Pyrrolidine derivative, pharmaceutical composition and use thereof in medicine

Abstract

The present invention relates to a pyrrolidine derivative represented by general formula (I), a pharmaceutical composition and a use thereof in medicine.

Description

Pyrrolidine derivatives, pharmaceutical compositions and their use in medicine Technical Field

[0001] The present invention relates to a pyrrolidine derivative, a pharmaceutical composition and the medical application thereof. Background Art

[0002] Toll-like receptors (TLRs) are a class of molecular pattern recognition receptors that are widely distributed in different tissues. They monitor and recognize different pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), and play an important role in both innate and adaptive immunity.

[0003] TLRs belong to type I transmembrane proteins. So far, 13 TLR family members have been discovered, 10 of which exist in humans. TLR1, TLR2, TLR4, TLR5, TLR6, TLR10 and TLR11 are located on the cell membrane and can recognize lipids, lipoproteins and other substances of microorganisms; while TLR3, TLR7, TLR8 and TLR9 are located in intracellular vesicle structures (such as lysosomes, endosomes and endoplasmic reticulum) and recognize the nucleic acids of microorganisms.

[0004] TLR7 and TLR8 are most similar in sequence and function. Numerous studies have shown that activation of TLR7 / 8 can trigger type I interferon responses and various inflammatory reactions. In autoimmune disorders such as systemic lupus erythematosus (SLE), abnormal and persistent activation of TLR7 / 8 leads to worsening of the disease state. Therefore, the development of compounds with selective and potent inhibitory activity to inhibit overactivated immune responses by antagonizing TLR7 / 8 is expected to become a new approach for treating autoimmune diseases.

[0005] Summary of the Invention

[0006] The purpose of the present invention is to provide a new pyrrolidine derivative or stereoisomer, a pharmaceutical composition thereof and use thereof in preparing autoimmune disease drugs.

[0007] One or more embodiments of the present invention provide a compound represented by general formula (I), or all stereoisomers, pharmaceutically acceptable salts or deuterated derivatives thereof:

[0008] in:

[0009] R2 is selected from C 1-6 Alkyl or C 3-10 Cycloalkyl, the C 1-6 Alkyl or C 3-10 The cycloalkyl group is optionally further substituted with one or more halogens;

[0010] R3 is selected from or R3 is optionally further represented by one or more selected from C 1-3 Halogenated alkyl, D, C 1-3 Alkyl, halogen, -C 1-3 Alkoxy, -OC 1-3 Substitution with a haloalkyl, cyano or -NO2 substituent;

[0011] R1 is selected from

[0012] And when R3 is selected from R1 is selected from When R2 is not -CF3;

[0013] R4 is selected from H, C 1-6 Alkyl, C 3-10 Cycloalkyl or halogen;

[0014] R5, R6, R7, R8, R9, R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 and R 17 are independently selected from H, C 1-6 Alkyl, halogen, 7-10 membered bridged ring or spiro ring, 3-10 membered monocyclic heterocycle, 4-7 membered monocyclic carbocycle, 2-6 membered heteroalkyl, alkynyl, -NH2, -C 1-3 Alkyl-NH2, -O-3-10 membered monocyclic heterocycle, -C 1-3 Alkoxy-3-10 membered monocyclic heterocycle, -NH-3-10 membered monocyclic heterocycle or -C 1-3 Alkyl-3-10 membered monocyclic heterocycle;

[0015] R5, R6, R7, R8, R9, R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 or R 17 are independently optionally further substituted or unsubstituted by one or more -NH-CHO, C 1-6 Alkyl, 2-6 membered heteroalkyl, -C 1-3 Substituted with alkyl-CO-NH2, =O, halogen, 3-10 membered cycloalkyl, hydroxyl or -NH2.

[0016] One or more embodiments of the present invention provide compounds, or all stereoisomers, pharmaceutically acceptable salts or deuterated derivatives thereof, wherein:

[0017] After replacement, R5, R6, R7, R8, R9, R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 or R 17 Further substituted by one or more selected from 3-10 membered carbocyclic alkyl, 3-10 membered heterocyclic alkyl, C 1-6 The substituent is substituted by alkyl, halogen or -N-(CH3)2.

[0018] One or more embodiments of the present invention provide compounds, or all stereoisomers, pharmaceutically acceptable salts or deuterated derivatives thereof, wherein:

[0019] R1 is selected from

[0020] R4 is selected from H, C 1-6 Alkyl or halogen;

[0021] R5, R6, R7, R8, R9, R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 and R 17 are independently selected from C 1-6 Alkyl, 2-6 membered heteroalkyl, alkynyl, -NH2, -C 1-3 Alkyl-NH2, -O-3-10 membered monocyclic heterocycle, -C 1-3 Alkoxy-3-10 membered monocyclic heterocycle, -NH-3-10 membered monocyclic heterocycle or -C 1-3 Alkyl-3-10 membered monocyclic heterocycle;

[0022] R5, R6, R7, R8, R9, R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 or R 17 are independently optionally further substituted or unsubstituted by one or more -NH-CHO, C 1-6 Alkyl, 2-6 membered heteroalkyl, -C1-3 Alkyl-CO-NH2, =O, halogen, 3-10 membered cycloalkyl, hydroxyl or -NH2 substitution;

[0023] After replacement, R5, R6, R7, R8, R9, R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 or R 17 Optionally further substituted by one or more selected from 3-10 membered carbocyclic alkyl, 3-10 membered heterocyclic alkyl, C 1-6 The substituent is substituted by alkyl, halogen or -N-(CH3)2.

[0024] One or more embodiments of the present invention provide compounds, or all stereoisomers, pharmaceutically acceptable salts or deuterated derivatives thereof, wherein:

[0025] R5 and R7 are independently selected from C 1-6 Alkyl, 2-6 membered heteroalkyl, alkynyl, -NH2, -C 1-3 Alkyl-NH2, -O- 3-10 membered monocyclic heterocycle, -C 1-3 Alkoxy-3-10 membered monocyclic heterocycle, -NH-3-10 membered monocyclic heterocycle or -C 1-3 Alkyl-3-10 membered monocyclic heterocycle;

[0026] R5 and R7 are each independently optionally further substituted with one or more substituted or unsubstituted C 1-6 Alkyl, 2-6 membered heteroalkyl or -NH2 substituted;

[0027] The substituted R5 or R7 may be further replaced by one or more 3-10 membered heterocycloalkyl, C 1-6 The substituent is substituted with an alkyl group or -N-(CH3)2.

[0028] One or more embodiments of the present invention provide compounds, or all stereoisomers, pharmaceutically acceptable salts or deuterated derivatives thereof, wherein:

[0029] R1 is selected from

[0030] R4 is selected from H or halogen;

[0031] R5, R6, R7, R8, R9, R 10 、R 11 、R 12 、R 14 、R 15、R 16 and R 17 are independently selected from 7-8 membered bridged rings, 7-9 membered heterospiro rings, 4-6 membered monocyclic heterocycles or 6 membered monocyclic carbocycles;

[0032] R5, R6, R7, R8, R9, R 10 、R 11 、R 12 、R 14 、R 15 、R 16 or R 17 are independently optionally further substituted or unsubstituted by one or more -NH-CHO, C 1-6 Alkyl, hydroxyl, -C 1-3 Alkyl-CO-NH2, =O, halogen, or -NH2 substitution;

[0033] After replacement, R5, R6, R7, R8, R9, R 10 、R 11 、R 12 、R 14 、R 15 、R 16 or R 17 Further substituted by one or more selected from 3-5 membered carbocyclic alkyl, 5-6 membered heterocyclic alkyl or C 1-6 The alkyl group is substituted with a substituent.

[0034] One or more embodiments of the present invention provide compounds, or all stereoisomers, pharmaceutically acceptable salts or deuterated derivatives thereof, wherein:

[0035] R5 is selected from a 4-6 membered non-aromatic nitrogen-containing monocyclic heterocycle, a 6 membered non-aromatic monocyclic carbocycle, an 8 membered carbon bridged ring, a 7-8 membered nitrogen-containing heterobridged ring or a 7-9 membered nitrogen-containing heterospirocycle;

[0036] The 4-6 membered non-aromatic nitrogen-containing monocyclic heterocycle is optionally further substituted by one or more selected from halogen, C 1-3 Alkyl, -C 1-3 Alkyl-CO-NH2, =O, -NH2, hydroxyl and C substituted by cyclopropyl 1-3 substituted by an alkyl substituent;

[0037] The 8-membered carbon bridge ring is optionally further substituted by one or more substituents selected from -NH2 or -NH-CHO, and the -NH2 or -NH-CHO is optionally further substituted by C 1-3 Alkyl or 6-membered nitrogen-containing heterocyclic group substitution;

[0038] The 7-8 membered nitrogen-containing heterobridged ring is optionally further substituted by one or more C 1-3 Alkyl substitution;

[0039] The 7-9 membered nitrogen-containing spirocyclic ring is optionally further substituted by one or more selected from -C 1-3 Alkyl-CO-NH2, C 1-3 Alkyl and cyclopropyl-substituted C 1-3 substituted by an alkyl substituent;

[0040] The 6-membered non-aromatic monocyclic carbocycle is optionally further substituted with one or more -NH2 or N-(CH3)2;

[0041] R6, R7, R8, R9, R 10 、R 11 、R 12 、R 14 、R 15 and R 16 are selected from 6-membered non-aromatic nitrogen-containing monocyclic heterocycles, wherein the 6-membered non-aromatic nitrogen-containing monocyclic heterocycles are optionally further replaced by one or more C 1-3 Alkyl substitution;

[0042] One or more embodiments of the present invention provide a compound, or all stereoisomers, pharmaceutically acceptable salts, or deuterated derivatives thereof, wherein the compound is selected from one of the following structures:

[0043] One or more embodiments of the present application provide a compound represented by general formula (I-1), or all stereoisomers, pharmaceutically acceptable salts or deuterated derivatives thereof:

[0044] in:

[0045] R2 is selected from C 1-6 Alkyl, which is optionally further substituted with 1 to more halogens;

[0046] R3 is selected from When R1 is selected from

[0047] R3 is selected from When R1 is selected from

[0048] R4 is selected from C 1-6 Alkyl or halogen.

[0049] One or more embodiments of the present application provide a compound represented by general formula (I-2), or all stereoisomers, pharmaceutically acceptable salts or deuterated derivatives thereof:

[0050] in:

[0051] R2 is selected from C 1-6 Alkyl, which is optionally further substituted with 1 to more halogens;

[0052] R3 is selected from

[0053] R1 is selected from

[0054] And when R3 is selected from R1 is selected from When R2 is not -CF3;

[0055] R4 is selected from C 1-6 Alkyl or halogen.

[0056] One or more embodiments of the present application provide a compound represented by general formula (I-3), or all stereoisomers, pharmaceutically acceptable salts or deuterated derivatives thereof:

[0057] in:

[0058] R2 is selected from C 1-6 Alkyl, which is optionally further substituted with 1 to more halogens;

[0059] R3 is selected from

[0060] R1 is selected from

[0061] And when R3 is selected from R1 is selected from When R2 is not -CF3;

[0062] R4 is selected from C 1-6 Alkyl or halogen;

[0063] R5 is selected from a 7-10 membered bridged ring or spiro ring, and R5 contains at least one N.

[0064] In one or more embodiments, R5 is selected from:

[0065] The attachment site of R5 is any attachable position thereon.

[0066] One or more embodiments of the present application provide a compound represented by general formula (I-4), or all stereoisomers, pharmaceutically acceptable salts or deuterated derivatives thereof:

[0067] in:

[0068] R2 is selected from C 1-6 Alkyl, which is optionally further substituted with 1 to more halogens;

[0069] R3 is selected from

[0070] R1 is selected from

[0071] And when R3 is selected from R1 is selected from When R2 is not -CF3;

[0072] R4 is selected from C 1-6 Alkyl or halogen;

[0073] R5 is selected from a 7-10 membered bridged ring or spiro ring, and R5 contains at least one N.

[0074] In one or more embodiments, R5 is selected from:

[0075] The attachment site of R5 is any attachable position thereon.

[0076] One or more embodiments of the present application provide a compound represented by general formula (I-5), or all stereoisomers, pharmaceutically acceptable salts or deuterated derivatives thereof:

[0077] in:

[0078] R2 is selected from C 1-6 Alkyl or C 3-10 Cycloalkyl, the C 1-6 Alkyl or C 3-10 The cycloalkyl group is optionally further substituted with one or more halogens;

[0079] R3 is selected from R3 is optionally substituted with one or more D;

[0080] R1 is selected from

[0081] And when R3 is selected from R1 is selected from When R2 is not -CF3;

[0082] R4 is selected from H, C 1-6 Alkyl, C 3-10 Cycloalkyl or halogen;

[0083] R5, R6, R7, R8, R9, R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 and R 17 are independently selected from H, C 1-6 Alkyl, halogen, 7-10 membered bridged ring or spiro ring, 3-10 membered monocyclic heterocycle, 4-7 membered monocyclic carbocycle, 2-6 membered heteroalkyl, alkynyl, -NH2, -O-3-10 membered monocyclic heterocycle, -NH-3-10 membered monocyclic heterocycle or -C 1-3 Alkyl-3-10 membered monocyclic heterocycle;

[0084] R5, R6, R7, R8, R9, R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 or R 17 are independently optionally further substituted or unsubstituted by one or more C 1-6 Alkyl, 2-6 membered heteroalkyl, -C 1-3 Substituted with alkyl-CO-NH2, =O, halogen, 3-10 membered cycloalkyl or -NH2.

[0085] One or more embodiments of the present application provide a compound represented by general formula (I-6), or all stereoisomers, pharmaceutically acceptable salts or deuterated derivatives thereof:

[0086] in:

[0087] R2 is selected from C 1-6 Alkyl or C 3-10 Cycloalkyl, the C 1-6 Alkyl or C 3-10 The cycloalkyl group is optionally further substituted with one or more halogens;

[0088] R3 is selected from R3 is optionally substituted with one or more D;

[0089] R1 is selected from

[0090] And when R3 is selected from R1 is selected from When R2 is not -CF3;

[0091] R4 is selected from H, C 1-6 Alkyl, C 3-10 Cycloalkyl or halogen;

[0092] R5, R6, R7, R8, R9, R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 and R 17 are independently selected from H, C 1-6 Alkyl, halogen, 7-10 membered bridged ring or spiro ring, 3-10 membered monocyclic heterocycle, 4-7 membered monocyclic carbocycle, 2-6 membered heteroalkyl, alkynyl, -NH2, -C 1-3 Alkyl-NH2, -O-3-10 membered monocyclic heterocycle, -C 1-3 Alkoxy-3-10 membered monocyclic heterocycle, -NH-3-10 membered monocyclic heterocycle or -C 1-3 Alkyl-3-10 membered monocyclic heterocycle;

[0093] R5, R6, R7, R8, R9, R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 or R 17 are independently optionally further substituted or unsubstituted by one or more C 1-6 Alkyl, 2-6 membered heteroalkyl, -C 1-3 Substituted with alkyl-CO-NH2, =O, halogen, 3-10 membered cycloalkyl or -NH2.

[0094] In one or more embodiments, the substituted R5, R6, R7, R8, R9, R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 or R 17 further substituted by one or more selected from 3-10 membered heterocycloalkyl, C 1-6The substituent is substituted by alkyl, halogen or -N-(CH3)2.

[0095] One or more embodiments of the present application provide a compound represented by general formula (I-7), or all stereoisomers, pharmaceutically acceptable salts or deuterated derivatives thereof:

[0096] in:

[0097] R2 is selected from C 1-6 Alkyl or C 3-10 Cycloalkyl, the C 1-6 Alkyl or C 3-10 The cycloalkyl group is optionally further substituted with one or more halogens;

[0098] R3 is selected from R3 is optionally further replaced by one or more selected from D, C 1-3 Alkyl, halogen, -C 1-3 Alkoxy, -OC 1-3 Substitution with a haloalkyl, cyano or -NO2 substituent;

[0099] R1 is selected from

[0100] And when R3 is selected from R1 is selected from When R2 is not -CF3;

[0101] R4 is selected from H, C 1-6 Alkyl, C 3-10 Cycloalkyl or halogen;

[0102] R5, R6, R7, R8, R9, R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 and R 17 are independently selected from H, C 1-6 Alkyl, halogen, 7-10 membered bridged ring or spiro ring, 3-10 membered monocyclic heterocycle, 4-7 membered monocyclic carbocycle, 2-6 membered heteroalkyl, alkynyl, -NH2, -C 1-3 Alkyl-NH2, -O-3-10 membered monocyclic heterocycle, -C 1-3 Alkoxy-3-10 membered monocyclic heterocycle, -NH-3-10 membered monocyclic heterocycle or -C 1-3 Alkyl-3-10 membered monocyclic heterocycle;

[0103] R5, R6, R7, R8, R9, R10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 or R 17 are independently optionally further substituted or unsubstituted by one or more C 1-6 Alkyl, 2-6 membered heteroalkyl, -C 1-3 Substituted with alkyl-CO-NH2, =O, halogen, 3-10 membered cycloalkyl or -NH2.

[0104] In one or more embodiments, the substituted R5, R6, R7, R8, R9, R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 or R 17 Further substituted by one or more selected from 3-10 membered carbocyclic alkyl, 3-10 membered heterocyclic alkyl, C 1-6 The substituent is substituted by alkyl, halogen or -N-(CH3)2.

[0105] One or more embodiments of the present application provide a compound represented by general formula (I-8), or all stereoisomers, pharmaceutically acceptable salts or deuterated derivatives thereof:

[0106] in:

[0107] R2 is selected from C 1-6 Alkyl or C 3-10 Cycloalkyl, the C 1-6 Alkyl or C 3-10 The cycloalkyl group is optionally further substituted with one or more halogens;

[0108] R3 is selected from R3 is optionally further represented by one or more selected from C 1-3 Halogenated alkyl, D, C 1-3 Alkyl, halogen, -C 1-3 Alkoxy, -OC 1-3 Substitution with a haloalkyl, cyano or -NO2 substituent;

[0109] R1 is selected from

[0110] And when R3 is selected from R1 is selected from When R2 is not -CF3;

[0111] R4 is selected from H, C 1-6 Alkyl, C 3-10 Cycloalkyl or halogen;

[0112] R5, R6, R7, R8, R9, R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 and R 17 are independently selected from H, C 1-6 Alkyl, halogen, 7-10 membered bridged ring or spiro ring, 3-10 membered monocyclic heterocycle, 4-7 membered monocyclic carbocycle, 2-6 membered heteroalkyl, alkynyl, -NH2, -C 1-3 Alkyl-NH2, -O-3-10 membered monocyclic heterocycle, -C 1-3 Alkoxy-3-10 membered monocyclic heterocycle, -NH-3-10 membered monocyclic heterocycle or -C 1-3 Alkyl-3-10 membered monocyclic heterocycle;

[0113] R5, R6, R7, R8, R9, R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 or R 17 are independently optionally further substituted or unsubstituted by one or more -NH-CHO, C 1-6 Alkyl, 2-6 membered heteroalkyl, -C 1-3 Substituted with alkyl-CO-NH2, =O, halogen, 3-10 membered cycloalkyl or -NH2.

[0114] In one or more embodiments, the substituted R5, R6, R7, R8, R9, R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 or R 17 Further substituted by one or more selected from 3-10 membered carbocyclic alkyl, 3-10 membered heterocyclic alkyl, C 1-6 The substituent is substituted by alkyl, halogen or -N-(CH3)2.

[0115] One or more embodiments of the present application provide a compound represented by general formula (I-9), or all stereoisomers, pharmaceutically acceptable salts or deuterated derivatives thereof:

[0116] in:

[0117] R2 is selected from C 1-6 Alkyl or C 3-10 Cycloalkyl, the C 1-6 Alkyl or C 3-10 The cycloalkyl group is optionally further substituted with one or more halogens;

[0118] R3 is selected from R3 is optionally further represented by one or more selected from C 1-3 Halogenated alkyl, D, C 1-3 Alkyl, halogen, -C 1-3 Alkoxy, -OC 1-3 Substitution with a haloalkyl, cyano or -NO2 substituent;

[0119] R1 is selected from

[0120] And when R3 is selected from R1 is selected from When R2 is not -CF3;

[0121] R4 is selected from H, C 1-6 Alkyl, C 3-10 Cycloalkyl or halogen;

[0122] R5, R6, R7, R8, R9, R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 and R 17 are independently selected from H, C 1-6 Alkyl, halogen, 7-10 membered bridged ring or spiro ring, 3-10 membered monocyclic heterocycle, 4-7 membered monocyclic carbocycle, 2-6 membered heteroalkyl, alkynyl, -NH2, -C 1-3 Alkyl-NH2, -O-3-10 membered monocyclic heterocycle, -C 1-3 Alkoxy-3-10 membered monocyclic heterocycle, -NH-3-10 membered monocyclic heterocycle or -C 1-3 Alkyl-3-10 membered monocyclic heterocycle;

[0123] R5, R6, R7, R8, R9, R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R16 or R 17 are independently optionally further substituted or unsubstituted by one or more -NH-CHO, C 1-6 Alkyl, 2-6 membered heteroalkyl, -C 1-3 Substituted with alkyl-CO-NH2, =O, halogen, 3-10 membered cycloalkyl or -NH2.

[0124] In one or more embodiments, the substituted R5, R6, R7, R8, R9, R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 or R 17 Further substituted by one or more selected from 3-10 membered carbocyclic alkyl, 3-10 membered heterocyclic alkyl, C 1-6 The substituent is substituted by alkyl, halogen or -N-(CH3)2.

[0125] One or more embodiments of the present application provide a compound represented by general formula (I-10), or all stereoisomers, pharmaceutically acceptable salts, or deuterated derivatives thereof:

[0126] in:

[0127] R2 is selected from C 1-6 Alkyl or C 3-10 Cycloalkyl, the C 1-6 Alkyl or C 3-10 The cycloalkyl group is optionally further substituted with one or more halogens;

[0128] R3 is selected from R3 is optionally further represented by one or more selected from C 1-3 Halogenated alkyl, D, C 1-3 Alkyl, halogen, -C 1-3 Alkoxy, -OC 1-3 Substitution with a haloalkyl, cyano or -NO2 substituent;

[0129] R1 is selected from

[0130] And when R3 is selected from R1 is selected from When R2 is not -CF3;

[0131] R4 is selected from H, C 1-6 Alkyl, C 3-10 Cycloalkyl or halogen;

[0132] R5, R6, R7, R8, R9, R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 and R 17 are independently selected from H, C 1-6 Alkyl, halogen, 7-10 membered bridged ring or spiro ring, 3-10 membered monocyclic heterocycle, 4-7 membered monocyclic carbocycle, 2-6 membered heteroalkyl, alkynyl, -NH2, -C 1-3 Alkyl-NH2, -O-3-10 membered monocyclic heterocycle, -C 1-3 Alkoxy-3-10 membered monocyclic heterocycle, -NH-3-10 membered monocyclic heterocycle or -C 1-3 Alkyl-3-10 membered monocyclic heterocycle;

[0133] R5, R6, R7, R8, R9, R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 or R 17 are independently optionally further substituted or unsubstituted by one or more -NH-CHO, C 1-6 Alkyl, 2-6 membered heteroalkyl, -C 1-3 Substituted with alkyl-CO-NH2, =O, halogen, 3-10 membered cycloalkyl, hydroxyl or -NH2.

[0134] In one or more embodiments, the substituted R5, R6, R7, R8, R9, R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 or R 17 Further substituted by one or more selected from 3-10 membered carbocyclic alkyl, 3-10 membered heterocyclic alkyl, C 1-6 The substituent is substituted by alkyl, halogen or -N-(CH3)2.

[0135] One or more embodiments of the present invention provide a compound represented by general formula (II), or all stereoisomers, pharmaceutically acceptable salts or deuterated derivatives thereof:

[0136] in:

[0137] R2 is selected from C1-6 Alkyl, which is optionally further substituted with 1 to more halogens;

[0138] R3 is selected from

[0139] R1 is selected from

[0140] And when R3 is selected from R1 is selected from When R2 is not -CF3;

[0141] R4 is selected from C 1-6 Alkyl or halogen;

[0142] R5 is selected from a 7-10 membered bridged ring or spiro ring, and R5 contains at least one N.

[0143] R5 is selected from:

[0144] The attachment site of R5 is any attachable position thereon.

[0145] One or more embodiments of the present invention provide a pharmaceutical composition comprising:

[0146] Any of the above compounds or their stereoisomers, pharmaceutically acceptable salts or deuterated derivatives;

[0147] optionally one or more other active ingredients; and

[0148] Pharmaceutically acceptable carriers and / or excipients.

[0149] One or more embodiments of the present invention provide the use of the compound of the present application or its stereoisomer, pharmaceutically acceptable salt or deuterated substance, or the above-mentioned pharmaceutical composition of the present application in the preparation of a medicament for treating and / or preventing autoimmune diseases.

[0150] One or more embodiments of the present application provide the compound of the present application or its stereoisomer, pharmaceutically acceptable salt or deuterated substance, and the above-mentioned pharmaceutical composition of the present application, which are used as drugs.

[0151] One or more embodiments of the present application provide the compound of the present application or its stereoisomer, pharmaceutically acceptable salt or deuterated substance, and the above-mentioned pharmaceutical composition of the present application, which are used for treating and / or preventing autoimmune diseases.

[0152] One or more embodiments of the present application provide a method for treating and / or preventing autoimmune diseases, which comprises administering to a subject in need thereof a therapeutically and / or preventatively effective amount of a compound of the present application or its stereoisomer, pharmaceutically acceptable salt or deuterated substance, or the above-mentioned pharmaceutical composition of the present application.

[0153] Unless stated otherwise, the terms used in the specification and claims have the following meanings.

[0154] The carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I involved in the groups and compounds of the present invention include their isotopes, and the carbon, hydrogen, oxygen, sulfur or nitrogen involved in the groups and compounds of the present invention are optionally further replaced by one or more of their corresponding isotopes, wherein the isotopes of carbon include 12 C. 13 C and 14 C, hydrogen isotopes include protium (H), deuterium (D, also called heavy hydrogen), tritium (T, also called super tritium), oxygen isotopes include 16 O. 17 O and 18 O, sulfur isotopes include 32 S. 33 S. 34 S and 36 S, nitrogen isotopes include 14 N and 15 N, fluorine isotopes include 17 F and 19 F, chlorine isotopes include 35 Cl and 37 Isotopes of Cl, bromine include 79 Br and 81 Br.

[0155] "Alkyl" refers to a straight-chain or branched saturated aliphatic hydrocarbon group of 1 to 20 carbon atoms, preferably an alkyl group of 1 to 8 (e.g., 1, 2, 3, 4, 5, 6, 7, 8) carbon atoms, more preferably an alkyl group of 1 to 6 carbon atoms, and even more preferably an alkyl group of 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl and various branched isomers thereof; when an alkyl group is substituted, it may optionally be further substituted by one or more substituents. "Alkoxy" refers to a group formed by replacing at least one carbon atom in an alkyl group with an oxygen atom. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexyl, cyclopropyloxy and cyclobutyloxy. The definition of alkyl is the same as that of "alkyl" described above.

[0156] "Alkenyl" refers to a straight-chain or branched unsaturated aliphatic hydrocarbon group consisting of 2 to 20 carbon atoms and containing 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) carbon-carbon double bonds, preferably an alkenyl group of 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) carbon atoms, more preferably an alkenyl group of 2 to 8 carbon atoms, and further preferably an alkenyl group of 2 to 6 carbon atoms. Non-limiting examples include ethenyl, propen-2-yl, buten-2-yl, buten-2-yl, penten-2-yl, penten-4-yl, hexen-2-yl, hexen-3-yl, hepten-2-yl, hepten-3-yl, hepten-4-yl, octen-3-yl, nonen-3-yl, decen-4-yl, and undecen-3-yl. The alkenyl group may be optionally further substituted by one or more substituents.

[0157] "Alkynyl" refers to a straight-chain or branched unsaturated aliphatic hydrocarbon group consisting of 2 to 20 carbon atoms and containing 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) carbon-carbon triple bonds, preferably an alkynyl group of 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms, more preferably an alkynyl group of 2 to 8 carbon atoms, and even more preferably an alkynyl group of 2 to 6 carbon atoms. Non-limiting examples include ethynyl, propyn-1-yl, propyn-2-yl, butyn-1-yl, butyn-2-yl, butyn-3-yl, 3,3-dimethylbutyn-2-yl, pentyn-1-yl, pentyn-2-yl, hexyn-1-yl, 1-heptyn-1-yl, heptyn-3-yl, heptyn-4-yl, octyn-3-yl, nonyn-3-yl, decyn-4-yl, undecyne-3-yl, dodecyne-4-yl. The alkynyl group may optionally be further substituted with one or more substituents.

[0158] "Aryl" refers to a substituted or unsubstituted aromatic ring, which can be a 5-8 membered (e.g., 5, 6, 7, 8 membered) monocyclic ring, a 5-12 membered (e.g., 5, 6, 7, 8, 9, 10, 11, 12 membered) bicyclic ring, or a 10-15 membered (e.g., 10, 11, 12, 13, 14, 15 membered) tricyclic ring system, which can be a bridged ring or a spirocyclic ring, non-limiting examples of which include phenyl and naphthyl. The aryl group may optionally be further substituted with one or more substituents.

[0159] "Heteroaryl" refers to a substituted or unsubstituted aromatic ring, which can be a 3-8 membered (e.g., 3, 4, 5, 6, 7, 8 membered) monocyclic ring, a 5-12 membered (e.g., 5, 6, 7, 8, 9, 10, 11, 12 membered) bicyclic ring or a 10-15 membered (e.g., 10, 11, 12, 13, 14, 15 membered) tricyclic ring system, and contains 1 to 6 (e.g., 1, 2, 3, 4, 5, 6) heteroatoms selected from N, O or S, preferably a 5- to 8-membered heteroaryl group, and the 1 to 4 (e.g., 1, 2, 3, 4) N and S optionally substituted in the heteroaryl ring can be oxidized to various oxidation states. The heteroaryl group may be attached to a heteroatom or a carbon atom, and may be a bridged ring or a spirocyclic ring. Non-limiting examples include cyclic pyridyl, furyl, thienyl, pyranyl, pyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinylbenzimidazolyl, benzopyridinyl, and pyrrolopyridinyl. The heteroaryl group may be further substituted with one or more substituents.

[0160] "Carbocyclyl" or "carbocycle" refers to a saturated or unsaturated aromatic or non-aromatic ring. When it is an aromatic ring, its definition is the same as the definition of "aryl" above; when it is a non-aromatic ring, it can be a 3- to 10-membered (e.g., 3, 4, 5, 6, 7, 8, 9, 10-membered) monocyclic ring, a 4- to 12-membered (e.g., 4, 5, 6, 7, 8, 9, 10, 11, 12-membered) bicyclic ring or a 10- to 15-membered (e.g., 10, 11, 12, 13, 14, 15-membered) tricyclic ring system, which can be a bridged ring or a spirocyclic ring. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl-3-enyl, cyclohexyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, The "carbocyclyl" or "carbocycle" may be further substituted by one or more substituents.

[0161] "Heterocyclo(alkyl)" or "heterocycle" refers to a saturated or unsaturated aromatic heterocycle or non-aromatic heterocycle. When it is an aromatic heterocycle, its definition is the same as the above "heteroaryl"; when it is a non-aromatic heterocycle, it can be a 3-10 membered (e.g., 3, 4, 5, 6, 7, 8, 9, 10 membered) monocyclic ring, a 4-12 membered (e.g., 4, 5, 6, 7, 8, 9, 10, 11, 12 membered) bicyclic ring or a 10-15 membered (e.g., 10, 11, 12, 13, 14, 15 membered) tricyclic ring system, and contains 1 to 4 (e.g., 1, 2, 3, 4) heteroatoms selected from N, O or S, and is preferably a 3- to 8-membered heterocyclyl. The 1 to 4 (e.g., 1, 2, 3, 4) N, S optionally substituted in the ring of "heterocyclyl" or "heterocycle" can be oxidized to various oxidation states; "heterocyclyl" or "heterocycle" can be attached to a heteroatom or a carbon atom; "heterocyclyl" or "heterocycle" can be a bridged ring or a spirocycle. Non-limiting examples of "heterocyclyl" or "heterocycle" include oxirane, glycidyl, aziridine, oxetanyl, azetidinyl, thietanyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxhexacyclyl, azepanyl, oxetanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, pyridyl, piperidinyl, homopiperidinyl, furanyl, thiophene, thiophene, oxazepinyl, thiophene, pyridyl, piperidinyl, homopiperidinyl, furanyl, thiophene ... pyranyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, homopiperazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, 1,3-dithianyl, dihydrofuranyl, dithiolanyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, oxazolyl, benzopyridinyl, pyrrolopyridinyl, benzodihydrofuranyl, 2-pyrrolinyl, 3-pyrrolinyl, dihydroindole, 2H-pyranyl, 4H-pyranyl, dioxane, 1,3-dioxolane, pyrazolinyl, dithianyl, dithiolanyl, dihydrothienyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 1,2,3,4-tetrahydroisoquinolinyl, 3-azabicyclo[3 1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, azabicyclo[2.2.2]hexyl, 3H-indolylquinolizinyl, N-pyridylurea, 1,1-dioxothiomorpholinyl, azabicyclo[3.2.1]octanyl, azabicyclo[5.2.0]nonyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl and oxaspiro[3.3]heptanyl. The "heterocyclyl" or "heterocycle" may be further substituted with one or more substituents.

[0162] "Heterospirocycle" and "heterobridged ring" refer to structures in which a carbon atom on a spirocycle or a bridged ring is replaced by a heteroatom (eg, N, O, S, etc.).

[0163] "Cycloalkyl" refers to a saturated cyclic hydrocarbon group, which can be a 3-10 membered (e.g., 3, 4, 5, 6, 7, 8, 9, 10 membered) monocyclic ring, a 4-12 membered (e.g., 4, 5, 6, 7, 8, 9, 10, 11, 12 membered) bicyclic ring, or a 10-20 membered (e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 membered) polycyclic ring system (the polycyclic ring can, for example, contain a bridged ring or a spirocyclic ring), preferably having 3 to 10 carbon atoms, more preferably 3 to 8 carbon atoms. Non-limiting examples of "cycloalkyl" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,5-cyclooctadienyl, 1,4-cyclohexadienyl, and cycloheptatrienyl. When a cycloalkyl group is substituted, it may be optionally further substituted with one or more substituents.

[0164] "Heterocycloalkyl" refers to a substituted or unsubstituted saturated non-aromatic ring group, which can be a 3-8 membered (e.g., 3, 4, 5, 6, 7, 8 membered) monocyclic ring, a 4-12 membered (e.g., 4, 5, 6, 7, 8, 9, 10, 11, 12 membered) bicyclic ring, or a 10-15 membered (e.g., 10, 11, 12, 13, 14, 15 membered) tricyclic ring system, and contains 1, 2, or 3 heteroatoms selected from N, O, or S, preferably a 3- to 8-membered heterocyclic ring. The 1, 2, or 3 N or S atoms optionally substituted in the "heterocycloalkyl" ring can be oxidized to various oxidation states; the "heterocycloalkyl" can be attached to a heteroatom or a carbon atom; the "heterocycloalkyl" can be a bridged ring or a spirocyclic ring. Non-limiting examples of "heterocycloalkyl" include oxiranyl, aziridinyl, oxetanyl, azetidinyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxanyl, azepanyl, piperidinyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithianyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, azabicyclo[3.2.1]octanyl, azabicyclo[5.2.0]nonanyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl, and oxaspiro[3.3]heptanyl.

[0165] When the above-mentioned "alkyl", "alkoxy", "alkenyl", "alkynyl", "aryl", "heteroaryl", "carbocyclyl", "carbocycle", "heterocyclyl", "heterocycle", "cycloalkyl", "heterocycloalkyl" or "heterocyclyl" is substituted, it can be further substituted by 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 groups selected from F, Cl, Br, I, hydroxyl, mercapto, nitro, cyano, amino, C1-6 alkylamino, =O, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, -NRq4 R q5 、=NR q6 、-C(=O)OC 1-6 Alkyl, -OC(=O)C 1-6 Alkyl, -C(=O)NR q4 R q5 、C 3-8 Cycloalkyl, C 3-8 Heterocycloalkyl, C 6-10 Aryl, C 5-10 Heteroaryl, -C(=O)OC 6-10 Aryl, -OC(=O)C 6-10 Aryl, -OC(=O)C 5-10 Heteroaryl, -C(=O)OC 5-10 Heteroaryl, -OC(=O)C 3-8 Heterocycloalkyl, -C(=O)OC 3-8 Heterocycloalkyl, -OC(=O)C 3-8 Cycloalkyl, -C(=O)OC 3-8 Cycloalkyl, -NHC(=O)C 3-8 Heterocycloalkyl, -NHC(=O)C 6-10 Aryl, -NHC(=O)C 5-10 Heteroaryl, -NHC(=O)C 3-8 Cycloalkyl, -NHC(=O)C 3-8 Heterocycloalkyl, -NHC(=O)C 2-6 Alkenyl or -NHC(=O)C 2-6 substituted by a substituent of an alkynyl group, wherein the substituent C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 3-8 Heterocycloalkyl, C 6-10 Aryl, C 5-10 Heteroaryl, -NHC(=O)C 6-10 Aryl, -NHC(=O)C 5-10 Heteroaryl, -NHC(=O)C 3-8 Heterocycloalkyl or -NHC(=O)C 3-8 The cycloalkyl group is optionally further substituted by 1 to 3 groups selected from OH, F, Cl, Br, I, C 1-6 Alkyl, C 1-6 Alkoxy, -NR q4 R q5 Or substituted by a substituent of =O; R q1 Selected from C 1-6 Alkyl, C 1-6 Alkoxy or C6-10 Aryl; R q2 、R q3 Selected from H or C 1-6 Alkyl; wherein R q4 、R q5 Selected from H, C 1-6 Alkyl, -NH(C=NR q1 )NR q2 R q3 、-S(=O)2NR q2 R q3 、-C(=O)R q1 or -C(=O)NR q2 R q3 , wherein the C 1-6 The alkyl group is optionally further substituted by one or more groups selected from OH, F, Cl, Br, I, C 1-6 Alkyl, C 1-6 Alkoxy, C 6-10 Aryl, C 5-10 Heteroaryl, C 3-8 Cycloalkyl or C 3-8 is substituted by a substituent of a heterocycloalkyl group; or R q4 With R q5 and the N atom form a 3- to 8-membered heterocyclic ring, which may contain one or more heteroatoms selected from N, O or S.

[0166] "Pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" refers to a salt of the compound of the present invention that retains the biological effectiveness and properties of the free acid or free base, and the free acid is obtained by reacting with a non-toxic inorganic base or organic base, or the free base is obtained by reacting with a non-toxic inorganic acid or organic acid.

[0167] "Pharmaceutical composition" refers to a mixture of one or more compounds of the present invention, their pharmaceutically acceptable salts or prodrugs and other chemical components, wherein "other chemical components" refers to pharmaceutically acceptable carriers, excipients and / or one or more other therapeutic agents.

[0168] "Carrier" refers to a material that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.

[0169] "Excipient" refers to an inert substance added to a pharmaceutical composition to facilitate administration of a compound. Non-limiting examples include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binders, and disintegrants.

[0170] "Prodrugs" refer to compounds of the present invention that can be converted into biologically active compounds through in vivo metabolism. Prodrugs of the present invention are prepared by modifying amino or carboxyl groups in compounds of the present invention. These modifications can be removed by conventional manipulation or in vivo to yield the parent compound. When the prodrugs of the present invention are administered to a mammalian subject, the prodrugs are cleaved to form free amino or carboxyl groups.

[0171] A "cocrystal" is a crystal formed by the active pharmaceutical ingredient (API) and cocrystal former (CCF) bound together by hydrogen bonds or other non-covalent bonds. Both the API and CCF are solid in their pure form at room temperature, and the components exist in a fixed stoichiometric ratio. A cocrystal is a multi-component crystal, encompassing both binary cocrystals formed between two neutral solids and multi-component cocrystals formed between a neutral solid and a salt or solvate.

[0172] "Stereoisomers" refer to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, and conformational isomers.

[0173] "Optional" or "optionally" or "selectively" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "heterocyclyl optionally substituted with alkyl" means that the alkyl group may but need not be present, and that the description includes instances where the heterocyclyl group is substituted with alkyl and instances where the heterocyclyl group is not substituted with alkyl. DETAILED DESCRIPTION

[0174] The following examples illustrate the technical solutions of the present invention in detail, but the protection scope of the present invention includes but is not limited to them.

