Substituted bridged ring inhibitor as well as preparation method and application thereof

Abstract

The invention relates to a substituted bridged ring inhibitor as well as a preparation method and application thereof. Specifically, the compound has a structure as shown in a formula (A0), the invention also discloses a preparation method of the compound and application of the compound as a KRASG12D inhibitor, and the compound has a very good selective inhibition effect on KRASG12D and has better pharmacodynamic and pharmacokinetic performance and lower toxic and side effects. # imgabs0 #

Description

Substituted bridge ring inhibitors and their preparation method and application Technical Field

[0001] The present invention belongs to the field of medicine, and in particular relates to a substituted bridge ring inhibitor, a preparation method and an application thereof. Background Art

[0002] About a quarter of all human tumors are caused by RAS mutations, and nearly one million people lose their lives each year. In the RAS family, KRAS mutations account for 85% of all RAS mutations. KRAS mutations are found in nearly 90% of pancreatic cancers, 30-40% of colon cancers, and 15-20% of lung cancers (mainly non-small cell lung cancer). The most common KRAS mutations are G12C and G12D mutations, of which G12C mutations mainly occur in HSCLC, while G12D mutations mainly occur in pancreatic cancer. So far, there is still no treatment for KRAS on the market. G12D The drug with the mutation was approved for marketing.

[0003] Currently, conventional treatment options for pancreatic cancer include gemcitabine monotherapy, gemcitabine combined with albumin-paclitaxel, and the FOLFIRINOX regimen (oxaliplatin + irinotecan + 5-FU / LV). Among them, liposomal irinotecan is suitable for use in combination with fluorouracil and folinic acid to treat patients with advanced pancreatic cancer who have not responded well to gemcitabine chemotherapy (second-line therapy). However, in general, there are currently limited effective treatments for pancreatic cancer, and the overall survival time of patients does not exceed 1 year. Although drug exploration for patients with advanced pancreatic cancer is ongoing, research progress has been relatively slow so far.

[0004] Due to KRAS G12D The target protein is pathologically associated with many diseases, especially pancreatic cancer, so new KRAS G12D Inhibitors are used in clinical treatment. Highly selective and highly active KRAS G12D Inhibitors can target KRAS G12D There is a more urgent clinical need for more effective treatments for diseases such as cancer caused by mutations, as well as the potential to reduce off-target effects.

[0005] Summary of the Invention

[0006] The purpose of the present invention is to provide a new type of KRAS G12D Compounds with selective inhibitory effects and / or better pharmacodynamic properties and uses thereof.

[0007] In a first aspect, the present invention provides a compound of formula (A0), its stereoisomers, tautomers, crystalline forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs:

[0008] Ring C is selected from the following groups:

[0009] Y is selected from the group consisting of: a bond, O, NH, N(C1-C3 alkyl);

[0010] Z is a substituted or unsubstituted C1-C6 alkylene group; wherein the substitution refers to substitution by one or more R;

[0011] W is selected from: substituted or unsubstituted C3-C 14 Cycloalkyl, or substituted or unsubstituted 4-14 membered saturated or unsaturated heterocyclic group; wherein the substitution refers to substitution by one or more R;

[0012] Selected from the following groups: Wherein, X is selected from: N, CH, CD, CF, C(CN);

[0013] R 1 Selected from: -L1-Q-L2-L3;

[0014] in:

[0015] L1 is selected from: substituted or unsubstituted C1-C6 alkylene; wherein the substitution refers to substitution by one or more R;

[0016] Q is selected from: O, S, SO2, NH, or N(C1-C3 alkyl);

[0017] L2 is selected from: none, substituted or unsubstituted C1-C6 alkylene; wherein the substitution refers to substitution by one or more R;

[0018] L3 is selected from the following substituted or unsubstituted groups: -C1-C6 alkyl, -C3-C6 cycloalkyl, -C4-C6 heterocyclyl, -C1-C6 alkylene (C3-C6 cycloalkyl), -C1-C6 alkylene (C4-C6 heterocyclyl), -C1-C6 alkylene (C1-C6 alkoxy), -C1-C6 alkylene (C3-C6 cycloalkyloxy), or -C1-C6 alkylene (C4-C6 heterocyclyloxy); wherein the substitution refers to substitution by one or more R;

[0019] n is an integer of 0, 1, 2, 3, 4, 5 or 6; provided that when W is a monocyclic or bicyclic ring, n is not 0;

[0020] R 10 Selected from the following substituted or unsubstituted groups: C6-C 14 Aryl, 5-14 membered heteroaryl; wherein the substitution refers to substitution by one or more Ra;

[0021] R 11 Each is independently selected from the following substituted or unsubstituted groups: H, deuterium, halogen, cyano, ester, amine, amide, sulfone, urea, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, C1-C6 alkyloxy, C3-C6 cycloalkyloxy, 4-6 membered heterocyclyloxy; wherein the substitution refers to substitution by one or more R;

[0022] Ra is independently selected from the following groups: substituted or unsubstituted: H, D, halogen, CN, NH2, OH, CONH2, NHCO (C1-C6 alkyl), NHCO (C3-C6 cycloalkyl), SONH2, SO2NH2, NHSO2 (C1-C6 alkyl), NHSO2 (C3-C6 cycloalkyl), C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 20 Cycloalkyl, 4-20 membered heterocycle, C3-C 20 Cycloalkyloxy, 4-20 membered heterocyclyloxy; wherein the substitution refers to substitution by one or more R;

[0023] m is an integer of 0, 1, 2, 3, 4, 5 or 6;

[0024] Each R is the same or different and is independently selected from: deuterium, C1-C 18 Alkyl, deuterated C1-C 18 Alkyl, halogenated C1-C 18 Alkyl, (C3-C 18 Cycloalkyl)C1-C 18 Alkyl, (4-20 membered heterocyclic) C1-C 18 Alkyl, (C1-C 18 Alkoxy) C1-C 18 Alkyl, (C3-C 18 Cycloalkyloxy)C1-C 18 Alkyl, (4-20 membered heterocyclyloxy) C1-C 18 Alkyl, vinyl, ethynyl, (C1-C6 alkyl) vinyl, deuterated (C1-C6 alkyl) vinyl, halogenated (C1-C6 alkyl) vinyl, (C1-C6 alkyl) ethynyl, deuterated (C1-C6 alkyl) ethynyl, halogenated (C1-C6 alkyl) ethynyl, (C3-C 14 cycloalkyl)ethynyl, (4-14 membered heterocyclic)ethynyl, C1-C 18 Alkoxy, deuterated C1-C 18 Alkoxy, halogenated C1-C 18Alkoxy, 4-20 membered heterocyclic C(O), C3-C 20 Cycloalkyl, 4-20 membered heterocyclic group, C6-C 14 aryl, 5-14 membered heteroaryl, halogen, nitro, hydroxy, oxo, cyano, ester, amine, amide, sulfonamide, sulfone or urea.

[0025] In another preferred embodiment, the compound, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug has a structure shown in formula (A):

[0026] Y is selected from the group consisting of: a bond, O, NH, N(C1-C3 alkyl);

[0027] Z is a substituted or unsubstituted C1-C6 alkylene group; wherein the substitution refers to substitution by one or more R;

[0028] W is selected from: substituted or unsubstituted C3-C 14 Cycloalkyl, or substituted or unsubstituted 4-14 membered saturated or unsaturated heterocyclic group; wherein the substitution refers to substitution by one or more R;

[0029] Selected from the following groups: Wherein, X is selected from: N, CH, CD, CF, C(CN);

[0030] R 1 Selected from: -L1-Q-L2-L3;

[0031] in:

[0032] L1 is selected from: substituted or unsubstituted C1-C6 alkylene; wherein the substitution refers to substitution by one or more R;

[0033] Q is selected from: O, S, SO2, NH, or N(C1-C3 alkyl);

[0034] L2 is selected from: none, substituted or unsubstituted C1-C6 alkylene; wherein the substitution refers to substitution by one or more R;

[0035] L3 is selected from the following substituted or unsubstituted groups: -C1-C6 alkyl, -C3-C6 cycloalkyl, -C4-C6 heterocyclyl, -C1-C6 alkylene (C3-C6 cycloalkyl), -C1-C6 alkylene (C4-C6 heterocyclyl), -C1-C6 alkylene (C1-C6 alkoxy), -C1-C6 alkylene (C3-C6 cycloalkyloxy), or -C1-C6 alkylene (C4-C6 heterocyclyloxy); wherein the substitution refers to substitution by one or more R;

[0036] n is an integer of 0, 1, 2, 3, 4, 5 or 6; provided that when W is a monocyclic or bicyclic ring, n is not 0;

[0037] R 10 Selected from the following substituted or unsubstituted groups: C6-C 14 Aryl, 5-14 membered heteroaryl; wherein the substitution refers to substitution by one or more Ra;

[0038] R 11 Each is independently selected from the following groups, substituted or unsubstituted: H, deuterium, halogen, cyano, ester, amine, amide, sulfone, urea, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, C1-C6 alkyloxy, C3-C6 cycloalkyloxy, 4-6 membered heterocyclyloxy;

[0039] Ra is independently selected from the following groups: substituted or unsubstituted: H, D, halogen, CN, NH2, OH, CONH2, NHCO (C1-C6 alkyl), NHCO (C3-C6 cycloalkyl), SONH2, SO2NH2, NHSO2 (C1-C6 alkyl), NHSO2 (C3-C6 cycloalkyl), C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 20 Cycloalkyl, 4-20 membered heterocyclic group, C3-C 20 Cycloalkyloxy, 4-20 membered heterocyclyloxy; wherein the substitution refers to substitution by one or more R;

[0040] m is an integer of 0, 1, 2, 3, 4, 5 or 6;

[0041] Each R is the same or different and is independently selected from: deuterium, C1-C 18 Alkyl, deuterated C1-C 18 Alkyl, halogenated C1-C 18 Alkyl, (C3-C 18 Cycloalkyl)C1-C 18 Alkyl, (4-20 membered heterocyclic) C1-C 18 Alkyl, (C1-C 18 Alkoxy) C1-C 18 Alkyl, (C3-C 18 Cycloalkyloxy)C1-C 18 Alkyl, (4-20 membered heterocyclyloxy) C1-C 18Alkyl, vinyl, ethynyl, (C1-C6 alkyl) vinyl, deuterated (C1-C6 alkyl) vinyl, halogenated (C1-C6 alkyl) vinyl, (C1-C6 alkyl) ethynyl, deuterated (C1-C6 alkyl) ethynyl, halogenated (C1-C6 alkyl) ethynyl, (C3-C 14 cycloalkyl)ethynyl, (4-14 membered heterocyclic)ethynyl, C1-C 18 Alkoxy, deuterated C1-C 18 Alkoxy, halogenated C1-C 18 Alkoxy, 4-20 membered heterocyclic C(O), C3-C 20 Cycloalkyl, 4-20 membered heterocyclic group, C6-C 14 aryl, 5-14 membered heteroaryl, halogen, nitro, hydroxy, oxo, cyano, ester, amine, amide, sulfonamide, sulfone or urea.

[0042] In another preferred embodiment, Ra are each independently selected from the following substituted or unsubstituted groups: H, D, halogen, CN, OH, SONH2, NHSO2CH3, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 20 Cycloalkyl, 4-20 membered heterocyclyl; wherein, the substitution refers to substitution by one or more R; R is as defined above.

[0043] In another preferred embodiment, the compound has the structure shown in A'

[0044] Preferably, it has the structure shown in A"

[0045] In the formula, n, Y, Z, W, L1, L2, L3, Q, R 10 、R 11 , m, and ring A are as defined above.

[0046] In another preferred embodiment, Selected from the following groups:

[0047] In another preferred embodiment, the compound has a structure shown in formula A'

[0048] R 2 and R 3the same or different, each independently selected from the following substituted or unsubstituted groups: H, D, halogen, CN, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C1-C6 alkoxy; wherein the substitution refers to substitution by one or more R;

[0049] X, Y, Z, W, R 1 , n and R 10 The definition of is as above.

[0050] In another preferred embodiment, R 3 Selected from the following substituted or unsubstituted groups: H, D, halogen, CN, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkyloxy, 4-6 membered heterocyclyl, 4-6 membered heterocyclyloxy; wherein the substitution refers to substitution by one or more R.

[0051] In another preferred embodiment, R 10 Selected from: selected from the following groups substituted or unsubstituted: phenyl, naphthyl, 5-6 membered monocyclic heteroaryl (such as pyridyl), 9-10 membered bicyclic heteroaryl (such as indazolyl, benzothiazole, benzothiophene, benzofuran), wherein the substitution is substituted by one or more groups selected from the following groups: halogen, hydroxyl, cyano, NH2, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, C2-C6 alkenyl, C2-C6 alkynyl: Preferably, R 10 Selected from:

[0052] In another preferred embodiment, R 8 Selected from: NH2, OH, SONH2, NHSO2CH3.

[0053] In another preferred embodiment, R 10 for

[0054] In another preferred embodiment, U is selected from: N, CH, CD, CF;

[0055] R 4 Selected from the group consisting of substituted or unsubstituted halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl;

[0056] R 5 、R 6 、R 7 、R 9the same or different, each independently selected from the following substituted or unsubstituted groups: H, D, halogen, CN, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C1-C6 alkoxy; wherein the substitution refers to substitution by one or more R;

[0057] R 8 Selected from: NH2, OH, SONH2, NHSO2CH3.

[0058] In another preferred embodiment, R 10 for Preferably, R 10 for Preferably, R 10 for

[0059] In another preferred embodiment, U' is selected from: O, or S;

[0060] U" is selected from: N, or C(CN);

[0061] R 7’ 、R 8’ 、R 9’ the same or different, each independently selected from the following substituted or unsubstituted groups: H, D, halogen, CN, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C1-C6 alkoxy; wherein the substitution refers to substitution by one or more R;

[0062] R 5’ Selected from: H, D, halogen, CN, NH2, OH, CONH2, NHCO(C1-C6 alkyl), NHCO(C3-C6 cycloalkyl), SONH2, SO2NH2, NHSO2(C1-C6 alkyl), NHSO2(C3-C6 cycloalkyl), C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C1-C6 alkoxy.

[0063] In another preferred embodiment, R 10 for Wherein, V1, V2, V3, V4 and V5 are each independently selected from: N, or CR v ; R vThe same or different, each independently selected from: H, C1-C3 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, C1-C3 alkoxy, C3-C6 cycloalkyloxy, 4-6 membered heterocyclyloxy, halo-C1-C3 alkyl, halo-C3-C6 cycloalkyl, halo-4-6 membered heterocyclyl, (HO)-C1-C3 alkyl, (HO)-C3-C6 cycloalkyl, (NH2)-C1-C3 alkyl, (NH2)-C3-C6 cycloalkyl, halogen, CN, -C≡CH, OH, NH2, CONH2, NHCO(C1-C6 alkyl), NHCO(C3-C6 cycloalkyl), SO2NH2, NHSO2(C1-C6 alkyl), NHSO2(C3-C6 cycloalkyl), wherein the heterocyclyl is optionally substituted by one or more oxo groups (=O).

[0064] In another preferred embodiment, R 10 for Among them, R v1 、R v2 、R v3 、R v4 and R v5 Each is independently selected from: H, C1-C3 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, C1-C3 alkoxy, C3-C6 cycloalkyloxy, 4-6 membered heterocyclyloxy, halogenated C1-C3 alkyl (such as CF3, CF2CF3), halogenated C3-C6 cycloalkyl, halogenated 4-6 membered heterocyclyl, (HO)-C1-C3 alkyl, (HO)-C3-C6 cycloalkyl, (NH2)-C1-C3 alkyl, (NH2)-C3-C6 cycloalkyl, halogen, CN, -C≡CH, OH, NH2, CONH2, NHCO(C1-C6 alkyl), NHCO(C3-C6 cycloalkyl, SO2NH2, NHSO2(C1-C6 alkyl), NHSO2(C3-C6 cycloalkyl)H, C1-C3 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, C1-C3 alkoxy, C3-C6 cycloalkyloxy, 4-6 membered heterocyclyloxy, halo-C1-C3 alkyl, halo-C3-C6 cycloalkyl, halo-4-6 membered heterocyclyl, (HO)-C1-C3 alkyl, (HO)-C3-C6 cycloalkyl, (NH2)-C1-C3 alkyl, (NH2)-C3-C6 cycloalkyl, halogen, CN, -C≡CH, OH, NH2, CONH2, NHCO(C1-C6 alkyl), NHCO(C3-C6 cycloalkyl), SO2NH2, NHSO2(C1-C6 alkyl), NHSO2(C3-C6 cycloalkyl), the heterocyclyl being optionally substituted by one or more oxo groups (=O).

[0065] In another preferred embodiment, R v5Selected from: halogenated C1-C3 alkyl (such as CF3, CF2CF3).

[0066] In another preferred embodiment, R v1 Selected from: H.

[0067] In another preferred embodiment, R v1 Selected from: NH2.

[0068] In another preferred embodiment, a compound of formula (IA) or formula (IB), its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs is provided:

[0069] Where,

[0070] U is selected from: N, CH, CD, CF;

[0071] U' is selected from: O, or S;

[0072] U" is selected from: N, or C(CN);

[0073] X is selected from the group consisting of: N, CH, CD, CF, C(CN);

[0074] Y is selected from the group consisting of: a bond, O, NH, N(C1-C3 alkyl);

[0075] Z is a substituted or unsubstituted C1-C6 alkylene group; wherein the substitution refers to substitution by one or more R;

[0076] W is selected from: substituted or unsubstituted C3-C 14 Cycloalkyl, or substituted or unsubstituted 4-14 membered saturated or unsaturated heterocyclic group; wherein the substitution refers to substitution by one or more R;

[0077] R 1 Selected from: -L1-Q-L2-L3; wherein:

[0078] L1 is selected from: substituted or unsubstituted C1-C6 alkylene; wherein the substitution refers to substitution by one or more R;

[0079] Q is selected from: O, S, SO2, NH, or N(C1-C3 alkyl);

[0080] L2 is selected from: none, substituted or unsubstituted C1-C6 alkylene; wherein the substitution refers to substitution by one or more R;

[0081] L3 is selected from the following substituted or unsubstituted groups: -C1-C6 alkyl, -C3-C6 cycloalkyl, -C4-C6 heterocyclyl, -C1-C6 alkylene (C3-C6 cycloalkyl), -C1-C6 alkylene (C4-C6 heterocyclyl), -C1-C6 alkylene (C1-C6 alkoxy), -C1-C6 alkylene (C3-C6 cycloalkyloxy), or -C1-C6 alkylene (C4-C6 heterocyclyloxy); wherein the substitution refers to substitution by one or more R;

[0082] n is an integer of 1, 2, 3, 4, 5 or 6;

[0083] R 2 and R 3 the same or different, each independently selected from the following substituted or unsubstituted groups: H, D, halogen, CN, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C1-C6 alkoxy; wherein the substitution refers to substitution by one or more R;

[0084] R 4 is selected from the group consisting of halogen, C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, substituted or unsubstituted; wherein the substitution refers to substitution by one or more R;

[0085] R 8 Selected from: OH, SONH2, NHSO2CH3;

[0086] R 5 、R 6 、R 7 、R 9 、R 7’ 、R 8’ 、R 9’ the same or different, each independently selected from the following substituted or unsubstituted groups: H, D, halogen, CN, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C1-C6 alkoxy; wherein the substitution refers to substitution by one or more R;

[0087] R 5’ Selected from: H, D, halogen, CN, NH2, OH, CONH2, NHCO(C1-C6 alkyl), NHCO(C3-C6 cycloalkyl), SONH2, SO2NH2, NHSO2(C1-C6 alkyl), NHSO2(C3-C6 cycloalkyl), C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C1-C6 alkoxy;

[0088] Each R is the same or different and is independently selected from: deuterium, C1-C 18 Alkyl, deuterated C1-C 18Alkyl, halogenated C1-C 18 Alkyl, (C3-C 18 Cycloalkyl)C1-C 18 Alkyl, (4-20 membered heterocyclic) C1-C 18 Alkyl, (C1-C 18 Alkoxy) C1-C 18 Alkyl, (C3-C 18 Cycloalkyloxy)C1-C 18 Alkyl, (4-20 membered heterocyclyloxy) C1-C 18 Alkyl, vinyl, ethynyl, (C1-C6 alkyl) vinyl, deuterated (C1-C6 alkyl) vinyl, halogenated (C1-C6 alkyl) vinyl, (C1-C6 alkyl) ethynyl, deuterated (C1-C6 alkyl) ethynyl, halogenated (C1-C6 alkyl) ethynyl, (C3-C 14 cycloalkyl)ethynyl, (4-14 membered heterocyclic)ethynyl, C1-C 18 Alkoxy, deuterated C1-C 18 Alkoxy, halogenated C1-C 18 Alkoxy, C3-C 20 Cycloalkyl, 4-20 membered heterocyclic group, C6-C 14 aryl, 5-14 membered heteroaryl, halogen, nitro, hydroxy, oxo, cyano, ester, amine, amide, sulfonamide, sulfone or urea.

[0089] In another preferred embodiment, each R is the same or different and is independently selected from: deuterium, C1-C 18 Alkyl, deuterated C1-C 18 Alkyl, halogenated C1-C 18 Alkyl, (C3-C 18 Cycloalkyl)C1-C 18 Alkyl, (4-20 membered heterocyclic) C1-C 18 Alkyl, (C1-C 18 Alkoxy) C1-C 18 Alkyl, (C3-C 18 Cycloalkyloxy)C1-C 18 Alkyl, (4-20 membered heterocyclyloxy) C1-C 18 Alkyl, vinyl, ethynyl, (C1-C6 alkyl) vinyl, deuterated (C1-C6 alkyl) vinyl, halogenated (C1-C6 alkyl) vinyl, (C1-C6 alkyl) ethynyl, deuterated (C1-C6 alkyl) ethynyl, halogenated (C1-C6 alkyl) ethynyl, (C3-C 14 cycloalkyl)ethynyl, (4-14 membered heterocyclic)ethynyl, C1-C 18 Alkoxy, deuterated C1-C 18Alkoxy, halogenated C1-C 18 Alkoxy, C3-C 20 Cycloalkyl, 4-20 membered heterocyclic group, C6-C 14 aryl, 5-14 membered heteroaryl, halogen, nitro, hydroxy, oxo, cyano, ester, amine, amide, sulfone or urea.

[0090] In another preferred embodiment, each R is the same or different and is independently selected from: deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkyl, (C3-C 10 (cycloalkyl) C1-C6 alkyl, (4-10 membered heterocyclyl) C1-C6 alkyl, (C1-C6 alkoxy) C1-C6 alkyl, (C3-C6 cycloalkyloxy) C1-C6 alkyl, (4-20 membered heterocyclyloxy) C1-C 18 Alkyl, vinyl, ethynyl, (C1-C6 alkyl) vinyl, deuterated (C1-C6 alkyl) vinyl, halogenated (C1-C6 alkyl) vinyl, (C1-C6 alkyl) ethynyl, deuterated (C1-C6 alkyl) ethynyl, halogenated (C1-C6 alkyl) ethynyl, (C3-C 10 cycloalkyl)ethynyl, (4-10 membered heterocyclic)ethynyl, C1-C6 alkoxy, deuterated C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 aryl, 5-10 membered heteroaryl, halogen, nitro, hydroxy, oxo, cyano, ester, amine, amide, sulfonamide, sulfone or urea.

[0091] In another preferred embodiment, the compound of formula I has the structure shown in formula (I'A) or formula (I'B)

[0092] Preferably, it has the structure shown in formula (I"A) or formula (I"B)

[0093] Among them, n, U, U', U", X, Y, Z, W, L1, L2, L3, Q, R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 5’ 、R 7’ 、R 8’ 、R 9’ The definitions of , are as described above.

[0094] In another preferred embodiment, the compound has a structure represented by formula (IIA) or formula (IIB):

[0095] Among them, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 5’ 、R 7’ 、R 8’ 、R 9’ , U, U', U", X, Z, W and n are defined as above.

[0096] In another preferred embodiment, the compound has a structure represented by formula (IIIA) or formula (IIIB):

[0097] Among them, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 5’ 、R 7’ 、R 8’ 、R 9’ , U, U', U", Z, W and n are defined as above.

[0098] In another preferred embodiment, R 3 Selected from: H, D, F, Cl, Br, CN, methyl, ethyl, propyl, isopropyl, deuterated methyl, CH2F, CHF2, CF3, methoxy, ethoxy, propoxy, OCH2F, OCHF2, OCF3.

[0099] In another preferred embodiment, the compound has a structure represented by formula (IVA) or formula (IVB):

[0100] Among them, R 1 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 5’ 、R 7’ 、R 8’ 、R9’ , U, U', U", Z, W and n are defined as above.

[0101] In another preferred embodiment, the compound has a structure represented by formula (VA) or formula (VB):

[0102] Among them, R 1 、R 4 、R 5 、R 6 、R 7 、R 9 、R 7’ 、R 8’ 、R 9’ , U, U', U", Z, W and n are defined as above.

[0103] In another preferred embodiment, the compound has a structure represented by formula (VIA) or formula (VIB):

[0104] Among them, R 1 、R 4 、R 5 、R 6 、R 7 、R 9 、R 7’ 、R 8’ 、R 9’ , U", Z, W and n are as defined above.

[0105] In another preferred embodiment, the compound has a structure represented by formula (VIIA) or formula (VIIB):

[0106] Among them, R 1 、R 4 、R 5 、R 7’ 、R 8’ 、R 9’ , Z, W and n are defined as above.

[0107] In another preferred embodiment, the compound has a structure represented by Formula (VIIIA) or Formula (VIIIB):

[0108] Among them, R 1 、R 4 、R 5 、R 7’ 、R 9’ , Z, W and n are defined as above.

[0109] In another preferred embodiment, W is substituted or unsubstituted by the following groups: C3-C6 monocyclic cycloalkyl, C7-C 10 Bicyclic or C7-C 11 tricyclic cycloalkyl, 4-6 membered saturated or unsaturated monocyclic heterocyclic group, 7-10 membered bicyclic or 7-11 membered tricyclic heterocyclic group; preferably, W is selected from: substituted or unsubstituted 7-10 membered saturated or unsaturated bridged heterocyclic group, substituted or unsubstituted 7-10 membered saturated or unsaturated fused heterocyclic group.

[0110] In another preferred embodiment, W is selected from:

[0111] wherein n' is an integer of 0, 1, 2, 3, 4, 5, or 6; and R is as defined above, and R may be substituted on any one of the polycyclic rings (eg, bridged ring or spiro ring).

[0112] In another preferred embodiment, when W is selected from:

[0113] When n' is 1 or 2, more preferably, n' is 1, and R is as defined above. R can be substituted on any one ring of a polycyclic ring (such as a bridged ring or a spiro ring).

[0114] In another preferred embodiment, when W is selected from:

[0115] When n' can be 0, 1 or 2, R is as defined above, and R can be substituted on any one ring of a polycyclic ring (such as a bridged ring or a spiro ring).

[0116] In another preferred embodiment, when W is selected from:

[0117] When n' can be 0, 1 or 2, R is as defined above, and R can be substituted on any one ring of a polycyclic ring (such as a bridged ring or a spiro ring).

[0118] In another preferred embodiment, R is selected from: deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkyl, (C3-C6 cycloalkyl) C1-C 18C1-C6 alkyl, (4-6 membered heterocyclyl) C1-C6 alkyl, (C1-C6 alkoxy) C1-C6 alkyl, (C3-C6 cycloalkyloxy) C1-C6 alkyl, (4-6 membered heterocyclyloxy) C1-C6 alkyl, vinyl, ethynyl, (C1-C6 alkyl) vinyl, deuterated (C1-C6 alkyl) vinyl, halo (C1-C6 alkyl) vinyl, (C1-C6 alkyl) ethynyl, deuterated (C1-C6 alkyl) ethynyl, halo (C1-C6 alkyl) ethynyl, (C3-C6 cycloalkyl) ethynyl, (4-6 membered heterocyclyl) ethynyl, C1-C6 alkoxy, deuterated C1-C6 alkoxy, halo C1-C6 alkoxy, 4-6 membered heterocyclyl C(O), C3-C6 cycloalkyl, 4-6 membered heterocyclyl, C6-C 10 Aryl, 5-10 membered heteroaryl (preferably 5-6 membered), halogen, nitro, hydroxy, oxo, cyano, COOC1-C6 alkyl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, CONH2, CONHC1-C6 alkyl, CON(C1-C6 alkyl)2, SO2C1-C6 alkyl, -NHCONH2, -NHCO NHC1-C6 alkyl, -NHCON(C1-C6 alkyl)2.

[0119] In another preferred embodiment, Z is a substituted or unsubstituted C1-C3 alkylene group, preferably a methylene group, an ethylene group, or a propylene group.

[0120] In another preferred embodiment, Z is CD2.

[0121] In another preferred embodiment, the compound has a structure represented by formula (IX):

[0122] wherein n' is an integer of 0, 1, 2, 3, 4, 5, or 6;

[0123] R 5 , R, L1, Q, L2, L3 and n are defined as above.

[0124] In another preferred embodiment, R 4 Selected from the group consisting of substituted or unsubstituted halogen, methyl, ethyl, propyl, vinyl, propenyl, allyl, butenyl, ethynyl, propynyl, butynyl.

[0125] In another preferred embodiment, Selected from:

[0126] In another preferred embodiment, the compound has a structure shown by formula (X):

[0127] V1, V2, V3, V4 and V5 are each independently selected from: N, or CR v ; R v the same or different, each independently selected from: H, C1-C3 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, C1-C3 alkoxy, C3-C6 cycloalkyloxy, 4-6 membered heterocyclyloxy, halo-C1-C3 alkyl, halo-C3-C6 cycloalkyl, halo-4-6 membered heterocyclyl, (HO)-C1-C3 alkyl, (HO)-C3-C6 cycloalkyl, (NH2)-C1-C3 alkyl, (NH2)-C3-C6 cycloalkyl, halogen, CN, -C≡CH, OH, NH2, CONH2, NHCO(C1-C6 alkyl), NHCO(C3-C6 cycloalkyl), SO2NH2, NHSO2(C1-C6 alkyl), NHSO2(C3-C6 cycloalkyl), wherein the heterocyclyl is optionally substituted with one or more oxo groups (=O);

[0128] R 2 and R 3 the same or different, each independently selected from the following substituted or unsubstituted groups: H, D, halogen, CN, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C1-C6 alkoxy; wherein the substitution refers to substitution by one or more R;

[0129] Ring C, R, X, Z, W and n are as defined above.

[0130] In another preferred embodiment, the compound has a structure shown in formula (XI):

[0131] V1, V2, V3, V4, and V5 are each independently selected from: N, or CR v ; R v the same or different, each independently selected from: H, C1-C3 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, C1-C3 alkoxy, C3-C6 cycloalkyloxy, 4-6 membered heterocyclyloxy, halo-C1-C3 alkyl, halo-C3-C6 cycloalkyl, halo-4-6 membered heterocyclyl, (HO)-C1-C3 alkyl, (HO)-C3-C6 cycloalkyl, (NH2)-C1-C3 alkyl, (NH2)-C3-C6 cycloalkyl, halogen, CN, -C≡CH, OH, NH2, CONH2, NHCO(C1-C6 alkyl), NHCO(C3-C6 cycloalkyl), SO2NH2, NHSO2(C1-C6 alkyl), NHSO2(C3-C6 cycloalkyl), wherein the heterocyclyl is optionally substituted with one or more oxo groups (=O);

[0132] R 2 and R 3the same or different, each independently selected from the following substituted or unsubstituted groups: H, D, halogen, CN, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C1-C6 alkoxy; wherein the substitution refers to substitution by one or more R;

[0133] Among them, R, R 1 , X, Z, W and n are defined as above.

[0134] In another preferred embodiment, the compound has a structure represented by formula (XII):

[0135] V1, V2, V3, V4, and V5 are each independently selected from: N, or CR v ; R v the same or different, each independently selected from: H, C1-C3 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, C1-C3 alkoxy, C3-C6 cycloalkyloxy, 4-6 membered heterocyclyloxy, halo-C1-C3 alkyl, halo-C3-C6 cycloalkyl, halo-4-6 membered heterocyclyl, (HO)-C1-C3 alkyl, (HO)-C3-C6 cycloalkyl, (NH2)-C1-C3 alkyl, (NH2)-C3-C6 cycloalkyl, halogen, CN, -C≡CH, OH, NH2, CONH2, NHCO(C1-C6 alkyl), NHCO(C3-C6 cycloalkyl), SO2NH2, NHSO2(C1-C6 alkyl), NHSO2(C3-C6 cycloalkyl), wherein the heterocyclyl is optionally substituted with one or more oxo groups (=O);

[0136] R 3 A substituted or unsubstituted group selected from the group consisting of H, D, halogen, CN, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, and C1-C6 alkoxy; wherein the substituted group refers to one or more R groups;

[0137] Among them, R, R 1 , X, Z, W and n are defined as above.

