-d6): δ10.50(s,1H),10.13(s,1H),8.86(dd,J=6.8,3.2Hz,1H),8.78(s,1H),8.56 (d,J=7.6Hz,1H),8.01(s,2H),7.75–7.62(m,1H),6.84(t,J=9.2Hz,1H),5.19–5.09(m,1H),4.35–4.1 6(m,2H),3.55(s,2H),3.32–3.16(m,4H),3.13–2.73(m,6H),2.67–2.59(m,1H),1.92(d,J=6.7Hz,1H ),1.80–1.76(m,2H),1.73–1.57(m,1H),1.48–1.45(m,2H),1.27(t,J=6.4Hz,3H),0.99–0.96(m,6H). LC-MS:[M+H] + =443.10.

[0919] Example 65. Synthesis of (2R)-N-((S)-1-(((R)-2-amino-6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)amino)-1-oxopropan-2-yl)-4-(difluoro(4-fluorophenyl)methyl)pyrrolidine-2-carboxamide (Compound L050)

[0920]

[0921] 65.1 Synthesis of Compound L050-1

[0922] L006-1 (2.70 g, 7.19 mmol) was dissolved in tetrahydrofuran (20 mL) and water (5 mL), and tetrakistriphenylphosphine palladium (1.66 g, 1.44 mmol) was added. After nitrogen replacement, the reaction solution was reacted at room temperature under a carbon monoxide atmosphere for 16 hours. Water (30 mL) was added to the reaction solution and the mixture was extracted with ethyl acetate (20 mL × 2). The combined organic phases were washed with saturated sodium bicarbonate aqueous solution (20 mL) and the organic phase was discarded. All aqueous phases were combined, the aqueous phase was adjusted to pH = 2 with dilute hydrochloric acid (2 M), and extracted with ethyl acetate (25 mL × 3). The organic phases were combined and washed with saturated sodium chloride aqueous solution (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound L050-1 (1.42 g, crude product). LC-MS: [M-tBu+H] + =216.00.

[0923] 65.2 Synthesis of Compound L050-2

[0924] At room temperature, L050-1 (1.42 g, crude product) was dissolved in methanol (10 mL) and tetrahydrofuran (10 mL). Triethylamine (529 mg, 5.23 mmol) and tristriphenylphosphine rhodium chloride (968 mg, 1.05 mmol) were added. The atmosphere was purged with nitrogen and then hydrogen, and the reaction mixture was allowed to react under a hydrogen atmosphere for 72 hours. The reaction mixture was concentrated under reduced pressure, and the residue was added to saturated aqueous sodium bicarbonate (15 mL). The pH was adjusted to 10 with aqueous sodium hydroxide (1 M), followed by extraction with ethyl acetate (15 mL). The organic phase was washed with saturated aqueous sodium bicarbonate (15 mL) and discarded. All aqueous phases were combined, the pH adjusted to 4-5 with dilute hydrochloric acid (1 M), and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated aqueous sodium chloride (40 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to yield compound L050-2 (1.1 g, crude product). LC-MS: [M-Boc+H] + =174.10.

[0925] 65.3 Synthesis of Compound L050-3

[0926] L050-2 (1.1 g, crude product) and L050-a (588 mg, 6.03 mmol) were dissolved in N,N-dimethylformamide (10 mL). 2-(7-Azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.83 g, 4.82 mmol) and N,N-diisopropylethylamine (1.56 g, 12.06 mmol) were added and reacted at room temperature for 16 hours. The reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated sodium chloride aqueous solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain compound L050-3 (800 mg). LC-MS: [M+H] + =317.05.

[0927] 65.4 Synthesis of Compound L050-4

[0928] L050-3 (700 mg, 2.21 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL) under nitrogen protection. The reaction solution was cooled to 0°C and L050-b (3.3 mL, 3.32 mmol, 1 M) was added dropwise. The reaction mixture was then warmed to room temperature and reacted for 3 hours. The reaction solution was quenched by adding saturated aqueous ammonium chloride solution (15 mL) and extracted with ethyl acetate (15 mL × 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to obtain compound L050-4 (144 mg). LC-MS: [M-Boc+H] + =252.05.

[0929] 65.5 Synthesis of Compound L050-5

[0930] L050-4 (130 mg, 0.37 mmol) was added to bis(2-methoxyethyl)aminosulfur trifluoride (5 mL) and reacted at 90°C under nitrogen for 6 hours. The reaction solution was cooled to room temperature and quenched by adding dropwise to a saturated aqueous sodium bicarbonate solution (20 mL) cooled to 0°C. The solution was then extracted with ethyl acetate (15 mL x 3). The combined organic phases were washed with a saturated aqueous sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain compound L050-5 (80 mg). LC-MS: [M-tBu+H] + =317.95.

[0931] 65.6 Synthesis of Compound L050-6

[0932] L050-5 (80 mg, 0.21 mmol) was dissolved in methanol (2 mL), tetrahydrofuran (2 mL), and water (1 mL). Lithium hydroxide monohydrate (27 mg, 0.64 mmol) was added and allowed to react at room temperature for 5 hours. The reaction solution was concentrated under reduced pressure, and the residue was poured into water (5 mL). The pH was adjusted to 4-5 with dilute aqueous hydrochloric acid (1 M), and extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated aqueous sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound L050-6 (80 mg, crude product). LC-MS: [M-tBu+H] + =303.95.

[0933] 65.7 Synthesis of Compound L050

[0934] The synthesis of compound L050 hydrochloride was carried out according to the synthesis method of compound L001-IS-01, except that L001-8 was replaced by L050-6. The crude product was purified by HPLC (0.1% hydrochloric acid) and freeze-dried to give compound L050 hydrochloride (42.5 mg).