[0175] Intermediate A

[0176] (3-(8-Cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid ethyl ester

[0177] ethyl-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylate

[0178] first step:

[0179] 1-Benzyl-4-(trifluoromethyl)-2,5-dihydro-1H-pyrrole-3-carboxylic acid ethyl ester A-1.3

[0180] ethyl-1-benzyl-4-(trifluoromethyl)-2,5-dihydro-1H-pyrrole-3-carboxylate

[0181] Under N₂ atmosphere, A-1.1 (10 g, 60 mmol) was dissolved in 30 mL of dichloromethane (DCM). A solution of A-1.2 (14.4 g, 60 mmol) in DCM (10 mL) was added dropwise under an ice bath. Subsequently, a solution of trifluoroacetic acid (684 mg, 6 mmol) in DCM (10 mL) was slowly added dropwise. The mixture was stirred at room temperature for 2 h. The reaction solution was added to 30 mL of water and extracted three times with DCM. The organic phase was washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, and then purified by silica gel column chromatography (ethyl acetate:petroleum ether = 1:10) to obtain the target product, ethyl 1-benzyl-4-(trifluoromethyl)-2,5-dihydro-1H-pyrrole-3-carboxylate A-1.3 (yellow oil, 15.5 g, 86% yield), which was used directly in the next reaction.

[0182] 1 H NMR (400MHz, DMSO-d6) δ7.34-7.24(m, 5H), 4.19(q, 2H), 3.79-3.78(m, 6H), 1.20(t, 3H).

[0183] LC-MS m / z(ESI)=300.1[M+1].

[0184] Step 2:

[0185] 3-Benzyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid ethyl ester A-1.4

[0186] ethyl-3-benzyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylate

[0187] Under a nitrogen atmosphere, trimethylsulfoxide iodide (3.5 g, 15.8 mmol) was dissolved in 10 mL of dimethylsulfoxide. A solution of sodium hydride (633.6 mg, 15.8 mmol) in dimethylsulfoxide (5 mL) was added portionwise under an ice bath and stirred at room temperature for 30 minutes. A solution of A-1.3 (4.3 g, 14.4 mmol) in dimethylsulfoxide (5 mL) was then added dropwise, and the mixture was allowed to react at 60°C for 5 hours. The reaction was quenched with saturated ammonium chloride, extracted with 30 mL of dimethyl sulfoxide (DCM), and washed with 30 mL of saturated brine. The organic phase was dried over anhydrous sodium sulfate, dried by spin drying, and purified by silica gel column chromatography (ethyl acetate:petroleum ether = 1:10) to obtain the desired product, ethyl 3-benzyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylate A-1.4 (a colorless oily liquid, 3.5 g, 78% yield), which was used directly in the next reaction.

[0188] 1 H NMR (400MHz, DMSO-d6) δ7.34-7.24 (m, 5H), 4.11 (q, 2H), 3.66 (s, 2H), 3.08-3.0 1(m, 2H), 2.86-2.82(m, 1H), 2.65-2.62(m, 1H), 1.82-1.79(m, 2H), 1.15(t, 3H).

[0189] LC-MS m / z(ESI)=314.1[M+1].

[0190] Step 3:

[0191] 5-(Trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid ethyl ester A-1.5

[0192] ethyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylate

[0193] A-1.4 (1 g, 3.2 mmol) was dissolved in 50 mL of ethanol, followed by the addition of Pd / C (681 mg, 0.64 mmol). The reaction system was purged twice with 1 atm of H₂ and heated to 60°C for 3 h. Filtered through Celite, the solvent was evaporated to afford the desired product, ethyl 5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylate A-1.5 (a colorless oily liquid, 1 g, 88% yield), which was used directly in the next step.

[0194] 1H NMR (400MHz, DMSO-d6) δ4.11(q, 2H), 3.20-2.75(m, 5H), 1.75(d, 1H), 1.48-1.47(m, 1H), 1.16(t, 3H).

[0195] LC-MS m / z(ESI)=224.1[M+1].

[0196] Step 4:

[0197] (3-(8-Cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid ethyl ester A

[0198] ethyl-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylate

[0199] Under N2 atmosphere, 5-bromoquinoline-8-carbonitrile A-1.6 (654 mg, 2.9 mmol) was dissolved in 30 mL of 1,4-dioxane, followed by the addition of A-1.5 (804 mg, 3.5 mmol). The atmosphere was replaced with N2 three times, followed by the addition of cesium carbonate (4.3 g, 13.05 mmol) and RuPhosPdG3 (486 mg, 0.58 mmol). The atmosphere was replaced with N2 three times, and the temperature was raised to 90°C for 2 h. The solvent was dried, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the solvent was dried, and the crude product A was directly used in the next step.

[0200] LC-MS m / z(ESI)=376.1[M+1], 398.1[M+23].

[0201] Intermediate B-2: (1R,5S)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid

[0202] (1R,5S)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid

[0203] first step:

[0204] 3-(8-Cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid B

[0205] 3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid

[0206] The crude product of compound A (2.02 g, 5.39 mmol) was dissolved in 10 mL of tetrahydrofuran. A 10 mL solution of anhydrous lithium hydroxide (1.29 g, 53.9 mmol) was added dropwise to the reaction mixture, and the mixture was stirred overnight at room temperature. After the reaction was complete, the tetrahydrofuran was dried and extracted with ethyl acetate. The aqueous phase was retained and the pH was adjusted to 3-4 with 2M hydrochloric acid. The organic phase was extracted with ethyl acetate and washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent removed in vacuo. MPLC separation (acetonitrile:water = 47:53) afforded the desired product, 3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid Compound B (yellow solid, 387 mg, 21%).

[0207] 1 H NMR (400MHz, DMSO-d6) δ13.26 (s, 1H), 9.02-9.00 (m, 1H), 8.64-8.62 (m, 1H), 8.16 ( d, J=8.0Hz, 1H), 7.61 (dd, 1H), 7.25 (d, 1H), 4.05-3.77 (m, 4H), 2.07-1.86 (m, 2H).

[0208] LC-MS m / z(ESI)=348.1[M+1], 370.1[M+23].

[0209] Step 6:

[0210] (1S,5R)-3-(8-Cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid

[0211] (1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid intermediate B-1

[0212] (1R,5S)-3-(8-Cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid

[0213] (1R,5S)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid intermediate B-2

[0214] Compound B-1 and Compound B-2 were separated by chiral prep-HPLC. Analytical method: Chiral column Ig-3, methanol as the mobile phase, flow rate 1 mL / min, retention time of intermediate B-1 was 3.619 min, and retention time of intermediate B-2 was 4.741 min.

[0215] Intermediate C

[0216] 2-(1-methylpiperidin-4-yl)-5-((1S,5R)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazole intermediate C

[0217] 2-(1-methylpiperidin-4-yl)-5-((1S,5R)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazole

[0218] first step:

[0219] (1S,5R)-3-Benzyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbohydrazide C-1.1

[0220] (1S,5R)-3-benzyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbohydrazide

[0221] Dissolve (1S,5R)-compound A-1.4 (5.0 g, 0.0167 mol) in 50 mL of ethanol solution, then add hydrazine hydrate (8.36 g, 0.167 mol), react at 70 ° C for 4 hours, and spin dry the solvent to obtain the target product (1S,5R)-3-benzyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbohydrazide compound C-1.1, which is directly used in the next step.

[0222] LC-MS m / z(ESI)=300.3[M+1].

[0223] Step 2:

[0224] (1S,5R)-3-Benzyl-N'-(1-methylpiperidine-4-carbonyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbohydrazide compound C-1.3

[0225] (1S,5R)-3-benzyl-N′-(1-methylpiperidine-4-carbonyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbohydrazide

[0226] Compound 1-methylpiperidine-4-carboxylic acid C-1.2 (2.08 g, 0.0147 mol) was dissolved in 20 mL of dichloromethane.

[0227] Thionyl chloride (4.96 mL, 0.067 mol) was slowly added at 0°C, and then the reaction system was heated to 40°C and the reaction was continued for 2 h. The solvent was concentrated and dissolved in 10 mL of dichloromethane. Compound (1S,5R)-3-benzyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbohydrazide compound C-1.1 (4.00 g, 0.0134 mol) was added and stirred at room temperature for 1 h. The reaction was monitored by TLC for completion, and the reaction was quenched with water. Dichloromethane was added for extraction, and the combined organic phases were washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain the target product (1S,5R)-3-benzyl-N'-(1-methylpiperidine-4-carbonyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbohydrazide C-1.3 (yellow liquid, 5.1 g, yield: 90.0%).

[0228] LC-MS m / z(ESI)=425.2[M+1].

[0229] Step 3:

[0230] 2-((1S,5R)-3-benzyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-5-(1-methylpiperidin-4-yl)-1,3,4-oxadiazole

[0231] 2-((1S,5R)-3-benzyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-5-(1-methylpiperidin-4-yl)-1,3,4-oxadiazole compound C-1.4

[0232] (1S,5R)-3-Benzyl-N′-(1-methylpiperidine-4-carbonyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbohydrazide compound C-1.3 (5.1 g, 0.012 mol) was dissolved in 20 mL of dichloromethane, followed by the addition of triethylamine (12.0 g, 0.12 mol) and p-toluenesulfonyl chloride (6.8 g, 0.036 mol). The mixture was stirred at room temperature for 5 hours. The reaction was monitored by TLC. The reaction solution was concentrated and purified by silica gel column chromatography to obtain the target product 2-((1S,5R)-3-benzyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-yl)-5-(1-methylpiperidin-4-yl)-1,3,4-oxadiazole compound C-1.4 (yellow liquid, 4.2 g, yield: 85%).

[0233] LC-MS m / z (ESI) = 407.2 [M+1].

[0234] Step 4:

[0235] 2-(1-methylpiperidin-4-yl)-5-((1S,5R)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazole intermediate C

[0236] 2-(1-methylpiperidin-4-yl)-5-((1S,5R)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazole

[0237] 2-((1S,5R)-3-benzyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-5-(1-methylpiperidin-4-yl)-1,3,4-oxadiazole compound C-1.4 (1.0 g, 2.5 mmol) was dissolved in 5 mL of methanol, and palladium hydroxide (35 mg, 0.25 mmol) and ammonium formate (464 mg, 3.69 mol) were added sequentially. The mixture was heated under reflux for 6 h. The reaction was monitored by TLC. The reaction solution was concentrated and purified by silica gel column chromatography to obtain the target product 2-(1-methylpiperidin-4-yl)-5-((1S,5R)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazole intermediate C (yellow liquid, 600 mg, yield: 76%).

[0238] LC-MS m / z (ESI) = 317.2 [M+1].

[0239] Example 1

[0240] 5-((1S,5R)-1-(5-(4-methylpiperazin-1-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoxaline-5-carbonitrile compound 1

[0241] 5-((1S,5R)-1-(5-(4-methylpiperazin-1-yl)-1,3,4-oxadiazol-2-yl)-5(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

[0242] first step:

[0243] 4-Methylpiperazine-1-carbohydrazide 1-2

[0244] 4-methylpiperazine-1-carbohydrazide

[0245] Triphosgene (5.92 g, 20.0 mmol) was dissolved in 10.0 mL of dichloromethane, and a mixed solution of methylpiperazine 1-1 (1.00 g, 10.0 mmol) and triethylamine (1.02 g, 10.0 mmol) in 10.0 mL of dichloromethane was slowly added dropwise at 0°C. After the reaction for 1 h, hydrazine hydrate (1.28 g, 40.0 mmol) was slowly added dropwise. After the reaction for 1 h, the sample was sent to LCMS for completion of the reaction. The solution was concentrated to give 1.7 g of crude product 4-methylpiperazine-1-carboxylic acid hydrazide 1-2 (white solid, 1.72 g).

[0246] LC-MS m / z (ESI) = 159.10 [M+1].

[0247] Step 2:

[0248] 5-((1S,5R)-1-(5-(4-methylpiperazin-1-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoxaline-5-carbonitrile compound 1

[0249] 5-((1S,5R)-1-(5-(4-methylpiperazin-1-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

[0250] The crude product 4-methylpiperazine-1-carboxylic acid hydrazide and (1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid B-1 (1.00 g, 2.87 mmol) were dissolved in 10.0 mL of phosphorus oxychloride and refluxed at 90° C. for 3 hrs. The mixture was sampled by LCMS. After the reaction was completed, sodium hydroxide solution was added to adjust the pH to 7-8 to quench the reaction. Lyophilize, add dichloromethane, filter, concentrate the organic phase, and reverse preparation, TLC (DCM: MeOH = 10: 1) to give the target product 5-((1S, 5R)-1-(5-(4-methylpiperazine)-1-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-3-yl)quinoxaline-5-carbonitrile compound 1 (pale red solid, 25 mg).

[0251] 1 H NMR (400MHz, Chloroform-d) δ9.12(dd, 1H), 8.39(dd, 1H), 8.07(d, 1H), 7.55(dd, 1H), 7.17(d, 1H), 4.04( d, 1H), 4.02-3.91 (m, 2H), 3.82 (d, 1H), 3.59 (d, 4H), 2.57 (s, 4H), 2.40 (s, 3H), 2.26 (d, 1H), 2.17 (d, 1H).

[0252] LC-MS m / z (ESI) = 470.10 [M+1].

[0253] Example 2

[0254] first step:

[0255] 2-((5R)-3-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-5-(1-methylpiperidin-4-yl)-1,3,4-oxadiazole compound 2

[0256] 2-((5R)-3-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-5-(1-methylpiperidin-4-yl)-1,3,4-oxadiazole

[0257] Under N2 atmosphere, 2-(1-methylpiperidin-4-yl)-5-((1S,5R)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazole intermediate C (200 mg, 0.63 mmol) was dissolved in 1,4-dioxane (3.00 mL), followed by the addition of 4-bromo-1,6-dimethyl-1H-pyrazolo[3,4-b]pyridine compound 2-1 (150 mg, 0.67 mmol), cesium carbonate (1.40 g, 2.68 mmol) and RuPhosPdG3 (48.5 mg, 0.067 mmol), the gas was replaced with N2 three times, and the temperature was raised to 90 ° C for 2 h. The solvent was dried, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was dried. TLC (DCM:MeOH=10:1) was performed to obtain the target product 2-((5R)-3-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-yl)-5-(1-methylpiperidin-4-yl)-1,3,4-oxadiazole compound 2 (yellow-white solid, 10 mg)

[0258] LC-MS m / z (ESI) = 462.10 [M+1].

[0259] 1 H NMR (400MHz, DMSO-d6) δ8.10 (s, 1H), 6.16 (s, 1H), 4.46-3.98 (m, 4H), 3.89 (s, 3H), 2.94 (td, 1H), 2.73 (d, J=11.3 Hz, 2H), 2.43 (s, 3H), 2.34 (d, 1H), 2.17 (s, 3H), 2.06 (d, 1H), 2.00-1.92 (m, 3H), 1.87 (d, 1H), 1.79-1.67 (m, 2H).

[0260] Example 3

[0261] 2-(4-fluoropiperidin-4-yl)-5-((1S,5R)-3-(8-(trifluoromethoxy)quinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-yl)-1,3,4-oxadiazole compound 3

[0262] 2-(4-fluoropiperidin-4-yl)-5-((1S,5R)-3-(8-(trifluoromethoxy)quinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazole

[0263] first step:

[0264] tert-Butyl 4-fluoro-4-(5-((1S,5R)-5-(trifluoromethyl)-3-(8-(trifluoromethyl)quinolin-5-yl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazol-2-yl)piperidine-1-carboxylate Compound 3-1

[0265] 4-fluoro-4-(5-((1S,5R)-5-(trifluoromethyl)-3-(8-(trifluoromethyl)quinolin-5-yl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazol-2-yl)piperidine-1-carboxylate

[0266] 1-(tert-Butyloxycarbonyl)-4-fluoropiperidine-4-carboxylic acid (230 mg, 0.93 mmol) was dissolved in anhydrous dichloromethane (7.5 mL). DIPEA (230 mg, 1.77 mmol) and HATU (506 mg, 1.33 mmol) were added. The mixture was stirred at 35°C for 30 minutes, then cooled to room temperature. (1S,5R)-3-(8-(trifluoromethoxy)quinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid hydrazide (373 mg, 0.88 mmol) was added. After completion, the atmosphere was purged with nitrogen three times and the reaction was allowed to proceed at room temperature for 1 hour. After completion of the reaction, as monitored by LCMS, DIPEA (344 mg, 2.66 mmol) and Burgess reagent (634 mg, 2.66 mmol) were added. The atmosphere was purged with nitrogen three times and the reaction was allowed to proceed at room temperature for 1 hour. After the reaction was completed, ethyl acetate and water were added for extraction three times, and the organic phase was dried over anhydrous sodium sulfate and then directly concentrated to dryness. The crude product was separated by reverse phase column chromatography to obtain tert-butyl 4-fluoro-4-(5-((1S,5R)-5-(trifluoromethyl)-3-(8-(trifluoromethyl)quinolin-5-yl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazol-2-yl)piperidine-1-carboxylate Compound 3-1 (300 mg, yellow solid, 52% yield).

[0267] LCMS m / z (ESI) = 616.21 [M+1].

[0268] Step 2:

[0269] 2-(4-fluoropiperidin-4-yl)-5-((1S,5R)-5-(trifluoromethyl)-3-(8-(trifluoromethyl)quinolin-5-yl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazole compound 3

[0270] 2-(4-fluoropiperidin-4-yl)-5-((1S,5R)-5-(trifluoromethyl)-3-(8-(trifluoromethyl)quinolin-5-yl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazole

[0271] tert-Butyl 4-fluoro-4-(5-((1S,5R)-5-(trifluoromethyl)-3-(8-(trifluoromethyl)quinolin-5-yl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazol-2-yl)piperidine-1-carboxylate 3-1 (300 mg, 0.48 mmol) was dissolved in anhydrous dichloromethane (6 mL), and trifluoroacetic acid (1.5 mL) was then added dropwise. After nitrogen replacement, the reaction was carried out at room temperature for 2 hours. After the reaction was completed, aqueous ammonia was added to the reaction solution to adjust the pH to alkaline, and dichloromethane and water were added to extract three times. The organic phase was dried over anhydrous sodium sulfate, concentrated, and passed through a column to obtain the target product 2-(4-fluoropiperidin-4-yl)-5-((1S,5R)-5-(trifluoromethyl)-3-(8-(trifluoromethyl)quinolin-5-yl)-3-azabicyclo[3.1.0]hexane-1-yl)-1,3,4-oxadiazole compound 3 (130 mg, yellow solid, yield 51%).

[0272] LCMS m / z (ESI) = 516.21 [M+1].

[0273] 1 H NMR(400MHz, Chloroform-d)δ 9.07(dd,,1H),8.36(dd,1H),8.00(d,1H),7.51(dd,1H),7.21(d,1H),4.08(d,1 H), 3.97-3.86 (m, 2H), 3.74 (d, 1H), 3.19 (q, 3H), 3.15-3.04 (m, 4H), 2.35 (m, 3H)

[0274] Example 4

[0275] 2-(1-methylazetidin-3-yl)-5-((1S,5R)-5-(trifluoromethyl)-3-(8-(trifluoromethyl)quinolin-5-yl)-3-azabicyclo[3.1.0]hexane-1-yl)-1,3,4-oxadiazole compound 4

[0276] 2-(1-methylazetidin-3-yl)-5-((1S,5R)-5-(trifluoromethyl)-3-(8-(trifluoromethyl)quinolin-5-yl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazole

[0277] first step:

[0278] 2-(1-methylazetidin-3-yl)-5-((1S,5R)-5-(trifluoromethyl)-3-(8-(trifluoromethyl)quinolin-5-yl)-3-azabicyclo[3.1.0]hexane-1-yl)-1,3,4-oxadiazole compound 4

[0279] 2-(1-methylazetidin-3-yl)-5-((1S,5R)-5-(trifluoromethyl)-3-(8-(trifluoromethyl)quinolin-5-yl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazole

[0280] 1-(tert-Butyloxycarbonyl)azetidine-3-carboxylic acid 4-1 (111 mg, 0.75 mmol) was dissolved in 20 ml of phosphorus oxychloride, and then (1S, 5R)-5-(trifluoromethyl)-3-(8-(trifluoromethyl)quinolin-5-yl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid hydrazide 95-3 (300 mg, 0.75 mmol) was added and stirred at 80 ° C for 2 hours. After the reaction was completed by LCMS, the reaction solution was poured into a sodium carbonate aqueous solution. The pH value of the solution was maintained at 8, and then dichloromethane was added for extraction three times. The combined organic phases were directly concentrated and purified by reverse phase C18 column chromatography (acid method) to obtain the crude target product 2-(1-methylazetidin-3-yl)-5-((1S,5R)-5-(trifluoromethyl)-3-(8-(trifluoromethyl)quinolin-5-yl)-3-azabicyclo[3.1.0]hexane-1-yl)-1,3,4-oxadiazole compound 4 (pale yellow solid, 30 mg, 46.2%).

[0281] LC-MS m / z (ESI) = 484.10 [M+1].

[0282] 1 H NMR (400MHz, Chloroform-d) δ9.10-9.04 (m, 1H), 8.37 (dd, 1H), 8.01 (d, 1H), 7.51 (dd, 1H), 7.20 (d, 1H), 4.07(d, 1H), 3.96(m, 1H), 3.90(ddt, 4H), 3.74(d, 1H), 3.51(t, 2H), 2.47(s, 3H), 2.32(s, 2H).

[0283] Example 5

[0284] 5-((1S,5R)-1-(4-methyl-5(1-methylpiperazine)-4-yl)-4H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-3-yl)quinoxaline-8-carbonitrile compound 5

[0285] 5-((1S,5R)-1-(4-methyl-5-(1-methylpiperidin-4-yl)-4H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

[0286] first step:

[0287] (1S,5R)-3-(8-cyanoquinolin-5-yl)-N′-(1-methylpiperidine-4-carbonyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbohydrazide 5-2

[0288] (1S,5R)-3-(8-cyanoquinolin-5-yl)-N′-(1-methylpiperidine-4-carbonyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbohydrazide

[0289] 1-Methylpiperidine-4-carboxylic acid 5-1 (119 mg, 83 mmol) was dissolved in 10 ml of N, N-dimethylformamide, and then HATU (378 mg, 0.99 mmol) and DIPEA (321 mg, 2.49 mmol) were added in an ice bath and stirred at low temperature for 5 minutes, and then (1S, 5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1 was added. -Carbohydrazide 3-1 (300 mg, 0.83 mmol) was stirred for half an hour. After the TLC reaction was completed, the reaction solution was directly concentrated and purified by reverse phase C18 column chromatography (alkaline method) to obtain the target product (1S, 5R)-3-(8-cyanoquinolin-5-yl)-N'-(1-methylpiperidine-4-carbonyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbohydrazide 5-2 (pale yellow solid, 380 mg, 89%).

[0290] LC-MS m / z (ESI) = 487.20 [M+1].

[0291] Step 2:

[0292] 5-(1S,5R)-1-(5-(1-methylpiperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-3-yl)quinoline-8-carbonitrile 5-3

[0293] 5-((1S,5R)-1-(5-(1-methylpiperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

[0294] (1S,5R)-3-(8-cyanoquinolin-5-yl)-N′-(1-methylpiperidine-4-carbonyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbohydrazide 5-2 (115 mg, 0.23 mmol) was dissolved in 6 ml of 1,2-dichloroethane, followed by the addition of triethylamine (47 mg, 0.46 mmol) and p-toluenesulfonyl chloride (66 mg, 0.345 mmol). The mixture was stirred at room temperature for 15 hours. The reaction was complete according to TLC. The reaction solution was directly concentrated and purified by reverse phase C18 column chromatography (alkaline method) to obtain the target compound (5-(1S,5R)-1-(5-(1-methylpiperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-3-yl)quinoline-8-carbonitrile 5-3 (pale yellow solid, 70 mg, 46%).

[0295] 1 H NMR (400MHz, DMSO-d6) δ9.03 (dd, 1H), 8.69 (dd, 1H), 8.20 (d, 1H), 7.63 (dd, 1H), 7.34 (d, 1H), 4.19 (d, 1H), 4.07 (dd, 2H) , 3.92(d, 1H), 2.97(td, 1H), 2.77(d, 2H), 2.24(d, 2H), 2.21(S, 3H), 2.12(S, 2H), 2.03-1.93(m, 2H), 1.81-1.65(m, 2H).

[0296] 19 F NMR(376MHz, DMSO-d6)δ-64.08.

[0297] LC-MS m / z (ESI) = 469.20 [M+1].

[0298] Step 3:

[0299] 5-((1S,5R)-1-(4-methyl-5(1-methylpiperazin-4-yl)-4H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-3-yl)quinoxaline-8-carbonitrile compound 5

[0300] 5-((1S,5R)-1-(4-methyl-5-(1-methylpiperidin-4-yl)-4H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

[0301] The above compound (5-(1S,5R)-1-(5-(1-methylpiperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-3-yl)quinoline-8-carbonitrile 5-3 (150 mg, 0.319 mmol) and methylamine hydrochloride (64.1 mg, 0.957 mmol), p-toluenesulfonic acid (109 mg, 638 mmol), DIEA (163 mg, 1.27 mmol) were dissolved in 2.00 The reaction mixture was added to mL of mesitylene and refluxed at 150°C for 3 hours, and the mixture was sampled by LCMS. After completion of the reaction, the mixture was cooled and TLC (DCM:MeOH=10:1) was performed, and the target product 5-((1S,5R)-1-(4-methyl-5(1-methylpiperazine)-4-yl)-4H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-3-yl)quinoline-8-carbonitrile compound 5 (pale yellow solid, 40 mg, yield: 25.9%) was obtained.

[0302] 1 H NMR (400MHz, DMSO-d6) δ9.01 (dd, 1H), 8.73 (dd, 1H), 8.18 (d, 1H), 7.61 (dd, 1H), 7.28 (d, 1H) , 4.13(d, 3H), 3.83(d, 1H), 3.68(s, 3H), 3.14-2.85(m, 3H), 2.29(m, 5H), 2.07-1.73(m, 6H).

[0303] LC-MS m / z (ESI) = 482.10 [M+1].

[0304] Example 6

[0305] 5-((1S,5R)-1-(5-((1-methylpiperidin)-4-yl)amine)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-3-yl)quinoxaline-8-carbonitrile compound 6

[0306] 5-((1S,5R)-1-(5-((1-methylpiperidin-4-yl)amino)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

[0307] first step:

[0308] N-(1-Methylpiperidin-4-yl)-carbohydrazide

[0309] N-(1-methylpiperidin-4-yl)hydrazinecarboxamide

[0310] Triphosgene (3.90 g, 13.2 mmol) was dissolved in 10.0 mL of dichloromethane, and a mixed solution of 4-amino-1-methylpiperidine 6-1 (1.00 g, 8.77 mmol) and triethylamine (1.75 g, 17.5 mmol) in 10.0 mL of dichloromethane was slowly added dropwise at 0°C. After the reaction for 1 h, hydrazine hydrate (1.28 g, 40.0 mmol) was slowly added dropwise. After the reaction for 1 h, the sample was sent to LCMS for completion of the reaction. The solution was concentrated to give 4.3 g of crude product N-(1-methylpiperidin-4-yl)-carbohydrazide 6-2 (yellow oily liquid).

[0311] LC-MS m / z (ESI) = 173.10 [M+1].

[0312] Step 2:

[0313] 2-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbonyl)-nitrogen-(1-methylpiperidin-4-yl)hydrazine-1-carboxamide compound 6-3

[0314] 2-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbonyl)-N-(1-methylpiperidin-4-yl)hydrazine-1-carboxamide

[0315] The crude N-(1-methylpiperidin-4-yl)-carbohydrazide 6-2 and (1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid B-1 (1.00 g, 2.87 mmol) were dissolved in 10.0 mL of phosphorus oxychloride and refluxed at 90 ° C for 3 hrs. The sample was sent to LCMS. After the reaction was completed, a sodium hydroxide solution was added. The solution was adjusted to pH = 7-8 for quenching, freeze-dried, dichloromethane was added, filtered, the organic phase was concentrated, and the target product 2-((1S, 5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbonyl)-nitrogen-(1-methylpiperidin-4-yl)hydrazine-1-carboxamide compound 6-3 was obtained by reverse preparation (yellow solid, 100 mg, yield: 2%).

[0316] Step 3

[0317] 5-((1S,5R)-1-(5-((1-methylpiperidin)-4-yl)amine)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-3-yl)quinoxaline-8-carbonitrile compound 6

[0318] 5-((1S,5R)-1-(5-((1-methylpiperidin-4-yl)amino)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

[0319] 2-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbonyl)-nitrogen-(1-methylpiperidin-4-yl)hydrazine-1-carboxamide 6-3 (100 mg, 0.19 mmol) was dissolved in 2.00 mL of dichloromethane, followed by the addition of triethylamine (58.1 mg, 0.57 mmol) and Burgess reagent (417 mg, 0.57 mmol). The mixture was stirred at room temperature for 5 hours. The reaction was monitored by TLC to completion. The reaction solution was concentrated, separated by MPLC, and purified by silica gel column chromatography to obtain the target product, 5-((1S,5R)-1-(5-((1-methylpiperidin-4-yl)amine)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoxaline-8-carbonitrile compound 6 (yellow solid, 10 mg, yield: 10.4%).

[0320] 1H NMR (400MHz, DMSO-d6) δ9.02 (s, 1H), 8.68 (d, 1H), 8.19 (d, 1H), 7.72 (d, 1H), 7.62 (s, 1H), 7.30 (d, 1H), 4.15 (d, 1H), 4 .07 (d, 1H), 3.92 (d, 2H), 3.50 (s, 1H), 2.77 (s, 2H), 2.21 (s, 3H), 2.07 (s, 3H), 1.89 (d, 2H), 1.51 (d, 2H), 1.36 (d, 1H).

[0321] LC-MS m / z (ESI) = 484.10 [M+1].

[0322] Example 7

[0323] 5-((1S,5R)-1-(5-amino-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-3-yl)quinoline-8-carbonitrile compound 7

[0324] 5-((1S,5R)-1-(5-amino-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

[0325] first step:

[0326] 5-((1S,5R)-1-(5-amino-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-3-yl)quinoline-8-carbonitrile compound 7

[0327] 5-((1S,5R)-1-(5-amino-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

[0328] (1S,5R)-3-(8-Cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid B-1 (347 mg, 1.00 mmol) was dissolved in 10 ml of phosphorus oxychloride, followed by the addition of hydrazinecarboxamide hydrochloride 7-1 (112 mg, 1.00 mmol). After the TLC reaction was complete, the reaction solution was directly concentrated and then added dropwise to a saturated aqueous sodium carbonate solution. The pH value of the aqueous phase was measured to be 9. The product was extracted with ethyl acetate (50 ml*3). The organic phases were combined, concentrated under reduced pressure, and purified by reverse phase C18 column chromatography (alkaline method) to obtain the target compound 5-((1S,5R)-1-(5-amino-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile compound 7 (pale yellow solid, 60 mg, 16%).

[0329] 1 H NMR (400MHz, DMSO-d6) δ9.02 (d, 1H), 8.85-8.64 (m, 1H), 8.19 (d, 1H), 7.62 (dd, 1H ), 7.30(d, 1H), 7.18(s, 2H), 4.15(d, 1H), 4.06(d, 1H), 3.90(dd, 2H), 2.07(q, 2H).

[0330] 19 F NMR(376MHz, DMSO-d6)δ-64.07.

[0331] LC-MS m / z (ESI) = 387.20 [M+1].

[0332] Example 8

[0333] 5-((1S,5R)-1-(5-(1,4-dimethylpiperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-3-yl)quinoline-8-carbonitrile compound 8

[0334] 5-((1S,5R)-1-(5-(1,4-dimethylpiperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

[0335] first step:

[0336] (1S, 5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbohydrazide compound 3-1

[0337] (1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo-[3.1.0]hexane-1-carbohydrazide

[0338] Ethyl (1S, 5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylate (1S, 5R)-A (1 g, 2.6 mmol) was dissolved in 5 ml of ethanol, followed by the addition of 5 ml of hydrazine hydrate, the temperature was raised to 85 ° C. and stirred for 3 hours. After the reaction was completed by TLC, the reaction solution was directly concentrated, and the crude product was slurried with acetonitrile (5 ml), filtered and spin-dried to obtain (1S, 5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbohydrazide 3-1 (pale yellow solid, 460 mg, 49%).

[0339] LC-MS m / z (ESI) = 362.20 [M+1].

[0340] Step 2:

[0341] 5-((1S,5R)-1-(5-(1,4-dimethylpiperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-3-yl)quinoline-8-carbonitrile compound 8

[0342] 5-((1S,5R)-1-(5-(1,4-dimethylpiperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

[0343] (1S,5R)-3-(8-cyanoquinolin-5-yl)-NC(1-methylpiperidine-4-carbonyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbohydrazide 3-1 (460 mg, 1.27 mmol) was dissolved in 10 ml of phosphorus oxychloride, and then 1,4-dimethylpiperidine-4-carboxylic acid 8-1 (400 mg, 2.54 mmol) was added. After the reaction was completed by TLC, the reaction solution was directly concentrated and added dropwise to a saturated sodium carbonate aqueous solution. The pH value of the aqueous phase was measured to be about 9, and the product was extracted with ethyl acetate (50 ml * 3). The organic phases were combined, concentrated under reduced pressure, and purified by reverse phase C18 column chromatography (alkaline method) to obtain the target compound 5-((1S, 5R)-1-(5-(1,4-dimethylpiperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-3-yl)quinoline-8-carbonitrile compound 8 (pale yellow solid, 190 mg, 31%).

[0344] 1 H NMR (400MHz, DMSO-d6) δ9.03 (dd, 1H), 8.69 (dd, 1H), 8.21 (d, 1H), 7.63 (dd, 1H), 7.34(d, 1H), 4.21(d, 1H), 4.17-4.00(m, 2H), 3.93(d, 1H), 2.75(s, 2H), 2.44-2.06(m, 9H), 1.77(t, 2H), 1.30(s, 3H).

[0345] 19 F NMR(376MHz, DMSO-d6)δ-64.06.

[0346] LC-MS m / z (ESI) = 483.20 [M+1].

[0347] Example 9

[0348] 5-((1S,5R)-1-(5-(1-methylpiperidin-4-yl)-4H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile compound 9

[0349] 5-((1S,5R)-1-(5-(1-methylpiperidin-4-yl)-4H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

[0350] first step:

[0351] 6-Azaspiro[3.4]acetate-2-one 9-2

[0352] methyl 1-methylpiperidine-4-carbimidate

[0353] 1-Methylpiperidine-4-carbonitrile raw material 9-1 (124 mg, 1.0 mmol) was added to methanol (1.5 ml). After nitrogen protection, the temperature was lowered to 0°C, and then acetyl chloride (1.0 ml) was slowly added dropwise. After the addition was completed, the temperature was slowly raised to room temperature and stirred overnight. After the reaction was completed, the mixture was concentrated under reduced pressure at low temperature. The crude 6-azaspiro[3.4]acetate-2-one 9-2 was directly used in the next step.

[0354] Step 2:

[0355] (1S,5R)-3-(8-cyanoquinolin-5-yl)-N'-(imino(1-methylpiperidin-4-yl)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid hydrazide 9-4

[0356] (1S,5R)-3-(8-cyanoquinolin-5-yl)-N′-(imino(1-methylpiperidin-4-yl)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbohydrazide

[0357] 6-Azaspiro[3.4]acetate-2-one starting material 2 was added to 20 ml of methanol. After nitrogen protection, the temperature was lowered to 0°C, and then sodium ethoxide (1.02 g, 15.0 mmol) was added, followed by (1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid hydrazide (361 mg, 1 mmol). The reaction solution was slowly warmed to room temperature and reacted for 4 hours, resulting in completion of the reaction. The reaction solution was concentrated under reduced pressure and directly purified by column chromatography to obtain (1S,5R)-3-(8-cyanoquinolin-5-yl)-N'-(imino(1-methylpiperidin-4-yl)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid hydrazide 9-4 (150 mg, 30.9% yield over two steps).

[0358] LC-MS m / z (ESI) = 486.20 [M+1].

[0359] Step 3:

[0360] 5-((1S,5R)-1-(5-(1-methylpiperidin-4-yl)-4H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile compound 9

[0361] 5-((1S,5R)-1-(5-(1-methylpiperidin-4-yl)-4H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

[0362] The raw material (1S,5R)-3-(8-cyanoquinolin-5-yl)-N'-(imino(1-methylpiperidin-4-yl)methyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid hydrazide 9-4 (150 mg, 0.31 mmol) was added to mesitylene (4 ml) under nitrogen protection and heated to 150°C for 4 hours. After completion of the reaction, it was directly purified by column to obtain 5-((1S,5R)-1-(5-(1-methylpiperidin-4-yl)-4H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile compound 9 (90 mg, yield 62.3%).

[0363] LC-MS m / z (ESI) = 468.20 [M+1].

[0364] 1 H NMR (400MHz, DMSO-d6) 613.68 (s, 1H), 9.00 (dd, 1H), 8.68 (dd, 1H), 8.16 (d, 1H), 7.60 (dd, 1H), 7.27 (d, 1H), 4.27-3.98 (m, 3H), 3.91 (d, 1H), 2.83 (d, 2H), 2.71 (tt, 1H), 2.22 (s, 3H), 2.16 (d, 1H), 2.07 (t, 2H), 1.90 (dd, 3H), 1.72 (ddt, 2H).

[0365] 19 F NMR(377MHz, DMSO-d6)δ-63.40.

[0366] Example 10

[0367] 5-((1S,5R)-1-(5-((1R,3S,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hex-3-yl)quinoline-8-carbonitrile compound 10

[0368] 5-((1S,5R)-1-(5-((1R,3S,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

[0369] first step:

[0370] tert-Butyl (1R,3S,5S)-3-(2-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbonyl)hydrazine-1-carbonyl)-8-azabicyclo[3.2.1]octane-8-carboxylate 10-2

[0371] tert-butyl(1R,3S,5S)-3-(2-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbonyl)hydrazine-1-carbonyl)-8-azabicyclo[3.2.1]octane-8-carboxylate

[0372] The raw material (1R, 3S, 5S)-8-(tert-butyloxycarbonyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid 10-1 (255 mg, 1.0 mmol) was added to N, N-dimethylformamide (5 ml), and then N, N, N', N'-tetramethyl-O-(7-azabenzotriazole-1-yl) urea hexafluorophosphate (570 mg, 1.5 mmol) and N, N-diisopropylethylamine (258 mg, 2.0 mmol) were added. The reaction mixture was stirred at room temperature for 0.5 hours, and then (1S, 5R)-3-(8-cyanoquinoline- The reaction mixture was stirred at room temperature for 6 hours and then purified by reverse phase column chromatography to obtain (1R,3S,5S)-3-(2-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbonyl)hydrazine-1-carbonyl)-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester 10-2 (398 mg, yield 66.4%).

[0373] LCMS m / z (ESI) = 599.2 [M+1].

[0374] Step 2:

[0375] (1R,3S,5S)-3-(5-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazol-2-yl)-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester 10-3

[0376] tert-butyl(1R,3S,5S)-3-(5-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazol-2-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate

[0377] Tert-butyl (1R, 3S, 5S)-3-(2-((1S, 5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbonyl)hydrazine-1-carbonyl)-8-azabicyclo[3.2.1]octane-8-carboxylate 10-2 (398 mg, 0.67 mmol) was dissolved in 10 mL of dichloromethane, followed by the addition of triethylamine (338 mg, 3.35 mmol), p-toluenesulfonyl chloride (382 mg, 2.01 mmol), and 4-nitropropanesulfonyl chloride (300 mg, 2.01 mmol). ol), stirred at room temperature for 5 hours. The reaction was monitored by TLC. The reaction solution was concentrated and purified by silica gel column chromatography to obtain the target product (1R,3S,5S)-3-(5-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazol-2-yl)-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester 10-3 (yellow solid, 300 mg, yield: 77.1%).

[0378] LC-MS m / z (ESI) = 581.2 [M+1].

[0379] Step 3:

[0380] 5-((1S,5R)-1-(5-((1R,3S,5S)-8-azabicyclo[3.2.1]oct-3-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hex-3-yl)quinoline-8-carbonitrile compound 10

[0381] 5-((1S,5R)-1-(5-((1R,3S,5S)-8-azabicyclo[3.2.1]octan-3-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

[0382] The raw material (1R, 3S, 5S)-3-(5-((1S, 5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazol-2-yl)-8-azabicyclo[2.2.1]octane-8-carboxylic acid tert-butyl ester 10-3 (300 mg, 0.5 mmol) was added to dichloromethane (6 ml), and trifluoroacetic acid ( The reaction solution was reacted at room temperature for 2 hours, concentrated under reduced pressure, and then purified by reverse column chromatography to obtain 5-((1S,5R)-1-(5-((1R,3S,5S)-8-azabicyclo[3.2.1]oct-3-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hex-3-yl)quinoline-8-carbonitrile compound 10 (215 mg, yield 89.4%).