[0138] In another preferred embodiment, the compound has a structure represented by formula (XIII):

[0139] V1, V2, V3, V4, and V5 are each independently selected from: N, or CR v ; R vthe same or different, each independently selected from: H, C1-C3 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, C1-C3 alkoxy, C3-C6 cycloalkyloxy, 4-6 membered heterocyclyloxy, halo-C1-C3 alkyl, halo-C3-C6 cycloalkyl, halo-4-6 membered heterocyclyl, (HO)-C1-C3 alkyl, (HO)-C3-C6 cycloalkyl, (NH2)-C1-C3 alkyl, (NH2)-C3-C6 cycloalkyl, halogen, CN, -C≡CH, OH, NH2, CONH2, NHCO(C1-C6 alkyl), NHCO(C3-C6 cycloalkyl), SO2NH2, NHSO2(C1-C6 alkyl), NHSO2(C3-C6 cycloalkyl), wherein the heterocyclyl is optionally substituted with one or more oxo groups (=O);

[0140] R 3 A substituted or unsubstituted group selected from the group consisting of H, D, halogen, CN, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, and C1-C6 alkoxy; wherein the substituted group refers to one or more R groups;

[0141] Among them, R, R 1 , Z, W and n are defined as above.

[0142] In another preferred embodiment, R v Each is independently selected from: H, halogen, CN, -C≡CH, or NH2.

[0143] In another preferred embodiment, L1 is selected from: substituted or unsubstituted methylene or substituted or unsubstituted ethylene; Q is selected from: O; L2 is selected from: none, substituted or unsubstituted methylene; L3 is selected from the following substituted or unsubstituted groups: -C1-C6 alkyl, -C3-C6 cycloalkyl, -C4-C6 heterocyclyl, -C1-C6 alkylene (C3-C6 cycloalkyl), -C1-C6 alkylene (C4-C6 heterocyclyl), -C1-C6 alkylene (C1-C6 alkoxy wherein the substitution refers to substitution by one or more groups selected from the group consisting of deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkyl, vinyl, ethynyl, C1-C6 alkoxy, deuterated C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, C6-C 14 aryl, 5-14 membered heteroaryl, halogen, nitro, hydroxy, oxo, cyano, ester, amine, amide, sulfone or urea.

[0144] In another preferred embodiment, -L1-Q-L2-L3 is selected from:

[0145] In another preferred embodiment, for Preferably

[0146] In another preferred embodiment, for Preferably

[0147] In another preferred embodiment, Selected from:

[0148] Or choose from:

[0149] wherein n' is an integer of 0, 1, 2, 3, 4, 5 or 6; R, R 1 and n are defined as above, R, R 1 It can be substituted on any ring of a polycyclic ring (such as a bridged ring or a spiro ring);

[0150] Or choose from:

[0151] wherein n' is an integer of 0, 1, 2, 3, 4, 5 or 6; and R is as defined above, and R may be substituted on any one of the polycyclic rings (eg, bridged ring or spiro ring).

[0152] In another preferred embodiment, Selected from:

[0153] In another preferred embodiment, W is selected from:

[0154] In another preferred embodiment, W is selected from:

[0155] In another preferred embodiment, W is selected from:

[0156] In another preferred embodiment, the prodrug of the compound has a structure shown in the following formula (XIV):

[0157] C' is selected from:

[0158] PG is selected from:

[0159] Y, Z, W, Ring A, R 1、R 10 、R 11 , m and n are defined as above.

[0160] In another preferred embodiment, m, A ring, n, U, X, Y, Z, W, L1, L2, L3, Q, R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 and R 11 It has the groups corresponding to the specific compounds in the examples.

[0161] In another preferred embodiment, V1, V2, V3, V4, V5, Ring C, and PG have groups corresponding to the specific compounds in the examples.

[0162] In another preferred embodiment, the compound is selected from the following group:

[0163] Or choose from:

[0164] Or choose from:

[0165] Or choose from:

[0166] Or choose from:

[0167] Or choose from:

[0168] Or choose from:

[0169] Or choose from:

[0170] In another preferred embodiment, the compound is preferably the compound prepared in the examples.

[0171] In a second aspect, the present invention provides a method for preparing a compound of formula (A0), its stereoisomers, tautomers, crystalline forms, pharmaceutically acceptable salts, hydrates, solvates, or prodrugs, comprising the steps (taking Formula IA as an example):

[0172] (i) reacting a compound of formula V-1 with a compound of formula V-2 in an inert solvent in the presence of a base, with or without a Pd catalyst, and with or without a condensing agent to obtain a compound of formula V-3;

[0173] (ii) reacting a compound of formula V-3 with a compound of formula V-4 in an inert solvent in the presence of a base with or without a Pd catalyst to obtain a compound of formula V-5;

[0174] (iii) reacting the compound of formula V-5 with the compound of formula V-6 in an inert solvent in the presence of a base and a Pd catalyst to obtain a compound of formula V-7;

[0175] (iv) removing the protecting group PG1 from the compound of formula V-7 under the action of an acid (such as TFA, HCl, etc.) or Pd-catalyzed hydrogenation to obtain a compound of formula (IA);

[0176] Where,

[0177] X1, X2 and X3 are each independently selected from: OH, halogen, OTf, OTs or OMs;

[0178] PG1 is selected from: Boc, Cbz, or Bn;

[0179] LG1 is selected from: -B(OH)2, -B(KBF3), -Sn( n Bu)3,

[0180] R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 , U, X, Y, Z, W and n are defined as above.

[0181] The third aspect of the present invention provides a pharmaceutical composition comprising one or more compounds described in the first aspect, their stereoisomers, tautomers, crystalline forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs; and a pharmaceutically acceptable carrier.

[0182] In another preferred embodiment, the pharmaceutical composition further comprises a drug selected from the group consisting of: PD-1 inhibitors (such as nivolumab, pembrolizumab, pidilizumab, cemiplimab, JS-001, SHR-120, BGB-A317, IBI-308, GLS-010, GB-226, STW204, HX008, HLX10, BAT 1306, AK105, LZM 009 or biosimilars thereof), PD-L1 inhibitors (such as durvalumab, atezolizumab, avelumab, CS1001, KN035, HLX20, SHR-1316, BGB-A333, JS003, CS1003, KL-A167, F 520, GR1405, MSB2311 or biosimilars of the above drugs, etc.), CD20 antibodies (such as rituximab, obinutuzumab, ofatumumab, veltuzumab, tositumomab, 131I-tositumomab, ibritumomab, 90Y-ibritumomab, 90In-ibritumomab, ibritumomabtiuxetan, etc.), CD47 antibodies (such as Hu5F9-G4, CC-90002, TTI-621, TTI-622, OSE-172, SRF-231, ALX-148, NI-1701, SHR-1603, IBI188, IMM01), ALK inhibitors (such as Ceritinib, Alectinib, Brigatinib, Lorlatinib, Ocatinib), PI3K inhibitors (such as Idelalisib, Duvelisib, Dactolisib, Taselisib, Bimiralisib, Omip alisib, Buparlisib, etc.), BTK inhibitors (such as Ibrutinib, Tirabrutinib, Acalabrutinib, Zanubrutinib, Vecabrutinib, etc.), EGFR inhibitors (such as Afatinib, Gefitinib, Erlotinib, Lapatinib, Dacomitinib, Icotinib, Canertinib, Sapitinib, Naquotinib, Pyrotinib, Rociletinib, Osimertinib, etc.), VEGFR inhibitors (such as Sorafenib, Pazopanib, Regorafenib, Sitravatinib, Ningetinib, Cabozantinib, Sunitinib, Donafenib, etc.), HDAC inhibitors (such as Givinostat, Tucidinostat, Vorinostat, Fimepinostat, Droxinostat, Entinostat, Dacinostat, Quisinostat, Tacedinaline, etc.), CDK inhibitors (such as Palbociclib , Ribociclib, Abemaciclib, Milciclib, Trilaciclib, Lerociclib, etc.), MEK inhibitors (such as Selumetinib (AZD6244), Trametinib (GSK1120212), PD0325901, U0126, Pimasertib (AS-703026), PD184352 (CI-1040), etc.), mTOR inhibitors (such as Visusertib, etc.), SHP2 inhibitors (such as RMC-4630, JAB-3068, TNO155, etc.) or a combination thereof.

[0183] In a fourth aspect, the present invention provides a use of the compound of the first aspect, its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs, or the pharmaceutical composition of the third aspect for the preparation of a method for preventing and / or treating KRAS-related diseases. G12D Drugs for diseases related to the activity or expression level of .

[0184] In another preferred embodiment, the disease is a tumor or a disorder.

[0185] In another preferred embodiment, the disease is selected from the following group: lung cancer, breast cancer, prostate cancer, esophageal cancer, colorectal cancer, bone cancer, kidney cancer, gastric cancer, liver cancer, colon cancer, melanoma, lymphoma, blood cancer, brain tumor, myeloma, soft tissue sarcoma, pancreatic cancer, skin cancer.

[0186] In a fourth aspect, the present invention provides a non-diagnostic, non-therapeutic method for inhibiting KRAS G12D A method comprising the steps of administering to a subject in need thereof an effective amount of the compound as described in the first aspect, its stereoisomers, tautomers, crystalline forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs, or administering the pharmaceutical composition as described above.

[0187] In another preferred embodiment, the subject is a mammal, preferably a human.

[0188] In a fifth aspect, the present invention provides an in vitro method for inhibiting KRAS G12D A method for inhibiting KRAS activity, comprising the steps of: contacting the compound of the first aspect, its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs, or the pharmaceutical composition as described above with a protein or cell, thereby inhibiting KRAS G12D activity.

[0189] In another preferred embodiment, the cells are selected from the group consisting of macrophages, intestinal cells (including intestinal stem cells, intestinal epithelial cells), or a combination thereof.

[0190] In another preferred embodiment, the cells are from rodents (such as mice and rats) or primates (such as humans).

[0191] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features described in detail below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be listed here one by one. DETAILED DESCRIPTION

[0192] After long and in-depth research, the inventors unexpectedly prepared a new type of KRAS G12DCompounds with selective inhibitory effects and / or better pharmacodynamic properties. On this basis, the inventors completed the present invention.

[0193] the term

[0194] In the present invention, unless otherwise specified, the terms used have the general meanings commonly known to those skilled in the art.

[0195] The term "alkyl" refers to a straight or branched chain alkane group containing 1 to 20 carbon atoms, such as 1 to 18 carbon atoms, especially 1 to 18 carbon atoms, preferably 1 to 10 carbon atoms (C1-C10), and more preferably 1 to 6 carbon atoms (C1-C6). Typical "alkyl" groups include methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, isobutyl, Pentyl, isopentyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl and the like. In the present invention, alkyl also includes substituted alkyl. "Substituted alkyl" means that one or more positions in the alkyl are substituted, especially 1-4 substituents, which can be substituted at any position. Typical substitutions include, but are not limited to, one or more of the following groups: such as hydrogen, deuterium, halogen (for example, a monohalogen substituent or a polyhalogen substituent, the latter such as a trifluoromethyl group or an alkyl group containing Cl3), cyano, nitro, oxygen (such as =O), trifluoromethyl, trifluoromethoxy, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aromatic ring, OR a SR a 、S(=O)R e 、S(=O)2R e 、P(=O)2R e 、S(=O)2OR e ,P(=O)2OR e NR b R c NR b S(=O)2R e NR b P(=O)2R e 、S(=O)2NR b R c 、P(=O)2NR b R c 、C(=O)OR d 、C(=O)R a 、C(=O)NR b R c 、OC(=O)R a 、OC(=O)NR b R c NR b C(=O)OR e ,NRd C(=O)NR b R c NR d S(=O)2NR b R c NR d P(=O)2NR b R c NR b C(=O)R a , or NR b P(=O)2R e , where R appears here a R may independently represent hydrogen, deuterium, C1-C6 alkyl, C3-C8 cycloalkyl, C2-C6 alkenyl, C3-C6 cycloalkenyl, C2-C6 alkynyl, 5-14 membered heterocyclic ring or C6-C14 aromatic ring, b 、R c and R d can independently represent hydrogen, deuterium, C1-C6 alkyl, C3-C8 cycloalkyl, 5-14 membered heterocyclic ring or C6-C14 aromatic ring, or R b and R c Together with the N atom, it can form a heterocyclic ring; R e and C-C alkyl, C-C cycloalkyl, C-C alkenyl, C-C cycloalkenyl, C-C alkynyl, 5-14 membered heterocyclic ring or C-C aromatic ring. The above typical substituents, such as alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic ring or aromatic ring, may be optionally substituted.

[0196] The term "alkylene" refers to a group formed by removing a hydrogen atom from an alkyl or substituted alkyl group, such as methylene, ethylene, propylene, isopropylene (such as ), butylene (such as ), pentylene (such as ), hexamethylene (such as ), heptylene (such as ), Etc. In addition, the term also includes a methylene group of an alkylene group (such as C1-C18 alkylene) replaced by a cycloalkylene group (such as C3-C20 cycloalkylene), for example, "C1-C18 alkylene C3-C20 cycloalkylene" or "C3-C20 cycloalkylene C1-C18 alkylene".

[0197] The term "C1-C18 alkylene C3-C20 cycloalkylene" or "C3-C20 cycloalkylene C1-C18 alkylene" has the same meaning and refers to a group formed by removing two hydrogen atoms from a cycloalkylalkyl or alkylcycloalkyl group, such as wait.

[0198] As used herein, the term "alkenyl" refers to a straight or branched hydrocarbon group containing one or more double bonds and typically having a length of 2 to 20 carbon atoms. Alkenyl is preferably C2-C6 alkenyl, more preferably C2-C4 alkenyl. Alkenyl includes, but is not limited to, vinyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, and the like. As used herein, alkenyl includes substituted alkenyl.

[0199] The term "alkynyl" refers to a straight or branched hydrocarbon group containing one or more triple bonds and typically having a length of 2 to 20 carbon atoms. Alkynyl groups are preferably C2-C6 alkynyl groups, more preferably C2-C4 alkynyl groups. Alkynyl groups include, but are not limited to, ethynyl, propynyl, and similar groups. In the present invention, alkynyl groups also include substituted alkynyl groups, and the substituents may be halo, hydroxyl, cyano, nitro, and the like.

[0200] In the present invention, the term "cycloalkyl" refers to a fully saturated cyclic hydrocarbon compound group, including 1-4 rings, each containing 3-8 carbon atoms. 20 " refers to a cycloalkyl group containing 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms. The cycloalkyl group is preferably C3-C 14 Cycloalkyl, more preferably C3-C 10 Cycloalkyl, more preferably C3-C6 monocyclic cycloalkyl, C7-C 10 Bicyclic or tricyclic cycloalkyl. "Substituted cycloalkyl" means that one or more positions in the cycloalkyl are substituted, especially 1-4 substituents, which can be substituted at any position. In the present invention, "cycloalkyl" includes substituted cycloalkyl, and typical substitutions include but are not limited to one or more of the following groups: such as hydrogen, deuterium, halogen (for example, a monohalogen substituent or a polyhalogen substituent, the latter such as trifluoromethyl or an alkyl containing Cl3), cyano, nitro, oxygen (such as =O), trifluoromethyl, trifluoromethoxy, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aromatic ring, OR a SR a 、S(=O)R e 、S(=O)2R e 、P(=O)2R e 、S(=O)2OR e 、P(=O)2OR e NR b R c NR b S(=O)2R e NR b P(=O)2R e 、S(=O)2NR b R c 、P(=O)2NRb R c 、C(=O)OR d 、C(=O)R a 、C(=O)NR b R c 、OC(=O)R a 、OC(=O)NR b R c NR b C(=O)OR e NR d C(=O)NR b R c NR d S(=O)2NR b R c NR d P(=O)2NR b R c NR b C(=O)R a , or NR b P(=O)2R e , where R appears here a R may independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic ring or aromatic ring, b 、R c and R d can independently represent hydrogen, deuterium, alkyl, cycloalkyl, heterocyclic or aromatic ring, or R b and R c Together with the N atom, it can form a heterocyclic ring; R e Can independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aromatic ring.Above-mentioned typical substituent can be optionally substituted.Typical substitution also comprises spirocycle, bridged ring or condensed ring substituent, especially spirocycloalkyl, spirocycloalkenyl, spirocyclic heterocycle (not including heteroaromatic ring), bridged ring alkyl, bridged ring alkenyl, bridged ring heterocycle (not including heteroaromatic ring), condensed ring alkyl, condensed ring alkenyl, condensed ring heterocyclic radical or condensed ring aromatic ring radical, above-mentioned cycloalkyl, cycloalkenyl, heterocyclic radical and heterocyclic aromatic radical can be optionally substituted.The example of cycloalkyl includes but is not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl etc.

[0201] The term "C3-C20 cycloalkylene" refers to a group formed by removing two hydrogen atoms from a cycloalkyl group, such as: wait.

[0202] As used herein, the term "heterocyclyl" refers to a fully saturated or partially unsaturated cyclic group (including but not limited to a 3-7 membered monocyclic, 4-7 membered monocyclic, 6-11 membered bicyclic, or 8-16 membered tricyclic or polycyclic ring system) wherein at least one heteroatom is present in the ring containing at least one carbon atom. The term "4-20 membered heterocyclyl" refers to a heterocyclyl group containing 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 ring atoms. "Heterocyclyl" has the same meaning as "saturated or unsaturated heterocyclyl." "Heterocyclyl" is preferably a 4-14 membered heterocyclyl (including but not limited to a 4-6 membered monocyclic, 7-10 membered bicyclic, or 8-14 membered tricyclic or polycyclic ring system), more preferably a 4-12 membered heterocyclyl, more preferably a 4-10 membered heterocyclyl, such as a 4-6 membered monocyclic heterocyclyl, a 7-10 membered bicyclic or tricyclic heterocyclyl, more preferably a 4-8 membered heterocyclyl, more preferably a 4-6 membered heterocyclyl. Each heterocyclic ring containing a heteroatom may have 1, 2, 3 or 4 heteroatoms selected from nitrogen atoms, oxygen atoms or sulfur atoms, wherein the nitrogen atoms or sulfur atoms may be oxidized and the nitrogen atoms may be quaternized. The heterocyclic group may be attached to any heteroatom or carbon atom residue of the ring or ring system molecule, preferably to an N or C atom of the ring or ring system molecule. Typical monocyclic heterocycles include, but are not limited to, azetidinyl, pyrrolidinyl, oxetanyl, pyrazolinyl, imidazolinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, hexahydroazepinyl, 4-piperidonyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1,3-dioxanyl, and tetrahydro-1,1-dioxythiophene, and the like. Polycyclic heterocyclic groups include spirocyclic, fused and bridged heterocyclic groups; wherein the spirocyclic, fused and bridged heterocyclic groups are optionally connected to other groups through single bonds, or further connected to other cycloalkyl, heterocyclic, aryl and heteroaryl groups through any two or more atoms on the ring; the heterocyclic group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more groups independently selected from alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, halogen, amino, nitro, hydroxyl, thiol, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylthio, oxo, carboxyl and carboxylate.

[0203] The term "C4-C20 heterocyclylene" refers to a group formed by removing two hydrogen atoms from a heterocyclyl group, such as: wait.

[0204] In the present invention, the term "aryl" refers to an aromatic cyclic hydrocarbon group having 1-5 rings, especially a monocyclic and bicyclic group. 14 "Aryl" refers to an aromatic cyclic hydrocarbon compound group containing 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring carbon atoms. Aryl includes phenyl, biphenyl or naphthyl. Where there are two or more aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group can be connected by a single bond (such as biphenyl) or fused (such as naphthalene, anthracene, etc.). "Substituted aryl" means that one or more positions in the aryl group are substituted, especially 1-3 substituents, which can be substituted at any position. Typical substitutions include, but are not limited to, one or more of the following groups: hydrogen, deuterium, halogen (for example, a monohalogen substituent or a polyhalogen substituent, the latter such as trifluoromethyl or an alkyl group containing Cl3), cyano, nitro, oxo (such as =O), trifluoromethyl, trifluoromethoxy, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aromatic ring, OR a SR a 、S(=O)R e 、S(=O)2R e 、P(=O)2R e 、S(=O)2OR e ,P(=O)2OR e NR b R c NR b S(=O)2R e NR b P(=O)2R e 、S(=O)2NR b R c 、P(=O)2NR b R c 、C(=O)OR d 、C(=O)R a 、C(=O)NR b R c 、OC(=O)R a 、OC(=O)NR b R c NR b C(=O)OR e ,NR d C(=O)NR b R c NR d S(=O)2NR b R c NR d P(=O)2NR b R c NR b C(=O)R a , or NRb P(=O)2R e , where R appears here a R may independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic ring or aromatic ring, b 、R c and R d can independently represent hydrogen, deuterium, alkyl, cycloalkyl, heterocyclic or aromatic ring, or R b and R c Together with the N atom, it can form a heterocyclic ring; R e The alkyl radicals may independently represent hydrogen, deuterium, an alkyl radical, a cycloalkyl radical, an alkenyl radical, a cycloalkenyl radical, an alkynyl radical, a heterocyclic ring, or an aromatic ring. The aforementioned typical substituents may optionally be substituted. Typical substitutions also include fused ring substituents, particularly fused ring alkyl radicals, fused ring alkenyl radicals, fused ring heterocyclic radicals, or fused ring aromatic radicals, wherein the aforementioned cycloalkyl radicals, cycloalkenyl radicals, heterocyclic radicals, and heterocyclic aromatic radicals may optionally be substituted.

[0205] The term "heteroaryl" refers to an aromatic cyclic hydrocarbon group containing 1-4 heteroatoms, wherein the heteroatoms are selected from oxygen, nitrogen and sulfur. Among them, "5-14 membered heteroaryl" refers to a heteroaromatic system containing 1-4 heteroatoms and 5-14 ring atoms. The heteroaryl group is preferably a 5- to 10-membered ring, more preferably a 5- or 6-membered ring, such as pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl and tetrazolyl. "Heteroaryl" may be substituted or unsubstituted. When substituted, the substituents are preferably one or more groups independently selected from alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, halogen, amino, nitro, hydroxy, mercapto, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylthio, oxo, carboxyl and carboxylate.

[0206] In the present invention, the term "alkoxy" refers to a linear or branched alkoxy group, including alkyl-O-, alkyl-O-alkyl, wherein "C1-C 18 "Alkoxy" refers to a straight or branched chain alkoxy group having 1 to 18 carbon atoms, including C1-C 18 Alkyl-O-, -C1-C6 alkyl-O-C1-C6 alkyl, including but not limited to methoxy, ethoxy, propoxy, isopropoxy and butoxy, etc. Preferably it is C1-C8 alkoxy, more preferably C1-C6 alkoxy.

[0207] In the present invention, the term "cycloalkyloxy" refers to cycloalkyl-O-, wherein "C3-C 20 "Cycloalkyloxy" refers to C3-C 20 Cycloalkyl-O-, wherein C3-C 20 Cycloalkyl is as defined above.

[0208] In the present invention, the term "heterocyclyloxy" refers to heterocyclyl-O-, wherein "4-20 membered heterocyclyloxy" refers to 4-20 membered heterocyclyl-O-, wherein the definition of 4-20 membered heterocyclyl is as described above.

[0209] In the present invention, the term "C1-C 18 "Alkyleneoxy" refers to "C1-C 18 Alkoxy is a group formed by removing a hydrogen atom.

[0210] In the present invention, the term "halogen" or "halo" refers to chlorine, bromine, fluorine, and iodine.

[0211] In the present invention, the term "halogenated" means substituted with halogen.

[0212] In the present invention, the term "deuterated" means substituted with deuterium.

[0213] In the present invention, the term "hydroxyl" refers to a group with the structure OH.

[0214] In the present invention, the term "nitro" refers to a group having the structure NO2.

[0215] In the present invention, the term "cyano" refers to a group having the structure CN.

[0216] In the present invention, the term "ester group" refers to a group having the structure -COOR, wherein R represents hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle. The ester group is preferably -COO C1-C6 alkyl.

[0217] The term "amine group" refers to a group having the structure -NRR', where R and R' can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above. R and R' can be the same or different in the dialkylamine moiety. The amine group is preferably NH2, NH C1-C6 alkyl, or N(C1-C6 alkyl)2.

[0218] The term "amido" refers to a group having the structure -CONRR' or -NRCOR', wherein R and R' can each independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above. The amide group is preferably CONH2, NHCO(C1-C6 alkyl), NHCO(C3-C6 cycloalkyl).

[0219] The term "sulfonamide" refers to a group having the structure -S2ONRR' or -NRSO2R', wherein R and R' can each independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above. Sulfonamide is preferably SO2NH2, NHSO2(C1-C6 alkyl), NHSO2(C3-C6 cycloalkyl).

[0220] The term "sulfone" refers to a group having the structure -SO2R, wherein R can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above.

[0221] The term "urea group" refers to a group having the structure -NRCONR'R", wherein R, R' and R" can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above. R, R' and R" can be the same or different in the dialkylamine moiety.

[0222] The term "alkylaminoalkyl" refers to a group having the structure -RNHR', where R and R' can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above. R and R' can be the same or different.

[0223] The term "dialkylaminoalkyl" refers to a group having the structure -RNHR'R", wherein R, R' and R" can independently represent alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above. R, R' and R" can be the same or different in the dialkylamino moiety.

[0224] The term "heterocyclylalkyl" refers to a group having the structure -RR', wherein R can independently represent alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl; and R' represents a heterocycle or a substituted heterocycle.

[0225] In the present invention, the term "substituted" refers to the replacement of one or more hydrogen atoms on a specific group with a specific substituent. The specific substituent is the substituent described above or the substituent appearing in the examples. Unless otherwise specified, a substituted group may have a substituent selected from the specific group at any substitutable position of the group, and the substituent may be the same or different at each position. It will be understood by those skilled in the art that the combinations of substituents contemplated by the present invention are those that are stable or chemically feasible. The substituents include, but are not limited to, halogen, hydroxyl, cyano, carboxyl (-COOH), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 12-membered heterocyclyl, aryl, heteroaryl, C1-C8 aldehyde, C2-C10 acyl, C2-C10 ester, amine, C1-C6 alkoxy, C1-C10 sulfonyl, and C1-C6 urea.

[0226] Unless otherwise stated, any heteroatom with insufficient valence is assumed to have sufficient hydrogen atoms to complete the valence.

[0227] When a substituent is non-terminal, it is a substituent of the corresponding group, for example, alkyl for alkylene, cycloalkyl for cycloalkylene, heterocyclyl for heterocyclylene, alkoxy for alkyleneoxy, and the like.

[0228] In the present invention, a plurality refers to 2, 3, 4, or 5.

[0229] Active ingredient

[0230] As used herein, "compounds of the present invention" refers to compounds represented by Formula I, and also includes stereoisomers or optical isomers, pharmaceutically acceptable salts, prodrugs or solvates of the compounds of Formula I.

[0231] The salts that may be formed by the compounds of the present invention also fall within the scope of the present invention. Unless otherwise indicated, the compounds of the present invention are understood to include their salts. The term "salt" as used herein refers to acidic or basic salts formed with inorganic or organic acids and bases. In addition, when the compound of the present invention contains a basic fragment, it includes but is not limited to pyridine or imidazole, and contains an acidic fragment, including but not limited to carboxylic acid, the zwitterions ("inner salts") that may be formed are included within the scope of the term "salt". Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful, for example, in separation or purification steps during the preparation process. The compounds of the present invention may form salts, for example, compound I reacts with a certain amount, such as an equivalent amount, of an acid or base, salts out in a medium, or is obtained by freeze-drying in an aqueous solution.

[0232] The compounds of the present invention contain basic moieties, including but not limited to amines or pyridine or imidazole rings, which may form salts with organic or inorganic acids. Typical acids that can form salts include acetates (e.g., acetic acid or trihaloacetic acid, such as trifluoroacetic acid), adipates, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphor, camphorsulfonate, cyclopentanepropionate, diglycolate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide,

[0014] Examples of the present invention include, for example, hydroxyethylsulfonates, lactates, maleates, methanesulfonates, naphthalenesulfonates (e.g., 2-naphthalenesulfonate), nicotinates, nitrates, oxalates, pectinates, persulfates, phenylpropionates (e.g., 3-phenylpropionate), phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates (e.g., with sulfuric acid), sulfonates, tartrates, thiocyanates, toluenesulfonates such as p-toluenesulfonate, dodecanoates, and the like.

[0233] Certain compounds of the present invention may contain acidic moieties, including but not limited to carboxylic acids, which may form salts with various organic or inorganic bases. Typical base-forming salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, and salts formed with organic bases (e.g., organic amines), such as benzathine, dicyclohexylamine, hepamine (salt formed with N,N-di(dehydroabietyl)ethylenediamine), N-methyl-D-glucamine, N-methyl-D-glucamide, tert-butylamine, and salts formed with amino acids such as arginine, lysine, and the like. Basic nitrogen-containing groups can react with halide quaternary ammonium salts, such as small molecular alkyl halides (such as chlorides, bromides and iodides of methyl, ethyl, propyl and butyl), dialkyl sulfates (such as dimethyl sulfate, diethyl sulfate, dibutyl sulfate and dipentyl sulfate), long chain halides (such as chlorides, bromides and iodides of decyl, dodecyl, tetradecyl and tetradecyl), aralkyl halides (such as benzyl and phenyl bromide), etc.

[0234] Prodrugs and solvates of the compounds of the present invention are also encompassed. The term "prodrug" herein refers to a compound that undergoes chemical transformation via metabolic or chemical processes to produce a compound, salt, or solvate of the present invention when used to treat a relevant disease. The compounds of the present invention include solvates, such as hydrates.

[0235] The compounds, salts or solvates of the present invention may exist in tautomeric forms (such as amides and imino ethers). All such tautomers are part of the present invention.

[0236] All stereoisomers of the compounds (e.g., those that may exist due to asymmetric carbon atoms for various substitutions), including enantiomeric and diastereomeric forms, are contemplated by the present invention. Individual stereoisomers of the compounds of the present invention may not exist with other isomers (e.g., as a pure or substantially pure optical isomer having a particular activity), or may be mixtures, such as racemates, or mixtures with all other stereoisomers or portions thereof. The chiral centers of the present invention have either S or R configurations, as defined by the 1974 recommendations of the International Union of Pure and Applied Chemistry (IUPAC). Racemic forms can be resolved by physical methods, such as fractional crystallization, or by crystallization of diastereomers derived from them, or by separation by chiral column chromatography. Individual optical isomers can be obtained from the racemate by suitable methods, including but not limited to conventional methods, such as salt formation with an optically active acid followed by recrystallization.

[0237] The compounds of the present invention, obtained by sequential preparation, isolation, and purification, are described in the text to a concentration of 90% or greater by weight, for example, 95% or greater, or 99% or greater ("very pure" compounds). Such "very pure" compounds of the present invention are also considered part of the present invention.

[0238] All configurational isomers of the compounds of the present invention are encompassed, whether in mixture, pure or very pure form. The definition of the compounds of the present invention includes both cis (Z) and trans (E) olefin isomers, as well as cis and trans isomers of carbocyclic and heterocyclic rings.

[0239] Throughout the specification, groups and substituents may be chosen to provide stable fragments and compounds.

[0240] Specific functional groups and chemical term definitions are detailed below. For the purposes of this invention, chemical elements are referred to as Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th The definitions of specific functional groups are consistent with those in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito, 1999, which is incorporated by reference in its entirety.

[0241] Certain compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention encompasses all compounds, including their cis and trans isomers, R and S enantiomers, diastereomers, (D) isomers, (L) isomers, racemic mixtures, and other mixtures. Additionally, asymmetric carbon atoms may represent substituents, such as alkyl groups. All isomers and mixtures thereof are encompassed by the present invention.

[0242] According to the present invention, mixtures of isomers can contain various ratios of isomers. For example, mixtures containing only two isomers can have the following ratios: 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0. All ratios of isomers are within the scope of the present invention. Similar ratios, as well as ratios for more complex mixtures of isomers, are readily understood by those skilled in the art and are also within the scope of the present invention.

[0243] The present invention also includes isotopically labeled compounds that are equivalent to the original compounds disclosed herein. However, in practice, it is common for one or more atoms to be replaced by atoms having a different atomic mass or mass number. Examples of isotopes of the compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine isotopes, such as 2 H. 3 H. 13 C. 11 C. 14 C. 15 N. 18 O. 17 O. 31 P. 32 P. 35 S. 18 F and 36 The compounds of the present invention, or enantiomers, diastereomers, isomers, or pharmaceutically acceptable salts or solvates thereof, which contain isotopes or other isotopic atoms of the above compounds are within the scope of the present invention. Certain isotopically labeled compounds of the present invention, such as 3 H and 14 Radioisotopes of C are also included and are useful in tissue distribution experiments of drugs and substrates. 3 H and carbon-14, i.e. 14 C, their preparation and detection are relatively easy. It is the first choice among isotopes. In addition, heavier isotope substitutions such as deuterium, i.e. 2H, due to its excellent metabolic stability, has advantages in certain therapeutics, such as increasing half-life in vivo or reducing dosage, and therefore, may be preferred in some cases. Isotopically labeled compounds can be prepared using conventional methods by replacing readily available isotopically labeled reagents with non-isotopic reagents using the protocols disclosed in the examples.