[0935] 1 H NMR (400MHz, DMSO-d6): δ10.47(s,1H),8.94–8.88(m,2H),8.55(s,1H),8.00(s ,2H),7.69–7.62(m,3H),7.38(t,J=8.8Hz,2H),6.82(d,J=8.8Hz,1H),5.18–5.1 2(m,1H),4.37–4.20(m,2H),3.26(s,1H),3.10–2.99(m,1H),2.96–2.85(m,1H), 2.47–2.44(m,1H),2.41–2.39(m,3H),2.03–1.73(m,2H),1.24(t,J=5.6Hz,3H). LC-MS: [M+H] + =462.00.

[0936] Example 66. Synthesis of (2R,4S)-N-((2S)-1-((3-amino-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl)amino)-1-oxopropan-2-yl)-4-(4-fluorobenzyl)pyrrolidine-2-carboxamide (Compound L051) Hydrochloride

[0937]

[0938] 66.1 Synthesis of Compound L051-1

[0939] At room temperature, L051-a (5 g, 36.35 mmol) and triphenylphosphine (9.5 g, 36.35 mmol) were dissolved in toluene (100 mL). After nitrogen substitution, the reaction solution was heated to 80°C and reacted for 16 hours, resulting in the formation of a large amount of white solid. The reaction solution was cooled to room temperature and filtered. The filter cake was washed with toluene (20 mL) and dried under reduced pressure to yield compound L051-1 (6.7 g, 50.72% yield). LC-MS: [M+H] + =363.95.

[0940] 66.2 Synthesis of Compound L051-2

[0941] L051-1 (6.7 g, 18.44 mmol) and L051-b (4.1 g, 18.44 mmol) were dissolved in dichloromethane (100 mL) and reacted at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain compound L051-2 (3.5 g, 62.17% yield). LC-MS: [M+H] + =306.85.

[0942] 66.3 Synthesis of Compound L051-3

[0943] L051-2 (3.5 g, 11.45 mmol) was dissolved in ethyl acetate (50 mL), and a rhodium / alumina complex (2 g) was added. The mixture was replaced with hydrogen and allowed to react at room temperature under a hydrogen atmosphere for 5 days. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain compound L051-3 (3.5 g, 99.43% yield). LC-MS: [M+H] + =308.85.

[0944] 66.4 Synthesis of Compound L051-4

[0945] L051-3 (3.5 g, 11.44 mmol) was dissolved in tetrahydrofuran (50 mL), the reaction system was cooled to -70 ° C, and n-butyl lithium (14 mL, 22.4 mmol, 1.6 M n-hexane solution) was slowly added dropwise. After the addition was complete, the reaction solution was continued to react at -70 ° C for 2 hours. The reaction solution was quenched by adding saturated aqueous ammonium chloride (20 mL) and extracted with ethyl acetate (50 mL × 3). The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain compound L051-4 (1.2 g, yield 62.83%). LC-MS: [M+H] + =168.05.

[0946] 66.5 Synthesis of Compound L051-5

[0947] At room temperature, L051-4 (1.2 g, 7.16 mmol) and tert-butyl carbamate (1.7 g, 14.32 mmol) were dissolved in 1,4-dioxane (50 mL). Palladium acetate (161 mg, 0.72 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (683 mg, 1.43 mmol), and cesium carbonate (4.7 g, 14.32 mmol) were added. The mixture was reacted at 80°C under nitrogen for 16 hours. The reaction solution was cooled to room temperature, poured into water (50 mL), diluted, and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain compound L051-5 (1.2 g, 67.42% yield). LC-MS: [M+H] + =249.05.

[0948] 66.6 Synthesis of Compound L051-6

[0949] L051-5 (1.17 g, 4.71 mmol) was dissolved in ethanol (20 mL) and water (10 mL), and sodium acetate (590 mg, 7.07 mmol) and L051-c (580 mg, 7.07 mmol) were added. The mixture was allowed to react at room temperature for 16 hours. The reaction solution was poured into water (20 mL) and diluted, and extracted with ethyl acetate (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain compound L051-6 (600 mg, 45.80% yield). LC-MS: [M+H] + =278.05.

[0950] 66.7 Synthesis of Compound L051-7

[0951] L051-6 (600 mg, 2.16 mmol) was dissolved in methanol (20 mL) and aqueous ammonia (2 mL), and Raney nickel (100 mg) was added. The mixture was reacted under a hydrogen atmosphere for 16 hours. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain compound L051-7 (450 mg, crude product), which was used directly in the next reaction. LC-MS: [M+H] + =250.05.

[0952] 66.8 Synthesis of Compound L051-8

[0953] L051-7 (200 mg, 0.53 mmol) was dissolved in dichloromethane (8 mL), and N,N-diisopropylethylamine (194 mg, 1.53 mmol) was added. After reacting at room temperature for 10 minutes, the reaction system was added to a solution of L034-2 (154 mg, 0.61 mmol) and 1-propylphosphonic anhydride (647 mg, 1.0 mmol, 50% ethyl acetate solution) in dichloromethane (8 mL). The reaction was continued at room temperature for 1 hour. The reaction solution was diluted with saturated aqueous sodium chloride solution (20 mL) and extracted with dichloromethane (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain compound L051-8 (250 mg, 43.31% yield). LC-MS: [M+H] + =626.10.

[0954] 66.9 Synthesis of Compound L051 Hydrochloride

[0955] L051-8 (230 mg, 0.35 mmol) was dissolved in dichloromethane (2 mL), and a solution of hydrogen chloride in 1,4-dioxane (2 mL, 4 M) was added. The mixture was allowed to react at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified by HPLC (0.1% hydrochloric acid) to obtain compound L051 hydrochloride (98.5 mg, 53.37% yield). LC-MS: [M+H] + =426.05.