[0383] LC-MS m / z (ESI) = 481.2 [M+1].

[0384] Example 11

[0385] 5-((1S,5R)-1-(5-((1R,3S,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hex-3-yl)quinoline-8-carbonitrile compound 11

[0386] 5-((1S,5R)-1-(5-((1R,3S,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

[0387] 5-((1S,5R)-1-(5-((1R,3S,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hex-3-yl)quinoline-8-carbonitrile compound 11

[0388] 5-((1S,5R)-1-(5-((1R,3S,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

[0389] 5-((1S,5R)-1-(5-((1R,3S,5S)-8-azabicyclo[3.2.1]octan-3-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile 10 (215 mg, 0.45 mmol) was dissolved in 5 mL of methanol, followed by the addition of paraformaldehyde (187 mg, 2.08 mmol), sodium cyanoborohydride (158 mg, 4.16 The reaction mixture was stirred at room temperature for 3 hours. After completion of the reaction by TLC, the reaction solution was directly concentrated and purified by reverse column chromatography to obtain the target product 5-((1S,5R)-1-(5-((1R,3S,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hex-3-yl)quinoline-8-carbonitrile compound 11 (pale yellow solid, 41 mg, 18.4%).

[0390] LC-MS m / z (ESI) = 495.2 [M+1].

[0391] 1 H NMR (400MHz, DMSO-d6) δ9.02 (d, 1H), 8.69 (dd, 1H), 8.21 (d, 1H), 7.63 (dd, 1H), 7.34 (d, 1H), 4.20 (d, 1H), 4.0 7(t, 2H), 3.93(d, 1H), 3.64(s, 3H), 3.50-3.34(m, 2H), 2.29(ddd, 4H), 2.15-1.93(m, 2H), 1.68-1.15(m, 5H).

[0392] 19 F NMR(377MHz, DMSO-d6)δ-63.82(d).

[0393] Example 12

[0394] 5-((1S,5R)-1-(5-(tetrahydro-2H-pyran-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-3-yl)quinoline-8-carbonitrile compound 12

[0395] 5-((1S,5R)-1-(5-(tetrahydro-2H-pyran-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

[0396] first step:

[0397] (1S,5R)-3-(8-cyanoquinolin-5-yl)-N'-(tetrahydro-2H-pyran-4-carbonyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid hydrazide 12-2

[0398] (1S,5R)-3-(8-cyanoquinolin-5-yl)-N′-(tetrahydro-2H-pyran-4-carbonyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbohydrazide

[0399] The raw material tetrahydro-2H-pyran-4-carboxylic acid 12-1 (195 mg, 1.5 mmol) was added to N,N-dimethylformamide (5 ml), and then N,N,N′,N′-tetramethyl-O-(7-azabenzotriazole-1-yl)urea hexafluorophosphate (570 mg, 1.5 mmol) was added. ol) and N,N-diisopropylethylamine (258 mg, 2.0 mmol), the reaction mixture was stirred at room temperature for 0.5 hour, and then (1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid hydrazide 3-1 (361 mg, 1.0 mmol) was added. The reaction mixture was stirred at room temperature for 6 hours and then purified by reverse phase column chromatography to obtain (1S,5R)-3-(8-cyanoquinolin-5-yl)-N'-(tetrahydro-2H-pyran-4-carbonyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid hydrazide 12-2 (320 mg, yield 67.5%).

[0400] LCMS m / z (ESI) = 474.2 [M+1].

[0401] Step 2:

[0402] 5-((1S,5R)-1-(5-(tetrahydro-2H-pyran-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-3-yl)quinoline-8-carbonitrile compound 12

[0403] 5-((1S,5R)-1-(5-(tetrahydro-2H-pyran-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

[0404] (1S,5R)-3-(8-cyanoquinolin-5-yl)-N'-(tetrahydro-2H-pyran-4-carbonyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid hydrazide 12-2 (320 mg, 0.68 mmol) was dissolved in 10 mL of dichloromethane, followed by the addition of triethylamine (338 mg, 3.35 mmol), p-toluenesulfonyl chloride (382 mg, 2.01 mmol) and 4-nitropropanesulfonyl chloride (300 mg, 2.01 mmol). ), stirred at room temperature for 5 hours, the reaction was monitored by TLC, the reaction solution was concentrated, and purified by silica gel column chromatography to obtain the target product 5-((1S,5R)-1-(5-(tetrahydro-2H-pyran-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-3-yl)quinoline-8-carbonitrile compound 12 (yellow solid, 185 mg, yield: 60.0%).

[0405] LC-MS m / z (ESI) = 456.2 [M+1].

[0406] Example 13

[0407] 5-((1S,5R)-1-(5-(2-methyl-2-azaspiro[3.5]nonyl7-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azacyclo[3.1.0]hexyl-3-yl)quinoline-8-carbonitrile compound 13

[0408] 5-((1S,5R)-1-(5-(2-methyl-2-azaspiro[3.5]nonan-7-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

[0409] first step:

[0410] tert-Butyl 7-(2-(1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azacyclo[3.1.0]hexane-1-carbonyl)hydrazine-1-carbonyl)-2-azacyclo[3.5]nonane-2-carboxylate

[0411] tert-butyl 7-(2-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbonyl)hydrazine-1-carbonyl)-2-azaspiro[3.5]nonane-2-carboxylate

[0412] 2-(tert-Butylcarbonyl)-2-azaspiro[3.5]nonane-7-carboxylic acid 13-1 (150 mg, 0.55 mmol) was dissolved in 5 mL of dichloromethane, followed by the addition of HATU (315 mg, 0.83 mmol) and DIEA (145 mg, 1.1 mmol). The mixture was stirred at room temperature for 15 minutes, and then (1S, 5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azacyclo[3.1.0]hexane-1 was added. -Carbohydrazide 3-1 (200 mg, 0.55 mmol) LCMS monitoring reaction was complete, the reaction solution was directly concentrated, and purified by reverse phase C18 column chromatography (acid method) to obtain 7-(2-(1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azacyclo[3.1.0]hexane-1-carbonyl)hydrazine-1-carbonyl)-2-azacyclo[3.5]nonane-2-carboxylate tert-butyl 13-2 (pale yellow solid, 250 mg, 41%)

[0413] LC-MS m / z (ESI) = 613.20 [M+H] + .

[0414] Step 2:

[0415] tert-Butyl 7-(5-(1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azacyclo[3.1.0]hexen-1-yl)-1,3,4-oxadiazol-2-yl)-2-azacyclo[3.5]nonane-2-carboxylate

[0416] tert-butyl 7-(5-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazol-2-yl)-2-azaspiro[3.5]nonane-2-carboxylate

[0417] 7-(2-(1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azacyclo[3.1.0]hexane-1-carbonyl)hydrazine-1-carbonyl)-2-azacyclo[3.5]nonane-2-carboxylate tert-butyl 13-2 (250 mg, 0.4 mmol) was dissolved in 1,4-dioxane 5 mL, followed by the addition of TsCl (155 mg, 0.8 mmol), Cs2CO3 (400 mg, 1. The reaction mixture was stirred at room temperature for 2 hours under nitrogen atmosphere (2 mmol). The reaction was monitored by LCMS for completion. Ethyl acetate and water were added for extraction, and the organic phase was spin-dried to give the crude target product tert-butyl 7-(5-(1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azacyclo[3.1.0]hexen-1-yl)-1,3,4-oxadiazol-2-yl)-2-azacyclo[3.5]nonane-2-carboxylate 13-3 (yellow oil, 200 mg).

[0418] LC-MS m / z (ESI) = 595.30 [M+H] + .

[0419] Step 3:

[0420] 5-((1S,5R)-1-(5-(2-azacyclo[3.5]nonyl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azacyclo[3.1.0]hexyl-3-yl)quinoline-8-carbonitrile 13-4

[0421] 5-((1S,5R)-1-(5-(2-azaspiro[3.5]nonan-7-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

[0422] 7-(5-(1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azacyclo[3.1.0]hexen-1-yl)-1,3,4-oxadiazol-2-yl)-2-azacyclo[3.5]nonane-2-carboxylate tert-butyl 13-3 (200 mg, 0.33 mmol) was dissolved in 10 mL of dichloromethane, and then 5 mL of trifluoroacetic acid was added and stirred at room temperature for 1 hour. The reaction was completed after LCMS monitoring, and the reaction solution was directly concentrated and purified by reverse phase C18 column chromatography (acid method) to obtain the target compound 5-((1S,5R)-1-(5-(2-azacyclo[3.5]nonyl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azacyclo[3.1.0]hexyl-3-yl)quinoline-8-carbonitrile 13-4 (yellow oil, 170 mg, 100%).

[0423] LC-MS m / z (ESI) = 495.20 [M+H] + .

[0424] Step 4:

[0425] 5-((1S,5R)-1-(5-(2-methyl-2-azaspiro[3.5]nonyl7-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azacyclo[3.1.0]hexyl-3-yl)quinoline-8-carbonitrile compound 13

[0426] 5-((1S,5R)-1-(5-(2-methyl-2-azaspiro[3.5]nonan-7-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

[0427] 5-((1S,5R)-1-(5-(2-azacyclo[3.5]nonyl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azacyclo[3.1.0]hexyl-3-yl)quinoline-8-carbonitrile 13-4 (170 mg, 0.35 mmol) was dissolved in 10 mL of dichloromethane, followed by the addition of paraformaldehyde (210 mg, 7 mmol), sodium cyanoborohydride (220 mg, 3.5 mmol) and the like. The mixture was stirred at room temperature for 6 hours. The reaction was completed as monitored by LCMS. The reaction solution was directly concentrated and purified by reverse phase C18 column chromatography (alkaline method) to obtain the target product 5-((1S,5R)-1-(5-(2-methyl-2-azaspiro[3.5]nonyl7-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azacyclo[3.1.0]hexyl-3-yl)quinoline-8-carbonitrile compound 13 (white solid, 50 mg, 28%).

[0428] 1 H NMR (400MHz, DMSO-d6) δ9.03 (dd, 1H), 8.69 (dd, 1H), 8.20 (d, 1H), 7.63 (dd, 1H), 7.34 (d, 1H), 4.19 (d, 1H), 4. 06(dd, 2H), 3.91(s, 1H), 2.97(s, 4H), 2.25(s, 3H), 2.21(d, 1H), 1.93-1.78(m, 4H), 1.53(d, 4H), 1.16(s, 2H).

[0429] LC-MS m / z (ESI) = 509.20 [M+H] + .

[0430] Example 14

[0431] 5-(1S,5R)-1-(5-(S)-4-methylmorpholin-2-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-3-yl)quinoline-8-carbonitrile compound 14

[0432] 5-((1S,5R)-1-(5-((S)-4-methylmorpholin-2-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

[0433] first step:

[0434] tert-Butyl 5-(2-(1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azacyclo[3.1.0]hexane-1-carbonyl)hydrazine-1-carbonyl)-2-azacyclo[2.2.1]heptane-2-carboxylate

[0435] tert-butyl 5-(2-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbonyl)hydrazine-1-carbonyl)-2-azabicyclo[2.2.1]heptane-2-carboxylate

[0436] 2-(tert-Butylcarbonyl)-2-azacyclo[2.2.1]heptane-5-carboxylic acid 14-1 (135 mg, 0.55 mmol) was dissolved in 5 mL of dichloromethane, and then HATU (320 mg, 0.83 mmol) and DIPEA (145 mg, 1.1 mmol) were added in an ice bath and stirred at low temperature for 1 minute. The mixture was stirred for 5 minutes, and then (1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azacyclo[3.1.0]hexane-1-carbohydrazide 3-1 (200 mg, 0.55 mmol) was added and stirred for 1 hour. The reaction was monitored by LCMS. The reaction solution was directly concentrated and purified by reverse phase C18 column chromatography (acid method) to obtain the target product 5-(2-(1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azacyclo[3.1.0]hexane-1-carbonyl)hydrazine-1-carbonyl)-2-azacyclo[2.2.1]heptane-2-carboxylate tert-butyl 14-2 (pale yellow solid, 130 mg, 45%).

[0437] LC-MS m / z (ESI) = 585.30 [M+H] + .

[0438] Step 2:

[0439] tert-Butyl 5-(5-(1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azacyclo[3.1.0]hexen-1-yl)-1,3,4-oxadiazol-2-yl)-2-azacyclo[2.2.1]heptane-2-carboxylate

[0440] tert-butyl 5-(5-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate

[0441] 5-(2-(1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azacyclo[3.1.0]hexane-1-carbonyl)hydrazine-1-carbonyl)-2-azacyclo[2.2.1]heptane-2-carboxylate tert-butyl 14-2 (110 mg, 0.2 mmol) was dissolved in 3 mL 1,4-dioxane was added, followed by the addition of TsCl (76 mg, 0.4 mmol) and Cs2CO3 (200 mg, 0.6 mmol), and the mixture was stirred at room temperature for 5 hours. The reaction was monitored by LCMS. The mixture was extracted with ethyl acetate and water, and the organic phase was spin-dried to give the crude target compound 5-(5-(1S, 5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azacyclo[3.1.0]hexen-1-yl)-1,3,4-oxadiazol-2-yl)-2-azacyclo[2.2.1]heptane-2-carboxylate tert-butyl 14-3 (yellow oil, 100 mg).

[0442] LC-MS m / z (ESI) = 567.30 [M+H] + .

[0443] Step 3:

[0444] 5-((1S,5R)-1-(5-(2-azacyclo[2.2.1]heptane-5-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azacyclo[3.1.0]hexane-3-yl)quinoline-8-carbonitrile 14-4

[0445] 5-((1S,5R)-1-(5-(2-azabicyclo[2.2.1]heptan-5-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

[0446] 5-(5-(1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azacyclo[3.1.0]hexen-1-yl)-1,3,4-oxadiazol-2-yl)-2-azacyclo[2.2.1]heptane-2-carboxylate tert-butyl 14-3 (100 mg, 0.18 mmol) was dissolved in 10 mL of dichloromethane, and then 5 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 1 hour. The reaction was completed after LCMS monitoring. The reaction solution was directly concentrated and purified by reverse phase C18 column chromatography (acid method) to obtain the target compound 5-((1S,5R)-1-(5-(2-azacyclo[2.2.1]heptane-5-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azacyclo[3.1.0]hexane-3-yl)quinoline-8-carbonitrile 14-4 (yellow solid, 90 mg, 97%).

[0447] LC-MS m / z (ESI) = 467.20 [M+H] + .

[0448] Step 4:

[0449] 5-((1S,5R)-1-(5-(2-methyl-2-azacyclo[2.2.1]heptane-5-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azacyclo[3.1.0]hexane-3-yl)quinoline-8-carbonitrile compound 14

[0450] 5-((1S,5R)-1-(5-(2-methyl-2-azabicyclo[2.2.1]heptan-5-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

[0451] 5-((1S,5R)-1-(5-(2-azacyclo[2.2.1]heptane-5-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azacyclo[3.1.0]hexane-3-yl)quinoline-8-carbonitrile 14-4 (90 mg, 0.2 mmol) was dissolved in 10 mL of dichloromethane, followed by the addition of paraformaldehyde (120 mg, 4 mmol) and sodium cyanoborohydride (130 mg, 2 mmol). The mixture was stirred at room temperature for 3 hours. The reaction was completed as monitored by LCMS. The reaction solution was directly concentrated and purified by reverse phase C18 column chromatography (alkaline method) to give the target product 5-((1S,5R)-1-(5-(2-methyl-2-azacyclo[2.2.1]heptane-5-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azacyclo[3.1.0]hexane-3-yl)quinoline-8-carbonitrile compound 14 (yellow solid, 90 mg, 97%).

[0452] 1 H NMR (400MHz, DMSO-d6) δ9.03 (d, 1H), 8.69 (d, 1H), 8.20 (d, 1H), 7.63 (dd, 1H), 7.34 (dd, 1H), 4.22 (d, 1H), 4.12-4.00 (m, 2H), 3.9 4(dd, 1H), 3.11(s, 1H), 2.66(s, 1H), 2.24-2.21(m, 3H), 2.18(s, 2H), 2.08(s, 3H), 1.94-1.82(m, 2H), 1.76(d, 1H), 1.53(d, 1H).

[0453] LC-MS m / z (ESI) = 481.20 [M+H] + .

[0454] Example 15

[0455] 5-((1S,5R)-1-(5-((1-methylpiperidin)-4-yl)oxy)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-3-yl)quinoxaline-8-carbonitrile Compound 15

[0456] 5-((1S,5R)-1-(5-((1-methylpiperidin-4-yl)oxy)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

[0457] first step:

[0458] Benzyl 1-methylpiperazine-4-hydrazinecarboxylate 15-2

[0459] methylpiperidin-4-yl hydrazinecarboxylate

[0460] Triphosgene (3.90 g, 13.2 mmol) was dissolved in 10.0 mL of dichloromethane, and a mixed solution of 4-oxy-1-methylpiperidine (1.00 g, 8.77 mmol) and triethylamine (1.75 g, 17.5 mmol) in 10.0 mL of dichloromethane was slowly added dropwise at 0°C. After the reaction for 1 h, hydrazine hydrate (1.28 g, 40.0 mmol) was slowly added dropwise. After the reaction for 1 h, the sample was sent to LCMS for completion of the reaction. The solution was concentrated to give 4.3 g of crude product 1-methylpiperazine-4-hydrazinecarboxylic acid benzyl ester 15-2 (yellow oily liquid).

[0461] Step 2:

[0462] 1-Methylpiperidin-4-yl-2-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxyl)hydrazine-1-carboxylic acid benzyl ester 15-3

[0463] 1-methylpiperidin-4-yl-2-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbonyl)hydrazine-1-carboxylate

[0464] The crude product of 1-methylpiperazine-4-hydrazinecarboxylic acid benzyl ester (1.00 g, crude) and (1S, 5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid B-1 (250 mg, 0.72 mmol) were dissolved in 10.0 mL of phosphorus oxychloride, refluxed at 90 ° C for 3 h, and sampled by LCMS. After the reaction was completed, a hydrogen peroxide was added. The solution was quenched by adjusting the pH to 7-8 with sodium hydroxide solution, freeze-dried, added with dichloromethane, filtered, and the organic phase was concentrated. The target product, 1-methylpiperidin-4-yl-2-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-formyl)hydrazine-1-carboxylic acid benzyl ester 15-3 (yellow solid, 120 mg, yield: 33%), was obtained by reverse preparation.

[0465] Step 3

[0466] 5-((1S,5R)-1-(5-((1-methylpiperidin)-4-yl)oxy)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-3-yl)quinoxaline-8-carbonitrile Compound 15

[0467] 5-((1S,5R)-1-(5-((1-methylpiperidin-4-yl)oxy)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

[0468] Benzyl 1-methylpiperidin-4-yl-2-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxyl)hydrazine-1-carboxylate 15-3 (90 mg, 0.19 mmol) was dissolved in 2.00 mL of acetonitrile, followed by addition of cesium carbonate (200 mg, 0.57 mmol) and p-toluene yellow acid chloride (113 mg, 0.57 mmol) at 80 °C. The mixture was stirred for 5 hours. The reaction was monitored by TLC to completion. The reaction solution was concentrated, separated by MPLC, and purified by silica gel column chromatography to obtain the target product 55-((1S,5R)-1-(5-((1-methylpiperidin-4-yl)oxy)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoxaline-8-carbonitrile compound 15 (yellow solid, 20 mg, yield: 23%).

[0469] 1 H NMR (400MHz, DMSO-d6) δ9.02 (dd, 1H), 8.68 (dd, 1H), 8.20 (d, 1H), 7.62 (dd, 1H), 7.32 (d, 1H), 4.90-4.83 (m, 1H), 4.14 (d, 1 H), 4.08(d, 1H), 3.99(d, 1H), 3.90(d, 1H), 3.30(s, 1H), 2.54(s, 2H), 2.22(s, 2H), 2.16(d, 4H), 2.03(s, 2H), 1.80(d, 2H).

[0470] LC-MS m / z (ESI) = 485.10 [M+1].

[0471] Example 16

[0472] 2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-(4-(m-tolyl)-4H-1,2,4-triazol-3-yl)hexahydrocyclopenta[c]pyrrole-1(2H)-one compound 16

[0473] 2-(6-methyl-4-(trifluoromethyl)-pyridin-2-yl)-3-(4-(m-tolyl)-4H-1,2,4-triazol-3-yl)hexahydrocyclopenta[c]pyrrol-1(2H)-one

[0474] first step:

[0475] 6-(2-((1S,5R)-5-(trifluoromethyl)-3-(8-(trifluoromethyl)quinolin-5-yl)-3-azabicyclo[3.1.0]hexane-1-carboxyl)hydrazine-1-carboxyl)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester Compound 16-1

[0476] tert-butyl 6-(2-((1S,5R)-5-(trifluoromethyl)-3-(8-(trifluoromethyl)quinolin-5-yl)-3-azabicyclo[3.1.0]hexane-1-carbonyl)hydrazine-1-carbonyl)-2-azaspiro[3.3]heptane-2-carboxylate

[0477] 2-(tert-Butyloxycarbonyl)-2-azaspiro[3.3]heptane-6-carboxylic acid (180 mg, 0.75 mmol) was dissolved in anhydrous dichloromethane (10 mL), followed by the addition of DIPEA (193 mg, 1.5 mmol) and HATU (427 mg, 1.12 mmol). After activation at 40°C for 30 minutes, (1S,5R)-5-(trifluoromethyl)-3-(8-(trifluoromethyl)quinolin-5-yl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid hydrazide 75-3 (303 mg, 0.75 mmol) was added. The mixture was reacted at room temperature under nitrogen for 1 hour. The mixture was extracted three times with water and dichloromethane. The organic phase was collected, dried, and concentrated to obtain the crude product. The crude product was separated by column chromatography to obtain tert-butyl 6-(2-((1S,5R)-5-(trifluoromethyl)-3-(8-(trifluoromethyl)quinolin-5-yl)-3-azabicyclo[3.1.0]hexane-1-formyl)hydrazine-1-formyl)-2-azaspiro[3.3]heptane-2-carboxylate compound 16-1 (300 mg, yellow solid, yield 63%).

[0478] LCMS m / z (ESI) = 628.23 [M+1].

[0479] Step 2:

[0480] 6-(5-((1S,5R)-5-(trifluoromethyl)-3-(8-(trifluoromethyl)quinolin-5-yl)-3-azabicyclo[3.1.0]hexane-1-yl)-1,3,4-oxadiazol-2-yl)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester Compound 16-2

[0481] tert-butyl 6-(5-((1S,5R)-5-(trifluoromethyl)-3-(8-(trifluoromethyl)quinolin-5-yl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazol-2-yl)-2-azaspiro[3.3]heptane-2-carboxylate

[0482] Tert-butyl 6-(2-((1S,5R)-5-(trifluoromethyl)-3-(8-(trifluoromethyl)quinolin-5-yl)-3-azabicyclo[3.1.0]hexane-1-formyl)hydrazine-1-formyl)-2-azaspiro[3.3]heptane-2-carboxylate 16-1 (300 mg, 0.47 mmol) was dissolved in anhydrous acetonitrile (6 mL), followed by the addition of cesium carbonate (311 mg, 0.95 mmol) and p-toluenesulfonyl chloride (181 mg, 0.95 mmol), and the reaction was carried out at 80°C for 2 hours. The reaction solution was then directly filtered, the filter cake was rinsed twice with methanol, the filtrate was concentrated to dryness, and the target product 6-(5-((1S, 5R)-5-(trifluoromethyl)-3-(8-(trifluoromethyl)quinolin-5-yl)-3-azabicyclo[3.1.0]hexane-1-yl)-1,3,4-oxadiazol-2-yl)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester compound 16-2 (200 mg, light yellow solid, yield 69%) was obtained after column chromatography.

[0483] LCMS m / z (ESI) = 610.22 [M+1].

[0484] Step 3:

[0485] 2-(2-azaspiro[3.3]heptane-6-yl)-5-((1S,5R)-5-(trifluoromethyl)-3-(8-(trifluoromethane)quinolin-5-yl)-3-azabicyclo[3.1.0]hexane-1-yl)-1,3,4-oxadiazole compound 16-3

[0486] 2-(2-azaspiro[3.3]heptan-6-yl)-5-((1S,5R)-5-(trifluoromethyl)-3-(8-(trifluoromethyl)quinolin-5-yl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazole

[0487] Tert-butyl 6-(5-((1S,5R)-5-(trifluoromethyl)-3-(8-(trifluoromethyl)quinolin-5-yl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazol-2-yl)-2-azaspiro[3.3]heptane-2-carboxylate 16-2 (200 mg, 0.32 mmol) was dissolved in anhydrous dichloromethane (4 mL), and trifluoroacetic acid (1 mL) was subsequently added and reacted at room temperature for 30 minutes. Subsequently, a saturated aqueous sodium carbonate solution was added to the reaction solution to adjust the pH to alkaline, and dichloromethane and water were added to extract three times. The organic phase was dried and concentrated to obtain compound 2-(2-azaspiro[3.3]heptane-6-yl)-5-((1S, 5R)-5-(trifluoromethyl)-3-(8-(trifluoromethane)quinolin-5-yl)-3-azabicyclo[3.1.0]hexane-1-yl)-1,3,4-oxadiazole compound 16-3 (130 mg, light yellow solid, yield 77%), which was directly used in the next reaction.

[0488] LCMS m / z=510.17[M+1].

[0489] Step 4:

[0490] 2-(2-methyl-2-azaspiro[3.3]heptane-6-yl)-5-((1S,5R)-5-(trifluoromethyl)-3-(8-(trifluoromethyl)quinolin-5-yl)-3-azabicyclo[3.1.0]hexane-1-yl)-1,3,4-oxadiazole compound 16

[0491] 2-(2-methyl-2-azaspiro[3.3]heptan-6-yl)-5-((1S,5R)-5-(trifluoromethyl)-3-(8-(trifluorom ethyl)quinolin-5-yl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazole

[0492] 2-(2-Azaspiro[3.3]heptane-6-yl)-5-((1S,5R)-5-(trifluoromethyl)-3-(8-(trifluoromethyl)quinolin-5-yl)-3-azabicyclo[3.1.0]hexane-1-yl)-1,3,4-oxadiazole 16-3 (130 mg, 0.25 mmol) was dissolved in 5 mL of methanol, followed by the addition of 1 mL of triethylamine, paraformaldehyde (250 mg, 9 mmol), sodium cyanoborohydride (506 mg, 13.5 mmol). ) was heated to 60 degrees and stirred for 3 hours. After the reaction was completed by TLC, the reaction solution was directly filtered and concentrated, and purified by TLC (DCM:MeOH=10:1) to obtain 2-(2-methyl-2-azaspiro[3.3]heptane-6-yl)-5-((1S,5R)-5-(trifluoromethyl)-3-(8-(trifluoromethyl)quinolin-5-yl)-3-azabicyclo[3.1.0]hexane-1-yl)-1,3,4-oxadiazole compound 16 (pale yellow solid, 30 mg, 23.8%).

[0493] LC-MS m / z (ESI) = 524.10 [M+1].

[0494] 1 H NMR (400MHz, Chloroform-d) δ9.00 (dt, 1H), 8.30 (dt, 1H), 7.93 (d, 1H), 7.44 (dd, 1H), 7.13 (dd, 1H), 4.10 (dd, 3H), 3.97 (d, 1H), 3.87-3.78 (m, 2H), 3.67 (t, 2H), 3.61-3.54 (m, 1H), 2.90-2.79 (m, 4H), 2.77 (s, 1H), 2.66 (dd, 2H), 2.24 (q, 2H).

[0495] Example 17

[0496] 2-(4-(5-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazol-2-yl)piperidin-1-yl)acetamide Compound 17

[0497] 2-(4-(5-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazol-2-yl)piperidin-1-yl)acetamide

[0498] first step:

[0499] 5-(1S,5R)-1-(5-(1-tert-butyloxycarbonylpiperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-3-yl)quinoline-8-carbonitrile 17-2

[0500] tert-butyl 4-(5-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazol-2-yl)piperidine-1-carboxylate

[0501] (1S, 5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbonic acid B-1 (250 mg, 0.718 mmol) was dissolved in 10 ml of dichloromethane, followed by the addition of HATU (411 mg, 1.08 mmol) and DIPEA (321 mg, 2.49 mmol). The mixture was stirred at low temperature for 5 minutes, and then 1-Boc-4-piperidinecarboxylic acid hydrazide 17-1 (210 mg, 0.862 mmol) was added and stirred for 2 minutes. After 1 h, the reaction was complete by TLC, and then Burgess reagent (1100 mg, 3.9 mmol) was added and stirred for 3 h. After the reaction was complete by LCMS, the reaction solution was directly concentrated and purified by reverse phase C18 column chromatography (acid method) to obtain the target product 5-(1S,5R)-1-(5-(1-tert-butyloxycarbonylpiperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-3-yl)quinoline-8-carbonitrile 17-2 (pale yellow solid, 380 mg crude product).

[0502] Step 2:

[0503] 5-((1S,5R)-1-(5-(1-piperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-3-yl)quinoline-8-carbonitrile 17-3

[0504] 5-((1S,5R)-1-(5-(piperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

[0505] 100 mg of the crude product 5-(1S,5R)-1-(5-(1-tert-butyloxycarbonylpiperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-3-yl)quinoline-8-carbonitrile 17-2 was added to 2.00 mL of hydrochloric acid and ethyl acetate solution. After stirring for half an hour, the reaction was completed by LCMS. The reaction solution was concentrated and adjusted to pH 7-8 with triethylamine. After TLC thin layer preparation (dichloromethane: methanol = 5:1), the product 17-3 (pale yellow solid, 30 mg, 37%) was obtained.

[0506] 1 H NMR (400MHz, DMSO-d6) δ9.02 (dd, 1H), 8.69 (dd, 1H), 8.20 (d, 1H), 7.63 (dd, 1H), 7.33 (d, 1H), 4.19 (d, 1H), 4.07 (dd, 2H), 3.93 (d, 1H), 3.10 (ddd, 1H), 3.04-2.94 (m, 2H), 2.65 (td, 2H), 2.22 (s, 2H), 1.93 (dd, 2H), 1.88 (s, 1H), 1.70-1.56 (m, 2H).

[0507] 19 F NMR(376MHz, DMSO-d6)δ-64.11.

[0508] LC-MS m / z (ESI) = 455.10 [M+1].

[0509] Step 3:

[0510] 2-(4-(5-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazol-2-yl)piperidin-1-yl)acetamide Compound 17

[0511] 2-(4-(5-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazol-2-yl)piperidin-1-yl)acetamide

[0512] The above product 5-(1S,5R)-1-(5-(1-piperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-3-yl)quinoline-8-carbonitrile 17-3 (120 mg, 0.263 mmol) was added to dichloroethane 3.00 mL, DBU (202 mg, 1.30 mmol), bromoacetamide (178 mg, 1.30 mmol), After stirring at 60°C for 3 hours, the reaction was completed by LCMS. The reaction solution was directly concentrated and purified by reverse phase C18 column chromatography (acid method) to obtain the target product 2-(4-(5-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazol-2-yl)piperidin-1-yl)acetamide compound 17 (pale yellow solid, 30 mg, 22%).

[0513] LC-MS m / z (ESI) = 512.10 [M+1].

[0514] 1 H NMR (400MHz, DMSO-d6) δ9.03 (dd, 1H), 8.69 (dd, 1H), 8.21 (d, 1H), 7.63 (dd, 1H), 7.34 (d, 1H), 7.17 (d, 2H), 4.20 (d, 1H), 4. 07(dd, 2H), 3.93(d, 1H), 2.97(s, 1H), 2.85(s, 2H), 2.79(d, 2H), 2.30-2.16(m, 3H), 1.97(d, 2H), 1.80(d, 2H), 1.23(s, 1H).

[0515] Example 18

[0516] 5-((1S,5R)-1-(5-(2-methyl-2-azaspiro[3.3]heptane-6-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-3-yl)quinoline-8-carbonitrile Compound 18

[0517] 5-((1S,5R)-1-(5-(2-methyl-2-azaspiro[3.3]heptan-6-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

[0518] first step:

[0519] tert-Butyl 6-(2-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbonyl)hydrazine-1-carbonyl)-2-azaspiro[3.3]heptane-2-carboxylate 18-2

[0520] tert-butyl 6-(2-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbonyl)hydrazine-1-carbonyl)-2-azaspiro[3.3]heptane-2-carboxylate

[0521] The raw material 2-(tert-butoxycarbonyl)-2-azaspiro[3.3]heptane-6-carboxylic acid 18-1 (724 mg, 1.5 mmol) was added to N,N-dimethylformamide (5 ml), and then N,N,N′,N′-tetramethyl-O-(7-azabenzotriazole-1-yl)uronium hexafluorophosphate (1140 mg, 1.5 mmol) and N,N-diisopropylethylamine (516 mg, 2.0 mmol) were added. The reaction mixture was stirred at room temperature for 0.5 hours, and then (1S,5R)-3-(8-cyanoquinoline) was added. -5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbohydrazide 3-1 (722 mg, 2.0 mmol), the reaction mixture was stirred at room temperature for 6 hours, and then purified by reverse phase column chromatography to obtain 6-(2-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbonyl)hydrazine-1-carbonyl)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester 18-2 (980 mg, yield 83.8%).

[0522] LCMS m / z (ESI) = 585.2 [M+1].

[0523] Step 2:

[0524] tert-Butyl 6-(5-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazol-2-yl)-2-azaspiro[3.3]heptane-2-carboxylate 18-3

[0525] tert-butyl 6-(5-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazol-2-yl)-2-azaspiro[3.3]heptane-2-carboxylate

[0526] Tert-butyl 6-(2-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbonyl)hydrazine-1-carbonyl)-2-azaspiro[3.3]heptane-2-carboxylate 18-2 (980 mg, 1.68 mmol) was dissolved in 10 mL of dichloromethane, followed by the addition of triethylamine (849 mg, 8.40 mmol), p-toluenesulfonyl chloride (962 mg, 5.04 mmol). ol), stirred at room temperature for 5 hours. The reaction was monitored by TLC. The reaction solution was concentrated and purified by silica gel column chromatography to obtain the target product 6-(5-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazol-2-yl)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester 18-3 (yellow solid, 675 mg, yield: 70.9%).

[0527] LC-MS m / z (ESI) = 567.2 [M+1].

[0528] Step 3:

[0529] 5-((1S,5R)-1-(5-(2-azaspiro[3.3]heptane-6-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-3-yl)quinoline-8-carbonitrile Compound 18

[0530] 5-((1S,5R)-1-(5-(2-azaspiro[3.3]heptan-6-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

[0531] The raw material 6-(5-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazol-2-yl)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester 18-3 (675 mg, 1.19 mmol) was added to dichloromethane (6 ml), and trifluoroacetic acid ( The reaction solution was reacted at room temperature for 2 hours, concentrated under reduced pressure, and then purified by reverse column to obtain 5-((1S,5R)-1-(5-(2-azaspiro[3.3]heptane-6-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-3-yl)quinoline-8-carbonitrile compound 18 (430 mg, yield 77.3%).

[0532] LC-MS m / z (ESI) = 467.2 [M+1].

[0533] 1 H NMR (400MHz, Chloroform-d) δ9.09 (dd, 1H), 8.37 (dd, 1H), 8.05 (d, 1H), 7.54 (dd, 1H), 7.17 (d, 1H), 4.39 (s, 1H), 4.11(d, 1H), 4.03-3.69(m, 7H), 3.59(m, 1H), 2.80-2.67(m, 2H), 2.60(h, 2H), 2.32(d, 1H), 2.23(d, 1H).

[0534] 19 F NMR (377MHz, Chloroform-d) δ-65.21.

[0535] Example 19

[0536] 5-((1S,5R)-1-(5-(2-methyl-2-azaspiro[3.3]heptane-6-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-3-yl)quinoline-8-carbonitrile Compound 19

[0537] 5-((1S,5R)-1-(5-(2-methyl-2-azaspiro[3.3]heptan-6-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

[0538] 5-((1S,5R)-1-(5-(2-methyl-2-azaspiro[3.3]heptane-6-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-3-yl)quinoline-8-carbonitrile Compound 19

[0539] 5-((1S,5R)-1-(5-(2-methyl-2-azaspiro[3.3]heptan-6-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

[0540] 5-((1S,5R)-1-(5-(2-azaspiro[3.3]heptane-6-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-3-yl)quinoline-8-carbonitrile compound 18 (380 mg, 0.81 mmol) was dissolved in 5 mL of methanol, followed by the addition of paraformaldehyde (243 mg, 8.1 mmol), sodium cyanoborohydride (1.02 g, 16.2 The reaction mixture was stirred at room temperature for 3 hours. After the reaction was completed by TLC, the reaction solution was directly concentrated and purified by reverse column chromatography to obtain the target product 5-((1S,5R)-1-(5-(2-methyl-2-azaspiro[3.3]heptane-6-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-3-yl)quinoline-8-carbonitrile compound 19 (pale yellow solid, 215 mg, 55.0%).

[0541] LC-MS m / z (ESI) = 481.2 [M+1].

[0542] 1 H NMR (400MHz, DMSO-d6) δ9.02 (s, 1H), 8.67 (d, 1H), 8.19 (d, 1H), 7.62 (s, 1H), 7.32 (d, 1H), 4.05(ddd, 4H), 3.63(s, 1H), 3.10(d, 4H), 2.34(s, 4H), 2.21(s, 2H), 2.13(s, 3H).

[0543] 19 F NMR(377MHz, DMSO-d6)δ-64.10.

[0544] Example 20

[0545] 5-((1S,5R)-1-(5-(((1R,4S)-4-aminocyclohexyl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hex-3-yl)quinoline-8-carbonitrile compound 20

[0546] 5-((1S,5R)-1-(5-((1R,4S)-4-aminocyclohexyl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

[0547] first step:

[0548] tert-Butyl (1S,4R)-4-(2-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbonyl)hydrazine-1-carbonyl)cyclohexyl)carbamate 20-2

[0549] tert-butyl((1S,4R)-4-(2-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo-[3.1.0]hexane-1-carbonyl)hydrazine-1-carbonyl)cyclohexyl)carbamate

[0550] The raw material (1r, 4r)-4-((tert-butoxycarbonyl)amino)cyclohexane-1-carboxylic acid 20-1 (243 mg, 1.0 mmol) was added to N, N-dimethylformamide (5 ml), and N, N, N', N'-tetramethyl-O-(7-azabenzotriazole-1-yl) urea hexafluorophosphate (570 mg, 1.5 mmol) and N, N-diisopropylethylamine (258 mg, 2.0 mmol) were added. The reaction mixture was stirred at room temperature for 0.5 hours, and then (1S, 5R)-3-(8-cyanoquinoline) was added. The reaction mixture was stirred at room temperature for 6 hours and then purified by reverse phase column chromatography to obtain tert-butyl (1S,4R)-4-(2-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbonyl)hydrazine-1-carbonyl)cyclohexyl)carbamate 20-2 (415 mg, yield 70.7%).

[0551] LCMS m / z (ESI) = 587.2 [M+1].

[0552] Step 2:

[0553] tert-Butyl (1S,4R)-4-(5-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazol-2-yl)cyclohexyl)carbamate 20-3

[0554] tert-butyl((1S,4R)-4-(5-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazol-2-yl)cyclohexyl)carbamate

[0555] Tert-butyl (1S,4R)-4-(2-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbonyl)hydrazine-1-carbonyl)cyclohexyl)carbamate 20-2 (415 mg, 0.71 mmol) was dissolved in 10 mL of dichloromethane, followed by the addition of triethylamine (338 mg, 3.35 mmol), p-toluenesulfonyl chloride (382 mg, 2.01 mmol). ol), stirred at room temperature for 5 hours. The reaction was monitored by TLC. The reaction solution was concentrated and purified by silica gel column chromatography to obtain the target product, tert-butyl (1S,4R)-4-(5-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazol-2-yl)cyclohexyl)carbamate 20-3 (yellow solid, 323 mg, yield: 80.0%).

[0556] LC-MS m / z (ESI) = 569.2 [M+1].

[0557] Step 3:

[0558] 5-((1S,5R)-1-(5-(((1R,4S)-4-aminocyclohexyl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hex-3-yl)quinoline-8-carbonitrile compound 20

[0559] 5-((1S,5R)-1-(5-((1R,4S)-4-aminocyclohexyl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

[0560] The raw material (1S,4R)-4-(5-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazol-2-yl)cyclohexyl)carbamic acid tert-butyl ester 20-3 (300 mg, 0.5 mmol) was added to dichloromethane (6 ml), and trifluoroacetic acid (3 ml) was added. The reaction solution was reacted at room temperature for 2 hours, concentrated under reduced pressure, and then purified by reverse column chromatography to obtain 5-((1S,5R)-1-(5-(((1R,4S)-4-aminocyclohexyl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile compound 20 (215 mg, yield 89.4%).