[0244] If a synthesis of a specific enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, followed by separation of the resulting diastereomeric mixture and removal of the chiral auxiliary to obtain the pure enantiomer. Alternatively, if the molecule contains a basic functional group, such as an amino acid, or an acidic functional group, such as a carboxyl group, diastereomeric salts can be formed with a suitable optically active acid or base, followed by separation by conventional means such as fractional crystallization or chromatography to obtain the pure enantiomer.

[0245] As described herein, the compounds of the present invention may be substituted with any number of substituents or functional groups to broaden their scope. Generally, the term "substituted," whether preceded or followed by the term "optionally," in formulas of the present invention including substituents, refers to the replacement of a hydrogen radical with a substituent of the specified structure. When multiple positions in a particular structure are substituted with multiple substituents of the specified structure, the substituents may be the same or different at each position. As used herein, the term "substituted" includes all permissible substitutions in organic compounds. Broadly speaking, permissible substituents include acyclic, cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic organic compounds. For example, heteroatoms such as nitrogen may be substituted with hydrogen or any of the permissible organic compounds described above to supplement their valences. Furthermore, the present invention is not intended to limit the permissible substitutions in any way to organic compounds. The present invention recognizes that combinations of substituents and variables are advantageous for providing stable compounds for the treatment of diseases, such as infectious or proliferative diseases. As used herein, the term "stable" refers to compounds that are stable and maintain the structural integrity of the compound over a period of time sufficient to be detected, preferably over a period of time sufficient to be effective, as used herein for the purposes described above.

[0246] The metabolites of the compounds and pharmaceutically acceptable salts thereof involved in this application, as well as prodrugs that can be converted into the structures of the compounds and pharmaceutically acceptable salts involved in this application in vivo, are also included in the claims of this application. In the present invention, the term "prodrug" refers to a compound that is inactive or less active in vitro after the drug is modified by chemical structure to introduce an easy-leaving group, but releases the active drug in vivo through conversion with the participation of enzymes (such as hydrolases, oxidases, etc.) or non-enzymes (such as pH, light, radiation, etc.) to exert its pharmacological effect. The prodrugs include (but are not limited to): carboxylates, phosphates, carbamates, carbonates, etc. The structure of the easy-leaving group is (but is not limited to):

[0247] Preparation method

[0248] The following describes in more detail the preparation methods of the compounds of formula (A0) of the present invention, but these specific methods do not limit the present invention in any way. The compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art. Such combinations can be easily performed by those skilled in the art.

[0249] Typically, the preparation process of the compound of the present invention is as follows, wherein the raw materials and reagents used can be purchased through commercial channels unless otherwise specified.

[0250] Preferably, the compound of the present invention is prepared by the following method (taking Formula IA as an example):

[0251] (i) reacting a compound of formula V-1 with a compound of formula V-2 in an inert solvent in the presence of a base, with or without a Pd catalyst, and with or without a condensing agent to obtain a compound of formula V-3;

[0252] (ii) reacting a compound of formula V-3 with a compound of formula V-4 in an inert solvent in the presence of a base with or without a Pd catalyst to obtain a compound of formula V-5;

[0253] (iii) reacting the compound of formula V-5 with the compound of formula V-6 in an inert solvent in the presence of a base and a Pd catalyst to obtain a compound of formula V-7;

[0254] (iv) removing the protecting group PG1 from the compound of formula V-7 under the action of an acid (such as TFA, HCl, etc.) or Pd-catalyzed hydrogenation to obtain a compound of formula (IA);

[0255] Where,

[0256] X1, X2 and X3 are each independently selected from: OH, halogen, OTf, OTs or OMs;

[0257] PG1 is selected from: Boc, Cbz, or Bn;

[0258] LG1 is selected from: -B(OH)2, -B(KBF3), -Sn( n Bu)3,

[0259] R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7、R 8 、R 9 , U, X, Y, Z, W and n are defined as above.

[0260] Pharmaceutical compositions and methods of administration

[0261] The pharmaceutical composition of the present invention is used to prevent and / or treat the following diseases: inflammation, cancer, cardiovascular disease, infection, immune disease, and metabolic disease.

[0262] The compounds of general formula (A0) can be used in combination with other drugs known to treat or improve similar conditions. When administered in combination, the administration route and dosage of the original drug can remain unchanged, while the compound of formula I is administered simultaneously or subsequently. When the compound of formula (A0) is administered simultaneously with one or more other drugs, a pharmaceutical composition containing one or more known drugs and the compound of formula I can be preferably used. Drug combination also includes administering the compound of formula (A0) and one or more other known drugs during overlapping time periods. When the compound of formula (A0) is administered in combination with one or more other drugs, the dosage of the compound of formula I or the known drug may be lower than the dosage of each drug administered alone.

[0263] Drugs or active ingredients that can be used in combination with the compound of formula (A0) include but are not limited to: PD-1 inhibitors (such as nivolumab, pembrolizumab, pidilizumab, cemiplimab, JS-001, SHR-120, BGB-A317, IBI-308, GLS-010, GB-226, STW204, HX008, HLX10, BAT 1306, AK105, LZM 009 or biosimilars of the above drugs, etc.), PD-L1 inhibitors (such as durvalumab, atezolizumab, avelumab, CS1001, KN035, HLX20, SHR-1316, BGB-A333, JS003, CS1003, KL-A167, F 520, GR1405, MSB2311 or biosimilars of the above drugs, etc.), CD20 antibodies (such as rituximab, obinutuzumab, ofatumumab, veltuzumab, tositumomab, 131I-tositumomab, ibritumomab, 90Y-ibritumomab, 90In-ibritumomab, ibritumomabtiuxetan, etc.), CD47 antibodies (such as Hu5F9-G4, CC-90002, TTI-621, TTI-622, OSE-172, SRF-231, ALX-148, NI-1701, SHR-1603, IBI188, IMM01), ALK inhibitors (such as Ceritinib, Alectinib, Brigatinib, Lorlatinib, Ocatinib), PI3K inhibitors (such as Idelalisib, Duvelisib, Dactolisib, Taselisib, Bimiralisib, Omip alisib, Buparlisib, etc.), BTK inhibitors (such as Ibrutinib, Tirabrutinib, Acalabrutinib, Zanubrutinib, Vecabrutinib, etc.), EGFR inhibitors (such as Afatinib, Gefitinib, Erlotinib, Lapatinib, Dacomitinib, Icotinib, Canertinib, Sapitinib, Naquotinib, Pyrotinib, Rociletinib, Osimertinib, etc.), VEGFR inhibitors (such as Sorafenib, Pazopanib, Regorafenib, Sitravatinib, Ningetinib, Cabozantinib, Sunitinib, Donafenib, etc.), HDAC inhibitors (such as Givinostat, Tucidinostat, Vorinostat, Fimepinostat, Droxinostat, Entinostat, Dacinostat, Quisinostat, Tacedinaline, etc.), CDK inhibitors (such as Palbociclib , Ribociclib, Abemaciclib, Milciclib, Trilaciclib, Lerociclib, etc.), MEK inhibitors (such as Selumetinib (AZD6244), Trametinib (GSK1120212), PD0325901, U0126, Pimasertib (AS-703026), PD184352 (CI-1040), etc.), mTOR inhibitors (such as Visusertib, etc.), SHP2 inhibitors (such as RMC-4630, JAB-3068, TNO155, etc.), or combinations thereof. The dosage forms of the pharmaceutical composition of the present invention include (but are not limited to): injection, tablet, capsule, aerosol, suppository, film, pill, external use ointment, controlled release or sustained release or nanoformulation.

[0264] The pharmaceutical composition of the present invention comprises a safe and effective amount of a compound of the present invention or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable excipient or carrier. "Safe and effective amount" means an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably 10-1000 mg of the compound of the present invention per dose. Preferably, "one dose" is one capsule or tablet.

[0265] "Pharmaceutically acceptable carriers" refer to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0266] There is no particular limitation on the administration of the compound or pharmaceutical composition of the present invention. Representative administration routes include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

[0267] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0268] Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compounds in such compositions can be delayed in a certain portion of the digestive tract. Examples of useful encapsulating components are polymeric substances and waxes. If desired, the active compound can also be microencapsulated with one or more of the above-mentioned excipients.

[0269] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, or mixtures thereof.

[0270] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0271] Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0272] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0273] Dosage forms for topical administration of the compounds of this invention include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required.

[0274] The treatment method of the present invention can be used alone or in combination with other treatment methods or therapeutic drugs.

[0275] When using a pharmaceutical composition, a safe and effective amount of the compound of the present invention is administered to a mammal (e.g., a human) in need of treatment, wherein the dosage is a pharmaceutically effective dosage. For a 60 kg human, the daily dosage is generally 1 to 2000 mg, preferably 50 to 1000 mg. Of course, the specific dosage will also take into account factors such as the route of administration and the patient's health condition, all of which are within the skill of a skilled physician.

[0276] The present invention also provides a method for preparing a pharmaceutical composition, comprising the steps of: mixing a pharmaceutically acceptable carrier with the compound of general formula (A0) of the present invention or its crystal form, pharmaceutically acceptable salt, hydrate or solvate, thereby forming a pharmaceutical composition.

[0277] The present invention also provides a method of treating a subject in need of treatment, comprising the steps of administering the compound of formula (A0) of the present invention, or its crystal form, pharmaceutically acceptable salt, hydrate or solvate, or administering the pharmaceutical composition of the present invention to selectively inhibit KRAS G12D .

[0278] Compared with the prior art, the present invention has the following main advantages:

[0279] (1) The compound has an effect on KRAS G12D It has a good selective inhibitory effect;

[0280] (2) The compound has better pharmacodynamics and pharmacokinetic properties and lower toxic side effects.

[0281] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit the scope of the present invention. The experimental methods in the following examples, for which specific conditions are not specified, were generally performed under conventional conditions such as those described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or according to the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0282] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those familiar to those skilled in the art. Furthermore, any methods and materials similar or equivalent to those described herein can be applied to the methods of the present invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0283] The structures of the compounds of the present invention are confirmed by nuclear magnetic resonance (NMR) and liquid chromatography-mass spectrometry (LC-MS).

[0284] NMR was measured using a Bruker AVANCE-400 nuclear magnetic spectrometer. The measurement solvents included deuterated dimethyl sulfoxide (DMSO-d6), deuterated acetone (CD3COCD3), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). Tetramethylsilane (TMS) was used as the internal standard, and chemical shifts were measured in parts per million (ppm).

[0285] Liquid chromatography-mass spectrometry (LC-MS) was performed using a Waters SQD2 mass spectrometer, and HPLC was performed using an Agilent 1100 high pressure chromatograph (Microsorb 5 micron C18 100 x 3.0 mm column).

[0286] TLC silica gel plates used were Qingdao GF254 silica gel plates, with a diameter of 0.15-0.20 mm for TLC and 0.4-0.5 mm for preparative thin layer chromatography. Column chromatography generally used Qingdao 200-300 mesh silica gel as a carrier.

[0287] The starting materials in the examples of the present invention are all known and commercially available, or can be synthesized using or according to literature data reported in the art.

[0288] Unless otherwise specified, all reactions of the present invention are carried out under the protection of dry inert gas (such as nitrogen or argon) with continuous magnetic stirring, and the reaction temperatures are all degrees Celsius.

[0289] Example

[0290] Preparation of Intermediate 1-1(3-(Methoxymethyl)tetrahydro-1H-bis-fused pyrrolidin-7a(5H)-yl)methanol

[0291] Step 1: Preparation of 1-benzyl 2-methyl 2-(but-3-en-1-yl)pyrroline-1,2-dicarboxylate

[0292] Under nitrogen, a solution of 1-benzyl 2-methyl (S)-pyrroline-1,2-dicarboxylate (50.0 g, 190 mmol, 1.00 eq) in THF (100 mL) was added dropwise to LiHMDS (1.00 M, 285 mL, 1.50 eq) at -70°C. The resulting reaction solution was allowed to react at -70°C for 2 h, followed by the dropwise addition of 4-bromobut-1-ene (51.2 g, 380 mmol, 38.6 mL, 2.00 eq). The resulting reaction solution was warmed to 25°C and allowed to react for 16 h. The mixture was then quenched with saturated aqueous NH4Cl (200 mL) and extracted with EtOAc (100 mL x 3). The combined organic phases were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to yield the desired product (38.0 g, 120 mmol, 63.1% yield).

[0293] 1 H NMR(400MHz, CDCl3)δ7.33(m,5H)5.77(m,1H)5.07(m,4H)3.72(m,3H)3.48(m,2H)2.01(m,8H)

[0294] Step 2: Preparation of 1-benzyl 2-methyl 2-(2-(epoxypropane-2-yl)ethyl)pyrroline-1,2-dicarboxylate

[0295] To a solution of 1-benzyl 2-methyl 2-(but-3-en-1-yl)pyrroline-1,2-dicarboxylate (37.5 g, 118 mmol, 1.00 eq) in DCM (650 mL) was added portionwise m-CPBA (60.0 g, 295 mmol, 85.0% purity, 2.50 eq) at 0°C. The resulting reaction mixture was reacted at 25°C for 16 h and then washed with saturated NaSO (300 mL x 3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was isolated by silica gel column chromatography to obtain the desired product (29.0 g, 87.0 mmol, 73.6% yield).

[0296] 1 H NMR (400MHz, CDCl3) δ7.33 (br d, J = 7.88Hz, 5H) 5.11 (m, 2H) 3.70 (m, 3H) 3.48 (m, 2H) 2.73 (m, 2H) 2.36 (m, 2H) 1.98 (m, 5H) 1.50 (m, 2H)

[0297] Step 3: Preparation of 3-(hydroxymethyl)tetrahydro-1H-bis-fused pyrrolidine-7a(5H)-methyl carboxylate

[0298] To a solution of 1-benzyl 2-methyl 2-(2-(epoxypropan-2-yl)ethyl)pyrroline-1,2-dicarboxylate (28.0 g, 84.0 mmol, 1.00 eq) in MeOH (600 mL) was added Pd / C (6.00 g, 10.0% wt). Under a hydrogen atmosphere, the reaction was allowed to react at 25°C for 16 h and then filtered. The filtrate was concentrated under reduced pressure to afford the desired product (16.8 g). This product was used directly in the next reaction without purification.

[0299] 3-(Hydroxymethyl)tetrahydro-1H-bis-fused pyrrolidine-7a(5H)-carboxylic acid methyl ester was subjected to chiral resolution to give cis-3-(hydroxymethyl)tetrahydro-1H-bis-fused pyrrolidine-7a(5H)-carboxylic acid methyl ester and trans-3-(hydroxymethyl)tetrahydro-1H-bis-fused pyrrolidine-7a(5H)-carboxylic acid methyl ester.

[0300] Step 4: Preparation of 3-(methoxymethyl)tetrahydro-1H-bis-fused pyrrolidine-7a(5H)-formic acid methyl ester

[0301] Under nitrogen, NaH (602 mg, 15.1 mmol, 60.0% wt, 3.00 eq) was added to a solution of methyl 3-(hydroxymethyl)tetrahydro-1H-bis-fused pyrrolidine-7a(5H)-carboxylate (1.00 g, 5.02 mmol, 1.00 eq) in THF (20 mL) at 0°C. The reaction was allowed to react at 25°C for 0.5 h, followed by the addition of MeI (1.42 g, 10.0 mmol, 625 uL, 2.00 eq). The resulting reaction was allowed to react at 25°C for 3 h, then quenched with H2O (10 mL) at 0°C and extracted with EtOAc (30 mL x 2). The combined organic phases were dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was isolated by silica gel column chromatography to yield the desired product (1.0 g, 1.88 mmol, 37.5% yield).

[0302] 1 H NMR (400MHz, CDCl3) δ3.66-3.72(m,3H)3.30-3.33(m,3H)2.22-2.43(m,1H)1.83-2.12(m,6H)1.56-1.72(m,1H).

[0303] Cis-3-(hydroxymethyl)tetrahydro-1H-bis-fused pyrrolidine-7a(5H)-carboxylic acid methyl ester and trans-3-(hydroxymethyl)tetrahydro-1H-bis-fused pyrrolidine-7a(5H)-carboxylic acid methyl ester were used as starting materials to obtain cis-3-(methoxymethyl)tetrahydro-1H-bis-fused pyrrolidine-7a(5H)-carboxylic acid methyl ester and trans-3-(methoxymethyl)tetrahydro-1H-bis-fused pyrrolidine-7a(5H)-carboxylic acid methyl ester, respectively.

[0304] Step 5: Preparation of (3-(methoxymethyl)tetrahydro-1H-bis-fused pyrrolidin-7a(5H)-yl)methanol

[0305] Under nitrogen, LiAlH₄ (356 mg, 9.38 mmol, 2.00 eq) was added to a solution of methyl 3-(methoxymethyl)tetrahydro-1H-bis-fused pyrrolidine-7a(5H)-carboxylate (1.00 g, 4.69 mmol, 1.00 eq) in THF (10 mL) at 0°C. The reaction mixture was allowed to react at 25°C for 1 h. H₂O (10 mL), 15% NaOH (10 mL), and H₂O (30 mL) were then added sequentially at 0°C, followed by extraction with EtOAc (50 mL x 2). The combined organic phases were dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was isolated by silica gel column chromatography to yield the desired product (1.1 g).

[0306] LC-MS: m / z 186 (M+H) + . 1H NMR (400MHz, CDCl3) δ4.39 (dd, J=10.54, 9.03Hz, 1H) 4.26 (br d,J=6.53Hz,1H)3.97-4.06(m,1H)3.80-3.96(m,2H)3.68-3.76(m,2H)3.50(s,3H)2.04-2.40(m,6H)1.78-1.93(m,2H)

[0307] The following compounds were synthesized using the same synthetic method as intermediate 1-1 with different starting materials:

[0308] Intermediate 1-1A and Intermediate 1-1B cis-(3-(methoxymethyl)tetrahydro-1H-bis-fused pyrrolidin-7a(5H)-yl)methanol and trans-(3-(methoxymethyl)tetrahydro-1H-bis-fused pyrrolidin-7a(5H)-yl)methanol

[0309] Intermediate 1-1A

[0310] LC-MS: m / z 186 (M+H) + .

[0311] Intermediate 1-1B

[0312] LC-MS: m / z 186 (M+H) + .

[0313] Intermediate 1-2 (3-((ethoxy)methyl)tetrahydro-1H-bis-fused pyrrolidin-7a(5H)-yl)methanol

[0314] LC-MS: m / z 200 (M+H) + .

[0315] Intermediate 1-3 (3-((isopropoxy)methyl)tetrahydro-1H-bis-fused pyrrolidin-7a(5H)-yl)methanol

[0316] LC-MS: m / z 214 (M+H) + .

[0317] Intermediate 1-4 (3-((cyclopropylmethoxy)methyl)tetrahydro-1H-bis-fused pyrrolidin-7a(5H)-yl)methanol

[0318] LC-MS: m / z 226 (M+H) + .

[0319] Intermediate 1-5 (3-(cyclopropyloxymethyl)tetrahydro-1H-bis-fused pyrrolidin-7a(5H)-yl)methanol

[0320] LC-MS: m / z 212 (M+H) + .

[0321] Intermediate 1-6 ((2R)-2-fluoro-5-(methoxymethyl)tetrahydro-1H-bis-fused pyrrolidin-7a(5H)-yl)methanol

[0322] LC-MS: m / z 204 (M+H) + .

[0323] Intermediate 1-7 ((2R)-2-fluoro-5-(cyclopropyloxymethyl)tetrahydro-1H-bis-fused pyrrolidin-7a(5H)-yl)methanol

[0324] LC-MS: m / z 230 (M+H) + .

[0325] Preparation of Intermediate 1-8 (Dihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methanol

[0326] Step 1: Preparation of (1-((Benzyloxy)methyl)cyclopropyl)methanol

[0327] To a solution of cyclopropane-1,1-dimethanol (25.0 g, 245 mmol, 1.00 eq) in THF (500 mL) at 0°C was added NaH (9.79 g, 245 mmol, 60.0% wt, 1.00 eq). The mixture was stirred at 25°C for 30 min, followed by the addition of BnBr (41.9 g, 245 mmol, 29.1 mL, 1.00 eq). The resulting reaction mixture was allowed to react at 25°C for 18 h, then quenched with saturated aqueous NH4Cl (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic phases were washed with saturated brine (20 mL x 3), dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was isolated by silica gel column chromatography to yield the desired product (26.00 g, 108 mmol, 44.1% yield).

[0328] 1 H NMR(400MHz, CDCl3)δ7.35(s,5H),4.56(s,2H),3.58(s,2H),3.47(s,2H),0.64-0.44(m,4H)

[0329] Step 2: Preparation of (((1-(bromomethyl)cyclopropyl)methoxy)methyl)benzene

[0330] To a solution of (1-((benzyloxy)methyl)cyclopropyl)methanol (26.0 g, 135 mmol, 1.00 eq) in DCM (300 mL) at 0°C were added PPh3 (39.0 g, 149 mmol, 1.10 eq) and NBS (26.5 g, 148 mmol, 1.10 eq). The reaction mixture was stirred at 25°C for 16 h and then concentrated under reduced pressure. The residue was isolated by silica gel column chromatography to obtain the desired product (24.0 g, 84.7 mmol, 62.6% yield).

[0331] 1 H NMR(400MHz, CDCl3)δ7.27(s,5H),4.47(s,2H),3.49(s,2H),3.38(s,2H),0.54-0.27(m,4H)

[0332] Step 3: Preparation of 1-(tert-butyl)2-methyl 2-((1-((benzyloxy)methyl)cyclopropyl)methyl)pyrrolidine-1,2-dicarboxylate

[0333] To a solution of 1-(tert-butyl)-2-methylpyrrolidine-1,2-dicarboxylate (15.0 g, 65.4 mmol, 1.00 eq) in THF (150 mL) at -70°C was added LiHMDS (1.00 M, 78.5 mL, 1.20 eq). The resulting reaction mixture was allowed to react at the current temperature for 2 h, followed by the addition of (((1-(bromomethyl)cyclopropyl)methoxy)methyl)benzene (21.7 g, 85.1 mmol, 1.30 eq) and HMPA (44.5 g, 249 mmol, 43.7 mL, 3.80 eq). The resulting reaction mixture was allowed to react at 25°C for 16 h, then quenched with water (100 mL) and extracted with EtOAc (100 mL x 2). The combined organic phases were washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain the desired product (12.0 g, 26.8 mmol, 40.9% yield).

[0334] 1 H NMR(400MHz,CD3OD)δ7.46-7.21(m,5H),4.68-4.35(m,2H),3.79-3.56 (m,4H),3.45-3.26(m,3H),2.59-2.38(m,2H),2.09-1.82(m,4H),1.47-1.37(m,9H),0.54-0.42(m,4H).

[0335] Step 4: Preparation of 1-(tert-butyl)2-methyl 2-((1-(hydroxymethyl)cyclopropyl)methyl)pyrrolidine-1,2-dicarboxylate

[0336] To a solution of 1-(tert-butyl)-2-methyl-2-((1-(benzyloxy)methyl)cyclopropyl)methyl)pyrrolidine-1,2-dicarboxylate (11.0 g, 27.3 mmol, 1.00 eq) in MeOH (100 mL) was added Pd / C (10% wt, 1.50 g) under nitrogen. The resulting reaction mixture was reacted at 25°C under a hydrogen atmosphere (15 psi) for 16 h. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was isolated by silica gel column chromatography to afford the desired product (10.0 g, 25.5 mmol, 93.6% yield).

[0337] 1 H NMR (400MHz, CD3OD) δ3.73-3.60(m,4H),3.37(s,5H),2.08-1.90(m,4H),1.48-1.42(m,9H),0.59-0.36(m,4H).

[0338] Step 5: Preparation of 1-(tert-butyl)2-methyl 2-((1-(bromomethyl)cyclopropyl)methyl)pyrrolidine-1,2-dicarboxylate

[0339] To a solution of 1-(tert-butyl)-2-methyl-2-((1-(hydroxymethyl)cyclopropyl)methyl)pyrrolidine-1,2-dicarboxylate (5.00 g, 16.0 mmol, 1.00 eq) in DCM (50 mL) were added CBr (7.94 g, 23.9 mmol, 1.50 eq) and PPh (6.11 g, 23.3 mmol, 1.46 eq). The resulting mixture was reacted at 25°C for 16 h and then concentrated under reduced pressure. The residue was isolated by silica gel column chromatography to afford the desired product (0.50 g, 1.20 mmol, 7.50% yield).

[0340] 1 H NMR (400MHz, CDCl3) δ3.80-3.70(m,5H),3.52-3.42(m,1H),3.19-3.02(m,1H),2.82(dd,J=7 .0,15.6Hz,1H),2.45-2.20(m,1H),2.13-1.89(m,4H),1.49-1.44(m,9H),1.00-0.51(m,4H).

[0341] Step 6: Preparation of methyl 2-((1-(bromomethyl)cyclopropyl)methyl)pyrrolidine-2-carboxylate

[0342] To a solution of 1-(tert-butyl)-2-methyl-2-((1-(bromomethyl)cyclopropyl)methyl)pyrrolidine-1,2-dicarboxylate (1.40 g, 3.72 mmol, 1.00 eq) in DCM (14 mL) was added TFA (64.7 g, 567.3 mmol, 42.0 mL, 152 eq). The reaction was allowed to proceed at 0°C for 2 h and then concentrated under reduced pressure to afford the desired product (0.60 g, 1.74 mmol, 46.7% yield). This product was used directly in the next step without purification.

[0343] Step 7: Preparation of dihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-methyl carboxylate

[0344] To a solution of methyl 2-((1-(bromomethyl)cyclopropyl)methyl)pyrrolidine-2-carboxylate (0.60 g, 2.17 mmol, 1.00 eq) in DMF (10 mL) was added KCO (1.20 g, 8.69 mmol, 4.00 eq). The resulting reaction mixture was reacted at 25°C for 16 h and then concentrated under reduced pressure. The residue was separated by silica gel column chromatography to obtain the desired product (0.60 g, 1.84 mmol, 84.9% yield).

[0345] 1 H NMR (400MHz, CDCl3) δ3.75 (s, 3H), 3.31-3.18 (m, 1H), 3.01 (d, J = 10.0Hz, 1H), 2.81 (s, 1H), 2.71 (d, J = 10.0Hz, 1H), 2.28-2.22 (m, 2H), 1.94-1.84 (m, 4H), 0.64-0.45 (m, 4H).

[0346] Step 8: Preparation of (dihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methanol

[0347] Under nitrogen, LAH (174.9 mg, 4.61 mmol, 1.50 eq) was added to a solution of methyl dihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-carboxylate (0.60 g, 3.07 mmol, 1.00 eq) in THF (1 mL). The resulting reaction mixture was reacted at 0°C for 4 h, then quenched by the addition of water (0.3 mL) and MgSO4 (2 g). The resulting reaction mixture was stirred at room temperature for 30 min and then filtered. The filtrate was concentrated under reduced pressure to obtain the desired product (0.200 g, 1.08 mmol, 35.0% yield).

[0348] LC-MS: m / z 168 (M+H) + .1 H NMR (400MHz, CDCl3) δ3.50-3.43(m,1H),3.39-3.31(m,1H),3.10-3.03(m,1H),2.90(d,J=10.3Hz ,1H),2.80(td,J=6.3,10.5Hz,1H),2.69(d,J=10.5Hz,1H),1.98-1.82(m,6H),0.62-0.46(m,4H).

[0349] The following compounds were synthesized using the same synthetic method as intermediate 1-8 with different starting materials:

[0350] Intermediate 1-9 ((6'R)-6'-fluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methanol

[0351] LC-MS: m / z 186 (M+H) + . 1 H NMR(400MHz, CDCl3)δ7.00(s,1H),5.44-4.99(m,1H),3.60-3.25(m,3H),3.23-2.95(m,3H),2 .88-2.51(m,1H),2.36-2.03(m,4H),1.96-1.57(m,1H),1.43-1.25(m,1H),0.67-0.38(m,4H)

[0352] Intermediate 1-10 ((6'S)-6'-fluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methanol

[0353] LC-MS: m / z 186 (M+H) + . 1 H NMR(400MHz, CDCl3)δ5.15-5.43(m,1H)3.41-3.54(m,3H)3.00-3.14(m,3H)2.56(d,J=11.22Hz,1H)2 .22-2.36(m,1H)2.00-2.17(m,1H)1.94(d,J=12.98Hz,1H)1.64(d,J=12.76Hz,1H)0.44-0.69(m,4H).

[0354] Preparation Route 1 of Intermediate 1-11A ((trans)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methanol and 1-11B and ((cis)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methanol

[0355] Step 1: Preparation of ethyl 2,2-difluoro-5'-oxodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-carboxylate (Intermediate 1-11-I)

[0356] To a solution of ethyl 2-methylene-5-oxotetrahydro-1H-bis-fused pyrrolidine-7a(5H)-carboxylate (4.8 g, 22.9 mmol, 1.00 eq) in toluene (75 mL) were added TBAB (222 mg, 688 umol, 0.03 eq) and [bromo(difluoro)methyl]-trimethylsilane (14.0 g, 68.8 mmol, 3.00 eq). The reaction mixture was stirred at 110°C for 16 h and then concentrated under reduced pressure. The residue was separated by silica gel column chromatography to obtain the desired product (5.2 g, 87.6% yield).

[0357] LC-MS: m / z 260 (M+H) + .

[0358] Step 2: Preparation of ((trans)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methanol and ((cis)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methanol (Intermediates 1-11A and 1-11B)

[0359] To a solution of ethyl 2,2-difluoro-5'-oxodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-carboxylate (2.40 g, 9.26 mmol, 1.00 eq) in THF (40 mL) at 0°C was added LAH (2.1 g, 57.6 mmol, 6.00 eq). The reaction mixture was allowed to react at 60°C for 2 h, then quenched with NaSO.10H2O (20 g) at 0°C and filtered. The filter cake was washed with THF (40 mL). The filtrate was concentrated under reduced pressure to afford Intermediate 1-11 ((2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methanol).

[0360] LC-MS: m / z 204 (M+H) + .

[0361] Intermediate 1-11 was separated by silica gel column chromatography (DCM:MeOH:NH3.H2O=20:1:0.05) to give ((trans)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methanol and ((cis)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methanol.

[0362] Isomer 1-11A ((trans)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methanol (0.50 g):

[0363] LC-MS: m / z 204 (M+H) + . 1 H NMR (400MHz, CDCl3) δ3.44-3.35(m,2H),3.19-3.13(m,2H),2.83(d,J=12.1Hz,1H),2.73-2.59(m,1H),2.73-2.59(m,1H),2.05(dd,J=6.3,1 3.3Hz,1H),1.93-1.84(m,3H),1.83-1.74(m,1H),1.74-1.63(m,1H),1.36(ddd,J=4.0,8.1,12.1Hz,1H),1.28(ddd,J=4.2,8.1,12.4Hz,1H).

[0364] Isomer 1-11B ((cis)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methanol (0.64 g):

[0365] LC-MS: m / z 204 (M+H) + . 1 H NMR (400MHz, CDCl3) δ3.32(d,J=2.0Hz,2H),3.24(d,J=11.0Hz,1H),3.12-3.02(m,1H),2.83-2.71(m,2 H), 2.05 (d, J = 13.2Hz, 1H), 1.98-1.89 (m, 2H), 1.89-1.81 (m, 1H), 1.81-1.70 (m, 2H), 1.36-1.28 (m, 2H).

[0366] Preparation Route 2 of Intermediates 1-11A ((trans)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methanol and 1-11B ((cis)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methanol

[0367] Step 1: Preparation of (trans)-2,2-difluoro-5'-oxydihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-carboxylic acid ethyl ester and (cis)-2,2-difluoro-5'-oxydihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-carboxylic acid ethyl ester (Intermediate 1-11-IA and Intermediate 1-11-IB)

[0368] Intermediate 1-11-I (6 g) was separated by silica gel column chromatography ( 40g Silica Flash Column, eluent: 0-50% THF / petroleum ether 40 mL / min) to give intermediate I-11-IA (2.80 g, 10.8 mmol, 47% yield) and intermediate I-11-IB (2.40 g, 9.26 mmol, 40% yield) in sequence.

[0369] Step 2: Preparation of ((trans)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methanol and ((cis)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methanol (Intermediate 1-11-A and Intermediate 1-11-B)

[0370] Intermediate 1-11A was synthesized from intermediate 1-11-IA in the same manner as in preparation route 1.

[0371] Intermediate 1-11B was synthesized from intermediate 1-11-IB in the same manner as in preparation route 1.

[0372] Isomer 1-11A was subjected to chiral separation to give isomer 1-11A-1 (((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methanol) and isomer 1-11A-2 (((1R,7a'R)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methanol).