[0956] 1 H NMR (400MHz, DMSO-d6): δ10.42(s,1H),8.94–8.89(m,1H),8.71–8.41(m,2H),8.05–8.02(m,2H),7.72–7 .68(m,1H),7.28(dd,J=8.4,5.6Hz,2H),7.11(t,J=8.8Hz,2H),6.85(s,1H),5.12(q,J=7.6Hz,1H),4.40 –4.35(m,1H),4.23–4.21(m,1H),3.33–3.19(m,1H),3.03–2.96(m,1H),2.92–2.78(m,2H),2.74–2.62(m ,2H),2.47–2.39(m,1H),2.38–2.26(m,1H),2.09–2.01(m,1H),1.95–1.83(m,2H),1.22(d,J=7.2Hz,3H). LC-MS:[M+H] + =426.05.

[0957] Example 67. Synthesis of (2R,4S)-N-((2S)-1-((2-amino-3-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)amino)-1-oxopropan-2-yl)-4-(4-fluorophenyl)piperidine-2-carboxamide (Compound L052) Hydrochloride

[0958]

[0959] 67.1 Synthesis of Compound L052-1

[0960] L001-d (1.5 g, 8.08 mmol) was dissolved in N,N-dimethylformamide (20 mL). 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.7 g, 8.89 mmol) and 1-hydroxybenzotriazole (1.2 g, 8.89 mmol) were added sequentially. The mixture was reacted at 25°C for 10 minutes. Then, a solution of N,N-diisopropylethylamine (5.2 g, 40.40 mmol) and L001-6 (1.5 g, 8.08 mmol) in N,N-dimethylformamide (10 mL) was added. The reaction was continued at 25°C for 30 minutes. The reaction solution was poured into water (30 mL) and extracted with ethyl acetate (30 mL x 3). The organic phase was washed with saturated aqueous ammonium chloride solution (20 mL×3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound L052-1 (1.5 g).

[0961] 67.2 Synthesis of Compound L052-2

[0962] L052-1 (200 mg, 0.66 mmol) was dissolved in acetonitrile (5 mL), and N-bromosuccinimide (134 mg, 0.75 mmol) was added. The mixture was allowed to react at room temperature for 2 hours. The reaction solution was diluted with water (10 mL) and extracted with dichloromethane (10 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / dichloromethane = 1 / 20) to obtain compound L052-2 (160 mg, 60% yield). LC-MS: [M+H] + =398.95.

[0963] 67.3 Synthesis of Compound L052-3

[0964] At room temperature, L052-2 (180 mg, 0.45 mmol) and trimethylboroxine (282 mg, 2.25 mmol) were dissolved in N,N-dimethylformamide (5 mL) and water (0.1 mL). Potassium carbonate (187 mg, 1.35 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (33 mg, 0.045 mmol) were added. The atmosphere was purged with nitrogen three times, and the reaction mixture was reacted at 110°C for 16 hours. The reaction mixture was cooled to room temperature, diluted with water (30 mL), and extracted with ethyl acetate (30 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / dichloromethane = 1 / 10) to obtain compound L052-3 (130 mg, 86.7% yield). LC-MS: [M+H] + =335.10.

[0965] 67.4 Synthesis of Compound L052-4

[0966] Dissolve L052-3 (130 mg, 0.39 mmol) in dichloromethane (1 mL) and add a 1,4-dioxane solution of hydrogen chloride (2 mL, 4 M). Allow to react at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to yield compound L052-4 (crude product), which was used directly in the next step. LC-MS: [M+H] + =235.15.

[0967] 67.5 Synthesis of Compound L052 Hydrochloride

[0968] The synthesis of compound L052 followed the synthesis method of compound L001, except that L001-11 was replaced with L033-IS-02-4 and L001-7 was replaced with L052-4. The crude product was purified by HPLC (0.1% hydrochloric acid) and freeze-dried to give compound L052 hydrochloride (8.3 mg).

[0969] 1H NMR (400MHz, DMSO-d6): δ9.59–9.42(m,1H),8.92–8.69(m,2H),8.54–8.48(m,1H),7.7 0(s,2H),7.58(d,J=8.0Hz,1H),7.27(d,J=8.0Hz,2H),7.17–7.15(m,2H),5.19–5.14(m ,1H),4.28(m,1H),3.94(s,1H),3.08–3.03(m,2H),2.91–2.89(m,2H),2.44–2.40(m,1 H), 2.32–2.30 (m, 1H), 2.15 (d, J = 8.0Hz, 2H), 2.04–1.61 (m, 5H), 1.24 (d, J = 8.0Hz, 4H). LC-MS:[M+H] + =440.05.

[0970] Example 68. Synthesis of (2R,4S)-N-((2S)-1-((2-amino-3-chloro-6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)amino)-1-oxopropan-2-yl)-4-(4-fluorobenzyl)pyrrolidine-2-carboxamide (Compound L053) Hydrochloride

[0971]

[0972] 68.1 Synthesis of Compound L053-1

[0973] L052-1 (400 mg, 1.2 mmol) was dissolved in acetonitrile (10 mL), and N-chlorosuccinimide (250 mg, 1.8 mmol) was added. The mixture was allowed to react at room temperature for 3 hours. The reaction solution was diluted with water (20 mL) and extracted with dichloromethane (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by high-performance liquid chromatography (0.1% ammonia solution) and freeze-dried to obtain compound L053-1 (90 mg, yield 21%). LC-MS: [M+H] + =355.05.

[0974] 68.2 Synthesis of Compound L053-2

[0975] Dissolve L053-1 (90 mg, 0.23 mmol) in dichloromethane (2 mL) and add a 1,4-dioxane solution of hydrogen chloride (4 M, 4 mL). Allow to react at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to yield compound L053-2 hydrochloride (67 mg), which was used directly in the next step. LC-MS: [M+H] + =255.05.