[0561] LC-MS m / z (ESI) = 469.2 [M+1].

[0562] 1 H NMR (400MHz, DMSO-d6) δ9.02 (dd, 1H), 8.68 (dd, 1H), 8.20 (d, 1H), 8.03 (s, 2H), 7.62 (dd, 1H), 7.33 (d, 1H), 4.19 (d, 1H), 4.06 (dd , 2H), 3.91(d, 1H), 3.13-3.02(m, 1H), 2.99-2.94(m, 1H), 2.22(s, 2H), 2.16-2.07(m, 2H), 2.06-1.98(m, 2H), 1.67-1.40(m, 4H).

[0563] 19 F NMR(377MHz, DMSO-d6)δ-64.11.

[0564] Example 21

[0565] 5-((1S,5R)-1-(5-((1R,4S)-4-(dimethylamino)cyclohexyl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hex-3-yl)quinoline-8-carbonitrile compound 21

[0566] 5-((1S,5R)-1-(5-((1R,4S)-4-(dimethylamino)cyclohexyl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

[0567] 5-((1S,5R)-1-(5-(((1R,4S)-4-aminocyclohexyl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile compound 20 (160 mg, 0.34 mmol) was dissolved in 5 mL of methanol, followed by the addition of paraformaldehyde (102 mg, 3.4 mmol), sodium cyanoborohydride (427 mg, 6. The reaction mixture was stirred at room temperature for 3 hours. After the reaction was completed by TLC, the reaction solution was directly concentrated and purified by reverse column chromatography to obtain the target product 5-((1S,5R)-1-(5-((1R,4S)-4-(dimethylamino)cyclohexyl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hex-3-yl)quinoline-8-carbonitrile compound 21 (pale yellow solid, 55 mg, 32.5%).

[0568] LC-MS m / z (ESI) = 497.2 [M+1].

[0569] 1 H NMR (400MHz, DMSO-d6) δ9.03 (dd, 1H), 8.69 (dd, 1H), 8.21 (d, 1H), 7.63 (dd, 1H), 7.33 (d, 1H), 4.19 (d, 1 H), 4.06(dd, 2H), 3.92(d, 1H), 3.17(s, 1H), 2.98(d, 1H), 2.65(s, 6H), 2.29-2.04(m, 6H), 1.58(q, 4H).

[0570] 19 F NMR(377MHz, DMSO-d6)δ-64.09.

[0571] Example 22

[0572] 5-((1S,5R)-1-(5-(2,5-dihydro-1H-pyrrol-3-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile Compound 22

[0573] 5-((1S,5R)-1-(5-(2,5-dihydro-1H-pyrrol-3-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

[0574] first step:

[0575] 3-(2-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbonyl)hydrazine-1-carbonyl)-2,5-dihydro-1H-pyrrole-1-carboxylic acid tert-butyl ester 22-2

[0576] tert-butyl 3-(2-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbonyl)hydrazine-1-carbonyl)-2,5-dihydro-1H-pyrrole-1-carboxylate

[0577] The raw material (3R, 4S)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-3-carboxylic acid 22-1 (233 mg, 1.0 mmol) was added to N, N-dimethylformamide (3 ml), and then N, N, N, N'-tetramethyl-O-(7-azabenzotriazole-1-yl) urea hexafluorophosphate (570 mg, 1.5 mmol) and N, N-diisopropylethylamine (258 mg, 2.0 mmol) were added. The reaction mixture was stirred at room temperature for 0.5 hours, and then (1S, 5R)-3-(8-cyanoquinoline) was added. -5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbohydrazide 3-1 (361 mg, 1.0 mmol), the reaction mixture was stirred at room temperature for 6 hours, and then purified by reverse phase column chromatography to obtain 3-(2-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbonyl)hydrazine-1-carbonyl)-2,5-dihydro-1H-pyrrole-1-carboxylic acid tert-butyl ester 22-2 (375 mg, yield 67.3%).

[0578] LCMS m / z (ESI) = 557.2 [M+1].

[0579] Step 2:

[0580] 3-(5-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazol-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylic acid tert-butyl ester 22-3

[0581] tert-butyl 3-(5-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazol-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate

[0582] Tert-butyl 3-(2-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbonyl)hydrazine-1-carbonyl)-2,5-dihydro-1H-pyrrole-1-carboxylate 22-2 (375 mg, 0.67 mmol) was dissolved in 10 mL of dichloromethane, followed by the addition of triethylamine (338 mg, 3.35 mmol), p-toluenesulfonyl chloride (382 mg, 2.01 mmol). ol), stirred at room temperature for 5 hours. The reaction was monitored by TLC. The reaction solution was concentrated and purified by silica gel column chromatography to obtain the target product 3-(5-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazol-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylic acid tert-butyl ester 22-3 (yellow solid, 215 mg, yield: 60.0%).

[0583] LC-MS m / z (ESI) = 539.2 [M+1].

[0584] Step 3

[0585] 5-((1S,5R)-1-(5-(2,5-dihydro-1H-pyrrol-3-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile compound 22

[0586] 5-((1S,5R)-1-(5-(2,5-dihydro-1H-pyrrol-3-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

[0587] The raw material 3-(5-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazol-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylic acid tert-butyl ester 22-3 (200 mg, 0.37 mmol) was added to dichloromethane (6 ml), and trifluoroacetic acid ( The reaction solution was reacted at room temperature for 2 hours, concentrated under reduced pressure, and then purified by reverse column to obtain 5-((1S,5R)-1-(5-(2,5-dihydro-1H-pyrrol-3-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile compound 22 (115 mg, yield 71.0%).

[0588] LC-MS m / z (ESI) = 439.2 [M+1].

[0589] 1 H NMR (400MHz, DMSO-d6) δ9.03 (s, 1H), 8.70 (d, 1H), 8.21 (d, 1H), 7.63 (dd, 1H), 7.35 (d, 1H), 6.89 (s, 1H), 4.27-3.80 (m, 8H), 2.40-2.15 (m, 2H).

[0590] 19 F NMR(377MHz, DMSO-d6)δ-63.92.

[0591] Example 23

[0592] 5-((1S,5R)-1-(1-(1-methylpiperidin-4-yl)-1H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile compound 23

[0593] 5-((1S,5R)-1-(1-(1-methylpiperidin-4-yl)-1H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

[0594] first step:

[0595] (1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide 23-1

[0596] (1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

[0597] The raw material (1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid B-1 (1.0 g, 2.88 mmol) was added to dichloromethane (15 ml), and a drop of N,N-dimethylformamide was added. The temperature was lowered to 0°C, and then oxalyl chloride (1.10 g, 8.64 mmol) was slowly added dropwise. The heat was abandoned and the temperature was slowly raised to room temperature. After stirring for 2 hours, the reaction mixture was reacted. The reaction mixture was completed and concentrated under reduced pressure to obtain a yellow solid, which was dissolved in dichloromethane and added dropwise to a 0.4 mol / L ammonia solution in 1,4-dioxane (20 ml). The mixture was concentrated under reduced pressure, slurried with water and filtered, and the filter cake was concentrated to dryness to obtain a crude product (1S, 5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide 23-1 (950 mg, yield 95.3%), which was directly used in the next step.

[0598] LCMS m / z (ESI) = 347.1 [M+1].

[0599] Step 2:

[0600] (1S,5R)-3-(8-cyanoquinolin-5-yl)-N-((E)-(dimethylamino)methylene)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide 23-2

[0601] (1S,5R)-3-(8-cyanoquinolin-5-yl)-N-((E)-(dimethylamino)methylene)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

[0602] The raw material from the previous step, (1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide 23-1 (950 mg, 2.74 mmol), was added to 1,4-dioxane (10 ml), followed by the addition of N,N-dimethylformamide dimethyl acetal (980 mg, 8.22 mmol). The reaction mixture was heated to reflux for 3 hours. After completion of the reaction, the mixture was concentrated under reduced pressure. The crude product (1S,5R)-3-(8-cyanoquinolin-5-yl)-N-((E)-(dimethylamino)methylene)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide 23-2 (1.05 g, 95.5% yield) was used directly in the next step.

[0603] LCMS m / z (ESI) = 402.2 [M+1].

[0604] Step 3:

[0605] 5-((1S,5R)-1-(1H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile 23-3

[0606] 5-((1S,5R)-1-(1H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

[0607] The raw material (1S, 5R) -3- (8-cyanoquinolin-5-yl) -N- ((E) - (dimethylamino) methylene) -5- (trifluoromethyl) -3- azabicyclo [3.1.0] hexane -1- carboxamide 23-2 (1.05 g, 2.61 mmol) of the previous step was added to acetic acid (10 ml), and then hydrazine hydrate (262 mg, 5.22 mmol) was added. After nitrogen protection, the temperature was raised to reflux for 3 hours. After completion of the reaction, the mixture was directly purified by acidic reverse column to obtain 5- ((1S, 5R) -1- (1H-1,2,4-triazol-3-yl) -5- (trifluoromethyl) -3- azabicyclo [3.1.0] hexane -3-yl) quinoline-8-carbonitrile 23-3 (900 mg, yield 93.0%).

[0608] LCMS m / z (ESI) = 371.2 [M+1].

[0609] Step 4:

[0610] 5-((1S,5R)-1-(1-(1-methylpiperidin-4-yl)-1H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile compound 23

[0611] 5-((1S,5R)-1-(1-(1-methylpiperidin-4-yl)-1H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

[0612] The raw material 5-((1S,5R)-1-(1H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-3-yl)quinoline-8-carbonitrile compound 23-3 (100 mg, 0.27 mmol) was dissolved in N,N-dimethylformamide (2 ml), and cesium carbonate (176 mg, 0.54 mmol) and 23-4 (0.4 m mol) reaction liquid was protected by nitrogen, and the temperature was raised to 100 ° C for 8 hours. After the reaction was completed, it was directly purified by column to obtain 5-((1S,5R)-1-(1-(1-methylpiperidin-4-yl)-1H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile compound 23 (60 mg, yield 47.6%).

[0613] LCMS m / z (ESI) = 468.2 [M+1].

[0614] 1 H NMR (400MHz, DMSO-d6) δ9.00 (d, 1H), 8.69 (d, 1H), 8.56 (s, 1H), 8.16 (d, 1H), 7.60 (dd, 1H), 7.27 (d, 1H ), 4.21(dq, 1H), 4.10(d, 2H), 4.03(d, 1H), 3.92(d, 1H), 2.84(d, 2H), 2.21(s, 3H), 2.18-1.89(m, 8H).

[0615] 19 F NMR (377MHz, DMSO-d6)δ-63.33.

[0616] Example 24

[0617] 5-((1S,5R)-1-(5-(3-morpholinoprop-1-yn-1-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-3-yl)quinoline-8-carbonitrile compound 24

[0618] 5-((1S,5R)-1-(5-(3-morpholinoprop-1-yn-1-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

[0619] first step:

[0620] (1S,5R)-3-(8-cyanoquinolin-5-yl)-N′-(4-phytolbut-2-ynyl)-5-(trifluoromethyl)-3-azacyclo[3.1.0]hexane-1-carbohydrazide 24-2

[0621] (1S,5R)-3-(8-cyanoquinolin-5-yl)N′-(4-morpholinobut-2-ynoyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbohydrazide

[0622] (1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azacyclo[3.1.0]hexane-1-carbohydrazide 3-1 (200 mg, 0.55 mmol) was dissolved in 4 mL of DMF, followed by the addition of 4-morpholinobutyl-2-nonanoic acid 24-1 (110 mg, 0.66 mmol), T3P (262 mg, 0.83 mmol), and DIEA (210 mg, 1.65 mmol). The mixture was stirred at room temperature for 2 hours. The reaction was monitored by LCMS and purified by reverse phase C18 column chromatography (acid method) to obtain the target compound (1S,5R)-3-(8-cyanoquinolin-5-yl)-n′-(4-phytolbut-2-ynyl)-5-(trifluoromethyl)-3-azacyclo[3.1.0]hexane-1-carbohydrazide 24-2 (orange solid, 150 mg).

[0623] LC-MS m / z (ESI) = 513.10 [M+H] + .

[0624] Step 2:

[0625] 5-((1S,5R)-1-(5-(3-morpholinoprop-1-yn-1-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-3-yl)quinoline-8-carbonitrile compound 24

[0626] 5-((1S,5R)-1-(5-(3-morpholinoprop-1-yn-1-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

[0627] (1S,5R)-3-(8-cyanoquinolin-5-yl)-N′-(4-phytolbut-2-ynyl)-5-(trifluoromethyl)-3-azacyclo[3.1.0]hexane-1-carbohydrazide 24-2 (150 mg, 0.3 mmol) was dissolved in 5 mL 1,4-dioxane was then added with TsCl (75 mg, 0.4 mmol) and Cs2CO3 (260 mg, 0.8 mmol). The mixture was stirred at room temperature for 3 hours under N2 protection. The reaction was completed after monitoring by LCMS. The reaction solution was directly concentrated and purified by reverse phase C18 column chromatography (alkaline method) to obtain the target compound 5-((1S,5R)-1-(5-(3-morpholinoprop-1-yn-1-yl)-1,3,4-oxadiazole-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-3-yl)quinoline-8-carbonitrile compound 24 (off-white solid, 50 mg, 41%).

[0628] 1 H NMR (400MHz, DMSO-d6) δ9.03 (dd, 1H), 8.68 (dd, 1H), 8.21 (d, 1H), 7.64 (dd, 1H), 7.34 (d, 1H), 4. 19 (d, 1H), 4.09 (t, 2H), 3.94 (d, 1H), 3.75 (s, 2H), 3.61 (t, 4H), 2.52 (d, 4H), 2.32-2.23 (m, 2H).

[0629] LC-MS m / z (ESI) = 495.10 [M+H] + .

[0630] Example 25

[0631] 5-((1S,5R)-1-(5-(3-(dimethylamino)prop-1-yn-1-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azacyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile compound 25

[0632] 5-((1S,5R)-1-(5-(3-(dimethylamino)prop-1-yn-1-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

[0633] first step:

[0634] (1S,5R)-3-(8-cyanoquinolin-5-yl)-N′-(4-(dimethylamino)-2-alkynyl)-5-(trifluoromethyl)-3-azacyclo[3.1.0]hexane-1-carbohydrazide 25-2

[0635] (1S,5R)-3-(8-cyanoquinolin-5-yl)-N′-(4-(dimethylamino)but-2-ynoyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbohydrazide

[0636] (1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azacyclo[3.1.0]hexane-1-carbohydrazide 3-1 (400 mg, 1.1 mmol) was dissolved in 4 mL of DMF, followed by the addition of 4-(dimethylamino)-2-acetic acid 25-2 (185 mg, 1.44 mmol), T3P (1.06 mg, 1.66 mmol), and DIEA (430 mg, 3.32 mmol). The mixture was stirred at room temperature for 2 hours. The reaction was monitored by LCMS and purified by reverse phase C18 column chromatography (acid method) to give the target compound (1S,5R)-3-(8-cyanoquinolin-5-yl)-n′-(4-(dimethylamino)-2-alkynyl)-5-(trifluoromethyl)-3-azacyclo[3.1.0]hexane-1-carbohydrazide 25-2 (orange solid, 670 mg).

[0637] LC-MS m / z (ESI) = 471.10 [M+H] + .

[0638] Step 2:

[0639] 5-((1S,5R)-1-(5-(3-(dimethylamino)prop-1-yn-1-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azacyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile compound 25

[0640] 5-((1S,5R)-1-(5-(3-(dimethylamino)prop-1-yn-1-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

[0641] (1S,5R)-3-(8-Cyanogenin-5-yl)-n′-(4-(dimethylamino)-2-alkynyl)-5-(trifluoromethyl)-3-azacyclo[3.1.0]hexane-1-carbohydrazide 25-2 (370 mg, 0.8 mmol) was dissolved in 4 mL of dichloromethane, and Burgess (565 mg, 2.36 mmol) was added. The mixture was stirred at room temperature for 3 hours. The reaction was monitored by LCMS to completion. The reaction solution was directly concentrated and purified by reverse phase C18 column chromatography (alkaline method) to obtain the target compound 5-((1S,5R)-1-(5-(3-(dimethylamino)prop-1-yn-1-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azacyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile compound 25 (white solid, 13 mg).

[0642] 1 H NMR (400MHz, DMSO-d6) δ9.03 (dd, 1H), 8.68 (dd, 1H), 8.21 (d, 1H), 7.63 (dd, 1H), 7.34 ( d, 1H), 4.20 (d, 1H), 4.09 (dd, 2H), 3.94 (d, 1H), 3.67 (s, 2H), 2.30 (d, 1H), 2.25 (s, 7H).

[0643] LC-MS m / z (ESI) = 453.10 [M+H] + .

[0644] Example 26

[0645] 5-((1S,5R)-1-(5-((2,2,6,6-tetramethylpiperidin-4-yl)methyl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azacyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile Compound 26

[0646] 5-((1S,5R)-1-(5-((2,2,6,6-tetramethylpiperidin-4-yl)methyl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

[0647] first step:

[0648] (1S,5R)-3-(8-cyanoquinolin-5-yl)-N′-(2-(2,2,6,6-tetramethylpiperidin-4-yl)acetyl)-5-(trifluoromethyl)-3-azacyclo[3.1.0]hexane-1-carbohydrazide 26-2

[0649] (1S,5R)-3-(8-cyanoquinolin-5-yl)-N′-(2-(2,2,6,6-tetramethylpiperidin-4-yl)acetyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbohydrazide

[0650] (1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azacyclo[3.1.0]hexane-1-carbohydrazide 3-1 (170 mg, 0.5 mmol) was dissolved in 2 mL DMF was added with 2-(2,2,6,6-tetramethylpiperidin-4-yl)acetic acid 26-1 (180 mg, 0.94 mmol), T3P (600 mg, 0.94 mmol), and DIEA (245 mg, 1.88 mmol). The mixture was stirred at room temperature for 2 hours. The reaction was monitored by LCMS. The mixture was purified by reverse phase C18 column chromatography (acid method) to obtain the target compound (1S,5R)-3-(8-cyanoquinolin-5-yl)-n′-(4-(dimethylamino)-2-alkynyl)-5-(trifluoromethyl)-3-azacyclo[3.1.0]hexane-1-carbohydrazide 26-2 (white solid, 1 g).

[0651] LC-MS m / z (ESI) = 543.20 [M+H] + .

[0652] Step 2:

[0653] 5-((1S,5R)-1-(5-((2,2,6,6-tetramethylpiperidin-4-yl)methyl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azacyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile Compound 26

[0654] 5-((1S,5R)-1-(5-((2,2,6,6-tetramethylpiperidin-4-yl)methyl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

[0655] (1S,5R)-3-(8-Cyanoquinolin-5-yl)-n′-(4-(dimethylamino)-2-alkynyl)-5-(trifluoromethyl)-3-azacyclo[3.1.0]hexane-1-carbohydrazide 26-2 (1 g, 1.85 mmol) was dissolved in 10 mL of dichloromethane, and Burgess (565 mg, 2.36 mmol) was added. The mixture was stirred at room temperature for 3 hours. The reaction was monitored by LCMS to completion. The reaction solution was directly concentrated and purified by reverse phase C18 column chromatography (alkaline method) to obtain the target compound 5-((1S,5R)-1-(5-((2,2,6,6-tetramethylpiperidin-4-yl)methyl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azacyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile compound 26 (white solid, 36 mg).

[0656] 1 H NMR (400MHz, DMSO-d6) δ9.03 (dd, 1H), 8.69 (dd, 1H), 8.21 (d, 1H), 7.63 (dd, 1H), 7.33 (d, 1H), 4.20 (d, 1H), 4.07 (dd, 2H), 3.94(d, 1H), 2.77(d, 2H), 2.22(s, 2H), 1.42(d, 2H), 1.23(s, 2H), 1.11(s, 6H), 0.99(s, 6H), 0.89-0.79(m, 2H).

[0657] LC-MS m / z (ESI) = 525.20 [M+H] + .

[0658] Example 27

[0659] 5-((1S,5R)-1-(5-aminoquinolin-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile Compound 27

[0660] 5-((1S,5R)-1-(5-morpholino-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

[0661] first step:

[0662] Morpholine-4-carbohydrazide 27-2

[0663] morpholine-4-carbohydrazide

[0664] Triphosgene (3.4 g, 11.5 mmol) was dissolved in 10 mL of dichloromethane, nitrogen was replaced, and the temperature was lowered to 0 ° C. Morpholine 27-1 (500 mg, 5.7 mmol) was dissolved in 3 mL of dichloromethane and then slowly added dropwise to the above system. Then triethylamine (3 g, 28.5 mmol) was added and stirred at room temperature for 5 hours. Then, hydrazine hydrate (2.8 g, 57 mmol) was added. LCMS monitoring showed that the reaction was complete, and the reaction solution was directly concentrated to give crude morpholine-4-carbohydrazide 27-2 (pale yellow oil, 1 g).

[0665] LC-MS m / z (ESI) = 146.10 [M+H] + .

[0666] Step 2:

[0667] N′-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbonyl)morpholine-4-carbohydrazide 27-3

[0668] N'-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbonyl)morpholine-4-carbohydrazide

[0669] (1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid B-1 (200 mg, 0.6 mmol) was dissolved in 10 mL of DMF, and then HATU (460 mg, 1.2 mmol) and DIPEA (230 mg, 1.8 mmol) were added in an ice bath and stirred at low temperature for 15 minutes. Then, morpholine-4-carbohydrazide 27-2 (1 g, 6.9 mmol) was added and stirred for 1 hour. The reaction was monitored by LCMS. The mixture was extracted with ethyl acetate and water, and the organic phase was dried to give the crude target product N′-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbonyl)morpholine-4-carbohydrazide 27-3 (pale yellow oil, 320 mg).

[0670] LC-MS m / z (ESI) = 475.10 [M+H] + .

[0671] Step 3:

[0672] 5-((1S,5R)-1-(5-aminoquinolin-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile compound 27

[0673] 5-((1S,5R)-1-(5-morpholino-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

[0674] N′-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbonyl)morpholine-4-carbohydrazide 27-3 (320 mg, 0.65 mmol) was dissolved in 10 mL 1,4-dioxane, and then TsCl (250 mg, 1.3 mmol) was added, and Cs2CO3 (640 mg, 1.95 mmol) was added. 1), stirred at room temperature for 5 hours. The reaction was monitored by LCMS. The mixture was extracted with ethyl acetate and water. The organic phase was spin-dried and purified by reverse-phase C18 column chromatography (alkaline method) to obtain the target compound 5-((1S,5R)-1-(5-aminoquinoline-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile compound 27 (white solid, 25 mg).

[0675] 1 H NMR (400MHz, DMSO-d6) δ9.02 (dd, 1H), 8.69 (dd, 1H), 8.20 (d, 1H), 7.62 (dd, 1H), 7.32 (d, 1H), 4.13 (d, 1H), 4.07(d, 1H), 3.99(d, 1H), 3.89(d, 1H), 3.73-3.65(m, 4H), 3.45-3.38(m, 4H), 2.20-2.11(m, 2H).

[0676] LC-MS m / z (ESI) = 457.10 [M+H] + .

[0677] Example 28

[0678] 5-((1S,5R)-1-(5-((1-methylpiperidin-4-yl)oxy)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoxaline-8-carbonitrile Compound 28

[0679] 5-((1S,5R)-1-(5-((1-methylpiperidin-4-yl)oxy)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

[0680] first step:

[0681] 1-Methylpiperazine-4-hydrazinecarboxylate 28-2

[0682] 1-methylpiperidin-4-yl hydrazinecarboxylate

[0683] Triphosgene (3.90 g, 13.2 mmol) was dissolved in 10.0 mL of dichloromethane, and a mixed solution of 4-oxy-1-methylpiperidine 28-1 (1.00 g, 8.77 mmol) and triethylamine (1.75 g, 17.5 mmol) in 10.0 mL of dichloromethane was slowly added dropwise at 0°C. After the reaction for 1 h, hydrazine hydrate (1.28 g, 40.0 mmol) was slowly added dropwise. After the reaction for 1 h, the sample was sent for LCMS. The reaction was complete and concentrated to give 4.3 g of crude product 28-2 (yellow oily liquid).

[0684] Step 2:

[0685] 1-Methylpiperidin-4-yl-2-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxyl)hydrazine-1-carboxylate 28-3

[0686] 1-methylpiperidin-4-yl-2-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbonyl)hydrazine-1-carboxylate

[0687] The above crude product 28-2 (1.00 g, crude) and (1S, 5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid B-1 (250 mg, 0.72 mmol) were dissolved in 10.0 mL of phosphorus oxychloride and refluxed at 90°C for 3 hrs. The reaction was quenched by adding sodium hydroxide solution to adjust the pH to 7-8, freeze-dried, added with dichloromethane, filtered, and the organic phase was concentrated. The target product 1-methylpiperidin-4-yl-2-((1S, 5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-formyl)hydrazine-1-carboxylate 28-3 (yellow solid, 120 mg, yield: 33%) was obtained by reverse preparation.

[0688] Step 3

[0689] 5-((1S,5R)-1-(5-((1-methylpiperidin-4-yl)oxy)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoxaline-8-carbonitrile Compound 28

[0690] 5-((1S,5R)-1-(5-((1-methylpiperidin-4-yl)oxy)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

[0691] 1-Methylpiperidin-4-yl-2-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxyl)hydrazine-1-carboxylate 28-3 (90 mg, 0.19 mmol) was dissolved in 2.00 mL of acetonitrile, followed by addition of cesium carbonate (200 mg, 0.57 mmol) and p-toluene yellow acid chloride (113 mg, 0.57 mmol), and the mixture was stirred at 80 °C. The mixture was stirred for 5 hours. The reaction was monitored by TLC to completion. The reaction solution was concentrated, separated by MPLC, and purified by silica gel column chromatography to obtain the target product 55-((1S,5R)-1-(5-((1-methylpiperidin-4-yl)oxy)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoxaline-8-carbonitrile compound 28 (yellow solid, 20 mg, yield: 23%).

[0692] 1H NMR (400MHz, DMSO-d6) δ9.02 (dd, 1H), 8.68 (dd, 1H), 8.20 (d, 1H), 7.62 (dd,, 1H), 7.32 (d, 1H), 4.90-4.83 (m, 1H), 4.14 (d, 1H), 4.08(d, 1H), 3.99(d, 1H), 3.90(d, 1H), 3.30(s, 1H), 2.54(s, 2H), 2.22(s, 2H), 2.16(d, 4H), 2.03(s, 2H), 1.80(d, 2H).

[0693] LC-MS m / z (ESI) = 485.10 [M+1].

[0694] Example 29

[0695] first step:

[0696] 5-((1S,5S)-1-methyl-5-(5-(1-methylpiperidin-4-yl)-1,3,4-oxadiazol-2-yl)-3-azabicyclo[3.1.0]hexane-3-yl)quinoline-8-carbonitrile Compound 29

[0697] 5-((1S,5S)-1-methyl-5-(5-(1-methylpiperidin-4-yl)-1,3,4-oxadiazol-2-yl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

[0698] 4-Methylpiperidine-1-carboxylic acid hydrazide 29-2 (59 mg, 0.375 mmol) and (1S, 5R)-3-(8-cyanoquinolin-5-yl)-5-(methyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid 29-1 (90 mg, 0.307 mmol) were dissolved in 10.0 mL of phosphorus oxychloride and refluxed at 90 ° C for 3 hrs. The sample was sent to LCMS. After the reaction was completed, sodium hydroxide solution was added to adjust the pH to 7. -8 was quenched, freeze-dried, dichloromethane was added, filtered, the organic phase was concentrated, and reverse preparation was performed. TLC (DCM:MeOH=10:1) gave the target product 5-((1S,5R)-1-(5-(4-methylpiperidinyl)-1-yl)-1,3,4-oxadiazol-2-yl)-5-(methyl)-3-azabicyclo[3.1.0]hexane-3-yl)quinoxaline-5-carbonitrile compound 29 (pale yellow solid, 24 mg, 18.9%).

[0699] LC-MS m / z (ESI) = 415.10 [M+1].

[0700] 1 H NMR (400MHz, Chloroform-d) δ9.05 (dd, 1H), 8.42 (dd, 1H), 8.00 (d, 1H), 7.47 (dd, 1H), 7.05 (d, 1H), 4.08 (d, 1H), 3.96 (d, 1H), 3. 87 (d, 1H), 3.36 (d, 1H), 2.41 (s, 3H), 2.33 (m, 2H), 2.16 (m, 2H), 2.04 (m, 3H), 1.84 (d, 1H), 1.55 (d, 1H), 1.38 (s, 3H), 1.26 (m, 2H).

[0701] Example 30

[0702] 2-((1-methylazetidin-3-yl)methyl)-5-((1S,5R)-5-(trifluoromethyl)-3-(8-(trifluoromethyl)quinolin-5-yl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazole Compound 30

[0703] 2-((1-methylazetidin-3-yl)methyl)-5-((1S,5R)-5-(trifluoromethyl)-3-(8-(trifluoromethyl)quinolin-5-yl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazole

[0704] first step:

[0705] Tert-butyl 2-((1S,5R)-3-(7-cyano-3-fluoropyrazolo[1,5-a]pyridin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbonyl)hydrazine-1-carboxylate compound 30-1

[0706] tert-butyl 2-((1S,5R)-3-(7-cyano-3-fluoropyrazolo[1,5-a]pyridin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbonyl)hydrazine-1-carboxylate

[0707] Under N2 atmosphere, (1S,5R)-3-(3-fluoro-7-(trifluoromethyl)pyrazolo[1,5-a]pyridin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid 80-3 (1.00 g, 2.52 mmol) was dissolved in 20 mL of dichloromethane, and then n-butylphosphonic anhydride (3.04 g, 3.78 mmol), DIEA (974 mg, 7.56 mmol) and tert-butyl carbazate (368 mg, 2.77 mmol) were added in sequence and stirred at room temperature for 2 h. The solvent was dried, extracted with ethyl acetate, the organic phase was concentrated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the solvent was dried, and MPLC was separated to obtain the target product tert-butyl 2-((1S,5R)-3-(7-cyano-3-fluoropyrazolo[1,5-a]pyridin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbonyl)hydrazine-1-carboxylate compound 30-1 (yellow solid, 1.23 g, 96%)

[0708] LC-MS m / z (ESI) = 469.10 [M+1].

[0709] Step 2:

[0710] (1S, 5R) -3- (7-cyano-3-fluoropyrazolo [1, 5-a] pyridin-4-yl) -5- (trifluoromethyl) -3-azabicyclo [3.1.0] hexane-1-carbohydrazide compound 30-2

[0711] (1S,5R)-3-(7-cyano-3-fluoropyrazolo[1,5-a]pyridin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbohydrazide

[0712] Under N2 atmosphere, -((1S,5R)-3-(7-cyano-3-fluoropyrazolo[1,5-a]pyridin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbonyl)hydrazine-1-carboxylic acid compound 30-1 (yellow solid, 1.23 g) was dissolved in dichloromethane (20.0 mL), and then trifluoroacetic acid (4 mL) was added in sequence and the reaction was stirred at room temperature for 1 h. The reaction was completed by LCMS detection, and the solvent was dried by spin drying. The pH value of the aqueous sodium carbonate solution was adjusted to 7-8, and the mixture was extracted with ethyl acetate. The organic phase was concentrated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was dried by spin drying to obtain the target product (1S, 5R)-3-(7-cyano-3-fluoropyrazolo[1,5-a]pyridin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbohydrazide compound 30-2 (yellow solid, 850 mg, 86.7%).

[0713] LC-MS m / z (ESI) = 369.10 [M+1].

[0714] Step 3:

[0715] Tert-butyl 3-(2-(2-((1S,5R)-3-(7-cyano-3-fluoropyrazolo[1,5-a]pyridin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbonyl)hydrazino)-2-oxoethyl)azetidine-1-carboxylate Compound 30-4

[0716] tert-butyl 3-(2-(2-((1S,5R)-3-(7-cyano-3-fluoropyrazolo[1,5-a]pyridin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbonyl)hydrazinyl)-2-oxoethyl)azetidine-1-carboxylate

[0717] Under N2 atmosphere, (1S,5R)-3-(7-cyano-3-fluoropyrazolo[1,5-a]pyridin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbohydrazide 30-2 (500 mg, 1.35 mmol) was dissolved in 10 mL of DMF, and then n-butylphosphonic anhydride (3.04 g, 3.78 mmol), DIEA (974 mg, 7.56 mmol), and 2-(1-(tert-butoxycarbonyl)azetidin-3-yl)acetic acid 30-3 (410 mg, 1.35 mmol) were added in sequence and stirred at room temperature for 2 h. The reaction was detected by LCMS and separated by MPLC to obtain the target product, tert-butyl 3-(2-(2-((1S,5R)-3-(7-cyano-3-fluoropyrazolo[1,5-a]pyridin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbonyl)hydrazine)-2-oxoethyl)azetidine-1-carboxylate compound 30-4 (yellow solid, 447 mg, 58.4%).

[0718] LC-MS m / z (ESI) = 566.2 [M+1].

[0719] Step 4:

[0720] Tert-butyl 3-((5-((1S,5R)-3-(7-cyano-3-fluoropyrazolo[1,5-a]pyridin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexen-1-yl)-1,3,4-oxadiazol-2-yl)methyl)azetidin-1-carboxylate Compound 30-5

[0721] tert-butyl 3-((5-((1S,5R)-3-(7-cyano-3-fluoropyrazolo[1,5-a]pyridin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazol-2-yl)methyl)azetidine-1-carboxylate

[0722] Under N2 atmosphere, 3-(2-(2-((1S,5R)-3-(7-cyano-3-fluoropyrazolo[1,5-a]pyridin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbonyl)hydrazino)-2-oxoethyl)azetidine-1-carboxylic acid compound 30-4 (447 mg, 0.789 mmol) was dissolved in 20 mL of dichloromethane, and then cesium carbonate (772 mg, 2.36 mmol) and p-toluenesulfonyl chloride (302 mg, 1.58 mmol) were added in sequence and the reaction was stirred at room temperature for 2 h. The solvent was dried and separated by MPLC to obtain the target product, tert-butyl 3-((5-((1S,5R)-3-(7-cyano-3-fluoropyrazolo[1,5-a]pyridin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexen-1-yl)-1,3,4-oxadiazol-2-yl)methyl)azetidin-1-carboxylate compound 30-5 (yellow solid, 124 mg, 28.7%).

[0723] LC-MS m / z (ESI) = 548.10 [M+1].

[0724] Step 5:

[0725] 4-((1S,5R)-1-(5-(aza-3-ylmethyl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-3-yl)-3-fluoropyrazolo[1,5-a]pyridine-7-carbonitrile compound 30-6

[0726] 4-((1S,5R)-1-(5-(azetidin-3-ylmethyl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)-3-fluoropyrazolo[1,5-a]pyridine-7-carbonitrile

[0727] Under N2 atmosphere, tert-butyl 3-((5-((1S,5R)-3-(7-cyano-3-fluoropyrazolo[1,5-a]pyridin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexen-1-yl)-1,3,4-oxadiazol-2-yl)methyl)azetidin-1-carboxylate 30-5

[0728] 124 mg was dissolved in dichloromethane (20.0 mL), and trifluoroacetic acid (4 mL) was subsequently added and stirred at room temperature for 1 h. LCMS detected the completion of the reaction, and the solvent was dried by spin-drying. The pH was adjusted to 7-8 with aqueous sodium carbonate solution, and the mixture was extracted with ethyl acetate. The organic phase was concentrated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was dried by spin-drying to obtain the target product 4-((1S,5R)-1-(5-(aza-3-ylmethyl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-3-yl)-3-fluoropyrazolo[1,5-a]pyridine-7-carbonitrile compound 30-6 (yellow solid, 110 mg, 99%).

[0729] LC-MS m / z (ESI) = 448.10 [M+1].

[0730] Step 6:

[0731] 3-Fluoro-4-((1S,5R)-1-(5-((1-methylazetidin-3-yl)methyl)-1,3,4-oxazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-3-yl)pyrazolo[1,5-a]pyridine-7-carbonitrile compound 30

[0732] 3-fluoro-4-((1S,5R)-1-(5-((1-methylazetidin-3-yl)methyl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)pyrazolo[1,5-a]pyridine-7-carbonitrile

[0733] 4-((1S,5R)-1-(5-(aza-3-ylmethyl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-3-yl)-3-fluoropyrazolo[1,5-a]pyridine-7-carbonitrile compound 30-6 (110 mg, 0.33 mmol) was dissolved in 5 mL of methanol, followed by the addition of 1 mL of triethylamine, paraformaldehyde (250 mg, 9 mmol), sodium cyanoborohydride (506 mg, 13.5 mmol) and 1 mL of ethanol. l) The temperature was raised to 60°C and stirred for 3 hours. After completion of the reaction by TLC, the reaction solution was directly filtered and concentrated, and purified by TLC (DCM:MeOH=10:1) to give 3-fluoro-4-((1S,5R)-1-(5-((1-methylazetidin-3-yl)methyl)-1,3,4-oxazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)pyrazolo[1,5-a]pyridine-7-carbonitrile compound 30 (pale yellow solid, 30 mg, 26.5%).

[0734] LC-MS m / z (ESI) = 462.10 [M+1].

[0735] 1 H NMR (400MHz, Chloroform-d) δ7.86 (d, 1H), 7.15-7.13 (m, 1H), 6.16 (d, 1H), 4.08 (s, 2H), 4.04 (dd, 1H), 3.78 (d, 1H), 3.48 (t, 2H), 3.12-3.04 (m, 4H), 2.32 (s, 3H), 2.26 (d, 1H).1.82 (m, 2H).

[0736] Example 31

[0737] 3-Fluoro-4-((1S,5R)-1-(5-((1-methylpiperidin-4-yl)oxy)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)pyrazolo[1,5-a]pyridine-7-carbonitrile Compound 31

[0738] 3-fluoro-4-((1S,5R)-1-(5-((1-methylpiperidin-4-yl)oxy)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)pyrazolo[1,5-a]pyridine-7-carbonitrile

[0739] (1S,5R)-3-(7-cyano-3-fluoropyrazolo[1,5-a]pyridin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid 80-3 (900 mg, 2.54 mmol) and 1-methylpiperidin-4-ylhydrazinecarboxylate 31-1 (5.5 g crude product) were dissolved in PO4. Cl3 (10 mL), react at 80 ° C for 2 hours. The reaction was completed after LCMS detection. After adjusting the pH to alkaline with sodium carbonate, the mixture was extracted with dichloromethane three times and dried by rotation. After reverse phase purification and large plate purification, 3-fluoro-4-((1S,5R)-1-(5-((1-methylpiperidin-4-yl)oxy)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-3-yl)pyrazolo[1,5-a]pyridine-7-carbonitrile compound 31 (27 mg, yellow solid) was obtained.

[0740] LCMS m / z (ESI) = 492.17 [M+1].

[0741] 1 H NMR (400MHz, Chloroform-d) δ8.26 (s, 1H), 7.75 (d, 1H), 6.08 (d, 1H), 4.95 (s, 1H), 4.85 (d, 1H), 4.76 (d, 1H) ), 4.30(d, 1H), 4.05(d, 1H), 2.73(s, 2H), 2.45(s, 2H), 2.33(d, 4H), 2.22(s, 2H), 2.01(s, 2H), 1.74(d, 1H).