[0373] Step 1: Preparation of Intermediates 1-11A-I1 and 1-11A-I2

[0374] To a solution of Intermediate 1-11A (9.00 g, 44.3 mmol, 1.00 eq) in DMF (100 mL) were added imidazole (6.03 g, 88.6 mmol, 2.00 eq) and TBDPSCl (14.6 g, 53.1 mmol, 13.6 mL, 1.20 eq). The reaction mixture was stirred at 25°C for 16 h and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford the desired product, Intermediate 1-11A-I (20.0 g, 41.7 mmol, 94.1% yield).

[0375] LC-MS: m / z 442 (M+H) + . 1 H NMR (400MHz, CDCl3) δ7.77-7.62(m,4H),7.53-7.34(m,6H),3.51(s,2H),3.14-3.02(m,2H),2.79(d,J=12.0Hz,1H),2.65-2. 54(m,1H),2.13-1.99(m,2H),1.90(d,J=13.3Hz,1H),1.86-1.77(m,1H),1.72-1.61(m,2H),1.23-1.16(m,2H),1.10(s,9H).

[0376] Intermediate 1-11A-I was separated by SFC chiral separation (column: DAICEL CHIRALPAK IC (250 mm*50 mm, 10 μm); mobile phase: [CO2-EtOH (0.1% NH3H2O)]; 15% B isocratic elution mode) to give two isomers:

[0377] Intermediate 1-11A-I1 (4.50 g, 10.2 mmol, 45.0% yield): RT 1.931 min. LC-MS: m / z 442 (M+H) + .

[0378] Intermediate 1-11A-I2 (4.20 g, 9.51 mmol, 42.0% yield): RT 2.412 min. LC-MS: m / z 442 (M+H) + .

[0379] Step 2: Preparation of Intermediates 1-11A-1 and 1-11A-2

[0380] To a solution of intermediate 1-11A-I1 (4.50 g, 10.2 mmol, 1.00 eq) in MeOH (50 mL) was added KHF2 (15.9 g, 203 mmol, 6.72 mL, 20.0 eq). The reaction mixture was reacted at 25°C for 16 h and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography ( 20g Silica Flash Column, eluent: 0-25% MeOH / DCM @ 40 mL / min) was used to separate the target product 1-11A-1 (1.71 g, 7.98 mmol, 78.3% yield). LC-MS: m / z 204 (M+H) + . 1 H NMR(400MHz, CDCl3) δ3.40-3.16(m,2H),3.03(dd,J=7.4,12.1Hz,2H),2.73(d,J=12.1Hz,1H), 2.66-2.43(m,1H),2.00-1.86(m,1H),1.84-1.73(m,3H),1.72-1.54(m,2H),1.33-1.10(m,2H).

[0381] Intermediate 1-11A-2 (1.79 g, 8.38 mmol, 88.1% yield) was synthesized using the same method:

[0382] LC-MS: m / z 204 (M+H) + . 1 H NMR (400MHz, CDCl3) δ3.35-3.20(m,2H),3.10-2.96(m,2H),2.73(d,J=12.1Hz,1H),2.63- 2.49(m,1H),1.97-1.87(m,1H),1.84-1.74(m,3H),1.72-1.53(m,2H),1.31-1.11(m,2H).

[0383] Intermediate D-1-11A-1 (((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl-5',5'-d2)methane-d2-ol) and intermediate D-1-11A-2 (((1R,7a'R)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl-5',5'-d2)methane-d2-ol) were synthesized using the same method as intermediate 1-11A-1 and intermediate 1-11A-2.

[0384] Intermediate D-1-11A-1. LC-MS: m / z 208 (M+H) + . 1 H NMR (400MHz, CDCl3) δ2.81-3.08(m,2H)2.73(d,J=12.13Hz,1H)1.92(dd,J=13.26,6.13Hz,1H)1.73-1.83(m,3H)1.52-1.71(m,2H)1.08-1.33(m,2H).

[0385] Intermediate D-1-11A-2. LC-MS: m / z 208 (M+H) + . 1 H NMR (400MHz, CDCl3) δ3.03 (dd, J=12.13, 7.25Hz, 2H) 2.73 (d, J=12.13Hz, 1H) 1.92 (dd,J=13.26,6.25Hz,1H)1.74-1.83(m,3H)1.53-1.70(m,2H)1.13-1.32(m,2H).

[0386] Preparation of Intermediate 1-12 (Tetrahydrospiro[cyclopropane-1,3'-bis-fused pyrrolidine]-7a'(5'H)-yl)methanol

[0387] Step 1: Preparation of (S)-5-(((tert-butylmethylsilyl)oxy)methyl)pyrroline-2-one

[0388] To a solution of (S)-5-(Hydroxymethyl)pyrrolidone (50.0 g, 434 mmol, 1.00 eq) and imidazole (59.1 g, 868 mmol, 2.00 eq) in DCM (1000 mL) was added TBSCl (78.6 g, 521 mmol, 63.9 mL, 1.20 eq) portionwise. The reaction mixture was allowed to react at 25°C for 2 h, then H₂O (1000 mL) was added dropwise at 0°C and diluted with DCM (1000 mL). The mixture was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to yield the desired product, which was used directly in the next step without purification.

[0389] 1 H NMR (400MHz, CDCl3) δ6.43(br s,1H)3.71(m,1H)3.57(m,1H)3.44(m,1H)2.30(m,2H)2.13(m,1H)1.74(m,1H)0.85(s,9H)0.02(m,6H).

[0390] Step 2: Preparation of (S)-1-benzyl-5-(((tert-butylmethylsilyl)oxy)methyl)pyrroline-2-one

[0391] Under nitrogen, NaH (72.7 g, 1.82 mol, 60.0% wt, 4.17 eq) was added portionwise to a 0°C solution of (S)-5-(((tert-butylmethylsilyl)oxy)methyl)pyrrolin-2-one (100 g, 436 mmol, 1.00 eq) in THF (1250 mL) over a 2-hour period. The mixture was reacted at 0°C for 0.5 h, followed by the addition of BnBr (112 g, 654 mmol, 77.7 mL, 1.50 eq). The resulting mixture was reacted at 25°C for 16 h, then quenched with saturated aqueous NH4Cl (1000 mL) at 0-10°C under nitrogen, followed by extraction with EtOAc (1000 mL x 2). The combined organic phases were washed with saturated brine (1000 mL), dried over anhydrous MgSO4, and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain the desired product (122 g, 382 mmol, 87.6% yield).

[0392] 1 H NMR(400MHz, CDCl3)δ7.29(m,5H)5.02(d,J=14.97Hz,1H)4.06(d,J=14.97Hz,1H)3.69(m ,1H)3.54(m,2H)2.55(m,1H)2.38(m,1H)2.05(m,1H)1.91(m,1H)0.89(s,9H)0.04(s,6H)

[0393] Step 3: Preparation of (S)-4-benzyl-5-(((tert-butylmethylsilyl)oxy)methyl)-4-azaspiro[2.4]heptane

[0394] Under nitrogen, Ti(OiPr) (224 g, 789 mmol, 2.25 eq) was added to a 0°C solution of TiCl (49.9 g, 263 mmol, 0.750 eq) in toluene (263 mL). The reaction was allowed to react at 25°C for 2 h, followed by the dropwise addition of MeLi (1.60 M, 657 mL, 3.00 eq) at 0°C. The resulting compound was allowed to react at 25°C for 1 h, followed by the addition of a solution of (S)-1-benzyl-5-(((tert-butylmethylsilyl)oxy)methyl)pyrrolin-2-one (112 g, 351 mmol, 1.00 eq) in THF (560 mL). EtMgBr (3.00 M, 400 mL, 3.42 eq) was then added dropwise at 0°C over 2 h. The resulting mixture was allowed to react at 25°C for 2 h, followed by the addition of water (700 mL) at 0°C, and the reaction was quenched before filtration. The filter cake was washed with EtOAc (1000 mL). The combined organic phases were washed with saturated brine (500 mL x 2), dried over anhydrous MgSO₄, and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain the desired product (19.0 g, 57.3 mmol, 16.4% yield).

[0395] 1 H NMR(400MHz, CDCl3)δ7.29(m,5H)3.75(d,J=13.82Hz,1H)3.54(d,J=13.82Hz,1H)3.40(m,2H)3.03(m,1H)2.07(m,1H)1.95(dt,J=11.80,8.22 Hz,1H)1.78(m,1H)1.55(ddd,J=12.01,8.04,4.40Hz,1H)0.84(s,9H)0.79(m,1H)0.56(m,1H)0.48(m,1H)0.41(m,1H)-0.06(d,J=9.17Hz,6H)

[0396] Step 4: Preparation of (S)-(4-benzyl-4-azaspiro[2.4]heptane-5-yl)methanol

[0397] To a solution of (S)-4-benzyl-5-(((tert-butylmethylsilyl)oxy)methyl)-4-azaspiro[2.4]heptane (19.0 g, 57.3 mmol, 1.00 eq) in THF (300 mL) was added TBAF (1.00 M, 57.3 mL, 1.00 eq). The mixture was reacted at 25°C for 16 h and then diluted with EtOAc (500 mL). The resulting mixture was washed sequentially with H2O (100 mL) and saturated brine (100 mL), dried over anhydrous MgSO4, and filtered. The filtrate was concentrated under reduced pressure, and the residue was isolated by silica gel column chromatography to obtain the desired product (5.30 g, 24.4 mmol, 42.6% yield).

[0398] 1 H NMR(400MHz, CDCl3)δ7.28(m,4H)7.20(m,1H)4.14(br t,J=5.39Hz,1H)3.67(d,J=14.09Hz,1H)3.50(d,J=14.08Hz,1H)3.24(m,1H)3.14(m,1H)2.91(m,1H )1.96(m,2H)1.65(m,1H)1.49(ddd,J=11.50,8.20,3.41Hz,1H)0.80(m,1H)0.45(m,2H)0.37(m,1H).

[0399] Step 5: Preparation of (S)-(4-azaspiro[2.4]heptane-5-yl)methanol hydrochloride

[0400] Under nitrogen, a solution of (S)-(4-benzyl-4-azaspiro[2.4]heptan-5-yl)methanol (5.00 g, 23.0 mmol, 1.00 eq) in MeOH (50.0 mL) was added with Pd / C (500 mg, 10.0% wt) and HCl (12.0 M, 8.00 mL, 4.17 eq). The mixture was reacted at 30°C under a hydrogen atmosphere for 3 days, then filtered and the filtrate was concentrated under reduced pressure to afford the desired product (4.50 g, crude product). This product was used directly in the next reaction without further purification.

[0401] 1 H NMR (400MHz, CDCl3) δ9.67(br s,1H)8.97(br s,1H)3.60(m,3H)2.07(m,1H)1.92(m,2H)1.79(m,1H)1.14(m,2H)0.77(m,2H).

[0402] Step 6: Preparation of tert-butyl (S)-5-(hydroxymethyl)-azaspiro[2.4]heptane-4-carboxylate

[0403] To a solution of (S)-(4-azaspiro[2.4]heptan-5-yl)methanol hydrochloride (4.50 g, 27.5 mmol, 1.00 eq) in DCM (90.0 mL) was added TEA (3.34 g, 33.0 mmol, 4.59 mL, 1.20 eq) and BoC₂O (7.20 g, 33.0 mmol, 7.58 mL, 1.20 eq). The mixture was reacted at 25°C for 16 h, then quenched by the addition of water (50 mL) at 0°C and extracted with DCM (50 mL x 2). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous MgSO₄, and filtered. The filtrate was concentrated under reduced pressure to afford the desired product (5.90 g, 26.0 mmol, 94.4% yield).

[0404] 1 H NMR (400MHz, CDCl3) δ3.85 (br d,J=5.94Hz,1H)3.52(ddd,J=9.96,5.56,3.85Hz,1H)3.25(ddd,J=10.12,8.58,5.94Hz,1H)2.14(m,1H)1.85(m,2H)1.50(br s,1H)1.35(s,9H)1.15(m,1H)0.84(m,1H)0.39(m,2H).

[0405] Step 7: Preparation of (S)-4-(tert-butyloxycarbonyl)-4-azaspiro[2.4]heptane-5-carboxylic acid

[0406] To a solution of NaIO4 (11.7 g, 54.7 mmol, 3.03 mL, 2.54 eq) in H2O (18.0 mL) at 0°C was added a mixture of (S)-tert-butyl 5-(hydroxymethyl)-azaspiro[2.4]heptane-4-carboxylate (4.90 g, 21.6 mmol, 1.00 eq) in ACN (12.0 mL) and CCl4 (12.0 mL), followed by the addition of RuCl3.H2O (206 mg, 912 μmol, 0.0423 eq). The mixture was reacted at 25°C for 16 h, then quenched by the dropwise addition of water (30 mL) at 0°C and extracted with DCM (50 mL x 2). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous MgSO4, and filtered. The filtrate was concentrated under reduced pressure to yield the desired product (4.70 g, crude product). This product was used directly in the next step without further purification.

[0407] LC-MS: m / z 242 (M+H) + .

[0408] Step 8: Preparation of (S)-4-(tert-butyloxycarbonyl)-4-azaspiro[2.4]heptane-5-carboxylic acid methyl ester

[0409] To a solution of (S)-4-(tert-butyloxycarbonyl)-4-azaspiro[2.4]heptane-5-carboxylic acid (4.70 g, 19.5 mmol, 1.00 eq) in acetone (50.0 mL) at 0°C were added MeI (5.53 g, 39.0 mmol, 2.43 mL, 2.00 eq) and KCO (8.08 g, 58.4 mmol, 3.00 eq). The mixture was reacted at 25°C for 16 h, then quenched by the dropwise addition of water (30 mL) at 0°C and extracted with DCM (50 mL x 2). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous MgSO, and filtered. The filtrate was concentrated under reduced pressure, and the residue was isolated by silica gel column chromatography to yield the desired product (1.10 g, 4.31 mmol, 22.1% yield).

[0410] 1 H NMR (400MHz, CDCl3) δ4.33(br dd,J=8.44,3.79Hz,1H)3.65(m,3H)2.20(m,1H)1.81(m,3H)1.39(m,1H)1.30(br s,9H)0.86(m,1H)0.48(br s,2H).

[0411] Step 9: Preparation of 4-(tert-butyl)5-methyl5-(3-chloropropyl)-4-azaspiro[2.4]heptane-4,5-dicarboxylate

[0412] Under nitrogen, to a solution of (S)-methyl 4-(tert-butyloxycarbonyl)-4-azaspiro[2.4]heptane-5-carboxylate (1.00 g, 3.92 mmol, 1.00 eq) in THF (10.0 mL) at -70°C was added LiHMDS (1.00 M, 5.88 mL, 1.50 eq). The reaction was allowed to react at -70°C for 1 h, followed by the addition of 1-chloro-3-iodopropane (2.40 g, 11.8 mmol, 1.26 mL, 3.00 eq). The resulting mixture was reacted at -70°C for 1 h and then at 25°C for 40 h. The mixture was quenched with saturated NH4Cl (20 mL) at -0°C and extracted with EtOAc (30 mL x 2). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous MgSO4, and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain the desired product (767 mg, 2.31 mmol, 59.0% yield).

[0413] 1H NMR (400MHz, CDCl3) δ3.73 (s, 3H) 3.59 (br t, J = 6.27Hz, 2H) 2.39 (m, 1H) 2.07 (m, 4H) 1.89 (m, 1H) 1.74 (m, 2H) 1.44 (m, 1H) 1.39 (m, 9H) 0.90 (br dd,J=14.97,7.04Hz,1H)0.50(m,2H).

[0414] Step 10: Preparation of 5-methyl 5-(3-chloropropyl)-4-azaspiro[2.4]heptane-5-carboxylate hydrochloride

[0415] To a solution of 4-(tert-butyl)-5-methyl-5-(3-chloropropyl)-4-azaspiro[2.4]heptane-4,5-dicarboxylate (700 mg, 2.11 mmol, 1.00 eq) in DCM (8.00 mL) was added HCl / dioxane (4.00 M, 4.00 mL, 7.58 eq). The mixture was reacted at 25°C for 1 h and then concentrated under reduced pressure to afford the desired product (698 mg, crude). This product was used in the next reaction without further purification.

[0416] LC-MS: m / z 232 (M+H) + .

[0417] Step 11: Preparation of tetrahydrospiro[cyclopropane-1,3'-bis-fused pyrrolidine]-7a'(5'H)-carboxylic acid methyl ester

[0418] To a solution of 5-methyl 5-(3-chloropropyl)-4-azaspiro[2.4]heptane-5-carboxylate hydrochloride (698 mg, 2.60 mmol, 1.00 eq) in ACN (8.00 mL) was added KCO (1.08 g, 7.81 mmol, 3.00 eq). The mixture was reacted at 25°C for 16 h, filtered, and the filtrate was concentrated under reduced pressure to afford the desired product (412 mg, 2.11 mmol, 81.1% yield). This product was used directly in the next reaction without further purification.

[0419] 1 H NMR(400MHz, CDCl3)δ3.74(m,3H)3.15(dt,J=9.24,4.62Hz,1H)2.73(m,1H)2.45(m,2H)2.13(t d,J=11.55,7.92Hz,1H)1.94(m,1H)1.77(m,4H)1.31(m,2H)0.97(m,1H)0.66(m,2H)0.37(m,1H)

[0420] Step 12: Preparation of (tetrahydrospiro[cyclopropane-1,3'-bis-fused pyrrolidine]-7a'(5'H)-yl)methanol

[0421] Under nitrogen, to a 0°C solution of methyl tetrahydrospiro[cyclopropane-1,3'-bis-fused pyrrolidine]-7a'(5'H)-carboxylate (412 mg, 1.78 mmol, 1.00 eq) in THF (4.00 mL) was added LiAlH4 (135 mg, 3.56 mmol, 2.00 eq). The reaction was allowed to react at 25°C for 1 h, then quenched with H2O (0.04 mL), aqueous NaOH (15% wt, 0.04 mL), and H2O (0.12 mL). The mixture was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to yield the desired product (263 mg, 1.57 mmol).

[0422] LC-MS: m / z 168 (M+H) + . 1 H NMR (400MHz, CDCl3) δ3.40 (d, J = 10.15Hz, 1H) 3.28(d,J=10.15Hz,1H)2.99(m,1H)2.73(m,1H)2.19(m,1H)1.91(m,2H)1.69(m,4H)1.26(m,2H)0.86(m ,1H)0.61(dt,J=9.81,5.73Hz,1H)0.50(dt,J=10.18,5.00Hz,1H)0.38(ddd,J=9.90,6.05,4.10Hz,1H).

[0423] Intermediates 1-13A and 13B were synthesized using the same method as intermediate 1-12: ((cis)-6'-fluorotetrahydrospiro[cyclopropane-1,3'-bis-fused pyrrolidine]-7a'(5'H)-yl)methanol and ((trans)-6'-fluorotetrahydrospiro[cyclopropane-1,3'-bis-fused pyrrolidine]-7a'(5'H)-yl)methanol

[0424] Intermediate 1-13A

[0425] LC-MS: m / z 186 (M+H) + . 1H NMR (400MHz, CDCl3) δ5.26-5.02(m,1H),3.48(d,J=10.8Hz,1H),3.42-3.13(m,3H),2.96-2.57(m,1H),2.52-2.29(m,2H),2.18- 1.94(m,2H),1.87-1.74(m,1H),1.40-1.29(m,1H),0.95-0.82(m,1H),0.76-0.59(m,2H),0.53-0.38(m,1H),0.53-0.38(m,1H).

[0426] Intermediate 1-13B

[0427] LC-MS: m / z 186 (M+H) + . 1 H NMR (400MHz, CDCl3) δ5.30-5.06(m,1H),3.57-3.41(m,2H),3.33(br dd,J=12.4,18.8Hz,1H),3.07-2.86(m,1H),2.82-2.42(m,1H),2.40-2.27(m,1H),2.25-2.12(m,1H),2.11-1.93(m,2H),1.73(ddd,J =2.0,8.8,12.5Hz,1H),1.34(ddd,J=1.8,7.8,12.2Hz,1H),0.92-0.81(m,1H),0.77-0.57(m,2H),0.44(ddd,J=3.8,5.9,9.6Hz,1H).

[0428] Intermediate 1-14 was synthesized using the same method as Intermediate 1-8 with different starting materials: (7',7'-difluorodihydro-3'H-spiro[cyclopropane-1,2'-indolizine]-8a'(1'H)-yl)methanol

[0429] LC-MS: m / z 218 (M+H) + . 1 H NMR (400MHz, CDCl3) δ3.66 (dd, J = 10.88, 2.32Hz, 1H) 3.24 (d, J = 10.88Hz, 1H) 2.97 (m, 4H) 2.26 (d, J = 11.62Hz, 1H) 1.95 (m, 6H) 0.58 (m, 4H).

[0430] Intermediate 1-15 was synthesized by the same method as Intermediate 1-8 using different starting materials: (6',6'-difluorodihydro-3'H-spiro[cyclopropane-1,2'-indolizine]-8a'(1'H)-yl)methanol

[0431] LC-MS: m / z 218 (M+H) + . 1 H NMR (400MHz, CDCl3) δ3.68 (d, J = 10.39Hz, 1H) 3.29 (m, 2H) 2.96 (m, 4H) 2.04 (m, 6H) 0.55 (m, 4H).

[0432] Preparation of Intermediates 1-16A and 1-16B ((1S,6'R,7a'S)-2,2,6'-trifluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methanol and ((1R,6'R,7a'S)-2,2,6'-trifluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methanol

[0433] Step 1: Preparation of (3R,6R,7aS)-3-(tert-butyl)-6-fluorotetrahydro-1H,3H-pyrrolo[1,2-c]oxazol-1-one

[0434] To a solution of (2S,4R)-4-fluoropyrrolidine-2-carboxylic acid (13.3 g, 100 mmol, 1.00 eq) in THF (40 mL) were added 2,2-dimethylpropanal (17.3 g, 200 mmol, 22.1 mL, 2.00 eq), trimethoxymethane (31.9 g, 300 mmol, 32.9 mL, 3.00 eq), and TFA (1.14 g, 10.0 mmol, 744 μL, 0.100 eq). The mixture was reacted at 57°C for 16 h and then concentrated under reduced pressure to afford the desired product (22.0 g, crude product). This product was used directly in the next step without purification.

[0435] 1 H NMR (400MHz, CDCl3) δppm 5.27 (m, 1H) 4.52 (s, 1H) 4.09 (t, J = 8.14Hz, 1H) 3.56 (m, 1H) 2.94 (m, 1H) 2.54 (m, 1H) 2.20 (m, 1H) 0.96 (m, 9H).

[0436] Step 2: Preparation of (3R,6R,7aS)-3-(tert-butyl)-7a-(2-(chloromethyl)propenyl)-6-fluorotetrahydro-1H,3H-pyrrolo[1,2-c]oxazol-1-one

[0437] Under nitrogen, LDA (2.00 M, 82.0 mL, 1.50 eq) and DMPU (28.0 g, 219 mmol, 26.3 mL, 2.00 eq) were added dropwise to a solution of (3R,6R,7aS)-3-(tert-butyl)-6-fluorotetrahydro-1H,3H-pyrrolo[1,2-c]oxazol-1-one (22.0 g, 109 mmol, 1.00 eq) in THF (220 mL) at -70°C. The mixture was reacted at -70°C for 2 h, followed by the addition of 3-chloro-2-(chloromethyl)prop-1-ene (17.8 g, 142 mmol, 16.5 mL, 1.30 eq). The resulting mixture was reacted at 25°C for 16 h, then quenched by the dropwise addition of saturated aqueous NH4Cl (250 mL) at 0°C and extracted with EtOAc (250 mL x 2). The combined organic phases were washed with saturated brine (250 mL), dried over anhydrous MgSO 4 , and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain the desired product (16.7 g, 57.6 mmol, 52.7% yield).

[0438] 1 H NMR(400MHz, CDCl3)δ5.37(m,1H)5.33(s,1H)5.24(m,1H)5.17(s,1H)4.21(m ,3H)3.43(m,1H)3.23(m,1H)2.72(s,2H)2.37(m,1H)2.12(m,1H)0.91(s,9H).

[0439] Step 3: Preparation of (2R,7aS)-2-fluoro-6-methyltetrahydro-1H-bis-fused pyrrolidine-7a(5H)-carboxylic acid methyl ester

[0440] To a solution of (3R,6R,7aS)-3-(tert-butyl)-7a-(2-(chloromethyl)propenyl)-6-fluorotetrahydro-1H,3H-pyrrolo[1,2-c]oxazol-1-one (11.2 g, 38.7 mmol, 1.00 eq) in MeOH (56 mL) was added NaI (6.95 g, 46.4 mmol, 1.20 eq). The mixture was reacted at 68°C for 16 h and then filtered. The filtrate was concentrated under reduced pressure. The residue was slurried with acetone (12 mL) at 25°C for 30 min and filtered. ACN (70 mL) and KCO (12 g) were added to the solid, followed by reaction at 25°C for 3 h and filtration. The filtrate was concentrated under reduced pressure, and the residue was added to THF (70 mL) and filtered. The filtrate was then concentrated under reduced pressure to yield the desired product (3.50 g, 17.6 mmol, 45.5% yield). This product was used directly in the next step without purification.

[0441] 1H NMR(400MHz, CDCl3)δ5.29(m,1H)4.97(dt,J=11.44,1.87Hz,2H)3.82(br d,J=13.86Hz,1H)3.72(m,3H)3.59(br d,J=13.86Hz,1H)3.26(m,2H)3.04(br d,J=16.07Hz,1H)2.81(br d,J=16.07Hz,1H)2.56(m,1H)2.30(m,1H).

[0442] Step 4: Preparation of (1S,6'R,7a'S)-2,2,6'-trifluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-carboxylic acid methyl ester and (1R,6'R,7a'S)-2,2,6'-trifluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-carboxylic acid methyl ester

[0443] Under nitrogen protection, NaI (752 mg, 5.02 mmol, 0.500 eq) and TMSCF3 (3.57 g, 25.1 mmol, 2.50 eq) were added to a solution of (2R,7aS)-2-fluoro-6-methyltetrahydro-1H-bis-fused pyrrolidine-7a(5H)-carboxylic acid methyl ester (2.00 g, 10.0 mmol, 1.00 eq) in THF (20 mL). The reaction solution was reacted at 80°C for 16 h and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography ( 20g Silica Flash Column, eluent: 10.3% THF / PE @ 60 mL / min) gave Isomer A (269 mg, 1.08 mmol, 10.8% yield) and Isomer B (372 mg, 1.49 mmol, 14.9% yield) in sequence.

[0444] Isomer A: 1 H NMR (400MHz, CDCl3) δ5.33 (m, 1H) 3.78 (s, 3H) 3.49 (d, J = 9.90Hz, 1H) 3.27 (m, 3H) 2.45 (m, 4H) 1.37 (m, 2H).

[0445] Isomer B: 1 H NMR (400MHz, CDCl3) δ5.26(m,1H)3.78(m,3H)3.31(m,4H)2.54(m,2H)2.35(m,2H)1.36(m,2H).

[0446] Step 5: Preparation of Intermediates 1-16A and 1-16B ((1S,6'R,7a'S)-2,2,6'-trifluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methanol and ((1R,6'R,7a'S)-2,2,6'-trifluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methanol

[0447] Under nitrogen, LAH (81.9 mg, 2.16 mmol, 2.00 eq) was added to a solution of isomer A (269 mg, 1.08 mmol, 1.00 eq) obtained in the previous step in THF (3 mL) at 0°C. The mixture was reacted at 25°C for 1 h, followed by the addition of H₂O (0.03 mL), aqueous NaOH (15% wt, 0.03 mL), and H₂O (0.09 mL) at 0°C. The resulting mixture was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford the desired intermediate 1-16A (193 mg, 871 μmol, 80.7% yield). This product was used directly in the next step without further purification.

[0448] LC-MS: m / z 222 (M+H) + . 1 H NMR (400MHz, CDCl3) δ5.34 (br s, 1H) 5.21 (br d, J = 2.64Hz, 1H) 3.24 (m, 5H) 2.77 (br s, 1H) 2.19 (m, 3H) 1.88 (d, J = 12.98Hz, 1H) 1.33 (m, 2H).

[0449] Intermediate 1-16B was synthesized using the same method using isomer B obtained in the previous step.

[0450] LC-MS: m / z 222 (M+H) + . 1 H NMR (400MHz, CDCl3) δ5.28(m,1H)5.14(m,1H)3.27(m,5H)2.80(m,1H)2.20(m,3H)1.82(br dd,J=13.31,4.73Hz,1H)1.30(m,2H).

[0451] The following compounds were synthesized using the same method as intermediates 1-16A and 1-16B with different starting materials:

[0452] Intermediates 1-16C and 1-16D: ((1S,6'R,7a'R)-2,2,6'-trifluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methanol and ((1R,6'R,7a'R)-2,2,6'-trifluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methanol

[0453] Intermediate 1-16C

[0454] LC-MS: m / z 222 (M+H) + . 1 H NMR (400MHz, CDCl3) δ5.31(m,1H)5.17(m,1H)3.56(m,1H)3.43(m,2H)3.21(dd,J=12.53,7.52Hz,1H)2.78(d,J=12.59Hz,2H)2.10(m,4H)1.29(s,2H).

[0455] Intermediate 1-16D

[0456] LC-MS: m / z 222 (M+H) + . 1 H NMR (400MHz, CDCl3) δ 5.38 (br t, J = 4.95Hz, 1H) 5.24 (m, 1H) 3.75 (m, 1H) 3.42 (m, 2H) 3.06 (m, 1H) 2.68 (m, 2H) 2.26 (m, 3H) 1.82 (m, 1H) 1.34 (m, 2H).

[0457] Intermediates 1-16E and 1-16F: ((1S,6'S,7a'S)-2,2,6'-trifluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methanol and ((1R,6'S,7a'S)-2,2,6'-trifluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methanol

[0458] Intermediate 1-16E

[0459] LC-MS: m / z 222 (M+H) + . 1H NMR(400MHz, CDCl3)δ5.31(m,1H)5.18(t,J=4.29Hz,1H)3.57(d,J=11.00Hz,1H) 3.45(m,2H)3.21(dd,J=12.54,7.48Hz,1H)2.83(m,2H)2.10(m,4H)1.34(m,2H).

[0460] Intermediate 1-16F

[0461] LC-MS: m / z 222 (M+H) + . 1 H NMR(400MHz, CDCl3)δ5.36(m,1H)5.22(br d,J=4.40Hz,1H)3.74(m,1H)3.42(m,2H)3.03(m,1H)2.72(m,2H)2.35(m,1H)2.13(m,2H)1.78(dd,J=13.53,6.05Hz,1H)1.33(m,2H).

[0462] Intermediates 1-16G and 1-16H: ((1S,6'S,7a'R)-2,2,6'-trifluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methanol and ((1R,6'S,7a'R)-2,2,6'-trifluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methanol

[0463] Intermediate 1-16G

[0464] LC-MS: m / z 222 (M+H) + . 1 H NMR (400MHz, CDCl3) δ5.35(br s,1H)5.18(m,1H)3.73(m,1H)3.28(m,5H)2.25(m,3H)1.87(m,1H)1.32(m,2H).

[0465] Intermediate 1-16H

[0466] LC-MS: m / z 222 (M+H) + . 1 H NMR (400MHz, CDCl3) δ5.05(m,1H)3.48(m,1H) 3.06(m,5H)2.03(m,3H)1.62(m,1H)1.08(m,2H).

[0467] Preparation of Intermediate 1-17 (1-methyltetrahydro-1H-spiro[cyclopenta[b]pyrrol-2,1'-cyclopropane]-3a(3H)-yl)methanol

[0468] Step 1: Preparation of methyl 1-(2-ethoxy-2-oxoethyl)-2-oxocyclopropane-1-carboxylate

[0469] To a solution of methyl 2-oxocyclopentane-1-carboxylate (20.0 g, 141 mmol, 17.5 mL, 1.00 eq) and ethyl 2-bromoacetate (25.9 g, 15.5 mmol, 17.1 mL, 1.10 eq) in ACN (200 mL) was added KCO (29.2 g, 211 mmol, 1.50 eq). The reaction mixture was reacted at 70°C for 16 h, then filtered and the filtrate was concentrated under reduced pressure to afford the desired product (32.0 g). This product was used directly in the next step without further purification.

[0470] 1 H NMR (400MHz, CDCl3) δ4.16-4.06(m,2H),3.71(s,3H),3.03-2.76(m,2H),2.65-2.53(m,1H),2.51-2.35(m,1H),2.5 1-2.35(m,1H),2.17-1.95(m,1H),2.17-1.95(m,2H),1.26-1.20(m,1H),1.26-1.20(m,1H),1.24(t,J=7.2Hz,1H).