[0976] 68.3 Synthesis of Compound L053 Hydrochloride

[0977] The synthesis of compound L053 was carried out according to the synthesis method of compound L001, except that L001-7 was replaced by L053-2. The crude product was purified by HPLC (0.1% hydrochloric acid) and freeze-dried to give compound L053 hydrochloride (26.3 mg).

[0978] 1 H NMR (400MHz, DMSO-d6): δ10.13(s,1H),8.81(d,J=8.0Hz,1H),8.52(t,J=8.0Hz,2H ),7.66(d,J=12Hz,1H),7.29–7.27(m,2H),7.13(t,J=8.4Hz,2H),5.13(dd,J=8.0,4 .0Hz,1H),4.41–4.32(m,3H),4.32–4.23(m,3H),3.34–3.21(m,1H),2.98–2.61(m,5 H),2.48–2.37(m,1H),2.12–1.98(m,1H),1.92–1.90(m,2H),1.23(d,J=4.0Hz,3H). LC-MS:[M+H] + =460.00.

[0979] Example 69. Synthesis of (2R)-N-((S)-1-(((R)-2-amino-6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)amino)-1-oxopropan-2-yl)-4-fluoro-4-(4-fluorophenyl)piperidine-2-carboxamide (Compound L054)

[0980]

[0981] 69.1 Synthesis of Compound L054-1

[0982] L022-a (1.0 g, 3.85 mmol) was added to tetrahydrofuran (10 mL) at room temperature. The reaction mixture was cooled to -78°C and lithium bis(trimethylsilyl)amide (4.2 mL, 4.2 mmol, 1 M solution in tetrahydrofuran) was added dropwise under nitrogen. After the addition was complete, the mixture was stirred at -78°C for 10 minutes. At the same temperature, a solution of N-(5-chloro-2-pyridyl)bis(trifluoromethanesulfonamide) (1.58 g, 4.04 mmol) in tetrahydrofuran (5 mL) was added. After the addition was complete, the mixture was warmed to room temperature and stirred for 1.5 hours. The reaction mixture was quenched by the addition of a saturated aqueous solution of ammonium chloride (20 mL) and extracted with ethyl acetate (20 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to yield compound L054-1 (600 mg, crude product).

[0983] 69.2 Synthesis of Compound L054-2

[0984] L054-1 (2.9 g, 7.45 mmol), L007-a (2.1 g, 14.90 mmol), bis(triphenylphosphine)palladium dichloride (523 mg, 0.74 mmol), and potassium carbonate (2.1 g, 14.90 mmol) were dissolved in tetrahydrofuran (50 mL) and water (10 mL). The mixture was reacted at 40°C under nitrogen for 3 hours. The reaction solution was poured into water (30 mL) and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 3) to obtain compound L054-2 (2.4 g, 95.56% yield). LC-MS: [M+H] + =336.05.

[0985] 69.3 Synthesis of Compound L054-3

[0986] At room temperature, L054-2 (1.0 g, 2.98 mmol) was dissolved in acetone (10 mL) and water (2 mL). A solution of N-bromosuccinimide (584 mg, 3.28 mmol) in acetone (10 mL) was slowly added dropwise. After the addition was complete, the reaction was continued at room temperature for 16 hours. The reaction solution was poured into water (10 mL) and extracted with ethyl acetate (20 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 2) to obtain compound L054-3 (867 mg, 67.18% yield). LC-MS: [M-Boc+H] + =331.85.

[0987] 69.4 Synthesis of Compound L054-4

[0988] L054-3 (1.2 g, 2.78 mmol) was dissolved in tetrahydrofuran (30 mL), and sodium acetate (685 mg, 8.35 mmol) and palladium on carbon (100 mg, 10%) were added. The mixture was reacted at room temperature under a hydrogen atmosphere for 16 hours. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by HPLC (0.1% aqueous ammonia) and freeze-dried to give compound L054-4 (388 mg, 39.55% yield). LC-MS: [M-Boc-OH]+ = 236.05.

[0989] 69.5 Synthesis of Compound L054-5

[0990] At room temperature, L054-4 (280 mg, 0.79 mmol) was dissolved in dichloromethane (10 mL). The reaction solution was cooled to -70°C and diethylaminosulfur trifluoride (153 mg, 0.95 mmol) was added dropwise. After the addition was complete, the temperature was raised to room temperature and the reaction was allowed to react for 5 hours. The reaction solution was quenched with saturated aqueous sodium bicarbonate (10 mL) and extracted with dichloromethane (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound L054-5 (300 mg, crude product), which was used directly in the next reaction. LC-MS: [M-Boc+H] + =256.05.

[0991] 69.6 Synthesis of Compound L054-6

[0992] L054-5 (280 mg, 0.79 mmol) was dissolved in tetrahydrofuran (5 mL), methanol (2 mL), and water (2 mL). Lithium hydroxide monohydrate (99 mg, 2.36 mmol) was added and allowed to react at room temperature for 1 hour. The pH of the reaction solution was adjusted to 3-4 with dilute hydrochloric acid (1 N). The mixture was extracted with dichloromethane (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by high-performance liquid chromatography (0.1% aqueous ammonia) and freeze-dried to obtain compound L054-6 (89 mg, 33.09% yield). LC-MS: [M-Boc+H] + =242.05.

[0993] 69.7 Synthesis of Compound L054

[0994] The synthesis of compound L054 was carried out according to the synthesis method of compound L001-IS-01, except that L001-8 was replaced by L054-6. The crude product was purified by HPLC (0.1% ammonia solution) and freeze-dried to give compound L054 (12.3 mg, yield 21.54%).