[0742] Example 32:

[0743] 5-((1S,5R)-1-(5-(3-fluoroazetidin-3-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-3-yl)quinoline-8-carbonitrile compound 32

[0744] 5-((1S,5R)-1-(5-(3-fluoroazetidin-3-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

[0745] first step:

[0746] tert-Butyl 3-(5-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazol-2-yl)-3-fluoroazetidine-1-carboxylate 32-2

[0747] 5-((1S,5R)-1-(5-(3-fluoro-1-methylazetidin-3-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

[0748] 1-(tert-Butyloxycarbonyl)-3-fluoroazetidine-3-carboxylic acid 32-1 (479 mg, 2.2 mmol) was dissolved in 20 ml of dichloromethane, followed by the addition of HATU (1.136 g, 2.98 mmol) and DIPEA (766 mg, 5.94 mmol). The mixture was stirred at low temperature for 5 minutes, and then (1S, 5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbohydrazide 3-1 (720 mg, 1.98 mmol) was added and stirred for 2 hours. When the reaction was complete by TLC, Burgess reagent (1100 mg, 3.9 mmol) was added and stirred for 3 hours. After the reaction was complete by LCMS, the reaction solution was directly concentrated and purified by reverse phase C18 column chromatography (acid method) to obtain the target product 3-(5-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazol-2-yl)-3-fluoroazetidine-1-carboxylic acid tert-butyl ester 32-2 (pale yellow solid, 500 mg, 46.2%)

[0749] Step 2:

[0750] 5-((1S,5R)-1-(5-(3-fluoroazetidin-3-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-3-yl)quinoline-8-carbonitrile compound 32

[0751] 5-((1S,5R)-1-(5-(3-fluoroazetidin-3-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

[0752] 500 mg of crude product tert-butyl 3-(5-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazol-2-yl)-3-fluoroazetidine-1-carboxylate was added to 5.00 mL of hydrochloric acid and ethyl acetate solution. After stirring for half an hour, the reaction was completed by LCMS. The reaction solution was concentrated to obtain the product compound 32 (pale yellow solid, 400 mg, 97%).

[0753] LC-MS m / z (ESI) = 445.10 [M+1].

[0754] 1 H NMR (400MHz, Chloroform-d) δ9.10 (d, 1H), 8.37 (d, 1H), 8.06 (d, 1H), 7.54 (dd, 1H), 7.1 9(d, 1H), 4.33-4.20(m, 3H), 4.17(d, 1H), 3.99(dd, 2H), 3.81(d, 1H), 2.46-2.25(m, 4H).

[0755] Example 33:

[0756] 5-((1S,5R)-1-(5-(3-fluoroazetidin-3-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-3-yl)quinoline-8-carbonitrile compound 33

[0757] 5-((1S,5R)-1-(5-(3-fluoroazetidin-3-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

[0758] first step:

[0759] tert-Butyl 4-(5-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazol-2-yl)-3-fluoropiperidine-1-carboxylate 33-2

[0760] tert-butyl4-(5-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazol-2-yl)-3-fluoropiperidine-1-carboxylate

[0761] 1-(tert-Butyloxycarbonyl)-3-fluoropiperidine-4-carboxylic acid 33-1 (543 mg, 2.2 mmol) was dissolved in 20 ml of dichloromethane, followed by the addition of HATU (789 mg, 2.07 mmol) and DIPEA (534 mg, 4.14 mmol) and stirred at low temperature for 5 minutes. Then, (1S, 5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbohydrazide 3-1 (500 mg, 1.98 mmol) was added and stirred for 2 hours. After the reaction was complete by TLC, Burgess reagent (1.53 g, 5.52 mmol) was added and stirred for 3 hours. After the reaction was complete by LCMS, the reaction solution was directly concentrated and purified by reverse phase C18 column chromatography (acid method) to obtain the target product 3-(5-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazol-2-yl)-3-fluoroazetidine-1-carboxylic acid tert-butyl ester 33-2 (pale yellow solid, 500 mg, 63.2%)

[0762] Step 2:

[0763] 5-((1S,5R)-1-(5-(3-fluoroazetidin-3-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-3-yl)quinoline-8-carbonitrile compound 33

[0764] 5-((1S,5R)-1-(5-(3-fluoroazetidin-3-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

[0765] The crude product 3-(5-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazol-2-yl)-3-fluoroazetidine-1-carboxylic acid tert-butyl ester (33-2500 mg) was added with 5.00 mL of hydrochloric acid and ethyl acetate solution. After stirring for half an hour, the reaction was completed by LCMS. The reaction solution was concentrated to obtain the product compound 33 (pale yellow solid, 380 mg, 92%).

[0766] LC-MS m / z (ESI) = 473.10 [M+1].

[0767] 1 H NMR (400MHz, Chloroform-d) δ9.09 (dd, 1H), 8.37 (dd, 1H), 8.05 (d, 1H), 7.53 (dd, 1H), 7.17 (d, 1H),, 4.13 (dd, 1H), 3.98 (dd, 2H) , 3.81(dd, 1H), 3.44-3.20(m, 3H), 2.91(dd, 1H), 2.78(t, 1H), 2.33(dd, 1H), 2.26-2.11(m, 2H), 2.04-1.93(m, 1H), 1.64(s, 2H).

[0768] Example 34

[0769] 2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-(4-(m-tolyl)-4H-1,2,4-triazol-3-yl)hexahydrocyclopenta[c]pyrrole-1(2H)-one compound 34

[0770] 2-(6-methyl-4-(trifluoromethyl)-pyridin-2-yl)-3-(4-(m-tolyl)-4H-1,2,4-triazol-3-yl)hexahydrocyclopenta[c]pyrrol-1(2H)-one

[0771] first step:

[0772] (1S,5R)-3-(8-cyanoquinolin-5-yl)-N′-(1-methyl-2-oxopiperidine-4-carbonyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid hydrazide 34-2

[0773] (1S,5R)-3-(8-cyanoquinolin-5-yl)-N′-(1-methyl-2-oxopiperidine-4-carbonyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbohydrazide

[0774] 1-Methyl-2-oxopiperidine-4-carboxylic acid 34-1 (314 mg, 2 mmol) was dissolved in DMF (3 mL), and DIPEA (517 mg, 4 mmol) and HATU (912 mg, 2.4 mmol) were added. After activation at room temperature for 15 minutes, (1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid hydrazide 3-1 (722 mg, 2 mmol) was added. The mixture was reacted at room temperature under nitrogen for 1 hour. Subsequently, 20 mL each of water and dichloromethane were added, the liquids were separated, and the organic phase was collected, dried, and concentrated to obtain the crude product. The crude product was separated by reverse phase chromatography to give (1S,5R)-3-(8-cyanoquinolin-5-yl)-N′-(1-methyl-2-oxopiperidine-4-carbonyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid hydrazide 34-2 (800 mg, yellow solid, yield 80%).

[0775] LCMS m / z (ESI) = 501.10 [M+1].

[0776] Step 2:

[0777] 2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-(4-(m-tolyl)-4H-1,2,4-triazol-3-yl)hexahydrocyclopenta[c]pyrrole-1(2H)-one compound 34

[0778] 2-(6-methyl-4-(trifluoromethyl)-pyridin-2-yl)-3-(4-(m-tolyl)-4H-1,2,4-triazol-3-yl)hexahydrocyclopenta[c]pyrrol-1(2H)-one

[0779] (1S,5R)-3-(8-cyanoquinolin-5-yl)-N′-(1-methyl-2-oxopiperidine-4-carbonyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbohydrazide 34-2 (125 mg, 0.25 mmol) was dissolved in 1,4-dioxane (2 mL), followed by the addition of TsCl (94 mg, 0.50 mmol) and Cs2CO3 (243 mg, 0.75 mmol). The mixture was reacted at 100°C under nitrogen for 2 hours. 20 mL each of water and dichloromethane were then added, the layers were separated, and the organic phase was collected, dried, and concentrated to obtain the crude product. The crude product was separated by reverse phase chromatography to give 2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-(4-(m-tolyl)-4H-1,2,4-triazol-3-yl)hexahydrocyclopenta[c]pyrrole-1(2H)-one compound 34 (30 mg, white solid, yield 24.8%).

[0780] LCMS m / z (ESI) = 483.10 [M+1].

[0781] 1 H NMR (400MHz, Chloroform-d) δ9.09 (dd, 1H), 8.36 (dd, 1H), 8.06 (d, 1H), 7.54 (dd, 1H), 7.17(d, 1H), 4.12(dd, 1H), 4.01-3.93(m, 2H), 3.79(dd, 1H), 3.45(ddt, 3H), 2 .99(s, 3H), 2.88(dd, 1H), 2.76-2.66(m, 1H), 2.39-2.29(m, 2H), 2.28-2.13(m, 2H).

[0782] Example 35

[0783] 5-((1S,5R)-1-(5-(azetidin-3-ylmethyl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-3-yl)quinoline-8-carbonitrile Compound 35

[0784] 5-((1S,5R)-1-(5-(azetidin-3-ylmethyl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

[0785] first step:

[0786] tert-Butyl 3-(2-((2-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxyl)hydrazino)-2-oxoethyl)azetidine-1-carboxylate 35-2

[0787] tert-butyl 3-(2-(2-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbonyl)hydrazineyl)-2-oxoethyl)azetidine-1-carboxylate

[0788] 2-(1-(tert-Butyloxycarbonyl)azetidin-3-yl)acetic acid 35-1 (1.07 g, 5 mmol) was dissolved in dichloromethane (10 mL), and DIPEA (1.29 g, 10 mmol) and HATU (2.28 g, 6 mmol) were added, followed by activation at room temperature for 15 minutes, and (1S, 5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid hydrazide 3-1 (1.70 g, 4.7 mmol) was added. The mixture was reacted at room temperature under nitrogen for 2 hours, and 200 mL of water and dichloromethane were added. The liquids were separated, and the organic phase was collected, dried, and concentrated to obtain a crude product. The crude product was separated by column chromatography to give tert-butyl 3-(2-((2-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-formyl)hydrazino)-2-oxoethyl)azetidine-1-carboxylate 35-2 (1.93 g, yellow solid, yield 73%).

[0789] LCMS m / z (ESI) = 559.10 [M+1].

[0790] Step 2:

[0791] Tert-butyl 3-((5-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazol-2-yl)methyl)azetidine-1-carboxylate 35-3

[0792] tert-butyl 3-((5-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazol-2-yl)methyl)azetidine-1-carboxylate

[0793] Tert-butyl 3-(2-((2-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxyl)hydrazino)-2-oxoethyl)azetidine-1-carboxylate 35-2 (1.93 g, 3.45 mmol) was dissolved in anhydrous dichloromethane (20 mL), followed by the addition of DIPEA (1.33 g, 10.3 mmol), Burgess reagent (2.46 g, 3.45 mmol). , then reacted at room temperature for 2 hours under nitrogen protection. 20 mL of water was then added, the liquids were separated, the organic phase was collected, dried, and concentrated to obtain a crude product. After column chromatography, the target product, tert-butyl 3-((5-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-yl)-1,3,4-oxadiazol-2-yl)methyl)azetidine-1-carboxylate 35-3 (1.86 g, yellow solid, yield 100%), was obtained.

[0794] LCMS m / z (ESI) = 541.20 [M+1].

[0795] Step 3:

[0796] 5-((1S,5R)-1-(5-(azetidin-3-ylmethyl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-3-yl)quinoline-8-carbonitrile Compound 35

[0797] 5-((1S,5R)-1-(5-(azetidin-3-ylmethyl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

[0798] tert-Butyl 3-((5-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-yl)-1,3,4-oxadiazol-2-yl)methyl)azetidine-1-carboxylate 35-3 (1.86 g, 3.45 mmol) was dissolved in dichloromethane (20 mL), trifluoroacetic acid (10 mL) was added, and the reaction was carried out at room temperature under nitrogen protection for 2 hours. The reaction solution was then concentrated directly to dryness and purified by reverse phase purification (0.1% TFA in water) to obtain compound 5-((1S,5R)-1-(5-(azetidin-3-ylmethyl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-3-yl)quinoline-8-carbonitrile compound 35 (1.50 g, yellow solid, yield 98%).

[0799] LCMS m / z=441.10[M+1].

[0800] 1 H NMR (400MHz, DMSO-d6) δ9.01 (d, 1H), 8.67 (d, 1H), 8.19 (d, 1H), 7.62 (dd, 1H), 7.32 (d, 1H), 4.18 (d, 1H), 4 .04(dd, 2H), 3.91(d, 1H), 3.26(t, 2H), 3.09(d, 2H), 2.81(t, 2H), 2.66(t, 1H), 2.20(s, 2H), 1.50(s, 1H).

[0801] Example 36

[0802] 5-((1S,5R)-1-(5-((1-methylazetidin-3-yl)methyl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-3-yl)quinoline-8-carbonitrile Compound 36

[0803] 5-((1S,5R)-1-(5-((1-methylazetidin-3-yl)methyl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

[0804] 5-((1S,5R)-1-(5-((1-methylazetidin-3-yl)methyl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-3-yl)quinoline-8-carbonitrile Compound 36

[0805] 5-((1S,5R)-1-(5-((1-methylazetidin-3-yl)methyl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

[0806] 5-((1S,5R)-1-(5-(azetidin-3-ylmethyl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-3-yl)quinoline-8-carbonitrile compound 35 (1.30 g, 2.95 mmol) was dissolved in methanol (20 mL), paraformaldehyde (1.77 g, 59 mmol) and sodium cyanoborohydride (3.70 g, 59 mmol) were added, and the temperature was raised to 80°C for 2 hours. The reaction solution was then filtered, the filtrate was concentrated to dryness, and the product was purified by reverse phase purification (0.1% TFA in Water) to give 5-((1S,5R)-1-(5-((1-methylazetidin-3-yl)methyl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile compound 36 (700 mg, yellow solid, 52%).

[0807] LCMS m / z=455.10[M+1].

[0808] 1 H NMR (400MHz, DMSO-d6) δ9.01 (d, 1H), 8.67 (d, 1H), 8.19 (d, 1H), 7.62 (dd, 1H), 7.32 (d, 1H), 4.18 (d, 1H), 4 .04(dd, 2H), 3.91(d, 1H), 3.26(t, 2H), 3.09(d, 2H), 2.81(t, 2H), 2.66(t, 1H), 2.20(s, 2H), 2.14(s, 3H).

[0809] Example 37

[0810] 5-((1S,5R)-1-(5-((1-methylpiperidin-4-yl)methyl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile Compound 37

[0811] 5-((1S,5R)-1-(5-((1-methylpiperidin-4-yl)methyl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

[0812] first step:

[0813] (1S,5R)-3-(8-cyanoquinolin-5-yl)-N′-(2-(1-methylpiperidin-4-yl)acetyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid hydrazide 37-2

[0814] (1S,5R)-3-(8-cyanoquinolin-5-yl)-N′-(2-(1-methylpiperidin-4-yl)acetyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbohydrazide

[0815] 2-(1-methylpiperidin-4-yl)acetic acid 37-1 (314 mg, 2 mmol) was dissolved in DMF (3 mL), and DIPEA (517 mg, 4 mmol) and HATU (912 mg, 2.4 mmol) were added. After activation at room temperature for 15 minutes, (1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid hydrazide 3-1 (722 mg, 2 mmol) was added. The mixture was reacted at room temperature under nitrogen for 1 hour. Subsequently, 20 mL each of water and dichloromethane were added, the liquids were separated, and the organic phase was collected, dried, and concentrated to obtain the crude product. The crude product was separated by reverse phase chromatography to give (1S,5R)-3-(8-cyanoquinolin-5-yl)-N′-(2-(1-methylpiperidin-4-yl)acetyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid hydrazide 37-2 (800 mg, yellow solid, yield 80%).

[0816] LCMS m / z (ESI) = 501.20 [M+1].

[0817] Step 2:

[0818] 5-((1S,5R)-1-(5-((1-methylpiperidin-4-yl)methyl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile Compound 37

[0819] 5-((1S,5R)-1-(5-((1-methylpiperidin-4-yl)methyl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

[0820] (1S,5R)-3-(8-cyanoquinolin-5-yl)-N′-(2-(1-methylpiperidin-4-yl)acetyl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid hydrazide 37-2 (500 mg, 1 mmol) was dissolved in dichloromethane (5 mL), followed by the addition of triethylamine (303 mg, 3 mmol) and Burgess reagent (714 mg, 3 mmol). The mixture was reacted at room temperature under nitrogen for 2 hours. 20 mL each of water and dichloromethane were then added, the layers separated, and the organic phase was collected, dried, and concentrated to obtain the crude product. The crude product was separated by reverse phase chromatography to give 5-((1S,5R)-1-(5-((1-methylpiperidin-4-yl)methyl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-3-yl)quinoline-8-carbonitrile compound 37 (385 mg, yellow solid, yield 80%).

[0821] LCMS m / z (ESI) = 483.20 [M+1].

[0822] 1 H NMR (400MHz, DMSO-d6) δ9.02 (d, 1H), 8.68 (d, 1H), 8.20 (d, 1H), 7.71-7.58 (m, 1H), 7.33 (d, 1H), 4.19 (d, 1H), 4.05 (dd, 2H), 3.92 (d, 1H), 3.08 (d, 3H), 2.91 (q, 3H), 2.71 (s, 3H), 2.22 (s, 2H), 1.99 (s, 1H), 1.82 (d, 2H), 1.52 (d, 2H).

[0823] Example 38

[0824] 2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-(4-(m-tolyl)-4H-1,2,4-triazol-3-yl)hexahydrocyclopenta[c]pyrrole-1(2H)-one compound 38

[0825] 2-(6-methyl-4-(trifluoromethyl)-pyridin-2-yl)-3-(4-(m-tolyl)-4H-1,2,4-triazol-3-yl)hexahydrocyclopenta[c]pyrrol-1(2H)-one

[0826] 5-((1S,5R)-1-(5-((1-methylpiperidin-4-yl)methyl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-3-yl)quinoline-8-carbonitrile compound 37 (145 mg, 0.3 mmol) was dissolved in mesitylene (2 mL), followed by the addition of TsOH (103 mg, 0.6 mmol), methylamine hydrochloride (61 mg, 0.9 mmol), and triethylamine (121 mg, 1.2 mmol), and the reaction was carried out at 150°C under nitrogen protection for 8 hours. The reaction solution was then separated by silica gel column to obtain 5-((1S,5R)-1-(4-methyl-5-((1-methylpiperidin-4-yl)methyl)-4H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-3-yl)quinoline-8-carbonitrile compound 38 (30 mg, yellow solid, yield 20%).

[0827] LCMS m / z (ESI) = 496.20 [M+1].

[0828] 1 H NMR (400MHz, DMSO-d6) δ9.01 (d, 1H), 8.72 (d, 1H), 8.18 (d, 1H), 7.61 (dd, 1H), 7.29 (d, 1H), 4.12 (d, 3H), 3 .82(d,1H),3.64(s,3H),2.88(d,3H),2.66(d,6H),2.55(d,2H),2.34(s,1H),,1.85(d,2H),1.74(d,2H).

[0829] Example 39

[0830] 5-((1S,5R)-1-(5-(1-methylazetidin-3-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-3-yl)quinoline-8-carbonitrile Compound 39

[0831] 5-((1S,5R)-1-(5-(1-methylazetidin-3-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

[0832] 5-((1S,5R)-1-(5-(1-methylazetidin-3-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-3-yl)quinoline-8-carbonitrile Compound 39

[0833] 5-((1S,5R)-1-(5-(1-methylazetidin-3-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

[0834] 1-Methylazetidine-3-carboxylic acid 39-1 (345 mg, 3 mmol) and (1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid hydrazide 3-1 (1.08 g, 3 mmol) were dissolved in phosphorus oxychloride (10 mL) and reacted at 60°C under nitrogen for 2 hours. The reaction solution was concentrated to remove most of the phosphorus oxychloride, and triethylamine was added to adjust the base. The crude product was separated by reverse phase chromatography to obtain 5-((1S,5R)-1-(5-(1-methylazetidin-3-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile compound 39 (200 mg, yellow solid, 15% yield).

[0835] LCMS m / z (ESI) = 441.20 [M+1].

[0836] 1H NMR (400MHz, Chloroform-d) δ9.14-9.01 (m, 1H), 8.36 (d, 1H), 8.05 (d, 1H), 7.53 (dd, 1H), 7.17 (d, 1H), 4.13 (d, 1H), 4.05-3.87 (m, 5H), 3.80 (d, 1H), 3.55 (s, 2H), 2.49 (s, 3H), 2.35 (d, 1H), 2.28-2.20 (m, 1H).

[0837] Example 40

[0838] 5-((1S,5R)-1-(5-(morpholinomethyl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile compound 40

[0839] 5-((1S,5R)-1-(5-(morpholinomethyl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

[0840] 2-Morpholineacetic acid 40-1 (301 mg, 2.07 mmol) was dissolved in 20 ml of dichloromethane, and then HATU (791 mg, 2.07 mmol) and DIPEA (534 mg, 4.14 mmol) were added and stirred at low temperature for 5 minutes. Then (1S, 5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbohydrazide 3-1 (500 mg, 1.38 mmol) was added and stirred for 2 minutes. After 1 hour, the reaction was complete by TLC, and then Burgess reagent (988 mg, 4.14 mmol) was added and stirred for 3 hours. After the reaction was complete by LCMS, the reaction solution was directly concentrated and purified by reverse phase C18 column chromatography (acid method) to obtain 5-((1S,5R)-1-(5-(morpholinomethyl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile compound 40 (pale yellow solid, 570 mg, 63.2%).

[0841] LC-MS m / z (ESI) = 471.10 [M+1].

[0842] 1H NMR (400MHz, Chloroform-d) δ9.10 (dd, 1H), 8.36 (dd, 1H), 8.06 (d, 1H), 7.54 (dd, 1H), 7.17 (d, 1H), 4 .15(d,1H),4.03-3.92(m,2H),3.87-3.78(m,3H),3.74(t,4H),2.57(s,4H),2.38(d,1H),2.25(d,1H)

[0843] Example 41

[0844] 5-((1S,5R)-1-(5-(pyrrolidin-1-ylmethyl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile Compound 41

[0845] 5-((1S,5R)-1-(5-(pyrrolidin-1-ylmethyl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

[0846] 2-(Pyrrolidin-1-yl)acetic acid 41-1 (268 mg, 2.07 mmol) was dissolved in 20 ml of dichloromethane, followed by the addition of HATU (791 mg, 2.07 mmol) and DIPEA (534 mg, 4.14 mmol) and stirred at low temperature for 5 minutes, followed by the addition of (1S, 5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbohydrazide 3-1 (500 mg, 1.38 mmol). The mixture was stirred for 2 hours and the reaction was completed by TLC. Burgess reagent (988 mg, 4.14 mmol) was then added and stirred for 3 hours. The reaction was completed by LCMS. The reaction solution was directly concentrated and purified by reverse phase C18 column chromatography (acid method) to obtain 5-((1S,5R)-1-(5-(morpholinomethyl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile compound 41 (pale yellow solid, 400 mg, 63.2%).

[0847] LC-MS m / z (ESI) = 455.10 [M+1].

[0848] 1H NMR(400 MHz, Chloroform-d) δ9.09 (dd, 1H), 8.36 (dd, 1H), 8.05 (d, 1H), 7.53 (dd, 1H), 7.17 (d, 1H), 4.1 6(d, 1H), 3.97(dd, 2H), 3.85-3.77(m, 3H), 2.40(d, 1H), 2.38(s, 6H), 2.24(d, 1H), 0.07(s, 2H).

[0849] Example 42

[0850] 5-((1S,5R)-1-(5-(((dimethylamino)methyl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile compound 42

[0851] 5-((1S,5R)-1-(5-((dimethylamino)methyl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

[0852] Dimethylglycine 31-1 (213 mg, 2.07 mmol) was dissolved in 20 ml of dichloromethane, followed by the addition of HATU (791 mg, 2.07 mmol) and DIPEA (534 mg, 4.14 mmol) and stirred at low temperature for 5 minutes. Then, (1S, 5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbohydrazide 3-1 (500 mg, 1.38 mmol) was added and stirred for 2 hours. After completion of the reaction by TLC, Burgess reagent (988 mg, 4.14 mmol) was added and stirred for 3 hours. After completion of the reaction by LCMS, the reaction solution was directly concentrated and purified by reverse-phase C18 column chromatography (acid method) to obtain 5-((1S,5R)-1-(5-(((dimethylamino)methyl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile compound 42 (pale yellow solid, 330 mg, 63.2%).

[0853] LC-MS m / z (ESI) = 429.10 [M+1].

[0854] 1H NMR (400MHz, Chloroform-d) δ9.09 (dd, 1H), 8.36 (dd, 1H), 8.05 (d, 1H), 7.53 (dd, 1H), 7.17(d, 1H), 4.16(d, 1H), 3.97(dd, 2H), 3.86-3.77(m, 3H), 2.38(d, 7H), 2.24(d, 1H),

[0855] Example 43

[0856] 5-((1S,5R)-1-(5-(morpholinoethyl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile compound 43

[0857] 5-((1S,5R)-1-(5-(2-morpholinoethyl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

[0858] 2-Morpholinepropionic acid 43-1 (330 mg, 2.07 mmol) was dissolved in 20 ml of dichloromethane, and then HATU (791 mg, 2.07 mmol) and DIPEA (534 mg, 4.14 mmol) were added and stirred at low temperature for 5 minutes. Then (1S, 5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbohydrazide 3-1 (500 mg, 1.38 mmol) was added and stirred for 2 minutes. After 1 h, the reaction was complete by TLC. Burgess reagent (988 mg, 4.14 mmol) was then added and stirred for 3 h. The reaction was complete by LCMS. The reaction solution was directly concentrated and purified by reverse-phase C18 column chromatography (acid method) to give 5-((1S,5R)-1-(5-(morpholinoethyl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile compound 43 (pale yellow solid, 700 mg, 63.2%).

[0859] LC-MS m / z (ESI) = 485.10 [M+1].

[0860] 1H NMR (400MHz, Methanol-d4) δ8.92-8.82 (m, 1H), 8.55 (dd, 1H), 8.03 (dd, 1H), 7.53 (dd, 1H), 7.24 (dd, 1 H), 4.09-3.87(m, 3H), 3.80(d, 1H), 3.54(t, 4H), 3.03(t, 2H), 2.71(t, 2H), 2.40(t, 4H), 2.22(s, 2H).

[0861] Example 44

[0862] 5-((1S,5R)-1-(4-methyl-5-(pyrrolidin-1-ylmethyl)-4H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile Compound 44

[0863] 5-((1S,5R)-1-(4-methyl-5-(pyrrolidin-1-ylmethyl)-4H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

[0864] 5-((1S,5R)-1-(5-(pyrrolidin-1-ylmethyl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile compound 41 (200 mg, 0.44 mmol) was dissolved in 5 ml of mesitylene, followed by the addition of methylamine hydrochloride (148 mg, 2.20 mmol), TEA (303 mg, 2.98 mmol), p-toluenesulfonic acid (15 The reaction mixture was stirred at low temperature for 5 minutes and then at 150°C for 1 hour. After LCMS detection, the reaction mixture was purified by column chromatography to obtain the target product 5-((1S,5R)-1-(4-methyl-5-(pyrrolidin-1-ylmethyl)-4H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile compound 44 (pale yellow solid, 80 mg, 38.0%).

[0865] LC-MS m / z (ESI) = 468.0 [M+1].

[0866] 1H NMR (400MHz, Methanol-d4) δ 8.94 (dd, 1H), 8.65 (dd, 1H), 8.09 (d, 1H), 7.60 (dd, 1H), 7.30 (d, 1 H), 4.08(d, 3H), 3.86(d, 6H), 2.57(qd, 4H), 2.22(d, 1H), 2.09-1.98(m, 1H), 1.87-1.74(m, 4H).

[0867] Example 45

[0868] 5-((1R,5S)-1-((difluoro-3-methyl)-12-fluorenyl)-5-(5-(5-fluoropiperidin-3-yl)-1,3,4-oxadiazol-2-yl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile compound 45

[0869] 5-((1R,5S)-1-((difluoro-l3-methyl)-l2-fluoraneyl)-5-(5-(5-fluoropiperidin-3-yl)-1,3,4-oxadiazol-2-yl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

[0870] first step:

[0871] tert-Butyl 3-(5-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazol-2-yl)-5-fluoropiperidine-1-carboxylate 45-2

[0872] tert-butyl 3-(5-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazol-2-yl)-5-fluoropiperidine-1-carboxylate

[0873] 4-(tert-Butyloxycarbonyl)morpholine-2-carboxylic acid 45-1 (643 mg, 2.6 mmol) was dissolved in 10 ml of dichloromethane, followed by the addition of HATU (1140 mg, 3.00 mmol) and DIPEA (840 mg, 6.00 mmol) and stirred at low temperature for 5 minutes. Then, (1S, 5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbohydrazide 3-1 (724 mg, 2.0 mmol) was added and stirred for 2 hours. After the reaction was completed by TLC, Burgess reagent (1100 mg, 3.9 mmol) was added and stirred for 3 hours. After the reaction was completed by LCMS, the reaction solution was directly concentrated and purified by reverse phase C18 column chromatography (acid method) to obtain the target product 3-(5-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazol-2-yl)-5-fluoropiperidine-1-carboxylic acid tert-butyl ester 45-2 (pale yellow solid, 500 mg crude product).

[0874] Step 2:

[0875] 5-((1R,5S)-1-((difluoro-3-methyl)-12-fluorenyl)-5-(5-(5-fluoropiperidin-3-yl)-1,3,4-oxadiazol-2-yl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile compound 45

[0876] 5-((1R,5S)-1-((difluoro-l3-methyl)-l2-fluoraneyl)-5-(5-(5-fluoropiperidin-3-yl)-1,3,4-oxadiazol-2-yl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

[0877] The above product 5-(1S,5R)-1-(5-(1-tert-butyloxycarbonylpiperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-3-yl)quinoline-8-carbonitrile 45-2 500 mg of the crude product was added with 2.00 mL of hydrochloric acid and ethyl acetate solution, and the mixture was stirred for half an hour. The reaction was completed by LCMS. The reaction solution was concentrated and adjusted to pH 7-8 with triethylamine. TLC thin layer preparation (dichloromethane:methanol=5:1) was performed to obtain the product 5-((1R,5S)-1-((difluoro-3-methyl)-12-fluorenyl)-5-(5-(5-fluoropiperidin-3-yl)-1,3,4-oxadiazol-2-yl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile compound 45 (pale yellow solid, 300 mg, 72.8%).

[0878] LC-MS m / z (ESI) = 473.10 [M+1].

[0879] 1 H NMR (400MHz, Chloroform-d) δ9.09 (dd, 1H), 8.36 (dd, 1H), 8.13-8.02 (m, 1H), 7.53 (dd, 1H), 7.17 (d, 1H), 4.12 (d, 1H), 4.02- 3.92(m, 2H), 3.80(d, 1H), 3.20(s, 1H), 3.12(s, 1H), 2.45-2.36(m, 3H), 2.33(d, 2H), 2.24(s, 2H), 1.78(q, 1H), 1.25(s, 1H).

[0880] Example 46

[0881] 5-((1S,5R)-1-(5-(3-fluoropyrrolidin-3-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile Compound 46

[0882] 5-((1S,5R)-1-(5-(3-fluoropyrrolidin-3-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

[0883] first step:

[0884] tert-Butyl 3-(5-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazol-2-yl)-3-fluoropyrrolidine-1-carboxylate 46-2

[0885] tert-butyl 3-(5-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazol-2-yl)-3-fluoropyrrolidine-1-carboxylate

[0886] 1-(tert-Butoxycarbonyl)-3-fluoropyrrolidine-3-carboxylic acid 46-1 (560 mg, 2.2 mmol) was dissolved in 20 ml of dichloromethane, followed by the addition of HATU (1.136 g, 2.98 mmol) and DIPEA (766 mg, 5.94 mmol). The mixture was stirred at low temperature for 5 minutes, and then (1S, 5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbohydrazide 3-1 (720 mg, 1.98 mmol) was added and stirred for 2 minutes. After 1 h, the reaction was complete by TLC, and then Burgess reagent (1100 mg, 3.9 mmol) was added and stirred for 3 h. After the reaction was complete by LCMS, the reaction solution was directly concentrated and purified by reverse phase C18 column chromatography (acid method) to obtain the target product 3-(5-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazol-2-yl)-3-fluoropyrrolidine-1-carboxylic acid tert-butyl ester 46-2 (pale yellow solid, 780 mg, 85.0%)

[0887] LC-MS m / z (ESI) = 559.10 [M+1].

[0888] Step 2:

[0889] 5-((1S,5R)-1-(5-(3-fluoropyrrolidin-3-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile Compound 46

[0890] 5-((1S,5R)-1-(5-(3-fluoropyrrolidin-3-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

[0891] The above product 3-(5-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazol-2-yl)-3-fluoroazetidine-1-carboxylic acid tert-butyl ester 46-2500 mg crude product R was dissolved in 5 mL of dichloromethane, and 5.00 mL of TFA was added. After stirring for half an hour, the reaction was completed by LCMS. The reaction solution was concentrated to obtain the product 5-((1S,5R)-1-(5-(3-fluoropyrrolidin-3-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile compound 46 (pale yellow solid, 700 mg, 97%).

[0892] LC-MS m / z (ESI) = 459.10 [M+1].

[0893] 1 H NMR (400MHz, Methanol-d4) δ8.87 (dd, 1H), 8.55 (dd, 1H), 8.03 (d, 1H), 7.53 (dd, 1H), 7.25 (d, 1H), 4.10-3.98 (m, 2H), 3.97 (d, 1H), 3.82 (d, 1H), 3.43 (ddd, 1H), 3.38-3.22 (m, 1H), 3.21-3.11 (m, 1H), 3.03 (dt, 1H), 2.53-2.31 (m, 2H), 2.27 (s, 2H).

[0894] Example 47

[0895] 5-((1S,5R)-1-(5-(3-fluoro-1-methylpyrrolidin-3-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile Compound 47

[0896] 5-((1S,5R)-1-(5-(3-fluoro-1-methylpyrrolidin-3-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

[0897] 200 mg of 5-((1S,5R)-1-(5-(3-fluoropyrrolidin-3-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile compound 46 (200 mg, 0.43 mmol) was dissolved in 5 mL of methanol, followed by the addition of 1 mL of triethylamine, paraformaldehyde (129 mg, 4.3 mmol), sodium cyanoborohydride (270.9 mg, 4. The reaction mixture was heated to 80°C and stirred for 3 hours. After completion of the TLC reaction, the reaction solution was directly concentrated and purified by reverse phase C18 column chromatography (alkaline method) to obtain the target product 55-((1S,5R)-1-(5-(3-fluoro-1-methylpyrrolidin-3-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile compound 47 (pale yellow solid, 30 mg, 13.7%).

[0898] LC-MS m / z (ESI) = 473.10 [M+1].

[0899] 1H NMR (400MHz, Chloroform-d) 69.09 (dd, 1H), 8.36 (dd, 1H), 8.06 (d, 1H), 7.54 (dd, 1H), 7.19 (d, 1H), 4.16 (d, 1H), 4 .04-3.93(m,2H),3.81(d,1H),3.31(dt,2H),3.12-3.01(m,1H),2.87-2.46(m,6H),2.39(d,1H),2.31-2.25(m,1H)

[0900] Example 48

[0901] 5-((1S,5R)-1-(5-(2-(pyrrolidin-1-yl)ethoxy)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile Compound 48

[0902] 5-((1S,5R)-1-(5-(2-(pyrrolidin-1-yl)ethoxy)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

[0903] first step:

[0904] 2-(Pyrrolidin-1-yl)ethyl-2-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbonyl)hydrazine-1-carboxylate 48-2

[0905] 2-(pyrrolidin-1-yl)ethyl-2-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbonyl)hydrazine-1-carboxylate

[0906] (1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbohydrazide 3-1 (724 mg, 2.0 mmol) was dissolved in 10 ml of dichloromethane, triphosgene (177.6 mg, 0.6 mmol) was dissolved in 10.0 mL of dichloromethane, and 2-(pyrrolidin-1-yl)ethane-1-ol 48-1 (272 mg, 2.0 mmol) and triethylamine (204 mg, 2.0 The reaction mixture was dissolved in 10.0 mL of a mixed solution of 15-nitropropane (15-nitropropane) and 10.0 mL of dichloromethane. After reacting for 1 h, the reaction was completed when the LCMS sample was sent for sampling. Methanol was added to quench the reaction. The reaction solution was directly concentrated and purified by reverse phase C18 column chromatography (acid method) to obtain the target product 2-(pyrrolidin-1-yl)ethyl-2-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbonyl)hydrazine-1-carboxylate 48-2 (pale yellow solid, 280 mg, 27.8%).

[0907] Step 2:

[0908] 5-((1S,5R)-1-(5-(2-(pyrrolidin-1-yl)ethoxy)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile Compound 48

[0909] 5-((1S,5R)-1-(5-(2-(pyrrolidin-1-yl)ethoxy)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

[0910] 2-(Pyrrolidin-1-yl)ethyl-2-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbonyl)hydrazine-1-carboxylate 48-2 (280 mg, 0.55 mmol) was dissolved in 10 ml of dichloromethane, DIEA (204 mg, 2.0 mmol) was added to the Burgess reagent (1100 mg, 3.9 mmol). After stirring for 3 hours, the reaction was completed by LCMS, and the reaction solution was directly concentrated and purified by reverse phase C18 column chromatography (acid method) to obtain the target product 5-((1S,5R)-1-(5-(2-(pyrrolidin-1-yl)ethoxy)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile compound 48 (pale yellow solid, 50 mg, 18.5%).

[0911] LC-MS m / z (ESI) = 485.2 [M+1].

[0912] 1 H NMR (400MHz, Chloroform-d) δ9.09 (dd, 1H), 8.34 (ddd, 1H), 8.04 (dd, 1H), 7.53 (dd, 1H), 7.14 (d, 1H), 4.62 (t, 2H), 4 .02(d,1H),3.96-3.90(m,2H),3.78(d,1H),2.95(t,2H),2.61(q,4H),2.27(d,1H),2.15(d,1H),,1.86-1.79(m,4H).

[0913] Example 49

[0914] 5-((1S,5R)-1-(5-(3-fluoro-1-methylazetidin-3-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-3-yl)quinoline-8-carbonitrile Compound 49

[0915] 5-((1S,5R)-1-(5-(3-fluoro-1-methylazetidin-3-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

[0916] 5-((1S,5R)-1-(5-(3-fluoroazetidin-3-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-3-yl)quinoline-8-carbonitrile compound 32 (400 mg, 0.9 mmol) was dissolved in 5 mL of methanol, followed by the addition of 1 mL of triethylamine, paraformaldehyde (250 mg, 9 mmol), sodium cyanoborohydride (506 mg, 13.5 mmol) and 1 mL of ethanol. mol) was heated to 80 degrees and stirred for 3 hours. After the reaction was completed by TLC, the reaction solution was directly concentrated and purified by reverse phase C18 column chromatography (alkaline method) to obtain the target product 5-(1S,5R)-1-(5-(S)-4-methylmorpholin-2-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile compound 49 (pale yellow solid, 110 mg, 26.7%).

[0917] LC-MS m / z (ESI) = 459.10 [M+1].

[0918] 1 H NMR (400MHz, Chloroform-d) δ9.10 (dd, 1H), 8.36 (dd, 1H), 8.06 (d, 1H), 7.54 (dd, 1H), 7.19 (d, 1H), 4.17 (d, 1 H), 4.14-4.02(m, 2H), 4.02-3.94(m, 2H), 3.81(d, 1H), 3.68(dd, 2H), 2.53(s, 3H), 2.40(d, 1H), 2.28(d, 1H).

[0919] Example 50

[0920] 5-((1S,5R)-1-(5-(3-fluoro-1-methylpiperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-3-yl)quinoline-8-carbonitrile Compound 50

[0921] 5-((1S,5R)-1-(5-(3-fluoro-1-methylpiperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

[0922] 5-((1S,5R)-1-(5-(3-fluoroazetidin-3-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-3-yl)quinoline-8-carbonitrile compound 33 (100 mg, 0.21 mmol) was dissolved in 5 mL of methanol, followed by the addition of 1 mL of triethylamine, paraformaldehyde (250 mg, 9 mmol), sodium cyanoborohydride (506 mg, 13.5 mmol) was heated to 80 degrees and stirred for 3 hours. After the reaction was completed by TLC, the reaction solution was directly concentrated and purified by reverse phase C18 column chromatography (alkaline method) to obtain the target product 5-(1S,5R)-1-(5-(S)-4-methylmorpholin-2-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-3-yl)quinoline-8-carbonitrile compound 50 (pale yellow solid, 20 mg, 19.6%).

[0923] LC-MS m / z (ESI) = 487.10 [M+1].

[0924] 1 H NMR (400MHz, Chloroform-d) δ9.09 (dd, 1H), 8.36 (dd, 1H), 8.05 (d, 1H), 7.53 (dd, 1H), 7.17 (dd, 1H), 5.07 (d, 1 H), 4.12(dd, 1H), 3.98(dd, 2H), 3.80(dd, 1H), 3.32-3.03(m, 3H), 2.51-2.29(m, 5H), 2.24(s, 2H), 2.09(s, 2H).