[0471] Step 2: Preparation of 1-methyl-2-oxohexahydrocyclopentane[b]pyrrole-3a(1H)-carboxylic acid methyl ester

[0472] To a solution of methyl 1-(2-ethoxy-2-oxoethyl)-2-oxocyclopropane-1-carboxylate (5.00 g, 21.9 mmol, 1.00 eq) in MeOH (50 mL) were added methanolic methylamine (2.0 M, 16.4 mL, 1.50 eq), AcOH (1.32 g, 21.9 mmol, 1.25 mL, 1.00 eq), and NaBH3CN (1.79 g, 28.5 mmol, 1.30 eq). The reaction mixture was stirred at 80°C for 24 h and then concentrated under reduced pressure. The residue was washed with 3.0 M HCl (50 mL) and extracted with DCM (500 mL x 3). The combined organic phases were dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was isolated by silica gel column chromatography to yield the desired product (700 mg, 3.02 mmol, 13.8% yield).

[0473] 1H NMR(400MHz, CDCl3) δ4.15(d,J=5.6Hz,1H),3.76-3.74(m,3H),3.10(d,J=17.9Hz,1H),2.8 1(s,3H),2.39(d,J=17.9Hz,1H),2.23-2.11(m,1H),1.91-1.73(m,4H),1.70-1.57(m,1H).

[0474] Step 3: Preparation of 3a-(hydroxymethyl)-1-methylhexahydrocyclopentane[b]pyrrol-2(1H)-one

[0475] To a solution of methyl 1-methyl-2-oxohexahydrocyclopenta[b]pyrrole-3a(1H)-carboxylate (650 mg, 3.30 mmol, 1.00 eq) in MeOH (10 mL) at 0°C was added NaBH4 (277 mg, 3.29 mmol, 2.20 eq) in MeOH (10 mL). The reaction mixture was allowed to react at 25°C for 4 h, then quenched with 2 mL of 1M HCl and concentrated under reduced pressure. The residue was diluted with DCM (200 mL), dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to yield the desired product (390 mg). This product was used directly in the next step without further purification.

[0476] LC-MS: m / z 170 (M+H) + .

[0477] Step 4: Preparation of 3a-(((tert-butyldiphenylsilyl)oxy)methyl)-1-methylhexahydrocyclopenta[b]pyrrol-2(1H)-one

[0478] To a solution of 3a-(hydroxymethyl)-1-methylhexahydrocyclopenta[b]pyrrol-2(1H)-one (360 mg, 2.13 mmol, 1.00 eq) in DCM (5 mL) was added TBDPSCl (702 mg, 2.55 mmol, 1.20 eq) and imidazole (290 mg, 4.25 mmol, 2.00 eq) at room temperature. The reaction mixture was allowed to react at room temperature for 2 h and then concentrated under reduced pressure. The residue was isolated by silica gel column chromatography to yield the desired product (540 mg, 1.19 mmol, 56.04% yield).

[0479] 1H NMR (400MHz, CDCl3) δ7.70-7.59(m,4H),7.52-7.37(m,6H),3.64-3.46(m,2H),2.80(s,3H),2.61(d,J=17.5Hz,1H) ,2.25(d,J=17.5Hz,1H),2.08-1.84(m,1H),1.83-1.75(m,1H),1.74-1.65(m,2H),1.65-1.51(m,3H),1.08(s,9H).

[0480] Step 5: Preparation of 3a-(((tert-butyldiphenylsilyl)oxy)methyl)-1-methylhexahydro-1H-spiro[cyclopenta[b]pyrrole-2,1'-cyclopropane]

[0481] Under nitrogen, MeTi(OiPr)3 (1.0 M, 3.07 mL, 2.50 eq) and EtMgBr (3.0 M, 2.45 mL, 6.00 eq) were added to a solution of 3a-(((tert-butyldiphenylsilyl)oxy)methyl)-1-methylhexahydrocyclopenta[b]pyrrol-2(1H)-one (500 mg, 1.23 mmol, 1.00 eq) in THF (10 mL) at 0°C. The reaction mixture was allowed to react at 25°C for 16 h, then diluted with water (10 mL) and extracted with EtOAc (100 mL x 2). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was isolated by silica gel column chromatography to yield the desired product (190 mg, 385 μmol, 31.4% yield).

[0482] 1 H NMR (400MHz, CDCl3) δ7.68 (br t,J=5.7Hz,4H),7.54-7.35(m,6H),3.73-3.42(m,2H),2.77-2.50(m,1H), 2.12-1.39(m,11H),1.09(s,9H),0.96--0.27(m,1H),0.96--0.31(m,1H).

[0483] Step 6: Preparation of (1-methyltetrahydro-1H-spiro[cyclopenta[b]pyrrol-2,1'-cyclopropane]-3a(3H)-yl)methanol: To a solution of 3a-(((tert-butyldiphenylsilyl)oxy)methyl)-1-methylhexahydro-1H-spiro[cyclopenta[b]pyrrol-2,1'-cyclopropane] (190 mg, 453 μmol, 1.00 eq) in MeOH (5 mL) was added KHF2 (707 mg, 9.05 mmol, 298 μL, 20.0 eq). The reaction mixture was stirred at 70°C for 16 h and then concentrated under reduced pressure. The residue was isolated by silica gel column chromatography to obtain the desired product (72.6 mg, 360 μmol, 79.6% yield).

[0484] 1 H NMR (400MHz, CDCl3) δ3.70-3.44(m,3H),3.70-3.44(m,1H),2.97-2.70(m,2H),2.21-1.94(m,3H),1.87(br d,J=13.4Hz,3H),1.73-1.50(m,3H),1.37(t,J=7.6Hz,1H),1.11-1.00(m,1H),0.99-0.73(m,1H),0.58-0.13(m,1H).

[0485] Preparation of Intermediate 2-1((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane

[0486] Step 1: Preparation of 7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1,3-diol

[0487] Under nitrogen, ruthenium dichloride (1-isopropyl-4-methylbenzene) (1.20 g, 1.96 mmol, 0.07 eq) was added to a solution of 7-fluoronaphthalene-1,3-diol (5 g, 28.1 mmol, 1 eq), (bromoethynyl)triisopropylsilane (7.33 g, 28.1 mmol, 1 eq), and potassium acetate (5.51 g, 56.1 mmol, 2 eq) in dioxane (120 mL) at room temperature. The reaction mixture was stirred at 110°C for 16 h and then filtered. The filter cake was washed with EtOAc (200 mL x 2). The combined organic phases were concentrated under reduced pressure. The residue was purified by silica gel column chromatography to yield the desired product (8 g, 22.3 mmol, 79.5% yield).

[0488] 1H NMR(400MHz, CDCl3)δ9.19(m,1H)7.60(dd,J=9.17,5.62Hz,1H)7.18(m,1H)6.73(m,2H)5.29(br s,1H)1.22(m,21H)

[0489] Step 2: Preparation of 7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-ol

[0490] To a solution of 7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1,3-diol (7 g, 19.5 mmol, 1 eq) and DIEA (5.05 g, 39.0 mmol, 6.80 mL, 2 eq) in DCM (100 mL) at 0°C was added MOMCl (1.66 g, 20.6 mmol, 1.57 mL, 1.06 eq). The resulting reaction mixture was allowed to react at 25°C for 1.5 h, then quenched with H2O (200 mL), adjusted to pH 6-7 with 1N HCl, and extracted with DCM (80.0 mL x 2). The combined organic phases were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was isolated by silica gel column chromatography to yield the desired product (4.2 g, 10.4 mmol, 53.4% ​​yield).

[0491] 1 H NMR(400MHz, DMSO-d6)δ8.94-9.20(m,1H)8.93-9.13(m,1H)7.58(dd,J=9.07,5.69Hz,1H)7.10(t,J=8. 82Hz,1H)6.89(d,J=2.50Hz,1H)6.73(d,J=1.88Hz,1H)5.12-5.24(m,2H)3.43(s,3H)1.09-1.13(m,21H)

[0492] Step 3: Preparation of 7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl trifluoromethanesulfonate

[0493] To a solution of 7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-ol (4 g, 9.94 mmol, 1 eq) in DCM (40 mL) at -40°C were added DIEA (3.85 g, 29.8 mmol, 5.19 mL, 3 eq) and TfO (4.21 g, 14.9 mmol, 2.46 mL, 1.5 eq). The resulting reaction mixture was allowed to react at -40°C for 0.5 h, then diluted with H2O (20 mL) and extracted with DCM (50 mL x 2). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to yield the desired product as a yellow oil (5 g, 8.88 mmol, 89.4% yield, 95% purity).

[0494] 1 H NMR (400MHz, CDCl3) δ7.72 (dd, J=9.03, 5.27Hz, 1H) 7.44 (d, J=2.26Hz, 1H) 7.36-7. 39(m,1H)7.31-7.35(m,1H)5.20-5.37(m,2H)3.46-3.63(m,3H)1.17-1.33(m,17H)

[0495] Step 4: Preparation of ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane

[0496] Under nitrogen, Pd(dppf)Cl2 (684 mg, 935 μmol, 0.1 eq) was added to a solution of 7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl trifluoromethanesulfonate (5 g, 9.35 mmol, 1 eq), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1,3,2-dioxaborolane (4.75 g, 18.70 mmol, 2 eq), and AcOK (2.75 g, 28.06 mmol, 3 eq) in toluene (100 mL). The resulting reaction mixture was reacted at 130°C for 8 h and then filtered. The filtrate was concentrated under reduced pressure, and the residue was isolated by silica gel column chromatography to obtain the desired product (3.5 g, 6.49 mmol, 69.3% yield).

[0497] 1H NMR (400MHz, CDCl3) δ7.68 (dd, J=8.93, 5.62Hz, 1H) 7.52 (d, J=2.45Hz, 1H) 7.39 (d, J=2.57Hz, 1H)7.24(t,J=8.80Hz,1H)5.18-5.39(m,2H)3.43-3.58(m,3H)1.45(s,12H)1.15-1.21(m,20H)

[0498] Preparation of Intermediate 3-1(1R,5S)-3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0499] Step 1: Preparation of 2-chloro-3-fluoro-5-iodopyridin-4-amine

[0500] To a solution of 2-chloro-3-fluoropyridin-4-amine (10 g, 68.5 mmol) and NIS (18.5 g, 82.2 mmol, 1.2 eq) in acetonitrile (50 mL) was added p-toluenesulfonic acid monohydrate (0.65 g, 3.43 mmol, 0.05 eq). The reaction mixture was stirred at 70°C for 16 hours, then diluted with water (30 mL) and EtOAc (200 mL). The separated organic phase was washed sequentially with sodium sulfate, sodium sulfate, and saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to yield the desired product (16.6 g, 61 mmol, 89% yield). This product was used directly in the next step without purification.

[0501] LC-MS: m / z 273 (M+H) + .

[0502] Step 2: Preparation of 4-amino-6-chloro-5-fluoronicotinate

[0503] Under a nitrogen atmosphere, Pd(PPh3)2Cl2 (2.1 g, 3 mmol, 0.1 eq) and TEA (11.1 g, 0.11 mmol, 3.6 eq) were added to a solution of 2-chloro-3-fluoro-5-iodopyridin-4-amine (8.2 g, 30 mmol, 1.0 eq) in EtOH (150 mL). The resulting reaction solution was reacted at 80°C under a CO2 atmosphere for 15 hours and then filtered. The filtrate was concentrated under reduced pressure to 70-80% of its original volume and then filtered again. The filter cake was collected, combined, and vacuum-dried to obtain the desired product (quantitative yield). It was used directly in the next reaction without purification.

[0504] LC-MS: m / z 219 (M+H) + .

[0505] Step 3: Preparation of 7-chloro-8-fluoropyrido[4,3-d]pyrimidine-2,4-diol

[0506] To a solution of the above-obtained ethyl 4-amino-6-chloro-5-fluoronicotinate (657 mg, 3 mmol) in THF (7 mL) at 0°C was added trichloroacetyl isocyanate (673 mg, 3.6 mmol, 1.2 eq). The reaction mixture was allowed to react at room temperature for 30 minutes and then concentrated under reduced pressure. MeOH (15 mL) was added to the residue, which was cooled to 0°C, followed by addition of methanolic NH3 (7 M in MeOH, 15 mL, 105 mmol). The resulting reaction mixture was allowed to react at room temperature for 16 hours and then filtered. The filter cake was washed with methanol and then dried under vacuum to obtain the desired product (quantitative yield). The product was used directly in the next step without purification.

[0507] LC-MS: m / z 216 (M+H) + .

[0508] Step 4: Preparation of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine

[0509] A solution of 7-chloro-8-fluoropyrido[4,3-d]pyrimidine-2,4-diol (500 mg, 2.4 mmol) and DIPEA (1.55 g, 12 mmol, 5.0 eq) in POCl₃ (5 mL) was reacted at 100°C for 1 hour and then concentrated under reduced pressure to afford the title compound in quantitative yield. This product was used directly in the next reaction without purification.

[0510] LC-MS: m / z 252 (M+H) + .

[0511] Step 5: Preparation of tert-butyl (1R,5S)-3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0512] To a solution of the above-obtained 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine and DIPEA (2 g, 15.5 mmol) in DCM (2 mL) was added tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (500 mg, 2.4 mmol) at -40°C. The resulting reaction mixture was allowed to react at the current temperature for 0.5 h, then diluted with water (2 mL) and extracted with DCM (2 x 2 mL). The organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the desired product (400 mg, crude yield: 38.9%). This product was used directly in the next step without purification.

[0513] LC-MS: m / z 428 (M+H) + .

[0514] Preparation of Intermediate 4-1(1R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthyl-1-yl)-2-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0515] Step 1: Preparation of tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0516] DIEA (7.24 g, 56.0 mmol, 9.76 mL, 3.00 eq) was added to tert-butyl (1R,5S)-3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (8.00 g, 18.7 mmol, 1.00 eq) and 2,2,2-trifluoroethanol (56.1 g, 560 mmol, 40.3 mL, 30.0 eq). The resulting reaction mixture was reacted at 70°C for 2 h and then concentrated under reduced pressure. The residue was diluted with H2O (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic phases were washed with saturated laboratory water (100 mL), dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to yield the desired product (9 g, 18.3 mmol, 97.9% yield).

[0517] LC-MS: m / z 492 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ8.71(s,1H),4.82(q, J=8.4Hz,2H),4.44(br d,J=12.0Hz,2H),4.31(br s,2H),3.63(br s,2H),1.95-1.83(m,2H),1.68-1.58(m,2H),1.45(s,9H)

[0518] Step 2: Preparation of tert-butyl (1R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthyl-1-yl)-2-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0519] Under nitrogen atmosphere, to a mixed solution of (1R,5S)-3-(7-chloro-8-fluoro-2-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (9.00 g, 18.3 mmol, 1.00 eq), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (9.85 g, 19.2 mmol, 1.05 eq) and Cs2CO3 (11.9 g, 36.6 mmol, 2.00 eq) in H2O (20.0 mL) and dioxane (100 mL) was added CataCXium Pd G2 (611 mg, 915 μmol, 0.05 eq). The resulting reaction solution was reacted at 100°C for 1 h, then quenched with H2O (50 mL) and extracted with EtOAc (100 mL x 3). The combined organic phases were dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain the desired product (14.8 g, 17.6 mmol, 96.10% yield).

[0520] LC-MS: m / z 842 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ9.25(s,1H),8.11(dd,J=5.9,9.2Hz,1H),7.75(d,J=2.5Hz,1H),7. 57(t,J=8.9Hz,1H),7.35(d,J=2.4Hz,1H),5.76(s,1H),5.46-5.27(m,2H),5.21-4.91(m,2 H),4.81(d,J=12.4Hz,1H),4.38-4.17(m,3H),3.81(d,J=12.0Hz,1H),3.60-3.52(m,1H),3 .43(s,3H),1.63(d,J=7.4Hz,1H),1.46(s,9H),0.80(t,J=7.8Hz,20H),0.57-0.38(m,3H).

[0521] According to the synthesis method of intermediate 4-1, the following compounds were synthesized with different starting materials:

[0522] Intermediate 4-2(1R,5S)-3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0523] LC-MS: m / z 872 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ9.15(s,1H),7.17(br d,J=8.4Hz,4H),6.88(br d,J=8.4Hz,4H),6.82(s,1H),5.08(q,J=8.9Hz,2H),4.69(br s,4H),4.55(br d,J=12.1Hz,2H),4.27(br s,2H),3.73(s,6H),3.70-3.62(m,2H),2.39(br s,3H),1.85-1.76(m,2H),1.68(br d,J=7.5Hz,2H),1.47(s,9H).

[0524] Intermediate 4-tert-Butyl(1R,5S)-3-(7-(2-((tert-Butoxycarbonyl)amino)-7-fluorobenzo[d]thiazol-4-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0525] LC-MS: m / z 724 (M+H) + .

[0526] Intermediate 4-(1R,5S)-3-(7-(2-((tert-Butyloxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0527] LC-MS: m / z 748 (M+H) + . 1H NMR (400MHz, DMSO-d6) δ11.79(s,1H),9.21(s,1H),7.61(dd,J=5.3,8.4Hz,1H),7.42(t,J=8.8Hz,1H),5.11(q,J=9.1Hz,2H),4.57(br d,J=12.5Hz,2H),4.28(br s,2H),3.78-3.67(m,2H),1.82(br d,J=4.8Hz,2H),1.61(br d,J=7.5Hz,2H),1.52(s,9H),1.48(s,9H).

[0528] Intermediate 4-5 (1R, 5S)-3-(8-fluoro-7-(6-fluoro-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-2-(2,2,2-trifluoroethoxy)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0529] LC-MS: m / z 690 (M+H) + . 1 H NMR(400MHz, DMSO-d6)δ9.29(s,1H)7.75-7.81(m,2H)5.86(dd,J=9.68,1.98Hz,1H)5.12(q,J=9.17Hz,2H)4.51-4.72(m,2H)4.29(br s,2H)3.91(br d,J=11.88Hz,1H)3.76-3.84(m,1H)3.62-3.75(m,2H)2.32-2.47(m,1H)2.16-2.24(m,1H)2.19(s,2H)1.94-2.08(m,2H)1.83(br d,J=3.30Hz,2H)1.70(br d,J=7.48Hz,3H)1.59(br s,2H)1.48(s,9H).

[0530] Intermediate 4-6 (1R, 5S)-3-(8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(2,2,2-trifluoroethoxy)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0531] LC-MS: m / z 782 (M+H) + . 1H NMR (400MHz, DMSO-d6) δ9.26 (s, 1H) 8.24 (m, 2H) 7.66 (m, 3H) 5.08 (m, 2H) 4.83 (br d, J = 12.59Hz, 1H) 4.34 (m, 3H) 3.83 (br d,J=11.86Hz,1H)3.41(m,1H)1.91(br d,J=8.44Hz,2H)1.82(m,1H)1.65(m,1H)1.48(s,9H)0.82(m,18H)0.50(m,3H).

[0532] Intermediate 4-7(1R,5S)-3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0533] LC-MS: m / z 690 (M+H) + . 1 H NMR(400MHz, CDCl3)δ9.08(s,1H)7.71(dd,J=9.01,5.88Hz,1H)7.55(d,J=2.63Hz,1H)7.28(s,1 H)7.23(d,J=2.50Hz,1H)5.31(d,J=2.13Hz,2H)4.94(q,J=8.38Hz,2H)4.54-4.67(m,2H)4.44(br s,2H)3.60-3.90(m,2H)3.53(s,3H)2.51(br dd,J=13.95,7.07Hz,1H)2.23(ddd,J=14.32,7.32,2.75Hz,1H)2.00-2.06(m,2H)1.81(br d,J=8.38Hz,2H)1.26(s,9H)0.85(t,J=7.44Hz,3H).

[0534] Intermediate 4-8 tert-Butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthyl-1-yl)-2-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,9-diazabicyclo[4.2.1]nonane-9-carboxylate

[0535] LC-MS: m / z 856 (M+H) + . 1H NMR(400MHz,DMSO-d6)δ9.15-9.32(m,1H)8.05-8.19(m,1H)7.76(br d,J=2.32Hz,1H)7.50-7.64(m,1H)7.14-7.46(m,1H)5.28-5.43(m,2H )4.94-5.20(m,2H)4.08-4.51(m,4H)3.49-3.80(m,1H)3.39-3.48(m,3 H)3.29-3.34(m,3H)2.01-2.21(m,2H)1.50-1.77(m,2H)1.44(s,3H)1. 20(s,3H)0.94-1.06(m,3H)0.81(t,J=6.48Hz,18H)0.40-0.61(m,3H).

[0536] Intermediate 4-9(tert-butyl 1-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthyl-1-yl)-2-(2,2,2-trifluoroethoxy)pyridin[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-yl)carbamate

[0537] LC-MS: m / z 842 (M+H) + . 1 H NMR(400MHz, DMSO-d6)δ9.01-9.27(m,1H)8.12(dd,J=9.17,5.87Hz,1H)7.73-7.80(m,1H)7.58(t,J=8.93Hz,1H)7 .35-7.41(m,1H)7.12-7.20(m,1H)6.41-6.65(m,1H)5.32-5.42(m,2H)5.08-5.19(m,1H)4.92-5.05(m,1H)4.40(br d,J=12.35Hz,1H)3.63-3.74(m,1H)3.44(s,3H)3.35-3.41(m,1H)3.28-3.34(m,2H)2.01-2.14(m,1H)1.84-1.9 5(m,1H)1.50-1.83(m,2H)1.30-1.41(m,3H)1.21-1.27(m,2H)1.12(s,6H)0.72-0.88(m,18H)0.34-0.58(m,3H)

[0538] Intermediate 4-10 (1R, 5S)-3-(7-(3-((bis-tert-butyloxycarbonyl)amino)-2-fluoro-5-methyl-6-(trifluoromethyl)phenyl)-8-fluoro-2-(2,2,2-trifluoroethoxy)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0539] LC-MS: m / z 849 (M+H) + . 1 H NMR(400MHz, DMSO-d6)δ9.24(s,1H)7.82(d,J=9.26Hz,1H)5.11(q,J=9.01Hz,2H)4.57(br d,J=12.38Hz,2H)4.29(br s,2H)3.69(br d,J=12.26Hz,2H)2.28(br s,3H)1.82(br d,J=4.13Hz,2H)1.66(br d,J=7.50Hz,2H)1.47(s,9H)1.38(s,18H).

[0540] Intermediate 4-11(1R,5S)-3-(7-(2-((bis-tert-butyloxycarbonyl)amino)-3,5-dichloro-6-fluorophenyl)-8-fluoro-2-(2,2,2-trifluoroethoxy)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0541] LC-MS: m / z 835 (M+H) + . 1 H NMR (400MHz, CDCl3) δ9.00 (s, 1H) 7.68 (d, J = 7.09Hz, 1H) 4.81-5.01 (m, 2H) 4.64-4.77 (m, 1H) 4.34-4.49 (m, 3H) 3.59-3.89 (m, 2H) 2.02 (br d,J=1.47Hz,2H)1.79-1.86(m,4H)1.78-1.86(m,1H)1.53-1.59(m,10H)1.43-1.51(m,9H)1.16-1.27(m,8H).

[0542] Intermediate 4-12(1R,5S)-3-(7-(5-((bis-tert-butyloxycarbonyl)amino)-3-chloro-2-(trifluoromethyl)phenyl)-8-fluoro-2-(2,2,2-trifluoroethoxy)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0543] LC-MS: m / z 851 (M+H) + . 1 H NMR(400MHz, DMSO-d6)δ9.06(br s,1H)7.52(s,1H)7.20(br s,1H)4.92(br d,J=7.46Hz,2H)4.44(br s,4H)3.74(br s,2H)2.02(br s,2H)1.78(br s,2H)1.55(s,9H)1.48(s,18H).

[0544] Intermediate 4-13 (1R,5S)-3-(7-(3-(bis(4-methoxybenzyl)amino)-2-fluoro-5-methyl-6-(trifluoromethyl)phenyl)-8-methoxy-2-(2,2,2-trifluoroethoxy)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0545] LC-MS: m / z 901 (M+H) + . 1 H NMR(400MHz,DMSO-d6)δ8.99-9.10(m,1H)7.26-7.45(m,1H)7.02-7.23(m ,4H)6.75-6.96(m,4H)4.98-5.21(m,2H)4.47-4.55(m,2H)4.21-4.29(m,2 H)4.04-4.13(m,4H)3.81-3.88(m,3H)3.71-3.78(m,6H)3.60-3.69(m,2H )2.00-2.12(m,3H)1.77-1.87(m,2H)1.62-1.71(m,2H)1.41-1.51(m,9H).

[0546] Intermediate 4-14 (1R, 5S)-3-(7-(5-(bis(tert-butylcarbonyl)amino)-3-chloro-2-(trifluoromethyl)phenyl)-8-yloxy-2-(2,2,2-trifluoroethoxy)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0547] LC-MS: m / z 863 (M+H) + . 1H NMR (400MHz, DMSO-d6) δ9.06(s,1H),7.88(s,1H),7.37-7.27(m,1H),5.09(br d,J=9.0Hz,2H),4.65-4.39(m,2H),4.28(br s,2H),3.95-3.87(m,3H),3.76-3.53(m,2H),1.82(br s,2H),1.74-1.57(m,2H),1.47(s,9H),1.42-1.39(m,18H)

[0548] Intermediate 4-15 (1R, 5S)-3-(7-(3-acetylamino-5-chloro-2-fluoro-6-(trifluoromethyl)phenyl)-8-fluoro-2-(2,2,2-trifluoroethoxy)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0549] LC-MS: m / z 711 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ10.37(s,1H),9.24(s,1H),8.68(br d,J=6.9Hz,1H),5.10(q,J=9.0Hz,2H),4.56(br d,J=8.6Hz,2H),4.29(br s,2H),3.69(br t,J=12.2Hz,2H),2.19(s,3H),1.82(br s,2H),1.71(br d,J=9.6Hz,2H),1.47(s,9H).

[0550] Intermediate 4-16 (1R, 5S)-3-(7-(3-acetylamino-2,5-dichloro-6-(trifluoromethyl)phenyl)-8-fluoro-2-(2,2,2-trifluoroethoxy)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0551] LC-MS: m / z 727 (M+H) + . 1H NMR(400MHz, DMSO-d6)δ9.99(s,1H)9.25(s,1H)8.51(s,1H)4.98-5.20(m,2H)4.54(br d,J=11.66Hz,2H)4.29(br s,2H)3.68(br d,J=7.48Hz,2H)2.21(s,3H)1.82(br d,J=3.30Hz,2H)1.70(br d,J=7.92Hz,2H)1.46(s,9H).

[0552] Intermediate 4-17 (1R, 5S)-3-(7-(3-acetylamino-2-chloro-5-fluoro-6-(trifluoromethyl)phenyl)-8-fluoro-2-(2,2,2-trifluoroethoxy)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0553] LC-MS: m / z 711 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ9.98 (s, 1H) 9.26 (s, 1H) 8.34 (d, J = 13.63Hz, 1H) 5.11 ( q,J=8.84Hz,2H)4.48-4.62(m,2H)4.22-4.36(m,2H)3.59-3.79(m,1H)3.69(br t,J=12.82Hz,1H)2.18-2.26(m,3H)1.79-1.88(m,2H)1.71(br d,J=7.75Hz,2H)1.42-1.51(m,9H).

[0554] Intermediate 4-18 (1R,5S)-3-(7-(3-amino-2,6-dichloro-5-fluorophenyl)-8-fluoro-2-(2,2,2-trifluoroethoxy)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0555] LC-MS: m / z 635 (M+H) + .

[0556] Intermediate 4-19 (1R, 5S)-3-(7-(5-acetylamino-3-chloro-2-(trifluoromethyl)phenyl)-8-fluoro-2-(2,2,2-trifluoroethoxy)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0557] LC-MS: m / z 693 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ10.60(s,1H),9.19(s,1H),8.09-7.97(m,1H),7.73(s,1H),5.10(q,J=9.1Hz,2H),4.56(br s,2H),4.28(br s,2H),3.76-3.63(m,2H),2.11(s,3H),1.82(br s,2H),1.73-1.63(m,2H),1.47(s,9H).

[0558] Intermediate 4-20 (1R,5S)-3-(7-(3-chloro-5-(methylsulfonamido)-2-(trifluoromethyl)phenyl)-8-fluoro-2-(2,2,2-trifluoroethoxy)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0559] LC-MS: m / z 729 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ10.81(s,1H),9.20(s,1H),7.58(d,J=1.8Hz,1H),7.22(d,J=1.9Hz,1H),5.10(q,J=9.0Hz,2H),4.56(br s,2H),4.28(br s,2H),3.69(br d,J=12.5Hz,2H),3.23(s,3H),1.81(br s,2H),1.68(br d,J=7.3Hz,2H),1.47(s,9H).

[0560] Intermediate 4-21 (1R, 5S)-3-(7-(5-(bis-tert-butoxycarbonylamino)-3-chloro-4-fluoro-2-(trifluoromethyl)phenyl)-8-fluoro-2-(2,2,2-trifluoroethoxy)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0561] LC-MS: m / z 869 (M+H) + . 1H NMR (400MHz, CDCl3) δ9.03(br s,1H),7.26-7.21(m,1H),4.90(br d,J=6.8Hz,2H),4.66-4.34(m,4H),3.85-3.59(m,2H),2.00(br s,2H),1.76(br s,2H),1.52(s,9H),1.45(s,18H)

[0562] Intermediate 4-22 (1R,5S)-3-(7-(5-(bis(4-methoxybenzyl)amino)-3-methyl-4-fluoro-2-(trifluoromethyl)phenyl)-8-fluoro-2-(2,2,2-trifluoroethoxy)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0563] LC-MS: m / z 889 (M+H) + . 1 H NMR(400MHz, DMSO-d6)δ8.93-8.86(m,1H),7.10-7.02(m,4H),6.85-6.71(m,4H),6.66-6.53(m,1H),4.94-4.76(m, 2H),4.57-4.29(m,4H),4.26(s,4H),3.72(s,6H),3.68-3.55(m,2H),2.47-2.32(m,3H),1.95-1.87(m,2H),1.68(br d,J=7.9Hz,2H),1.45(s,9H).

[0564] Intermediate 4-23 (1R,5S)-3-(7-(5-amino-3-fluoro-2-(trifluoromethyl)phenyl)-8-fluoro-2-(2,2,2-trifluoroethoxy)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0565] LC-MS: m / z 635 (M+H) + .

[0566] Intermediate 4-24 (1R,5S)-3-(7-(5-amino-3-cyano-2-(trifluoromethyl)phenyl)-8-fluoro-2-(2,2,2-trifluoroethoxy)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0567] LC-MS: m / z 642 (M+H)+ . 1 H NMR (400MHz, CDCl3) δ9.39-8.96(m,1H),7.41(br s,1H),6.91-6.73(m,1H),6.62(br s,2H),5.24-4.96(m,2H),4.54(br s,2H),4.28(br s,2H),3.68(br d,J=10.4Hz,2H),1.81(br s,2H),1.68(br s,2H),1.55-1.36(m,9H).

[0568] Intermediate 4-25 (1R,5S)-3-(7-(5-amino-3-chloro-2-fluorophenyl)-8-fluoro-2-(2,2,2-trifluoroethoxy)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0569] LC-MS: m / z 601 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ9.20 (s, 1H), 6.82 (m, 2H), 5.50 (s, 2H), 5.11 (q, J = 9.0Hz, 2H), 4.57 (d, J = 1 2.5Hz,2H),4.28(s,2H),3.68(d,J=12.3Hz,2H),1.80(s,2H),1.68(d,J=7.3Hz,2H),1.44(s,9H).

[0570] Intermediate 4-26 (1R,5S)-3-(7-(5-amino-3-chloro-2-cyanophenyl)-8-fluoro-2-(2,2,2-trifluoroethoxy)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0571] LC-MS: m / z 608 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ9.21 (s, 1H), 6.87 (d, J = 2.1Hz, 1H), 6.80 (d, J = 1.8Hz, 1H), 5.10 (q, J = 9.0Hz, 2H), 4. 56(d,J=12.1Hz,2H),4.28(s,2H),3.68(d,J=12.2Hz,2H),1.81(s,2H),1.68(d,J=7.4Hz,2H),1.47(s,9H).

[0572] Intermediate 4-27 (1R, 5S)-3-(7-(5-amino-2-chloro-3-(trifluoromethyl)phenyl)-8-fluoro-2-(2,2,2-trifluoroethoxy)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0573] LC-MS: m / z 651 (M+H) + .

[0574] Intermediate 4-28 (1R,5S)-3-(7-(5-amino-2-cyano-3-(trifluoromethyl)phenyl)-8-fluoro-2-(2,2,2-trifluoroethoxy)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0575] LC-MS: m / z 642 (M+H) + .

[0576] Intermediate 4-29 (1R,5S)-3-(7-(5-amino-2-chloro-3-cyanophenyl)-8-fluoro-2-(2,2,2-trifluoroethoxy)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0577] LC-MS: m / z 608 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ9.21(s,1H),7.14(d,J=2.7Hz,1H),7.02(d,J=2.7Hz,1H),5.10(dt,J=9.1,7.0Hz ,2H),4.56(s,2H),4.29(s,2H),3.68(d,J=12.2Hz,2H),1.81(s,2H),1.69(d,J=7.5Hz,2H),1.48(s,11H).