[0995] 1H NMR (400MHz, DMSO-d6): δ8.13(d,J=8.4Hz,1H),7.93(s,1H),7.45–7.41(m,2H),7.26– 7.14(m,3H),6.22(d,J=8.0Hz,1H),5.81(s,2H),5.08(dd,J=14.4,7.6Hz,1H),4.25–4. 18(m,1H),3.50(d,J=11.6Hz,1H),3.05–3.01(m,1H),2.91–2.85(m,1H),2.76–2.67(m ,1H),2.65–2.56(m,1H),2.35–2.27(m,1H),2.14–1.64(m,5H),1.21(d,J=10.0Hz,3H). LC-MS:[M+H] + =444.05.

[0996] Example 70, (1R,2S,5S)-N-((R)-2-amino-6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)-3-((2R,4S)-4-(4-fluorobenzyl)pyrrolidine-2-carbonyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide (Compound L055-IS-01 or L055-IS-02 ) and (1S,2R,5R)-N-((R)-2-amino-6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)-3-((2R,4S)-4-(4-fluorobenzyl)pyrrolidine-2-carbonyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide (compound L055-IS-02 or L055-IS-01)

[0997]

[0998] 70.1 Synthesis of Compound L055-1

[0999] L001-IS-01-7 (27.0 g, 77.3 mmol) was dissolved in dichloromethane (300 mL), and a solution of hydrogen chloride in 1,4-dioxane (150 mL, 4 M) was added. The mixture was allowed to react at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was slurried with dichloromethane (100 mL) for 1 hour, filtered, and the filter cake was dried under vacuum to obtain compound L055-1 (18.0 g). LC-MS: [M+H] ...

Claims

1. A compound represented by formula (I'), its racemate, stereoisomer, tautomer or pharmaceutically acceptable salt thereof: in: Cy 3 Selected from R 1 、R 2 and R 3 are independently selected from H, halogen, -NH2, -OH, -NO2, -CN, C 1-6 Alkyl, C 1-6 aminoalkyl or C 1-6 alkoxy; X is N; Y is selected from -CH2-, -C(C 1-3 alkyl) 2-, -NH-, -O- or -S-; m is selected from 0, 1, 2 or 3; Each R is the same or different and is independently selected from H, halogen, C 1-6 Alkyl or C 1-6 alkoxy; p is selected from 0, 1, 2, 3 or 4; R 5 Selected from H, C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Haloalkyl or C 3-6 Cycloalkyl; R 5’ Selected from H or C 1-6 alkyl; or R 5 and R 5’ Together with the carbon atom to which they are attached, they form C 3-6 Cycloalkyl; R 6 Selected from H or C 1-6 alkyl; or R 5 and R 6 Together with the C and N atoms to which they are attached, they form a 3-12 membered heterocycloalkyl group which is unsubstituted or optionally substituted with 1, 2 or 3 R 5a replaced by; Each R 5a the same or different, independently selected from halogen, C 1-6 Alkyl, -OH, -NO2, -CN, oxo (=O), C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy; or R on the same carbon or on two adjacent carbons 5a Together with the carbon atom to which they are attached, they form C 3-6 Cycloalkyl, the C 3-6 Cycloalkyl is unsubstituted or optionally substituted with 1, 2 or 3 halogens; Cy 1 Selected from unsubstituted or substituted with 1 or 2 R 7 Substituted from the following: tetrahydropyrrolyl, 2,5-dihydro-1H-pyrrolyl, pyrrolyl, piperidinyl, 1,2,3,6-tetrahydropyridinyl, 1,2,5,6-tetrahydropyridinyl, piperazinyl, 4-azaspiro[2.5]octanyl, 1,2-dihydropyridinyl or 1,4-dihydropyrazinyl; Each R 7 The same or different, independently selected from H, oxo (=O), halogen or C 1-6 alkyl; L is absent or selected from -C(R a )(R b )-,R a and R b The same or different, independently selected from H, halogen or C 1-6 Alkyl, or R a and R b Together with the carbon atom to which they are attached, they form C 3-6 Cycloalkyl; Cy 2 is selected from unsubstituted or optionally substituted with 1, 2, 3 or 4 R 8 Substituted with the following groups: C 6-10 aryl, 5-9 membered heteroaryl or 6-11 membered heterocyclic group; Each R 8 the same or different, independently selected from -CN, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 3-10 Cycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl.

2. The compound according to claim 1, its racemate, stereoisomer, tautomer or pharmaceutically acceptable salt thereof, characterized in that: The compound represented by formula (I') has the structure represented by formula (I): in: R 1 、R 2 and R 3 are independently selected from H, halogen, -NH2, -OH, -NO2, -CN, C 1-6 Alkyl, C 1-6 aminoalkyl or C 1-6 alkoxy; X is selected from N; Y is selected from -CH2-, -C(C 1-3 alkyl) 2-, -NH-, -O- or -S-; m is selected from 0, 1, 2 or 3; Each R is the same or different and is independently selected from H, halogen, C 1-6 Alkyl or C 1-6 alkoxy; p is selected from 0, 1, 2, 3 or 4; R 5 Selected from H, C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Haloalkyl or C 3-6 Cycloalkyl; R 6 Selected from H or C 1-6 Alkyl, or R 5 and R 6 Together with the C and N atoms to which they are attached, they form a 3-12 membered heterocycloalkyl group which is unsubstituted or optionally substituted with 1, 2 or 3 R 5a replaced by; Each R 5a the same or different, independently selected from halogen, C 1-6 Alkyl, -OH, -NO2, -CN, oxo (=O), C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy; or R on the same carbon or on two adjacent carbons 5a Together with the carbon atom to which they are attached, they form C 3-6 Cycloalkyl, the C 3-6 Cycloalkyl is unsubstituted or optionally substituted with 1, 2 or 3 halogens; Cy 1 Selected from unsubstituted or substituted with 1 or 2 R 7 Substituted from the following: tetrahydropyrrolyl, 2,5-dihydro-1H-pyrrolyl, pyrrolyl, piperidinyl, 1,2,3,6-tetrahydropyridinyl, 1,2,5,6-tetrahydropyridinyl, piperazinyl, 4-azaspiro[2.5]octanyl, 1,2-dihydropyridinyl or 1,4-dihydropyrazinyl; Each R 7 The same or different, independently selected from H, oxo (=O), halogen or C 1-6 alkyl; L is absent or selected from -C(R a )(R b )-,R a and R b The same or different, independently selected from H, halogen or C 1-6 Alkyl, or R a and R b Together with the carbon atom to which they are attached, they form C 3-6 Cycloalkyl; Cy 2 is selected from unsubstituted or optionally substituted with 1, 2, 3 or 4 R 8 Substituted with the following groups: C 6-10 aryl, 5-9 membered heteroaryl or 6-11 membered heterocyclic group; Each R 8 the same or different, independently selected from -CN, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 3-10 Cycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl.