[0925] Example 51

[0926] 5-((1S,5R)-1-(5-(2-(dimethylamino)ethyl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-3-yl)quinoline-8-carbonitrile compound 51

[0927] 5-((1S,5R)-1-(5-(2-(dimethylamino)ethyl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

[0928] The raw materials (1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbohydrazide 3-1 (500 mg, 1.38 mmol) and 3-(dimethylamino)propionic acid 51-1 (161 mg, 1.38 mmol) were added to phosphorus oxychloride (3 ml), and the reaction mixture was protected by nitrogen and heated to 100 degrees for 3 hours. After the reaction was completed, dichloromethane was added to dissolve the mixture, and the mixture was slowly added dropwise to an ice-cold saturated aqueous sodium carbonate solution. After stirring for 0.5 hour, the pH was remeasured to about 9, and ethyl acetate was added for extraction three times. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then purified by column chromatography to obtain 5-((1S,5R)-1-(5-(2-(dimethylamino)ethyl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-3-yl)quinoline-8-carbonitrile compound 51 (220 mg, yield 36.0%).

[0929] LCMS m / z (ESI) = 443.2 [M+1].

[0930] 1 H NMR (400MHz, DMSO-d6) δ9.02 (dd, 1H), 8.69 (dd, 1H), 8.20 (d, 1H), 7.62 (dd, 1H), 7.33 (d, 1H), 4. 23-4.16(m, 1H), 4.06(dd, 2H), 3.93(d, 1H), 3.01(t, 2H), 2.63(t, 2H), 2.21(s, 2H), 2.15(s, 6H).

[0931] 19 F NMR(377MHz, DMSO-d6)δ-64.05.

[0932] Example 52

[0933] 5-((1S,5R)-1-(5-(4-aminobicyclo[2.2.2]oct-1-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hex-3-yl)quinoline-8-carbonitrile compound 52

[0934] 5-((1S,5R)-1-(5-(4-aminobicyclo[2.2.2]octan-1-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

[0935] first step:

[0936] Tert-butyl (4-(5-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazol-2-yl)bicyclo[2.2.2]octan-1-yl)carbamate 52-2

[0937] tert-butyl(4-(5-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazol-2-yl)bicyclo[2.2.2]octan-1-yl)carbamate

[0938] The raw materials (1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbohydrazide 3-1 (700 mg, 1.94 mmol) and 4-((tert-butyloxycarbonyl)amino)bicyclo[2.2.2]octane-1-carboxylic acid 52-1 (522 mg, 1.94 mmol) were added to N,N-dimethylformamide (10 ml), and then 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (737 mg, 1.94 mmol) and N,N-diisopropylethylamine (752 mg, 1.94 mmol) were added. The reaction mixture was reacted at room temperature for 3 hours. After the reaction was completed by LCMS, Burgess reagent (1.39 g, 5.82 mmol) was added, and the reaction mixture was reacted at room temperature for 16 hours. After the reaction was completed, it was directly purified by rapid reverse phase chromatography to obtain tert-butyl (4-(5-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazol-2-yl)bicyclo[2.2.2]octan-1-yl)carbamate 52-2 (560 mg, yield 48.5%).

[0939] LCMS m / z (ESI) = 595.3 [M+1].

[0940] Step 2:

[0941] 5-((1S,5R)-1-(5-(4-aminobicyclo[2.2.2]oct-1-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hex-3-yl)quinoline-8-carbonitrile compound 52

[0942] 5-((1S,5R)-1-(5-(4-aminobicyclo[2.2.2]octan-1-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

[0943] The raw material tert-butyl (4-(5-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazol-2-yl)bicyclo[2.2.2]octan-1-yl)carbamate 52-2 (560 mg, 0.941 mmol) was added to dichloromethane (3 ml), and trifluoroacetic acid (3 ml) was added. l), the reaction mixture was reacted at room temperature for 1 hour. After the reaction was completed, it was concentrated under reduced pressure and the crude product was purified by column chromatography to obtain 5-((1S,5R)-1-(5-(4-aminobicyclo[2.2.2]oct-1-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hex-3-yl)quinoline-8-carbonitrile compound 52 (440 mg, yield 94.4%).

[0944] LCMS m / z (ESI) = 495.3 [M+1].

[0945] 1 H NMR (400MHz, Chloroform-d) δ9.08 (dd, 1H), 8.36 (dd, 1H), 8.04 (d, 1H), 7.53 (dd, 1H), 7.16 (d, 1H), 4.10 (d, 1H), 4 .06-3.89(m, 2H), 3.79(d, 1H), 3.01(s, 2H), 2.29(d, 1H), 2.25-2.18(m, 1H), 2.16-2.00(m, 6H), 1.80-1.69(m, 6H).

[0946] 19F NMR (377MHz, Chloroform-d) δ -65.27, -75.64.

[0947] Example 53

[0948] 5-((1S,5R)-1-(5-(4-(dimethylamino)bicyclo[2.2.2]oct-1-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hex-3-yl)quinoline-8-carbonitrile compound 53

[0949] 5-((1S,5R)-1-(5-(4-(dimethylamino)bicyclo[2.2.2]octan-1-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

[0950] 5-((1S,5R)-1-(5-(4-aminobicyclo[2.2.2]octan-1-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile compound 52 (150 mg, 0.30 mmol) was added to dichloromethane (10 ml), and then paraformaldehyde (90 mg, 3.0 mmol) and sodium cyanoborohydride (377 mg, 6 .0mmol), the reaction mixture was reacted at room temperature overnight. After the reaction was completed, it was filtered, the filtrate was spin-dried, and then purified by flash chromatography to obtain 5-((1S,5R)-1-(5-(4-(dimethylamino)bicyclo[2.2.2]oct-1-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hex-3-yl)quinoline-8-carbonitrile compound 53 (56 mg, yield 35.7%).

[0951] LCMS m / z (ESI) = 523.2 [M+1].

[0952] 1H NMR (400MHz, Chloroform-d) δ9.06 (d, 1H), 8.38 (d, 1H), 8.03 (d, 1H), 7.53 (dd, 1H), 7.17 (d, 1H), 4.11 (d, 1H) , 4.04-3.88(m, 3H), 3.77(dd, 2H), 3.63-3.45(m, 2H), 3.38(dd, 1H), 2.92(dt, 2H), 2.30(d, 1H), 2.05(s, 12H).

[0953] 19 F NMR (377MHz, Chloroform-d) δ-65.27.

[0954] Example 54

[0955] (S)-N-(4-(5-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazol-2-yl)bicyclo[2.2.2]octan-1-yl)morpholine-3-carboxamide Compound 54

[0956] (S)-N-(4-(5-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazol-2-yl)bicyclo[2.2.2]octan-1-yl)morpholine-3-carboxamide

[0957] first step:

[0958] (S)-tert-Butyl 3-((4-(5-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazol-2-yl)bicyclo[2.2.2]octan-1-yl)carbamoyl)morpholine-4-carboxylate 54-2

[0959] tert-butyl(S)-3-((4-(5-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1. 0]hexan-1-yl)-1,3,4-oxadiazol-2-yl)bicyclo[2.2.2]octan-1-yl)carbamoyl)morpholine-4-carboxylate

[0960] The raw material 5-((1S,5R)-1-(5-(4-aminobicyclo[2.2.2]octan-1-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile compound 52 (150 mg, 0.30 mmol) and (S)-4-(tert-butyloxycarbonyl)morpholine-3-carboxylic acid 54-1 (69 mg, 0.30 mmol) were added to N,N-dimethylformamide (2 ml), and then 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (22 The reaction mixture was reacted at room temperature for 3 hours. After the reaction was completed by LCMS, it was directly purified by rapid reverse phase chromatography to obtain (S)-3-((4-(5-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazol-2-yl)bicyclo[2.2.2]octan-1-yl)carbamoyl)morpholine-4-carboxylic acid tert-butyl ester 54-2 (110 mg, yield 51.9%).

[0961] LCMS m / z (ESI) = 708.3 [M+1].

[0962] Step 2:

[0963] (S)-N-(4-(5-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazol-2-yl)bicyclo[2.2.2]octan-1-yl)morpholine-3-carboxamide Compound 54

[0964] (S)-N-(4-(5-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazol-2-yl)bicyclo[2.2.2]octan-1-yl)morpholine-3-carboxamide

[0965] The raw material (S)-3-((4-(5-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazol-2-yl)bicyclo[2.2.2]octan-1-yl)carbamoyl)morpholine-4-carboxylic acid tert-butyl ester 54-2 (110 mg, 0.156 mmol) was added to dichloromethane (1 ml), and trifluoroacetic acid (1 ml) was added. l), the reaction mixture was reacted at room temperature for 1 hour. After the reaction was completed, it was concentrated under reduced pressure and the crude product was purified by column chromatography to obtain (S)-N-(4-(5-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazol-2-yl)bicyclo[2.2.2]octan-1-yl)morpholine-3-carboxamide compound 54 (62 mg, yield 65.4%).

[0966] LCMS m / z (ESI) = 608.3 [M+1].

[0967] 1 H NMR (400MHz, Chloroform-d) δ9.08 (dd, 1H), 8.37 (dd, 1H), 8.05 (d, 1H), 7.53 (dd, 1H), 7.18 (d, 1H), 4.11 (d, 1H), 3 .97(dd, 2H), 3.79(d, 1H), 3.41(br, 2H), 2.60(s, 6H), 2.30(d, 1H), 2.23(d, 1H), 2.19-2.05(m, 7H), 1.95(dd, 6H).

[0968] 19 F NMR(377MHz, DMSO-d6)δ-64.01.

[0969] Example 55

[0970] 5-((1S,5R)-1-(1-(piperidin-4-yl)-1H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile compound 55

[0971] 5-((1S,5R)-1-(1-(piperidin-4-yl)-1H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

[0972] first step:

[0973] tert-Butyl 4-(3-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1H-1,2,4-triazol-1-yl)piperidine-1-carboxylate 55-2

[0974] tert-butyl 4-(3-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1H-1,2,4-triazol-1-yl)piperidine-1-carboxylate

[0975] The raw material 5-((1S,5R)-1-(1H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-3-yl)quinoline-8-carbonitrile 23-3 (300 mg, 0.81 mmol) was added to N,N-dimethylformamide (5 ml), and then cesium carbonate (792 mg, 2.43 mmol) and tert-butyl 4-bromopiperidin-1-carboxylate 55-1 (642 mg) were added. g, 2.43 mmol), the reaction mixture was reacted at 100 ° C for 6 hours. After the reaction was completed, it was filtered and then purified by reverse phase chromatography to obtain 4-(3-((1S, 5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1H-1,2,4-triazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester compound 55-2 (178 mg, yield 39.6%).

[0976] LCMS m / z (ESI) = 554.2 [M+1].

[0977] Step 2:

[0978] 5-((1S,5R)-1-(1-(piperidin-4-yl)-1H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile compound 55

[0979] 5-((1S,5R)-1-(1-(piperidin-4-yl)-1H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

[0980] The raw material tert-butyl 4-(3-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1H-1,2,4-triazol-1-yl)piperidine-1-carboxylate 55-2 (178 mg, 0.32 mmol) was added to dichloromethane (3 ml), and trifluoroacetic acid (3 ml) was added. The reaction mixture was reacted at room temperature for 1 hour. After the reaction was completed, it was concentrated under reduced pressure and the crude product was purified by reverse phase chromatography to obtain 5-((1S,5R)-1-(1-(piperidin-4-yl)-1H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile compound 55 (103 mg, yield 70.7%).

[0981] LCMS m / z (ESI) = 454.2 [M+1].

[0982] 1 H NMR (400MHz, DMSO-d6) δ9.00 (dd, 1H), 8.69 (dd, 1H), 8.61 (s, 1H), 8.16 (d, 1H), 7.60 (dd, 1H), 7.27 (d, 1H), 4.61 ( tt, 1H), 4.10 (s, 2H), 4.04 (d, 1H), 3.92 (d, 1H), 3.11-3.01 (m, 3H), 2.29-2.03 (m, 5H), 1.93 (d, 1H), 1.19 (t, 2H).

[0983] 19 F NMR(377MHz, DMSO-d6)δ-63.32.

[0984] Example 56

[0985] 2-((R)-2-(5-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazol-2-yl)morpholinyl)acetamide Compound 56

[0986] 2-((R)-2-(5-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(tri(luoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazol-2-yl)morpholino)acetamide

[0987] first step:

[0988] 5-((1S,5R)-1-(5-(((R)-morpholin-2-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile 56-2

[0989] 5-((1S,5R)-1-(5-((R)-morpholin-2-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

[0990] The raw materials (1S, 5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbohydrazide 3-1 (723 mg, 2.0 mmol) and (R)-4-(tert-butoxycarbonyl)morpholine-2-carboxylic acid 56-1 (463 mg, 2.0 mmol) were added to phosphorus oxychloride (5 ml). After nitrogen protection, the temperature was raised to 100°C. After the reaction mixture was reacted at 100°C for 4 hours, the reaction was completed. The reaction solution was cooled to room temperature, diluted with dichloromethane (50 ml), and then slowly added dropwise to a saturated aqueous sodium carbonate solution. After stirring for half an hour, ethyl acetate (100 ml*3) was added for extraction. The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The filtered solution was spin-dried and the crude product was purified by reverse column chromatography to give 5-((1S,5R)-1-(5-(((R)-morpholin-2-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile 56-2 (138 mg, yield 14.7%).

[0991] LCMS m / z (ESI) = 457.2 [M+1].

[0992] Step 2:

[0993] 2-((R)-2-(5-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazol-2-yl)morpholinyl)acetamide Compound 56

[0994] 2-((R)-2-(5-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazol-2-yl)morpholino)acetamide

[0995] The raw material 5-((1S,5R)-1-(5-(((R)-morpholin-2-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile 56-2 (150 mg, 0.33 mmol) was added to N,N-dimethylformamide (3 ml), and then cesium carbonate (326 mg, 1.0 mmol) and bromoacetamide (4 The reaction mixture was reacted at room temperature for 4 hours. After the reaction was completed, it was directly purified by reverse phase chromatography to obtain 2-((R)-2-(5-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazol-2-yl)morpholinyl)acetamide compound 56 (78 mg, yield 46.3%).

[0996] LCMS m / z (ESI) = 514.2 [M+1].

[0997] 1 H NMR (400MHz, DMSO-d6) δ9.02 (d, 1H), 8.68 (d, 1H), 8.20 (d, 1H), 7.62 (dd, 1H), 7.49-7.27 (m, 2H), 7.24 (s, 1H), 5.01 (d, 1H) ), 4.20(d, 1H), 4.15-4.01(m, 2H), 3.94(d, 1H), 3.77(dt, 2H), 3.09-2.83(m, 3H), 2.69(dd, 2H), 2.43(d, 1H), 2.24(d, 2H).

[0998] 19F NMR(377MHz, DMSO-d6)δ-64.01.

[0999] Example 57

[1000] 3-Fluoro-4-((1S,5R)-1-(5-(1-methylpiperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)pyrazolo[1,5-a]pyridine-7-carbonitrile Compound 57

[1001] 3-fluoro-4-((1S,5R)-1-(5-(1-methylpiperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)pyrazolo[1,5-a]pyridine-7-carbonitrile

[1002] The starting material 3,4-difluoropyrazolo[1,5-a]pyridine-7-carbonitrile 57-1 (358 mg, 2.0 mmol) and 2-(1-methylpiperidin-4-yl)-5-((1S,5R)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazole intermediate C (949 mg, 3.0 mmol) were added to dimethyl sulfoxide (3 ml), and then N,N-diisopropylethylamine (2.58 g, The reaction mixture was protected by nitrogen and then heated to 130°C for 6 hours. After completion of the reaction, it was directly purified by reverse phase chromatography to obtain 3-fluoro-4-((1S,5R)-1-(5-(1-methylpiperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-3-yl)pyrazolo[1,5-a]pyridine-7-carbonitrile compound 57 (136 mg, yield 14.3%).

[1003] LC-MS m / z (ESI) = 476.20 [M+1].

[1004] 1H NMR (400MHz, DMSO-d6) δ 8.27 (d, 1H), 7.65 (d, 1H), 6.50 (d, 1H), 4.24 (d, 1H), 4.16 (t, 2H), 3.99 ( d, 1H), 2.93 (tt, 1H), 2.72 (d, 2H), 2.28 (d, 1H), 2.16 (s, 3H), 2.08-1.85 (m, 5H), 1.71 (tdd, 2H).

[1005] 19 F NMR (377MHz, DMSO-d6) δ-64.46, -167.61.

[1006] Example 58

[1007] 2-Chloro-5-((1S,5R)-1-(5-(1-methylpiperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile Compound 58

[1008] 2-chloro-5-((1S,5R)-1-(5-(1-methylpiperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

[1009] first step:

[1010] N-(5-bromo-2-iodophenyl)-3,3-dimethoxypropionamide compound 58-3

[1011] N-(5-bromo-2-iodophenyl)-3,3-dimethoxypropanamide

[1012] The raw materials, 5-bromo-2-iodoaniline 58-1 (10.0 g, 33.6 mmol) and methyl 3,3-dimethoxypropionate 58-2 (5.97 g, 40.3 mmol), were added to anhydrous tetrahydrofuran (100 ml). Under nitrogen, the mixture was cooled to 0°C and a 50 ml, 1 mol / L sodium bis(trimethylsilyl)amide solution in tetrahydrofuran was slowly added dropwise. The reaction mixture was slowly warmed to room temperature and allowed to react for 6 hours, resulting in completion. Extraction was then performed with saturated aqueous ammonium chloride and ethyl acetate (100 ml x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford N-(5-bromo-2-iodophenyl)-3,3-dimethoxypropionamide 58-3 (12.0 g, 86.4% yield).

[1013] LC-MS m / z (ESI) = 413.90 [M+1].

[1014] Step 2:

[1015] 5-Bromo-8-iodoquinolin-2(1H)-one 58-4

[1016] 5-bromo-8-iodoquinolin-2(1H)-one

[1017] The raw material N-(5-bromo-2-iodophenyl)-3,3-dimethoxypropionamide 58-3 (12.0 g, 29.0 mmol) was dissolved in dichloromethane (200 ml). The reaction mixture was cooled to 0°C and then concentrated sulfuric acid (300 ml) was added. The reaction mixture was slowly heated to a temperature of 8 hours. After the reaction was complete, the layers were separated and the lower sulfuric acid layer was slowly added dropwise to ice water (1 L). A large amount of solid precipitated, which was filtered and the filter cake dried to obtain 5-bromo-8-iodoquinolin-2(1H)-one 58-4 (9.0 g, 88.7% yield).

[1018] LC-MS m / z (ESI) = 349.90 [M+1].

[1019] Step 3:

[1020] 5-Bromo-2-oxo-1,2-dihydroquinoline-8-carbonitrile 58-5

[1021] 5-bromo-2-oxo-1,2-dihydroquinoline-8-carbonitrile

[1022] The raw material 5-bromo-8-iodoquinolin-2(1H)-one 58-4 (9.0 g, 25.7 mmol) was added to N,N-dimethylformamide (90 ml), and then zinc cyanide (1.5 g, 12.9 mmol) and tetrakistriphenylphosphine palladium (2.97 g, 2.57 mmol) were added. After the reaction mixture was protected by nitrogen, it was heated to 100 ° C and reacted for 3 hours. After the reaction was completed, purified water (300 ml) was added, and a large amount of solid precipitated. After filtration, the filter cake was purified by column chromatography to obtain 5-bromo-2-oxo-1,2-dihydroquinoline-8-carbonitrile 58-5 (3.5 g, yield 54.9%).

[1023] LC-MS m / z (ESI) = 248.90 [M+1].

[1024] Step 4:

[1025] 5-((1S,5R)-1-(5-(1-methylpiperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)-2-oxo-1,2-dihydroquinoline-8-carbonitrile 58-6

[1026] 5-((1S,5R)-1-(5-(1-methylpiperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)-2-oxo-1,2-dihydroquinoline-8-carbonitrile

[1027] The starting material 5-bromo-2-oxo-1,2-dihydroquinoline-8-carbonitrile 58-5 (249 mg, 1.0 mmol) and 2-(1-methylpiperidin-4-yl)-5-((1S,5R)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazole intermediate C (476 mg, 1.5 mmol) were added to 1,4-dioxane (3 ml), followed by cesium carbonate (977 mg, 3.0 mmol) and methanesulfonic acid (2-dicyclohexylphosphino-2′,6′-diisopropyloxy-1,3,4-dioxadiazole). , 1′-biphenyl)(2-amino-1,1′-biphenyl-2-yl)palladium(II) (84 mg, 0.1 mmol), the reaction mixture was protected by nitrogen, and the temperature was raised to 100°C for 3 hours. After the reaction was completed, it was directly purified by reverse chromatography to obtain 5-((1S,5R)-1-(5-(1-methylpiperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)-2-oxo-1,2-dihydroquinoline-8-carbonitrile 58-6 (89 mg, yield 18.4%).

[1028] LC-MS m / z (ESI) = 485.20 [M+1].

[1029] 1 H NMR (400MHz, DMSO-d6) δ8.17 (d, 1H), 7.87 (d, 1H), 7.07 (d, 1H), 6.59 (d, 1H), 4.10-4.01 (m, 2H), 3.96 (d, 1H), 3.8 8(d,1H), 2.93(ddt,1H), 2.73(d,2H), 2.23-2.12(m,5H), 2.10-2.04(m,2H), 2.00-1.92(m,2H), 1.72(dddd,2H).

[1030] 19 F NMR(377MHz, DMSO-d6)δ-64.03.

[1031] Step 5:

[1032] 2-Chloro-5-((1S,5R)-1-(5-(1-methylpiperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile Compound 58

[1033] 2-chloro-5-((1S,5R)-1-(5-(1-methylpiperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

[1034] The raw material 5-((1S,5R)-1-(5-(1-methylpiperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)-2-oxo-1,2-dihydroquinoline-8-carbonitrile 58-6 (30 mg, 0.062 mmol) was added to phosphorus oxychloride (1 ml), and the reaction mixture was heated to 100 ° C for 3 hours. After the reaction was completed, saturated sodium carbonate solution was added. The mixture was stirred for 2 h and then added with 4% paraformaldehyde (5% ethanol) and 4% paraformaldehyde (1% ethanol). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by reverse phase chromatography to give 2-chloro-5-((1S, 5R)-1-(5-(1-methylpiperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-3-yl)quinoline-8-carbonitrile compound 58 (15 mg, yield 48.1%).

[1035] LC-MS m / z (ESI) = 503.20 [M+1].

[1036] 1 H NMR (400MHz, DMSO-d6) δ 8.75 (d, 1H), 8.24 (d, 1H), 7.63 (d, 1H), 7.34 (d, 1H), 4.22 (d, 1H), 4.12 (dd, 2H), 3.98 (d, 1H), 3.64 (d, 1H), 3.21 (dd, 1H), 2.85 (d, 1H), 2.67 (d, 4H), 2.34-1.94 (m, 7H).

[1037] 19 F NMR(377MHz, DMSO-d6)δ-64.12.

[1038] Example 59

[1039] 4-((1S,5R)-1-(5-(1-methylpiperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)pyrazolo[1,5-a]pyridine-7-carbonitrile Compound 59

[1040] 4-((1S,5R)-1-(5-(1-methylpiperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)pyrazolo[1,5-a]pyridine-7-carbonitrile

[1041] Under N2 atmosphere, (2S,6S)-2-methyl-6-(5-(1-methylpiperidin-4-yl)-1,3,4-oxadiazol-2-yl)morpholine intermediate C (500 mg, 1.16 mmol) was dissolved in 1,4-dioxane (4.00 mL), followed by the addition of 4-chloropyrazolo[1,5-a]pyridine-7-carbonitrile 59-1 (281 mg, 1.16 mmol), cesium carbonate (3.10 g, 8.12 mmol) and RuPhosPdG3 (92.4 mg, 0.11 mmol), water (1.0 mL), and N2 gas replacement three times. The temperature was raised to 80 ° C for 2 h. The solvent was dried, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was dried. The reaction solution was directly concentrated and purified by reverse phase C18 column chromatography (acid method) to give 450 mg of crude product. TLC (DCM:MeOH=10:1) gave the target product 4-((1S,5R)-1-(5-(1-methylpiperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)pyrazolo[1,5-a]pyridine-7-carbonitrile compound 59 (yellow-white solid, 90 mg, yield 12.4%).

[1042] LC-MS m / z (ESI) = 458.10 [M+1].

[1043] 1 H NMR (400MHz, Chloroform-d) δ7.94 (d, 1H), 7.16 (d, 1H), 6.78 (d, 1H), 6.01 (d, 1H), 4.38 (d, 1H), 4.27 (d, 1H), 4 .19 (d, 1H), 4.04 (d, 1H), 2.85 (d, 3H), 2.35 (d, 1H), 2.28 (s, 3H), 2.19-1.99 (m, 4H), 1.91 (q, 2H), 1.69 (dd, 1H).

[1044] Example 60

[1045] 5-((1S,5R)-1-(5-(4-fluoropiperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile compound 60

[1046] 5-((1S,5R)-1-(5-(4-fluoropiperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

[1047] first step:

[1048] 4-(5-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazol-2-yl)-4-fluoropiperidine-1-carboxylic acid tert-butyl compound 60-2

[1049] 4-(5-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazol-2-yl)-4-fluoropiperidine-1-carboxylate

[1050] 1-(tert-Butyloxycarbonyl)-4-fluoropiperidine-4-carboxylic acid 60-1 (49 mg, 0.2 mmol) was dissolved in 20 ml of dichloromethane, followed by the addition of HATU (91 mg, 0.24 mmol) and DIPEA (77 mg, 0.6 mmol) and stirred at low temperature for 5 minutes. Then, (1S, 5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbohydrazide 3-1 (72 mg, 0.2 mmol) was added and stirred for 2 hours. After the reaction was complete by TLC, Burgess reagent (142 mg, 0.6 mmol) was added and stirred for 3 hours. After the reaction was complete by LCMS, the reaction solution was directly concentrated and purified by reverse phase C18 column chromatography (acid method) to obtain the target product 4-(5-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazol-2-yl)-4-fluoropiperidine-1-carboxylic acid tert-butyl ester 60-2 (pale yellow solid, 70 mg, 61.4%)

[1051] LC-MS m / z (ESI) = 573.10 [M+1].

[1052] Step 2:

[1053] 5-((1S,5R)-1-(5-(4-fluoropiperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile Compound 60

[1054] 5-((1S,5R)-1-(5-(4-fluoropiperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

[1055] To the crude product 4-(5-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazol-2-yl)-4-fluoropiperidine-1-carboxylic acid tert-butyl ester 60-2 (70 mg) were added 5.6 mL of dichloromethane and 1.4 mL of trifluoroacetic acid. After stirring for half an hour, the reaction was completed by LCMS. The reaction solution was concentrated to obtain the product compound 60 (pale yellow solid, 20 mg, 36.3%).

[1056] LC-MS m / z (ESI) = 473.10 [M+1].

[1057] 1 H NMR (400MHz, Chloroform-d) δ9.02 (dd, 1H), 8.30 (dd, 1H), 7.98 (d, 1H), 7.47 (dd, 1H), 7.11 (d, 1H), 4.09 (d, 1H), 3 .92(dd, 2H), 3.74(d, 1H), 3.06(dt, 2H), 2.91(ddt, 2H), 2.31(d, 1H), 2.21(s, 2H), 2.22-2.11(m, 3H), 1.97(s, 1H).

[1058] Example 61

[1059] 2-Methoxy-5-((1S,5R)-1-(5-(1-methylpiperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile Compound 61

[1060] 2-methoxy-5-((1S,5R)-1-(5-(1-methylpiperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

[1061] 2-Methoxy-5-((1S,5R)-1-(5-(1-methylpiperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile Compound 61

[1062] 2-methoxy-5-((1S,5R)-1-(5-(1-methylpiperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

[1063] Under N2 atmosphere, 2-(1-methylpiperidin-4-yl)-5-((1S,5R)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazole intermediate C (442 mg, 1.4 mmol) was dissolved in 1,4-dioxane (28.0 mL), followed by the addition of 5-bromo-2-methoxyquinoline-8-carbonitrile 61-1 (403 mg, 1.54 mmol), cesium carbonate (3.80 g, 9.8 mmol) and RuPhosPdG3 (117 mg, 0.14 mmol), water (2.8 mL), and N2 gas replacement three times. The temperature was raised to 80°C and the reaction was carried out for 2 h. The solvent was dried, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was dried. The reaction solution was directly concentrated and purified by reverse phase C18 column chromatography (acid method) to give 450 mg of crude product. TLC (DCM:MeOH=10:1) gave the target product 2-methoxy-5-((1S,5R)-1-(5-(1-methylpiperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-3-yl)quinoline-8-carbonitrile compound 61 (yellow-white solid, 50 mg, yield 7.2%).

[1064] LC-MS m / z (ESI) = 499.10 [M+1].

[1065] 1 H NMR (400MHz, Chloroform-d) δ 8.14 (d, 1H), 7.91 (d, 1H), 6.99 (dd, 2H), 4.16 (s, 3H), 4.07 (d, 1H), 3.9 0(dd, 3H), 3.75(d, 1H), 2.91(d, 2H), 2.34(s, 3H), 2.27(d, 1H), 2.18(d, 2H), 2.10(d, 3H), 1.97(q, 2H)

[1066] Example 62

[1067] 2-(1-methylpiperidin-4-yl)-5-((1S,5R)-3-(8-nitroquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazole compound 62

[1068] 2-(1-methylpiperidin-4-yl)-5-((1S,5R)-3-(8-nitroquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazole

[1069] Under N2 atmosphere, 2-(1-methylpiperidin-4-yl)-5-((1S,5R)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazole intermediate C (500 mg, 1.57 mmol) was dissolved in 1,4-dioxane (28.0 mL), followed by the addition of 5-bromo-8-nitroquinoline 62-1 (279 mg, 1.57 mmol), cesium carbonate (6.00 g, 11.0 mmol) and RuPh osPdG3 (132 mg, 0.16 mmol), water (2.8 mL), and N2 gas replacement three times. The temperature was raised to 80°C and the reaction was carried out for 2 h. The solvent was dried, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was dried. The reaction solution was directly concentrated and purified by reverse phase C18 column chromatography (acid method) to give 450 mg of crude product. TLC (DCM:MeOH=10:1) gave the target product 2-methoxy-5-((1S,5R)-1-(5-(1-methylpiperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-3-yl)quinoline-8-carbonitrile compound 62 (yellow-white solid, 44 mg, yield 5.7%).

[1070] LC-MS m / z (ESI) = 489.10 [M+1].

[1071] 1 H NMR (400MHz, Chloroform-d) δ9.09 (dd, 1H), 8.38 (dd, 1H), 8.10 (d, 1H), 7.55 (dd, 1H), 7.16 (d, 1H), 4.11 ( d, 1H), 4.00-3.90 (m, 2H), 3.78 (d, 1H), 2.98 (d, 3H), 2.42 (s, 3H), 2.31 (s, 2H), 2.05 (d, 3H), 1.81 (s, 3H).

[1072] Example 63

[1073] 3-Fluoro-4-((1S,5R)-1-(5-(4-methylpiperazin-1-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-3-yl)pyrazolo[1,5-a]pyridine-7-carbonitrile compound 63

[1074] 3-fluoro-4-((1S,5R)-1-(5-(4-methylpiperazin-1-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)pyrazolo[1,5-a]pyridine-7-carbonitrile

[1075] (1S,5R)-3-(7-cyano-3-fluoropyrazolo[1,5-a]pyridin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid 80-3 (900 mg, 2.54 mmol) and 4-methylpiperazine-1-carboxylic acid 63-1 (5.5 g crude product) were dissolved in POCl3 (10 mL) and reacted at 80°C for 2 hours. The reaction was completed after LCMS detection. After adjusting the pH to alkaline with sodium carbonate, the mixture was extracted with dichloromethane three times and dried by rotary evaporation. After reverse phase purification, the mixture was purified on a large plate to obtain 3-fluoro-4-((1S,5R)-1-(5-(4-methylpiperazin-1-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-3-yl)pyrazolo[1,5-a]pyridine-7-carbonitrile compound 63 (27 mg, yellow solid).

[1076] LCMS m / z (ESI) = 477.16 [M+1].

[1077] 1 H NMR (400MHz, Chloroform-d) δ7.93 (d, 1H), 7.20 (d, 1H), 6.20 (d, 1H), 4.08 (t, 2H ), 3.85(d, 1H), 3.69(s, 4H), 2.69(s, 4H), 2.48(s, 4H), 2.25(d, 1H), 1.81(d, 1H).

[1078] Example 64

[1079] 2-(1-methylpiperidin-4-yl)-5-((1S,5R)-3-(8-nitroquinolin-5-yl)-5-(trifluoromethoxy)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazole compound 64

[1080] 2-(1-methylpiperidin-4-yl)-5-((1S,5R)-3-(8-nitroquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazole

[1081] 2-(1-methylpiperidin-4-yl)-5-((1S,5R)-5-(trifluoromethyl)-3-(8-(trifluoromethoxy)quinolin-5-yl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazole compound 64

[1082] 2-(1-methylpiperidin-4-yl)-5-((1S,5R)-3-(8-(trifluoromethoxy)quinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazole

[1083] Under N2 atmosphere, 2-(1-methylpiperidin-4-yl)-5-((1S,5R)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazole intermediate C (500 mg, 1.57 mmol) was dissolved in 1,4-dioxane (28.0 mL), followed by the addition of 5-bromo-8-trifluoromethylquinoline 64-1 (440 mg, 1.57 mmol), cesium carbonate (6.00 g, 11.0 mmol) and RuPhosPdG3 (132 mg, 0.16 mmol), water (2.8 mL), and N2 gas replacement three times. The temperature was raised to 80°C and the reaction was carried out for 2 h. The solvent was dried, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was dried. The reaction solution was directly concentrated and purified by reverse phase C18 column chromatography (acid method) to obtain 450 mg of crude product. TLC (DCM:MeOH=10:1) gave the target product 2-(1-methylpiperidin-4-yl)-5-((1S,5R)-5-(trifluoromethyl)-3-(8-(trifluoromethoxy)quinolin-5-yl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazole compound 64 (yellow-white solid, 200 mg, yield 24.8%).

[1084] LC-MS m / z (ESI) = 528.10 [M+1].

[1085] 1 H NMR (400MHz, Chloroform-d) δ9.04 (dd, 1H), 8.37 (dd, 1H), 7.63-7.45 (m, 2H), 7.22 (d, 1H), 4.00 ( d, 1H), 3.85-3.72 (m, 2H), 3.67 (d, 1H), 2.95 (d, 3H), 2.37 (d, 4H), 2.27 (d, 2H), 2.17-2.03 (m, 5H).

[1086] Example 65

[1087] 2-(1-methylpiperidin-4-yl)-5-((1S,5R)-3-(8-nitroquinolin-5-yl)-5-(trifluoromethoxy)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazole compound 65

[1088] 2-(1-methylpiperidin-4-yl)-5-((1S,5R)-3-(8-nitroquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazole

[1089] 2-(1-methylpiperidin-4-yl)-5-((1S,5R)-5-(trifluoromethyl)-3-(8-methylquinolin-5-yl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazole compound 65

[1090] 2-(1-methylpiperidin-4-yl)-5-((1S,5R)-3-(8-methylquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazole

[1091] Under N2 atmosphere, 2-(1-methylpiperidin-4-yl)-5-((1S,5R)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazole intermediate C (500 mg, 1.57 mmol) was dissolved in 1,4-dioxane (28.0 mL), followed by the addition of 5-bromo-8-methylquinoline 65-1 (386 mg, 1.57 mmol), cesium carbonate (6.00 g, 11.0 mmol) and RuPhos PdG3 (132 mg, 0.16 mmol), water (2.8 mL), and N2 gas replacement three times. The temperature was raised to 80 ° C for 2 h. The solvent was dried, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was dried. The reaction solution was directly concentrated and purified by reverse phase C18 column chromatography (acid method) to give 450 mg of crude product. TLC (DCM:MeOH=10:1) gave the target product 2-(1-methylpiperidin-4-yl)-5-((1S,5R)-5-(trifluoromethyl)-3-(8-methylquinolin-5-yl)-3-azabicyclo[3.1.0]hex-1-yl)-1,3,4-oxadiazole compound 65 (yellow-white solid, 210 mg, yield 24.8%).

[1092] LC-MS m / z (ESI) = 458.10 [M+1].

[1093] 1H NMR (400MHz, DMSO-d6) δ 8.91 (dd, 1H), 8.52 (dd, 1H), 7.57-7.49 (m, 2H), 7.33 (d, 1H), 3.83 (d, 1H), 3.82-3.72 (m, 2H), 3.63 ( d, 1H), 2.93 (tt, 1H), 2.72 (d, 2H), 2.65 (s, 3H), 2.47 (d, 1H), 2.18 (d, 1H), 2.16 (s, 3H), 2.08-1.91 (m, 4H), 1.72 (dddd, 2H).

[1094] Example 66

[1095] 2-((1S,5R)-3-(8-methoxyquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-5-(1-methylpiperidin-4-yl)-1,3,4-oxadiazole Compound 66

[1096] 2-((1S,5R)-3-(8-methoxyquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-5-(1-methylpiperidin-4-yl)-1,3,4-oxadiazole

[1097] Under N2 atmosphere, 2-(1-methylpiperidin-4-yl)-5-((1S,5R)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-l,3,4-oxadiazole intermediate C (500 mg, 1.57 mmol) was dissolved in 1,4-dioxane (28.0 mL), followed by the addition of 5-bromo-8-methoxyquinoline 66-1 (276 mg, 1.57 mmol), cesium carbonate (6.00 g, 11.0 mmol) and RuP hosPdG3 (132 mg, 0.16 mmol), water (2.8 mL), and N2 gas replacement three times. The temperature was raised to 80 ° C for 2 h. The solvent was dried, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was dried. The reaction solution was directly concentrated and purified by reverse phase C18 column chromatography (acid method) to give 450 mg of crude product. TLC (DCM:MeOH=10:1) gave the target product 2-((1S,5R)-3-(8-methoxyquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-5-(1-methylpiperidin-4-yl)-1,3,4-oxadiazole compound 66 (yellow-white solid, 70 mg, yield 9.3%).

[1098] LC-MS m / z (ESI) = 474.10 [M+1].

[1099] 1 H NMR (400MHz, Chloroform-d) δ 8.95 (dd, 1H), 8.35 (dd, 1H), 7.47 (dd, 1H), 7.27 (d, 1H), 6.99 (d, 1H), 4.09 (s, 3H) , 3.93 (d, 1H), 3.74-3.65 (m, 2H), 3.59 (d, 1H), 2.92 (d, 3H), 2.37 (d, 4H), 2.30-2.07 (m, 5H), 2.07-1.94 (m, 2H).

[1100] Example 67

[1101] 2-((1S,5R)-3-(8-chloro-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hex-1-yl)-5-(1-methylpiperidin-4-yl)-1,3,4-oxadiazole compound 67

[1102] 2-((1S,5R)-3-(8-chloroquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-5-(1-methylpiperidin-4-yl)-1,3,4-oxadiazole

[1103] Under N2 atmosphere, 2-(1-methylpiperidin-4-yl)-5-((1S,5R)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazole intermediate C (500 mg, 1.57 mmol) was dissolved in 1,4-dioxane (28.0 mL), followed by the addition of 5-bromo-8-chloroquinoline 67-1 (281 mg, 1.57 mmol), cesium carbonate (6.00 g, 11.0 mmol) and RuPhosPd G3 (132 mg, 0.16 mmol), water (2.8 mL), and N2 gas replacement three times. The temperature was raised to 80 ° C for 2 h. The solvent was dried, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was dried. The reaction solution was directly concentrated and purified by reverse phase C18 column chromatography (acid method) to give 450 mg of crude product. TLC (DCM:MeOH=10:1) gave the target product 2-((1S,5R)-3-(8-chloroquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-5-(1-methylpiperidin-4-yl)-1,3,4-oxadiazole compound 67 (yellow-white solid, 40 mg, yield 5.3%).

[1104] LC-MS m / z (ESI) = 478.10 [M+1].

[1105] 1 H NMR (400MHz, Chloroform-d) δ9.06 (dd, 1H), 8.38 (dd, 1H), 7.78 (d, 1H), 7.50 (dd, 1H), 7.20 (d, 1H), 3.98 ( d, 1H), 3.83-3.71 (m, 2H), 3.65 (d, 1H), 2.94 (d, 3H), 2.36 (d, 4H), 2.26 (d, 2H), 2.14 (s, 2H), 2.01 (d, 3H).