[0578] Intermediate 4-30 (1R,5S)-3-(7-(5-amino-2,3-dichlorophenyl)-8-fluoro-2-(2,2,2-trifluoroethoxy)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0579] LC-MS: m / z 617 (M+H) + .

[0580] Intermediate 4-31 (1R,5S)-3-(7-(3-amino-6-chloro-2-cyanophenyl)-8-fluoro-2-(2,2,2-trifluoroethoxy)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0581] LC-MS: m / z 608 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ9.27(s,1H),7.53(d,J=9.1Hz,1H),6.97(d,J=9.1Hz,1H),6.46(s,2H),5.10(q,J=9.0Hz,2H),4.64(d,J=12.3Hz, 1H),4.47(d,J=11.9Hz,1H),4.28(s,2H),3.76(d,J=11.4Hz,1H),3.59(s,1H),1.83–1.64(m,4H),1.47(s,8H).

[0582] Intermediate 4-32 (1R,5S)-3-(7-(5-(benzyloxy)-3-chloro-2-(trifluoromethyl)phenyl)-8-fluoro-2-(2,2,2-trifluoroethoxy)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0583] LC-MS: m / z 742 (M+H) + .

[0584] Intermediate 4-33 (1R,5S)-3-(7-(5-amino-2-(trifluoromethyl)pyridin-3-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0585] LC-MS: m / z 618 (M+H) + . 1H NMR(400MHz, DMSO-d6)δ9.18(s,1H)8.12(d,J=2.20Hz,1H)6.87(s,1H)6.32(br d,J=4.18Hz,2H)5.09(q,J=9.17Hz,2H)4.55(br d,J=12.10Hz,2H)4.27(br s,2H)3.67(br d,J=11.44Hz,2H)1.93(br s,2H)1.80(br s,2H)1.35(s,9H).

[0586] Intermediate 4-34 (1R,5S)-3-(7-(5-amino-4-(trifluoromethyl)pyridin-3-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0587] LC-MS: m / z 618 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ9.18(s,1H),8.38(s,1H),7.73(s,1H),6.26(s,2H),5.09(q,J=9.0Hz,2H),4.55(br d,J=11.6Hz,2H),4.28(br s,2H),3.67(br d,J=10.3Hz,2H),1.82(br s,2H),1.67(br d,J=7.5Hz,2H),1.47(s,9

[0588] H).

[0589] Intermediate 4-35 (1R,5S)-3-(7-(5-amino-4-methyl-2-(trifluoromethyl)pyridin-3-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0590] LC-MS: m / z 632 (M+H) + . 1H NMR(400MHz, DMSO-d6)δ9.23(s,1H)8.12(s,1H) 6.02-6.16(m,2H)5.00-5.21(m,2H)4.55(br t,J=14.42Hz,2H)4.30(br s,2H)3.60-3.80(m,2H)2.40-2.48(m,3H)1.83(br d,J=1.76Hz,2H)1.70(br d,J=7.92Hz,2H)1.47(s,9H).

[0591] Intermediate 4-36 (1R,5S)-3-(7-(6-(bis(4-methoxybenzyl)amino)-2-methyl-3-(trifluoromethyl)pyridin-4-yl)-8-fluoro-2-(2,2,2-trifluoroethoxy)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0592] LC-MS: m / z 872 (M+H) + . 1 H NMR(400MHz, DMSO-d6)δ9.12(s,1H),7.26–7.11(m,4H),6.89(d,J=8.4Hz,4H),6.50(s,1H),5.07(q,J=9.0Hz,2H),4.85–4.68(m,4H), 4.59–4.43(m,2H),4.32–4.21(m,2H),3.73(s,6H),3.70–3.60(m,2H),2.60(s,3H),1.85–1.76(m,2H),1.69–1.60(m,2H),1.46(s,9H).

[0593] Intermediate 4-37 (1R,5S)-3-(8-fluoro-7-(1-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4-yl)-2-(2,2,2-trifluoroethoxy)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0594] LC-MS: m / z 726 (M+H) + . 1H NMR (400MHz, DMSO-d6) δ9.27(d,J=5.0Hz,1H),8.12(d,J=8.9Hz,1H),7.91(d, J=8.2Hz,2H),6.09-5.93(m,1H),5.21-5.02(m,2H),4.59(t,J=12.0Hz,2H),4. 45-4.18(m,2H),3.92(d,J=7.8Hz,1H),3.85-3.54(m,3H),2.38(dd,J=22.2,12 .9Hz,1H),2.03(d,J=6.9Hz,2H),1.94-1.66(m,5H),1.61(s,2H),1.47(s,9H).

[0595] Example 1 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((3-(methoxymethyl)tetrahydro-1H-bis-fused pyrrolidin-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

[0596] Step 1: Preparation of tert-butyl (1R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((3-(methoxymethyl)tetrahydro-1H-bis-fused pyrrolidin-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0597] To a solution of (3-(methoxymethyl)tetrahydro-1H-bisfused pyrrolidin-7a(5H)-yl)methanol (1.01 g, 5.45 mmol, 4.59 eq) and (1R,5S)-tert-butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthyl-1-yl)-2-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.00 g, 1.19 mmol, 1.00 eq) in THF (20 mL) was added t-BuONa (913 mg, 9.50 mmol, 8.00 eq). The reaction mixture was allowed to react at 25°C for 16 h, then quenched with H₂O (10 mL) and extracted with EtOAc (30 mL x 3). The combined organic phases were washed with saturated laboratory water (100 mL), dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain the desired product (723 mg, 257 μmol, 21.7% yield, 33.0% purity). This product was used directly in the next reaction without purification.

[0598] Step 2: Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((3-(methoxymethyl)tetrahydro-1H-bis-fused pyrrolidin-7a(5H)-yl)methoxymethyl)pyridin[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol

[0599] To a solution of tert-butyl (1R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((3-(methoxymethyl)tetrahydro-1H-bis-fused pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (670 mg, 238 μmol, 33.0% purity, 1.00 eq) in DCM (6 mL) was added HCl / dioxane (4.00 M, 945 μL, 15.8 eq). The reaction mixture was stirred at 25°C for 2 h and then concentrated under reduced pressure to afford the desired product (430 mg, crude). This product was used directly in the next step without purification.

[0600] Step 3: Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((3-(methoxymethyl)tetrahydro-1H-bis-fused pyrrolidin-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

[0601] To a solution of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((3-(methoxymethyl)tetrahydro-1H-bis-fused pyrrolidin-7a(5H)-yl)methoxymethyl)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol (400 mg, 163 μmol, 32.0% purity, 1.00 eq) in DMF (6 mL) was added CsF (497 mg, 3.27 mmol, 121 μL, 20.0 eq). The reaction mixture was reacted at 25°C for 16 h and then filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by prep-HPLC to obtain the desired product (63.0 mg).

[0602] LC-MS: m / z 627 (M+H) + .

[0603] Chiral SFC separation gave Example 1 Isomer 1 (11.3 mg, 17.6 umol, 10.8% yield) and Example 1 Isomer 2 (19.2 mg, 29.9 umol, 18.3% yield).

[0604] Example 1 Isomer 1

[0605] LC-MS: m / z 627 (M+H) + . 1 H NMR(400MHz,DMSO-d6)δ10.17(br s,1H)9.03(s,1H)7.98(dd,J=9.16,5.90Hz,1H)7.47(t,J=8.91Hz,1H)7.39(d,J=2.51Hz,1H)7.18(d,J=2.26Hz,1H)4.48(br d,J=11.80Hz,1H)4.31(br d,J=12.30Hz,1H)3.95-4.08(m,2H)3.94(s,1H)3.64(br d,J=12.05Hz,1H)3.57(br s,3H)3.17-3.28(m,5H)2.79-2.94(m,2H)2.65-2.70(m,1H)1.90-2.06(m,2H)1.78(br d,J=4.52Hz,3H)1.51-1.69(m,8H).

[0606] Example 1 Isomer 2

[0607] LC-MS: m / z 627 (M+H) + . 1H NMR(400MHz,DMSO-d6)δ10.17(br s,1H)9.04(s,1H)7.98(dd,J=9.16,5.90Hz,1H)7.47(t,J=9.03Hz,1H)7.40(d,J=2.51Hz,1H)7.18(d,J=2.26Hz,1H)4.49(br d,J=12.05Hz,1H)4.32(br d,J=12.30Hz,1H)3.96-4.10(m,2H)3.94(s,1H)3.65(br d,J=14.31Hz,1H)3.56-3.62(br s,3H)3.17-3.28(m,5H)2.80-2.95(m,2H)2.68(br d,J=1.76Hz,1H)1.90-2.03(m,2H)1.78(br s,3H)1.51-1.72(m,8H).

[0608] Example 1 Isomer 1 and Example 1 Isomer 2 were separated again by SFC to give Example 1 Isomer 1A, Example 1 Isomer 1B, Example 1 Isomer 2A and Example 1 Isomer 2B: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((3S,7aR)-(3-(methoxymethyl)tetrahydro-1H- Bis-fused pyrrolidin-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol, 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((3R,7aS)-(3-(methoxymethyl)tetrahydro-1H-bis-fused pyrrolidin-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((3R,7aR)-(3-(methoxymethyl)tetrahydro-1H-bis-fused pyrrolidin-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol, 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((3R,7aR)-(3-(methoxymethyl)tetrahydro-1H-bis-fused pyrrolidin-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((3S,7aS)-(3-(methoxymethyl)tetrahydro-1H-bis-fused pyrrolidin-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

[0609] Example 1 Isomer 1A

[0610] LC-MS: m / z 627 (M+H) + . 1 H NMR(400MHz,DMSO-d6)δ10.14(s,1H),9.03(s,1H),7.98(dd,J=9.20,5.92Hz,1H), 7.46(t,J=9.00Hz,1H),7.39(d,J=2.64Hz,1H),7.17(d,J=2.56Hz,1H),4.47(d,J=1 2.44Hz,1H),4.30(d,J=12.32Hz,1H),3.97-4.07(m,2H),3.92(s,1H),3.56-3.66(m ,4H),3.17-3.27(m,5H),2.79-2.92(m,2H),2.63-2.69(m,1H),1.51–2.03(m,13H).

[0611] Example 1 Isomer 1B

[0612] LC-MS: m / z 627 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ10.14 (s, 1H), 9.03 (s, 1H), 7.98 (dd, J = 9.24, 5.92Hz, 1H), 7.46(t,J=9.00Hz,1H),7.39(d,J=2.56Hz,1H),7.17(d,J=2.60Hz,1H),4.47(d,J=1 2.32Hz,1H),4.30(d,J=12.24Hz,1H),3.97-4.07(m,2H),3.92(s,1H),3.56-3.66(m ,4H),3.17-3.27(m,5H),2.80-2.92(m,2H),2.63-2.68(m,1H),1.51–2.04(m,13H).

[0613] Example 1 Isomer 2A

[0614] LC-MS: m / z 627 (M+H) + . 1H NMR (400MHz, DMSO-d6) δ10.15(s,1H),9.03(s,1H),7.99-7.95(m,1H),7.46(t,J=8Hz,1H),7.39(s,1H),7.18(s,1H),4.47(d,J=8Hz,1H), 4.30(d,J=8Hz,1H),4.11(d,J=4Hz,1H),4.01(d,J=4Hz,1H),3.93(s,1H),3.63(d,J=8Hz,1H),3.57-3.53(m,3H),3.4 4-3.40(m,1H),3.25(s,3H),3.19(s,2H),2.72-2.64(m,2H),2.05-1.97(m,2H),1.71-1.56(m,9H),1.52-1.44(m,1H).

[0615] Example 1 Isomer 2B

[0616] LC-MS: m / z 627 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ10.15(s,1H),9.04(s,1H),7.96(m,1H),7.46(t,J=8Hz,1H),7.39(m,1H),7. 18(m,1H),4.65-4.56(m,1H),4.48-4.39(m,1H),4.30(d,J=8Hz,1H),4.15-4.06(m,1H),4.02(t,J=4 Hz,1H),3.93(s,1H),3.85-3.75(m,1H),3.63(d,J=4Hz,1H),3.58-3.54(m,3H),3.44-3.40(m,2H),3 .25(s,3H),3.18(s,2H),2.72-2.66(m,2H),2.07-2.02(m,3H),1.71-1.57(m,7H),1.51-1.44(m,1H).

[0617] The following examples were synthesized using different starting materials according to the method of Example 1:

[0618] Example 2 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((3-((ethoxy)methyl)tetrahydro-1H-bis-fused pyrrolidin-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

[0619] LCMS: m / z 641 (M+H) + .

[0620] Example 3 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((3-((isopropoxy)methyl)tetrahydro-1H-bis-fused pyrrolidin-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

[0621] LCMS: m / z 655 (M+H) + .

[0622] Example 4 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((3-((cyclopropylmethyloxy)methyl)tetrahydro-1H-bis-fused pyrrolidin-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

[0623] LCMS: m / z 667 (M+H) + .

[0624] Example 5 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((3-(cyclopropyloxymethyl)tetrahydro-1H-bis-fused pyrrolidin-7a(5H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

[0625] LCMS: m / z 653 (M+H) + .

[0626] Example 6 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R)-2-fluoro-5-(methoxymethyl)tetrahydro-1H-bis-fused pyrrolidin-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

[0627] LCMS: m / z 645 (M+H) + .

[0628] Isomer 6A and isomer 6B were obtained by chiral separation: cis-4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R)-2-fluoro-5-(methoxymethyl)tetrahydro-1H-bis-fused pyrrolidin-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl -6-fluoronaphthalen-2-ol and trans-4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R)-2-fluoro-5-(methoxymethyl)tetrahydro-1H-bis-fused pyrrolidin-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

[0629] Isomer 6A

[0630] LCMS: m / z 645 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ10.17(s,1H),9.03(s,1H),7.97(q,J=8Hz,1H),7.47(t,J=8Hz,1H ),7.39(s,1H),7.18(d,J=4Hz,1H),5.47-5.32(m,1H),4.50(d,J=8Hz,1H),4.31(d,J=8Hz, 1H),4.07(s,2H),3.96(s,1H),3.66(d,J=12Hz,1H),3.56(s,3H),3.28-3.21(m,6H),3.00- 2.85(m,3H),2.36-2.24(m,1H),2.087-1.92(m,3H),1.86-1.82(m,1H),1.73-1.58(m,6H).

[0631] Isomer 6B

[0632] LCMS: m / z 645 (M+H) + . 1H NMR (400MHz, DMSO-d6) δ10.14 (s, 1H), 9.03 (s, 1H), 7.98 (dd, J = 5.92Hz, 9.20Hz, 1H), 7.46(t,J=9.00Hz,1H),7.38(d,J=2.52Hz,1H),7.17(d,J=2.48Hz,1H),5.34(m,0.5H) ,5.20(m,0.5H),4.47(m,1H),4.29(m,1H),4.18(m,1H),4.10(m,1H),3.94(d,J=5.28H z,1H),3.63(m,1H),3.48(m,5H),3.26(s,3H),3.00(m,2H),2.29(m,1H),1.72(m,9H).

[0633] Example 7 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((2R)-5-(cyclopropyloxymethyl)-2-fluorotetrahydro-1H-bis-fused pyrrolidin-7a(5H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

[0634] LCMS: m / z 671 (M+H)+.

[0635] Example 8A and Example 8B cis 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((3-(trifluoromethoxymethyl)tetrahydro-1H-bis-fused pyrrolidin-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol and trans 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((3-(trifluoromethoxymethyl)tetrahydro-1H-bis-fused pyrrolidin-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

[0636] Example 8A

[0637] LCMS: m / z 681 (M+H) + .

[0638] Example 8B

[0639] LCMS: m / z 681 (M+H) + .

[0640] Example 9 4-(4-(1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(dihydro-1'H,3'H-spiro[1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoro-naphthalen-2-ol

[0641] LCMS: m / z 609 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ10.15(s,1H),9.03(m,1H),7.97(t,J=8Hz,1H),7.46(t,J=8Hz,1H ),7.39(d,J=4Hz,1H),7.18-7.17(m,1H),4.47(t,J=8Hz,1H),4.34-4.21(m,2H),4.08-4. 04(m,1H),3.94(d,J=4Hz,1H),3.63(t,J=8Hz,1H),3.55(s,3H),2.99-2.94(m,1H),2.74- 2.61(m,3H),2.03-1.85(m,3H),1.83-1.76(m,3H),1.71-1.66(m,4H),0.49-0.45(m,4H).

[0642] Example 10 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((6'R)-6'-fluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

[0643] LCMS: m / z 627 (M+H) + .

[0644] Example 10 was chiral resolved to give isomers 10A and 10B: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((6'R,7a'S)-6'-fluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl Alkynyl-6-fluoronaphthalen-2-ol and 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((6'R,7a'R)-6'-fluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

[0645] Isomer 10A:

[0646] LCMS: m / z 627 (M+H) + . 1 H NMR(400MHz,DMSO-d6)δ10.18(s,1H),9.06(s,1H),7.99(dd,J=5.92,9.24Hz,1H), 7.48(t,J=9.00Hz,1H),7.40(d,J=2.56Hz,1H),7.19(m,1H),5.41(m,0.5H),5.28( m,0.5H),4.49(m,1H),4.35(m,2H),4.09(d,J=10.24Hz,1H),3.95(m,1H),3.58(m, 4H),3.27(m,2H),3.11(m,3H),2.70(m,1H),2.16(m,3H),1.68(m,4H),0.51(m,4H).

[0647] Isomer 10B:

[0648] LCMS: m / z 627 (M+H) + . 1H NMR (400MHz, DMSO-d6) δ9.02 (s, 1H), 7.99 (dd, J = 5.96, 9.16Hz, 1H), 7.48 (t, J = 9.04Hz, 1H), 7.4 0(d,J=2.52Hz,1H),7.16(m,1H),5.48(m,0.5H),5.35(m,0.5H),4.48(m,1H),4.30(m,2H),4.12 (m,1H),3.93(s,1H),3.58(m,4H),3.26(m,2H),3.01(m,0.5H),2.89(m,0.5H),2.80(d,J=9.92H z, 1H), 2.62 (d, J = 9.92Hz, 1H), 2.32 (m, 1H), 2.03 (m, 2H), 1.82 (m, 3H), 1.65 (m, 3H), 0.48 (m, 4H).

[0649] Example 11 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((tetrahydrospiro[cyclopropane-1,3'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)pyrido[4,3d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

[0650] LCMS: m / z 609 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ9.03 (m, 1H), 7.95 (dd, J = 6.00, 9.28Hz, 1H), 7.45 (t, J =9.00Hz,1H),7.37(d,J=2.56Hz,1H),7.18(m,1H),4.49(m,2H),4.32(m,1H),4 .14(m,2H),3.92(m,1H),3.76(m,1H),3.62(m,1H),3.58(m,1H),2.90(m,1H), 2.63(m,1H),2.04(m,7H),1.63(m,6H),1.24(m,1H),0.75(m,1H),0.58(m,1H), 0.43(m,1H),0.33(m,1H).

[0651] Examples 12A and 12B were synthesized using intermediates 1-13A and 1-13B as raw materials: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((trans)-6'-fluorotetrahydrospiro[cyclopropane-1,3'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)pyrido[4,3-d]pyrimidine-7- 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((cis)-6'-fluorotetrahydrospiro[cyclopropane-1,3'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

[0652] Example 12A

[0653] LCMS: m / z 627 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ10.15(s,1H),9.04(s,1H),7.99-7.95(m,1H),7.46(t,J=8Hz,1H),7.39(d,J=4Hz 1H),7.18(d,J=4Hz 1H),5.25(d,J=4Hz,1H),4.49(d,J=12Hz,1H),4.32(d,J=12Hz,1H),4.25-4.17(m ,2H),3.94(s,1H),3.65(d,J=12Hz,1H),3.57(d,J=8Hz,3H),3.26-3.14(m,1H),3. 05-2.96(m,1H),2.39-2.22(m,2H),2.15-2.05(m,1H),2.00-1.95(m,2H),1.65(s ,4H),1.34-1.23(m,1H),0.85-0.75(m,1H),0.61-0.55(m,1H),0.45-0.37(m,2H).

[0654] Example 12B

[0655] LCMS: m / z 627 (M+H) + . 1H NMR (400MHz, DMSO-d6) δ10.19(s,1H),9.03(s,1H),7.99-7.95(m,1H),7.46(t,J=8Hz,1H),7.39(d,J=4Hz 1H),7.18(d,J=4Hz 1H),5.34(d,J=4Hz,1H),4.50(d,J=12Hz,1H),4.31-4.27(m,1H),4.27-4.16(m,2H),3. 95(d,J=4Hz,1H),3.66(d,J=12Hz,1H),3.57(d,J=12Hz,3H),3.23-3.15(m,1H),2.99-2. 85(m,1H),2.40-2.31(m,1H),2.17-2.09(m,1H),2.05-1.86(m,3H),1.65(s,4H),1.34-1 .23(m,2H),0.81-0.76(m,1H),0.64-0.58(m,1H),0.52-0.46(m,1H),0.38-0.33(m,1H).

[0656] Example 13 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((7',7'-difluorotetrahydro-3'-H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-8a'(1'H)-yl)methoxy)-8-fluoropyrido[4,3d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol trifluoroacetate

[0657] LCMS: m / z 659 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ10.25(br,1H),9.42(m,1H),9.15(m,2H),8.00(dd,J=6.00,9.20Hz,1H),7.47(t,J=9.20Hz,1H),7.42(d,J=2.40Hz,1H), 7.19(m,1H),4.63(m,5H),4.23(s,2H),3.91(m,4H),3.52(m,1H),3.39( m,4H),3.52(m,1H),3.39(m,1H),2.53(m,1H),1.97(m,5H),0.74(m,4H).

[0658] Example 14 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((6',6'-difluorotetrahydro-3'-H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-8a'(1'H)-yl)methoxy)-8-fluoropyrido[4,3d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

[0659] LCMS: m / z 645 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ10.15(s,1H),9.05(s,1H),7.97(dd,J=5.92,9.24Hz,1H),7.46 (t,J=9.00Hz,1H),7.39(d,J=2.60Hz,1H),7.18(s,1H),4.64(dd,J=2.92,10.88Hz,1H) ,4.47(d,J=12.64Hz,1H),4.35(m,2H),3.93(m,1H),3.60(m,4H),3.10(m,4H),2.81(dd ,J=3.96,8.68Hz,1H),2.84(m,1H),2.02(m,1H),1.91(m,3H),1.68(m,5H),0.52(m,4H).

[0660] Intermediates 1-16A and 1-16B were used to synthesize Examples 15A and 15B according to the method of Example 1:

[0661] 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((1S,6'R,7a'S)-2,2,6'-trifluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol and 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((1R,6'R,7a'S)-2,2,6'-trifluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

[0662] Example 15A

[0663] LCMS: m / z 663 (M+H) + .1 H NMR(400MHz,DMSO-d6)δ10.16(s,1H),9.05(s,1H),7.98(dd,J=5.92,9.16Hz,1 H),7.47(t,J=9.04Hz,1H),7.40(d,J=2.64Hz,1H),7.18(m,1H),5.43(m,0.5H) ,5.29(m,0.5H),4.51(t,J=12.16Hz,1H),4.31(m,1H),4.05(m,2H),3.94(d,J= 4.16Hz,1H),3.61(m,4H),3.12(m,4H),2.22(m,5H),1.69(s,4H),1.54(m,2H).

[0664] Example 15B

[0665] LCMS: m / z 663 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ10.17(s,1H),9.06(s,1H),7.98(dd,J=5.92,9.12H z,1H),7.47(t,J=9.00Hz,1H),7.40(d,J=2.68Hz,1H),7.18(m,1H),5.35(m, 0.5H),521(m,0.5H),4.48(m,1H),4.31(m,2H),4.18(m,1H),3.94(s,1H),3. 61(m,4H),3.21(m,2H),3.01(m,2H),2.16(m,5H),1.69(s,4H),1.54(m,2H).

[0666] Example 15C and 15D were synthesized using intermediates 1-16C and 1-16D according to the method of Example 1.

[0667] 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((1S,6'R,7a'R)-2,2,6'-trifluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol and 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((1R,6'R,7a'R)-2,2,6'-trifluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

[0668] Example 15C

[0669] LCMS: m / z 663 (M+H) + . 1 H NMR(400MHz,DMSO-d6)δ10.20(s,1H),9.05(s,1H),7.98(dd,J=5.92,9.28Hz,1H) ,7.48(t,J=8.96Hz,1H),7.40(d,J=2.52Hz,1H),7.19(d,J=2.52Hz,1H),5.45(m, 0.5H),5.32(m,0.5H),4.48(d,J=11.56Hz,1H),4.30(m,3H),3.96(d,J=2.88Hz,1 H),3.59(m,4H),3.31(m,2H),3.01(m,2H),2.16(m,5H),1.69(s,4H),1.54(m,2H).

[0670] Example 15D

[0671] LCMS: m / z 663 (M+H) + . 1H NMR(400MHz,DMSO-d6)δ10.16(s,1H),9.04(s,1H),7.98(dd,J=6.00,9.28Hz ,1H),7.48(t,J=9.04Hz,1H),7.40(d,J=2.44Hz,1H),7.19(m,1H),5.51(m,0 .5H),5.37(m,0.5H),4.50(m,1H),4.30(m,1H),4.16(m,1H),3.98(m,2H),3. 61(m,4H),3.28(m,1H),3.07(m,1H),2.79(m,1H),2.21(m,5H),1.59(s,6H).

[0672] Example 15E and 15F were synthesized using intermediates 1-16E and 1-16F according to the method of Example 1.

[0673] 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((1S,6'S,7a'S)-2,2,6'-trifluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol and 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((1R,6'S,7a'S)-2,2,6'-trifluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

[0674] Example 15E

[0675] LCMS: m / z 663 (M+H) + . 1H NMR (400MHz, DMSO-d6) δ10.15 (s, 1H), 9.05 (s, 1H), 7.97 (dd, J = 5.92, 9.16Hz, 1H), 7.46 (t, J = 9.00Hz, 1H), 7.39 (d, J = 2.52Hz, 1H), 7.17 (d, J = 2.52Hz, 1H), 5. 44(m,0.5H), 5.30(m,0.5H), 4.48(d,J=11.72Hz,1H), 4.30(m,3H), 3.93(d,J= 2.84Hz,1H), 3.61(m,4H), 3.16(m,2H), 2.77(m,2H), 2.14(m,5H), 1.61(s,6H).

[0676] Example 15F

[0677] LCMS: m / z 663 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ 10.16 (s, 1H), 9.04 (s, 1H), 7.97 (dd, J = 5.92, 9.16Hz, 1H), 7.46 (t, J = 8.96Hz, 1H), 7.39 (d, J = 2.60Hz, 1H), 7.18 (m, 1H), 5.50(m,0.5H), 5.36(m,0.5H), 4.50(m,1H), 4.29(m,1H), 4.14(m,1H), 4.01(m,1H), 3.9 4(s,1H), 3.60(m,4H), 3.28(m,1H), 3.03(m,2H), 2.78(m,1H), 2.16(m,5H), 1.65(s,6H).

[0678] Intermediates 1-16G and 1-16H were used to synthesize Examples 15G and 15H according to the method of Example 1:

[0679] 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((1S,6'S,7a'R)-2,2,6'-trifluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol and 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((1R,6'S,7a'R)-2,2,6'-trifluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

[0680] Example 15G

[0681] LCMS: m / z 663 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ10.17(s,1H), 9.04(s,1H), 7.97(dd,J=5.96,9.20Hz,1H), 7.46(t,J=9.00Hz,1H), 7.39(d,J=2.56Hz,1H), 7.17(m,1 H), 5.42(m,0.5H), 5.28(m,0.5H), 4.49(m,1H), 4.29(m,1H), 4.04(m, 2H), 3.93(m,1H), 3.62(m,4H), 3.09(m,4H), 2.11(m,5H), 1.56(s,6H).

[0682] Example 15H

[0683] LCMS: m / z 663 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ9.01(s,1H), 7.66(m,1H), 7.21(m,1H), 7.01(m,2H), 5.34(m,0.5H), 5.20(m ,0.5H), 4.28(m,4H), 3.75(m,1H), 3.58(m,3H), 3.17(m,3H), 2.99(m,2H), 2.19(m,5H), 1.56(s,6H).

[0684] The following examples were synthesized using intermediates 1-11A and 1-11B as starting materials according to the method of Example 1:

[0685] Examples 16A and 16B 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((cis)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol and 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((trans)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

[0686] Example 16A 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((cis)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

[0687] LCMS: m / z 645 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ10.14(s,1H),9.03(s,1H),7.99-7.95(m,1H),7.46(t,J=8Hz,1H),7.39(s,1H),7.18 (t,J=4Hz,1H),4.49(t,J=12Hz,1H),4.31(t,J=12Hz,1H),4.09(d,J=12Hz,1H),3.98(d,J=4Hz,1H),3.95-3. 93(m,1H),3.65(t,J=8Hz,1H),3.59-3.56(m,3H),3.06(d,J=12Hz,1H),3.00-2.95(m,1H),2.80-2.76(m,1H) ,2.71-2.65(m,1H),2.14-2.10(m,1H),1.96-1.87(m,3H),1.84-1.75(m,2H),1.66(s,4H),1.56-1.51(m,2H).

[0688] Example 16B 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((trans)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

[0689] LCMS: m / z 645 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ10.17(s,1H),9.04(s,1H),7.99-7.95(m,1H),7.46(t,J=8Hz,1H),7.39(s,1H),7.18 (d,J=4Hz,1H),4.49(t,J=12Hz,1H),4.33(d,J=12Hz,1H),4.22-4.15(m,2H),3.92(s,1H),3.95-3.93(m,1H) ,3.65(d,J=12Hz,1H),3.58-3.56(m,3H),3.12-3.08(m,1H),3.04-3.00(m,1H),2.73(d,J=12Hz,1H),2.56-2 .54(m,1H),2.10-2.05(m,1H),2.01-1.97(m,1H),1.92(d,J=16Hz,1H),1.84-1.75(m,2H),1.66-1.44(m,7H).

[0690] Example 16B was separated by chiral HPLC (SFC-150 (Waters), column: IG 20*250 mm, 10 um (Daicel), column temperature: 35°C, mobile phase: CO2 / EtOH [0.5% NH3 (7M in MeOH)] = 120 / 40) to give isomers Example 16B-1 and Example 16B-2.

[0691] Example 16B-1 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

[0692] RT: 15.079min. LCMS:m / z 645(M+H) + . 1H NMR (400MHz, DMSO-d6) δ9.04 (s, 1H), 7.93-7.89 (m, 1H), 7.41 (d, J = 8Hz, 1H), 7.32 (s, 1H), 7.1 7(s,1H),4.49(d,J=12Hz,1H),4.35(d,J=12Hz,1H),4.20-4.16(m,2H),3.89(s,1H),3.64-3. 55(m,5H),3.13-3.09(m,1H),3.05-3.00(m,1H),2.74(d,J=12Hz,1H),2.57-2.55(m,1H),2.1 1-2.06(m,1H),2.02-1.98(m,1H),1.92(d,J=12Hz,1H),1.84-1.75(m,3H),1.66-1.47(m,8H).

[0693] Example 16B-2 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1R,7a'R)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

[0694] RT: 20.572min. LCMS:m / z 645(M+H) + . 1 H NMR (400MHz, DMSO-d6) δ9.04 (s, 1H), 7.95-7.99 (m, 1H), 7.46 (t, J = 8Hz, 1H), 7.39 (s, 1H), 7.1 8(s,1H),4.49(d,J=12Hz,1H),4.35(d,J=12Hz,1H),4.20-4.18(m,2H),392(s,1H),3.65-3.5 6(m,5H),3.13-3.09(m,1H),3.05-3.00(m,1H),2.74(d,J=12Hz,1H),2.57-2.55(m,1H),2.11 -2.06(m,1H),2.02-1.98(m,1H),1.92(d,J=12Hz,1H),1.84-1.74(m,3H),1.67-1.45(m,8H).

[0695] The following examples were synthesized using intermediate 1-11A as the starting material according to the method of Example 1:

[0696] Example 17: 4-(4-(1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((trans)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol

[0697] LCMS: m / z 649 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ10.01(s,1H),9.10(s,1H),7.77(q,J=4Hz,1H),7.38(d,J=8Hz,1H),7.34(d,J=4Hz,1H) ,7.03(d,J=4Hz,1H),4.44(d,J=12Hz,2H),4.26-4.17(m,2H),3.62(t,J=12Hz,2H),3.55(s,2H),3.13(q,J=8Hz ,1H),3.04-2.99(m,1H),2.74(d,J=12Hz,1H),2.57-2.55(m,1H),2.39-2.34(m,1H),2.15(t,J=8Hz,1H),2.12- 2.06(m,1H),2.02-1.98(m,1H),1.92(d,J=12Hz,1H),1.80-1.73(m,2H),1.63-1.44(m,7H),7.38(t,J=8Hz,3H).