3. The compound according to claim 2, its racemate, stereoisomer, tautomer or pharmaceutically acceptable salt thereof, characterized in that: The compound represented by formula (I') has the structure represented by formula (II): Among them, R 5 Selected from C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Haloalkyl or C 3-6 Cycloalkyl; m, p, X, Y, R, R 1 、R 2 、R 3 、R 6 ,L,Cy 1 and Cy 2 The definitions of claim 2 apply independently of one another.

4. The compound according to claim 3, its racemate, stereoisomer, tautomer or pharmaceutically acceptable salt thereof, characterized in that: The compound represented by formula (I') has a structure represented by any one of the following formulas (Ia) to (I-j'): Among them, R 5 Selected from C 1-3 Alkyl, C 2-3 Alkynyl, C 1-3 Haloalkyl or C 3-4 Cycloalkyl; R 5a are independently selected from halogen, C 1-3 Alkyl, -OH, -NO2, -CN, oxo (=O), C 1-3 Halogenated alkyl, C 1-3 Alkoxy or C 1-3 Haloalkoxy; or R on the same carbon or on two adjacent carbons 5a Together with the carbon atom to which they are attached, they form C 3-6 Cycloalkyl, the C 3-6 Cycloalkyl is unsubstituted or optionally substituted with 1, 2 or 3 halogens; n is 0, 1, 2 or 3; m, X, R 1 、R 2 、R 3 、R 7 , L and Cy 2 The definitions of claim 2 apply independently of one another.

5. The compound according to claim 3, its racemate, stereoisomer, tautomer or pharmaceutically acceptable salt thereof, characterized in that: The compound represented by formula (I') has a structure represented by any one of the following formulas (Il) to (I-u'): Among them, R 5 Selected from C 1-3 Alkyl, C 2-3 Alkynyl, C 1-3 Haloalkyl or C 3-4 Cycloalkyl; R 5a are independently selected from halogen, C 1-3 Alkyl, -OH, -NO2, -CN, oxo (=O), C 1-3 Halogenated alkyl, C 1-3 Alkoxy or C 1-3 Haloalkoxy; or R on the same carbon or on two adjacent carbons 5a Together with the carbon atom to which they are attached, they form C 3-6 Cycloalkyl, the C 3-6 Cycloalkyl is unsubstituted or optionally substituted with 1, 2 or 3 halogens; n is 0, 1, 2 or 3; m, X, R 1 、R 2 、R 3 、R 7 , L and Cy 2 The definitions of claim 2 apply independently of one another.

6. The compound according to claim 3, its racemate, stereoisomer, tautomer or pharmaceutically acceptable salt thereof, characterized in that: The compound represented by formula (I') has a structure represented by any one of the following formulas (Iv) to (I-z'): Among them, R 5 is selected from methyl, ethyl, ethynyl, propynyl, -CH2F, -CHF2, -CF3 or cyclopropyl; R 5a are independently selected from halogen, methyl, ethyl, -CH2F, -CHF2, -CF3 or methoxy; or R on the same carbon or on two adjacent carbons 5a Together with the carbon atoms to which they are attached, they form a cyclopropyl or cyclobutyl group, said cyclopropyl and cyclobutyl groups being unsubstituted or optionally substituted with 1, 2 or 3 halogens; n is 0, 1, 2 or 3; m, X, R 1 、R 2 、R 3 、R 7 , L and Cy 2 The definitions of claim 2 apply independently of one another.

7. The compound according to claim 1, its racemate, stereoisomer, tautomer or pharmaceutically acceptable salt thereof, characterized in that: Cy 3 Select from the following structures:

8. The compound according to claim 1, its racemate, stereoisomer, tautomer or pharmaceutically acceptable salt thereof, characterized in that: Cy 3 Select from the following structures:

9. The compound according to claim 1, its racemate, stereoisomer, tautomer or pharmaceutically acceptable salt thereof, characterized in that: R 5 Selected from H, C 1-3 Alkyl, C 2-3 Alkynyl, C 1-3 Haloalkyl or C 3-4 Cycloalkyl; R 5’ Selected from H or C 1-3 alkyl; or R 5 and R 5’ Together with the carbon atom to which they are attached, they form C 3-4 Cycloalkyl.

10. The compound according to claim 1, its racemate, stereoisomer, tautomer or pharmaceutically acceptable salt thereof, characterized in that: R 5 is selected from H, methyl, ethyl, ethynyl, propynyl, -CH2F, -CHF2, -CF3 or cyclopropyl; R 5’ Selected from H, methyl or ethyl; or R 5 and R 5’ Together with the carbon atom to which they are attached they form a cyclopropyl group.