[1106] Example 68

[1107] 5-((1S,5R)-1-(5-(1-methylpiperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,7-naphthyridine-8-carbonitrile Compound 68

[1108] 5-((1S,5R)-1-(5-(1-methylpiperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,7-naphthyridine-8-carbonitrile

[1109] Under N2 atmosphere, 2-(1-methylpiperidin-4-yl)-5-((1S,5R)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazole intermediate C (300 mg, 0.697 mmol) was dissolved in 1,4-dioxane (28.0 mL), followed by the addition of 5-bromo-1,7-naphthyridine-8-carbonitrile 68-1 (162 mg, 1.57 mmol), cesium carbonate (1.585 g, 4.88 mmol) and RuPhosPdG3 (118 mg, 0.14 mmol), water (2.8 mL), and N2 gas replacement three times. The temperature was raised to 80°C and the reaction was carried out for 2 h. The solvent was dried, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was dried. The reaction solution was directly concentrated and purified by reverse phase C18 column chromatography (acid method) to obtain 450 mg of crude product. TLC (DCM:MeOH=10:1) gave the target product 5-((1S,5R)-1-(5-(1-methylpiperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,7-naphthyridine-8-carbonitrile compound 68 (yellow-white solid, 40 mg, yield 12.23%).

[1110] LC-MS m / z (ESI) = 470.10 [M+1].

[1111] 1 H NMR (400MHz, Chloroform-d) δ9.21-9.14 (m, 1H), 8.44-8.31 (m, 2H), 7.70 (ddd, 1H), 4.31 (dd, 1H), 4.17-4.07 (m, 2H), 3.98 (d, 1H), 3.80-3.72 (m, 1H), 3.50 (d, 2H), 3.19 (s, 1H), 3.03 (s, 1H), 2.62 (t, 2H), 2.42-2.34 (m, 2H), 2.17 (d, 1H) 2.09 (s, 4H)

[1112] Example 69

[1113] 2-((1S,5R))-3-(8-fluoroquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-5-(1-methylpiperidin-4-yl)-1,3,4-oxadiazole Compound 69

[1114] 2-((1S,5R)-3-(8-fluoroquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-5-(1-methylpiperidin-4-yl)-1,3,4-oxadiazole

[1115] Under N2 atmosphere, 2-(1-methylpiperidin-4-yl)-5-((1S,5R)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazole intermediate C (723 mg, 2.28 mmol) was dissolved in 1,4-dioxane (20.0 mL), followed by the addition of 5-bromo-8-fluoroquinoline 69-1 (452 ​​mg, 2.00 mmol), cesium carbonate (2.6 g, 8.00 mmol) and RuPhosPdG3 (335 mg, 0.40 mmol), water (2.0 mL), and N2 replacement gas three times. The temperature was raised to 90 ° C for 2 h. The solvent was dried, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was dried. The reaction solution was directly concentrated and purified by reverse phase C18 column chromatography (acid method) to give 450 mg of crude product. TLC (DCM:MeOH=10:1) gave the target product 2-((1S,5R))-3-(8-fluoroquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-yl)-5-(1-methylpiperidin-4-yl)-1,3,4-oxadiazole compound 69 (yellow-white solid, 148 mg, yield 16.8%).

[1116] LC-MS m / z (ESI) = 462.18 [M+1].

[1117] 1H NMR (400MHz, Chloroform-d) δ8.96 (dd, 1H), 8.38-8.32 (m, 1H), 7.48 (dd, 1H), 7.33 (dd, 1H), 7.21 (dd, 1H), 3.94 (d, 1H), 3 .71(dd, 2H), 3.61(d, 1H), 2.89(dtd, 3H), 2.40-2.31(m, 1H), 2.30(s, 3H), 2.23(d, 1H), 2.16-2.03(m, 4H), 1.95(ddd, 2H).

[1118] Example 70

[1119] 2,3-Diethyl-8-((1S,5R))-1-(5-(1-methylpiperidin-4-yl))-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoxaline-5-carbonitrile Compound 70

[1120] 2,3-diethyl-8-((1S,5R)-1-(5-(1-methylpiperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoxaline-5-carbonitrile

[1121] Under N2 atmosphere, 2-(1-methylpiperidin-4-yl)-5-((1S,5R)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazole intermediate C (175 mg, 0.55 mmol) was dissolved in 1,4-dioxane (4.0 mL), followed by the addition of 8-bromo-2,3-diethylquinoxaline-5-carbonitrile 70-1 (145 mg, 0.50 mmol), cesium carbonate (975 mg, 3.0 mmol) and RuPhosPdG3 (84 mg, 0.1 mmol), water (0.4 mL), and N2 gas replacement three times. The temperature was raised to 90 ° C for 2 h. The solvent was dried, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was dried. The reaction solution was directly concentrated and purified by reverse phase C18 column chromatography (acid method) to give 450 mg of crude product. TLC (DCM:MeOH=10:1) gave the target product 2,3-diethyl-8-((1S,5R))-1-(5-(1-methylpiperidin-4-yl))-1,3,4-oxadiazole-2-Yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-3-Yl)quinoxaline-5-carbonitrile compound 70 (yellow-white solid, 10 mg, yield 3.8%).

[1122] LC-MS m / z (ESI) = 526.25 [M+1].

[1123] 1 H NMR (400MHz, Chloroform-d) δ7.79 (d, 1H), 6.64 (d, 1H), 4.94 (d, 1H), 4.73 (d, 1H), 4.31 (d, J=1H), 4.06 (d, 1H), 3. 42(s, 3H), 2.98(m, 5H), 2.38(s, 2H), 2.30(d, 1H), 2.03(s, 2H), 1.75(d, 1H) 1.55(m, 4H), 1.39(t, 3H), 1.33(t, 3H).

[1124] Example 71

[1125] 5-((1S,5R)-1-(1-(1-methylpiperidin-4-yl)-1H-1,2,3-triazol-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile Compound 71

[1126] 5-((1S,5R)-1-(1-(1-methylpiperidin-4-yl)-1H-1,2,3-triazol-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

[1127] first step:

[1128] ((1S,5R)-3-Benzyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)methanol 71-2

[1129] ((1S,5R)-3-benzyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)methanol

[1130] Under N2 atmosphere, compound 71-1 (3.0 g, 10 mmol) was dissolved in 10 mL of tetrahydrofuran, and lithium aluminum hydride (0.38 g, 10 mmol) was added in batches under ice bath, and stirred at room temperature for 2 h. After the reaction was completed, it was quenched with saturated ammonium chloride, extracted with DCM, washed with saturated brine, dried over anhydrous sodium sulfate, spin-dried, and purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:5) to obtain the target product ((1S, 5R)-3-benzyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)methanol 71-2 (light yellow liquid, 2.5 g, yield 93%).

[1131] LC-MS m / z(ESI)=272.1[M+1].

[1132] Step 2:

[1133] (1S,5R)-3-Benzyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbaldehyde 71-3

[1134] (1S,5R)-3-benzyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbaldehyde

[1135] Under N2 atmosphere, compound 1-2 (1.0 g, 3.7 mmol) was dissolved in 5 mL of dichloromethane, and then DMP (2-iodobenzoic acid) oxidant was added in batches and stirred at room temperature for 1 h. After the reaction was completed, it was quenched with saturated sodium bicarbonate, extracted with DCM, washed with saturated brine, dried over anhydrous sodium sulfate, spin-dried, and purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:10) to obtain the target product (1S,5R)-3-benzyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbaldehyde 71-3 (colorless liquid, 0.54 g, yield 54%).

[1136] LC-MS m / z(ESI)=270.1[M+1].

[1137] Step 3:

[1138] (1S,5R)-3-Benzyl-1-ethynyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane 71-4

[1139] (1S,5R)-3-benzyl-1-ethynyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane

[1140] Under N2 atmosphere, compound 71-3 (0.54 g, 2.0 mmol) and potassium carbonate (0.96 g, 7.0 mmol) were dissolved in 5 mL of methanol, and then a methanol solution of (1-diazo-2-oxopropyl)phosphonic acid dimethyl ester (0.94 g, 5.0 mmol) was added to the reaction system and stirred at room temperature for 0.5 h. After the reaction was completed, the solvent was dried and purified by column chromatography (ethyl acetate: petroleum ether = 1:50) to obtain the target compound (1S,5R)-3-benzyl-1-ethynyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane 71-4 (colorless liquid, 0.50 g, yield 94%).

[1141] LC-MS m / z(ESI)=266.1[M+1].

[1142] Step 4:

[1143] Tert-butyl 4-(4-((1S,5R)-3-benzyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate 71-6

[1144] tert-butyl4-(4-((1S,5R)-3-benzyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate

[1145] The compound 71-4 (0.50 g, 1.9 mmol) obtained in the previous step was dissolved in 5 mL of dichloromethane, and tert-butyl 4-azidopiperidine-1-carboxylate compound 71-5 (0.52 g, 2.1 mmol) was added, followed by cuprous iodide (38 mg, 0.2 mmol). The mixture was reacted at room temperature for 1 h. After the reaction was completed, the organic phase was dried and purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:20) to obtain the target product tert-butyl 4-(4-((1S,5R)-3-benzyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate 71-6 (colorless liquid, 0.56 g, yield 61%).

[1146] LC-MS m / z(ESI)=492.2[M+1].

[1147] Step 5:

[1148] tert-Butyl 4-(4-((1S,5R)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate

[1149] tert-butyl 4-(4-((1S,5R)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate

[1150] The raw material 4-(4-((1S,5R)-3-benzyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester 71-6 (500 mg, 1.02 mmol) was added to methanol (5 ml), and palladium carbon (250 mg, 10% palladium supported on carbon slurry) and palladium hydroxide (100 mg) were added. The gas was replaced 4 times with a hydrogen balloon and the reaction was allowed to react at room temperature overnight. After the reaction was completed, the mixture was filtered on diatomaceous earth. The filtrate was dried and the crude product (402 mg, yield 98.5%) was used directly in the next step.

[1151] LCMS m / z (ESI) = 402.2 [M+1].

[1152] Step 6:

[1153] tert-Butyl 4-(4-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate 71-9

[1154] tert-butyl 4-(4-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate

[1155] The raw material of the previous step, tert-butyl 4-(4-((1S, 5R)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate 71-7 (402 mg, 1.0 mmol) was added to 1,4-dioxane (4 ml), and then 5-bromoquinoline-8-carbonitrile 71-8 (233 mg, 1.0 mmol), cesium carbonate (652 mg, 2.0 mmol) and methanesulfonic acid (2-dicyclohexylphosphino-2′, 6′-diisopropoxy-1, 1′-biphenyl)(2-amino-1,1′-biphenyl-2-yl)palladium(II) (84 mg, 0.1 mmol), the reaction mixture was nitrogen-purified 4 times, and then heated to 100 degrees for 4 hours. After the reaction was completed, it was directly purified by silica gel column to obtain 4-(4-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester 71-9 (380 mg, yield 68.6%).

[1156] LCMS m / z (ESI) = 554.2 [M+1].

[1157] Step 7:

[1158] 5-((1S,5R)-1-(1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile 71-10

[1159] 5-((1S,5R)-1-(1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

[1160] The raw material tert-butyl 4-(4-((1S,5R)-3-(8-cyanoquinolin-5-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate 71-9 (380 mg, 0.686 mmol) was added to dichloromethane (3 ml), and trifluoroacetic acid (3 ml) was added. The reaction mixture was reacted at room temperature for 1 hour. After the reaction was completed, it was concentrated under reduced pressure. The crude product 5-((1S,5R)-1-(1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile 71-10 was directly used in the next step.

[1161] LCMS m / z (ESI) = 454.2 [M+1].

[1162] Step 8:

[1163] 5-((1S,5R)-1-(1-(1-methylpiperidin-4-yl)-1H-1,2,3-triazol-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile Compound 71

[1164] 5-((1S,5R)-1-(1-(1-methylpiperidin-4-yl)-1H-1,2,3-triazol-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

[1165] The 5-((1S,5R)-1-(1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-3-yl)quinoline-8-carbonitrile 71-10 (320 mg, 0.70 mmol) obtained in the previous step was added to dichloromethane (10 ml), and then paraformaldehyde (210 mg, 7.0 mmol) and sodium cyanoborohydride (879 mg, 1.0 mmol) were added. The reaction mixture was reacted at room temperature overnight. After the reaction was completed, it was filtered, the filtrate was spin-dried, and then purified by flash chromatography to obtain 5-((1S,5R)-1-(1-(1-methylpiperidin-4-yl)-1H-1,2,3-triazol-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile compound 71 (110 mg, yield 33.6%).

[1166] LCMS m / z (ESI) = 468.2 [M+1].

[1167] 1 H NMR (400MHz, DMSO-d6) δ9.01 (dd, 1H), 8.70 (dd, 1H), 8.38 (s, 1H), 8.19 (d, 1H), 7.61 (dd, 1H), 7.28 (d, 1H), 4.77 (s, 1H), 4.08 (d, 2H), 4.05 (s, 1H), 3.92 (d, 1H), 3.58 (s, 2H), 3.36 (s, 2H), 3.27-3.12 (m, 2H), 2.83 (s, 3H), 2.36 (d, 2H), 2.23-2.08 (m, 2H).

[1168] Example 72

[1169] 1-Methyl-5-((1S,5R)-1-(5-(1-methylpiperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)-2-oxo-1,2-dihydroquinoline-8-carbonitrile Compound 72

[1170] 1-methyl-5-((1S,5R)-1-(5-(1-methylpiperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)-2-oxo-1,2-dihydroquinoline-8-carbonitrile

[1171] first step:

[1172] 5-Bromo-1-methyl-2-oxo-1,2-dihydroquinoline-8-carbonitrile compound 72-2

[1173] 5-bromo-1-methyl-2-oxo-1,2-dihydroquinoline-8-carbonitrile

[1174] The raw material 5-bromo-2-oxo-1,2-dihydroquinoline-8-carbonitrile 72-1 (800 mg, 3.21 mmol) was added to dimethyl sulfoxide (20 ml), and then potassium carbonate (886 mg, 6.42 mmol) was added, and then iodomethane (912 mg, 6.42 mmol) was added. The reaction mixture was reacted at room temperature for 4 hours. After the reaction was completed, purified water and ethyl acetate (100 ml * 3 times) were added, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column to obtain 5-bromo-1-methyl-2-oxo-1,2-dihydroquinoline-8-carbonitrile 72-2 (80 mg, yield 9.4%).

[1175] LC-MS m / z (ESI) = 262.90 [M+1].

[1176] Step 2:

[1177] 1-Methyl-5-((1S,5R)-1-(5-(1-methylpiperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)-2-oxo-1,2-dihydroquinoline-8-carbonitrile Compound 72

[1178] 1-methyl-5-((1S,5R)-1-(5-(1-methylpiperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)-2-oxo-1,2-dihydroquinoline-8-carbonitrile

[1179] The starting material 5-bromo-2-oxo-1,2-dihydroquinoline-8-carbonitrile 72-2 (249 mg, 1.0 mmol) and 2-(1-methylpiperidin-4-yl)-5-((1S,5R)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazole intermediate C (476 mg, 1.5 mmol) were added to 1,4-dioxane (3 ml), and then cesium carbonate (977 mg, 3.0 mmol) and methanesulfonic acid (2-dicyclohexylphosphino-2′,6′-diisopropyloxy-1,1′ -biphenyl)(2-amino-1,1′-biphenyl-2-yl)palladium(II)(84 mg, 0.1 mmol), the reaction mixture was protected by nitrogen, and the temperature was raised to 100°C for 3 hours. After the reaction was completed, it was directly purified by reverse chromatography to obtain 1-methyl-5-((1S,5R)-1-(5-(1-methylpiperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)-2-oxo-1,2-dihydroquinoline-8-carbonitrile compound 72 (89 mg, yield 17.8%).

[1180] LC-MS m / z (ESI) = 499.20 [M+1].

[1181] 1 H NMR (400MHz, DMSO-d6) δ8.06 (d, 1H), 7.90 (d, 1H), 7.18 (d, 1H), 6.61 (d, 1H), 4.00 (s, 2H), 3.92 (s, 3H), 3.88(d, 2H), 2.92(ddd, 1H), 2.71(d, 2H), 2.16(d, 4H), 2.10-1.91(m, 5H), 1.80-1.65(m, 2H).

[1182] 19 F NMR(376MHz, DMSO-d6)δ-64.03.

[1183] Example 73

[1184] 2-Methyl-5-((1S,5R)-1-(5-(1-methylpiperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile Compound 73

[1185] 2-methyl-5-((1S,5R)-1-(5-(1-methylpiperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

[1186] first step:

[1187] N-(2-bromo-5-fluorophenyl)-3,3-dimethoxypropionamide compound 73-3

[1188] N-(2-bromo-5-fluorophenyl)-3,3-dimethoxypropanamide

[1189] The raw materials, 5-fluoro-2-bromoaniline 73-1 (10.0 g, 52.6 mmol) and methyl 3,3-dimethoxypropionate 73-2 (9.35 g, 63.1 mmol), were added to anhydrous tetrahydrofuran (100 ml). Under nitrogen, the mixture was cooled to 0°C and slowly added dropwise with a solution of sodium bis(trimethylsilyl)amide (80 ml, 1 mol / L in tetrahydrofuran). The reaction mixture was slowly warmed to room temperature and allowed to react for 6 hours, resulting in completion. Extraction was then performed with saturated aqueous ammonium chloride and ethyl acetate (100 ml x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to yield N-(2-bromo-5-fluorophenyl)-3,3-dimethoxypropionamide 73-3 (12.0 g, 74.5% yield).

[1190] LC-MS m / z (ESI) = 306.00 [M+1].

[1191] Step 2:

[1192] 8-Bromo-5-fluoroquinolin-2(1H)-one compound 73-4

[1193] 8-bromo-5-fluoroquinolin-2(1H)-one

[1194] The raw material N-(2-bromo-5-fluorophenyl)-3,3-dimethoxypropionamide 73-3 (12.0 g, 39.2 mmol) was dissolved in dichloromethane (200 ml). The reaction mixture was cooled to 0°C, and then concentrated sulfuric acid (300 ml) was added. The reaction mixture was slowly heated to a temperature of 8 hours. After the reaction was completed, the layers were separated, and the lower sulfuric acid layer was slowly added dropwise to ice water (1 L). A large amount of solid precipitated, which was filtered and the filter cake dried to obtain 8-bromo-5-fluoroquinolin-2(1H)-one 73-4 (9.0 g, 94.9% yield).

[1195] LC-MS m / z (ESI) = 241.90 [M+1].

[1196] Step 3:

[1197] 5-Fluoro-2-oxo-1,2-dihydroquinoline-8-carbonitrile 73-5

[1198] 5-fluoro-2-oxo-1,2-dihydroquinoline-8-carbonitrile

[1199] The raw material 8-bromo-5-fluoroquinolin-2(1H)-one 73-4 (9.0 g, 37.2 mmol) was added to N,N-dimethylformamide (90 ml), and then zinc cyanide (8.73 g, 74.4 mmol) and tetrakistriphenylphosphine palladium (4.30 g, 3.72 mmol) were added. After the reaction mixture was protected by nitrogen, it was heated to 100°C and reacted for 6 hours. After the reaction was completed, purified water (300 ml) was added, and a large amount of solid precipitated. The solid was filtered and the filter cake was purified by column chromatography to obtain 5-fluoro-2-oxo-1,2-dihydroquinoline-8-carbonitrile 73-5 (3.5 g, yield 49.8%).

[1200] LC-MS m / z (ESI) = 189.00 [M+1].

[1201] Step 4:

[1202] 2-Chloro-5-fluoroquinoline-8-carbonitrile compound 73-6

[1203] 2-chloro-5-fluoroquinoline-8-carbonitrile

[1204] The raw material 5-fluoro-2-oxo-1,2-dihydroquinoline-8-carbonitrile 73-5 (3.5 g, 18.5 mmol) was added to phosphorus oxychloride (30 ml), the temperature was raised to 110° C. and the reaction was carried out for 4 hours. After the reaction was completed, the mixture was concentrated under reduced pressure. The crude product was added to a saturated aqueous sodium bicarbonate solution and the pH value was adjusted to 8. Ethyl acetate (50 ml * 3) was added for extraction. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 2-chloro-5-fluoroquinoline-8-carbonitrile 73-6 (3.4 g, yield 88.8%).

[1205] LC-MS m / z (ESI) = 207.00 [M+1].

[1206] Step 5:

[1207] 5-Fluoro-2-methylquinoline-8-carbonitrile compound 73-7

[1208] 5-fluoro-2-methylquinoline-8-carbonitrile

[1209] The raw material 2-chloro-5-fluoroquinoline-8-carbonitrile 73-6 (3.0 g, 14.5 mmol), methylboric acid (2.6 g, 43.5 mmol), tetrakistriphenylphosphine palladium (1.7 g, 1.45 mmol) and potassium phosphate (9.2 g, 43.5 mmol) were added to 1,4-dioxane (30 ml). After nitrogen replacement 4 times, the temperature was raised to 100 ° C. After reacting for 4 hours, the reaction was completed, purified water (100 ml) and ethyl acetate (80 ml * 3ci) were added, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and dried, and the crude product was purified by column chromatography to obtain 5-fluoro-2-methylquinoline-8-carbonitrile 73-7 (850 mg, yield 31.4%).

[1210] LC-MS m / z (ESI) = 187.10 [M+1].

[1211] Step 6:

[1212] 2-Methyl-5-((1S,5R)-1-(5-(1-methylpiperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile Compound 73

[1213] 2-methyl-5-((1S,5R)-1-(5-(1-methylpiperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile

[1214] The starting material 5-fluoro-2-methylquinoline-8-carbonitrile 73-7 (374 mg, 2.0 mmol) and 2-(1-methylpiperidin-4-yl)-5-((1S,5R)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazole intermediate C (316 mg, 1.0 mmol) were added to dimethyl sulfoxide (1 ml) and N,N-diisopropylethylamine (1 ml). The reaction mixture was heated to 130° C. and reacted for 24 hours. After completion of the reaction, it was purified by reverse phase chromatography to obtain 2-methyl-5-((1S,5R)-1-(5-(1-methylpiperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-8-carbonitrile compound 73 (22 mg, yield 4.6%) as a white solid.

[1215] LC-MS m / z (ESI) = 483.20 [M+1].

[1216] 1 H NMR (400MHz, DMSO-d6) δ8.55(d,1H), 8.13(d,1H), 7.50(d,1H), 7.25(d,1H), 4.16(d,1H ), 4.04(dd, 2H), 3.89(d, 1H), 3.25(d, 2H), 2.70(s, 7H), 2.22(d, 5H), 2.13-1.92(m, 3H).

[1217] Example 74

[1218] 3-Fluoro-4-((1S,5R)-1-(1-(1-methylpiperidin-4-yl)-1H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)pyrazolo[1,5-a]pyridine-7-carbonitrile Compound 74

[1219] 3-fluoro-4-((1S,5R)-1-(1-(1-methylpiperidin-4-yl)-1H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)pyrazolo[1,5-a]pyridine-7-carbonitrile

[1220] first step:

[1221] (1S, 5R)-3-benzyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid compound 74-1

[1222] (1S,5R)-3-benzyl-5-(triflluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid

[1223] The raw material (1S, 5R) -3-benzyl-5- (trifluoromethyl) -3-azabicyclo [3.1.0] hexane-1-carboxylic acid methyl ester A-1.4 (40g, 133.6mmol) was added to a mixed solution of methanol / water (400ml / 100ml), and then sodium hydroxide (16.0g, 400.8mmol) was added. The reaction mixture was heated to 50 ° C and reacted for 2 hours. After the reaction was completed, the pressure was reduced and concentrated, and the pH value was adjusted to 7-8 with dilute hydrochloric acid. Ethyl acetate (400ml * 3) was added for extraction. The organic phases were combined and then washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain an off-white solid (1S, 5R) -3-benzyl-5- (trifluoromethyl) -3-azabicyclo [3.1.0] hexane-1-carboxylic acid compound 74-1 (35.0g, yield 91.8%).

[1224] LC-MS m / z (ESI) = 286.10 [M+1].

[1225] Step 2:

[1226] (1S, 5R)-3-benzyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide compound 74-2

[1227] (1S,5R)-3-benzyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

[1228] The raw material (1S, 5R)-3-benzyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid 74-1 (15.0 g, 52.6 mmol) was added to anhydrous tetrahydrofuran (300 ml), and then N, N-dimethylformamide (0.2 ml) was added, followed by slow dropwise addition of oxalyl chloride (13.3 g, 105.2 mmol). The temperature was controlled at about 25°C, and the reaction mixture was reacted at room temperature for 2 hours, and then concentrated under reduced pressure to remove The excess oxalyl chloride was dissolved in tetrahydrofuran and then slowly dripped into ice concentrated ammonia water. After the temperature was raised to room temperature and the reaction was reacted for 2 hours, the reaction was completed. Ethyl acetate (100 ml * 3) was added for extraction. The organic phases were combined and then washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a yellow viscous liquid (1S, 5R)-3-benzyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide 74-2 (13.5 g, yield 90%).

[1229] LC-MS m / z (ESI) = 285.10 [M+1].

[1230] Step 3:

[1231] (1S,5R)-3-benzyl-N-((E)-(dimethylamino)methylene)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide Compound 74-4

[1232] (1S,5R)-3-benzyl-N-((E)-(dimethylamino)methylene)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide

[1233] The raw material (1S,5R)-3-benzyl-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide 74-2 (13.5 g, 47.4 mmol) was added to 1,4-dioxane (150 ml), followed by the addition of N,N-dimethylformamide dimethyl acetal 74-3 (11.3 g, 94.8 mmol). The reaction mixture was protected by nitrogen and heated to reflux for 2 hours. After completion of the reaction, it was directly concentrated to obtain a yellow viscous liquid (1S,5R)-3-benzyl-N-((E)-(dimethylamino)methylene)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide 74-4 (16.1 g, 100.0%).

[1234] LC-MS m / z (ESI) = 340.20 [M+1].

[1235] Step 4:

[1236] (1S,5R)-3-benzyl-1-(1H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane Compound 74-5

[1237] (1S,5R)-3-benzyl-1-(1H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane

[1238] The raw material (1S, 5R)-3-benzyl-N-((E)-(dimethylamino)methylene)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide 74-4 (16.1 g, 47.4 mmol) was added to glacial acetic acid (100 ml), and then hydrazine hydrochloride (4.87 g, 71.1 mmol) was added. The reaction mixture was protected by nitrogen and heated to reflux for 4 hours. After the reaction was completed, the temperature was cooled to room temperature, and saturated sodium carbonate was added to dissolve it. The pH value was adjusted to 8-9, and then ethyl acetate (1 The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column to give (1S,5R)-3-benzyl-1-(1H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane 74-5 (13.0 g, yield 88.7%).

[1239] LC-MS m / z (ESI) = 309.10 [M+1].

[1240] 1 H NMR (400MHz, DMSO-d6) δ13.90 (s, 1H), 8.00 (d, 1H), 7.50-7.10 (m, 5H), 3.80-3.59 (m, 2H), 3.19-2.96 (m, 3H), 2.72 (d, 1H), 1.86 (d, 2H).

[1241] Step 5:

[1242] (1S,5R)-3-Benzyl-1-(1-(1-methylpiperidin-4-yl)-1H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane Compound 74-7

[1243] (1S,5R)-3-benzyl-1-(1-(1-methylpiperidin-4-yl)-1H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane

[1244] The raw material (1S, 5R) -3-benzyl-1- (1H-1, 2, 4-triazol-3-yl) -5- (trifluoromethyl) -3- azabicyclo [3.1.0] hexane 74-5 (2.0 g, 6.5 mmol) was added to N, N-dimethylformamide (15 ml) and purified water (5 ml), and then 4-bromo-1-methylpiperidine 74-6 (4.63 g, 26.0 mmol) was added, followed by cesium carbonate (8.48 g, 26.0 mmol). After the reaction mixture was protected by nitrogen, it was heated to 100 ° C and reacted for 2 days. After the reaction was completed, purified water (50 ml) and ethyl acetate (50 ml * 3) were added, extracted, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and dried. The crude product was purified by silica gel column to give (1S,5R)-3-benzyl-1-(1-(1-methylpiperidin-4-yl)-1H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane 74-7 (1.5 g, yield 57.0%).

[1245] LC-MS m / z (ESI) = 406.20 [M+1].

[1246] Step 6:

[1247] (1S,5R)-1-(1-(1-methylpiperidin-4-yl)-1H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane Compound 74-8

[1248] (1S,5R)-1-(1-(1-methylpiperidin-4-yl)-1H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane

[1249] The raw material (1S, 5R)-3-benzyl-1-(1H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane 74-7 (1.5 g, 3.7 mmol) was added to methanol (15 ml), and then 10% palladium / carbon (750 mg) and 20% palladium hydroxide / carbon (150 mg) were added. After hydrogen replacement 4 times, the temperature was raised to 45°C and the reaction was carried out for 4 hours. After the reaction was completed, the mixture was filtered on diatomaceous earth and the filtrate was concentrated to obtain (1S, 5R)-1-(1-(1-methylpiperidin-4-yl)-1H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane 74-8 (1.2 g, yield 102.6%).

[1250] LC-MS m / z (ESI) = 316.20 [M+1].

[1251] Step 7:

[1252] 3-Fluoro-4-((1S,5R)-1-(1-(1-methylpiperidin-4-yl)-1H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-3-

[1253] Azabicyclo[3.1.0]hexane-3-yl)pyrazolo[1,5-a]pyridine-7-carbonitrile compound 74

[1254] 3-fluoro-4-((1S,5R)-1-(1-(1-methylpiperidin-4-yl)-1H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)pyrazolo[1,5-a]pyridine-7-carbonitrile

[1255] The raw materials 3,4-difluoropyrazolo[1,5-a]pyridine-7-carbonitrile 74-9 (250 mg, 1.40 mmol) and (1S,5R)-1-(1-(1-methylpiperidin-4-yl)-1H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane 74-8 (300 mg, 0.95 mmol) were added to dimethyl sulfoxide (1 ml), and then N,N-diisopropylethylamine (1 ml) was added. l), the reaction mixture was protected by nitrogen, heated to 130°C and reacted for 4 hours. After the reaction was completed, it was directly purified by reverse column chromatography to obtain a white solid 3-fluoro-4-((1S,5R)-1-(1-(1-methylpiperidin-4-yl)-1H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)pyrazolo[1,5-a]pyridine-7-carbonitrile compound 74 (190 mg, yield 42.1%).

[1256] LC-MS m / z (ESI) = 475.20 [M+1].

[1257] 1 H NMR (400MHz, DMSO-d6) δ8.57 (s, 1H), 8.24 (d, 1H), 7.60 (d, 1H), 6.44 (d, 1H), 4.29-4 .09(m, 4H), 3.97(d, 1H), 2.82(d, 2H), 2.20(d, 4H), 2.05-1.93(m, 6H), 1.62(d, 1H).

[1258] Example 75

[1259] 2-(Piperidin-4-yl)-5-((1S,5R)-5-(trifluoromethyl)-3-(8-(trifluoromethane)quinolin-5-yl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazole Compound 75

[1260] 2-(piperidin-4-yl)-5-((1S,5R)-5-(trifluoromethyl)-3-(8-(trifluoromethyl)quinolin-5-yl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazole

[1261] first step:

[1262] (1S,5R)-5-(trifluoromethyl)-3-(8-(trifluoromethyl)quinolin-5-yl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid methyl ester Compound 75-2

[1263] (1S,5R)-5-(trifluoromethyl)-3-(8-(trifluoromethyl)quinolin-5-yl)-3-azabicyclo[3.1.0]hexane-1-carboxylate

[1264] Under N2 atmosphere, 2-(1-methylpiperidin-4-yl)-5-((1S,5R)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazole intermediate A-1.5A (2.30 g, 10.9 mmol) was dissolved in 1,4-dioxane (45.00 mL), and then 5-bromo-8-trifluoromethylquinoline 75-1 (3.00 g, 10.9 mmol), cesium carbonate (14.2 g, 43.6 mmol) and RuPhosPdG3 (920 mg, 1.1 mmol) were added in sequence. The gas was replaced with N2 three times, and the temperature was raised to 90°C for reaction for 2 h. The solvent was dried, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was dried. TLC (DCM: MeOH = 10: 1) was performed to obtain the target product (1S, 5R)-5-(trifluoromethyl)-3-(8-(trifluoromethyl)quinolin-5-yl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid methyl ester 75-2 (yellow solid, 5.00 g).

[1265] LC-MS m / z (ESI) = 405.10 [M+1].

[1266] Step 2:

[1267] (1S, 5R)-5-(trifluoromethyl)-3-(8-(trifluoromethyl)quinolin-5-yl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid hydrazide compound 75-3

[1268] (1S,5R)-5-(trifluoromethyl)-3-(8-(trifluoromethyl)quinolin-5-yl)-3-azabicyclo[3.1.0]hexane-1-carbohydrazide

[1269] Under N2 atmosphere, 2(1S,5R)-5-(trifluoromethyl)-3-(8-(trifluoromethyl)quinolin-5-yl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid methyl ester 75-2 (yellow solid, 5.00 g) was dissolved in 1 methanol (50.0 mL), and then DBU (6.67 g, 43.6 mmol) and hydrazine hydrochloride (2.6 g, 43.6 mmol) were added in sequence and the temperature was raised to 90°C for reaction for 2 h. The solvent was dried, extracted with ethyl acetate, the organic phase was concentrated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the solvent was dried, and column chromatography (petroleum ether: ethyl acetate = 1:3) was performed to obtain the target product (1S, 5R)-5-(trifluoromethyl)-3-(8-(trifluoromethyl)quinolin-5-yl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid hydrazide compound 75-3 (yellow solid, 2.26 g, 51%).

[1270] LC-MS m / z (ESI) = 405.10 [M+1].

[1271] Step 3:

[1272] tert-Butyl 4-(2-((1S,5R)-5-(trifluoromethyl)-3-(8-(trifluoromethyl)quinolin-5-yl)-3-azabicyclo[3.1.0]hexane-1-carbonyl)hydrazine-1-carbonyl)piperidine-1-carboxylate Compound 75-5

[1273] tert-butyl 4-(2-((1S,5R)-5-(tri(luoromethyl)-3-(8-(trifluoromethyl)quinolin-5-yl)-3-azabicyclo[3.1.0]hexane-1-carbonyl)hydrazine-1-carbonyl)piperidine-1-carboxylate

[1274] The raw material 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid 75-4 (688 mg, 3.0 mmol) was added to N,N-dimethylformamide (5 ml), and then N,N,N′,N′-tetramethyl-O-(7-azabenzotriazole-1-yl)urea hexafluorophosphate (2.28 g, 3.0 mmol) and N,N-diisopropylethylamine (580 mg, 4.5 mmol) were added. The reaction mixture was stirred at room temperature for 0.5 hours, and then (1S,5R)-5-(trifluoromethyl)-3-(8- The reaction mixture was stirred at room temperature for 6 hours and then purified by reverse phase column chromatography to obtain tert-butyl 4-(2-((1S,5R)-5-(trifluoromethyl)-3-(8-(trifluoromethyl)quinolin-5-yl)-3-azabicyclo[3.1.0]hexane-1-carbonyl)hydrazine-1-carbonyl)piperidine-1-carboxylate 75-5 (1.1 g, yield 59.5%).

[1275] LCMS m / z (ESI) = 616.2 [M+1].

[1276] Step 4:

[1277] tert-Butyl 4-(5-((1S,5R)-5-(trifluoromethyl)-3-(8-(trifluoromethyl)quinolin-5-yl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazol-2-yl)piperidine-1-carboxylate Compound 75-6

[1278] tert-butyl 4-(5-((1S,5R)-5-(trifluoromethyl)-3-(8-(trifluoromethyl)quinolin-5-yl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazol-2-yl)piperidine-1-carboxylate

[1279] Tert-butyl 4-(2-((1S,5R)-5-(trifluoromethyl)-3-(8-(trifluoromethyl)quinolin-5-yl)-3-azabicyclo[3.1.0]hexane-1-carbonyl)hydrazine-1-carbonyl)piperidine-1-carboxylate 75-5 (1.1 g, 1.79 mmol) was dissolved in 20 mL of dichloromethane, followed by the addition of triethylamine (904 mg, 8.95 mmol), p-toluenesulfonyl chloride (1.02 g, 5.37 mmol) and 4-(2-((1S,5R)-5-(trifluoromethyl)-3-(8-(trifluoromethyl)quinolin-5-yl)-3-azabicyclo[3.1.0]hexane-1-carbonyl)hydrazine-1-carbonyl)piperidine-1-carboxylate 75-5 (1.1 g, 1.79 mmol) The mixture was stirred at room temperature for 5 hours. The reaction was monitored by TLC. The reaction solution was concentrated and purified by silica gel column chromatography to obtain the target product, tert-butyl 4-(5-((1S,5R)-5-(trifluoromethyl)-3-(8-(trifluoromethyl)quinolin-5-yl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazol-2-yl)piperidine-1-carboxylate 75-6 (yellow solid, 875 mg, yield: 81.8%).

[1280] LC-MS m / z (ESI) = 598.2 [M+1].

[1281] Step 5:

[1282] 2-(Piperidin-4-yl)-5-((1S,5R)-5-(trifluoromethyl)-3-(8-(trifluoromethane)quinolin-5-yl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazole Compound 75

[1283] 2-(piperidin-4-yl)-5-((1S,5R)-5-(trifluoromethyl)-3-(8-(trifluoromethyl)quinolin-5-yl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazole

[1284] The raw material tert-butyl 4-(5-((1S,5R)-5-(trifluoromethyl)-3-(8-(trifluoromethyl)quinolin-5-yl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazol-2-yl)piperidine-1-carboxylate 75-6 (875 mg, 1.46 mmol) was added to dichloromethane (6 ml), and trifluoroacetic acid (3 ml) was added. The reaction solution was reacted at room temperature for 2 hours, concentrated under reduced pressure, and then purified by reverse column to obtain 2-(piperidin-4-yl)-5-((1S,5R)-5-(trifluoromethyl)-3-(8-(trifluoromethane)quinolin-5-yl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazole compound 75 (530 mg, yield 72.9%).

[1285] LC-MS m / z (ESI) = 498.2 [M+1].

[1286] 1 H NMR (400MHz, DMSO-d6) δ9.01 (dd, 1H), 8.66 (dd, 1H), 8.04 (d, 1H), 7.63 (dd, 1H), 7.38 (d, 1H), 4.09 (d, 1H), 3.97 (d d, 2H), 3.82 (d, 1H), 3.13 (td, 1H), 3.03 (d, 2H), 2.70 (t, 2H), 2.34 (d, 1H), 2.22 (d, 1H), 1.95 (dd, 2H), 1.65 (q, 2H).

[1287] 19 F NMR (376MHz, DMSO-d6) δ-58.08, -64.08, -73.52.

[1288] Example 76

[1289] 2-(1-(cyclopropylmethyl)piperidin-4-yl)-5-((1S,5R)-5-(trifluoromethyl)-3-(8-(trifluoromethane)quinolin-5-yl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazole Compound 76

[1290] 2-(1-(cyclopropylmethyl)piperidin-4-yl)-5-((1S,5R)-5-(trifluoromethyl)-3-(8-(trifluoromethyl)quinolin-5-yl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazole

[1291] 2-(1-(cyclopropylmethyl)piperidin-4-yl)-5-((1S,5R)-5-(trifluoromethyl)-3-(8-(trifluoromethane)quinolin-5-yl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazole Compound 76

[1292] 2-(1-(cyclopropylmethyl)piperidin-4-yl)-5-((1S,5R)-5-(trifluoromethyl)-3-(8-(trifluoromethyl)quinolin-5-yl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazole

[1293] 2-(Piperidin-4-yl)-5-((1S,5R)-5-(trifluoromethyl)-3-(8-(trifluoromethane)quinolin-5-yl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazole compound 75 (100 mg, 0.20 mmol) was dissolved in N,N-dimethylformamide (1 mL), followed by the addition of cesium carbonate (130 mg, 0.4 mmol) and bromomethylcyclopropane (34 The reaction mixture was stirred at room temperature overnight. After the reaction was completed, it was directly purified by reverse column purification to obtain the target product 2-(1-(cyclopropylmethyl)piperidin-4-yl)-5-((1S, 5R)-5-(trifluoromethyl)-3-(8-(trifluoromethane)quinolin-5-yl)-3-azabicyclo[3.1.0]hexane-1-yl)-1,3,4-oxadiazole compound 76 (white solid, 15 mg, 13.6%).

[1294] LC-MS m / z (ESI) = 552.2 [M+1].

[1295] 1 H NMR (400MHz, DMSO-d6) δ9.01 (dd, 1H), 8.65 (dd, 1H), 8.04 (d, 1H), 7.63 (dd, 1H), 7.38 (d, 1H), 4.08 (d, 1H), 3.97 (t, 2H), 3.82 (d, 1H), 2.99-2. 85(m,3H),2.33(d,1H),2.23(d,1H),2.14(dd,4H),1.96(dd,2H),1.87 -1.67(m, 2H), 0.96-0.63(m, 1H), 0.57-0.34(m, 2H), 0.14-0.01(m, 2H).