[0698] Two isomers were obtained by chiral HPLC separation:

[0699] Example 17A: 4-(4-(1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol

[0700] RT: 14.093 min (U3000 (ThermoFisher); column: CHIRALPAK IF-3 4.6 mm*150 mm, 3 μm; column temperature: 40°C; mobile phase: n-hexane:ethanol-diethylamine=85 / 15-0.1%). LCMS: m / z 649 (M+H) + . 1H NMR (400MHz, DMSO-d6) δ9.94(s,1H),9.11(s,1H),7.77(q,J=4Hz,1H),7.38(d,J=8Hz,1H),7.34(s,1H),7.04(d,J=4Hz,1H),4.44(d,J=12H z,2H),4.26-4.17(m,2H),3.65-3.56(m,4H),3.13(q,J=8Hz,1H),3.04-2.99(m,1H),2.74(d,J=12Hz,1H),2.57-2.54(m,1H),2.39-2.34(m, 1H), 2.17-2.00 (m, 2H), 2.00-1.98 (m, 1H), 1.92 (d, J = 12Hz, 1H), 1.82-1.44 (m, 10H), 0.73 (t, J = 8Hz, 3H).

[0701] Example 17B: 4-(4-(1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1R,7a'R)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol

[0702] RT: 14.840 min (U3000 (ThermoFisher); column: CHIRALPAK IF-3 4.6 mm*150 mm, 3 μm; column temperature: 40°C; mobile phase: n-hexane:ethanol-diethylamine=85 / 15-0.1%). LCMS: m / z 649 (M+H) + .1H NMR (400MHz, DMSO-d6) δ9.96 (s, 1H), 9.11 (s, 1H), 7.77 (q, J = 4Hz, 1H), 7.38 (d, J = 8Hz, 1H), 7.34 (s,1H),7.03(d,J=4Hz,1H),4.45(d,J=16Hz,2H),4.26-4.17(m,2H),3.65-3.55(m,4H),3.13(q ,J=8Hz,1H),3.04-2.99(m,1H),2.74(d,J=12Hz,1H),2.57-2.54(m,1H),2.39-2.34(m,1H),2.1 7-2.00(m,2H),2.00-1.98(m,1H),1.92(d,J=12Hz,1H),1.80-1.44(m,10H),0.73(t,J=8Hz,3H).

[0703] Example 18: 6-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((trans)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3d]pyrimidin-7-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine

[0704] LCMS: m / z 635 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ9.01 (s, 1H), 6.78 (s, 1H), 4.36 (d, J = 9.20Hz, 1H), 4.17 (m, 2H), 3.55 (m, 4H), 3.09 (m, 1H), 2. 99(m,1H),2.70(m,2H),2.54(m,1H),2.36(m,3H),2.05(m,1H),1.97(m,1H),1.99(m,1H),1.79(m,2H),1.56(m,7H).

[0705] Example 19: 6-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((trans)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3d]pyrimidin-7-yl)-4-methyl-5-(pentafluoroethyl)pyridin-2-amine

[0706] LCMS: m / z 685 (M+H) + .

[0707] The following examples were synthesized using intermediate 1-11A-1 as the starting material according to the method of Example 1:

[0708] Example 20: 4-(2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoro-4-(1-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthol-2-ol

[0709] LCMS: m / z 659 (M+H) + . 1H NMR (400MHz, DMSO-d6) δ10.20(br,1H),9.06(s,1H),7.98(dd,J=5.88Hz,J=9.20Hz,1H),7.48(t,J=9.00Hz,1H),7.40(d,J=2.64Hz,1H),7.19(s,1H ),4.30(m,4H),3.94(s,1H),3.58(m,2H),3.11(m,1H),3.02(m,1H),2.71 (d,J=11.96Hz,1H),2.55(m,1H),2.06(m,2H),1.71(m,10H),1.25(m,5H).

[0710] Chiral separation (SFC-150 (Waters); column: OD 20*250 mm, 10 um (Daicel)) gave isomers 20A and 20B: 4-(2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoro-4-((1S,5R)-1-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin-7-yl )-5-ethynyl-6-fluoronaphthol-2-ol and 4-(2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidino]-7a'(5'H)-yl)methoxy)-8-fluoro-4-((1R,5S)-1-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthol-2-ol

[0711] Isomer 20A

[0712] RT:0.905min. LCMS:m / z 659(M+H) + . 1H NMR (400MHz, DMSO-d6) δ10.18(s,1H),9.07(s,1H),8.01-7.97(m,1H),7.48(t,J=8Hz,1H),7.4 0(d,J=4Hz,1H),7.19(s,1H),4.44(t,J=12Hz,1H),4.35-4.15(m,3H),3.94(s,1H),3.60-3.57( m,2H),3.38(s,1H),3.13-3.09(m,1H),3.05-3.00(m,1H),2.74(d,J=12Hz,1H),2.57-2.55(m,1 H), 2.11-1.99 (m, 2H), 1.93 (d, J = 16Hz, 1H), 1.84-1.46 (m, 9H), 1.38-1.32 (m, 1H), 1.26 (s, 3H).

[0713] Isomer 20B

[0714] RT:1.419min. LCMS:m / z 659(M+H) + . 1 H NMR(400MHz,DMSO-d6)δ10.20(s,1H),9.07(s,1H),8.01-7.97(m,1H),7.48(t ,J=8Hz,1H),7.40(d,J=4Hz,1H),7.20(s,1H),4.49-4.35(m,2H),4.31(d,J=1 2Hz,1H),4.20(s,2H),3.95(s,1H),3.64-3.56(m,2H),3.43(d,J=16Hz,1H),3 .13-3.09(m,1H),3.04-3.00(m,1H),2.74(d,J=12Hz,1H),2.57-2.55(m,1H), 2.11-2.07(m,1H),2.02-1.99(m,1H),1.82-1.35(m,10H),1.29-1.24(m,3H).

[0715] Example 21: (1S,7a'S)-7a'-(((4-(1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethynyl-7-fluoronaphthol-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]

[0716] LC-MS: m / z 609 (M+H) + .1 H NMR (400MHz, DMSO-d6) δ9.07 (s, 1H), 8.25 (d, J = 8Hz, 1H), 8.22 (d, J = 8Hz, 1H), 7.7 9-7.60(m,3H),4.51(d,J=12Hz,1H),4.38(d,J=12Hz,1H),4.24-4.19(m,2H),4.02 (s,1H),3.67-3.62(m,4H),3.14-3.09(m,1H),3.05-3.00(m,1H),2.74(d,J=12Hz ,1H),2.57-2.55(m,1H),2.11-2.06(m,1H),2.02-1.90(m,2H),1.82-1.45(m,9H).

[0717] Example 22: (1S,7a'S)-7a'-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-7-(6-fluoro-5-methyl-1H-indazol-4-yl)pyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]

[0718] LC-MS: m / z 609 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ13.21(s,1H),9.20(s,1H),7.74(s,1H),7.50(d,J=8Hz,1H),4.47(s,2H),4.25-4.19(m,2H),3.64-3.58 (m,3H),3.14(q,J=7Hz,J=5Hz,1H),3.05-3.00(m,1H),2.74(d,J=12Hz,1H),2.57-2.55(m,4H),2.19(s,2H),2.12-1.45(m,8H).

[0719] Example 23: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-7-fluorobenzo[d]thiazol-2-amine

[0720] LC-MS: m / z 627 (M+H) + .1 H NMR (400MHz, DMSO-d6) δ9.08(s,1H),7.91(s,1H),7.42(dd,J=5.80,8.48Hz,1H),7.07(t,J=8.88Hz,1H),4.38(d,J=12.12Hz,2H),4.19(m,2H) ,3.57(m,4H),3.09(m,1H),3.01(m,1H),2.70(d,J=11.84Hz,1H),2.54( m,1H),2.08(m,1H),1.98(m,1H),1.88(d,J=13.32Hz,1H),1.63(m,9H).

[0721] Example 24: 4-(4-((1R,5S)-diazabicyclo[3.2.1]octan-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile

[0722] LC-MS: m / z 651 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ9.07 (s, 1H), 8.10 (s, 2H), 7.44-7.40 (m, 1H), 7.15 (t, J = 8Hz, 1H),4.43(d,J=12Hz,2H),4.23-4.17(m,2H),3.63(d,J=12Hz,2H),3.53(s,2H),3.13 -3.09(m,1H),3.05-3.00(m,1H),2.74(d,J=12Hz,1H),2.57-2.55(m,1H),2.12-2.07 (m,1H),2.03-1.97(m,1H),1.92-1.89(m,2H),1.86-1.71(m,2H),1.64-1.44(m,7H).

[0723] Example 25: 2-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-4,6-dichloro-3-fluoroaniline

[0724] LC-MS: m / z 638 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ10.18(s,1H),9.59(s,1H),9.36(s,1H),9.25(s,1H),7.71(d,J=7.56Hz,1H),5 .76(s,2H),4.67(m,4H),4.21(m,2H),3.64(m,2H),3.13(m,1H),2.47(m,1H),2.28(m,4H),1.88(m,9H).

[0725] Example 26: 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-2-fluoro-5-methyl-4-(trifluoromethyl)aniline

[0726] LC-MS: m / z 652 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ9.09 (s, 1H), 7.31 (d, J = 11.76Hz, 1H), 5.86 (s, 1H), 4.42 (d, J = 11.40Hz, 2H), 4.19 (d, J = 3.24Hz, 2H), 3.61 (m, 4H), 3. 11(m,1H),3.02(m,1H),2.71(d,J=11.84Hz,1H),2.55(m,1H),2.17(s, 3H), 2.09 (m, 1H), 2.00 (m, 1H), 1.88 (d, J = 13.32Hz, 1H), 1.64 (m, 10H).

[0727] Example 27: 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-chloro-4-(trifluoromethyl)aniline

[0728] LC-MS: m / z 654 (M+H) + . 1H NMR(400MHz, DMSO-d6)δ9.06(s,1H),6.89(s,1H),6.48(s,1H),6.34(s,1H),4.39(d,J=12.08Hz,2H),4.20(m,2H),3.59(m,4H),3 .10(m,1H),3.02(m,1H),2.71(d,J=11.88Hz,1H),2.56(m,1H),2.07(m,1H),1.99(m,1H),1.88(d,J=13.32Hz,1H),1.62(m,10H).

[0729] Example 28: 4-(4-(3,9-diazabicyclo[4.2.1]non-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

[0730] LC-MS: m / z 659 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ10.20 (s, 1H), 9.09 (d, J = 16Hz, 1H), 8.00-7.95 (m, 1H), 7.47 (t, J = 8Hz, 1H), 7. 40(s,1H),7.22-7.19(m,1H),4.71(d,J=12Hz,1H),4.42(d,J=12Hz,1H),4.25-4.15(m,2H),4.09-3.9 9(m,2H),3.92-3.82(m,2H),3.73-3.67(m,2H),3.13-3.08(m,1H),3.04-3.00(m,1H),2.74(d,J=12Hz ,1H),2.57-2.55(m,1H),2.11-1.95(m,3H),1.92-1.89(m,3H),1.84-1.72(m,3H),1.65-1.45(m,5H).

[0731] Example 29: 4-(4-(3-amino-3-methylpiperidin-1-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

[0732] LC-MS: m / z 647 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ10.16 (s, 2H), 9.25 (d, J = 56Hz, 1H), 7.99-7.96 (m, 1H), 7 .46(t,J=8Hz,1H),7.40(d,J=4Hz,1H),7.22-7.20(m,1H),4.24-4.16(m,2H),4.1 0(m,1H),4.03-4.00(d,J=12Hz,1H),3.95(s,1H),3.89(d,J=12Hz,1H),3.73-3. 65(m,1H),3.60-3.47(m,2H),3.13-2.99(m,2H),2.73(d,J=12Hz,1H),2.56-2.54 (m,1H),2.10-2.05(m,1H),2.02-1.97(m,2H),1.92(s,1H),1.89(s,1H),1.83-1.74(m,3H),1.64-1.44(m,5H),1.10(d,J=4Hz,3H).

[0733] Example 30 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-methoxypyrido[4,3-d]pyrimidin-7-yl)-2-fluoro-5-methyl-4-(trifluoromethyl)aniline

[0734] LC-MS: m / z 664 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ8.96 (s, 1H), 7.18 (d, J = 11.68Hz, 1H), 5.67 (s, 2H), 4.35 (d, J = 12.40Hz, 2 H), 4.20(m,2H), 3.85(s,3H), 3.53(m,4H), 3.11(m,1H), 3.02(m,1H), 2.71(m,1H), 1.73(m,17H).

[0735] Example 31: 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-methoxypyrido[4,3-d]pyrimidin-7-yl)-5-chloro-4-(trifluoromethyl)aniline

[0736] LC-MS: m / z 666 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ8.92 (s, 1H), 6.82 (d, J = 2.24Hz, 1H), 6.36 (d, J = 2.28Hz, 1H), 6.19 (s, 2H), 4.36 (m, 2H ), 4.20(m,2H), 3.89(s,3H), 3.57(m,4H), 3.09(m,1H), 3.00(m,1H), 2.70(m,1H), 2.55(m,1H), 1.64(m,13H).

[0737] Example 32: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-2-amino-6-fluorobenzo[b]thiophene-3-carbonitrile

[0738] LC-MS: m / z 651 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ 9.07 (s, 1H), 7.82-7.80 (m, 2H), 7.28-7.25 (m, 1H), 4.42 (d, J = 12Hz, 2H), 4.22-4.16 (m, 2H) ),3.62(d,J=12Hz,2H),3.51(s,2H),3.12-3.08(m,1H),3.04-2.99(m,1H),2.73(d,J=12Hz,1H),2.56-2.54(m,1H), 2.11-2.06(m,1H),2.02-1.96(m,1H),1.91-1.71(m,4H),1.63-1.45(m,7H).

[0739] Example 33: (1S,7a'S)-7a'-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-7-(5-(trifluoromethyl)-1H-indazol-4-yl)pyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)-2,2-difluorotetrahydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]

[0740] LC-MS: m / z 645 (M+H) + . 1 H NMR(400MHz,DMSO-d6)δ13.71(s,1H),9.17(s,1H),7.86(m,3H),4.46(m,2H),4.21(m,2H),3.63(m,4H),3 .10(m,1H), 3.02(m,1H), 2.71(m,1H), 2.55(m,1H), 2.08(m,1H), 2.00(m,1H), 1.89(m,1H), 1.67(m,10H).

[0741] Example 34: 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-chloro-2-fluoro-4-(trifluoromethyl)aniline

[0742] LC-MS: m / z 672 (M+H) + . 1 H NMR(400MHz,DMSO-d6)δ9.11(s,1H),7.09(d,J=7.92Hz,1H),6.48(s,2H),4.39(m,2H),4.20(m,2H),3.61(m,4 H),3.10(m,1H),3.00(m,1H),2.70(m,1H),2.54(m,1H),2.06(m,1H),1.99(m,1H),1.88(m,1H),1.64(m,10H).

[0743] Example 35: 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-2,5-dichloro-4-(trifluoromethyl)aniline

[0744] LC-MS: m / z 688 (M+H) + . 1 H NMR(400MHz,DMSO-d6)δ9.12(s,1H),7.15(s,1H),6.64(s,2H),4.39(m,2H),4.20(m,2H),3.59(m,4H),3 .10(m,1H),3.00(m,1H),2.70(m,1H),2.54(m,1H),2.06(m,1H),1.97(m,1H),1.88(m,1H),1.64(m,10H).

[0745] Example 36: 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-2-chloro-5-fluoro-4-(trifluoromethyl)aniline

[0746] LC-MS: m / z 672 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ9.13(s,1H),6.86(d,J=13.68Hz,1H),6.68(s,2H),4.38(d,J=12.32Hz,2H),4.19(m,2H),3. 58(m,4H),3.10(m,1H),3.00(m,1H),2.71(m,1H),2.53(m,1H),2.07(m,1H),2.00(m,1H),1.89(m,1H),1.65(m,10H).

[0747] Example 37: 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-2,4-dichloro-5-fluoroaniline

[0748] LC-MS: m / z 638 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ9.18 (s, 1H), 6.94 (d, J = 12Hz, 1H), 6.05 (s, 2H), 4.49 (d, J=12Hz,2H),4.25-4.18(m,2H),3.78(s,2H),3.71(d,J=16Hz,2H),3.12-3.08(m, 1H),3.04-2.99(m,1H),2.74(d,J=12Hz,1H),2.57-2.55(m,1H),2.10-2.05(m,1H ),2.02-1.95(m,1H),1.92(d,J=16Hz,1H),1.84-1.70(m,6H),1.65-1.44(m,4H).

[0749] Example 38: N-(3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-chloro-4-(trifluoromethyl)phenyl)acetamide

[0750] LC-MS: m / z 696 (M+H) + . 1 H NMR(400MHz,DMSO-d6)δ10.50(s,1H),9.09(s,1H),8.03(s,1H),7.70(s,1H),4.43-4.40(m,2H),4.22-4.15(m,2H),3.58(m,4H),3.12-3.0 7(m,1H),3.03-2.98(m,1H),2.73(d,J=12Hz,1H),2.55-2.53(m,1H), 2.10(s,3H),2.08-1.95(m,2H),1.91-1.70(m,3H),1.63-1.44(m,8H).

[0751] Example 39: N-(3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-chloro-4-(trifluoromethyl)phenyl)methanesulfonamide

[0752] LC-MS: m / z 732 (M+H) + . 1 H NMR(400MHz,DMSO-d6)δ9.12(s,1H),8.03(s,1H),7.33(s,1H),6.99(s,1H),4.51(t, J=12Hz,2H),4.25-4.19(m,2H),3.85(s,2H),3.75-3.65(m,2H),3.14-3.09(m,1H),3 .05-3.01(m,1H),2.99(s,3H),2.75(d,J=12Hz,1H),2.58-2.55(m,1H),2.11-2.05(m ,1H),2.03-1.97(m,1H),1.92(d,J=12Hz,1H),1.83-1.78(m,6H),1.65-1.45(m,4H).

[0753] Example 40: 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl))-5-chloro-4-(trifluoromethyl)phenol

[0754] LC-MS: m / z 655 (M+H) + . 1H NMR (400MHz, DMSO-d6) δ9.08(s,1H),7.20(d,J=2.44Hz,1H),6.80(d,J=2.40Hz,1H),4.40(d,J=12.04Hz,2H),4.20(m,2H ),3.59(m,4H),3.10(m,1H),3.01(m,1H),2.71(m,1H),2.55(m,1H),2.07(m,1H),1.99(m,1H),1.87(m,1H),1.64(m,10H).

[0755] Example 41: 5-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-3-chloro-2-fluoro-4-(trifluoromethyl)aniline

[0756] LC-MS: m / z 672 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ9.05(s,1H),6.69(d,J=8.28Hz,1H),6.49(s,2H),4.38(d,J=12.44Hz,2H),4.18(m,2H),3.5 7(m,4H),3.09(m,1H),3.00(m,1H),2.70(m,1H),2.53(m,1H),2.06(m,1H),1.99(m,1H),1.87(m,1H),1.61(m,10H).

[0757] Example 42: 5-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-2-fluoro-3-methyl-4-(trifluoromethyl)aniline

[0758] LC-MS: m / z 652 (M+H) + . 1H NMR (400MHz, DMSO-d6) δ9.04 (s, 1H), 6.57 (d, J = 8Hz, 1H), 6.02 (s, 2H), 4.43 (d, J =12Hz,2H),4.21-4.15(m,2H),3.62-3.59(m,4H),3.12-3.07(m,1H),3.03-2.98 (m,1H),2.73(d,J=12Hz,1H),2.56-2.54(m,1H),2.34(s,3H),2.09-2.04(m,1H) ,2.01-1.95(m,1H),1.91(d,J=16Hz,1H),1.83-1.70(m,3H),1.65-1.44(m,7H).

[0759] Example 43: 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-amino-2-(trifluoromethyl)benzonitrile

[0760] LC-MS: m / z 645 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ9.07(s,1H),7.22(d,J=2.40Hz,1H),6.83(d,J=2.32Hz,1H),6.61(s,2H),4.39(m,2H),4.20(m,2H ),3.58(m,4H),3.10(m,1H),3.00(m,1H),2.71(m,1H),2.55(m,1H),2.07(m,1H),2.00(m,1H),1.88(m,1H),1.64(m,10H).

[0761] Example 44: 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-fluoro-4-(trifluoromethyl)aniline

[0762] LC-MS: m / z 638 (M+H) + . 1H NMR(400MHz,DMSO-d6)δ9.06(s,1H),6.60(d,J=16Hz,1H),6.39(d,J=4Hz,3H),4 .42(d,J=12Hz,2H),4.22-4.16(m,2H),3.62(s,1H),3.59(s,3H),3.13-3.08(m,1 H),3.04-2.99(m,1H),2.74(d,J=12Hz,1H),2.57-2.54(m,1H),2.10-2.05(m,1H ),2.02-1.95(m,1H),1.92(d,J=16Hz,1H),1.83-1.71(m,3H),1.63-1.44(m,7H).

[0763] Example 45: 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-4-chloro-5-(trifluoromethyl)aniline

[0764] LC-MS: m / z 654 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ9.11(s,1H),7.17(d,J=4Hz,1H),6.91(d,J=4Hz,1H),5.95( s,2H),4.44(d,J=12Hz,2H),4.24-4.18(m,2H),3.62(s,1H),3.59(s,3H),3.13-3.0 8(m,1H),3.04-3.00(m,1H),2.74(d,J=12Hz,1H),2.58-2.54(m,1H),2.11-2.05(m, 1H), 2.02-1.96 (m, 1H), 1.92 (d, J = 12Hz, 1H), 1.84-1.73 (m, 3H), 1.67-1.45 (m, 7H).

[0765] Example 46: 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-chloro-4-fluoroaniline

[0766] LC-MS: m / z 604 (M+H) + . 1 H NMR(400MHz,DMSO-d6)δ9.10(s,1H),6.85-6.82(m,1H),6.78-6.75(m,1H),5.47(s,2 H),4.42(d,J=12Hz,2H),4.23-4.17(m,2H),3.60(d,J=12Hz,2H),3.53(s,2H),3.13- 3.08(m,1H),3.04-3.00(m,1H),2.74(d,J=12Hz,1H),2.57-2.55(m,1H),2.11-2.06( m,1H),2.02-1.97(m,1H),1.92(d,J=12Hz,1H),1.85-1.71(m,3H),1.64-1.45(m,7H).

[0767] Example 47: 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-4,5-dichloroaniline

[0768] LC-MS: m / z 620 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ9.08 (s, 1H), 6.89 (d, J = 2.60Hz, 2H), 6.65 (d, J = 2.68Hz, 2H), 5.74 (s, 2H), 4.38 (d, J = 11.84Hz, 2H), 4.18 (m,2H),3.54(m,4H),3.10(m,1H),3.00(m,1H),2.70(m,1H),2.53(m,1H),2.06(m,1H),1.98(m,1H),1.87(m,1H),1.58(m,10H).

[0769] Example 48: 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-amino-2-chlorobenzonitrile

[0770] LC-MS: m / z 611 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ9.11 (s, 1H), 7.13 (d, J = 2.72Hz, 1H), 7.01 (d, J = 2.76Hz, 1H), 6.01 (s, 2H), 4.40 (d, J = 12.00Hz, 2H), 4.20 (m,2H),3.60(m,4H),3.10(m,1H),3.01(m,1H),2.70(m,1H),2.54(m,1H),2.09(m,1H),1.99(m,1H),1.88(m,1H),1.61(m,10H).

[0771] Example 49: 2-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-4-amino-6-chlorobenzonitrile

[0772] LC-MS: m / z 611 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ9.11(s,1H),6.86(d,J=4Hz,1H),6.79(d,J=4Hz,1H),6.71(s ,2H),4.42(d,J=12Hz,2H),4.23-4.17(m,2H),3.62(d,J=12Hz,1H),3.55(s,3H),3.12 -3.07(m,1H),3.03-2.99(m,1H),2.73(d,J=12Hz,1H),2.56-2.54(m,1H),2.10-2.05( m,1H),2.02-1.96(m,1H),1.91(d,J=12Hz,1H),1.83-1.70(m,3H),1.65-1.44(m,7H).

[0773] Example 50: 2-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-4-amino-6-(trifluoromethyl)benzonitrile

[0774] LC-MS: m / z 645 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ9.14(s,1H),7.17(d,J=4Hz,1H),7.02(d,J=4Hz,1H),6.95( s,2H),4.45(d,J=12Hz,2H),4.25-4.19(m,2H),3.65(s,1H),3.62(s,3H),3.13-3.0 9(m,1H),3.05-3.00(m,1H),2.74(d,J=12Hz,1H),2.57-2.55(m,1H),2.13-2.05(m, 1H), 2.03-1.97 (m, 1H), 1.92 (d, J = 12Hz, 1H), 1.83-1.76 (m, 3H), 1.65-1.45 (m, 7H).

[0775] Example 51: 2-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-6-amino-3-chlorobenzonitrile

[0776] LC-MS: m / z 611 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ9.17(s,1H),7.51(d,J=9.04Hz,1H),6.95(d,J=9.04Hz,1H),6.45(s,2H),4.50(m,1H),4.34(m,1H),4.2 0(m,2H),3.64(m,4H),3.09(m,1H),3.01(m,1H),2.70(m,1H),2.56(m,1H),2.07(m,1H),1.99(m,1H),1.91(m,1H),1.67(m,10H).

[0777] Example 52: 5-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-6-(trifluoromethyl)pyridin-3-amine

[0778] LC-MS: m / z 621 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ9.12 (s, 1H), 8.13 (d, J = 4Hz, 1H), 6.97 (d, J = 4Hz, 1H), 6.31 (s ,2H),4.51(d,J=12Hz,2H),4.25-4.19(m,2H),3.83(s,2H),3.73(d,J=12Hz,2H),3.13 -3.09(m,1H),3.04-3.00(m,1H),2.75(d,J=12Hz,1H),2.58-2.55(m,1H),2.11-2.06( m,1H),2.02-1.96(m,1H),1.93(d,J=12Hz,1H),1.84-1.74(m,3H),1.65-1.45(m,7H).

[0779] Example 53: 5-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-4-(trifluoromethyl)pyridin-3-amine

[0780] LC-MS: m / z 621 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ9.09 (s, 1H), 8.38 (s, 1H), 7.14 (s, 1H), 6.24 (s, 2H), 4.42 (d, J = 12.24Hz, 2H), 4.19 (m, 2H), 3. 62(m,4H),3.10(m,1H),3.01(m,1H),2.71(m,1H),2.55(m,1H),2.07(m,1H),1.98(m,1H),1.89(m,1H),1.64(m,10H).

[0781] Example 54: 5-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-4-methyl-6-(trifluoromethyl)pyridin-3-amine

[0782] LC-MS: m / z 635 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ9.12 (s, 1H), 8.10 (s, 1H), 6.06 (s, 2H), 4.41 (d, J = 12Hz ,2H),4.23-4.15(m,2H),3.63(d,J=12Hz,1H),3.57(s,3H),3.12-3.07(m,1H), 3.03-2.98(m,1H),2.73(d,J=12Hz,1H),2.56-2.54(m,1H),2.09-2.05(m,1H), 2.01-1.95(m,1H),1.91(d,J=12Hz,1H),1.83-1.76(m,6H),1.64-1.43(m,7H).

[0783] Example 55: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-6-methyl-5-(trifluoromethyl)pyridin-2-amine

[0784] LC-MS: m / z 635 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ9.10 (s, 1H), 6.69 (s, 2H), 6.26 (s, 1H), 4.51 (d, J = 13.00Hz, 2H), 4.21 (m, 2H), 3.94 (m, 2H), 3.79 (d, J = 13. 16Hz,2H),3.10(m,1H),3.03(m,1H),2.72(m,1H),2.54(m,1H),2.49(m,3H),2.08(m,1H),1.99(m,1H),1.89(m,1H),1.65(m,10H).

[0785] Example 56: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-2-chloro-3-(trifluoromethyl)aniline

[0786] LC-MS: m / z 654 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ9.12 (s, 1H), 7.47 (d, J = 8Hz, 1H), 7.14 (d, J = 8Hz, 1H) ,6.09(s,2H),4.48(d,J=12Hz,2H),4.24-4.19(m,2H),3.69-3.65(m,4H),3.1 3-3.08(m,1H),3.04-2.99(m,1H),2.74(d,J=12Hz,1H),2.57-2.54(m,1H),2. 12-2.05(m,1H),2.01-1.97(m,1H),1.92(d,J=16Hz,1H),1.83-1.44(m,10H).

[0787] The following examples were synthesized using intermediate D-1-11A-1 as the starting material according to the method of Example 1:

[0788] Example D01: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl-5',5'-d2)methoxy-d2)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

[0789] LC-MS: m / z 649 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ10.15 (s, 1H), 9.05 (s, 1H), 7.98 (dd, J = 5.92, 9.24Hz, 1H ), 7.47(t,J=9.04Hz,1H), 7.40(d,J=2.60Hz,1H), 7.18(d,J=2.64Hz,1H), 4.47(d ,J=12.36Hz,1H), 4.31(m,1H), 3.94(s,1H), 3.63(m,4H), 3.29(m,1H), 3.10(m,1 H), 2.71(d,J=11.72Hz,1H), 2.07(m,1H), 1.99(m,1H), 1.89(m,1H), 1.67(m,1H).

[0790] The following examples were synthesized using intermediate D-1-11A-2 as the starting material according to the method of Example 1:

[0791] Example D02: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1R,7a'R)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl-5',5'-d2)methoxy-d2)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

[0792] LC-MS: m / z 649 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ10.15 (s, 1H), 9.05 (s, 1H), 7.98 (dd, J = 5.96, 9.20Hz, 1H ), 7.47(t,J=9.04Hz,1H), 7.40(d,J=2.60Hz,1H), 7.18(d,J=2.56Hz,1H), 4.47(d ,J=12.20Hz,1H), 4.32(m,1H), 3.94(s,1H), 3.63(m,4H), 3.29(m,1H), 3.10(m,1 H), 2.71(d,J=11.72Hz,1H), 2.07(m,1H), 1.99(m,1H), 1.89(m,1H), 1.67(m,1H).

[0793] Using intermediate D-1-11A-1 as the starting material, the following examples were synthesized according to the method of Example 1: Example D03: 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy-d2)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-chloro-4-(trifluoromethyl)aniline

[0794] LC-MS: m / z 658 (M+H) + . 1H NMR (400MHz, DMSO-d6) δ9.07 (s, 1H), 6.90 (d, J = 4Hz, 1H), 6.48 (d, J = 4Hz, 1H), 6.34 (s, 2H), 4.46 (d, J = 12Hz, 2H), 3.69-3.63 (m, 4H), 3.1 3-3.08(m,1H),2.74(d,J=12Hz,1H),2.10-2.05(m,1H),2.02-1.95(m,1H),1.92(d,J=16Hz,1H),1.84-1.73(m,3H),1.69-1.45(m,7H).

[0795] The following examples were synthesized using intermediate 1-17 as the starting material according to the method of Example 1:

[0796] Example E01: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((1-methyltetrahydro-1H-spiro[cyclopenta[b]pyrrol-2,1'-cyclopropane]-3a(3H)-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

[0797] LC-MS: m / z 623 (M+H) + .

[0798] Example P01: Preparation of ((1R,5S)-3-(2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-bis-fused pyrrolidine]-7a'(5'H)-yl)methoxy)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methyl isobutyrate trifluoroacetate

[0799] Example 16B-1 (100 mg, 0.155 mmol) was dissolved in THF (5 mL), and 2,6-lutidine (83 mg, 0.775 mmol) and iodomethyl isobutyrate (189 mg, 0.775 mmol) were added sequentially. After complete addition, the mixture was stirred at room temperature for 16 h. Acetonitrile was then added to dissolve the mixture, and the desired product (28 mg) was obtained by preparative HPLC.

[0800] LC-MS: m / z 745 (M+H) + . 1H NMR (400MHz, DMSO-d6) δ10.28(s,1H),9.45(d,J=9.64Hz,1H),9.19(m,2H),8.00(dd,J= 5.96,9.20Hz,1H),7.49(t,J=9.04Hz,1H),7.43(d,J=2.52Hz,1H),7.18(d,J=2.60Hz,1 H),5.59(m,2H),4.95(s,2H),4.72(m,1H),4.56(m,1H),4.25(s,2H),4.12(m,1H),3.88 (m,5H),3.73(m,2H),2.70(m,2H),2.40(m,2H),2.22(m,3H),1.98(m,7H),1.15(m,6H).