11. The compound according to any one of claims 1 to 10, its racemate, stereoisomer, tautomer or pharmaceutically acceptable salt thereof, characterized in that: R 1 、R 2 and R 3 are independently selected from H, F, Cl, Br, -NH2, -OH, -CN, methyl, ethyl, -CH2NH2 or methoxy; X is selected from N; Y is selected from -CH2-, -C(CH3)2-, -NH- or -O-; m is selected from 0, 1 or 2; and / or Each R is the same or different and is independently selected from H, halogen, C 1-3 Alkyl or C 1-3 Alkoxy; p is selected from 0, 1 or 2.

12. The compound according to any one of claims 1 to 10, its racemate, stereoisomer, tautomer or pharmaceutically acceptable salt thereof, characterized in that: R 6 is selected from H, methyl or ethyl; or, R 5 and R 6 Together with the C and N atoms to which they are attached, they form a 4-, 5- or 6-membered heterocycloalkyl group which is unsubstituted or optionally substituted with 1, 2 or 3 R 5a Replaced by; R 5a independently selected from F, Cl, Br, methyl or ethyl; or R on the same carbon or on two adjacent carbons 5a Together with the carbon atom to which they are attached they form a cyclopropyl or cyclobutyl group, said cyclopropyl and cyclobutyl groups being unsubstituted or optionally substituted with 1, 2 or 3 halogens.

13. The compound according to any one of claims 1 to 10, its racemate, stereoisomer, tautomer or pharmaceutically acceptable salt thereof, characterized in that: R 5 and R 6 Together with the C and N atoms to which they are attached, they form the following structure:

14. The compound according to any one of claims 1 to 10, its racemate, stereoisomer, tautomer or pharmaceutically acceptable salt thereof, characterized in that: R 5 and R 6 Together with the C and N atoms to which they are attached, they form the following structure:

15. The compound according to any one of claims 1 to 10, its racemate, stereoisomer, tautomer or pharmaceutically acceptable salt thereof, characterized in that: L is absent or selected from -CH2-, -CH(CH3)-, -CF2- or 16. The compound according to any one of claims 1 to 10, its racemate, stereoisomer, tautomer or pharmaceutically acceptable salt thereof, characterized in that: Each R 7 are the same or different and are independently selected from H, oxo (=O), F, Cl or -CH3.

17. The compound according to any one of claims 1 to 10, its racemate, stereoisomer, tautomer or pharmaceutically acceptable salt thereof, characterized in that: Cy 1 Select from the following structures:

18. The compound according to any one of claims 1 to 10, its racemate, stereoisomer, tautomer or pharmaceutically acceptable salt thereof, characterized in that: Cy 1 Select from the following structures:

19. The compound according to any one of claims 1 to 10, its racemate, stereoisomer, tautomer or pharmaceutically acceptable salt thereof, characterized in that: Cy 2 is selected from unsubstituted or optionally substituted with 1, 2, 3 or 4 R 8 Substituted with the following groups: C 6-10 Aryl or 5-9 membered heteroaryl; each R 8 are the same or different and are independently selected from -CN, F, Br, Cl, -CH2F, -CHF2, -CF3, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, methoxy, ethoxy, phenyl, pyridyl or trifluoromethoxy.

20. The compound according to any one of claims 1 to 10, its racemate, stereoisomer, tautomer or pharmaceutically acceptable salt thereof, characterized in that: Cy 2 Selected from unsubstituted or substituted with 1, 2, 3 or 4 R 8 Substituted from the following groups: phenyl, naphthyl, pyrrolyl, pyridyl, benzothiazolyl, piperidinyl; each R 8 are the same or different and are independently selected from -CN, F, Br, Cl, -CH2F, -CHF2, -CF3, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, methoxy, ethoxy, phenyl, pyridyl or trifluoromethoxy.

21. The compound according to any one of claims 1 to 10, its racemate, stereoisomer, tautomer or pharmaceutically acceptable salt thereof, characterized in that: Cy 2 Select from the following structures:

22. The compound according to claim 1, its racemate, stereoisomer, tautomer or pharmaceutically acceptable salt thereof, characterized in that: Cy 3 Select from the following structures: R 1 、R 2 and R 3 independently selected from H, F, Cl, Br, -NH2, -OH, -CN, C 1-3 Alkyl or C 1-3 aminoalkyl; Y is selected from -CH2-, -C(CH3)2-, -NH- or -O-; m is selected from 0, 1 or 2; Each R is the same or different and is independently selected from H, halogen or C 1-3 Alkyl; p is selected from 0, 1 or 2; R 5 Selected from H, C 1-3 Alkyl, C 2-3 Alkynyl, C 1-3 Haloalkyl or C 3-4 Cycloalkyl; R 5’ Selected from H or C 1-3 alkyl; or R 5 and R 5’ Together with the carbon atom to which they are attached, they form C 3-4 Cycloalkyl; R 6 Selected from H or C 1-3 alkyl; Or, R 5 and R 6 Together with the C and N atoms to which they are attached, they form a 4-, 5- or 6-membered heterocycloalkyl group which is unsubstituted or optionally substituted with 1, 2 or 3 R 5a Replaced by; R 5a independently selected from F, Cl, Br, methyl or ethyl; or R on the same carbon or on two adjacent carbons 5a Together with the carbon atom to which they are attached, they form cyclopropyl or cyclobutyl, said cyclopropyl and cyclobutyl being unsubstituted or optionally substituted with 1, 2 or 3 halogens; L is absent or selected from -C(R a )(R b )-,R a and R b are independently selected from H, halogen or C 1-3 Alkyl, or R a and R b Together with the carbon atom to which they are attached, they form a cyclopropyl group; Cy 1 Selected from unsubstituted or substituted with 1 or 2 R 7 Substituted from the following groups: tetrahydropyrrolyl, 2,5-dihydro-1H-pyrrolyl, pyrrolyl, piperidinyl, 1,2,3,6-tetrahydropyridinyl, 1,2,5,6-tetrahydropyridinyl, piperazinyl, 4-azaspiro[2.5]octanyl, 1,2-dihydropyridinyl or 1,4-dihydropyrazinyl; each R 7 are the same or different and are independently selected from H, oxo (=O), F or Cl; Cy 2 Selected from unsubstituted or substituted with 1, 2, 3 or 4 R 8 Substituted from the following groups: phenyl, naphthyl, pyrrolyl, pyridyl, benzothiazolyl, piperidinyl, 6-azaspiro[2.5]octyl, 7-azaspiro[3.5]nonyl, 8-azaspiro[4.5]decane or 3-azaspiro[5.5]undecyl; Each R 8 are the same or different and are independently selected from -CN, F, Cl, -CH2F, -CHF2, CF3, methyl, ethyl, n-propyl, isopropyl, tert-butyl, methoxy, phenyl, pyridyl or trifluoromethoxy.