[1296] 19 F NMR (376MHz, DMSO-d6) δ-58.07, -64.05.

[1297] Example 77

[1298] 2-(4-(5-((1S,5R)-5-(trifluoromethyl)-3-(8-(trifluoromethane)quinolin-5-yl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazol-2-yl)piperidin-1-yl)acetamide Compound 77

[1299] 2-(4-(5-((1 S,5R)-5-(trifluoromethyl)-3-(8-(trifluoromethyl)quinolin-5-yl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazol-2-yl)piperidin-1-yl)acetamide

[1300] 2-(4-(5-((1S,5R)-5-(trifluoromethyl)-3-(8-(trifluoromethane)quinolin-5-yl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazol-2-yl)piperidin-1-yl)acetamide Compound 77

[1301] 2-(4-(5-((1S,5R)-5-(trifluoromethyl)-3-(8-(trifluoromethyl)quinolin-5-yl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazol-2-yl)piperidin-1-yl)acetamide

[1302] 2-(Piperidin-4-yl)-5-((1S,5R)-5-(trifluoromethyl)-3-(8-(trifluoromethane)quinolin-5-yl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazole compound 75 (100 mg, 0.20 mmol) was dissolved in N,N-dimethylformamide (1 mL), followed by the addition of cesium carbonate (130 mg, 0.4 mmol) and bromoacetamide (35 mL). g, 0.25 mmol), stirred at room temperature overnight, and after completion of the reaction, directly purified by reverse column to obtain the target product 2-(1-(cyclopropylmethyl)piperidin-4-yl)-5-((1S, 5R)-5-(trifluoromethyl)-3-(8-(trifluoromethane)quinolin-5-yl)-3-azabicyclo[3.1.0]hexane-1-yl)-1,3,4-oxadiazole compound 77 (white solid, 43 mg, 38.7%).

[1303] LC-MS m / z (ESI) = 555.2 [M+1].

[1304] 1H NMR (400MHz, DMSO-d6) δ9.15-8.89 (m, 1H), 8.81-8.55 (m, 1H), 8.04 (d, 1H), 7.62 (dd, 1H), 7.37 (d, 1H), 7.22 (s, 1H), 7.11 (s, 1H), 4.08 (d, 1H), 4.06-3.89(m, 2H), 3.81(d, 1H), 2.97(tt, 1H), 2.85(s, 2H), 2.79(d, 2H), 2.34(d, 1H), 2.22(q, 3H), 2.05-1.90(m, 2H), 1.82(dd, 2H).

[1305] 19 F NMR (376MHz, DMSO-d6) δ-58.08, -64.06.

[1306] Example 78

[1307] 2-((1R,3R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-5-((1S,5R)-5-(trifluoromethyl)-3-(8-(trifluoromethane)quinolin-5-yl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazole Compound 78

[1308] 2-((1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-5-((1S,5R)-5-(trifluoromethyl)-3-(8-(trifluoromethyl)quinolin-5-yl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazole

[1309] first step:

[1310] (1R,3R,5S)-3-(2-(1S,5R)-5-(trifluoromethyl)-3-(8-(trifluoromethane)quinolin-5-yl)-3-azabicyclo[3.1.0]hexane-1-carbonyl)hydrazine-1-carbonyl)-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester Compound 78-2

[1311] tert-butyl(1R,3r,5S)-3-(2-((1S,5R)-5-(trifluoromethyl)-3-(8-(trifluoromethyl)quinolin-5-yl)-3-azabicyclo[3.1.0]hexane-1-carbonyl)hydrazine-1-carbonyl)-8-azabicyclo[3.2.1]octane-8-carboxylate

[1312] The raw material (1R, 3R, 5S)-8-(tert-butoxycarbonyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid 78-1 (255 mg, 1.0 mmol) was added to N, N-dimethylformamide (1 ml), and N, N, N', N'-tetramethyl-O-(7-azabenzotriazol-1-yl) urea hexafluorophosphate (380 mg, 1.0 mmol) and N, N-diisopropylethylamine (357 mg, 3.0 mmol) were added. The reaction mixture was stirred at room temperature for 0.5 hours, and then (1S, 5R)-5-(trifluoromethyl)-3-(8- The reaction mixture was stirred at room temperature for 6 hours and then purified by reverse phase column chromatography to obtain tert-butyl (1R, 3r, 5S)-3-(2-(1S, 5R)-5-(trifluoromethyl)-3-(8-(trifluoromethane)quinolin-5-yl)-3-azabicyclo[3.1.0]hexane-1-carbonyl)hydrazine-1-carbonyl)-8-azabicyclo[3.2.1]octane-8-carboxylate 78-2 (380 mg, yield 59.2%).

[1313] LCMS m / z (ESI) = 642.2 [M+1].

[1314] Step 2:

[1315] (1R,3R,5S)-3-(5-((1S,5R)-5-(trifluoromethyl)-3-(8-(trifluoromethyl)quinolin-5-yl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazol-2-yl)-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester Compound 78-3

[1316] tert-butyl(1R,3r,5S)-3-(5-((1S,5R)-5-(trifluoromethyl)-3-(8-(trifluoromethyl)quinolin-5-yl)- 3-azabicyclo[3.1.0]hexan-1-yl)-1, 3,4-oxadiazol-2-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate

[1317] Tert-butyl (1R,3R,5S)-3-(2-(1S,5R)-5-(trifluoromethyl)-3-(8-(trifluoromethane)quinolin-5-yl)-3-azabicyclo[3.1.0]hexane-1-carbonyl)hydrazine-1-carbonyl)-8-azabicyclo[3.2.1]octane-8-carboxylate 78-2 (380 mg, 0.59 mmol) was dissolved in 5 mL of dichloromethane, followed by the addition of triethylamine (303 mg, 3.0 mmol), p-toluenesulfonyl chloride (338 mg, 1.77 mmol). ), stirred at room temperature for 5 hours. The reaction was monitored by TLC. The reaction solution was concentrated and purified by silica gel column chromatography to obtain the target product (1R,3R,5S)-3-(5-((1S,5R)-5-(trifluoromethyl)-3-(8-(trifluoromethyl)quinolin-5-yl)-3-azabicyclo[3.1.0]hexane-1-yl)-1,3,4-oxadiazol-2-yl)-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester 78-3 (yellow solid, 257 mg, yield: 69.8%).

[1318] LC-MS m / z (ESI) = 624.2 [M+1].

[1319] Step 3:

[1320] 2-((1R,3R,5S)-8-azabicyclo[3.2.1]octan-3-yl)-5-((1S,5R)-5-(trifluoromethyl)-3-(8-(trifluoromethane)quinolin-5-yl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazole compound 78-4

[1321] 2-((1R,3r,5S)-8-azabicyclo[3.2.1]octan-3-yl)-5-((1S,5R)-5-(trifluoromethyl)-3-(8-(trifluoromethyl)quinolin-5-yl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazole

[1322] The raw material (1R,3R,5S)-3-(5-((1S,5R)-5-(trifluoromethyl)-3-(8-(trifluoromethyl)quinolin-5-yl)-3-azabicyclo[3.1.0]hexane-1-yl)-1,3,4-oxadiazol-2-yl)-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester 78-3 (257 mg, 0.41 mmol) was added to dichloromethane (4 ml), and trifluoroacetic acid was added. (2 ml), the reaction solution was reacted at room temperature for 2 hours, concentrated under reduced pressure, and then purified by reverse column to obtain 2-((1R,3R,5S)-8-azabicyclo[3.2.1]octan-3-yl)-5-((1S,5R)-5-(trifluoromethyl)-3-(8-(trifluoromethane)quinolin-5-yl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazole 78-4 (110 mg, yield 51.2%).

[1323] LC-MS m / z (ESI) = 524.2 [M+1].

[1324] Step 4:

[1325] 2-((1R,3R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-5-((1S,5R)-5-(trifluoromethyl)-3-(8-(trifluoromethane)quinolin-5-yl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazole Compound 78

[1326] 2-((1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-5-((1S,5R)-5-(trifluoromethyl)-3-(8-(trifluoromethyl)quinolin-5-yl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazole

[1327] The raw material 2-((1R,3R,5S)-8-azabicyclo[3.2.1]octan-3-yl)-5-((1S,5R)-5-(trifluoromethyl)-3-(8-(trifluoromethane)quinolin-5-yl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazole 78-4 (110 mg, 0.21 mmol) was added to methanol (5 ml), and then paraformaldehyde (63 mg, 2.1 mmol) and sodium cyanoborohydride (264 mg) were added. , 4.2 mmol), the reaction mixture was reacted at room temperature overnight. After the reaction was completed, it was directly filtered and then purified by reverse column chromatography to obtain 2-((1R,3R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-5-((1S,5R)-5-(trifluoromethyl)-3-(8-(trifluoromethane)quinolin-5-yl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazole compound 78 (38 mg, yield 33.6%).

[1328] LC-MS m / z (ESI) = 538.2 [M+1].

[1329] 1 H NMR (400MHz, DMSO-d6) δ9.02 (dd, 1H), 8.66 (dd, 1H), 8.05 (d, 1H), 7.63 (dd, 1H), 7.37 (d, 1H), 4.09 (d, 1H), 3.97 (dd, 2H), 3.81(d, 1H), 3.59(s, 1H), 3.50(s, 3H), 2.45(s, 2H), 2.34(t, 1H), 2.21(d, 1H), 2.18-2.05(m, 2H), 1.89(d, 6H).

[1330] 19 F NMR (376MHz, DMSO-d6) δ-58.07, -64.03.

[1331] Example 79

[1332] 2-((1R,3S,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-5-((1S,5R)-5-(trifluoromethyl)-3-(8-(trifluoromethane)quinolin-5-yl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazole Compound 79

[1333] 2-((1R,3S,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-5-((1S,5R)-5-(trifluoromethyl)-3-(8-(trifluoromethyl)quinolin-5-yl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazole

[1334] first step:

[1335] (1R,3S,5S)-3-(2-(1S,5R)-5-(trifluoromethyl)-3-(8-(trifluoromethane)quinolin-5-yl)-3-azabicyclo[3.1.0]hexane-1-carbonyl)hydrazine-1-carbonyl)-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester Compound 79-2

[1336] tert-butyl(1R,3S,5S)-3-(2-((1S,5R)-5-(trifluoromethyl)-3-(8-(trifluoromethyl)quinolin-5-yl)-3-azabicyclo[3.1.0]hexane-1-carbonyl)hydrazine-1-carbonyl)-8-azabicyclo[3.2.1]octane-8-carboxylate

[1337] The raw material (1R, 3S, 5S)-8-(tert-butyloxycarbonyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid 79-1 (255 mg, 1.0 mmol) was added to N, N-dimethylformamide (1 ml), and N, N, N', N'-tetramethyl-O-(7-azabenzotriazole-1-yl) urea hexafluorophosphate (380 mg, 1.0 mmol) and N, N-diisopropylethylamine (357 mg, 3.0 mmol) were added. The reaction mixture was stirred at room temperature for 0.5 hours, and then (1S, 5R)-5-(trifluoromethyl)-3-(8-( The reaction mixture was stirred at room temperature for 6 hours and then purified by reverse phase column chromatography to obtain (1R,3S,5S)-3-(2-(1S,5R)-5-(trifluoromethyl)-3-(8-(trifluoromethane)quinolin-5-yl)-3-azabicyclo[3.1.0]hexane-1-carbonyl)hydrazine-1-carbonyl)-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester compound 79-2 (380 mg, yield 59.2%).

[1338] LCMS m / z (ESI) = 642.2 [M+1].

[1339] Step 2:

[1340] (1R,3S,5S)-3-(5-((1S,5R)-5-(trifluoromethyl)-3-(8-(trifluoromethyl)quinolin-5-yl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazol-2-yl)-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester Compound 79-3

[1341] tert-butyl(1R,3S,5S)-3-(5-((1S,5R)-5-(trifluoromethyl)-3-(8-(trifluoromethyl)quinolin-5-yl)- 3-azabicyclo[3.1.0]hexan-1-yl)-1, 3,4-oxadiazol-2-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate

[1342] Tert-butyl (1R,3S,5S)-3-(2-(1S,5R)-5-(trifluoromethyl)-3-(8-(trifluoromethane)quinolin-5-yl)-3-azabicyclo[3.1.0]hexane-1-carbonyl)hydrazine-1-carbonyl)-8-azabicyclo[3.2.1]octane-8-carboxylate 79-2 (380 mg, 0.59 mmol) was dissolved in 5 mL of dichloromethane, followed by the addition of triethylamine (303 mg, 3.0 mmol), p-toluenesulfonyl chloride (338 mg, 1.77 mmol). ), stirred at room temperature for 5 hours. The reaction was monitored by TLC. The reaction solution was concentrated and purified by silica gel column chromatography to obtain the target product (1R,3S,5S)-3-(5-((1S,5R)-5-(trifluoromethyl)-3-(8-(trifluoromethyl)quinolin-5-yl)-3-azabicyclo[3.1.0]hexane-1-yl)-1,3,4-oxadiazol-2-yl)-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester 79-3 (yellow solid, 257 mg, yield: 69.8%).

[1343] LC-MS m / z (ESI) = 624.2 [M+1].

[1344] Step 3:

[1345] 2-((1R,3S,5S)-8-azabicyclo[3.2.1]octan-3-yl)-5-((1S,5R)-5-(trifluoromethyl)-3-(8-(trifluoromethane)quinolin-5-yl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazole compound 79-4

[1346] 2-((1R,3S,5S)-8-azabicyclo[3.2.1]octan-3-yl)-5-((1S,5R)-5-(trifluoromethyl)-3-(8-(trifluoromethyl)quinolin-5-yl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazole

[1347] The raw material (1R,3S,5S)-3-(5-((1S,5R)-5-(trifluoromethyl)-3-(8-(trifluoromethyl)quinolin-5-yl)-3-azabicyclo[3.1.0]hexane-1-yl)-1,3,4-oxadiazol-2-yl)-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester 79-3 (257 mg, 0.41 mmol) was added to dichloromethane (4 ml), and trifluoroacetic acid ( The reaction solution was reacted at room temperature for 2 hours, concentrated under reduced pressure, and then purified by reverse column to obtain 2-((1R,3S,5S)-8-azabicyclo[3.2.1]oct-3-yl)-5-((1S,5R)-5-(trifluoromethyl)-3-(8-(trifluoromethane)quinolin-5-yl)-3-azabicyclo[3.1.0]hexane-1-yl)-1,3,4-oxadiazole compound 79-4 (110 mg, yield 51.2%).

[1348] LC-MS m / z (ESI) = 524.2 [M+1].

[1349] Step 4:

[1350] 2-((1R,3S,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-5-((1S,5R)-5-(trifluoromethyl)-3-(8-(trifluoromethane)quinolin-5-yl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazole Compound 79

[1351] 2-((1R,3S,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-5-((1S,5R)-5-(trifluoromethyl)-3-(8-(trifluoromethyl)quinolin-5-yl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazole

[1352] The raw material 2-((1R,3S,5S)-8-azabicyclo[3.2.1]octan-3-yl)-5-((1S,5R)-5-(trifluoromethyl)-3-(8-(trifluoromethane)quinolin-5-yl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazole 79-4 (110 mg, 0.21 mmol) was added to methanol (5 ml), and then paraformaldehyde (63 mg, 2.1 mmol) and sodium cyanoborohydride (264 mg) were added. , 4.2 mmol), the reaction mixture was reacted at room temperature overnight. After the reaction was completed, it was directly filtered and then purified by reverse column chromatography to obtain 2-((1R,3S,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-5-((1S,5R)-5-(trifluoromethyl)-3-(8-(trifluoromethane)quinolin-5-yl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazole compound 79 (38 mg, yield 33.6%).

[1353] LC-MS m / z (ESI) = 538.2 [M+1].

[1354] 1 H NMR (400MHz, DMSO-d6) δ9.01 (dd, 1H), 8.66 (dd, 1H), 8.05 (d, 1H), 7.63 (dd, 1H), 7.38 (d, 1H), 4.09 (d, 1H), 3.98(t, 2H), 3.83(d, 1H), 3.50(s, 2H), 2.43-2.20(m, 9H), 2.01-1.84(m, 2H), 1.50-1.29(m, 3H).

[1355] 19 F NMR (376MHz, DMSO-d6) δ-58.07, -63.79.

[1356] Example 80

[1357] 3-Fluoro-4-((1S,5R)-1-(5-(piperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)pyrazolo[1,5-a]pyridine-7-carbonitrile Compound 80

[1358] 3-fluoro-4-((1S,5R)-1-(5-(piperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)pyrazolo[1,5-a]pyridine-7-carbonitrile

[1359] first step:

[1360] (1S,5R)-3-(7-cyano-3-fluoropyrazolo[1,5-a]pyridin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid methyl ester Compound 80-2

[1361] methyl(1S,5R)-3-(7-cyano-3-fluoropyrazolo[1,5-a]pyridin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylate

[1362] The raw materials 3,4-difluoropyrazolo[1,5-a]pyridine-7-carbonitrile 80-1 (716 mg, 4.0 mmol) and (1S,5R)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid methyl ester A-1.SA hydrochloride (982 mg, 4.0 mmol) were added to dimethyl sulfoxide (4 ml), and then N,N-diisopropylethylamine (4 ml) was added, and the reaction mixture was heated to 130 ° C for 4 hours. After the reaction is completed, purified water (50 ml) and ethyl acetate (50 ml * 3 times) are added for extraction, and the organic phases are combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and spin-dried, and the crude product is purified by column chromatography to obtain (1S, 5R)-3-(7-cyano-3-fluoropyrazolo[1,5-a]pyridin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid methyl ester 80-2 (1.1 g, yield 74.5%).

[1363] LCMS m / z (ESI) = 369.1 [M+1].

[1364] Step 2:

[1365] (1S,5R)-3-(7-cyano-3-fluoropyrazolo[1,5-a]pyridin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid compound 80-3

[1366] (1S,5R)-3-(7-cyano-3-fluoropyrazolo[1,5-a]pyridin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid

[1367] The raw material (1S,5R)-3-(7-cyano-3-fluoropyrazolo[1,5-a]pyridin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid methyl ester 80-2 (500 mg, 1.36 mmol) was added to a mixed solution of methanol (5 ml) and water (5 ml). Then, solid lithium hydroxide (65 mg, 2.72 mmol) was added, and the reaction mixture was reacted at room temperature overnight. After the reaction was completed, purified water (50 ml) and ethyl acetate (50 ml * 3 times) were added for extraction, and the organic phases were combined. The organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried. The crude product was purified by column chromatography to obtain (1S, 5R)-3-(7-cyano-3-fluoropyrazolo[1,5-a]pyridin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid 80-3 (380 mg, yield 78.7%).

[1368] LCMS m / z (ESI) = 355.1 [M+1].

[1369] Step 3:

[1370] tert-Butyl 4-(2-((1S,5R)-3-(7-cyano-3-fluoropyrazolo[1,5-a]pyridin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbonyl)hydrazine-1-carbonyl)piperidine-1-carboxylate Compound 80-5

[1371] tert-butyl 4-(2-((1S,5R)-3-(7-cyano-3-fluoropyrazolo[1,5-a]pyridin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbonyl)hydrazine-1-carbonyl)piperidine-1-carboxylate

[1372] The raw material (1S, 5R) -3- (7-cyano-3-fluoropyrazolo [1, 5-a] pyridin-4-yl) -5- (trifluoromethyl) -3- azabicyclo [3.1.0] hexane-1-carboxylic acid 80-3 (355 mg, 1.0 mmol) was added to N, N- dimethylformamide (1 ml), and N, N, N', N'-tetramethyl-O- (7-azabenzotriazole-1-yl) urea hexafluorophosphate (380 mg, 1.0 mmol) and N, N- diisopropylethylamine (357 mg, 3.0 mmol) were added to the reaction mixture. The combined solution was stirred at room temperature for 0.5 hours, and then tert-butyl 4-(hydrazinecarbonyl)piperidine-1-carboxylate 80-4 (243 mg, 1.0 mmol) was added. The reaction mixture was stirred at room temperature for 6 hours and then purified by reverse phase column chromatography to obtain tert-butyl 4-(2-((1S,5R)-3-(7-cyano-3-fluoropyrazolo[1,5-a]pyridin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbonyl)hydrazine-1-carbonyl)piperidine-1-carboxylate 80-5 (362 mg, yield 62.4%).

[1373] LCMS m / z (ESI) = 580.2 [M+1].

[1374] Step 4:

[1375] tert-Butyl 4-(5-((1S,5R)-3-(7-cyano-3-fluoropyrazolo[1,5-a]pyridin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazol-2-yl)piperidine-1-carboxylate Compound 80-6

[1376] tert-butyl 4-(5-((1S,5R)-3-(7-cyano-3-fluoropyrazolo[1,5-a]pyridin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazol-2-yl)piperidine-1-carboxylate

[1377] 4-(2-((1S,5R)-3-(7-cyano-3-fluoropyrazolo[1,5-a]pyridin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-carbonyl)hydrazine-1-carbonyl)piperidine-1-carboxylic acid tert-butyl ester 80-5 (362 mg, 0.62 mmol) was dissolved in 5 mL of dichloromethane, followed by the addition of triethylamine (303 mg, 3.0 mmol) and p-toluenesulfonyl chloride (338 mg, 1.77 mmol). , stirred at room temperature for 5 hours. The reaction was monitored by TLC. The reaction solution was concentrated and purified by silica gel column chromatography to obtain the target product 4-(5-((1S,5R)-3-(7-cyano-3-fluoropyrazolo[1,5-a]pyridin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-yl)-1,3,4-oxadiazol-2-yl)piperidine-1-carboxylic acid tert-butyl ester compound 80-6 (yellow solid, 251 mg, yield: 72.1%).

[1378] LC-MS m / z (ESI) = 562.2 [M+1].

[1379] Step 5:

[1380] 3-Fluoro-4-((1S,5R)-1-(5-(piperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)pyrazolo[1,5-a]pyridine-7-carbonitrile Compound 80

[1381] 3-fluoro-4-((1S,5R)-1-(5-(piperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)pyrazolo[1,5-a]pyridine-7-carbonitrile

[1382] The raw material (4-(5-((1S,5R)-3-(7-cyano-3-fluoropyrazolo[1,5-a]pyridin-4-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-1-yl)-1,3,4-oxadiazol-2-yl)piperidine-1-carboxylic acid tert-butyl ester 80-6 (251 mg, 0.45 mmol) was added to dichloromethane (4 ml), and trifluoroacetic acid was added. (2 ml), the reaction solution was reacted at room temperature for 2 hours, concentrated under reduced pressure, and then purified by reverse column to obtain 3-fluoro-4-((1S, 5R)-1-(5-(piperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-3-yl)pyrazolo[1,5-a]pyridine-7-carbonitrile compound 80 (110 mg, yield 52.9%).

[1383] LC-MS m / z (ESI) = 462.2 [M+1].

[1384] 1 H NMR (400MHz, DMSO-d6) δ8.25 (s, 1H), 7.62 (d, 1H), 6.48 (d, 1H), 4.40-3.94 (m, 4H), 3.04(dd, 3H), 2.63(t, 2H), 2.40-2.20(m, 1H), 1.90(s, 3H), 1.62(q, 2H).

[1385] 19 F NMR (376MHz, DMSO-d6) δ-64.50, -167.63.

[1386] Example 81

[1387] 4-(5-((1S,5R)-5-(trifluoromethyl)-3-(8-(trifluoromethane)quinolin-5-yl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazol-2-yl)bicyclo[2.2.2]octan-1-amine Compound 81

[1388] 4-(5-((1S,5R)-5-(trifluoromethyl)-3-(8-(trifluoromethyl)quinolin-5-yl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazol-2-yl)bicyclo[2.2.2]octan-1-amine

[1389] first step:

[1390] tert-Butyl (4-(2-((1S,5R)-5-(trifluoromethyl)-3-(8-(trifluoromethane)quinolin-5-yl)-3-azabicyclo[3.1.0]hexane-1-carbonyl)hydrazine-1-carbonyl)bicyclo[2.2.2]octan-1-yl)carbamate Compound 81-2

[1391] tert-butyl(4-(2-((1S,5R)-5-(trifluoromethyl)-3-(8-(trifluoromethyl)quinolin-5-yl)-3-azabicyclo[3.1.0]hexane-1-carbonyl)hydrazine-1-carbonyl)bicyclo[2.2.2]octan-1-yl)carbamate

[1392] The raw material 4-((tert-butyloxycarbonyl)amino)bicyclo[2.2.2]octane-1-carboxylic acid 81-1 (269 mg, 1.0 mmol) was added to N,N-dimethylformamide (1 ml), and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazole-1-yl)urea hexafluorophosphate (380 mg, 1.0 mmol) and N,N-diisopropylethylamine (357 mg, 3.0 mmol) were added. The reaction mixture was stirred at room temperature for 0.5 hours, and then (1S,5R)-5-(trifluoromethyl)-3-(8-( The reaction mixture was stirred at room temperature for 6 hours and then purified by reverse phase column chromatography to obtain tert-butyl (4-(2-((1S,5R)-5-(trifluoromethyl)-3-(8-(trifluoromethane)quinolin-5-yl)-3-azabicyclo[3.1.0]hexane-1-carbonyl)hydrazine-1-carbonyl)bicyclo[2.2.2]octan-1-yl)carbamate 81-2 (391 mg, yield 59.6%).

[1393] LCMS m / z (ESI) = 656.2 [M+1].

[1394] Step 2:

[1395] tert-Butyl (4-(5-((1S,5R)-5-(trifluoromethyl)-3-(8-(trifluoromethane)quinolin-5-yl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazol-2-yl)bicyclo[2.2.2]octan-1-yl)carbamate Compound 81-3

[1396] tert-butyl(4-(5-((1S,5R)-5-(trifluoromethyl)-3-(8-(trifluoromethyl)quinolin-5-yl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazol-2-yl)bicyclo[2.2.2]octan-1-yl)carbamate

[1397] Tert-butyl (4-(2-((1S,5R)-5-(trifluoromethyl)-3-(8-(trifluoromethane)quinolin-5-yl)-3-azabicyclo[3.1.0]hexane-1-carbonyl)hydrazine-1-carbonyl)bicyclo[2.2.2]octan-1-yl)carbamate 81-2 (391 mg, 0.60 mmol) was dissolved in 5 mL of dichloromethane, followed by the addition of triethylamine (303 mg, 3.0 mmol), p-toluenesulfonyl chloride (340 mg, 1.80 mmol) and 4-nitropropane (500 mg, 2.0 mmol). The mixture was stirred at room temperature for 5 hours. The reaction was monitored by TLC. The reaction solution was concentrated and purified by silica gel column chromatography to obtain the target product (tert-butyl 4-(5-((1S,5R)-5-(trifluoromethyl)-3-(8-(trifluoromethane)quinolin-5-yl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazol-2-yl)bicyclo[2.2.2]octan-1-yl)carbamate 81-3 (yellow solid, 303 mg, yield: 79.3%).

[1398] LC-MS m / z (ESI) = 638.2 [M+1].

[1399] Step 3:

[1400] 4-(5-((1S,5R)-5-(trifluoromethyl)-3-(8-(trifluoromethane)quinolin-5-yl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazol-2-yl)bicyclo[2.2.2]octan-1-amine Compound 81

[1401] 4-(5-((1S,5R)-5-(trifluoromethyl)-3-(8-(trifluoromethyl)quinolin-5-yl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazol-2-yl)bicyclo[2.2.2]octan-1-amine

[1402] The raw material (4-(5-((1S,5R)-5-(trifluoromethyl)-3-(8-(trifluoromethane)quinolin-5-yl)-3-azabicyclo[3.1.0]hexane-1-yl)-1,3,4-oxadiazol-2-yl)bicyclo[2.2.2]octan-1-yl)carbamic acid tert-butyl ester 81-3 (303 mg, 0.48 mmol) was added to dichloromethane (4 ml), and trifluoroacetic acid was added. (2 ml), the reaction solution was reacted at room temperature for 2 hours, concentrated under reduced pressure, and then purified by reverse column to obtain 4-(5-((1S, 5R)-5-(trifluoromethyl)-3-(8-(trifluoromethane)quinolin-5-yl)-3-azabicyclo[3.1.0]hexane-1-yl)-1,3,4-oxadiazol-2-yl)bicyclo[2.2.2]octane-1-amine compound 81 (220 mg, yield 86.3%).

[1403] LC-MS m / z (ESI) = 538.2 [M+1].

[1404] 1 H NMR (400MHz, DMSO-d6) δ9.01 (dd, 1H), 8.65 (dd, 1H), 8.04 (d, 1H), 7.63 (dd, 1H), 7.38 (d, 1H), 5.75 (br , 2H), 4.08(d, 1H), 3.97(dd, 2H), 3.81(d, 1H), 2.34(d, 1H), 2.22(d, 1H), 1.95(dd, 6H), 1.68(dd, 6H).

[1405] 19 F NMR (376MHz, DMSO-d6) δ-58.06, -64.09.

[1406] Example 82

[1407] N,N-dimethyl-4-(5-((1S,5R)-5-(trifluoromethyl)-3-(8-(trifluoromethane)quinolin-5-yl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazol-2-yl)bicyclo[2.2.2]octan-1-amine Compound 82

[1408] N,N-dimethyl-4-(5-((1S,5R)-5-(trifluoromethyl)-3-(8-(trifluoromethyl)quinolin-5-yl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazol-2-yl)bicyclo[2.2.2]octan-1-amine

[1409] N,N-dimethyl-4-(5-((1S,5R)-5-(trifluoromethyl)-3-(8-(trifluoromethane)quinolin-5-yl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazol-2-yl)bicyclo[2.2.2]octan-1-amine Compound 82

[1410] N,N-dimethyl-4-(5-((1S,5R)-5-(trifluoromethyl)-3-(8-(trifluoromethyl)quinolin-5-yl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazol-2-yl)bicyclo[2.2.2]octan-1-amine

[1411] The raw material 4-(5-((1S,5R)-5-(trifluoromethyl)-3-(8-(trifluoromethane)quinolin-5-yl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazol-2-yl)bicyclo[2.2.2]octane-1-amine compound 81 (100 mg, 0.19 mmol) was added to methanol (5 ml), and then paraformaldehyde (57 mg, 1.9 mmol) and sodium cyanoborohydride (258 mg, The reaction mixture was reacted at room temperature overnight. After completion of the reaction, it was directly filtered and then purified by reverse phase chromatography to obtain N,N-dimethyl-4-(5-((1S,5R)-5-(trifluoromethyl)-3-(8-(trifluoromethane)quinolin-5-yl)-3-azabicyclo[3.1.0]hexan-1-yl)-1,3,4-oxadiazol-2-yl)bicyclo[2.2.2]octan-1-amine compound 82 (56 mg, yield 52.1%).

[1412] LC-MS m / z (ESI) = 566.2 [M+1].

[1413] 1 H NMR (400MHz, DMSO-d6) δ9.01(dd, 1H), 8.65(dd, 1H), 8.04(d, 1H), 7.62(dd, 1H), 7.38(d, 1H), 4.08( d, 1H), 3.96 (dd, 2H), 3.81 (d, 1H), 2.33 (d, 1H), 2.30-2.12 (m, 7H), 1.99-1.88 (m, 6H), 1.67 (dd, 6H).

[1414] 19F NMR (376MHz, DMSO-d6) δ-58.07, -64.10.

[1415] Example 83

[1416] 3-Bromo-4-((1S,5R)-1-(5-(1-methylpiperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)pyrazolo[1,5-a]pyridine-7-carbonitrile Compound 83

[1417] 3-bromo-4-((1S,5R)-1-(5-(1-methylpiperidin-4-yl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)pyrazolo[1,5-a]pyridine-7-carbonitrile

[1418] first step:

[1419] 3-Bromo-4-chloropyrazolo[1,5-a]pyridine-7-carbonitrile compound 83-2

[1420] 3-bromo-4-chloropyrazolo[1,5-a]pyridine-7-carbonitrile

[1421] The starting material, 4-chloropyrazolo[1,5-a]pyridine-7-carbonitrile 83-1 (300 mg, 1.69 mmol), was disso...

Claims

1. A compound represented by the general formula (I), or any stereoisomer, pharmaceutically acceptable salt or deuterated substance thereof: in: R2 is selected from C 1-6 Alkyl or C 3-10 Cycloalkyl, the C 1-6 Alkyl or C 3-10 The cycloalkyl group is optionally further substituted with one or more halogens; R3 is selected from R3 is optionally further selected from one or more C 1-3 Halogenated alkyl, D, C 1-3 Alkyl, halogen, -C 1-3 Alkoxy, -OC 1-3 Substitution with haloalkyl, cyano or -NO2; R1 is selected from And when R3 is selected from R1 is selected from When R2 is not -CF3; R4 is selected from H, C 1-6 Alkyl, C 3-10 Cycloalkyl or halogen; R5, R6, R7, R8, R9, R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 and R 17 are independently selected from H, C 1-6 Alkyl, halogen, 7-10 membered bridged ring or spiro ring, 3-10 membered monocyclic heterocycle, 4-7 membered monocyclic carbocycle, 2-6 membered heteroalkyl, alkynyl, -NH2, -C 1-3 Alkyl-NH2, -O-3-10 membered monocyclic heterocycle, -C 1-3 Alkoxy-3-10 membered monocyclic heterocycle, -NH-3-10 membered monocyclic heterocycle or -C 1-3 Alkyl-3-10 membered monocyclic heterocycle; R5, R6, R7, R8, R9, R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 or R 17 are independently optionally further substituted or unsubstituted by one or more -NH-CHO, C 1-6 Alkyl, 2-6 membered heteroalkyl, -C 1-3 The group may be substituted with alkyl-CO-NH2, =O, halogen, 3-10 membered cycloalkyl, hydroxyl or -NH2.

2. The compound according to claim 1, or any stereoisomer, pharmaceutically acceptable salt or deuterated substance thereof, wherein: After replacement, R5, R6, R7, R8, R9, R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 or R 17 Further one or more selected from 3-10 membered carbocyclic alkyl, 3-10 membered heterocyclic alkyl, C 1-6 The substituent is substituted by alkyl, halogen or -N-(CH3)2.

3. The compound according to claim 1 or 2, or any stereoisomer, pharmaceutically acceptable salt or deuterated substance thereof, wherein: R1 is selected from R4 is selected from H, C 1-6 Alkyl or halogen; R5, R6, R7, R8, R9, R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 and R 17 are independently selected from C 1-6 Alkyl, 2-6 membered heteroalkyl, alkynyl, -NH2, -C 1-3 Alkyl-NH2, -O-3-10 membered monocyclic heterocycle, -C 1-3 Alkoxy-3-10 membered monocyclic heterocycle, -NH-3-10 membered monocyclic heterocycle or -C 1-3 Alkyl-3-10 membered monocyclic heterocycle; R5, R6, R7, R8, R9, R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 or R 17 are independently optionally further substituted or unsubstituted by one or more -NH-CHO, C 1-6 Alkyl, 2-6 membered heteroalkyl, -C 1-3 Alkyl-CO-NH2, =O, halogen, 3-10 membered cycloalkyl, hydroxyl or -NH2 substituted; After replacement, R5, R6, R7, R8, R9, R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 or R 17 Optionally, it is further substituted by one or more selected from 3-10 membered carbocyclic alkyl, 3-10 membered heterocyclic alkyl, C 1-6 The substituent is substituted by alkyl, halogen or -N-(CH3)2.

4. The compound according to claim 3, or any stereoisomer, pharmaceutically acceptable salt or deuterated substance thereof, wherein: R5 and R7 are independently selected from C 1-6 Alkyl, 2-6 membered heteroalkyl, alkynyl, -NH2, -C 1-3 Alkyl-NH2, -O-3-10 membered monocyclic heterocycle, -C 1-3 Alkoxy-3-10 membered monocyclic heterocycle, -NH-3-10 membered monocyclic heterocycle or -C 1-3 Alkyl-3-10 membered monocyclic heterocycle; R5 and R7 are independently optionally further substituted or unsubstituted by one or more C 1-6 Alkyl, 2-6 membered heteroalkyl or -NH2 substituted; The substituted R5 or R7 may be further substituted by one or more 3-10 membered heterocycloalkyl, C 1-6 The substituent is substituted by alkyl or -N-(CH3)2.

5. The compound according to claim 1 or 2, or any stereoisomer, pharmaceutically acceptable salt or deuterated substance thereof, wherein: R1 is selected from R4 is selected from H or halogen; R5, R6, R7, R8, R9, R 10 , R 11 , R 12 , R 14 , R 15 , R 16 and R 17 are independently selected from 7-8 membered bridged rings, 7-9 membered heterospiro rings, 4-6 membered monocyclic heterocycles or 6 membered monocyclic carbocycles; R5, R6, R7, R8, R9, R 10 , R 11 , R 12 , R 14 , R 15 , R 16 or R 17 are independently optionally further substituted or unsubstituted by one or more -NH-CHO, C 1-6 Alkyl, hydroxyl, -C 1-3 Alkyl-CO-NH2, =O, halogen, or -NH2 substitution; After replacement, R5, R6, R7, R8, R9, R 10 , R 11 , R 12 , R 14 , R 15 , R 16 or R 17 Further substituted by one or more selected from 3-5 membered carbocyclic alkyl, 5-6 membered heterocyclic alkyl or C 1-6 The alkyl group is substituted with a substituent.

6. [Corrected 06.01.2025 in accordance with Rule 26] A compound according to claim 5, or any stereoisomer, pharmaceutically acceptable salt or deuterated form thereof, wherein: R5 is selected from a 4-6 membered non-aromatic nitrogen-containing monocyclic heterocycle, a 6 membered non-aromatic monocyclic carbocycle, an 8 membered carbon bridged ring, a 7-8 membered nitrogen-containing heterobridged ring or a 7-9 membered nitrogen-containing heterospirocycle; The 4-6 membered non-aromatic nitrogen-containing monocyclic heterocyclic ring is optionally further substituted by one or more selected from halogen, C 1-3 Alkyl, -C 1-3 Alkyl-CO-NH2, =O, -NH2, hydroxyl and C substituted by cyclopropyl 1-3 substituted by an alkyl substituent; The 8-membered carbon bridge ring is optionally further substituted by one or more substituents selected from -NH2 or -NH-CHO, and the -NH2 or -NH-CHO is optionally further substituted by C 1-3 Alkyl or 6-membered nitrogen-containing heterocyclic group substitution; The 7-8 membered nitrogen-containing hetero-bridged ring is optionally further substituted by one or more C 1-3 Alkyl substitution; The 7-9 membered nitrogen-containing spirocyclic ring is optionally further substituted by one or more selected from -C 1-3 Alkyl-CO-NH2, C 1-3 Alkyl and cyclopropyl-substituted C 1-3 substituted by an alkyl substituent; The 6-membered non-aromatic monocyclic carbocyclic ring is optionally further substituted with one or more -NH2 or N-(CH3)2; R6, R7, R8, R9, R 10 , R 11 , R 12 , R 14 , R 15 and R 16 are selected from 6-membered non-aromatic nitrogen-containing monocyclic heterocyclic rings, wherein the 6-membered non-aromatic nitrogen-containing monocyclic heterocyclic rings are optionally further substituted by one or more C 1-3 Alkyl substitution.

7. The compound according to any one of claims 1 to 6, or any stereoisomers, pharmaceutically acceptable salts or deuterated derivatives thereof, wherein the compound is selected from one of the following structures:

8. The compound represented by the general formula (II), or any stereoisomer, pharmaceutically acceptable salt or deuterated substance thereof: in: R2 is selected from C 1-6 Alkyl, which is optionally further substituted with 1 to more halogens; R3 is selected from R1 is selected from And when R3 is selected from R1 is selected from When R2 is not -CF3; R4 is selected from C 1-6 Alkyl or halogen; R5 is selected from a 7-10 membered bridged ring or spiro ring, and R5 contains at least 1 N; R5 is selected from: The attachment site of R5 is any attachable position thereon.

9. A pharmaceutical composition, comprising: The compound according to any one of claims 1 to 8 or its stereoisomer, pharmaceutically acceptable salt or deuterated substance; optionally one or more other active ingredients; as well as Pharmaceutically acceptable carriers and / or excipients.

10. Use of the compound according to any one of claims 1 to 8 or its stereoisomer, pharmaceutically acceptable salt or deuterated substance, or the pharmaceutical composition according to claim 9 in the preparation of a medicament for treating and / or preventing autoimmune diseases.