[0801] The following compounds were synthesized in the same manner as in Example P01:

[0802] Example P02: (1R,5S)-3-(2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid isopropyl ester

[0803] LC-MS: m / z 731 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ9.07(s,1H),7.97(dd,J=5.96,9.24Hz,1H),7.46(t,J=9.04Hz,1H),7.39(d,J=2.56Hz,1H),7.18(d,J=2.48Hz,1H),4.87(m, 1H),4.56(m,1H),4.41(m,3H),4.20(m,2H),3.92(s,1H),3.64(m,2H),3.10(m,1H),3.01(m,1H),2.70(d, J=11.84Hz,1H),2.54(m,1H),2.06(m,1H),1.99(m,1H),1.81(m,7H),1.61(m,3H),1.24(d,J=6.48Hz,6H).

[0804] Example P03: ((1R,5S)-3-(2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methyl isopropyl carbonate

[0805] LC-MS: m / z 761 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ10.28(s,1H),9.57(s,1H),9.29(s,1H),9.19(s,1H),8.01(t,J=8Hz,1H ),7.52-7.44(m,2H),7.19(s,1H),5.65-5.56(m,2H),4.95(s,2H),4.87-4.74(m,2H),4.60(d,J= 12Hz,1H),4.25(s,2H),4.18(d,J=12Hz,1H),3.93-3.86(m,5H),3.77-3.74(m,2H),2.70-2.66( m,2H),2.60(s,1H),2.43-2.34(m,2H),2.25-2.18(m,3H),1.99-1.90(m,6H),1.25-1.24(m,6H).

[0806] Example P04 and Example P05: 1-(Isobutyryloxy)ethyl(1R,5S)-3-(2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-7-(8-ethynyl-7-fluoro-3-(((1-(isobutyryloxy)ethoxy)carbonyl)oxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo Preparation of [3.2.1]octane-8-carboxylate and 1-(isobutyryloxy)ethyl (1R,5S)-3-(2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0807] Step 1: Preparation of 1-(isobutyryloxy)ethyl(1R,5S)-3-(2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-7-(8-ethynyl-7-fluoro-3-(((1-(isobutyryloxy)ethoxy)carbonyl)oxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0808] Example 16B-1 (100 mg, 0.155 mmol) was dissolved in DCM (4 mL), and DIPEA (100 mg, 0.775 mmol) was added, followed by ethyl 1-(((4-nitrophenoxy)carbonyl)oxy)isobutyrate (184 mg, 0.62 mmol). The mixture was stirred at room temperature for 16 h. After completion of the reaction, the reaction solution was concentrated to dryness, clarified with acetonitrile, and directly isolated by preparative HPLC to obtain the desired product (65 mg).

[0809] LC-MS: m / z 961 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ9.08 (s, 1H), 8.25 (dd, J=5.92Hz, 9.28Hz, 1H), 8.15 (d, J= 2.52Hz,1H),7.68(t,J=9.00Hz,1H),7.62(m,1H),6.75(m,2H),4.46(m,4H),4.20( m,2H),4.08(s,1H),3.68(m,2H),3.09(m,1H),3.00(m,1H),2.07(d,J=11.84Hz,1H ),2.61(m,3H),2.09(m,1H),1.99(m,1H),1.85(m,7H),1.57(m,9H),1.09(m,12H).

[0810] Step 1: Preparation of 1-(isobutyryloxy)ethyl(1R,5S)-3-(2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0811] Example P04 (105 mg, 0.109 mmol) was dissolved in acetonitrile (4 mL) and aqueous ammonia (10 drops) was added. The mixture was stirred at room temperature for 2 h. After the reaction was complete, the reaction solution was concentrated to dryness, clarified by adding acetonitrile, and then directly isolated by preparative HPLC to obtain the desired product (65 mg).

[0812] LC-MS: m / z 803 (M+H) + . 1 H NMR (400MHz, DMSO-d6): 10.16 (s, 1H), 9.06 (s, 1H), 7.98 (dd, J = 5.92, 9.24Hz, 1H), 7 .47(t,J=9.00Hz,1H),7.40(d,J=2.60Hz,1H),7.18(d,J=2.52Hz,1H),6.74(m,1H), 4.59(m,1H),4.39(m,3H),4.22(m,2H),3.93(s,1H),3.67(m,2H),3.11(m,2H),2.71 (d,J=11.84Hz,1H),2.55(m,1H),1.98(m,10H),1.56(m,6H),1.08(d,J=7.16Hz,6H).

[0813] The following compounds were synthesized in the same manner as in Example P05:

[0814] Example P06: 1-(Isobutyryloxy)ethyl (1R,5S)-3-(7-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-2-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0815] LC-MS: m / z 812 (M+H) + . 1H NMR (400MHz, DMSO-d6): 9.07 (s, 1H), 6.89 (d, J = 2.20Hz, 1H), 6.73 (dd, J = 5.32Hz, J = 10.76Hz, 1H), 6.47 (d, J = 2.28Hz, 1H), 6.35 (s, 2H), 4.53 (m,2H), 4.36(m,2H), 4.23(m,2H), 3.67(m,2H), 3.10(m,1H), 3.01(m,1 H), 2.71(m,1H), 2.55(m,1H), 2.09(m,1H), 1.98(m,1H), 1.65(m,14H).

[0816] Biological test examples

[0817] The following biological test examples further describe and explain the present invention, but these examples are not intended to limit the scope of the present invention.

[0818] KRAS Gl2D Binding inhibition assay

[0819] Experimental procedures

[0820] TR-FRET technology was used to detect the interaction of compounds with KRAS G12D The binding capacity of the protein. Biotin-labeled GDP was loaded onto KRAS G12D Recombinant human protein was incubated with a Cy5-labeled tracer, europium-labeled streptavidin, and the compound (final concentration: 2% DMSO) in a buffer containing HEPES (pH 7.5), MgCl2, Tween-20, and DTT. After incubation at 22°C for 60 minutes, the reaction activity was measured using dual-wavelength technology on an EnVision multi-function microplate reader, and the protein-bound capacity (POC) was calculated using the ratiometric emission factor.

[0821] 100POC means no compound; 0POC means the control compound completely inhibits the tracer and KRAS at this concentration. G12D The POC value was fitted using a four-parameter logistic model curve, and IC 50 Indicates 50POC concentration value.

[0822] The results showed that the compounds of the present invention have an inhibitory effect on KRAS G12D It showed good inhibitory activity.

[0823] ERK phosphorylation inhibition assay

[0824] Experimental procedures

[0825] KRAS was seeded in 384-well plates G12DMutant cells (such as GP2D, AGS, etc.) were cultured in a 37°C, 5% CO2 incubator overnight.

[0826] 200 nL of the diluted compound was added using Echo 500 to a final DMSO concentration of 0.5%, and the cells were incubated at 37°C in a 5% CO2 incubator for 1 hour. hEGF was then added and allowed to react for 10 minutes.

[0827] Remove the culture medium, add cell fixative, and fix the cells.

[0828] Wash once with PBS and incubate in cold 100% methanol.

[0829] Remove the methanol and add PBS to wash once.

[0830] Remove PBS, add Li-Cor blocking buffer to each well, and block at room temperature for 1 hr.

[0831] Remove the blocking solution, add primary antibody mixture to each well, and incubate at 4°C overnight.

[0832] Remove the primary antibody mixture and wash three times with PBST.

[0833] Add the secondary antibody mixture and incubate at room temperature in the dark for 45 minutes.

[0834] Remove the secondary antibody mixture, add PBST and wash three times, finally aspirate the PBST, turn the tube upside down and centrifuge at 1000 rpm for 1 min.

[0835] Odyssey CLx readings. The test results are shown in Tables 1 and 2 below.

[0836] The structure of the reference compound MRTX1133 is as follows:

[0837] Table 1 Results of GP2D ERK phosphorylation inhibition experiments

[0838] Table 2 Results of AGS ERK phosphorylation inhibition experiment

[0839] The results showed that the compounds of the present invention have an inhibitory effect on KRAS G12D The mutant cells showed good inhibitory activity on ERK phosphorylation.

[0840] Inhibitory effect of compounds on KRAS G12D mutant cell proliferation

[0841] Experimental procedures

[0842] 1. Cell Culture

[0843] (a) Resuscitate cells in T75 cell culture flasks:

[0844] (b) When the cell confluence reached 80-90%, the cells were passaged.

[0845] 2. Cell Proliferation Assay

[0846] Experimental procedures

[0847] Use a nanoliter pipette system to add the diluted test compound to a 384-well cell culture plate, setting up duplicate wells. Add an equal volume of culture medium to the positive control group; add an equal volume of DMSO to the negative control group. Centrifuge at 1000 rpm for 1 minute at room temperature.

[0848] A) Seed the cells into a 384 culture plate. For the negative control group, add an equal volume of cells, while for the positive control group, add an equal volume of culture medium alone. Centrifuge at 1000 rpm for 1 minute at room temperature. Add the final compound to a DMSO concentration of 0.5%. Incubate in a 37°C, 5% CO2 incubator for 7 days.

[0849] Add 20 μL / well 3D to b) Place in a 384-well cell culture plate, shake at 320 rpm for 20 min in the dark, and incubate at room temperature for 2 hrs in the dark.

[0850] The luminescence value was read using Envision multi-function microplate reader.

[0851] 3. Data Analysis

[0852] The inhibition rate (IR) of the test compound was calculated using the following formula: IR (%) = (1 – (RLU compound – RLU blank control) / (RLU vehicle control – RLU blank control)) * 100%. The inhibition rate of the compound at different concentrations was calculated in Excel, and then the inhibition curve was plotted and relevant parameters, including minimum inhibition rate, maximum inhibition rate, and IC, were calculated using GraphPad Prism software. 50 The experimental results are shown in Table 3.

[0853] Table 3 Cell proliferation inhibitory activity of the compounds in the examples of the present invention

[0854] Pharmacokinetic test evaluation

[0855] Male ICR mice weighing 22-24 g were fasted overnight and then orally administered with a 30 mg / kg solution of the compound of the invention or a control compound [10% DMSO + 60% PEG400 + 30% aqueous solution]. Blood was collected at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 12.0, and 24 h after administration of the compound of the invention, and the plasma concentration of the compound of the invention or the control compound was determined by LC / MS / MS.

[0856] Table 4 Main pharmacokinetic parameters in plasma

[0857] BLOQ: below the limit of detection; NA: not obtained

[0858] The test results show that the compound of the present invention has good oral pharmacokinetic properties.

[0859] Pharmacokinetic test evaluation

[0860] Male SD rats weighing approximately 220 g were fasted overnight and orally administered with a 30 mg / kg solution of the compound of the present invention or a control compound [10% DMSO + 60% PEG400 + 30% aqueous solution]. Blood was collected 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 12.0, and 24 hours after administration of the compound of the present invention, and the plasma concentrations of the compound of the present invention or the control compound were determined by LC / MS / MS.

[0861] The test results show that the compound of the present invention has good pharmacokinetic properties.

[0862] Pharmacodynamic evaluation of antitumor activity (AsPC-1CDX tumor model)

[0863] 100uL containing 5x10 6 AsPC-1 tumor cell suspension was subcutaneously inoculated into the right posterior abdomen of nude mice. The health of the mice was monitored daily, and measurements were taken when the tumor grew to a palpable size. Tumor volume was calculated using the formula: 0.5 x L x W 2 , where L and W represent the length and width of the tumor, respectively. The tumor grows to 200 mm 3 Mice were randomly divided into groups. The corresponding dose of compound was administered intraperitoneally or orally daily, and their general condition was monitored. Tumors were measured three times a week, and body weights were measured twice a week.

[0864] The test results show that the compound of the present invention has a good anti-tumor effect.

[0865] All documents mentioned in this application are incorporated herein by reference, just as if each document were incorporated herein by reference individually. It should also be understood that after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and that such equivalents also fall within the scope of the claims appended hereto.

Claims

1. A compound of formula (A0), its stereoisomers, tautomers, crystalline forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs: Ring C is selected from the following groups: Y is selected from the group consisting of: a bond, O, NH, N(C1-C3 alkyl); Z is a substituted or unsubstituted C1-C6 alkylene group; wherein, The substitution refers to substitution by one or more R; W is selected from: substituted or unsubstituted C3-C 14 Cycloalkyl, or substituted or unsubstituted 4-14 membered saturated or unsaturated heterocyclic group; wherein the substitution refers to substitution by one or more R; Selected from the following groups: Wherein, X is selected from: N, CH, CD, CF, C(CN); R 1 Selected from: -L1-Q-L2-L3; in: L1 is selected from: substituted or unsubstituted C1-C6 alkylene; wherein the substitution refers to substitution by one or more R; Q is selected from: O, S, SO2, NH, or N(C1-C3 alkyl); L2 is selected from: none, substituted or unsubstituted C1-C6 alkylene; wherein the substitution refers to substitution by one or more R; L3 is selected from the following substituted or unsubstituted groups: -C1-C6 alkyl, -C3-C6 cycloalkyl, -C4-C6 heterocyclyl, -C1-C6 alkylene (C3-C6 cycloalkyl), -C1-C6 alkylene (C4-C6 heterocyclyl), -C1-C6 alkylene (C1-C6 alkoxy), -C1-C6 alkylene (C3-C6 cycloalkyloxy), or -C1-C6 alkylene (C4-C6 heterocyclyloxy); wherein the substitution refers to substitution by one or more R; n is an integer of 0, 1, 2, 3, 4, 5 or 6; provided that when W is a monocyclic or bicyclic ring, n is not 0; R 10 Selected from the following substituted or unsubstituted groups: C6-C 14 Aryl, 5-14 membered heteroaryl; wherein the substitution refers to substitution by one or more Ra; R 11 Each independently selected from the following groups substituted or unsubstituted: H, deuterium, halogen, cyano, ester, amino, amide, sulfone, urea, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, C1-C6 alkyloxy, C3-C6 cycloalkyloxy, 4-6 membered heterocyclyloxy; wherein the substitution refers to the substitution of One or more R substitutions; Ra is independently selected from the following groups: substituted or unsubstituted: H, D, halogen, CN, NH2, OH, CONH2, NHCO (C1-C6 alkyl), NHCO (C3-C6 cycloalkyl), SONH2, SO2NH2, NHSO2 (C1-C6 alkyl), NHSO2 (C3-C6 cycloalkyl), C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 20 Cycloalkyl, 4-20 membered heterocyclic group, C3-C 20 Cycloalkyloxy, 4-20 membered heterocyclyloxy; wherein the substitution refers to substitution by one or more R; m is an integer of 0, 1, 2, 3, 4, 5 or 6; Each R is the same or different and is independently selected from: deuterium, C1-C 18 Alkyl, deuterated C1-C 18 Alkyl, halogenated C1-C 18 Alkyl, (C3-C 18 Cycloalkyl)C1-C 18 Alkyl, (4-20 membered heterocyclic) C1-C 18 Alkyl, (C1-C 18 Alkoxy) C1-C 18 Alkyl, (C3-C 18 Cycloalkyloxy)C1-C 18 Alkyl, (4-20 membered heterocyclyloxy) C1-C 18 Alkyl, vinyl, ethynyl, (C1-C6 alkyl) vinyl, deuterated (C1-C6 alkyl) vinyl, halogenated (C1-C6 alkyl) vinyl, (C1-C6 alkyl) ethynyl, deuterated (C1-C6 alkyl) ethynyl, halogenated (C1-C6 alkyl) ethynyl, (C3-C 14 cycloalkyl)ethynyl, (4-14 membered heterocyclic)ethynyl, C1-C 18 Alkoxy, deuterated C1-C 18 Alkoxy, halogenated C1-C 18 Alkoxy, 4-20 membered heterocyclic C(O), C3-C 20 Cycloalkyl, 4-20 membered heterocyclic group, C6-C 14 aryl, 5-14 membered heteroaryl, halogen, nitro, hydroxy, oxo, cyano, ester, amine, amide, sulfonamide, sulfone or urea.

2. The compound according to claim 1, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, wherein: It has the structure shown in formula (A): Y is selected from the group consisting of: a bond, O, NH, N(C1-C3 alkyl); Z is a substituted or unsubstituted C1-C6 alkylene group; wherein the substitution refers to substitution by one or more R; W is selected from: substituted or unsubstituted C3-C 14 Cycloalkyl, or substituted or unsubstituted 4-14 membered saturated or unsaturated heterocyclic group; wherein the substitution refers to substitution by one or more R; Selected from the following groups: Wherein, X is selected from: N, CH, CD, CF, C(CN); R 1 Selected from: -L1-Q-L2-L3; in: L1 is selected from: substituted or unsubstituted C1-C6 alkylene; wherein the substitution refers to substitution by one or more R; Q is selected from: O, S, SO2, NH, or N(C1-C3 alkyl); L2 is selected from: none, substituted or unsubstituted C1-C6 alkylene; wherein the substitution refers to substitution by one or more R; L3 is selected from the following substituted or unsubstituted groups: -C1-C6 alkyl, -C3-C6 cycloalkyl, -C4-C6 heterocyclyl, -C1-C6 alkylene (C3-C6 cycloalkyl), -C1-C6 alkylene (C4-C6 heterocyclyl), -C1-C6 alkylene (C1-C6 alkoxy), -C1-C6 alkylene (C3-C6 cycloalkyloxy), or -C1-C6 alkylene (C4-C6 heterocyclyloxy); wherein the substitution refers to substitution by one or more R; n is an integer of 0, 1, 2, 3, 4, 5 or 6; provided that when W is a monocyclic or bicyclic ring, n is not 0; R 10 Selected from the following substituted or unsubstituted groups: C6-C 14 Aryl, 5-14 membered heteroaryl; wherein the substitution refers to substitution by one or more Ra; R 11 Each is independently selected from the following groups, substituted or unsubstituted: H, deuterium, halogen, cyano, ester, amine, amide, sulfone, urea, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, C1-C6 alkyloxy, C3-C6 cycloalkyloxy, 4-6 membered heterocyclyloxy; Ra is independently selected from the following groups: substituted or unsubstituted: H, D, halogen, CN, NH2, OH, CONH2, NHCO (C1-C6 alkyl), NHCO (C3-C6 cycloalkyl), SONH2, SO2NH2, NHSO2 (C1-C6 alkyl), NHSO2 (C3-C6 cycloalkyl), C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 20 Cycloalkyl, 4-20 membered heterocyclic group, C3-C 20 Cycloalkyloxy, 4-20 membered heterocyclyloxy; wherein the substitution refers to substitution by one or more R; m is an integer of 0, 1, 2, 3, 4, 5 or 6; Each R is the same or different and is independently selected from: deuterium, C1-C 18 Alkyl, deuterated C1-C 18 Alkyl, halogenated C1-C 18 Alkyl, (C3-C 18 Cycloalkyl)C1-C 18 Alkyl, (4-20 membered heterocyclic) C1-C 18 Alkyl, (C1-C 18 Alkoxy) C1-C 18 Alkyl, (C3-C 18 Cycloalkyloxy)C1-C 18 Alkyl, (4-20 membered heterocyclyloxy) C1-C 18 Alkyl, vinyl, ethynyl, (C1-C6 alkyl) vinyl, deuterated (C1-C6 alkyl) vinyl, halogenated (C1-C6 alkyl) vinyl, (C1-C6 alkyl) ethynyl, deuterated (C1-C6 alkyl) ethynyl, halogenated (C1-C6 alkyl) ethynyl, (C3-C 14 cycloalkyl)ethynyl, (4-14 membered heterocyclic)ethynyl, C1-C 18 Alkoxy, deuterated C1-C 18 Alkoxy, halogenated C1-C 18 Alkoxy, 4-20 membered heterocyclic C(O), C3-C 20 Cycloalkyl, 4-20 membered heterocyclic group, C6-C 14 aryl, 5-14 membered heteroaryl, halogen, nitro, hydroxy, oxo, cyano, ester, amine, amide, sulfonamide, sulfone or urea.

3. The compound according to any one of claims 1 to 2, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, characterized in that: It has a structure shown in formula (IA) or formula (IB): Where, U is selected from: N, CH, CD, CF; U' is selected from: O, or S; U" is selected from: N, or C(CN); X is selected from the group consisting of: N, CH, CD, CF, C(CN); Y is selected from the group consisting of: a bond, O, NH, N(C1-C3 alkyl); Z is a substituted or unsubstituted C1-C6 alkylene group; wherein the substitution refers to substitution by one or more R; W is selected from: substituted or unsubstituted C3-C 14 Cycloalkyl, or substituted or unsubstituted 4-14 membered saturated or unsaturated heterocyclic group; wherein the substitution refers to substitution by one or more R; R 1 Selected from: -L1-Q-L2-L3; wherein: L1 is selected from: substituted or unsubstituted C1-C6 alkylene; wherein the substitution refers to substitution by one or more R; Q is selected from: O, S, SO2, NH, or N(C1-C3 alkyl); L2 is selected from: none, substituted or unsubstituted C1-C6 alkylene; wherein the substitution refers to substitution by one or more R; L3 is selected from the following substituted or unsubstituted groups: -C1-C6 alkyl, -C3-C6 cycloalkyl, -C4-C6 heterocyclyl, -C1-C6 alkylene (C3-C6 cycloalkyl), -C1-C6 alkylene (C4-C6 heterocyclyl), -C1-C6 alkylene (C1-C6 alkoxy), -C1-C6 alkylene (C3-C6 cycloalkyloxy), or -C1-C6 alkylene (C4-C6 heterocyclyloxy); wherein the substitution refers to substitution by one or more R; n is an integer of 1, 2, 3, 4, 5 or 6; R 2 and R 3 the same or different, each independently selected from the following substituted or unsubstituted groups: H, D, halogen, CN, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C1-C6 alkoxy; wherein the substitution refers to substitution by one or more R; R 4 is selected from the group consisting of halogen, C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, substituted or unsubstituted; wherein the substitution refers to substitution by one or more R; R 8 Selected from: OH, SONH2, NHSO2CH3; R 5 、R 6 、R 7 、R 9 、R 7’ 、R 8’ 、R 9’ the same or different, each independently selected from the following substituted or unsubstituted groups: H, D, halogen, CN, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C1-C6 alkoxy; wherein the substitution refers to substitution by one or more R; R 5’ Selected from: H, D, halogen, CN, NH2, OH, CONH2, NHCO(C1-C6 alkyl), NHCO(C3-C6 cycloalkyl), SONH2, SO2NH2, NHSO2(C1-C6 alkyl), NHSO2(C3-C6 cycloalkyl), C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C1-C6 alkoxy; Each R is the same or different and is independently selected from: deuterium, C1-C 18 Alkyl, deuterated C1-C 18 Alkyl, halogenated C1-C 18 Alkyl, (C3-C 18 Cycloalkyl)C1-C 18 Alkyl, (4-20 membered heterocyclic) C1-C 18 Alkyl, (C1-C 18 Alkoxy) C1-C 18 Alkyl, (C3-C 18 Cycloalkyloxy)C1-C 18 Alkyl, (4-20 membered heterocyclyloxy) C1-C 18 Alkyl, vinyl, ethynyl, (C1-C6 alkyl) vinyl, deuterated (C1-C6 alkyl) vinyl, halogenated (C1-C6 alkyl) vinyl, (C1-C6 alkyl) ethynyl, deuterated (C1-C6 alkyl) ethynyl, halogenated (C1-C6 alkyl) ethynyl, (C3-C 14 cycloalkyl)ethynyl, (4-14 membered heterocyclic)ethynyl, C1-C 18 Alkoxy, deuterated C1-C 18 Alkoxy, halogenated C1-C 18 Alkoxy, C3-C 20 Cycloalkyl, 4-20 membered heterocyclic group, C6-C 14 aryl, 5-14 membered heteroaryl, halogen, nitro, hydroxy, oxo, cyano, ester, amine, amide, sulfonamide, sulfone or urea.

4. The compound according to any one of claims 1 to 3, its stereoisomer, tautomer, crystalline form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, characterized in that: It has a structure shown in formula (IIA) or formula (IIB): Among them, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 5’ 、R 7’ 、R 8’ 、R 9’ , U, U', U", X, Z, W and n are as defined in claim 3.

5. The compound according to any one of claims 1 to 4, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, characterized in that: It has a structure shown in formula (VA) or formula (VB): Among them, R 1 、R 4 、R 5 、R 6 、R 7 、R 9 、R 7’ 、R 8’ 、R 9’ , U, U', U", Z, W and n are as defined in claim 3.

6. The compound according to any one of claims 1 to 5, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, characterized in that: It has a structure shown in formula (VIA) or formula (VIB): Among them, R 1 、R 4 、R 5 、R 6 、R 7 、R 9 、R 7’ 、R 8’ 、R 9’ , U", Z, W and n are defined as in claim 3 As stated.

7. The compound according to any one of claims 1 to 6, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, characterized in that: It has a structure represented by formula (VIIA) or formula (VIIB): Among them, R 1 、R 4 、R 5 、R 7’ 、R 8’ 、R 9’ , Z, W and n are defined as described in claim 3.

8. The compound according to any one of claims 1 to 7, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, characterized in that: It has a structure represented by formula (VIIIA) or formula (VIIIB): Among them, R 1 、R 4 、R 5 、R 7’ 、R 9’ , Z, W and n are defined as described in claim 3.

9. The compound according to claim 1, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, wherein: It has a structure shown in formula (IXA) or formula (IXB): wherein n' is an integer of 0, 1, 2, 3, 4, 5, or 6; R 5 , R, R 7 、R 9 、R 7’ 、R 9’ , L1, Q, L2, L3 and n are defined as described in claim 3.

10. The compound according to claim 1, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, wherein: It has the structure shown in formula (X): in, V1, V2, V3, V4 and V5 are each independently selected from: N, or CR v ; R v the same or different, each independently selected from: H, C1-C3 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, C1-C3 alkoxy, C3-C6 cycloalkyloxy, 4-6 membered heterocyclyloxy, halo-C1-C3 alkyl, halo-C3-C6 cycloalkyl, halo-4-6 membered heterocyclyl, (HO)-C1-C3 alkyl, (HO)-C3-C6 cycloalkyl, (NH2)-C1-C3 alkyl, (NH2)-C3-C6 cycloalkyl, halogen, CN, -C≡CH, OH, NH2, CONH2, NHCO(C1-C6 alkyl), NHCO(C3-C6 cycloalkyl), SO2NH2, NHSO2(C1-C6 alkyl), NHSO2(C3-C6 cycloalkyl), wherein the heterocyclyl is optionally substituted with one or more oxo groups (=O); R 2 and R 3 the same or different, each independently selected from the following substituted or unsubstituted groups: H, D, halogen, CN, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C1-C6 alkoxy; wherein the substitution refers to substitution by one or more R; Ring C, R, R 1 , X, Z, W and n are as defined in claim 1; Preferably, the compound has a structure shown in formula (XI): V1, V2, V3, V4, and V5 are each independently selected from: N, or CR v ; R v the same or different, each independently selected from: H, C1-C3 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, C1-C3 alkoxy, C3-C6 cycloalkyloxy, 4-6 membered heterocyclyloxy, halo-C1-C3 alkyl, halo-C3-C6 cycloalkyl, halo-4-6 membered heterocyclyl, (HO)-C1-C3 alkyl, (HO)-C3-C6 cycloalkyl, (NH2)-C1-C3 alkyl, (NH2)-C3-C6 cycloalkyl, halogen, CN, -C≡CH, OH, NH2, CONH2, NHCO(C1-C6 alkyl), NHCO(C3-C6 cycloalkyl), SO2NH2, NHSO2(C1-C6 alkyl), NHSO2(C3-C6 cycloalkyl), wherein the heterocyclyl is optionally substituted with one or more oxo groups (=O); R 2 and R 3 the same or different, each independently selected from the following substituted or unsubstituted groups: H, D, halogen, CN, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C1-C6 alkoxy; wherein the substitution refers to substitution by one or more R; Among them, R, R 1 , X, Z, W and n are as defined in claim 1; Preferably, the compound has a structure shown in formula (XII): V1, V2, V3, V4, and V5 are each independently selected from: N, or CR v ; R v the same or different, each independently selected from: H, C1-C3 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, C1-C3 alkoxy, C3-C6 cycloalkyloxy, 4-6 membered heterocyclyloxy, halo-C1-C3 alkyl, halo-C3-C6 cycloalkyl, halo-4-6 membered heterocyclyl, (HO)-C1-C3 alkyl, (HO)-C3-C6 cycloalkyl, (NH2)-C1-C3 alkyl, (NH2)-C3-C6 cycloalkyl, halogen, CN, -C≡CH, OH, NH2, CONH2, NHCO(C1-C6 alkyl), NHCO(C3-C6 cycloalkyl), SO2NH2, NHSO2(C1-C6 alkyl), NHSO2(C3-C6 cycloalkyl), wherein the heterocyclyl is optionally substituted with one or more oxo groups (=O); R 3 A substituted or unsubstituted group selected from the group consisting of H, D, halogen, CN, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, and C1-C6 alkoxy; wherein the substituted group refers to one or more R groups; Among them, R, R 1 , X, Z, W and n are as defined in claim 1; Preferably, the compound has a structure shown in formula (XIII): V1, V2, V3, V4, and V5 are each independently selected from: N, or CR v ; R v the same or different, each independently selected from: H, C1-C3 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, C1-C3 alkoxy, C3-C6 cycloalkyloxy, 4-6 membered heterocyclyloxy, halo-C1-C3 alkyl, halo-C3-C6 cycloalkyl, halo-4-6 membered heterocyclyl, (HO)-C1-C3 alkyl, (HO)-C3-C6 cycloalkyl, (NH2)-C1-C3 alkyl, (NH2)-C3-C6 cycloalkyl, halogen, CN, -C≡CH, OH, NH2, CONH2, NHCO(C1-C6 alkyl), NHCO(C3-C6 cycloalkyl), SO2NH2, NHSO2(C1-C6 alkyl), NHSO2(C3-C6 cycloalkyl), wherein the heterocyclyl is optionally substituted with one or more oxo groups (=O); R 3 A substituted or unsubstituted group selected from the group consisting of H, D, halogen, CN, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, and C1-C6 alkoxy; wherein the substituted group refers to one or more R groups; Among them, R, R 1 , Z, W and n are as defined in claim 1.

11. The compound according to claim 1, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, wherein: R 10 for Preferably, R 10 for Among them, R v1 、R v2 、R v3 、R v4 and R v5 Each is independently selected from: H, C1-C3 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, C1-C3 alkoxy, C3-C6 cycloalkyloxy, 4-6 membered heterocyclyloxy, halogenated C1-C3 alkyl (such as CF3, CF2CF3), halogenated C3-C6 cycloalkyl, halogenated 4-6 membered heterocyclyl, (HO)-C1-C3 alkyl, (HO)-C3-C6 cycloalkyl, (NH2)-C1-C3 alkyl, (NH2)-C3-C6 cycloalkyl, halogen, CN, -C≡CH, OH, NH2, CONH2, NHCO(C1-C6 alkyl), NHCO(C3-C6 cycloalkyl, SO2NH2, NHSO2(C1-C6 alkyl), NHSO2(C3-C6 cycloalkyl)H, C1-C3 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, C1-C3 alkoxy, C3-C6 cycloalkyloxy, 4-6 membered heterocyclyloxy, halo-C1-C3 alkyl, halo-C3-C6 cycloalkyl, halo-4-6 membered heterocyclyl, (HO)-C1-C3 alkyl, (HO)-C3-C6 cycloalkyl, (NH2)-C1-C3 alkyl, (NH2)-C3-C6 cycloalkyl, halogen, CN, -C≡CH, OH, NH2, CONH2, NHCO(C1-C6 alkyl), NHCO(C3-C6 cycloalkyl), SO2NH2, NHSO2(C1-C6 alkyl), NHSO2(C3-C6 cycloalkyl), the heterocyclyl being optionally substituted by one or more oxo groups (=O).

12. The compound according to any one of claims 1 to 10, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, characterized in that: R 10 is selected from the following substituted or unsubstituted groups: phenyl, naphthyl, 5-6 membered monocyclic heteroaryl (such as pyridyl), 9-10 membered bicyclic heteroaryl (such as indazolyl, benzothiazole, benzothiophene, benzofuran), wherein the substitution is substituted by one or more groups selected from the following groups: halogen, hydroxyl, cyano, NH2, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, C2-C6 alkenyl, C2-C6 alkynyl; preferably, R 10 Selected from:

13. The compound according to any one of claims 1 to 12, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, characterized in that: W is selected from: wherein n' is an integer of 0, 1, 2, 3, 4, 5, or 6; preferably, when W is selected from: When n' can be 0, 1 or 2, R is defined as in claim 1, and R can be substituted on any one ring of a polycyclic ring (such as a bridged ring or a spiro ring).

14. The compound according to any one of claims 1 to 13, its stereoisomer, tautomer, crystalline form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, characterized in that: The compound is selected from the group consisting of: Or choose from: Or choose from: Or choose from: Or choose from: Or choose from: Or choose from: Or choose from:

15. A pharmaceutical composition, characterized in that Comprising one or more compounds according to any one of claims 1 to 14, stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof; and a pharmaceutically acceptable carrier.

16. Use of the compound according to any one of claims 1 to 14, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, or the pharmaceutical composition according to claim 15, characterized in that: Preparation for prevention and / or treatment of KRAS G12D Drugs for diseases related to the activity or expression level of .

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