23. The compound according to claim 1, its racemate, stereoisomer, tautomer or pharmaceutically acceptable salt thereof, characterized in that: Cy 3 Select from the following structures: R 1 Selected from H, F, Cl, -NH2 or methyl; R 2 Selected from H, F, Cl, -CN or methyl; R 3 Selected from H, F, -NH2, -OH, -CH2NH2 or methoxy; Y is selected from -CH2-, -C(CH3)2-, -NH- or -O-; m is 1 or 2; R is selected from H, methyl or ethyl; R 5 is selected from H, methyl, ethyl, ethynyl, propynyl, -CH2F, -CHF2, -CF3 or cyclopropyl; R 5’ Selected from H, methyl or ethyl; or R 5 and R 5’ Together with the carbon atom to which they are attached, they form a cyclopropyl group; R 6 Selected from H; Or, R 5 and R 6 Together with the C and N atoms to which they are attached, they form the following structure:

24. The compound according to any one of claims 1 to 10, its racemate, stereoisomer, tautomer or pharmaceutically acceptable salt thereof, characterized in that: The compound is selected from the structures shown below:

25. The compound according to any one of claims 1 to 10, its racemate, stereoisomer, tautomer or pharmaceutically acceptable salt thereof, characterized in that: The compound is selected from the structures shown below:

26. A method for preparing the compound according to any one of claims 1 to 25, comprising the following steps: Compound I-A' and compound I-B' undergo condensation reaction to generate compound I-1', and then compound I-1' is deprotected to obtain a compound represented by formula (I'); or Compound I-C' undergoes a condensation reaction with compound I-D' to generate compound I-1', and then compound I-1' is deprotected to obtain a compound represented by formula (I'); Among them, R 5 、R 5’ 、R 6 ,L,Cy 1 、Cy 2 and Cy 3 Independently of each other, they have the definitions described in any one of claims 1 to 25; Cy is Cy 1 The active group in the reaction is protected by PG; PG is a protecting group.

27. The preparation method according to claim 26, characterized in that The preparation method comprises the following steps: Compound IA and compound IB undergo condensation reaction to generate compound I-1, and then compound I-1 is deprotected to obtain the compound represented by formula (I); or Compound IC and compound ID undergo condensation reaction to generate compound I-1, and then compound I-1 is deprotected to obtain the compound represented by formula (I); Among them, R 1 、R 2 、R 3 、R 5 、R 6 , R, X, Y, L, Cy 1 、Cy 2 , m and p are independently defined in any one of claims 1 to 25; Cy is Cy 1 The active group in the reaction is protected by PG; PG is an amino protecting group.

28. The preparation method according to claim 26 or 27, characterized in that PG is tert-butyloxycarbonyl.

29. A compound represented by formula (IC), its racemate, stereoisomer or its hydrochloride: in, R 1 、R 2 、R 3 、R 5 、R 6 , R, X, m, and p independently have the definitions described in any one of claims 1-25.

30. The compound described below, its racemate, stereoisomer or its hydrochloride:

31. A pharmaceutical composition comprising a therapeutically effective amount of at least one of the compound according to any one of claims 1 to 25, its racemate, stereoisomer, tautomer or pharmaceutically acceptable salts thereof.

32. Use of the compound according to any one of claims 1 to 25, its racemate, stereoisomer, tautomer or pharmaceutically acceptable salts thereof, and the pharmaceutical composition according to claim 31 in the preparation of a medicament for preventing and / or treating diseases associated with the complement lectin pathway.

33. The use according to claim 32, characterized in that The disease associated with the complement lectin pathway is selected from thrombotic microangiopathy (TMA), kidney disease, respiratory distress syndrome caused by coronavirus infection, complications caused by type I or type II diabetes, central nervous system disorders or injuries, ischemia-reperfusion injury or autoimmune diseases.

34. The use according to claim 33, characterized in that The thrombotic microangiopathy is selected from atypical hemolytic syndrome (aHUS) or hematopoietic stem cell transplantation-associated TMA (HSCT-TMA).

35. The use according to claim 33, characterized in that The renal disease is selected from IgA nephropathy, mesangial proliferative glomerulonephritis, membranous glomerulonephritis, membranoproliferative glomerulonephritis, acute post-infectious glomerulonephritis, cryoglobulinemic glomerulonephritis, pauci-immune necrotizing crescentic glomerulonephritis or lupus nephritis.

36. The use according to claim 33, characterized in that The autoimmune disease is selected from systemic lupus erythematosus.

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